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[0] Schmidt EM, McIntosh JS, Durelli L, Bak MJ, Fine control of operantly conditioned firing patterns of cortical neurons.Exp Neurol 61:2, 349-69 (1978 Sep 1)[1] Serruya MD, Hatsopoulos NG, Paninski L, Fellows MR, Donoghue JP, Instant neural control of a movement signal.Nature 416:6877, 141-2 (2002 Mar 14)[2] Fetz EE, Operant conditioning of cortical unit activity.Science 163:870, 955-8 (1969 Feb 28)[3] Fetz EE, Finocchio DV, Operant conditioning of specific patterns of neural and muscular activity.Science 174:7, 431-5 (1971 Oct 22)[4] Fetz EE, Finocchio DV, Operant conditioning of isolated activity in specific muscles and precentral cells.Brain Res 40:1, 19-23 (1972 May 12)[5] Fetz EE, Baker MA, Operantly conditioned patterns on precentral unit activity and correlated responses in adjacent cells and contralateral muscles.J Neurophysiol 36:2, 179-204 (1973 Mar)

[0] Suner S, Fellows MR, Vargas-Irwin C, Nakata GK, Donoghue JP, Reliability of signals from a chronically implanted, silicon-based electrode array in non-human primate primary motor cortex.IEEE Trans Neural Syst Rehabil Eng 13:4, 524-41 (2005 Dec)

[0] Westby GW, Wang H, A floating microwire technique for multichannel chronic neural recording and stimulation in the awake freely moving rat.J Neurosci Methods 76:2, 123-33 (1997 Oct 3)

[0] Mehring C, Rickert J, Vaadia E, Cardosa de Oliveira S, Aertsen A, Rotter S, Inference of hand movements from local field potentials in monkey motor cortex.Nat Neurosci 6:12, 1253-4 (2003 Dec)

[0] Rousche PJ, Normann RA, Chronic recording capability of the Utah Intracortical Electrode Array in cat sensory cortex.J Neurosci Methods 82:1, 1-15 (1998 Jul 1)

[0] Bergman H, Wichmann T, DeLong MR, Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.Science 249:4975, 1436-8 (1990 Sep 21)

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ref: -2010 tags: neural signaling rate code patch clamp barrel cortex date: 03-18-2021 18:41 gmt revision:0 [head]

PMID-20596024 Sensitivity to perturbations in vivo implies high noise and suggests rate coding in cortex

  • How did I not know of this paper before.
  • Solid study showing that, while a single spike can elicit 28 spikes in post-synaptic neurons, the associated level of noise is indistinguishable from intrinsic noise.
  • Hence the cortex should communicate / compute in rate codes or large synchronized burst firing.
    • They found large bursts to be infrequent, timing precision to be low, hence rate codes.
    • Of course other examples, e.g auditory cortex, exist.

Cortical reliability amid noise and chaos

  • Noise is primarily of synaptic origin. (Dropout)
  • Recurrent cortical connectivity supports sensitivity to precise timing of thalamocortical inputs.

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ref: -0 tags: cortical computation learning predictive coding reviews date: 02-23-2021 20:15 gmt revision:2 [1] [0] [head]

PMID-30359606 Predictive Processing: A Canonical Cortical Computation

  • Georg B Keller, Thomas D Mrsic-Flogel
  • Their model includes on two error signals: positive and negative for reconciling the sensory experience with the top-down predictions. I haven't read the full article, and disagree that such errors are explicit to the form of neurons, but the model is plausible. Hence worth recording the paper here.

PMID-23177956 Canonical microcircuits for predictive coding

  • Andre M Bastos, W Martin Usrey, Rick A Adams, George R Mangun, Pascal Fries, Karl J Friston
  • We revisit the established idea that message passing among hierarchical cortical areas implements a form of Bayesian inference-paying careful attention to the implications for intrinsic connections among neuronal populations.
  • Have these algorithms been put to practical use? I don't know...

Control of synaptic plasticity in deep cortical networks

  • Pieter R. Roelfsema & Anthony Holtmaat
  • Basically argue for a many-factor learning rule at the feedforward and feedback synapses, taking into account pre, post, attention, and reinforcement signals.
  • See comment by Tim Lillicrap and Blake Richards.

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ref: -0 tags: protein engineering structure evolution date: 02-23-2021 19:57 gmt revision:1 [0] [head]

From Protein Structure to Function with Bioinformatics

  • Dense and useful resource!
  • Few new folds have been discovered since 2010 -- the total number of extand protein folds is around 100,000. Evolution re-uses existing folds + the protein fold space is highly convergent. Amazing. link

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ref: -2013 tags: larkum calcium spikes dendrites association cortex binding date: 02-23-2021 19:52 gmt revision:3 [2] [1] [0] [head]

PMID-23273272 A cellular mechanism for cortical associations: and organizing principle for the cerebral cortex

  • Distal tuft dendrites have a second spike-initiation zone, where depolarization can induce a calcium plateau of up to 50ms long.  This depolarization can cause multiple spikes in the soma, and can be more effective at inducing spikes than depolarization through the basal dendrites.  Such spikes are frequently bursts of 2-4 at 200hz. 
  • Bursts of spikes can also be triggered by backpropagation activated calcium (BAC), which can half the current threshold for a dendritic spike. That is, there is enough signal propagation for information to propagate both down the dendritic arbor and up, and the two interact non-linearly.  
  • This nonlinear calcium-dependent association pairing can be blocked by inhibition to the dendrites (presumably apical?). 
    • Larkum argues that the different timelines of GABA inhibition offer 'exquisite control' of the dendrites; but these sorts of arguments as to computational power always seem lame compared to stating what their actual role might be. 
  • Quote: "Dendritic calcium spikes have been recorded in vivo [57, 84, 85] that correlate to behavior [78, 86].  The recordings are population-level, though, and do not seem to measure individual dendrites (?). 

See also:

PMID-25174710 Sensory-evoked LTP driven by dendritic plateau potentials in vivo

  • We demonstrate that rhythmic sensory whisker stimulation efficiently induces synaptic LTP in layer 2/3 (L2/3) pyramidal cells in the absence of somatic spikes.
  • It instead depends on NMDA-dependent dendritic spikes.
  • And this is dependent on afferents from the POm thalamus.

And: The binding solution?, a blog post covering Bittner 2015 that looks at rapid dendritic plasticity in the hippocampus as a means of binding stimuli to place fields.

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ref: -0 tags: tennenbaum compositional learning character recognition one-shot learning date: 02-23-2021 18:56 gmt revision:2 [1] [0] [head]

One-shot learning by inverting a compositional causal process

  • Brenden Lake, Russ Salakhutdinov, Josh Tennenbaum
  • This is the paper that preceded the 2015 Science publication "Human level concept learning through probabalistic program induction"
  • Because it's a NIPS paper, and not a science paper, this one is a bit more accessible: the logic to the details and developments is apparent.
  • General idea: build up a fully probabilistic model of multi-language (omniglot corpus) characters / tokens. This model includes things like character type / alphabet, number of strokes, curvature of strokes (parameterized via bezier splines), where strokes attach to others (spatial relations), stroke scale, and character scale. The model (won't repeat the formal definition) is factorized to be both compositional and causal, though all the details of the conditional probs are left to the supplemental material.
  • They fit the complete model to the Omniglot data using gradient descent + image-space noising, e.g tweak the free parameters of the model to generate images that look like the human created characters. (This too is in the supplement).
  • Because the model is high-dimensional and hard to invert, they generate a perceptual model by winnowing down the image into a skeleton, then breaking this into a variable number of strokes.
    • The probabilistic model then assigns a log-likelihood to each of the parses.
    • They then use the model with Metropolis-Hastings MCMC to sample a region in parameter space around each parse -- and they extra sample ψ\psi (the character type) to get a greater weighted diversity of types.
      • Surprisingly, they don't estimate the image likelihood - which is expensive - they here just re-do the parsing based on aggregate info embedded in the statistical model. Clever.
  • ψ\psi is the character type (a, b, c..), ψ=κ,S,R\psi = { \kappa, S, R } where kappa are the number of strokes, S is a set of parameterized strokes, R are the relations between strokes.
  • θ\theta are the per-token stroke parameters.
  • II is the image, obvi.
  • Classification task: one image of a new character (c) vs 20 characters new characters from the same alphabet (test, (t)). In the 20 there is one character of the same type -- task is to find it.
  • With 'hierarchical bayesian program learning', they not only anneal the type to the parameters (with MCMC, above) for the test image, but they also fit the parameters using gradient descent to the image.
    • Subsequently parses the test image onto the class image (c)
    • Hence the best classification is the one where both are in the best agreement: argmaxcP(c|t)P(c)P(t|c)\underset{c}{argmax} \frac{P(c|t)}{P(c)} P(t|c) where P(c)P(c) is approximated as the parse weights.
      • Again, this is clever as it allows significant information leakage between (c) and (t) ...
      • The other models (Affine, Deep Boltzman Machines, Hierarchical Deep Model) have nothing like this -- they are feed-forward.
  • No wonder HBPL performs better. It's a better model of the data, that has a bidirectional fitting routine.

  • As i read the paper, had a few vague 'hedons':
    • Model building is essential. But unidirectional models are insufficient; if the models include the mechanism for their own inversion many fitting and inference problems are solved. (Such is my intuition)
      • As a corrolary of this, having both forward and backward tags (links) can be used to neatly solve the binding problem. This should be easy in a computer w/ pointers, though in the brain I'm not sure how it might work (?!) without some sort of combinatorial explosion?
    • The fitting process has to be multi-pass or at least re-entrant. Both this paper and the Vicarious CAPTCHA paper feature statistical message passing to infer or estimate hidden explanatory variables. Seems correct.
    • The model here includes relations that are conditional on stroke parameters that occurred / were parsed beforehand; this is very appealing in that the model/generator/AI needs to be flexibly re-entrant to support hierarchical planning ...

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ref: -2020 tags: current opinion in neurobiology Kriegeskorte review article deep learning neural nets circles date: 02-23-2021 17:40 gmt revision:2 [1] [0] [head]

Going in circles is the way forward: the role of recurrence in visual inference

I think the best part of this article are the references -- a nicely complete listing of, well, the current opinion in Neurobiology! (Note that this issue is edited by our own Karel Svoboda, hence there are a good number of Janelians in the author list..)

The gestalt of the review is that deep neural networks need to be recurrent, not purely feed-forward. This results in savings in overall network size, and increase in the achievable computational complexity, perhaps via the incorporation of priors and temporal-spatial information. All this again makes perfect sense and matches my sense of prevailing opinion. Of course, we are left wanting more: all this recurrence ought to be structured in some way.

To me, a rather naive way of thinking about it is that feed-forward layers cause weak activations, which are 'amplified' or 'selected for' in downstream neurons. These neurons proximally code for 'causes' or local reasons, based on the supported hypothesis that the brain has a good temporal-spatial model of the visuo-motor world. The causes then can either explain away the visual input, leading to balanced E-I, or fail to explain it, in which the excess activity is either rectified by engaging more circuits or engaging synaptic plasticity.

A critical part of this hypothesis is some degree of binding / disentanglement / spatio-temporal re-assignment. While not all models of computation require registers / variables -- RNNs are Turning-complete, e.g., I remain stuck on the idea that, to explain phenomenological experience and practical cognition, the brain much have some means of 'binding'. A reasonable place to look is the apical tuft dendrites, which are capable of storing temporary state (calcium spikes, NMDA spikes), undergo rapid synaptic plasticity, and are so dense that they can reasonably store the outer-product space of binding.

There is mounting evidence for apical tufts working independently / in parallel is investigations of high-gamma in ECoG: PMID-32851172 Dissociation of broadband high-frequency activity and neuronal firing in the neocortex. "High gamma" shows little correlation with MUA when you differentiate early-deep and late-superficial responses, "consistent with the view it reflects dendritic processing separable from local neuronal firing"

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ref: -2009 tags: Baldwin effect finches date: 02-22-2021 17:35 gmt revision:0 [head]

Evolutionary significance of phenotypic accommodation in novel environments: an empirical test of the Baldwin effect

Up until reading this, I had thought that the Balwin effect refers to the fact that when animals gain an ability to learn, this allows them to take new ecological roles without genotypic adaptation. This is a component of the effect, but is not the original meaning, which is opposite: when species adapt to a novel environment through phenotypic adptation (say adapting to colder weather through within-lifetime variation), evolution tends to push these changes into the germ line. This is something to the effect of Lamarkian evolution.

In the case of house finches, as discussed in the link above, this pertains to increased brood variability and sexual dimorphism due to varied maternal habits and hormones due to environmental stress. This variance is then rapidly operated on by natural selection to tune the finch to it's new enviroment, including Montana, where the single author did most of his investigation.

There are of course countless other details here, but still this is an illuminating demonstration of how evolution works to move information into the genome.

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ref: -2013 tags: synaptic learning rules calcium harris stdp date: 02-18-2021 19:48 gmt revision:3 [2] [1] [0] [head]

PMID-24204224 The Convallis rule for unsupervised learning in cortical networks 2013 - Pierre Yger  1 , Kenneth D Harris

This paper aims to unify and reconcile experimental evidence of in-vivo learning rules with  established STDP rules.  In particular, the STDP rule fails to accurately predict change in strength in response to spike triplets, e.g. pre-post-pre or post-pre-post.  Their model instead involves the competition between two time-constant threshold circuits / coincidence detectors, one which controls LTD and another LTP, and is such an extension of the classical BCM rule.  (BCM: inputs below a threshold will weaken a synapse; those above it will strengthen. )

They derive the model from optimization criteria that neurons should try to optimize the skewedness of the distribution of their membrane potential: much time spent either firing spikes or strongly inhibited.  This maps to a objective function F that looks like a valley - hence the 'convallis' in the name (latin for valley); the objective is differentiated to yield a weighting function for weight changes; they also add a shrinkage function (line + heaviside function) to gate weight changes 'off' at resting membrane potential. 

A network of firing neurons successfully groups correlated rate-encoded inputs, better than the STDP rule.  it can also cluster auditory inputs of spoken digits converted into cochleogram.  But this all seems relatively toy-like: of course algorithms can associate inputs that co-occur.  The same result was found for a recurrent balanced E-I network with the same cochleogram, and convalis performed better than STDP.   Meh.

Perhaps the biggest thing I got from the paper was how poorly STDP fares with spike triplets:

Pre following post does not 'necessarily' cause LTD; it's more complicated than that, and more consistent with the two different-timeconstant coincidence detectors.  This is satisfying as it allows for apical dendritic depolarization to serve as a contextual binding signal - without negatively impacting the associated synaptic weights. 

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ref: -2020 tags: dreamcoder ellis program induction ai date: 02-01-2021 18:39 gmt revision:0 [head]

DreamCoder: Growing generalizable, interpretable knowledge with wake-sleep Bayesian program learning

  • Kevin Ellis, Catherine Wong, Maxwell Nye, Mathias Sable-Meyer, Luc Cary, Lucas Morales, Luke Hewitt, Armando Solar-Lezama, Joshua B. Tenenbaum

This paper describes a system for adaptively finding programs which succinctly and accurately produce desired output.  These desired outputs are provided by the user / test system, and come from a number of domains:

  • list (as in lisp) processing,
  • text editing,
  • regular expressions,
  • line graphics,
  • 2d lego block stacking,
  • symbolic regression (ish),
  • functional programming,
  • and physcial laws.  
Some of these domains are naturally toy-like, eg. the text processing, but others are deeply impressive: the system was able to "re-derive" basic physical laws of vector calculus in the process of looking for S-expression forms of cheat-sheet physics equations.  These advancements result from a long lineage of work, perhaps starting from the Helmholtz machine PMID-7584891 introduced by Peter Dayan, Geoff Hinton and others, where onemodel is trained to generate patterns given context (e.g.) while a second recognition module is trained to invert this model: derive context from the patterns.  The two work simultaneously to allow model-exploration in high dimensions.  

Also in the lineage is the EC2 algorithm, which most of the same authors above published in 2018.  EC2 centers around the idea of "explore - compress" : explore solutions to your program induction problem during the 'wake' phase, then compress the observed programs into a library by extracting/factoring out commonalities during the 'sleep' phase.  This of course is one of the core algorithms of human learning: explore options, keep track of both what worked and what didn't, search for commonalities among the options & their effects, and use these inferred laws or heuristics to further guide search and goal-setting, thereby building a buffer attack the curse of dimensionality.  Making the inferred laws themselves functions in a programming library allows hierarchically factoring the search task, making exploration of unbounded spaces possible.  This advantage is unique to the program synthesis approach. 

This much is said in the introduction, though perhaps with more clarity.  DreamCoder is an improved, more-accessible version of EC2, though the underlying ideas are the same.   It differs in that the method for constructing libraries has improved through the addition of a powerful version space for enumerating and evaluating refactors of the solutions generated during the wake phase.  (I will admit that I don't much understand the version space system.)  This version space allows DreamCoder to collapse the search space for re-factorings by many orders of magnitude, and seems to be a clear advancement.  Furthermore, DreamCoder incorporates a second phase of sleep: "dreaming", hence the moniker.  During dreaming the library is used to create 'dreams' consisting of combinations of the library primitives, which are then executed with training data as input.  These dreams are then used to train up a neural network to predict which library and atomic objects to use in given contexts.  Context in this case is where in the parse tree a given object has been inserted (it's parent and which argument number it sits in); how the data-context is incorporated to make this decision is not clear to me (???). 

This neural dream and replay-trained neural network is either a GRU recurrent net with 64 hidden states, or a convolutional network feeding into a RNN.  The final stage is a linear ReLu (???) which again is not clear how it feeds into the prediction of "which unit to use when".  The authors clearly demonstrate that the network, or the probabalistic context-free grammar that it controls (?) is capable of straightforward optimizations, like breaking symmetries due to commutativity, avoiding adding zero, avoiding multiplying by one, etc.  Beyond this, they do demonstrate via an ablation study that the presence of the neural network affords significant algorithmic leverage in all of the problem domains tested.  The network also seems to learn a reasonable representation of the sub-type of task encountered -- but a thorough investigation of how it works, or how it might be made to work better, remains desired. 

I've spent a little time looking around the code, which is a mix of python high-level experimental control code, and lower-level OCaml code responsible for running (emulating) the lisp-like DSL, inferring type in it's polymorphic system / reconciling types in evaluated program instances, maintaining the library, and recompressing it using aforementioned version spaces.  The code, like many things experimental, is clearly a work-in progress, with some old or unused code scattered about, glue to run the many experiments & record / analyze the data, and personal notes from the first author for making his job talks (! :).  The description in the supplemental materials, which is satisfyingly thorough (if again impenetrable wrt version spaces), is readily understandable, suggesting that one (presumably the first) author has a clear understanding of the system.  It doesn't appear that much is being hidden or glossed over, which is not the case for all scientific papers. 


With the caveat that I don't claim to understand the system to completion, there are some clear areas where the existing system could be augmented further.  The 'recognition' or perceptual module, which guides actual synthesis of candidate programs, realistically can use as much information as is available in DreamCoder as is available: full lexical and semantic scope, full input-output specifications, type information, possibly runtime binding of variables when filling holes.  This is motivated by the way that humans solve problems, at least as observed by introspection:
  • Examine problem, specification; extract patterns (via perceptual modules)
  • Compare patterns with existing library (memory) of compositionally-factored 'useful solutions' (this is identical to the library in DreamCoder)* Do something like beam-search or quasi stochastic search on selected useful solutions.  This is the same as DreamCoder, however human engineers make decisions progressively, at runtime so-to-speak: you fill not one hole per cycle, but many holes.  The addition of recursion to DreamCoder, provided a wider breadth of input information, could support this functionality. 
  • Run the program to observe input-output .. but also observe the inner workings of the program, eg. dataflow patterns.  These dataflow patterns are useful to human engineers when both debugging and when learning-by-inspection what library elements do.   DreamCoder does not really have this facility. 
  • Compare the current program results to the desired program output.  Make a stochastic decision whether to try to fix it, or to try another beam in the search.  Since this would be on a computer, this could be in parallel (as DreamCoder is); the ability to 'fix' or change a DUT is directly absent dreamcoder.   As an 'deeply philosophical' aside, this loop itself might be the effect of running a language-of-thought program, as was suggested by pioneers in AI (ref).  The loop itself is subject to modification and replacement based on goal-seeking success in the domain of interest, in a deeply-satisfying and deeply recursive manner ...
At each stage in the pipeline, the perceptual modules would have access to relevant variables in the current problem-solving context.  This is modeled on Jacques Pitrat's work.  Humans of course are even more flexible than that -- context includes roughly the whole brain, and if anything we're mushy on which level of the hierarchy we are working. 

Critical to making this work is to have, as I've written in my notes many years ago, a 'self compressing and factorizing memory'.  The version space magic + library could be considered a working example of this.  In the realm of ANNs, per recent OpenAI results with CLIP and Dall-E, really big transformers also seem to have strong compositional abilities, with the caveat that they need to be trained on segments of the whole web.  (This wouldn't be an issue here, as Dreamcoder generates a lot of its own training data via dreams).  Despite the data-inefficiency of DNN / transformers, they should be sufficient for making something in the spirit of above work, with a lot of compute, at least until more efficient models are available (which they should be shortly; see AlphaZero vs MuZero). 

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ref: -0 tags: inductive logic programming deepmind formal propositions prolog date: 11-21-2020 04:07 gmt revision:0 [head]

Learning Explanatory Rules from Noisy Data

  • From a dense background of inductive logic programming (ILP): given a set of statements, and rules for transformation and substitution, generate clauses that satisfy a set of 'background knowledge'.
  • Programs like Metagol can do this using search and simplify logic built into Prolog.
    • Actually kinda surprising how very dense this program is -- only 330 lines!
  • This task can be transformed into a SAT problem via rules of logic, for which there are many fast solvers.
  • The trick here (instead) is that a neural network is used to turn 'on' or 'off' clauses that fit the background knowledge
    • BK is typically very small, a few examples, consistent with the small size of the learned networks.
  • These weight matrices are represented as the outer product of composed or combined clauses, which makes the weight matrix very large!
  • They then do gradient descent, while passing the cross-entropy errors through nonlinearities (including clauses themselves? I think this is how recursion is handled.) to update the weights.
    • Hence, SGD is used as a means of heuristic search.
  • Compare this to Metagol, which is brittle to any noise in the input; unsurprisingly, due to SGD, this is much more robust.
  • Way too many words and symbols in this paper for what it seems to be doing. Just seems to be obfuscating the work (which is perfectly good). Again: Metagol is only 330 lines!

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ref: -2011 tags: two photon cross section fluorescent protein photobleaching Drobizhev gcamp date: 11-04-2020 18:07 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

PMID-21527931 Two-photon absorption properties of fluorescent proteins

  • Significant 2-photon cross section of red fluorescent proteins (same chromophore as DsRed) in the 700 - 770nm range, accessible to Ti:sapphire lasers ...
    • This corresponds to a S 0S nS_0 \rightarrow S_n transition
    • But but, photobleaching is an order of magnitude slower when excited by the direct S 0S 1S_0 \rightarrow S_1 transition (but the fluorophores can be significantly less bright in this regime).
      • Quote: the photobleaching of DsRed slows down by an order of magnitude when the excitation wavelength is shifted to the red, from 750 to 950 nm (32).
    • See also PMID-18027924
  • Further work by same authors: Absolute Two-Photon Absorption Spectra and Two-Photon Brightness of Orange and Red Fluorescent Proteins
    • " TagRFP possesses the highest two-photon cross section, σ2 = 315 GM, and brightness, σ2φ = 130 GM, where φ is the fluorescence quantum yield. At longer wavelengths, 1000–1100 nm, tdTomato has the largest values, σ2 = 216 GM and σ2φ = 120 GM, per protein chain. Compared to the benchmark EGFP, these proteins present 3–4 times improvement in two-photon brightness."
    • "Single-photon properties of the FPs are poor predictors of which fluorescent proteins will be optimal in two-photon applications. It follows that additional mutagenesis efforts to improve two-photon cross section will benefit the field."
  • 2P cross-section in both the 700-800nm and 1000-1100 nm range corresponds to the chromophore polarizability, and is not related to 1p cross section.
  • This can be useflu for multicolor imaging: excitation of the higher S0 → Sn transition of TagRFP simultaneously with the first, S0 → S1, transition of mKalama1 makes dual-color two-photon imaging possible with a single excitation laser wavelength (13)
  • Why are red GECIs based on mApple (rGECO1) or mRuby (RCaMP)? dsRed2 or TagRFP are much better .. but maybe they don't have CP variants.
  • from https://elifesciences.org/articles/12727

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ref: -2017 tags: schema networks reinforcement learning atari breakout vicarious date: 09-29-2020 02:32 gmt revision:2 [1] [0] [head]

Schema networks: zero-shot transfer with a generative causal model of intuitive physics

  • Like a lot of papers, the title has more flash than the actual results.
  • Results which would be state of the art (as of 2017) in playing Atari breakout, then transferring performance to modifications of the game (paddle moved up a bit, wall added in the middle of the bricks, brick respawning, juggling).
  • Schema network is based on 'entities' (objects) which have binary 'attributes'. These attributes can include continuous-valued signals, in which case each binary variable is like a place fields (i think).
    • This is clever an interesting -- rather than just low-level features pointing to high-level features, this means that high-level entities can have records of low-level features -- an arrow pointing in the opposite direction, one which can (also) be learned.
    • The same idea is present in other Vicarious work, including the CAPTCHA paper and more-recent (and less good) Bio-RNN paper.
  • Entities and attributes are propagated forward in time based on 'ungrounded schemas' -- basically free-floating transition matrices. The grounded schemas are entities and action groups that have evidence in observation.
    • There doesn't seem to be much math describing exactly how this works; only exposition. Or maybe it's all hand-waving over the actual, much simpler math.
      • Get the impression that the authors are reaching to a level of formalism when in fact they just made something that works for the breakout task... I infer Dileep prefers the empirical for the formal, so this is likely primarily the first author.
  • There are no perceptual modules here -- game state is fed to the network directly as entities and attributes (and, to be fair, to the A3C model).
  • Entity-attributes vectors are concatenated into a column vector length NTNT , where NN are the number of entities, and TT are time slices.
    • For each entity of N over time T, a row-vector is made of length MRMR , where MM are the number of attributes (fixed per task) and R1R-1 are the number of neighbors in a fixed radius. That is, each entity is related to its neighbors attributes over time.
    • This is a (large, sparse) binary matrix, XX .
  • yy is the vector of actions; task is to predict actions from XX .
    • How is X learned?? Very unclear in the paper vs. figure 2.
  • The solution is approximated as y=XW1¯y = X W \bar{1 } where WW is a binary weight matrix.
    • Minimize the solution based on an objective function on the error and the complexity of ww .
    • This is found via linear programming relaxation. "This procedure monotonically decreases the prediction error of the overall schema network, while increasing its complexity".
      • As it's a issue of binary conjunctions, this seems like a SAT problem!
    • Note that it's not probabilistic: "For this algorithm to work, no contradictions can exist in the input data" -- they instead remove them!
  • Actual behavior includes maximum-product belief propagation, to look for series of transitions that set the reward variable without setting the fail variable.
    • Because the network is loopy, this has to occur several times to set entity variables eg & includes backtracking.

  • Have there been any further papers exploring schema networks? What happened to this?
  • The later paper from Vicarious on zero-shot task transfer are rather less interesting (to me) than this.

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ref: -2004 tags: neural synchrony binding robot date: 09-13-2020 02:00 gmt revision:0 [head]

PMID-15142952 Visual binding through reentrant connectivity and dynamic synchronization in a brain-based device

  • Controlled a robot with a complete (for the time) model of the occipital-inferotemporal visual pathway (V1 V2 V4 IT), auditory cortex, colliculus, 'value cortex'.
  • Synapses had a timing-dependent assoicative BCM learning rule
  • Robot had reflexes to orient toward preferred auditory stimuli
  • Subsequently, robot 'learned' to orient toward a preferred stimuli (e.g. one that caused orientation).
  • Visual stimuli were either diamonds or squares, either red or green.
    • Discrimination task could have been carried out by (it seems) one perceptron layer.
  • This was 16 years ago, and the results look quaint compared to the modern deep-learning revolution. That said, 'the binding problem' is imho still outstanding or at least interesting. Actual human perception is far more compositional than a deep CNN can support.

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ref: -2020 tags: Neuralink commentary BMI pigs date: 08-31-2020 18:01 gmt revision:1 [0] [head]

Neuralink progress update August 28 2020

Some commentary.

The good:

  • Ian hit the nail on the head @ 1:05:47. That is not a side-benefit -- that was the original and true purpose. Thank you.
  • The electronics, amplify / record / sort / stim ASIC, as well as interconnect all advance the state of the art in density, power efficiency, and capability. (I always liked higher sampling rates, but w/e)
  • Puck is an ideal form factor, again SOTA. 25mm diameter craniotomy should give plenty of space for 32 x 32-channel depth electrodes (say).
  • I would estimate that the high-density per electrode feed-through is also SOTA, but it might also be a non-hermetic pass-through via the thin-film (e.g. some water vapor diffusion along the length of the polyimide (if that polymer is being used)).
  • Robot looks nice dressed in those fancy robes. Also looks like there is a revolute joint along the coronal axis.
  • Stim on every channel is cool.
  • Pigs seem like an ethical substitute for monkeys.

The mixed:

  • Neurons are not wires.
  • $2000 outpatient neurosurgery?! Will need to address the ~3% complication rate for most neurosurgery.
  • Where is the monkey data? Does it not work in monkeys? Insufficient longevity or yield? Was it strategic to not mention any monkeys, to avoid bad PR or the wrath of PETA?
    • I can't imagine getting into humans without demonstrating both safety and effectiveness on monkeys. Pigs are fine for the safety part, but monkeys are the present standard for efficacy.
  • How long do the electrodes last in pigs? What is the recording quality? How stable are the traces?
    • Judging from the commentary, assume this is a electrode material problem? What does Neuralink do if they are not significantly different in yield and longevity than the Utah array? (The other problems might well be easier than this one.)
      • That said, a thousand channels of EMG should be sufficient for some of the intended applications (below).
    • It really remains to be seen how well the brain tolerates these somewhat-large somewhat-thin electrodes, what percentage of the brain is disrupted in the process of insertion, and how much of the disruption is transient / how much is irrecoverable.
    • Pig-snout somatosensory cortex is an unusual recording location, making comparison difficult, but what was shown seemed rather correlated (?) We'd have to read an actual scientific publication to evaluate.
  • This slide is deceptive, as not all the applications are equally .. applicable. You don't need an extracellular ephys device to solve these problems that "almost everyone" will encounter over the course of their lives.
    • Memory loss -- Probably better dealt with via cellular / biological therapies, or treating the causes (stroke, infection, inflammation, neuroendocrine or neuromodulatory disregulation)
    • Hearing loss -- Reasonable. Nice complement to improved cochlear implants too. (Maybe the Neuralink ASIC could be used for that, too).
      • With this and the other reasonable applications, best to keep in context that stereo EEG, which is fairly disruptive w/ large probes, is well tolerated in epilepsy patients. (It has unclear effect on IQ or memory, but still, the sewing machine should be less invasive.)
    • Blindness -- Reasonable. Mating the puck to a Second Sight style thin film would improve channel count dramatically, and be less invasive. Otherwise you have to sew into the calcarine fissure, destroying a fair bit of cortex in the process & possibly hitting an artery or sulcal vein.
    • Paralysis -- Absolutely. This application is well demonstrated, and the Neuralink device should be able to help SCI patients. Presumably this will occupy them for the next five years; other applications would be a distraction.
      • Being able to sew flexible electrodes into the spinal cord is a great application.
    • Depression -- Need deeper targets for this. Research to treat depression via basal ganglia stim is ongoing; no reason it could not be mated to the Neuralink puck + long electrodes.
    • Insomina -- I guess?
    • Extreme pain -- Simpler approaches are likely better, but sure?
    • Seizures -- Yes, but note that Neuropace burned through $250M and wasn't significantly better than sham surgery. Again, likely better dealt with biologically: recombinant ion channels, glial or interneuron stem cell therapy.
    • Anxiety -- maybe? Designer drugs seem safer. Or drugs + CBT. Elon likes root causes: spotlight on the structural ills of our society.
    • Addiction -- Yes. It seems possible to rewire the brain with the right record / stim strategy, via for example a combination of DBS and cortical recording. Social restructuring is again a better root-cause fix.
    • Strokes -- No, despite best efforts, the robot causes (small) strokes.
    • Brain Damage -- Insertion of electrodes causes brain damage. Again, better dealt with via cellular (e.g. stem cells) or biological approaches.
      • This, of course, will take time as our understanding of brain development is limited; the good thing is that sufficient guidance signals remain in the adult brain, so AFAIK it's possible. From his comments, seems Alan's attitude is more aligned with this.
    • Not really bad per-se, but right panel could be better. I assume this was a design decision trade-off between working distance, NA, illumination, and mechanical constraints.
    • Despite Elon's claims, there is always bleeding when you poke electrodes that large into the cortex; the capillary bed is too dense. Let's assume Elon meant 'macro' bleeding, which is true. At least the robot avoids visible vessels.
    • Predicting joint angles for cyclical behavior is not challenging; can be done with EMG or microphonic noise correlated to some part of the gait. Hence the request for monkey BMI data.
  • Given the risk, pretty much any of the "sci-fi" applications mentioned in response to dorky twitter comments can be better provided to neurologically normal people through electronics, without the risk of brain surgery.
  • Regarding sci-fi application linguistic telepathy:
    • First, agreed, clarifying thoughts into language takes effort. This is a mostly unavoidable and largely good task. Interfacing with the external world is a vital part of cognition; shortcutting it, in my estimation, will just lead to sloppy & half-formed ideas not worth communicating. The compression of thoughts into words (as lossy as it may be) is the primary way to make them discrete enough to be meaningful to both other people and yourself.
    • Secondly: speech (or again any of the many other forms of communication) is not that much slower than cognition. If it was, we'd have much larger vocabularies, much more complicated and meaning-conveying grammar, etc (Like Latin?). The limit is the average persons cognition and memory. I disagree with Elon's conceit.
  • Regarding visual telepathy, with sufficient recording capabilities, I see no reason why you couldn't have a video-out port on the brain. Difficult given the currently mostly unknown representation of higher-level visual cortices, but as Ian says, once you have a good oscilloscope, this can be deduced.
  • Regarding AI symbiosis @1:09:19; this logic is not entirely clear to me. AI is a tool that will automate & facilitate the production and translation of knowledge much the same way electricity etc automated & facilitated the production and transportation of physical goods. We will necessarily need to interface with it, but to the point that we are thoroughly modifying our own development & biology, those interfaces will likely be based on presently extant computer interfaces.
    • If we do start modifying the biological wiring structure of our brains, I can't imagine that there will many limits! (Outside hard metabolic limits that brain vasculature takes pains to allocate and optimize.)
    • So, I guess the central tenet might be vaguely ok if you allow that humans are presently symbiotic with cell phones. (A more realistic interpretation is that cell phones are tools, and maybe Google etc are the symbionts / parasites). This is arguably contributing to current political existential crises -- no need to look further. If you do look further, it's not clear that stabbing the brains of healthy individuals will help.
    • I find the MC to be slightly unctuous and ingratiating in a way appropriate for a video game company, but not for a medical device company. That, of course, is a judgement call & matter of taste. Yet, as this was partly a recruiting event ... you will find who you set the table for.

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ref: -0 tags: synaptic plasticity 2-photon imaging inhibition excitation spines dendrites synapses 2p date: 08-14-2020 01:35 gmt revision:3 [2] [1] [0] [head]

PMID-22542188 Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex.

  • Cre-recombinase-dependent labeling of postsynapitc scaffolding via Gephryn-Teal fluorophore fusion.
  • Also added Cre-eYFP to label the neurons
  • Electroporated in utero e16 mice.
    • Low concentration of Cre, high concentrations of Gephryn-Teal and Cre-eYFP constructs to attain sparse labeling.
  • Located the same dendrite imaged in-vivo in fixed tissue - !! - using serial-section electron microscopy.
  • 2230 dendritic spines and 1211 inhibitory synapses from 83 dendritic segments in 14 cells of 6 animals.
  • Some spines had inhibitory synapses on them -- 0.7 / 10um, vs 4.4 / 10um dendrite for excitatory spines. ~ 1.7 inhibitory
  • Suggest that the data support the idea that inhibitory inputs maybe gating excitation.
  • Furthermore, co-inervated spines are stable, both during mormal experience and during monocular deprivation.
  • Monocular deprivation induces a pronounced loss of inhibitory synapses in binocular cortex.

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ref: -0 tags: synaptic plasticity LTP LTD synapses NMDA glutamate uncaging date: 08-11-2020 22:40 gmt revision:0 [head]

PMID-31780899 Single Synapse LTP: A matter of context?

  • Not a great name for a thorough and reasonably well-written review of glutamate uncaging studies as related to LTP (and to a lesser extent LTD).
  • Lots of refernces from many familiar names. Nice to have them all in one place!
  • I'm left wondering, between CaMKII, PKA, PKC, Ras, other GTP dependent molecules -- how much of the regulatory network in synapse is known? E.g. if you pull down all proteins in the synaptosome & their interacting partners, how many are unknown, or have an unknown function? I know something like this has been done for flies, but in mammals - ?

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ref: -2015 tags: spiking neural networks causality inference demixing date: 07-22-2020 18:13 gmt revision:1 [0] [head]

PMID-26621426 Causal Inference and Explaining Away in a Spiking Network

  • Rubén Moreno-Bote & Jan Drugowitsch
  • Use linear non-negative mixing plus nose to generate a series of sensory stimuli.
  • Pass these through a one-layer spiking or non-spiking neural network with adaptive global inhibition and adaptive reset voltage to solve this quadratic programming problem with non-negative constraints.
  • N causes, one observation: μ=Σ i=1 Nu ir i+ε \mu = \Sigma_{i=1}^{N} u_i r_i + \epsilon ,
    • r i0r_i \geq 0 -- causes can be present or not present, but not negative.
    • cause coefficients drawn from a truncated (positive only) Gaussian.
  • linear spiking network with symmetric weight matrix J=U TUβI J = -U^TU - \beta I (see figure above)
    • That is ... J looks like a correlation matrix!
    • UU is M x N; columns are the mixing vectors.
    • U is known beforehand and not learned
      • That said, as a quasi-correlation matrix, it might not be so hard to learn. See ref [44].
  • Can solve this problem by minimizing the negative log-posterior function: $$ L(\mu, r) = \frac{1}{2}(\mu - Ur)^T(\mu - Ur) + \alpha1^Tr + \frac{\beta}{2}r^Tr $$
    • That is, want to maximize the joint probability of the data and observations given the probabilistic model p(μ,r)exp(L(μ,r))Π i=1 NH(r i) p(\mu, r) \propto exp(-L(\mu, r)) \Pi_{i=1}^{N} H(r_i)
    • First term quadratically penalizes difference between prediction and measurement.
    • second term, alpha is a L1 regularization term, and third term w beta is a L2 regularization.
  • The negative log-likelihood is then converted to an energy function (linear algebra): W=U TUW = -U^T U , h=U Tμ h = U^T \mu then E(r)=0.5r TWrr Th+α1 Tr+0.5βr TrE(r) = 0.5 r^T W r - r^T h + \alpha 1^T r + 0.5 \beta r^T r
    • This is where they get the weight matrix J or W. If the vectors U are linearly independent, then it is negative semidefinite.
  • The dynamics of individual neurons w/ global inhibition and variable reset voltage serves to minimize this energy -- hence, solve the problem. (They gloss over this derivation in the main text).
  • Next, show that a spike-based network can similarly 'relax' or descent the objective gradient to arrive at the quadratic programming solution.
    • Network is N leaky integrate and fire neurons, with variable synaptic integration kernels.
    • α\alpha translates then to global inhibition, and β\beta to lowered reset voltage.
  • Yes, it can solve the problem .. and do so in the presence of firing noise in a finite period of time .. but a little bit meh, because the problem is not that hard, and there is no learning in the network.

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ref: -0 tags: bleaching STED dye phosphorus japan date: 07-16-2020 14:06 gmt revision:1 [0] [head]

Super-Photostable Phosphole-Based Dye for Multiple-Acquisition Stimulated Emission Depletion Imaging

  • Use the electron withdrawing ability of a phosphole group (P = O) to reduce photobleaching
  • Derived from another photostable dye, C-Naphox, only with a different mechanism of fluorescence -- pi-pi* transfer rather than intramolecular charge transfer (ICT).
  • Much more stable than Alexa 488 (aka sulfonated fluorescein, which is not the most stable dye..)
  • Suitable for multiple STED images, unlike the other dyes. (Note!)

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ref: -2017 tags: google deepmind compositional variational autoencoder date: 04-08-2020 01:16 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

SCAN: learning hierarchical compositional concepts

  • From DeepMind, first version Jul 2017 / v3 June 2018.
  • Starts broad and strong:
    • "The seemingly infinite diversity of the natural world from a relatively small set of coherent rules"
      • Relative to what? What's the order of magnitude here? In personal experience, each domain involves a large pile of relevant details..
    • "We conjecture that these rules dive rise to regularities that can be discovered through primarily unsupervised experiences and represented as abstract concepts"
    • "If such representations are compositional and hierarchical, they can be recombined into an exponentially large set of new concepts."
    • "Compositionality is at the core of such human abilities as creativity, imagination, and language-based communication.
    • This addresses the limitations of deep learning, which are overly data hungry (low sample efficiency), tend to overfit the data, and require human supervision.
  • Approach:
    • Factorize the visual world with a Β\Beta -VAE to learn a set of representational primitives through unsupervised exposure to visual data.
    • Expose SCAN (or rather, a module of it) to a small number of symbol-image pairs, from which the algorithm identifies the set if visual primitives (features from beta-VAE) that the examples have in common.
      • E.g. this is purely associative learning, with a finite one-layer association matrix.
    • Test on both image 2 symbols and symbols to image directions. For the latter, allow irrelevant attributes to be filled in from the priors (this is important later in the paper..)
    • Add in a third module, which allows learning of compositions of the features, ala set notation: AND ( \cup ), IN-COMMON ( \cap ) & IGNORE ( \setminus or '-'). This is via a low-parameter convolutional model.
  • Notation:
    • q ϕ(z x|x)q_{\phi}(z_x|x) is the encoder model. ϕ\phi are the encoder parameters, xx is the visual input, z xz_x are the latent parameters inferred from the scene.
    • p theta(x|z x)p_{theta}(x|z_x) is the decoder model. xp θ(x|z x)x \propto p_{\theta}(x|z_x) , θ\theta are the decoder parameters. xx is now the reconstructed scene.
  • From this, the loss function of the beta-VAE is:
    • 𝕃(θ,ϕ;x,z x,β)=𝔼 q ϕ(z x|x)[logp θ(x|z x)]βD KL(q ϕ(z x|x)||p(z x)) \mathbb{L}(\theta, \phi; x, z_x, \beta) = \mathbb{E}_{q_{\phi}(z_x|x)} [log p_{\theta}(x|z_x)] - \beta D_{KL} (q_{\phi}(z_x|x)|| p(z_x)) where Β>1\Beta \gt 1
      • That is, maximize the auto-encoder fit (the expectation of the decoder, over the encoder output -- aka the pixel log-likelihood) minus the KL divergence between the encoder distribution and p(z x)p(z_x)
        • p(z)𝒩(0,I)p(z) \propto \mathcal{N}(0, I) -- diagonal normal matrix.
        • β\beta comes from the Lagrangian solution to the constrained optimization problem:
        • max ϕ,θ𝔼 xD[𝔼 q ϕ(z|x)[logp θ(x|z)]]\max_{\phi,\theta} \mathbb{E}_{x \sim D} [\mathbb{E}_{q_{\phi}(z|x)}[log p_{\theta}(x|z)]] subject to D KL(q ϕ(z|x)||p(z))<εD_{KL}(q_{\phi}(z|x)||p(z)) \lt \epsilon where D is the domain of images etc.
      • Claim that this loss function tips the scale too far away from accurate reconstruction with sufficient visual de-tangling (that is: if significant features correspond to small details in pixel space, they are likely to be ignored); instead they adopt the approach of the denoising auto-encoder ref, which uses the feature L2 norm instead of the pixel log-likelihood:
    • 𝕃(θ,ϕ;X,z x,β)=𝔼 q ϕ(z x|x)||J(x^)J(x)|| 2 2βD KL(q ϕ(z x|x)||p(z x)) \mathbb{L}(\theta, \phi; X, z_x, \beta) = -\mathbb{E}_{q_{\phi}(z_x|x)}||J(\hat{x}) - J(x)||_2^2 - \beta D_{KL} (q_{\phi}(z_x|x)|| p(z_x)) where J: WxHxC NJ : \mathbb{R}^{W x H x C} \rightarrow \mathbb{R}^N maps from images to high-level features.
      • This J(x)J(x) is from another neural network (transfer learning) which learns features beforehand.
      • It's a multilayer perceptron denoising autoencoder [Vincent 2010].
  • The SCAN architecture includes an additional element, another VAE which is trained simultaneously on the labeled inputs yy and the latent outputs from encoder z xz_x given xx .
  • In this way, they can present a description yy to the network, which is then recomposed into z yz_y , that then produces an image x^\hat{x} .
    • The whole network is trained by minimizing:
    • 𝕃 y(θ y,ϕ y;y,x,z y,β,λ)=1 st2 nd3 rd \mathbb{L}_y(\theta_y, \phi_y; y, x, z_y, \beta, \lambda) = 1^{st} - 2^{nd} - 3^{rd}
      • 1st term: 𝔼 q ϕ y(z y|y)[logp θ y(y|z y)] \mathbb{E}_{q_{\phi_y}(z_y|y)}[log p_{\theta_y} (y|z_y)] log-likelihood of the decoded symbols given encoded latents z yz_y
      • 2nd term: βD KL(q ϕ y(z y|y)||p(z y)) \beta D_{KL}(q_{\phi_y}(z_y|y) || p(z_y)) weighted KL divergence between encoded latents and diagonal normal prior.
      • 3rd term: λD KL(q ϕ x(z x|y)||q ϕ y(z y|y))\lambda D_{KL}(q_{\phi_x}(z_x|y) || q_{\phi_y}(z_y|y)) weighted KL divergence between latents from the images and latents from the description yy .
        • They note that the direction of the divergence matters; I suspect it took some experimentation to see what's right.
  • Final element! A convolutional recombination element, implemented as a tensor product between z y1z_{y1} and z y2z_{y2} that outputs a one-hot encoding of set-operation that's fed to a (hardcoded?) transformation matrix.
    • I don't think this is great shakes. Could have done this with a small function; no need for a neural network.
    • Trained with very similar loss function as SCAN or the beta-VAE.

  • Testing:
  • They seem to have used a very limited subset of "DeepMind Lab" -- all of the concept or class labels could have been implimented easily, e.g. single pixel detector for the wall color. Quite disappointing.
  • This is marginally more interesting -- the network learns to eliminate latent factors as it's exposed to examples (just like perhaps a Bayesian network.)
  • Similarly, the CelebA tests are meh ... not a clear improvement over the existing VAEs.

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ref: -0 tags: asymmetric locality sensitive hash maximum inner product search sparsity date: 03-30-2020 02:17 gmt revision:5 [4] [3] [2] [1] [0] [head]

Improved asymmetric locality sensitive hashing for maximum inner product search

  • Like many other papers, this one is based on a long lineage of locality-sensitive hashing papers.
  • Key innovation, in [23] The power of asymmetry in binary hashing, was the development of asymmetric hashing -- the hash function of the query is different than the hash function used for storage. Roughly, this allows additional degrees of freedom since the similarity-function is (in the non-normalized case) non-symmetric.
    • For example, take query Q = [1 1] with keys A = [1 -1] and B = [3 3]. The nearest neighbor is A (distance 2), whereas the maximum inner product is B (inner product 6).
    • Alternately: self-inner product for Q and A is 2, whereas for B it's 18. Self-similarity is not the highest with inner products.
    • Norm of the query does not have an effect on the arg max of the search, though. Hence, for the paper assume that the query has been normalized for MIPS.
  • In this paper instead they convert MIPS into approximate cosine similarity search (which is like normalized MIPS), which can be efficiently solved with signed random projections.
  • (Established): LSH-L2 distance:
    • Sample a random vector a, iid normal N(0,1)
    • Sample a random normal b between 0 and r
      • r is the window size / radius (free parameters?)
    • Hash function is then the floor of the inner product of the vector a and input x + b divided by the radius.
      • I'm not sure about how the floor op is converted to bits of the actual hash -- ?
  • (Established): LSH-correlation, signed random projections h signh^{sign} :
    • Hash is the sign of the inner product of the input vector and a uniform random vector a.
    • This is a two-bit random projection [13][14].
  • (New) Asymmetric-LSH-L2:
    • P(x)=[x;||x|| 2 2;||x|| 2 4;....;||x|| 2 2 m]P(x) = [x;||x||^2_2; ||x||^4_2; .... ; ||x||^{2^m}_2] -- this is the pre-processing hashing of the 'keys'.
      • Requires that then norm of these keys, {||x||}_2 < U < 1$$
      • m3 m \geq 3
    • Q(x)=[x;1/2;1/2;...;1/2]Q(x) = [x;1/2; 1/2; ... ; 1/2] -- hashing of the queries.
    • See the mathematical explanation in the paper, but roughly "transformations P and Q, when normas are less than 1, provide correction to the L2 distance ||Q(p)P(x i)|| 2||Q(p) - P(x_i)||_2 , making in rank correlate with un-normalized inner product."
  • They then change the augmentation to:
    • P(x)=[x;1/2||x|| 2 2;1/2||x|| 2 4;...;1/2||x|| 2 2 m]P(x) = [x; 1/2 - ||x||^2_2; 1/2 - ||x||^4_2; ... ; 1/2 - ||x||^{2^m}_2]
    • Q(x)=[x;0;...;0]Q(x) = [x; 0; ...; 0]
    • This allows use of signed nearest-neighbor search to be used in the MIPS problem. (e.g. the hash is the sign of P and Q, per above; I assume this is still a 2-bit operation?)
  • Then the expand the U,M compromise function ρ\rho to allow for non-normalized queries. U depends on m and c (m is the codeword extension, and c is the ratio between o-target and off-target hash hits.
  • Tested on Movielens and Netflix databases, this using SVD preprocessing on the user-item matrix (full rank matrix indicating every user rating on every movie (mostly zeros!)) to get at the latent vectors.
  • In the above plots, recall (hah) that precision is the number of true positives / number of false positives as the number of draws k increases; recall is the number of true positives / number of draws k.
    • Clearly, the curve bends up and to the right when there are a lot of hash tables K.
    • Example datapoint: 50% precision at 40% recall, top 5. So on average you get 2 correct hits in 4 draws. Or: 40% precision, 20% recall, top 10: 2 hits in 5 draws. 20/40: 4 hits in 20 draws. (hit: correctly within the top-N)
    • So ... it's not that great.

Use case: Capsule: a camera based positioning system using learning
  • Uses 512 SIFT features as keys and queries to LSH. Hashing is computed via sparse addition / subtraction algorithm, with K bits per hash table (not quite random projections) and L hash tables. K = 22 and L = 24. ~ 1000 training images.
  • Best matching image is used as the location of the current image.

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ref: -0 tags: reinforcement learning distribution DQN Deepmind dopamine date: 03-30-2020 02:14 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-31942076 A distributional code for value in dopamine based reinforcement learning

  • Synopsis is staggeringly simple: dopamine neurons encode / learn to encode a distribution of reward expectations, not just the mean (aka the expected value) of the reward at a given state-action pair.
  • This is almost obvious neurally -- of course dopamine neurons in the striatum represent different levels of reward expectation; there is population diversity in nearly everything in neuroscience. The new interpretation is that neurons have different slopes for their susceptibility to positive and negative rewards (or rather, reward predictions), which results in different inflection points where the neurons are neutral about a reward.
    • This constitutes more optimistic and pessimistic neurons.
  • There is already substantial evidence that such a distributional representation enhances performance in DQN (Deep q-networks) from circa 2017; the innovation here is that it has been extended to experiments from 2015 where mice learned to anticipate water rewards with varying volume, or varying probability of arrival.
  • The model predicts a diversity of asymmetry below and above the reversal point
  • Also predicts that the distribution of reward responses should be decoded by neural activity ... which it is ... but it is not surprising that a bespoke decoder can find this information in the neural firing rates. (Have not examined in depth the decoding methods)
  • Still, this is a clear and well-written, well-thought out paper; glad to see new parsimonious theories about dopamine out there.

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ref: -2016 tags: locality sensitive hash deep learning regularization date: 03-30-2020 02:07 gmt revision:5 [4] [3] [2] [1] [0] [head]

Scalable and sustainable deep learning via randomized hashing

  • Central idea: replace dropout, adaptive dropout, or winner-take-all with a fast (sublinear time) hash based selection of active nodes based on approximate MIPS (maximum inner product search) using asymmetric locality-sensitive hashing.
    • This avoids a lot of the expensive inner-product multiply-accumulate work & energy associated with nodes that will either be completely off due to the ReLU or other nonlinearity -- or just not important for the algorithm + current input.
    • The result shows that you don't need very many neurons active in a given layer for successful training.
  • C.f: adaptive dropout adaptively chooses the nodes based on their activations. A few nodes are sampled from the network probabalistically based on the node activations dependent on their current input.
    • Adaptive dropouts demonstrate better performance than vanilla dropout [44]
    • It is possible to drop significantly more nodes adaptively than without while retaining superior performance.
  • WTA is an extreme form of adaptive dropout that uses mini-batch statistics to enforce a sparsity constraint. [28] {1507} Winner take all autoencoders
  • Our approach uses the insight that selecting a very sparse set of hidden nodes with the highest activations can be reformulated as dynamic approximate query processing, solvable with LSH.
    • LSH can be sub-linear time; normal processing involves the inner product.
    • LSH maps similar vectors into the same bucket with high probability. That is, it maps vectors into integers (bucket number)
  • Similar approach: Hashed nets [6], which aimed to decrease the number of parameters in a network by using a universal random hash function to tie weights. Compressing neural networks with the Hashing trick
    • "HashedNets uses a low-cost hash function to randomly group connection weights into hash buckets, and all connections within the same hash bucket share a single parameter value."
  • Ref [38] shows how asymmetric hash functions allow LSH to be converted to a sub-linear time algorithm for maximum inner product search (MIPS).
  • Used multi-probe LSH: rather than having a large number of hash tables (L) which increases hash time and memory use, they probe close-by buckets in the hash tables. That is, they probe bucket at B_j(Q) and those for slightly perturbed query Q. See ref [26].
  • See reference [2] for theory...
  • Following ref [42], use K randomized hash functions to generate the K data bits per vector. Each bit is the sign of the asymmetric random projection. Buckets contain a pointer to the node (neuron); only active buckets are kept around.
    • The K hash functions serve to increase the precision of the fingerprint -- found nodes are more expected to be active.
    • Have L hash tables for each hidden layer; these are used to increase the probability of finding useful / active nodes due to the randomness of the hash function.
    • Hash is asymmetric in the sense that the query and collection data are hashed independently.
  • In every layer during SGD, compute K x L hashes of the input, probe about 10 L buckets, and take their union. Experiments: K = 6 and L = 5.
  • See ref [30] where authors show around 500x reduction in computations for image search following different algorithmic and systems choices. Capsule: a camera based positioning system using learning {1506}
  • Use relatively small test data sets -- MNIST 8M, NORB, Convex, Rectangles -- each resized to have small-ish input vectors.

  • Really want more analysis of what exactly is going on here -- what happens when you change the hashing function, for example? How much is the training dependent on suitable ROC or precision/recall on the activation?
    • For example, they could have calculated the actual real activation & WTA selection, and compared it to the results from the hash function; how correlated are they?

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ref: -2002 tags: hashing frequent items count sketch algorithm google date: 03-30-2020 02:04 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

Finding frequent items in data streams

  • Notation:
    • S is a data stream, S=q 1,q 2,...,q n S = q_1, q_2, ..., q_n length n.
    • Each object q iO=o 1,...o mq_i \in O = {o_1, ... o_m} That is, there are m total possible objects (e.g. English words).
    • Object o i o_i occurs n in_i times in S. The o no_n are ordered so that n 1n 2n m n_1 \geq n_2 \geq n_m .
  • Task:
    • Given an input stream S, integer k, and real ε\epsilon
    • Output a list of k elements from S such that each element has n i>(1ε)n k n_i \gt (1-\epsilon)n_k .
      • That is, if the ordering is perfect, n in k n_i \geq n_k , with equality on the last element.
  • Algorithm:
    • h 1,...,h th_1, ..., h_t hashes from object q to buckets 1,...,b{1, ..., b}
    • s 1,...,s ts_1, ..., s_t hashes from object q to 1,+1{-1, +1}
    • For each symbol, add it to the 2D hash array by hashing first with h ih_i , then increment that counter with s is_i .
      • The double-hasihing is to reduce the effect of collisions with high-frequency items.
    • When querying for frequency of a object, hash like others, and take the median over i of h i[q]*s i[q] h_i[q] * s_i[q]
    • t=O(log(nδ))t = O(log(\frac{n}{\delta})) where the algorithm fails with at most probability δ\delta
  • Demonstrate proof of convergence / function with Zipfian distributions with varying exponent. (I did not read through this).
  • Also showed that it's possible to compare these hash-counts directly to see what's changed,or importantly if the documents are different.


Mission: Ultra large-scale feature selection using Count-Sketches
  • Task:
    • Given a labeled dataset (X i,y i)(X_i, y_i) for i1,2,...,ni \in {1,2, ..., n} and X i p,y iX_i \in \mathbb{R}^p, y_i \in \mathbb{R}
    • Find the k-sparse feature vector / linear regression for the mean squares problem min||B|| 0=k||yXΒ|| 2 \frac{min}{||B||_0=k} ||y-X\Beta||_2
      • ||B|| 0=k ||B||_0=k counts the non-zero elements in the feature vector.
    • THE number of features pp is so large that a dense Β\Beta cannot be stored in memory. (X is of course sparse).
  • Such data may be from ad click-throughs, or from genomic analyses ...
  • Use the count-sketch algorithm (above) for capturing & continually updating the features for gradient update.
    • That is, treat the stream of gradient updates, in the normal form g i=2λ(y iX iΒ iX t) tX ig_i = 2 \lambda (y_i - X_i \Beta_i X^t)^t X_i , as the semi-continuous time series used above as SS
  • Compare this with greedy thresholding, Iterative hard thresholding (IHT) e.g. throw away gradient information after each batch.
    • This discards small gradients which may be useful for the regression problem.
  • Works better, but not necessarily better than straight feature hashing (FH).
  • Meh.

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ref: -2015 tags: winner take all sparsity artificial neural networks date: 03-28-2020 01:15 gmt revision:0 [head]

Winner-take-all Autoencoders

  • During training of fully connected layers, they enforce a winner-take all lifetime sparsity constraint.
    • That is: when training using mini-batches, they keep the k percent largest activation of a given hidden unit across all samples presented in the mini-batch. The remainder of the activations are set to zero. The units are not competing with each other; they are competing with themselves.
    • The rest of the network is a stack of ReLU layers (upon which the sparsity constraint is applied) followed by a linear decoding layer (which makes interpretation simple).
    • They stack them via sequential training: train one layer from the output of another & not backprop the errors.
  • Works, with lower sparsity targets, also for RBMs.
  • Extended the result to WTA covnets -- here enforce both spatial and temporal (mini-batch) sparsity.
    • Spatial sparsity involves selecting the single largest hidden unit activity within each feature map. The other activities and derivatives are set to zero.
    • At test time, this sparsity constraint is released, and instead they use a 4 x 4 max-pooling layer & use that for classification or deconvolution.
  • To apply both spatial and temporal sparsity, select the highest spatial response (e.g. one unit in a 2d plane of convolutions; all have the same weights) for each feature map. Do this for every image in a mini-batch, and then apply the temporal sparsity: each feature map gets to be active exactly once, and in that time only one hidden unit (or really, one location of the input and common weights (depending on stride)) undergoes SGD.
    • Seems like it might train very slowly. Authors didn't note how many epochs were required.
  • This, too can be stacked.
  • To train on larger image sets, they first extract 48 x 48 patches & again stack...
  • Test on MNIST, SVHN, CIFAR-10 -- works ok, and well even with few labeled examples (which is consistent with their goals)

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ref: -0 tags: VARNUM GEVI genetically encoded voltage indicators FRET Ace date: 03-18-2020 17:12 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-30420685 Fast in-vivo voltage imaging using a red fluorescent indicator

  • Kannan M, Vasan G, Huang C, Haziza S, Li JZ, Inan H, Schnitzer MJ, Pieribone VA.
  • Other genetically encoded voltage indicators (GEVI):
    • PMID-22958819 ArcLight (Peribone also last author) ; sign of ΔF/F\Delta F / F negative, but large, 35%! Slow tho? improvement in speed
    • ASAP3 ΔF/F\Delta F / F large, τ=3ms.\tau = 3 ms.
    • PMID-26586188 Ace-mNeon FRET based, Acetabularia opsin, fast kinetics + brightness of mNeonGreen.
    • Archon1 -- fast and sensitive, found (like VARNUM) using a robotic directed evolution or direct search strategy.
  • VARNAM is based on Acetabularia (Ace) + mRuby3, also FRET based, found via high-throughput voltage screen.
  • Archaerhodopsin require 1-12 W/mm^2 of illumination, vs. 50 mw/mm^2 for GFP based probes. Lots of light!
  • Systematic optimization of voltage sensor function: both the linker region (288 mutants), which affects FRET efficiency, as well as the opsin fluorophore region (768 mutants), which affects the wavelength of absorption / emission.
  • Some intracellular clumping (which will negatively affect sensitivity), but mostly localized to the membrane.
  • Sensitivity is still imperfect -- 4% in-vivo cortical neurons, though it’s fast enough to resolve 100 Hz spiking.
  • Can resolve post-synaptic EPSCs, but < 1 % ΔF/F\Delta F/F .
  • Tested all-optical ephys using VARNAM + blueshifted channelrhodopsin, CheRiff, both sparsely, and in PV targeted transgenetic model. Both work, but this is a technique paper; no real results.
  • Tested TEMPO fiber-optic recording in freely behaving mice (ish) -- induced ketamine waves, 0.5-4Hz.
  • And odor-induced activity in flies, using split-Gal4 expression tools. So many experiments.

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ref: -2019 tags: Vale photostability bioarxiv DNA oragami photobleaching date: 03-10-2020 21:59 gmt revision:5 [4] [3] [2] [1] [0] [head]

A 6-nm ultra-photostable DNA Fluorocube for fluorescence imaging

  • Cy3n = sulfonated version of Cy3.
  • JF549 = azetidine modified version of tetramethyl rhodamine.

Also including some correspondence with the authors:

Me

Nice work and nice paper, thanks for sharing .. and not at all what I had expected from Ron's comments! Below are some comments ... would love your opinion.

I'd expect that the molar absorption coefficients for the fluorocubes should be ~6x larger than for the free dyes and the single dye cubes (measured?), yet the photon yields for all except Cy3N maybe are around the yield for one dye molecule. So the quantum yield must be decreased by ~6x?

This in turn might be from a middling FRET which reduces lifetime, thereby the probability of ISC, photoelectron transfer, and hence photobleaching.

I wonder if in the case of ATTO 647N Cy5 and Cy3, the DNA is partly shielding the fluorphores from solvent (ala ethidium bromide), which also helps with stability, just like in fluorescent proteins. ATTO 647N generates a lot of singlet oxygen, who knows what it's doing to DNA.

Can you do a log-log autocorrelation of the blinking timeseries of the constructs? This may reveal different rate constants controlling dark/light states (though, for 6 coupled objects, might not be interpretable!)

Also, given the effect of DNA shielding, have you compared to free dyes to single-dye cubes other than supp fig 10? The fact that sulfonation made such a huge effect in brightness is suggestive.

Again, these are super interesting & exciting results!

Author

I haven't directly looked at the molar absorption coefficient but judging from the data that I collected for the absorption spectra, there is certainly an increase for the fluorocubes compared to single dyes. I agree that this would be an interesting experiment and I am planning collect data to measure the molar absorption coefficient. I would also expect a ~6 fold increase for the Fluorocubes.

Yes, we suspect homo FRET to help reduce photobleaching. So far we only measured lifetimes in bulk but are planning to obtain lifetime data on the single-molecule level soon.

We also wondered if the DNA is providing some kind of shield for the fluorophores but could not design an experiment to directly test this hypothesis. If you have a suggestion, that would be wonderful.

The log-log autocorrelation of blinking events is indeed difficult to interpret. Already individual intensity traces of fluorocubes are difficult to analyze as many of them get brighter before they bleach. We are also wondering if some fluorocubes are emitting two photons simultaneously. We will hopefully be able to measure this soon.

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ref: -0 tags: Na Ji 2p two photon fluorescent imaging pulse splitting damage bleaching date: 03-10-2020 21:44 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-18204458 High-speed, low-photodamage nonlinear imaging using passive pulse splitters

  • Core idea: take a single pulse and spread it out to N=2 kN= 2^k pulses using reflections and delay lines.
  • Assume two optical processes, signal SI αS \propto I^{\alpha} and photobleaching/damage DI βD \propto I^{\beta} , β>α>1\beta \gt \alpha \gt 1
  • Then an NN pulse splitter requires N 11/αN^{1-1/\alpha} greater average power but reduces the damage by N 1β/α.N^{1-\beta/\alpha}.
  • At constant signal, the same NN pulse splitter requires N\sqrt{N} more power, consistent with two photon excitation (proportional to the square of the intensity: N pulses of N/N\sqrt{N}/N intensity, 1/N per pulse fluorescence, Σ1\Sigma \rightarrow 1 overall fluorescence.)
  • This allows for shorter dwell times, higher power at the sample, lower damage, slower photobleaching, and better SNR for fluorescently labeled slices.
  • Examine the list of references too, e.g. "Multiphoton multifocal microscopy exploiting a diffractive optical element" (2003)

  • In practice, a pulse picker is useful when power is limited and bleaching is not a problem (as is with GCaMP6x)

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ref: -0 tags: DNA paint FRET tag superresolution imaging oligos date: 02-20-2020 16:28 gmt revision:1 [0] [head]

Accelerated FRET-PAINT Microscopy

  • Well isn't that smart -- they use a FRET donor, which is free to associate and dissociate form a host DNA strand, and a more-permanently attached DNA acceptor, which blinks due to FRET, for superresolution imaging.
  • As FRET acceptors aren't subject to bleaching (or, perhaps, much less subject to bleaching), this eliminates that problem...
  • However, the light levels used ~1kW / cm^2, does damage the short DNA oligos, which interferes with reversible association.
  • Interestingly, CF488 donor showed very little photobleaching; DNA damage was instead the limiting problem.
    • Are dyes that bleach more slowly better at exporting their singlet oxygen (?) or aberrant excited states (?) to neighboring molecules?

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ref: -0 tags: rhodamine derivatives imidazole bacterial resistance date: 02-19-2020 19:10 gmt revision:2 [1] [0] [head]

A diversity-oriented rhodamine library for wide-spectrum bactericidal agents with low inducible resistance against resistant pathogens

  • Tested a wide number of rhodamine derivatives, which were synthesized with a 'mild' route. This includes all sorts of substitutions on the carbon opposite the oxygen.
  • Tested the fluorescence properties ... many if not all are fluorescent. Supplementary information lists the abs/em spectra, which is kind of a goldmine (if it can be trusted).
  • No mention of light or dark in the paper. I suspect that these rhodamine derivatives are killing via singlet oxygen production. (Then again, I only skimmed the paper..)
    • Yes but: "Rhodamine dyes mainly adopted the ring-close forms exhibit no antibacterial activity against ATCC43300 or ATCC19606"
    • That's because they are colorless and can't emit any singlet oxygen!

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ref: -0 tags: two photon scanning microscope mirror relay date: 01-31-2020 02:46 gmt revision:1 [0] [head]

PMID-24877017 Optimal lens design and use in laser-scanning microscopy

  • Detail careful design of a scanning two-photon microscope, with custom scan lens, tube lens, and standard 25x objective.
  • Near diffraction limited performance for both the scan and tube lenses across a broad excitation range -- 690 to 1400nm.
  • Interestingly, use a parabolic mirror relay to conjugate the two galvos to each other; seems like a good idea, why has this not been done elsewhere?

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ref: -0 tags: lavis jf dyes fluorine zwitterion lactone date: 01-22-2020 20:06 gmt revision:0 [head]

Optimization and functionalization of red-shifted rhodamine dyes

  • Zwitterion form is fluorescent and colored; lactone form is not and colorless.
  • Lactone form is lipophyllic; some mix seems more bioavailable and also results in fluorogenic dyes.
  • Good many experiments with either putting fluorine on the azetidines or on the benzyl ring.
  • Fluorine on the azetidine pushes the K ZLK_{Z-L} toward lactone form; fluorine on the benzyl ring pushes it toward the zwitterion.
  • Si-rhodamine and P-rhodamine adopt the lactone form, and adding appropriate fluorines can make them fluorescent again. Which makes for good red-shifted dyes, ala JF669
  • N-CH3 can be substituted in the oxygen position too, resulting in blue-shifted dye which is a good stand-in for EGFP.

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ref: -0 tags: multifactor synaptic learning rules date: 01-22-2020 01:45 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

Why multifactor?

  • Take a simple MLP. Let xx be the layer activation. X 0X^0 is the input, X 1X^1 is the second layer (first hidden layer). These are vectors, indexed like x i ax^a_i .
  • Then X 1=WX 0X^1 = W X^0 or x j 1=ϕ(Σ i=1 Nw ijx i 0)x^1_j = \phi(\Sigma_{i=1}^N w_{ij} x^0_i) . ϕ\phi is the nonlinear activation function (ReLU, sigmoid, etc.)
  • In standard STDP the learning rule follows Δwf(x pre(t),x post(t)) \Delta w \propto f(x_{pre}(t), x_{post}(t)) or if layer number is aa Δw a+1f(x a(t),x a+1(t))\Delta w^{a+1} \propto f(x^a(t), x^{a+1}(t))
    • (but of course nobody thinks there 'numbers' on the 'layers' of the brain -- this is just referring to pre and post synaptic).
  • In an artificial neural network, Δw aEw ij aδ j ax i \Delta w^a \propto - \frac{\partial E}{\partial w_{ij}^a} \propto - \delta_{j}^a x_{i} (Intuitively: the weight change is proportional to the error propagated from higher layers times the input activity) where δ j a=(Σ k=1 Nw jkδ k a+1)ϕ \delta_{j}^a = (\Sigma_{k=1}^{N} w_{jk} \delta_k^{a+1}) \partial \phi where ϕ\partial \phi is the derivative of the nonlinear activation function, evaluated at a given activation.
  • f(i,j)[x,y,θ,ϕ] f(i, j) \rightarrow [x, y, \theta, \phi]
  • k=13.165 k = 13.165
  • x=round(i/k) x = round(i / k)
  • y=round(j/k) y = round(j / k)
  • θ=a(ikx)+b(ikx) 2 \theta = a (\frac{i}{k} - x) + b (\frac{i}{k} - x)^2
  • ϕ=a(jky)+b(jky) 2 \phi = a (\frac{j}{k} - y) + b (\frac{j}{k} - y)^2

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ref: -2017 tags: human level concept learning through probabalistic program induction date: 01-20-2020 15:45 gmt revision:0 [head]

PMID-26659050 Human level concept learning through probabalistic program induction

  • Preface:
    • How do people learn new concepts from just one or a few examples?
    • And how do people learn such abstract, rich, and flexible representations?
    • How can learning succeed from such sparse dataset also produce such rich representations?
    • For any theory of learning, fitting a more complicated model requires more data, not less, to achieve some measure of good generalization, usually in the difference between new and old examples.
  • Learning proceeds bu constructing programs that best explain the observations under a Bayesian criterion, and the model 'learns to learn' by developing hierarchical priors that allow previous experience with related concepts to ease learning of new concepts.
  • These priors represent learned inductive bias that abstracts the key regularities and dimensions of variation holding actoss both types of concepts and across instances.
  • BPL can construct new programs by reusing pieced of existing ones, capturing the causal and compositional properties of real-world generative processes operating on multiple scales.
  • Posterior inference requires searching the large combinatorial space of programs that could have generated a raw image.
    • Our strategy uses fast bottom-up methods (31) to propose a range of candidate parses.
    • That is, they reduce the character to a set of lines (series of line segments), then simply the intersection of those lines, and run a series of parses to estimate the generation of those lines, with heuristic criteria to encourage continuity (e.g. no sharp angles, penalty for abruptly changing direction, etc).
    • The most promising candidates are refined by using continuous optimization and local search, forming a discrete approximation to the posterior distribution P(program, parameters | image).

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ref: -2017 tags: locality sensitive hashing olfaction kenyon cells neuron sparse representation date: 01-18-2020 21:13 gmt revision:1 [0] [head]

PMID-29123069 A neural algorithm for a fundamental computing problem

  • Ceneral idea: locality-sensitive hashing, e.g. hashing that is sensitive to the high-dimensional locality of the input space, can be efficiently solved using a circuit inspired by the insect olfactory system.
  • Here, activation of 50 different types of ORNs is mapped to 50 projection neurons, which 'centers the mean' -- concentration dependence is removed.
  • This is then projected via a random matrix of sparse binary weights to a much larger set of Kenyon cells, which in turn are inhibited by one APL neuron.
  • Normal locality-sensitive hashing uses dense matrices of Gaussian-distributed random weights, which means higher computational complexity...
  • ... these projections are governed by the Johnson-Lindenstrauss lemma, which says that projection from high-d to low-d space can preserve locality (distance between points) within an error bound.
  • Show that the WTA selection of the top 5% plus random binary weight preserves locality as measured by overlap with exact input locality on toy data sets, including MNIST and SIFT.
  • Flashy title as much as anything else got this into Science... indeed, has only been cited 6 times in Pubmed.

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ref: -2014 tags: dopamine medium spiny neurons calcium STDP PKA date: 01-07-2020 03:43 gmt revision:2 [1] [0] [head]

PMID-25258080 A critical time window for dopamine actions on the structural plasticity of dendritic spines

  • Remarkably short time window for dopamine to modulate / modify (aggressive) STDP protocol.
  • Showed with the low-affinity calcium indicator Fluo4-FF that peak calcium concentrations in spines is not affected by optogenetic stimulation of dopamine fibers.
  • However, CaMKII activity is modulated by DA activity -- when glutamate uncaging and depolarization was followed by optogenetic stimulation of DA fibers followed, the FRET sensor Camui-CR reported significant increases of CaMKII activity.
  • This increase was abolished by the application of DRAPP-32 inhibiting peptide, which blocks the interaction of dopamine and cAMP-regulated phospoprotein - 32kDa (DRAPP-32) with protein phosphatase 1 (PP-1)
    • Spine enlargement was induced in the absence of optogenetic dopamine when PP-1 was inhibited by calculin A...
    • Hence, phosphorylation of DRAPP-32 by PKA inhibits PP-1 and disinihibts CaMKII. (This causal inference seems loopy; they reference a hippocampal paper, [18])
  • To further test this, they used a FRET probe of PKA activity, AKAR2-CR. This sensor showed that PKA activity extends throughout the dendrite, not just the stimulated spine, and can respond to DA release directly.

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ref: -0 tags: nonlinear hebbian synaptic learning rules projection pursuit date: 12-12-2019 00:21 gmt revision:4 [3] [2] [1] [0] [head]

PMID-27690349 Nonlinear Hebbian Learning as a Unifying Principle in Receptive Field Formation

  • Here we show that the principle of nonlinear Hebbian learning is sufficient for receptive field development under rather general conditions.
  • The nonlinearity is defined by the neuron’s f-I curve combined with the nonlinearity of the plasticity function. The outcome of such nonlinear learning is equivalent to projection pursuit [18, 19, 20], which focuses on features with non-trivial statistical structure, and therefore links receptive field development to optimality principles.
  • Δwxh(g(w Tx))\Delta w \propto x h(g(w^T x)) where h is the hebbian plasticity term, and g is the neurons f-I curve (input-output relation), and x is the (sensory) input.
  • The relevant property of natural image statistics is that the distribution of features derived from typical localized oriented patterns has high kurtosis [5,6, 39]
  • Model is a generalized leaky integrate and fire neuron, with triplet STDP

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ref: -2016 tags: spiking neural network self supervised learning date: 12-10-2019 03:41 gmt revision:2 [1] [0] [head]

PMID: Spiking neurons can discover predictive features by aggregate-label learning

  • This is a meandering, somewhat long-winded, and complicated paper, even for the journal Science. It's not been cited a great many times, but none-the-less is of interest.
  • The goal of the derived network is to detect fixed-pattern presynaptic sequences, and fire a prespecified number of spikes to each occurrence.
  • One key innovation is the use of a spike-threshold-surface for a 'tempotron' [12], the derivative of which is used to update the weights of synapses after trials. As the author says, spikes are hard to differentiate; the STS makes this more possible. This is hence standard gradient descent: if the neuron missed a spike then the weight is increased based on aggregate STS (for the whole trial -- hence the neuron / SGD has to perform temporal and spatial credit assignment).
    • As common, the SGD is appended with a momentum term.
  • Since STS differentiation is biologically implausible -- where would the memory lie? -- he also implements a correlational synaptic eligibility trace. The correlation is between the postsynaptic voltage and the EPSC, which seems kinda circular.
    • Unsurprisingly, it does not work as well as the SGD approximation. But does work...
  • Second innovation is the incorporation of self-supervised learning: a 'supervisory' neuron integrates the activity of a number (50) of feature detector neurons, and reinforces them to basically all fire at the same event, WTA style. This effects a unsupervised feature detection.
  • This system can be used with sort-of lateral inhibition to reinforce multiple features. Not so dramatic -- continuous feature maps.

Editorializing a bit: I said this was interesting, but why? The first part of the paper is another form of SGD, albeit in a spiking neural network, where the gradient is harder compute hence is done numerically.

It's the aggregate part that is new -- pulling in repeated patterns through synaptic learning rules. Of course, to do this, the full trace of pre and post synaptic activity must be recorded (??) for estimating the STS (i think). An eligibility trace moves in the right direction as a biologically plausible approximation, but as always nothing matches the precision of SGD. Can the eligibility trace be amended with e.g. neuromodulators to push the performance near that of SGD?

The next step of adding self supervised singular and multiple features is perhaps toward the way the brain organizes itself -- small local feedback loops. These features annotate repeated occurrences of stimuli, or tile a continuous feature space.

Still, the fact that I haven't seen any follow-up work is suggestive...


Editorializing further, there is a limited quantity of work that a single human can do. In this paper, it's a great deal of work, no doubt, and the author offers some good intuitions for the design decisions. Yet still, the total complexity that even a very determined individual can amass is limited, and likely far below the structural complexity of a mammalian brain.

This implies that inference either must be distributed and compositional (the normal path of science), or the process of evaluating & constraining models must be significantly accelerated. This later option is appealing, as current progress in neuroscience seems highly technology limited -- old results become less meaningful when the next wave of measurement tools comes around, irrespective of how much work went into it. (Though: the impedtus for measuring a particular thing in biology is only discovered through these 'less meaningful' studies...).

A third option, perhaps one which many theoretical neuroscientists believe in, is that there are some broader, physics-level organizing principles to the brain. Karl Friston's free energy principle is a good example of this. Perhaps at a meta level some organizing theory can be found, or likely a set of theories; but IMHO, you'll need at least one theory per brain area, at least, just the same as each area is morphologically, cytoarchitecturaly, and topologically distinct. (There may be only a few theories of the cortex, despite all the areas, which is why so many are eager to investigate it!)

So what constitutes a theory? Well, you have to meaningfully describe what a brain region does. (Why is almost as important; how more important to the path there.) From a sensory standpoint: what information is stored? What processing gain is enacted? How does the stored information impress itself on behavior? From a motor standpoint: how are goals selected? How are the behavioral segments to attain them sequenced? Is the goal / behavior even a reasonable way of factoring the problem?

Our dual problem, building the bridge from the other direction, is perhaps easier. Or it could be a lot more money has gone into it. Either way, much progress has been made in AI. One arm is deep function approximation / database compression for fast and organized indexing, aka deep learning. Many people are thinking about that; no need to add to the pile; anyway, as OpenAI has proven, the common solution to many problems is to simply throw more compute at it. A second is deep reinforcement learning, which is hideously sample and path inefficient, hence ripe for improvement. One side is motor: rather than indexing raw motor variables (LRUD in a video game, or joint torques with a robot..) you can index motor primitives, perhaps hierarchically built; likewise, for the sensory input, the model needs to infer structure about the world. This inference should decompose overwhelming sensory experience into navigable causes ...

But how can we do this decomposition? The cortex is more than adept at it, but now we're at the original problem, one that the paper above purports to make a stab at.

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ref: -0 tags: dLight1 dopamine imaging Tian date: 12-05-2019 17:27 gmt revision:0 [head]

PMID-29853555 Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors

  • cpGFP based sensor. ΔF/F~3\Delta F / F ~ 3 .

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ref: -0 tags: surface plasmon resonance voltage sensing antennas PEDOT imaging spectroscopy date: 12-05-2019 16:47 gmt revision:1 [0] [head]

Electro-plasmonic nanoantenna: A nonfluorescent optical probe for ultrasensitive label-free detection of electrophysiological signals

  • Use spectroscopy to measure extracellular voltage, via plasmon concentrated electrochromic effects in doped PEDOT.

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ref: -0 tags: multimode fiber imaging date: 11-15-2019 03:10 gmt revision:2 [1] [0] [head]

PMID-30588295 Subcellular spatial resolution achieved for deep-brain imaging in vivo using a minimally invasive multimode fiber

  • Oh wow wowww
  • Imaged through a 50um multimode optical fiber!
  • Multimode scattering matrix was inverted through a LC-SLM

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ref: -0 tags: adaptive optics sensorless retina fluorescence imaging optimization zernicke polynomials date: 11-15-2019 02:51 gmt revision:0 [head]

PMID-26819812 Wavefront sensorless adaptive optics fluorescence biomicroscope for in vivo retinal imaging in mice

  • Idea: use backscattered and fluorescence light to optimize the confocal image through imperfect optics ... and the lens of the mouse eye.
    • Optimization was based on hill-climbing / line search of each Zernicke polynomial term for the deformable mirror. (The mirror had to be characterized beforehand, naturally).
    • No guidestar was needed!
  • Were able to resolve the dendritic processes of EGFP labeled Thy1 ganglion cells and Cx3 glia.

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ref: -2015 tags: PaRAC1 photoactivatable Rac1 synapse memory optogenetics 2p imaging mouse motor skill learning date: 10-30-2019 20:35 gmt revision:1 [0] [head]

PMID-26352471 Labelling and optical erasure of synaptic memory traces in the motor cortex

  • Idea: use Rac1, which has been shown to induce spine shrinkage, coupled to a light-activated domain to allow for optogenetic manipulation of active synapses.
  • PaRac1 was coupled to a deletion mutant of PSD95, PSD delta 1.2, which concentrates at the postsynaptic site, but cannot bind to postsynaptic proteins, thus minimizing the undesirable effects of PSD-95 overexpression.
    • PSD-95 is rapidly degraded by proteosomes
    • This gives spatial selectivity.
  • They then exploited the dendritic targeting element (DTE) of Arc mRNA which is selectively targeted and translated in activiated dendritic segments in response to synaptic activation in an an NMDA receptor dependent manner.
    • Thereby giving temporal selectivity.
  • Construct is then PSD-PaRac1-DTE; this was tested on hippocampal slice cultures.
  • Improved sparsity and labelling further by driving it with the Arc promoter.
  • Motor learning is impaired in Arc KO mice; hence inferred that the induction of AS-PaRac1 by the Arc promoter would enhance labeling during learning-induced potentiation.
  • Delivered construct via in-utero electroporation.
  • Observed rotarod-induced learning; the PaRac signal decayed after two days, but the spine volume persisted in spines that showed Arc / DTE hence PA labeled activity.
  • Now, since they had a good label, performed rotarod training followed by (at variable delay) light pulses to activate Rac, thereby suppressing recently-active synapses.
    • Observed both a depression of behavioral performance.
    • Controlled with a second task; could selectively impair performance on one of the tasks based on ordering/timing of light activation.
  • The localized probe also allowed them to image the synapse populations active for each task, which were largely non-overlapping.

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ref: -0 tags: carbon capture links date: 10-18-2019 14:20 gmt revision:0 [head]

Carbon capture links:

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ref: -0 tags: Lucy Flavin mononucelotide FAD FMN fluorescent protein reporter date: 10-17-2019 19:54 gmt revision:1 [0] [head]

PMID-25906065 LucY: A Versatile New Fluorescent Reporter Protein

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ref: -2019 tags: meta learning feature reuse deepmind date: 10-06-2019 04:14 gmt revision:1 [0] [head]

Rapid learning or feature reuse? Towards understanding the effectiveness of MAML

  • It's feature re-use!
  • Show this by freezing the weights of a 5-layer convolutional network when training on Mini-imagenet, either 5shot 1 way, or 5shot 5 way.
  • From this derive ANIL, where only the last network layer is updated in task-specific training.
  • Show that ANIL works for basic RL learning tasks.
  • This means that roughly the network does not benefit much from join encoding -- encoding both the task at hand and the feature set. Features can be learned independently from the task (at least these tasks), with little loss.

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ref: -2012 tags: cortex striatum learning carmena costa basal ganglia date: 09-13-2019 18:30 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-22388818 Corticostriatal plasticity is necessary for learning intentional neuroprosthetic skills.

  • Trained a mouse to control an auditory cursor, as in Kipke's task {99}. Did not cite that paper, claimed it was 'novel'. oops.
  • Summed neuronal firing rate of groups of 2 or 4 M1 neurons.
  • Auditory feedback was essential for the operant learning.
    • One group increased the frequency with increased firing rate; the other decreased tone with increasing FR.
  • Specific deletion of striatal NMDA receptors impairs the ability to learn neuroprosthetic skills.
    • Hence, they argue, cortico-striatal plastciity is required to learn abstract skills, such as this tone to firing rate target acquisition task.
  • Controlled by recording EMG of the vibrissae + injection of lidocane into the whisker pad.
  • One reward was sucrose solution; the other was a food pellet. When the rat was satiated on one modality, they showed increased preference for the opposite reward during BMI control -- thereby demonstrating intentionality. Clever!.
  • Noticed pronounced oscillatory spike coupling, the coherence of which was increased in low-frequency bands in late learning relative to early learning (figure 3).
  • Genetic manipulations: knockin line that expresses Cre recombinase in both striatonigral and striatopallidal medium spiny neurons, crossed with mice carrying a floxed allele of the NMDAR1 gene.
    • These animals are relatively normal, and can learn to perform rapid sequential movements, but are unable to learn precise motor sequences.
    • Acute pharmacological blockade of NMDAR did not affect performance of the neuroprosthetic skill.
    • Hence the deficits in the transgenic mice are due to an inability to perform the skill.

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ref: -2019 tags: Kleinfeld Harris record every neuron date: 09-13-2019 01:51 gmt revision:0 [head]

PMID-31495645 Can One Concurrently Record Electrical Spikes from Every Neuron in a Mammalian Brain?

  • Argues for a concrete arrangement of 6um diamond (1.2TPa modulus) shanks, 2mm long, on 40um hexagonal grid. Each would be patterned with 5 layers of metal, 30nm x 30nm Au traces (what about surface roughness?), high dielectric insulation, 9um x 14um TiN contacts.
  • This will be mated to state of the art adaptive amplifiers, which would be biased to only burn necessary power needed to sort spikes.
  • The sharpened spikes should penetrate the brain; 4um diameter diamond shanks should also work...
  • Overall volume displacement ~ 2% (which still seems high).
  • Suggest that the shanks can push capillaries out of the way, or puncture them while making a seal. Clearly, that's possible ...
  • ... but realistically, unless these are inserted glacially slowly, it will cause possibly catastrophic / cascading inflammation. (Which can spread on the order of 100-150um).
  • Does not cite Marblestone 2013.

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ref: -2017 tags: two photon holographic imaging Arch optogenetics GCaMP6 date: 09-12-2019 19:24 gmt revision:1 [0] [head]

PMID-28053310 Simultaneous high-speed imaging and optogenetic inhibition in the intact mouse brain.

  • Bovetti S1, Moretti C1, Zucca S1, Dal Maschio M1, Bonifazi P2,3, Fellin T1.
  • Image GCamp6 in either scanned mode (high resolution, slow) or holographically (SLM, redshirt 80x80 NeuroCCD, activate opsin Arch, simultaneously record juxtasomal action potentials.

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ref: -2007 tags: photobleaching GFP date: 09-10-2019 01:42 gmt revision:1 [0] [head]

PMID-17179937 Major signal increase in fluorescence microscopy through dark-state relaxation (2007)

  • 5-25x increase in fluorescence yields.
  • Idea: allow the (dark) triplet states to decay naturally by keeping inter-pulse intervals of illumination greater than 1us.
  • Works for both 1p and 2p.
  • For volume imaging via 2p, I don’t think that 1um decay time is much of an issue; revisit given fluorophores after >1ms!
  • Suggests again that transition from triplet dark state to excited higher state is a prominent or significant cause of photobleaching; also suggests that triple quenching will have limited utility in scanned or pulsed 2p systems (will have more utility in 1p systems, perhaps..)
  • Atto532 dye has low intersystem crossing to the triplet state (1%) [3,5,14] .. humm.
  • 2p total photon emission seems to flatten above 100GW/cm^2 intensity.
  • 2p absorption is easily saturated independent of pulse width: for short pulses, high intensity leads to absorption to T1 state, which has high cross-section to the Tn>1 state; longer pulses give more time for single-photon absorption.
  • τp by m = 200 and hence the pulse energy by 14-fold does not have a considerable effect on G2p. This obviously indicates that the saturation of the S0 → S1 or of the T1 → Tn > 1 excitation eliminates any dependence on pulse peak intensity or energy.

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ref: -0 tags: computational neuroscience opinion tony zador konrad kording lillicrap date: 07-30-2019 21:04 gmt revision:0 [head]

Two papers out recently in Arxive and Biorxiv:

  • A critique of pure learning: what artificial neural networks can learn from animal brains
    • Animals learn rapidly and robustly, without the need for labeled sensory data, largely through innate mechanisms as arrived at and encoded genetically through evolution.
    • Still, this cannot account for the connectivity of the human brain, which is much to large for the genome; with us, there are cannonical circuits and patterns of intra-area connectivity which act as the 'innate' learning biases.
    • Mice and men are not so far apart evolutionary. (I've heard this also from people FIB-SEM imaging cortex) Hence, understanding one should appreciably lead us to understand the other. (I agree with this sentiment, but for the fact that lab mice are dumb, and have pretty stereotyped behaviors).
    • References Long short term memory and learning to learn in networks of spiking neurons -- which claims that a hybrid algorithm (BPTT with neuronal rewiring) with realistic neuronal dynamics markedly increases the computational power of spiking neural networks.
  • What does it mean to understand a neural network?
    • As has been the intuition with a lot of neuroscientists probably for a long time, posits that we have to investigate the developmental rules (wiring and connectivity, same as above) plus the local-ish learning rules (synaptic, dendritic, other .. astrocytic).
      • The weights themselves, in either biological neural networks, or in ANN's, are not at all informative! (Duh).
    • Emphasizes the concept of compressability: how much information can be discarded without impacting performance? With some modern ANN's, 30-50x compression is possible. Authors here argue that little compression is possible in the human brain -- the wealth of all those details about the world are needed! In other words, no compact description is possible.
    • Hence, you need to learn how the network learns those details, and how it's structured so that important things are learned rapidly and robustly, as seen in animals (very similar to above).

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ref: -2019 tags: neuromorphic optical computing date: 06-19-2019 14:47 gmt revision:1 [0] [head]

Large-Scale Optical Neural Networks based on Photoelectric Multiplication

  • Critical idea: use coherent homodyne detection, and quantum photoelectric multiplication for the MACs.
    • That is, E-fields from coherent light multiplies rather than adds within a (logarithmic) photodiode detector.
    • Other lit suggests rather limited SNR for this effect -- 11db.
  • Hence need EO modulators and OE detectors followed by nonlinearity etc.
  • Pure theory, suggests that you can compute with as few as 10's of photons per MAC -- or less! Near Landauer's limit.

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ref: -2016 tags: fluorescent proteins photobleaching quantum yield piston GFP date: 06-19-2019 14:33 gmt revision:0 [head]

PMID-27240257 Quantitative assessment of fluorescent proteins.

  • Cranfill PJ1,2, Sell BR1, Baird MA1, Allen JR1, Lavagnino Z2,3, de Gruiter HM4, Kremers GJ4, Davidson MW1, Ustione A2,3, Piston DW
  • Model bleaching as log(F)=αlog(P)+clog(F) = -\alpha log(P) + c or k bleach=bI αk_{bleach} = b I^{\alpha} where F is the fluorescence intensity, P is the illumination power, and b and c are constants.
    • Most fluorescent proteins have α\alpha > 1, which means superlinear photobleaching -- more power, bleaches faster.
  • Catalog the degree to which each protein tends to form aggregates by tagging to the ER and measuring ER morphology. Fairly thorough -- 10k cells each FP.

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ref: -2017 tags: neuromorphic optical computing nanophotonics date: 06-17-2019 14:46 gmt revision:5 [4] [3] [2] [1] [0] [head]

Progress in neuromorphic photonics

  • Similar idea as what I had -- use lasers as the optical nonlinearity.
    • They add to this the idea of WDM and 'MRR' (micro-ring resonator) weight bank -- they don't talk about the ability to change the weihts, just specify them with some precision.
  • Definitely makes the case that III-V semiconductor integrated photonic systems have the capability, in MMACs/mm^2/pj, to exceed silicon.

See also :

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ref: -2013 tags: microscopy space bandwidth product imaging resolution UCSF date: 06-17-2019 14:45 gmt revision:0 [head]

How much information does your microscope transmit?

  • Typical objectives 1x - 5x, about 200 Mpix!

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ref: -0 tags: nanophotonics interferometry neural network mach zehnder interferometer optics date: 06-13-2019 21:55 gmt revision:3 [2] [1] [0] [head]

Deep Learning with Coherent Nanophotonic Circuits

  • Used a series of Mach-Zehnder interferometers with thermoelectric phase-shift elements to realize the unitary component of individual layer weight-matrix computation.
    • Weight matrix was decomposed via SVD into UV*, which formed the unitary matrix (4x4, Special unitary 4 group, SU(4)), as well as Σ\Sigma diagonal matrix via amplitude modulators. See figure above / original paper.
    • Note that interfereometric matrix multiplication can (theoretically) be zero energy with an optical system (modulo loss).
      • In practice, you need to run the phase-moduator heaters.
  • Nonlinearity was implemented electronically after the photodetector (e.g. they had only one photonic circuit; to get multiple layers, fed activations repeatedly through it. This was a demonstration!)
  • Fed network FFT'd / banded recordings of consonants through the network to get near-simulated vowel recognition.
    • Claim that noise was from imperfect phase setting in the MZI + lower resolution photodiode read-out.
  • They note that the network can more easily (??) be trained via the finite difference algorithm (e.g. test out an incremental change per weight / parameter) since running the network forward is so (relatively) low-energy and fast.
    • Well, that's not totally true -- you need to update multiple weights at once in a large / deep network to descend any high-dimensional valleys.

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ref: -2012 tags: phase change materials neuromorphic computing synapses STDP date: 06-13-2019 21:19 gmt revision:3 [2] [1] [0] [head]

Nanoelectronic Programmable Synapses Based on Phase Change Materials for Brain-Inspired Computing

  • Here, we report a new nanoscale electronic synapse based on technologically mature phase change materials employed in optical data storage and nonvolatile memory applications.
  • We utilize continuous resistance transitions in phase change materials to mimic the analog nature of biological synapses, enabling the implementation of a synaptic learning rule.
  • We demonstrate different forms of spike-timing-dependent plasticity using the same nanoscale synapse with picojoule level energy consumption.
  • Again uses GST germanium-antimony-tellurium alloy.
  • 50pJ to reset (depress) the synapse, 0.675pJ to potentiate.
    • Reducing the size will linearly decrease this current.
  • Synapse resistance changes from 200k to 2M approx.

See also: Experimental Demonstration and Tolerancing of a Large-Scale Neural Network (165 000 Synapses) Using Phase-Change Memory as the Synaptic Weight Element

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ref: -0 tags: optical gain media lasers cross section dye date: 06-13-2019 15:13 gmt revision:2 [1] [0] [head]

Eminently useful. Source: https://ocw.mit.edu/courses/electrical-engineering-and-computer-science/6-974-fundamentals-of-photonics-quantum-electronics-spring-2006/lecture-notes/chapter7.pdf

Laser Dye technology by Peter Hammond

  • This paper is another great resource!
  • Lists the stimulated emission cross-section for Rhodamine-6G as 4e-16 @ 550nm, consistent with the table above.
  • At a (high) concentration of 2mMol (1 g/l), 1/e penetration depth is 20um.
    • Depending on the solvent, there may be aggregation and stacking / quenching.
  • Tumbling time of Rhodamine 6G in ethanol is 20 to 300ps; fluorescence lifetime in oscillators is 10's of ps, so there is definitely polarization sensitive amplification.
  • Generally in dye lasers, the emission cross-section must be higher than the excited state absorption, σ eσ \sigma_e - \sigma^\star most important.
  • Bacteria can actually subsist on rhodamine-similar sulfonated dyes in aqueous solutions! Wow.

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ref: -2019 tags: optical neural networks spiking phase change material learning date: 06-01-2019 19:00 gmt revision:4 [3] [2] [1] [0] [head]

All-optical spiking neurosynaptic networks with self-learning capabilities

  • J. Feldmann, N. Youngblood, C. D. Wright, H. Bhaskaran & W. H. P. Pernice
  • Idea: use phase-change material to either block or pass the light in waveguides.
    • In this case, they used GST -- germanium-antimony-tellurium. This material is less reflective in the amorphous phase, which can be reached by heating to ~150C and rapidly quenching. It is more reflective in the crystalline phase, which occurs on annealing.
  • This is used for both plastic synapses (phase change driven by the intensity of the light) and the nonlinear output of optical neurons (via a ring resonator).
  • Uses optical resonators with very high Q factors to couple different wavelengths of light into the 'dendrite'.
  • Ring resonator on the output: to match the polarity of the phase-change material. Is this for reset? Storing light until trigger?
  • Were able to get correlative-like or hebbian learning (which I suppose is not dissimilar from really slow photographic film, just re-branded, and most importantly with nonlinear feedback.)
  • Issue: every weight needs a different source wavelength! Hence they have not demonstrated a multi-layer network.
  • Previous paper: All-optical nonlinear activation function for photonic neural networks
    • Only 3db and 7db extinction ratios for induced transparency and inverse saturation

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ref: -0 tags: phosphorescence fluorescence magnetic imaging slicing adam cohen date: 05-29-2019 19:41 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

A friend postulated using the triplet state phosphorescence as a magnetically-modulatable dye. E.g. magnetically slice a scattering biological sample, rather than slicing optically (light sheet, 2p) or mechanically. After a little digging:

I'd imagine that it should be possible to design a molecule -- a protein cage, perhaps a (fully unsaturated) terpine -- which isolates the excited state from oxygen quenching.

Adam Cohen at Harvard has been working a bit on this very idea, albeit with fluorescence not phosphorescence --

  • Optical imaging through scattering media via magnetically modulated fluorescence (2010)
    • The two species, pyrene and dimethylaniline are in solution.
    • Dimethylaniline absorbs photons and transfers an electron to pyrene to produce a singlet radical pair.
    • The magnetic field represses conversion of this singlet into a triplet; when two singlet electrons combine, they produce exciplex fluorescence.
  • Addition of an aliphatic-ether 12-O-2 linker improves things significantly --
  • Mapping Nanomagnetic Fields Using a Radical Pair Reaction (2011)
  • Which can be used with a 2p microscope:
  • Two-photon imaging of a magneto-fluorescent indicator for 3D optical magnetometry (2015)
    • Notably, use decay kinetics of the excited state to yield measurements that are insensitive to photobleaching, indicator concentration, or local variations in optical excitation or collection efficiency. (As opposed to ΔF/F\Delta F / F )
    • Used phenanthrene (3 aromatic rings, not 4 in pyrene) as the excited electron acceptor, dimethylaniline again as the photo-electron generator.
    • Clear description:
      • A molecule with a singlet ground state absorbs a photon.
      • The photon drives electron transfer from a donor moiety to an acceptor moiety (either inter or intra molecular).
      • The electrons [ground state and excited state, donor] become sufficiently separated so that their spins do not interact, yet initially they preserve the spin coherence arising from their starting singlet state.
      • Each electron experiences a distinct set of hyperfine couplings to it's surrounding protons (?) leading to a gradual loss of coherence and intersystem crossing (ISC) into a triplet state.
      • An external magnetic field can lock the precession of both electrons to the field axis, partially preserving coherence and supressing ISC.
      • In some chemical systems, the triplet state is non-fluorescence, whereas the singlet pair can recombine and emit a photon.
      • Magnetochemical effects are remarkable because they arise at a magnetic field strengths comparable to hyperfine energy (typically 1-10mT).
        • Compare this to the Zeeman effect, where overt splitting is at 0.1T.
    • phenylanthrene-dimethylaniline was dissolved in dimethylformamide (DMF). The solution was carefully degassed in nitrogen to prevent molecular oxygen quenching.

Yet! Magnetic field effects do exist in solution:

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ref: -2019 tags: super-resolution microscopy fluorescent protein molecules date: 05-28-2019 16:02 gmt revision:3 [2] [1] [0] [head]

PMID-30997987 Chemistry of Photosensitive Fluorophores for Single-Molecule Localization Microscopy

  • Excellent review of all the photo-convertable, photo-switchable, and more complex (photo-oxidation or reddening) of both proteins and small molecule fluorophore.
    • E.g. PA-GFP is one of the best -- good photoactivation quantum yield, good N ~ 300
    • Other small molecules, like Alexa Fluor 647 have a photon yield > 6700, which can be increased with triplet quenchers and antioxidants.
  • Describes the chemical mechanism of the various photo switching -- review is targeted at (bio)chemists interested in getting into imaging.
  • Emphasize that critical figures of merit are photoactivation quantum yield Φ pa\Phi_{pa} and N, overall photon yield before photobleaching.
  • See also Colorado lecture

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ref: -2018 tags: Michael Levin youtube talk NIPS 2018 regeneration bioelectricity organism patterning flatworm date: 04-09-2019 18:50 gmt revision:1 [0] [head]

What Bodies Think About: Bioelectric Computation Outside the Nervous System - NeurIPS 2018

  • Short notes from watching the video, mostly interesting factoids: (This is a somewhat more coordinated narrative in the video. Am resisting ending each of these statements with and exclamation point).
  • Human children up to 7-11 years old can regenerate their fingertips.
  • Human embryos, when split in half early, develop into two normal humans; mouse embryos, when squished together, make one normal mouse.
  • Butterflies retain memories from their caterpillar stage, despite their brains liquefying during metamorphosis.
  • Flatworms are immortal, and can both grow and contract, as the environment requires.
    • They can also regenerate a whole body from segments, and know to make one head, tail, gut etc.
  • Single cell organisms, e.g. Lacrymaria, can have complex (and fast!) foraging / hunting plans -- without a brain or anything like it.
  • Axolotl can regenerate many parts of their body (appendages etc), including parts of the nervous system.
  • Frog embryos can self-organize an experimenter jumbled body plan, despite the initial organization having never been experienced in evolution.
  • Salamanders, when their tail is grafted into a foot/leg position, remodel the transplant into a leg and foot.
  • Neurotransmitters are ancient; fungi, who diverged from other forms of life about 1.5 billion years ago, still use the same set of inter-cell transmitters e.g. serotonin, which is why modulatory substances from them have high affinity & a strong effect on humans.
  • Levin, collaborators and other developmental biologists have been using voltage indicators in embryos ... this is not just for neurons.
  • Can make different species head shapes in flatworms by exposing them to ion-channel modulating drugs. This despite the fact that the respective head shapes are from species that have been evolving separately for 150 million years.
  • Indeed, you can reprogram (with light gated ion channels, drugs, etc) to body shapes not seen in nature or not explored by evolution.
    • That said, this was experimental, not by design; Levin himself remarks that the biology that generates these body plans is not known.
  • Flatworms can sore memory in bioelectric networks.
  • Frogs don't normally regenerate their limbs. But, with a drug cocktail targeting bioelectric signaling, they can regenerate semi-functional legs, complete with nerves, muscle, bones, and cartilage. The legs are functional (enough).
  • Manipulations of bioelectric signaling can reverse very serious genetic problems, e.g. deletion of Notch, to the point that tadpoles regain some ability for memory creation & recall.

  • I wonder how so much information can go through a the apparently scalar channel of membrane voltage. It seems you'd get symbol interference, and that many more signals would be required to pattern organs.
  • That said, calcium is used a great many places in the cell for all sorts of signaling tasks, over many different timescales as well, and it doesn't seem to be plagued by interference.
    • First question from the audience was how cells differentiate organismal patterning signals and behavioral signals, e.g. muscle contraction.

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ref: -2014 tags: gold nanowires intracellular recording korea date: 03-18-2019 23:02 gmt revision:1 [0] [head]

PMID-25112683 Subcellular Neural Probes from Single-Crystal Gold Nanowires

  • Korean authors... Mijeong Kang,† Seungmoon Jung,‡ Huanan Zhang,⊥ Taejoon Kang,∥ Hosuk Kang,† Youngdong Yoo,† Jin-Pyo Hong,# Jae-Pyoung Ahn,⊗ Juhyoun Kwak,† Daejong Jeon,‡* Nicholas A. Kotov,⊥* and Bongsoo Kim†*
  • 100nm single-crystal Au.
  • Able to get SUA despite size.
  • Springy, despite properties of bulk Au.
  • Nanowires fabricated on a sapphire substrae and picked up by a fine shapr W probe, then varnished with nail polish.

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ref: -2011 tags: ttianium micromachining chlorine argon plasma etch oxide nitride penetrating probes Kevin Otto date: 03-18-2019 22:57 gmt revision:1 [0] [head]

PMID-21360044 Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining

  • Patrick T. McCarthyKevin J. OttoMasaru P. Rao
  • Used Cl / Ar plasma to deep etch titanium film, 0.001 / 25um thick. Fine Metals Corp Ashland VA.
  • Discuss various insulation (oxide /nitride) failure modes, lithography issues.

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ref: -2018 tags: biologically inspired deep learning feedback alignment direct difference target propagation date: 03-15-2019 05:51 gmt revision:5 [4] [3] [2] [1] [0] [head]

Assessing the Scalability of Biologically-Motivated Deep Learning Algorithms and Architectures

  • Sergey Bartunov, Adam Santoro, Blake A. Richards, Luke Marris, Geoffrey E. Hinton, Timothy Lillicrap
  • As is known, many algorithms work well on MNIST, but fail on more complicated tasks, like CIFAR and ImageNet.
  • In their experiments, backprop still fares better than any of the biologically inspired / biologically plausible learning rules. This includes:
    • Feedback alignment {1432} {1423}
    • Vanilla target propagation
      • Problem: with convergent networks, layer inverses (top-down) will map all items of the same class to one target vector in each layer, which is very limiting.
      • Hence this algorithm was not directly investigated.
    • Difference target propagation (2015)
      • Uses the per-layer target as h^ l=g(h^ l+1;λ l+1)+[h lg(h l+1;λ l+1)]\hat{h}_l = g(\hat{h}_{l+1}; \lambda_{l+1}) + [h_l - g(h_{l+1};\lambda_{l+1})]
      • Or: h^ l=h l+g(h^ l+1;λ l+1)g(h l+1;λ l+1)\hat{h}_l = h_l + g(\hat{h}_{l+1}; \lambda_{l+1}) - g(h_{l+1};\lambda_{l+1}) where λ l\lambda_{l} are the parameters for the inverse model; g()g() is the sum and nonlinearity.
      • That is, the target is modified ala delta rule by the difference between inverse-propagated higher layer target and inverse-propagated higher level activity.
        • Why? h lh_{l} should approach h^ l\hat{h}_{l} as h l+1h_{l+1} approaches h^ l+1\hat{h}_{l+1} .
        • Otherwise, the parameters in lower layers continue to be updated even when low loss is reached in the upper layers. (from original paper).
      • The last to penultimate layer weights is trained via backprop to prevent template impoverishment as noted above.
    • Simplified difference target propagation
      • The substitute a biologically plausible learning rule for the penultimate layer,
      • h^ L1=h L1+g(h^ L;λ L)g(h L;λ L)\hat{h}_{L-1} = h_{L-1} + g(\hat{h}_L;\lambda_L) - g(h_L;\lambda_L) where there are LL layers.
      • It's the same rule as the other layers.
      • Hence subject to impoverishment problem with low-entropy labels.
    • Auxiliary output simplified difference target propagation
      • Add a vector zz to the last layer activation, which carries information about the input vector.
      • zz is just a set of random features from the activation h L1h_{L-1} .
  • Used both fully connected and locally-connected (e.g. convolution without weight sharing) MLP.
  • It's not so great:
  • Target propagation seems like a weak learner, worse than feedback alignment; not only is the feedback limited, but it does not take advantage of the statistics of the input.
    • Hence, some of these schemes may work better when combined with unsupervised learning rules.
    • Still, in the original paper they use difference-target propagation with autoencoders, and get reasonable stroke features..
  • Their general result that networks and learning rules need to be tested on more difficult tasks rings true, and might well be the main point of this otherwise meh paper.

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ref: -2019 tags: lillicrap google brain backpropagation through time temporal credit assignment date: 03-14-2019 20:24 gmt revision:2 [1] [0] [head]

PMID-22325196 Backpropagation through time and the brain

  • Timothy Lillicrap and Adam Santoro
  • Backpropagation through time: the 'canonical' expansion of backprop to assign credit in recurrent neural networks used in machine learning.
    • E.g. variable rol-outs, where the error is propagated many times through the recurrent weight matrix, W TW^T .
    • This leads to the exploding or vanishing gradient problem.
  • TCA = temporal credit assignment. What lead to this reward or error? How to affect memory to encourage or avoid this?
  • One approach is to simply truncate the error: truncated backpropagation through time (TBPTT). But this of course limits the horizon of learning.
  • The brain may do BPTT via replay in both the hippocampus and cortex Nat. Neuroscience 2007, thereby alleviating the need to retain long time histories of neuron activations (needed for derivative and credit assignment).
  • Less known method of TCA uses RTRL Real-time recurrent learning forward mode differentiation -- δh t/δθ\delta h_t / \delta \theta is computed and maintained online, often with synaptic weight updates being applied at each time step in which there is non-zero error. See A learning algorithm for continually running fully recurrent neural networks.
    • Big problem: A network with NN recurrent units requires O(N 3)O(N^3) storage and O(N 4)O(N^4) computation at each time-step.
    • Can be solved with Unbiased Online Recurrent optimization, which stores approximate but unbiased gradient estimates to reduce comp / storage.
  • Attention seems like a much better way of approaching the TCA problem: past events are stored externally, and the network learns a differentiable attention-alignment module for selecting these events.
    • Memory can be finite size, extending, or self-compressing.
    • Highlight the utility/necessity of content-addressable memory.
    • Attentional gating can eliminate the exploding / vanishing / corrupting gradient problems -- the gradient paths are skip-connections.
  • Biologically plausible: partial reactivation of CA3 memories induces re-activation of neocortical neurons responsible for initial encoding PMID-15685217 The organization of recent and remote memories. 2005

  • I remain reserved about the utility of thinking in terms of gradients when describing how the brain learns. Correlations, yes; causation, absolutely; credit assignment, for sure. Yet propagating gradients as a means for changing netwrok weights seems at best a part of the puzzle. So much of behavior and internal cognitive life involves explicit, conscious computation of cause and credit.
  • This leaves me much more sanguine about the use of external memory to guide behavior ... but differentiable attention? Hmm.

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ref: -2012 tags: DiCarlo Visual object recognition inferior temporal cortex dorsal ventral stream V1 date: 03-13-2019 22:24 gmt revision:1 [0] [head]

PMID-22325196 How Does the Brain Solve Visual Object Recognition

  • James DiCarlo, Davide Zoccolan, Nicole C Rust.
  • Infero-temporal cortex is organized into behaviorally relevant categories, not necessarily retinotopically, as demonstrated with TMS studies in humans, and lesion studies in other primates.
    • Synaptic transmission takes 1-2ms; dendritic propagation ?, axonal propagation ~1ms (e.g. pyramidal antidromic activation latency 1.2-1.3ms), so each layer can use several synapses for computation.
  • Results from the ventral stream computation can be well described by a firing rate code binned at ~ 50ms. Such a code can reliably describe and predict behavior
    • Though: this does not rule out codes with finer temporal resolution.
    • Though anyway: it may be inferential issue, as behavior operates at this timescale.
  • IT neurons' responses are sparse, but still contain information about position and size.
    • They are not narrowly tuned detectors, not grandmother cells; they are selective and complex but not narrow.
    • Indeed, IT neurons with the highest shape selectivities are the least tolerate to changes in position, scale, contrast, and visual clutter. (Zoccolan et al 2007)
    • Position information avoids the need to re-bind attributes with perceptual categories -- no need for syncrhony binding.
  • Decoded IT population activity of ~100 neurons exceeds artificial vision systems (Pinto et al 2010).
  • As in {1448}, there is a ~ 30x expansion of the number of neurons (axons?) in V1 vs the optic tract; serves to allow controlled sparsity.
  • Dispute in the field over primarily hierarchical & feed-forward vs. highly structured feedback being essential for performance (and learning?) of the system.
    • One could hypothesize that feedback signals help lower levels perform inference with noisy inputs; or feedback from higher layers, which is prevalent and manifest (and must be important; all that membrane is not wasted..)
    • DiCarlo questions if the re-entrant intra-area and inter-area communication is necessary for building object representations.
      • This could be tested with optogenetic approaches; since the publication, it may have been..
      • Feedback-type active perception may be evinced in binocular rivalry, or in visual illusions;
      • Yet 150ms immediate object recognition probably does not require it.
  • Authors propose thinking about neurons/local circuits as having 'job descriptions', an metaphor that couples neuroscience to human organization: who is providing feedback to the workers? Who is providing feeback as to job function? (Hinton 1995).
  • Propose local subspace untangling; when this is tacked and tiled, this is sufficient for object perception.
    • Indeed, modern deep convolutional networks behave this way; yet they still can't match human performance (perhaps not sparse enough, not enough representational capability)
    • Cite Hinton & Salakhutdinov 2006.
  • The AND-OR or conv-pooling architecture was proposed by Hubbel and Weisel back in 1962! In their paper's formulatin, they call it a Normalized non-linear model, NLN.
  1. Nonlinearities tend to flatten object manifolds; even with random weights, NLN models tend to produce easier to decode object identities, based on strength of normalization. See also {714}.
  2. NLNs are tuned / become tuned to the statistics of real images. But they do not get into discrimination / perception thereof..
  3. NLNs learn temporally: inputs that occur temporally adjacent lead to similar responses.
    1. But: scaades? Humans saccade 100 million times per year!
      1. This could be seen as a continuity prior: the world is unlikely to change between saccades, so one can infer the identity and positions of objects on the retina, which say can be used to tune different retinotopic IT neurons..
    2. See Li & DiCarlo -- manipulation of image statistics changing visual responses.
  • Regarding (3) above, perhaps attention is a modifier / learning gate?

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ref: Schmidt-1978.09 tags: Schmidt BMI original operant conditioning cortex HOT pyramidal information antidromic date: 03-12-2019 23:35 gmt revision:11 [10] [9] [8] [7] [6] [5] [head]

PMID-101388[0] Fine control of operantly conditioned firing patterns of cortical neurons.

  • Hand-arm area of M1, 11 or 12 chronic recording electrodes, 3 monkeys.
    • But, they only used one unit at a time in the conditioning task.
  • Observed conditioning in 77% of single units and 65% of combined units (multiunits?).
  • Trained to move a handle to a position indicated by 8 annular cursor lights.
    • Cursor was updated at 50hz -- this was just a series of lights! talk about simple feedback...
    • Investigated different smoothing: too fast, FR does not stay in target; too slow, cursor acquires target too slowly.
      • My gamma function is very similar to their lowpass filter used for smoothing the firing rates.
    • 4 or 8 target random tracking task
    • Time-out of 8 seconds
    • Run of 40 trials
      • The conditioning reached a significant level of performance after 2.2 runs of 40 trials (in well-trained monkeys); typically, they did 18 runs/day (720 trials)
  • Recordings:
    • Scalar mapping of unit firing rate to cursor position.
    • Filtered 600-6kHz
    • Each accepted spike triggered a generator that produced a pulse of of constant amplitude and width -> this was fed into a lowpass filter (1.5 to 2.5 & 3.5Hz cutoff), and a gain stage, then a ADC, then (presumably) the PDP.
      • can determine if these units were in the pyramidal tract by measuring antidromic delay.
    • recorded one neuron for 108 days!!
      • Neuronal activity is still being recorded from one monkey 24 months after chronic implantation of the microelectrodes.
    • Average period in which conditioning was attempted was 3.12 days.
  • Successful conditioning was always associated with specific repeatable limb movements
    • "However, what appears to be conditioned in these experiments is a movement, and the neuron under study is correlated with that movement." YES.
    • The monkeys clearly learned to make (increasingly refined) movement to modulate the firing activity of the recorded units.
    • The monkey learned to turn off certain units with specific limb positions; the monkey used exaggerated movements for these purposes.
      • e.g. finger and shoulder movements, isometric contraction in one case.
  • Trained some monkeys or > 15 months; animals got better at the task over time.
  • PDP-12 computer.
  • Information measure: 0 bits for missed targets, 2 for a 4 target task, 3 for 8 target task; information rate = total number of bits / time to acquire targets.
    • 3.85 bits/sec peak with 4 targets, 500ms hold time
    • With this, monkeys were able to exert fine control of firing rate.
    • Damn! compare to Paninski! [1]
  • 4.29 bits/sec when the same task was performed with a manipulandum & wrist movement
  • they were able to condition 77% of individual neurons and 65% of combined units.
  • Implanted a pyramidal tract electrode in one monkey; both cells recorded at that time were pyramidal tract neurons, antidromic latencies of 1.2 - 1.3ms.
    • Failures had no relation to over movements of the monkey.
  • Fetz and Baker [2,3,4,5] found that 65% of precentral neurons could be conditioned for increased or decreased firing rates.
    • and it only took 6.5 minutes, on average, for the units to change firing rates!
  • Summarized in [1].

____References____

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ref: -0 tags: sparse coding reference list olshausen field date: 03-11-2019 21:59 gmt revision:3 [2] [1] [0] [head]

This was compiled from searching papers which referenced Olhausen and Field 1996 PMID-8637596 Emergence of simple-cell receptive field properties by learning a sparse code for natural images.

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ref: -2018 tags: sparse representation auditory cortex excitatation inhibition balance date: 03-11-2019 20:47 gmt revision:1 [0] [head]

PMID-30307493 Sparse Representation in Awake Auditory Cortex: Cell-type Dependence, Synaptic Mechanisms, Developmental Emergence, and Modulation.

  • Sparse representation arises during development in an experience-dependent manner, accompanied by differential changes of excitatory input strength and a transition from unimodal to bimodal distribution of E/I ratios.

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ref: -2015 tags: conjugate light electron tomography mouse visual cortex fluorescent label UNC cryoembedding date: 03-11-2019 19:37 gmt revision:1 [0] [head]

PMID-25855189 Mapping Synapses by Conjugate Light-Electron Array Tomography

  • Use aligned interleaved immunofluorescence imaging follwed by array EM (FESEM). 70nm thick sections.
  • Of IHC, tissue must be dehydrated & embedded in a resin.
  • However, the dehydration disrupts cell membranes and ultrastructural details viewed via EM ...
  • Hence, EM microscopy uses osmium tetroxide to cross-link the lipids.
  • ... Yet that also disrupt / refolds the poteins, making IHC fail.
  • Solution is to dehydrate & embed at cryo temp, -70C, where the lipids do not dissolve. They used Lowicryl HM-20.
  • We show that cryoembedding provides markedly improved ultrastructure while still permitting multiplexed immunohistochemistry.

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ref: -2012 tags: octopamine STDP locust LTP LTD olfactory bulb date: 03-11-2019 18:59 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-22278062 Conditional modulation of spike-timing-dependent plasticity for olfactory learning.

  • Looked at the synapes from the Muschroom body (Kenyon cells, sparse code) to the beta-lobe (bLN) in locusts.
  • Used in-vivo dendrite patch, sharp micropipette.
  • Found that, with a controlled mushroom body extracellular stim for plasticity induction protocol at the KC-> bLN synapese, were able to get potentiation and depression in accord with STDP.
  • This STDP became pure depression in the presence of octopamine
  • See also / supercedes: Synaptic Learning Rules and Sparse Coding in a Model Sensory System Luca A. Finelli ,Seth Haney, Maxim Bazhenov, Mark Stopfer, Terrence J. Sejnowski 2008

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ref: -2004 tags: Olshausen sparse coding review date: 03-08-2019 07:02 gmt revision:0 [head]

PMID-15321069 Sparse coding of sensory inputs

  • Classic review, Olshausen and Field. 15 years old now!
  • Note the sparsity here is in neuronal activation, not synaptic activity (though one should follow the other).
  • References Lewicki's auditory studies, Efficient coding of natural sounds 2002; properties of early auditory neurons are well suited for producing a sparse independent code.
    • Studies have found near binary encoding of stimuli in rat auditory cortex -- e.g. one spike per noise.
  • Suggests that overcomplete representations (e.g. where there are more 'second layer' neurons than inputs or pixels) are useful for flattening manifolds in the input space, making feature extraction easier.
    • But then you have an under-determined problem, where presumably sparsity metrics step in to restrict the actual coding space. Authors mention that this could lead to degeneracy.
    • Example is the early visual cortex, where axons to higher layers exceed those from the LGN by a factor of 25. Which, they say, may be a compromise between over-representation and degeneracy.
  • Sparse coding is a necessity from an energy standpoint -- only one in 50 neurons can be active at any given time.
  • Sparsity increases when classical receptive field stimuli in V1 is expanded with a real-world-statistics surround. (Gallant 2002).

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ref: -2006 tags: Mark Bear reward visual cortex cholinergic date: 03-06-2019 04:54 gmt revision:1 [0] [head]

PMID-16543459 Reward timing in the primary visual cortex

  • Used 192-IgG-Saporin (saporin immunotoxin)to selectively lesion cholinergic fibers locally in V1 following a visual stimulus -> licking reward delay behavior.
  • Visual stimulus is full-field light, delivered to either the left or right eye.
    • This is scarcely a challenging task; perhaps they or others have followed up?
  • These examples illustrate that both cue 1-dominant and cue 2-dominant neurons recorded from intact animals express NRTs that appropriately reflect the new policy. Conversely, although cue 1- and cue 2-dominant neurons recorded from 192-IgG-saporin-infused animals are capable of displaying all forms of reward timing activity, ‘’’they do not update their NRTs but rather persist in reporting the now outdated policy.’’’
    • NRT = neural reaction time.
  • This needs to be controlled with recordings from other cortical areas.
  • Acquisition of reward based response is simultaneously interesting and boring -- what about the normal, discriminative and perceptual function of the cortex?
  • See also follow-up work PMID-23439124 A cholinergic mechanism for reward timing within primary visual cortex.

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ref: -2017 tags: vicarious dileep george captcha message passing inference heuristic network date: 03-06-2019 04:31 gmt revision:2 [1] [0] [head]

PMID-29074582 A generative vision model that trains with high data efficiency and breaks text-based CAPTCHAs

  • Vicarious supplementary materials on their RCN (recursive cortical network).
  • Factor scene into shape and appearance, which CNN or DCNN do not do -- they conflate (ish? what about the style networks?)
    • They call this the coloring book approach -- extract shape then attach appearance.
  • Hierarchy of feature layers F frcF_{f r c} (binary) and pooling layer H frcH_{f r c} (multinomial), where f is feature, r is row, c is column (e.g. over image space).
  • Each layer is exclusively conditional on the layer above it, and all features in a layer are conditionally independent given the layer above.
  • Pool variables H frcH_{f r c} is multinomial, and each value associated with a feature, plus one off feature.
    • These features form a ‘pool’, which can/does have translation invariance.
  • If any of the pool variables are set to enable FF , then that feature is set (or-operation). Many pools can contain a given feature.
  • One can think of members of a pool as different alternatives of similar features.
  • Pools can be connected laterally, so each is dependent on the activity of its neighbors. This can be used to enforce edge continuity.
  • Each bottom-level feature corresponds to an edge, which defines ‘in’ and ‘out’ to define shape, YY .
  • These variables YY are also interconnected, and form a conditional random field, a ‘Potts model’. YY is generated by gibbs sampling given the F-H hierarchy above it.
  • Below Y, the per-pixel model X specifies texture with some conditional radial dependence.
  • The model amounts to a probabalistic model for which exact inference is impossible -- hence you must do approximate, where a bottom up pass estimates the category (with lateral connections turned off), and a top down estimates the object mask. Multiple passes can be done for multiple objects.
  • Model has a hard time moving from rgb pixels to edge ‘in’ and ‘out’; they use edge detection pre-processing stage, e.g. Gabor filter.
  • Training follows a very intuitive, hierarchical feature building heuristic, where if some object or collection of lower level features is not present, it’s added to the feature-pool tree.
    • This includes some winner-take-all heuristic for sparsification.
    • Also greedily learn some sort of feature ‘’dictionary’’ from individual unlabeled images.
  • Lateral connections are learned similarly, with a quasi-hebbian heuristic.
  • Neuroscience inspiration: see refs 9, 98 for message-passing based Bayesian inference.

  • Overall, a very heuristic, detail-centric, iteratively generated model and set of algorithms. You get the sense that this was really the work of Dileep George or only a few people; that it was generated by successively patching and improving the model/algo to make up for observed failures and problems.
    • As such, it offers little long-term vision for what is possible, or how perception and cognition occurs.
    • Instead, proof is shown that, well, engineering works, and the space of possible solutions -- including relatively simple elements like dictionaries and WTA -- is large and fecund.
      • Unclear how this will scale to even more complex real-world problems, where one would desire a solution that does not have to have each level carefully engineered.
      • Modern DCNN, at least, do not seem to have this property -- the structure is learned from the (alas, labeled) data.
  • This extends to the fact that yes, their purpose-built system achieves state of the art performance on the designated CAPATCHA tasks.
  • Check: B. M. Lake, R. Salakhutdinov, J. B. Tenenbaum, Human-level concept learning through probabilistic program induction. Science 350, 1332–1338 (2015). doi:10.1126/science.aab3050 Medline

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ref: -2018 tags: cortex layer martinotti interneuron somatostatin S1 V1 morphology cell type morphological recovery patch seq date: 03-06-2019 02:51 gmt revision:3 [2] [1] [0] [head]

Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas

  • Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1).
  • Nearly all excitatory neurons were pyramidal and almost all Somatostatin-positive (SOM+) neurons were Martinotti cells.
  • In contrast, in somatosensory cortex (S1), excitatory cells were mostly stellate and SOM+ cells were non-Martinotti.
  • These morphologically distinct SOM+ interneurons correspond to different transcriptomic cell types and are differentially integrated into the local circuit with only S1 cells receiving local excitatory input.
  • Our results challenge the classical view of a canonical microcircuit repeated through the neocortex.
  • Instead we propose that cell-type specific circuit motifs, such as the Martinotti/pyramidal pair, are optionally used across the cortex as building blocks to assemble cortical circuits.
  • Note preponderance of axons.
  • Classifications:
    • Pyr pyramidal cells
    • BC Basket cells
    • MC Martinotti cells
    • BPC bipolar cells
    • NFC neurogliaform cells
    • SC shrub cells
    • DBC double bouquet cells
    • HEC horizontally elongated cells.
  • Using Patch-seq

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ref: -2012 tags: parvalbumin interneurons V1 perceptual discrimination mice date: 03-06-2019 01:46 gmt revision:0 [head]

PMID-22878719 Activation of specific interneurons improves V1 feature selectivity and visual perception

  • Lee SH1, Kwan AC, Zhang S, Phoumthipphavong V, Flannery JG, Masmanidis SC, Taniguchi H, Huang ZJ, Zhang F, Boyden ES, Deisseroth K, Dan Y.
  • Optogenetic Activation of PV+ interneurons improves neuronal feature selectivity and improves perceptual discrimination (!!!)

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ref: -2019 tags: three photon imaging visual cortex THG chirp NOPA mice GCaMP6 MIT date: 03-01-2019 18:46 gmt revision:2 [1] [0] [head]

PMID-30635577 Functional imaging of visual cortical layers and subplate in awake mice with optimized three photon microscopy

  • Murat Yildirim, Hiroki Sugihara, Peter T.C. So & Mriganka Sur'
  • Used a fs Ti:Saphirre 16W pump into a non-colinear optical parametric amplifier (both from Spectra-Physics) to generate the 1300nm light.
  • Used pulse compensation to get the pulse width at the output of the objective to 40 fS.
    • Three-photon cross section is inverse quadratic in pulse width:
    • NP 3δ(τR) 2(NA 22hcλ) 3 N \sim \frac{P^3 \delta}{(\tau R)^2} (\frac{NA^2}{2hc\lambda})^3
    • P is power, δ\delta is 3p cross-section, τ\tau is pulse width, R repetition rate, NA is the numerical aperture (sixth power of NA!!!), h c and λ\lambda Planks constant, speed of light, and wavelength respectively.
  • Optimized excitation per depth by monitoring damage levels. varied from 0.5nJ to 5 nJ.
  • Imaged up to 1.5mm deep! All the way to the white matter / subplate.
  • Allegedly used a custom scan and tube lens to minimize aberrations in the excitation path (hence improve 3p excitation)
  • Layer 5 neurons are more broadly tuned for orientation than other layers. But the data is not dramatic.
  • Used straightforward metrics for tuning, using a positive and negative bump gaussian fit, then vector averaging to get global orientation selectivity.
  • Interesting that the variance between layers seems higher than between mice.

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ref: -2006 tags: hinton contrastive divergence deep belief nets date: 02-20-2019 02:38 gmt revision:0 [head]

PMID-16764513 A fast learning algorithm for deep belief nets.

  • Hinton GE1, Osindero S, Teh YW.
  • Very highly cited contrastive divergence paper.
  • Back in 2006 yielded state of the art MNIST performance.
  • And, being CD, can be used in an unsupervised mode.

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ref: -2015 tags: CWEETS amplified Fourier imaging raman amplification date: 02-19-2019 06:46 gmt revision:1 [0] [head]

Amplified dispersive Fourier-Transform Imaging for Ultrafast Displacement sensing and Barcode Reading

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ref: -2011 tags: HiLo speckle imaging confocal boston university optical sectioning date: 02-19-2019 06:18 gmt revision:2 [1] [0] [head]

PMID-21280920 Optically sectioned in vivo imaging with speckle illumination HiLo microscopy

  • Ah, brilliant! Illuminate a sample with a speckle pattern from a laser, and use this to optically section the data -- the contrast of the speckle pattern shows how in focus the sample is.
    • Hanece, the contrast indicates the in-focus vs out-of-focus ratio in a region.
  • The speckle statistics are invariant even in a scattering media, as scattering only further randomizes an already random laser phase front. (Within some limits.)
  • HiLo microscopy involves illuminating with a speckle pattern, then illuminating with standard uniform illumination, resulting in a diffraction-limited optically sectioned image. PMID-18709098
  • Algorithm is :
    • Take the speckle image and subtract the uniform image δI\delta I
    • Bandpass δI\delta I
    • Measure the standard deviation of the δI\delta I to get a weighting function C δs 2C^2_{\delta s}
    • Debias this estimate based on sensor..
    • Generate low-passed image from the weighted uniform image, LP[C δsI u] LP[C_{\delta s} I_u] , and high-pass from the difference HP=1LPHP = 1 - LP
    • Resultand image is a weighted sum of highpassed and lowpassed images.
  • Looks about as good as confocal.
  • Cited by...

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ref: -0 tags: Airy light sheet microscopy attenuation compensation LSM imaging date: 02-19-2019 04:51 gmt revision:1 [0] [head]

Light-sheet microscopy with attenuation-compensated propagation-invariant beams

  • Ah ... beautiful illustration of the airy light sheet concept.
  • In practice, used a LCOS SLM to generate the beam (as .. phase matters!) plus an AOM to scan the beam.
    • Microscope can operate either in SPIM (single plane imaging microscope) or DSLM (digital scanning light sheet microscope),
  • Improves signal-to-background ratio (SBR) and contrast-to-noise ratio (CNR) (not sure why they don't use SNR..?)

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ref: -0 tags: variational free energy inference learning bayes curiosity insight Karl Friston date: 02-15-2019 02:09 gmt revision:1 [0] [head]

PMID-28777724 Active inference, curiosity and insight. Karl J. Friston, Marco Lin, Christopher D. Frith, Giovanni Pezzulo,

  • This has been my intuition for a while; you can learn abstract rules via active probing of the environment. This paper supports such intuitions with extensive scholarship.
  • “The basic theme of this article is that one can cast learning, inference, and decision making as processes that resolve uncertanty about the world.
    • References Schmidhuber 1991
  • “A learner should choose a policy that also maximizes the learner’s predictive power. This makes the world both interesting and exploitable.” (Still and Precup 2012)
  • “Our approach rests on the free energy principle, which asserts that any sentient creature must minimize the entropy of its sensory exchanges with the world.” Ok, that might be generalizing things too far..
  • Levels of uncertainty:
    • Perceptual inference, the causes of sensory outcomes under a particular policy
    • Uncertainty about policies or about future states of the world, outcomes, and the probabilistic contingencies that bind them.
  • For the last element (probabilistic contingencies between the world and outcomes), they employ Bayesian model selection / Bayesian model reduction
    • Can occur not only on the data, but exclusively on the initial model itself.
    • “We use simulations of abstract rule learning to show that context-sensitive contingiencies, which are manifest in a high-dimensional space of latent or hidden states, can be learned with straightforward variational principles (ie. minimization of free energy).
  • Assume that initial states and state transitions are known.
  • Perception or inference about hidden states (i.e. state estimation) corresponds to inverting a generative model gievn a sequence of outcomes, while learning involves updating the parameters of the model.
  • The actual task is quite simple: central fixation leads to a color cue. The cue + peripheral color determines either which way to saccade.
  • Gestalt: Good intuitions, but I’m left with the impression that the authors overexplain and / or make the description more complicated that it need be.
    • The actual number of parameters to to be inferred is rather small -- 3 states in 4 (?) dimensions, and these parameters are not hard to learn by minimizing the variational free energy:
    • F=D[Q(x)||P(x)]E q[ln(P(o t|x)]F = D[Q(x)||P(x)] - E_q[ln(P(o_t|x)] where D is the Kullback-Leibler divergence.
      • Mean field approximation: Q(x)Q(x) is fully factored (not here). many more notes

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ref: -2014 tags: Lillicrap Random feedback alignment weights synaptic learning backprop MNIST date: 02-14-2019 01:02 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-27824044 Random synaptic feedback weights support error backpropagation for deep learning.

  • "Here we present a surprisingly simple algorithm for deep learning, which assigns blame by multiplying error signals by a random synaptic weights.
  • Backprop multiplies error signals e by the weight matrix W T W^T , the transpose of the forward synaptic weights.
  • But the feedback weights do not need to be exactly W T W^T ; any matrix B will suffice, so long as on average:
  • e TWBe>0 e^T W B e &gt; 0
    • Meaning that the teaching signal Be B e lies within 90deg of the signal used by backprop, W Te W^T e
  • Feedback alignment actually seems to work better than backprop in some cases. This relies on starting the weights very small (can't be zero -- no output)

Our proof says that weights W0 and W
evolve to equilibrium manifolds, but simulations (Fig. 4) and analytic results (Supple-
mentary Proof 2) hint at something more specific: that when the weights begin near
0, feedback alignment encourages W to act like a local pseudoinverse of B around
the error manifold. This fact is important because if B were exactly W + (the Moore-
Penrose pseudoinverse of W ), then the network would be performing Gauss-Newton
optimization (Supplementary Proof 3). We call this update rule for the hidden units
pseudobackprop and denote it by ∆hPBP = W + e. Experiments with the linear net-
work show that the angle, ∆hFA ]∆hPBP quickly becomes smaller than ∆hFA ]∆hBP
(Fig. 4b, c; see Methods). In other words feedback alignment, despite its simplicity,
displays elements of second-order learning.

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ref: -0 tags: diffraction terahertz 3d print ucla deep learning optical neural networks date: 02-13-2019 23:16 gmt revision:1 [0] [head]

All-optical machine learning using diffractive deep neural networks

  • Pretty clever: use 3D printed plastic as diffractive media in a 0.4 THz all-optical all-interference (some attenuation) linear convolutional multi-layer 'neural network'.
  • In the arxive publication there are few details on how they calculated or optimized given diffractive layers.
  • Absence of nonlinearity will limit things greatly.
  • Actual observed performance (where thy had to print out the handwritten digits) rather poor, ~ 60%.

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ref: -2017 tags: calcium imaging seeded iterative demixing light field microscopy mouse cortex hippocampus date: 02-13-2019 22:44 gmt revision:1 [0] [head]

PMID-28650477 Video rate volumetric Ca2+ imaging across cortex using seeded iterative demixing (SID) microscopy

  • Tobias Nöbauer, Oliver Skocek, Alejandro J Pernía-Andrade, Lukas Weilguny, Francisca Martínez Traub, Maxim I Molodtsov & Alipasha Vaziri
  • Cell-scale imaging at video rates of hundreds of GCaMP6 labeled neurons with light-field imaging followed by computationally-efficient deconvolution and iterative demixing based on non-negative factorization in space and time.
  • Utilized a hybrid light-field and 2p microscope, but didn't use the latter to inform the SID algorithm.
  • Algorithm:
    • Remove motion artifacts
    • Time iteration:
      • Compute the standard deviation versus time (subtract mean over time, measure standard deviance)
      • Deconvolve standard deviation image using Richardson-Lucy algo, with non-negativity, sparsity constraints, and a simulated PSF.
      • Yields hotspots of activity, putative neurons.
      • These neuron lcoations are convolved with the PSF, thereby estimating its ballistic image on the LFM.
      • This is converted to a binary mask of pixels which contribute information to the activity of a given neuron, a 'footprint'
        • Form a matrix of these footprints, p * n, S 0S_0 (p pixels, n neurons)
      • Also get the corresponding image data YY , p * t, (t time)
      • Solve: minimize over T ||YST|| 2|| Y - ST||_2 subject to T0T \geq 0
        • That is, find a non-negative matrix of temporal components TT which predicts data YY from masks SS .
    • Space iteration:
      • Start with the masks again, SS , find all sets O kO^k of spatially overlapping components s is_i (e.g. where footprints overlap)
      • Extract the corresponding data columns t it_i of T (from temporal step above) from O kO^k to yield T kT^k . Each column corresponds to temporal data corresponding to the spatial overlap sets. (additively?)
      • Also get the data matrix Y kY^k that is image data in the overlapping regions in the same way.
      • Minimize over S kS^k ||Y kS kT k|| 2|| Y^k - S^k T^k||_2
      • Subject to S k>=0S^k &gt;= 0
        • That is, solve over the footprints S kS^k to best predict the data from the corresponding temporal components T kT^k .
        • They also impose spatial constraints on this non-negative least squares problem (not explained).
    • This process repeats.
    • allegedly 1000x better than existing deconvolution / blind source segmentation algorithms, such as those used in CaImAn

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ref: -0 tags: Hinton google tech talk dropout deep neural networks Boltzmann date: 02-12-2019 08:03 gmt revision:2 [1] [0] [head]

Brains, sex, and machine learning -- Hinton google tech talk.

  • Hinton believes in the the power of crowds -- he thinks that the brain fits many, many different models to the data, then selects afterward.
    • Random forests, as used in predator, is an example of this: they average many simple to fit and simple to run decision trees. (is apparently what Kinect does)
  • Talk focuses on dropout, a clever new form of model averaging where only half of the units in the hidden layers are trained for a given example.
    • He is inspired by biological evolution, where sexual reproduction often spontaneously adds or removes genes, hence individual genes or small linked genes must be self-sufficient. This equates to a 'rugged individualism' of units.
    • Likewise, dropout forces neurons to be robust to the loss of co-workers.
    • This is also great for parallelization: each unit or sub-network can be trained independently, on it's own core, with little need for communication! Later, the units can be combined via genetic algorithms then re-trained.
  • Hinton then observes that sending a real value p (output of logistic function) with probability 0.5 is the same as sending 0.5 with probability p. Hence, it makes sense to try pure binary neurons, like biological neurons in the brain.
    • Indeed, if you replace the backpropagation with single bit propagation, the resulting neural network is trained more slowly and needs to be bigger, but it generalizes better.
    • Neurons (allegedly) do something very similar to this by poisson spiking. Hinton claims this is the right thing to do (rather than sending real numbers via precise spike timing) if you want to robustly fit models to data.
      • Sending stochastic spikes is a very good way to average over the large number of models fit to incoming data.
      • Yes but this really explains little in neuroscience...
  • Paper referred to in intro: Livnat, Papadimitriou and Feldman, PMID-19073912 and later by the same authors PMID-20080594
    • A mixability theory for the role of sex in evolution. -- "We define a measure that represents the ability of alleles to perform well across different combinations and, using numerical iterations within a classical population-genetic framework, show that selection in the presence of sex favors this ability in a highly robust manner"
    • Plus David MacKay's concise illustration of why you need sex, pg 269, __Information theory, inference, and learning algorithms__
      • With rather simple assumptions, asexual reproduction yields 1 bit per generation,
      • Whereas sexual reproduction yields G\sqrt G , where G is the genome size.

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ref: -0 tags: superresolution imaging scanning lens nanoscale date: 02-04-2019 20:34 gmt revision:1 [0] [head]

PMID-27934860 Scanning superlens microscopy for non-invasive large field-of-view visible light nanoscale imaging

  • Recently, the diffraction barrier has been surpassed by simply introducing dielectrics with a micro-scale spherical configuration when using conventional optical microscopes by transforming evanescent waves into propagating waves. 18,19,20,21,22,23,24,25,26,27,28,29,30
  • The resolution of this superlens-based microscopy has been decreased to ∼50 nm (ref. 26) from an initial resolution of ∼200 nm (ref. 21).
  • This method can be further enhanced to ∼25 nm when coupled with a scanning laser confocal microscope 31.
  • It has achieved fast development in biological applications, as the sub-diffraction-limited resolution of high-index liquid-immersed microspheres has now been demonstrated23,32, enabling its application in the aqueous environment required to maintain biological activity.
  • Microlens is a 57 um diameter BaTiO3 microsphere, resolution of lambda / 6.3 under partial and inclined illumination
  • Microshpere is in contact with the surface during imaging, by gluing it to the cantilever tip of an AFM.
  • Get an image with the microsphere-lens, which improves imaging performance by ~ 200x. (with a loss in quality, naturally).

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ref: -0 tags: Kato fear conditioning GABA auditory cortex mice optogenetics SOM PV date: 02-04-2019 19:09 gmt revision:0 [head]

PMID-29375323 Fear learning regulates cortical sensory representation by suppressing habituation

  • Trained mice on CS+ and CS --> lick task.
    • CS+ = auditory tone followed by tailshock
    • CS- = auditory tone (both FM modulated, separated by 0.5 - 1.0 octave).
    • US = licking.
  • VGAT2-ChR2 or PV-ChR2
  • GABA-ergic silencing of auditory cortex through blue light illumination abolished behavior difference following CS+ and CS-.
  • Used intrinsic imaging to locate A1 cortex, then AAV - GCaMP6 imaging to lcoated pyramidal cells.
  • In contrast to reports of enhanced tone responses following simple fear conditioning (Quirk et al., 1997; Weinberger, 2004, 2015), discriminative learning under our conditions caused no change in the average fraction of pyramidal cells responsive to the CS+ tone.
    • Seemed to be an increase in suppression, and reduced cortical responses, which is consistent with habituation.
  • Whereas -- and this is by no means surprising -- cortical responses to CS+ were sustained at end of tone following fear conditioning.
  • ----
  • Then examined this effect relative to the two populations of interneurons, using PV-cre and SOM-cre mice.
    • In PV cells, fear conditioning resulted in a decreased fraction of cells responsive, and a decreased magnitude of responses.
    • In SOM cells, CS- responses were enhanced, while CS+ were less enhanced (the main text seems like an exaggeration c.f. figure 6E)
  • This is possibly the more interesting result of the paper, but even then the result is not super strong.

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ref: -0 tags: curiosity exploration forward inverse models trevor darrell date: 02-01-2019 03:42 gmt revision:1 [0] [head]

Curiosity-driven exploration by Self-supervised prediction

  • Deepak Pathak, Pulkit Agrawal, Alexei A. Efros, Trevor Darrell
  • Key insight: “we only predict the changes in the environment that could possibly be due to actions of our agent or affect the agent, and ignore the rest”.
    • Instead of making predictions in the sensory space (e.g. pixels), we transform the sensory input into a feature space where only the information relevant to the agent is represented.
    • We learn this feature space using self-supervision -- training a neural network via a proxy inverse dynamics task -- predicting the agent’s action from the past and future sensory states.
  • We then use this inverse model to train a forward dynamics model to predict feature representation of the next state from present feature representation and action.
      • The difference between expected and actual representation serves as a reward signal for the agent.
  • Quasi actor-critic / adversarial agent design, again.
  • Used the asynchronous advantage actor critic policy gradient method (Mnih et al 2016 Asynchronous Methods for Deep Reinforcement Learning).
  • Compare with variational information maximization (VIME) trained with TRPO (Trust region policy optimization) which is “more sample efficient than A3C but takes more wall time”.
  • References / concurrent work: Several methods propose improving data efficiency of RL algorithms using self-supervised prediction based auxiliary tasks (Jaderberg et al., 2017; Shelhamer et al., 2017).
  • An interesting direction for future research is to use the learned exploration behavior / skill as a motor primitive / low level policy in a more complex, hierarchical system. For example, the skill of walking along corridors could be used as part of a navigation system.

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ref: -0 tags: lillicrap segregated dendrites deep learning backprop date: 01-31-2019 19:24 gmt revision:2 [1] [0] [head]

PMID-29205151 Towards deep learning with segregated dendrites https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716677/

  • Much emphasis on the problem of credit assignment in biological neural networks.
    • That is: given complex behavior, how do upstream neurons change to improve the task of downstream neurons?
    • Or: given downstream neurons, how do upstream neurons receive ‘credit’ for informing behavior?
      • I find this a very limiting framework, and is one of my chief beefs with the work.
      • Spatiotemporal Bayesian structure seems like a much better axis (axes) to cast function against.
      • Or, it could be segregation into ‘signal’ and ‘error’ or ‘figure/ground’ based on hierarchical spatio-temporal statistical properties that matters ...
      • ... with proper integration of non-stochastic spike timing + neoSTDP.
        • This still requires some solution of the credit-assignment problem, i know i know.
  • Outline a spiking neuron model with zero one or two hidden layers, and a segregated apical (feedback) and basal (feedforward) dendrites, as per a layer 5 pyramidal neuron.
  • The apical dendrites have plateau potentials, which are stimulated through (random) feedback weights from the output neurons.
  • Output neurons are forced to one-hot activation at maximum firing rate during training.
    • In order to assign credit, feedforward information must be integrated separately from any feedback signals used to calculate error for synaptic updates (the error is indicated here with δ). (B) Illustration of the segregated dendrites proposal. Rather than using a separate pathway to calculate error based on feedback, segregated dendritic compartments could receive feedback and calculate the error signals locally.
  • Uses the MNIST database, naturally.
  • Poisson spiking input neurons, 784, again natch.
  • Derive local loss function learning rules to make the plateau potential (from the feedback weights) match the feedforward potential
    • This encourages the hidden layer -> output layer to approximate the inverse of the random feedback weight network -- which it does! (At least, the jacobians are inverses of each other).
    • The matching is performed in two phases -- feedforward and feedback. This itself is not biologically implausible, just unlikely.
  • Achieved moderate performance on MNIST, ~ 4%, which improved with 2 hidden layers.
  • Very good, interesting scholarship on the relevant latest findings ‘’in vivo’’.
  • While the model seems workable though ad-hoc or just-so, the scholarship points to something better: use of multiple neuron subtypes to accomplish different elements (variables) in the random-feedback credit assignment algorithm.
    • These small models can be tuned to do this somewhat simple task through enough fiddling & manual (e.g. in the algorithmic space, not weight space) backpropagation of errors.
  • They suggest that the early phases of learning may entail learning the feedback weights -- fascinating.
  • ‘’Things are definitely moving forward’’.

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ref: -0 tags: STDP dopamine hippocampus date: 01-16-2019 21:56 gmt revision:1 [0] [head]

PMID-26516682 Retroactive modulation of spike timing-dependent plasticity by dopamine.

  • Here we show that dopamine, a positive reinforcement signal, can retroactively convert hippocampal timing-dependent synaptic depression into potentiation.
  • This effect requires functional NMDA receptors and is mediated in part through the activation of the cAMP/PKA cascade.
  • Mouse horizontal slices.
  • Plasticity induced by 100 pairings of a single EPSP followed by a postsynaptic spike (heavy-handed?)
  • Pre-before-post @ 10ms -> LTP
  • Post-before-pre @ -20ms -> LTD
  • Post-before-pre @ -10ms -> LTP (?!)
    • Addition of Dopamine antagonist (D2: sulpiride, D1/D5: SCH23390) prevented LTP and resulted in LTD.
  • Post-before-pre @ -20ms -> LTP in the presence of 20 uM DA.
    • The presence of DA during coordinated spiking activity widense the timing interval for induction of LTP.
  • What about if it's applied afterward?
  • 20 uM DA applied 1 minute (for 10-12 minutes) after LTD induction @ -20 mS converted LTD into LTP.
    • This was corrected by addition of the DA agonists.
    • Did not work if DA was applied 10 or 30 minutes after the LTD induction.
  • Others have shown that this requires functional NMDA receptors.
    • Application of NMDA agonist D-AP5 after post-before-pre -20ms did not affect LTD.
    • Application of D-AP5 before DA partially blocked conversion of LTD to LTP.
    • Application of D-AP5 alone before induction did not affect LTD.
  • This is dependent on the cAMP/PKA signaling cascade:
    • Application of forskolin (andenylyl cyclase AC activator) converts LTD -> LTP.
    • Dependent on NMDA.
  • PKA inhibitor H-89 alsoblocked LTD -> P.

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ref: -0 tags: cutting plane manifold learning classification date: 10-31-2018 23:49 gmt revision:0 [head]

Learning data manifolds with a Cutting Plane method

  • Looks approximately like SVM: perform binary classification on a high-dimensional manifold (or sets of manifolds in this case).
  • The general idea behind Mcp_simple is to start with a finite number of training examples, find the maximum margin solution for that training set, augment the draining set by finiding a poing on the manifolds that violates the constraints, iterating the process until a tolerance criteria is met.
  • The more complicated cutting plane SVM uses slack variables to allow solution where classification is not linearly separable.
    • Propose using one slack variable per manifold, plus a manifold center, which strictly obeys the margin (classification) constraint.
  • Much effort put to proving the convergence properties of these algorithms; admittedly I couldn't be bothered to read...

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ref: -0 tags: hahnloser zebrafinch LMAN HVC song learning internal model date: 10-12-2018 00:33 gmt revision:1 [0] [head]

PMID-24711417 Evidence for a causal inverse model in an avian cortico-basal ganglia circuit

  • Recorded an stimulated the LMAN (upstream, modulatory) region of the zebrafinch song-production & learning pathway.
  • Found evidence, albeit weak, for a mirror arrangement or 'causal inverse' there: neurons fire bursts prior syllable production with some motor delay, ~30ms, and also fire single spikes with a delay ~10 ms to the same syllables.
    • This leads to an overall 'mirroring offset' of about 40 ms, which is sufficiently supported by the data.
    • The mirroring offset is quantified by looking at the cross-covariance of audio-synchronized motor and sensory firing rates.
  • Causal inverse: a sensory target input generates a motor activity pattern required to cause, or generate that same sensory target.
    • Similar to the idea of temporal inversion via memory.
  • Data is interesting, but not super strong; per the discussion, the authors were going for a much broader theory:
    • Normal Hebbian learning says that if a presynaptic neuron fires before a postsynaptic neuron, then the synapse is potentiated.
    • However, there is another side of the coin: if the presynaptic neuron fires after the postsynaptic neuron, the synapse can be similarly strengthened, permitting the learning of inverse models.
      • "This order allows sensory feedback arriving at motor neurons to be associated with past postsynaptic patterns of motor activity that could have caused this sensory feedback. " So: stimulate the sensory neuron (here hypothetically in LMAN) to get motor output; motor output is indexed in the sensory space.
      • In mammals, a similar rule has been found to describe synaptic connections from the cortex to the basal ganglia [37].
      • ... or, based on anatomy, a causal inverse could be connected to a dopaminergic VTA, thereby linking with reinforcement learning theories.
      • Simple reinforcement learning strategies can be enhanced with inverse models as a means to solve the structural credit assignment problem [49].
  • Need to review literature here, see how well these theories of cortical-> BG synapse match the data.

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ref: -0 tags: deeplabcut markerless tracking DCN transfer learning date: 10-03-2018 23:56 gmt revision:0 [head]

Markerless tracking of user-defined features with deep learning

  • Human - level tracking with as few as 200 labeled frames.
  • No dynamics - could be even better with a Kalman filter.
  • Uses a Google-trained DCN, 50 or 101 layers deep.
    • Network has a distinct read-out layer per feature to localize the probability of a body part to a pixel location.
  • Uses the DeeperCut network architecture / algorithm for pose estimation.
  • These deep features were trained on ImageNet
  • Trained on examples with both only the readout layers (rest fixed per ResNet), as well as end-to-end; latter performs better, unsurprising.

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ref: -0 tags: NMDA spike hebbian learning states pyramidal cell dendrites date: 10-03-2018 01:15 gmt revision:0 [head]

PMID-20544831 The decade of the dendritic NMDA spike.

  • NMDA spikes occur in the finer basal, oblique, and tuft dendrites.
  • Typically 40-50 mV, up to 100's of ms in duration.
  • Look similar to cortical up-down states.
  • Permit / form the substrate for spatially and temporally local computation on the dendrites that can enhance the representational or computational repertoire of individual neurons.

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ref: -0 tags: kernel regression structure discovery fitting gaussian process date: 09-24-2018 22:09 gmt revision:1 [0] [head]

Structure discovery in Nonparametric Regression through Compositional Kernel Search

  • Use Gaussian process kernels (squared exponential, periodic, linear, and ratio-quadratic)
  • to model a kernel function, k(x,x)k(x,x') which specifies how similar or correlated outputs yy and yy' are expected to be at two points $$x$ and xx' .
    • By defining the measure of similarity between inputs, the kernel determines the pattern of inductive generalization.
    • This is different than modeling the mapping y=f(x)y = f(x) .
    • It's something more like y=N(m(x)+k(x,x))y' = N(m(x') + k(x,x')) -- check the appendix.
    • See also: http://rsta.royalsocietypublishing.org/content/371/1984/20110550
  • Gaussian process models use a kernel to define the covariance between any two function values: Cov(y,y)=k(x,x)Cov(y,y') = k(x,x') .
  • This kernel family is closed under addition and multiplication, and provides an interpretable structure.
  • Search for kernel structure greedily & compositionally,
    • then optimize parameters with conjugate gradients with restarts.
    • This seems straightforwardly intuitive...
  • Kernels are scored with the BIC.
  • C.f. {842} -- "Because we learn expressions describing the covariance structure rather than the functions themselves, we are able to capture structure which does not have a simple parametric form."
  • All their figure examples are 1-D time-series, which is kinda boring, but makes sense for creating figures.
    • Tested on multidimensional (d=4) synthetic data too.
    • Not sure how they back out modeling the covariance into actual predictions -- just draw (integrate) from the distribution?

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ref: work-0 tags: distilling free-form natural laws from experimental data Schmidt Cornell automatic programming genetic algorithms date: 09-14-2018 01:34 gmt revision:5 [4] [3] [2] [1] [0] [head]

Distilling free-form natural laws from experimental data

  • There critical step was to use partial derivatives to evaluate the search for invariants. Even yet, with a 4D data set the search for natural laws took ~ 30 hours.
    • Then again, how long did it take humans to figure out these invariants? (Went about it in a decidedly different way..)
    • Further, how long did it take for biology to discover similar invariants?
      • They claim elsewhere that the same algorithm has been applied to biological data - a metabolic pathway - with some success.
      • Of course evolution had to explore a much larger space - proteins and reculatory pathways, not simpler mathematical expressions / linkages.

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ref: -2018 tags: machine learning manifold deep neural net geometry regularization date: 08-29-2018 14:30 gmt revision:0 [head]

LDMNet: Low dimensional manifold regularized neural nets.

  • Synopsis of the math:
    • Fit a manifold formed from the concatenated input ‘’and’’ output variables, and use this set the loss of (hence, train) a deep convolutional neural network.
      • Manifold is fit via point integral method.
      • This requires both SGD and variational steps -- alternate between fitting the parameters, and fitting the manifold.
      • Uses a standard deep neural network.
    • Measure the dimensionality of this manifold to regularize the network. Using a 'elegant trick', whatever that means.
  • Still yet he results, in terms of error, seem not very significantly better than previous work (compared to weight decay, which is weak sauce, and dropout)
    • That said, the results in terms of feature projection, figures 1 and 2, ‘’do’’ look clearly better.
    • Of course, they apply the regularizer to same image recognition / classification problems (MNIST), and this might well be better adapted to something else.
  • Not completely thorough analysis, perhaps due to space and deadlines.

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ref: -0 tags: tissue probe neural insertion force damage wound speed date: 06-02-2018 00:03 gmt revision:0 [head]

PMID-21896383 Effect of Insertion Speed on Tissue Response and Insertion Mechanics of a Chronically Implanted Silicon-Based Neural Probe

  • Two speeds, 10um/sec and 100um/sec, monitored out to 6 weeks.
  • Once the probes were fully advanced into the brain, we observed a decline in the compression force over time.
    • However, the compression force never decreased to zero.
    • This may indicate that chronically implanted probes experience a constant compression force when inserted in the brain, which may push the probe out of the brain over time if there is nothing to keep it in a fixed position.
      • Yet ... the Utah probe seems fine, up to many months in humans.
    • This may be a drawback for flexible probes [24], [25]. The approach to reduce tissue damage by reducing micromotion by not tethering the probe to the skull can also have this disadvantage [26]. Furthermore, the upward movement may lead to the inability of the contacts to record signals from the same neurons over long periods of time.
  • We did not observe a difference in initial insertion force, amount of dimpling, or the rest force after a 3-min rest period, but the force at the end of the insertion was significantly higher when inserting at 100 μm/s compared to 10 μm/s.
  • No significant difference in histological response observed between the two speeds.

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ref: -0 tags: insertion speed needle neural electrodes force damage injury cassanova date: 06-01-2018 23:51 gmt revision:0 [head]

Effect of Needle Insertion Speed on Tissue Injury, Stress, and Backflow Distribution for Convection-Enhanced Delivery in the Rat Brain

  • Tissue damage, evaluated as the size of the hole left by the needle after retraction, bleeding, and tissue fracturing, was found to increase for increasing insertion speeds and was higher within white matter regions.
    • A statistically significant difference in hole areas with respect to insertion speed was found.
  • While there are no previous needle insertion speed studies with which to directly compare, previous electrode insertion studies have noted greater brain surface dimpling and insertion forces with increasing insertion speed [43–45]. These higher deformation and force measures may indicate greater brain tissue damage which is in agreement with the present study.
  • There are also studies which have found that fast insertion of sharp tip electrodes produced less blood vessel rupture and bleeding [28,29].
    • These differences in rate dependent damage may be due to differences in tip geometry (diameter and tip) or tissue region, since these electrode studies focus mainly on the cortex [28,29].
    • In the present study, hole measurements were small in the cortex, and no substantial bleeding was observed in the cortex except when it was produced during dura mater removal.
    • Any hemorrhage was observed primarily in white matter regions of the external capsule and the CPu.

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ref: -0 tags: insertion speed neural electrodes force damage date: 06-01-2018 23:38 gmt revision:2 [1] [0] [head]

In vivo evaluation of needle force and friction stress during insertion at varying insertion speed into the brain

  • Targeted at CED procedures, but probably applicable elsewhere.
  • Used a blunted 32ga CA glue filled hypodermic needle.
  • Sprague-dawley rats.
  • Increased insertion speed corresponds with increased force, unlike cardiac tissue.
  • Greatuer surface dimpling before failure results in larger regions of deformed tissue and more energy storage before needle penetration.
  • In this study (blunt needle) dimpling increased with insertion speed, indicating that more energy was transferred over a larger region and increasing the potential for injury.
  • However, friction stresses likely decrease with insertion speed since larger tissue holes were measured with increasing insertion speeds indicating lower frictional stresses.
    • Rapid deformation results in greater pressurization of fluid filled spaces if fluid does not have time to redistribute, making the tissue effectively stiffer. This may occur in compacted tissues below or surrounding the needle and result in increasing needle forces with increasing needle speed.

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ref: -0 tags: tissue response indwelling implants dialysis kozai date: 04-04-2018 00:28 gmt revision:1 [0] [head]

PMID-25546652 Brain Tissue Responses to Neural Implants Impact Signal Sensitivity and Intervention Strategies

  • (Interesting): eight identical electrode arrays implanted into the same region of different animals have shown that half the arrays continue to record neural signals for >14 weeks while in the other half of the arrays, single-unit yield rapidly degraded and ultimately failed over the same timescale.
  • In another study, aimed at uncovering the time course of insertion-related bleeding and coagulation, electrodes were implanted into the cortex of rats at varying time intervals (−120, −90, −60, −30, −15, and 0 min) using a micromanipulator and linear motor with an insertion speed of 2 mm/s.40 The results showed dramatic variability in BBB leakage that washed out any trend (Figure 3), suggesting that a separate underlying cause was responsible for the large inter- and intra-animal variability.

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ref: -0 tags: recurrent cortical model adaptation gain V1 LTD date: 03-27-2018 17:48 gmt revision:1 [0] [head]

PMID-18336081 Adaptive integration in the visual cortex by depressing recurrent cortical circuits.

  • Mainly focused on the experimental observation that decreasing contrast increases latency to both behavioral and neural response (latter in the later visual areas..)
  • Idea is that synaptic depression in recurrent cortical connections mediates this 'adaptive integration' time-constant to maintain reliability.
  • Model also explains persistent activity after a flashed stimulus.
  • No plasticity or learning, though.
  • Rather elegant and well explained.

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ref: -2016 tags: somatostatin interneurons review date: 02-11-2018 18:08 gmt revision:0 [head]

PMID-27225074 Somatostatin-expressing neurons in cortical networks.

  • Urban-Ciecko J1, Barth AL1.
  • High (~ 10hz) tonic (constitutive) firing rate. All GABA.
  • Somatostatin, a neuropeptide, is of ill-defined role. Unknown when it is released.
  • SST interneurons receive diffuse input from cortical pyramidal cells, but each synapse is of low strength.
  • SST intererneurons are frequently electrically connected through gap junctions, but almost never through electrical synapses. The resulting network can extend for hundreds of microns, and has been shown to cause synchronized firing when cells are active.
  • Common anesthetics (isoflurane, urethane) profoundly silence the SSTs.
  • Wide diversity of axonal and dendritic branching patterns, targeting both apical (20%) and distal pyramidal cell dendrites.
  • SST neuron activity is reduced in Dravet syndrome.
  • SST neurons have also been implicated in schizophrenia; affected individuals show decreased SST mRNA and mislocalization of SST interneurons.

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ref: -0 tags: NET probes SU-8 microfabrication sewing machine carbon fiber electrode insertion mice histology 2p date: 12-29-2017 04:38 gmt revision:1 [0] [head]

PMID-28246640 Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration

  • SU-8 asymptotic H2O absorption is 3.3% in PBS -- quite a bit higher than I expected, and higher than PI.
  • Faced yield problems with contact litho at 2-3um trace/space.
  • Good recordings out to 4 months!
  • 3 minutes / probe insertion.
  • Fab:
    • Ni release layer, Su-8 2000.5. "excellent tensile strength" --
      • Tensile strength 60 MPa
      • Youngs modulus 2.0 GPa
      • Elongation at break 6.5%
      • Water absorption, per spec sheet, 0.65% (but not PBS)
    • 500nm dielectric; < 1% crosstalk; see figure S12.
    • Pt or Au rec sites, 10um x 20um or 30 x 30um.
    • FFC connector, with Si substrate remaining.
  • Used transgenic mice, YFP expressed in neurons.
  • CA glue used before metabond, followed by Kwik-sil silicone.
  • Neuron yield not so great -- they need to plate the electrodes down to acceptable impedance. (figure S5)
    • Measured impedance ~ 1M at 1khz.
  • Unclear if 50um x 1um is really that much worse than 10um x 1.5um.
  • Histology looks realyl great, (figure S10).
  • Manuscript did not mention (though the did at the poster) problems with electrode pull-out; they deal with it in the same way, application of ACSF.

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ref: Salcman-1973.07 tags: Salcman MEA microelectrodes chronic recording glass cyanocrylate date: 12-29-2017 04:33 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-4708761 Design, Fabrication, and In Vivo Behavior of Chronic Recording Intracortical Microelectrodes

  • Teflon-coated 25um Pt-Ir (90/10)
  • Heat fuse this with a glass micropipette & backfill with cyanoacrylate. {1011}
    • Isobutyl acrylate is hydrolysed more slowly and hence is less toxic to the surronding tissue
    • cyanoacrylate is apparently biodegradable.
  • Durable, stable: one electrode displayed a single cortical spike (though not necessarily the same one) for more than 90 consecutive days.
  • unacceptably low impedance = 100K or less
  • Unit activity was present only 10-24H after surgery.
  • formal review of even older microelectrode studies.
  • 10nA should be 100x too small to have any effect on a platinum tip [17]
  • A seperable cell with a SNR of 3:1 would become lost if the electrode tip moved 15um away from a 20um soma.
    • "It becomes clear that the problem of holding single units for prolonged periods in the unrestrained animal is not achieved without considerable difficulty". Yet they think they have solved it.

____References____

Salcman, Michael and Bak, Martin J. Design, Fabrication, and In Vivo Behavior of Chronic Recording Intracortical Microelectrodes Biomedical Engineering, IEEE Transactions on BME-20 4 253 -260 (1973)

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ref: -0 tags: robinson pasquali carbon nanotube fiber fluidic injection dextran neural electrode date: 12-28-2017 04:20 gmt revision:0 [head]

PMID-29220192 Fluidic Microactuation of Flexible Electrodes for Neural Recording.

  • Use viscous dextran solution + PDMS channel system
  • Durotomy (of course)
  • Parylene-C insulated carbon fiber electrodes, cut with FIB or razor blade
  • Used silver ink to electrically / mechanically attach for recordings.
  • Tested in hydra, rat brain slice (reticular formation of thalamus), and in-vivo rat.
  • Electrodes, at 12um diameter, E=120GPa, are approximately 127x stiffer than one 4x20um PI (E=9GPa) probe. Less damage though.

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ref: -0 tags: Lieber nanoFET review silicon neural recording intracellular date: 12-28-2017 04:04 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-23451719 Synthetic Nanoelectronic Probes for Biological Cells and Tissue

  • Review of nanowireFETS for biological sensing
  • Silicon nanowires can be grown via vapor-liquid-solid or vapor-solid-solid, 1D catalyzed growth, usually with a Au nanoparticle.
  • Interestingly, kinks can be introduced via "iterative control over nucleation and growth", 'allowing the synthesis of complex 2D and 3D structures akin to organic chemistry"
    • Doping can similarly be introduced in highly localized areas.
    • This bottom-up synthesis is adaptable to flexible and organic substrates.
  • Initial tests used polylysine patterning to encourage axonal and dendritic growth across a nanoFET.
    • Positively charged amino group interacts with negative surface charge phospholipid
    • Lieber's group coats their SU-8 electrodes in poly-d-lysine as well {1352}
  • Have tested multiple configurations of the nanowire FET, including kinked, one with a SiO2 nanopipette channel for integration with the cell membrane, and one where the cell-attached fluid membrane functions as the semiconductor; see figure 4.
    • Were able to show recordings as one of the electrodes was endovascularized.
  • It's not entirely clear how stable and scalable these are; Si and SiO2 gradually dissolve in physiological fluid, and no mention was made of longevity.

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ref: Gilgunn-2012 tags: kozai neural recording electrodes compliant parylene flexible dissolve date: 12-28-2017 03:50 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

IEEE-6170092 (pdf) An ultra-compliant, scalable neural probe with molded biodissolvable delivery vehicle

    • Optical coherence tomography is cool.
  • Large footprint - 150 or 300um, 135um thick (13500 or 40500 um^2; c.f. tungsten needle 1963 (50um) or 490 (25um) um^2.)
  • Delivery vehicle is fabricated from biodissolvable carboxy-methylcellulose (CMC).
    • Device dissolves within three minutes of implantation.
    • Yet stiff enough to penetrate the dura of rats (with what degree of dimpling?)
    • Lithographic patterning process pretty clever, actually.
    • Parylene-X is ~ 1.1 um thick.
    • 500nm Pt is patterned via ion milling with a photoresist mask.
    • Use thin 20nm Cr etch mask for both DRIE (STS ICP) and parylene etch.
  • Probes are tiny -- 10um wide, 2.7um thick, coated in parylene-X.
  • CMC polymer tends to bend and warp due to stress -- must be clamped in a special jig.
  • No histology. Follow-up: {1399}

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ref: -0 tags: kozai CMC dissolving insertion shuttle parylene date: 12-28-2017 03:19 gmt revision:1 [0] [head]

PMID-25128375 Chronic tissue response to carboxymethyl cellulose based dissolvable insertion needle for ultra-small neural probes.

  • CMC = carboxymethyl cellulose, commonly used as a food additive, in toothpaste, etc.
  • To address CMC dissolution, we developed a sophisticated targeting, high speed insertion (∼80 mm/s), and release system to implant shuttles.
  • Cross section of the probes are large, 300 x 125um and 100 x 125um.
  • Beautiful histology: the wound does gradually close up as the CMC dissolves, but no e-phys.

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ref: Kozai-2009.11 tags: electrodes insertion Kozai flexible polymer momolayer date: 12-28-2017 02:59 gmt revision:12 [11] [10] [9] [8] [7] [6] [head]

PMID-19666051[0] Insertion shuttle with carboxyl terminated self-assembled monolayer coatings for implanting flexible polymer neural probes in the brain.

  • This study investigated the use of an electronegative (hydrophillic) self-assembled monolayer (SAM) as a coating on a stiff insertion shuttle to carry a polymer probe into the cerebral cortex, and then the detachment of the shuttle from the probe by altering the shuttle's hydrophobicity.
    • Used 11-mercaptoundecanoic acid.
    • Cr/Au (of course) evaporated on 15um thick Si shuttle.
    • SAM attracts water once inserted, causing the hydrophobic polymer to move away.
      • Why not make the polymer hydrophillic?
      • Is this just soap?
  • Used agarose brain model.
  • Good list of references for the justification of soft electrodes, and researched means for addressing this, mostly usnig polymer stiffeners.
    • "Computer models and experimental studies of the probe–tissue interface suggest that flexible and soft probes that approach the brain’s bulk material characteristics may help to minimize micromotion between the probe and surrounding tissue ({737}; {1203}; {1102}; {1200}; LaPlaca et al., 2005; {1216}; Neary et al., 2003 PMID-12657694; {1198})"
  • "However, polymer probes stick to metallic and silicon surfaces through hydrophobic interactions, causing the polymer probe to be carried out of the brain when the insertion shuttle is removed. The solution is to use a highly hydrophillic, electronegative, self-assembled monolayer coating on the shuttle.
  • Biran et al 2005 suggests that incremental damage due to stab wounds from the shuttle (needle) should be minor.
  • Probes: 12.5 um thick, 196 um wide, and 1.2cm long, polymide substrate and custom designed lithographed PDMS probes.
  • Polymer probes were inserted deep - 8.5 mm.
  • PDMS probes inserted with non-coated insertion shuttle resulted in explantation of the PDMS probe.

____References____

[0] Kozai TD, Kipke DR, Insertion shuttle with carboxyl terminated self-assembled monolayer coatings for implanting flexible polymer neural probes in the brain.J Neurosci Methods 184:2, 199-205 (2009 Nov 15)

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ref: -0 tags: platinum parylene electrodes brush dissolving stiffener gelatin date: 12-28-2017 02:44 gmt revision:0 [head]

PMID-27159159 Embedded Ultrathin Cluster Electrodes for Long-Term Recordings in Deep Brain Centers.

  • 12.5um pure Pt wires
  • Coated in 4um parylene-C
  • stiffened with gelatin
  • further protected with Kollicoat to retard dissolution.
  • Used a pulsed UV laser to ablate parylene, cut the platinum, and roughen the recording site.
  • See also {311}

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ref: -0 tags: polyimide electrodes immune response foreign body inflammation stiffener steiglitz date: 12-28-2017 02:37 gmt revision:0 [head]

PMID-27534649 Intracortical polyimide electrodes with a bioresorbable coating.

  • Molten saccharose was used as coating material.
  • 270 x 10um polyimide recording probes. (large!)
  • Tissue reaction seems to peak at 2 weeks-4weeks, and decline somewhere thereafter. (though there were not a great number of samples.)

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ref: -0 tags: rogers thermal oxide barrier neural implants ECoG coating accelerated lifetime test date: 12-28-2017 02:29 gmt revision:0 [head]

PMID-27791052 Ultrathin, transferred layers of thermally grown silicon dioxide as biofluid barriers for biointegrated flexible electronic systems

  • Thermal oxide proved the superior -- by far -- water barrier for encapsulation.
    • What about the edges?
  • Many of the polymer barrier layers look like inward-rectifiers:
  • Extensive simulations showing that the failure mode is from gradual dissolution of the SiO2 -> Si(OH)4.
    • Even then a 100nm layer is expected to last years.
    • Perhaps the same principle could be applied with barrier metals. Anodization or thermal oxidation to create a thick, nonporous passivation layer.
    • Should be possible with Al, Ta...

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ref: -0 tags: Courtine e-dura PDMS silicone gold platinum composite stretch locomotion restoration rats date: 12-22-2017 01:59 gmt revision:0 [head]

PMID-25574019 Biomaterials. Electronic dura mater for long-term multimodal neural interfaces.

  • Fabrication:
    • 120um total PDMS thickness, made through soft lithography, covalent (O2 plasma) bonding between layers
    • 35nm of Au (thin!) deposited through a stencil mask.
    • 300um Pt-PDMS composite for electrode sites, deposited via screenprinting
  • 100 x 200um cross section drug delivery channel.
  • Compared vs. stiff 25um thick PI film electrode.
    • stiff implants showed motor impairments 1-2 weeks after implantation.
  • Showed remarkable recovery of supported locomotion with stimulation and drug infusion (to be followed by monkeys).

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ref: -0 tags: Courtine PDMS soft biomaterials spinal cord e-dura date: 12-22-2017 01:29 gmt revision:0 [head]

Materials and technologies for soft implantable neuroprostheses

  • Quote: In humans, both the spinal cord and its meningeal protective membranes can experience as much as 10–20% tensile strain and
displacement (relative to the spinal canal) during normal postural movements. This motion corresponds to displacements on the order of centimetres17. The deformations relative to the spinal cord in animal models, such as rodents or non-human primates, are likely to be even larger.

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ref: -0 tags: lieber mesh electronics SU-8 recording electrodes flexible polymer glass capillary date: 12-22-2017 00:14 gmt revision:0 [head]

PMID-29109247 Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology

  • Key change was the addition of multiple conductor traces per longitudinal mesh line; this allows them to get 64 or 128 channels per mesh without a dramatic increase in modulus.
  • The latitudinal / diagonal lines still displace tissue ...
  • And the injection mechanism, glass pipette, 650um OD, 400um ID, is pretty large, even for 128 channels.
  • Use carbon nanotube ink, custom CNC printer, to connect to FPC.
    • Pretty impressive that they can manipulate ~800nm thick Su-8 film intraop and have it work well!

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ref: -0 tags: photoacoustic tomography mouse imaging q-switched laser date: 05-11-2017 05:23 gmt revision:1 [0] [head]

Single-impulse panoramic photoacoustic computed tomography of small-animal whole-body dynamics at high spatiotemporal resolution

  • Used Q-switched Nd:YAG and Ti:Sapphire lasers to illuminate mice axially (from the top, through a diffuser and conical lens), exciting the photoacuostic effect, from which they were able to image at 125um resolution a full slice of the mouse.
    • I'm surprised at their mode of illumination -- how do they eliminate the out-of-plane photoacoustic effect?
  • Images look low contrast, but structures, e.g. cortical vasculature, are visible.
  • Can image at the rep rate of the laser (50 Hz), and thereby record cardiac and pulmonary rhythms.
  • Suggest that the photoacoustic effect can be used to image brain activity, but spatial and temporal resolution are limited.

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ref: -0 tags: photoacoustic tomography mouse imaging q-switched laser date: 05-11-2017 05:21 gmt revision:0 [head]

Single-impulse panoramic photoacoustic computed tomography of small-animal whole-body dynamics at high spatiotemporal resolution

  • Used Q-switched Nd:YAG and Ti:Sapphire lasers to illuminate mice axially, exciting the photoacuostic effect, from which they were able to image at 125um resolution a full slice of the mouse.
  • Images look low contrast, but structures, e.g. cortical vasculature, are visible.
  • Can image at the rep rate of the laser (50 Hz), and thereby record cardiac and pulmonary rhythms.
  • Suggest that the photoacoustic effect can be used to image brain activity, but spatial and temporal resolution are limited.

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ref: -0 tags: PEDOT PSS electroplate eletrodeposition neural recording michigan probe stimulation CSC date: 04-27-2017 01:36 gmt revision:1 [0] [head]

PMID-19543541 Poly(3,4-ethylenedioxythiophene) as a micro-neural interface material for electrostimulation

  • 23k on a 177um^2 site.
  • demonstrated in-vitro durable stimulation.
  • Electrodeposited with 6na for 900 seconds per electrode.
    • Which is high -- c.f. 100pA for 600 seconds {1356}
  • Greater CSC and lower impedance / phase than (comparable?) Ir or IrOx plating.

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ref: -1977 tags: polyethylene surface treatment plasma electron irradiation mechanical testing saline seawater accelerated lifetime date: 04-15-2017 06:06 gmt revision:0 [head]

Enhancement of resistance of polyethylene to seawater-promoted degradation by surface modification

  • Polyethylene, when repeatedly stressed and exposed to seawater (e.g. ships' ropes), undergoes mechanical and chemical degradation.
  • Surface treatments of the polyethlyene can improve resistance to this degradation.
  • The author studied two methods of surface treatment:
    • Plasma (glow discharge, air) followed by diacid (adipic acid) or triisocyanate (DM100, = ?) co-polymerization
    • Electron irradiation with 500 kEV electrons.
  • Also mention CASING (crosslinking by activated species of inert gasses) as a popular method of surface treatment.
    • Diffuse-in crosslinkers is a third, popular these days ...
    • Others diffuse in at temperature e.g. a fatty acid - derived molecule, which is then bonded to e.g. heparin to reduce the thrombogenicity of a plastic.
  • Measured surface modifications via ATR IR (attenuated total reflectance, IR) and ESCA (aka XPS)
    • Expected results, carbonyl following the air glow discharge ...
  • Results:
    • Triisocyanate, ~ 6x improvement
    • diacid, ~ 50 x improvement.
    • electron irradiation, no apparent degradation!
      • Author's opinion that this is due to carbon-carbon crosslink leading to mechanical toughening (hmm, evidence?)
  • Quote: since the PE formulation studied here was low-weight, it was expected to lose crystallinity upon cyclic flexing; high density PE's have in fact been observed to become more crystalline with working.
    • Very interesting, kinda like copper. This could definitely be put to good use.
  • Low density polyethylene has greater chain branching and entanglement than high-density resins; when stressed the crystallites are diminished in total bulk, degrading tensile properties ... for high-density resins, mechanical working loosens up the structure enough to allow new crystallization to exceed stress-induced shrinkage of crystallites; hence, the crystallinity increases.

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ref: -0 tags: tungsten eletropolishing hydroxide cleaning bath tartarate date: 03-28-2017 16:34 gmt revision:0 [head]

Method of electropolishing tungsten wire US 3287238 A

  • The bath is formed of 15% by weight sodium hydroxide, 30% by weight sodium potassium tartrate, and 55% by weight distilled water, with the bath temperature being between 70 and 100 F.
    • If the concentration of either the hydroxide or the tartrate is below the indicated minimum, the wire is electrocleaned rather than electropolished, and a matte finish is obtained rather than a specular surface.
    • If the concentration of either the hydroxide or the tartrate is greater than the indicated maximum, the electropolishing process is quite slow.
  • The voltage which is applied between the two electrodes 18 and 20 is from 16 to 18.5 volts, the current through the bath is 20 to 24 amperes, and the current density is 3,000 to 4,000 amperes per square foot of surface of wire in the bath.

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ref: -0 tags: polyimide electrodes thermosonic bonding Stieglitz adhesion delamination date: 03-06-2017 21:58 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

IEEE-6347149 (pdf) Improved polyimide thin-film electrodes for neural implants 2012

  • Tested adhesion to Pt / SiC using accelerated aging in saline solution.
  • Targeted at retinal prostheses.
  • Layer stack:
    • 50nm SiC deposited through PECVD @ 100C using SPS, with low frequency RF modulation.
    • 100nm Pt
    • 100nm Au
    • 100nm Pt
      • These layers will alloy during cure, and hence reduce stress.
    • 30nm SiC
    • 10nm DLC (not needed, imho; PI sticks exceptionally well to clean SiC)
  • Recent studies have concluded that adhesion to PI is through carbon bindings and not through oxide formation.
    • Adhesion of polyimide to amorphous diamond-like carbon and SiC deteriorates at a minimal rate.
  • Delamination is caused by residual stress, which is not only inevetable but a major driving force for cracking in thin films.
    • Different CTE in layer stack -> different contraction when cooling from process temperature.
  • Platinum, which evaporates at 1770C, and is deposited ~100C (photoresists only withstand ~115C) results in a high-stress interface.
    • Pt - Carbon bonds only occur above 1000C
  • After 9 and 13 days of incubation the probes with 400 nm and 300nm of SiC, respectively, which were not tempered, showed complete delamination of the Pt from the SiC.
    • 60C, 0.9 M NaCl, 1 year.
    • The SiC remained attached to the PI.
      • Tempering: repeated treatment at 450C for 15 min in a N2 atmosphere.
    • All other probes remained stable.
  • Notably, used thermosonic bonding to the PI films, using sputtered (seed layer) then 12um electroplated Au.
  • Also: fully cured the base layer PI film.
  • Used oxygen plasma de-scum after patterning with resists to get better SiC adhesion to PI.
    • And better inter-layer adhesion (fully cured the first polyimide layer @ 450C).
  • Conclusion: "The fact that none of the tempered samples delaminated even after ~5 years of lifetime (extrapolated for 37 C) shows a tremendous increase in adhesion.

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ref: Seymour-2007.09 tags: neural probe design recording Kipke Seymour parelene MEA histology PEDOT date: 02-23-2017 23:52 gmt revision:13 [12] [11] [10] [9] [8] [7] [head]

PMID-17517431[0] Neural probe design for reduced tissue encapsulation in CNS.

  • See conference proceedings too: PMID-17947102[1] Fabrication of polymer neural probes with sub-cellular features for reduced tissue encapsulation.
    • -- useful information.
  • They use SU8 - photoresist! - as a structural material. See also this.
    • They use silicon as a substrate for the fabrication, but ultimately remove it. Electrodes could be made of titanium, modulo low conductivity.
  • Did not / could not record from these devices. Only immunochemistry.
  • Polymer fibers smaller than 7um are basically invisible to the immune system. See [2]
  • Their peripheral recording site is 4 x 5um - but still not invisible to microglia. Perhaps this is because of residual insertion trauma, or movement trauma? They implanted the device flush with the cortical surface, so there should have been little cranial tethering.
  • Checked the animals 4 weeks after implantation.
  • Peripheral electrode site was better than shank location, but still not perfect. Well, any improvement is a good one...
  • No statistical difference between 4x5um lattice probes, 10x4um probes, 30x4um, and solid (100um) knife edge.
    • Think that this may be because of electrode micromotion -- the lateral edge sites are still relatively well connected to the thick, rigid shank.
  • Observed two classes of immune reactivity --
    • GFAP reactive hypertrophied astrocytes.
    • devoid of GFAP, neurofilament, and NEuN, but always OX-42 and often firbronectin and laminin positive as well.
    • Think that the second may be from meningeal cells pulled in with the stab wound.
  • Sensitivity is expected to increase with decreased surface area (but similar low impedance -- platinum black or oxidized iridium or PEDOT {1112} ).
  • Thoughts: it may be possible to put 'barbs' to relieve mechanical stress slightly after the probe location, preferably spikes that expand after implantation.
  • His thesis {1110}

____References____

[0] Seymour JP, Kipke DR, Neural probe design for reduced tissue encapsulation in CNS.Biomaterials 28:25, 3594-607 (2007 Sep)
[1] Seymour JP, Kipke DR, Fabrication of polymer neural probes with sub-cellular features for reduced tissue encapsulation.Conf Proc IEEE Eng Med Biol Soc 1no Issue 4606-9 (2006)
[2] Sanders JE, Stiles CE, Hayes CL, Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density.J Biomed Mater Res 52:1, 231-7 (2000 Oct)

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ref: -0 tags: iridium oxide nanotube intracellular recording electroplate MEA date: 02-22-2017 22:41 gmt revision:0 [head]

PMID-24487777 Iridium oxide nanotube electrodes for sensitive and prolonged intracellular measurement of action potentials.

  • Electrodeposition of IrOx "magically" forms 500nm tubes.
  • Holes in Si3N4 / SiO2 were formed via e-beam lithography; underlying Pt wires via liftoff.
  • Showed long (minutes) intracellular access, though it tended to dip with time.

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ref: -0 tags: glassy carbon SU-8 pyrolysis CEC microelectrode stimulation stability platinum PEDOT date: 02-17-2017 00:05 gmt revision:2 [1] [0] [head]

A novel pattern transfer technique for mounting glassy carbon microelectrodes on polymeric flexible substrates

  • Use inert-atmosphere pyrolysis @ 900 - 1000 C of 20um SU-8 (which is aromatic) on a thermal oxide wafer.
  • Followed by spin & cure of PI.
  • Demonstrate strong carbonyl bonding of the glassy carbon with mechanical and FTIR testing.
  • Use of photosensitive PI allows through-vias to connect Cr/Au conductive traces.

PMID-28084398 Highly Stable Glassy Carbon Interfaces for Long-Term Neural Stimulation and Low-Noise Recording of Brain Activity

  • Use EIS to show superior charge-injection properties + stability of glassy carbon electrodes vs. Pt electrodes.
    • GC lasted > 5e6 pulses; Pt electrodes delaminated after 1e6 pulses.
    • Hydrogen bonding (above) clearly superior than neat PI-Pt interface
  • GC electrodes were, true to their name, glassy and much smoother than the platinum electrodes.
  • Further reduced impedance with PEDOT-PSS coating.
    • PEDOT-PSS coating on glassy carbon was, in their hands, far more stable than PEDOT-PSS on platinum.
  • All devices, GC, PEDOT:PSS, and Pt, had similar biocompatibility in their assay (figure 7)

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ref: -0 tags: myoelectric EMG recording TMR prosthetics date: 02-13-2017 20:43 gmt revision:0 [head]

PMID: Man/machine interface based on the discharge timings of spinal motor neurons after targeted muscle reinnervation

  • General idea: deconvolve a grid-recorded EMG signal to infer the spinal motorneron spikes, and use this to more accurately decode user intention.
  • EMG envelope is still fairly good...

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ref: -0 tags: carbon fiber thread spinning Pasquali Kemere nanotube stimulation date: 02-09-2017 01:09 gmt revision:0 [head]

PMID-25803728 Neural stimulation and recording with bidirectional, soft carbon nanotube fiber microelectrodes.

  • Poulin et al. demonstrated that microelectrodes made solely of CNT fibers22 show remarkable electrochemical activity, sensitivity, and resistance to biofouling compared to conventional carbon fibers when used for bioanalyte detection in vitro.23-25
  • Fibers were insulated with 3 um of block copolymer polystyrene-polybutadiene (PS-b-PBD) (polybutadiene is sythetic rubber)
    • Selected for good properties of biocompatibility, flexibility, resistance to flextural fatigue.
    • Available from Sigma-Aldrich.
    • Custom continuous dip-coating process.
  • 18um diameter, 15 - 20 x lower impedance than equivalently size PtIr.
    • 2.5 - 6x lower than W.
    • In practice, 43um dia, 1450um^2, impedance of 11.2 k; 12.6um, 151k.
  • Charge storage capacity 327 mC / cm^2; PtIr = 1.2 mC/cm^2
  • Wide water window of -1.5V - 1.5V, consistent with noble electrochemical properties of C.
  • Lasts for over 97e6 pulsing cycles beyond the water window, vs 43e6 for PEDOT.
  • Tested via 6-OHDA model of PD disease vs. standard PtIr stimulating electrodes, implanted via 100um PI shuttled attached with PEG.
  • Yes, debatable...
  • Tested out to 3 weeks durability. Appear to function as well or better than metal electrodes.

PMID-23307737 Strong, light, multifunctional fibers of carbon nanotubes with ultrahigh conductivity.

  • Full process:
    1. Dissolve high-quality, 5um long CNT in chlorosulfonic acid (the only known solvent for CNTs)
    2. Filter to remove particles
    3. Extrude liquid crystal dope through a spinneret, 65 or 130um orifice
    4. Into a coagulant, acetone or water
    5. Onto a rotating drum to put tension on the thread & align the CNTs.
    6. Wash in water and dry at 115C.
  • Properties:
    • Tensile strength 1 GPa +- 0.2 GPa.
    • Tensile modulus 120 GPa +- 50, best value 200 GPa
      • Pt: 168 GPa ; Au: 79 GPa.
    • Elongation to break 1.4 %
    • Conductivity: 0.3 MS/m, Iodine doped 5 +- 0.5 MS/m (22 +- 4 microhm cm)
      • Cu: 59.6 MS/m ; Pt: 9.4 MS/m ; Au: 41 MS/m
      • Electrical conductivity drops after annealing @ 600C
      • But does not drop after kinking and repeated mechanical cycling.
  • Theoretical modulus of MWCNT ~ 350 GPa.
  • Fibers well-aligned at ~ 90% the density (measure 1.3 g/cc) of close-packed CNT.

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ref: -0 tags: nanoprobe transmembrane intracellular thiol gold AFM juxtacellular date: 02-06-2017 23:45 gmt revision:3 [2] [1] [0] [head]

PMID-20212151 Fusion of biomimetic stealth probes into lipid bilayer cores

  • Used e-beam evaporation of Cr/Au/Cr 10/10/10 or 10/5/10 onto a Si AFM tip.
    • Approx 200nm diameter; 1800 lipid interaction at the circumference.
  • Exposed the Au in the sandwich via FIB
  • Functionalized the Au with butanethiol or dodecanthiol; former is mobile on the surface, latter is polycrystaline.
    • Butanethiol showed higher adhesion to the synthetic membranes
  • Measured the penetration force & displacement through synthetic multi-layer lipid bilayers.
    • These were made via a custom protocol with 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) and cholesterol

PMID-21469728 '''Molecular Structure Influences the Stability of Membrane Penetrating Biointerfaces.

  • Surprisingly, hydrophobicity is found to be a secondary factor with monolayer crystallinity the major determinate of interface strength
  • Previous studies using ellipsometry and IR spectroscopy have shown that alkanethiol self-assembled monolayers display an abrupt transition from a fluid to a crystalline phase between hexanethiol and octanethiol.
    • This suggests the weakening of the membrane stealth probe interface is due to the crystallinity of the molecular surface with fluid, disordered monolayers promoting a high strength interface regime and rigid, crystalline SAMs forming weak interfaces.

{1377}
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ref: -0 tags: nanopore membrane nanostraws melosh surface adhesion intracellular date: 02-06-2017 23:34 gmt revision:0 [head]

PMID-22166016 Nanostraws for Direct Fluidic Intracellular Access

  1. Used track-etched polycarbonate membranes, which have controlled pore density & ID.
  2. Deposited alumina on the pores & external surfaces using ALD
  3. Then etched away the top alumina
  4. and finally used O2 RIE to etch away the polycarbonate.
  • Show that these nanopores have cytosolic access (via Fluor 488 - hydrazide membrane impermeant dye
  • Also used nanostraws to deliver Co+2 to quench GFP fluorescence.

PMID-24710350, Quantification of nanowire penetration into living cells.

  • We discover that penetration is a rare event: 7.1±2.7% of the nanostraws penetrate the cell to provide cytosolic access for an extended period for an average of 10.7±5.8 penetrations per cell.
  • Using time-resolved delivery, the kinetics of the first penetration event are shown to be adhesion dependent and coincident with recruitment of focal adhesion-associated proteins.
    • Hours for unmodified, 5 minutes for adhesion-promoting surface.
  • Chinese hamster oviary cells expressing GFP, Co+2 quenching, EDTA chelation.
  • To modulate cell adhesion, nanostraw substrates were incubated in 10 μg ml−1 fibronectin, a well-characterized cell adhesion molecule, in addition to the standard polyornithine coating.

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ref: -0 tags: review neural recording penn state extensive biopolymers date: 02-06-2017 23:09 gmt revision:0 [head]

PMID-24677434 A Review of Organic and Inorganic Biomaterials for Neural Interfaces

  • Not necessarily insightful, but certainly exhaustive review of all the various problems and strategies for neural interfacing.
  • Some emphasis on graphene, conductive polymers, and biological surface treatments for reducing FBR.
  • Cites 467 articles!

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ref: -0 tags: intracellular juxtacellular recording tungsten nanowire whole cell patch date: 02-06-2017 22:39 gmt revision:2 [1] [0] [head]

PMID-22905231 Neuronal recordings with solid-conductor intracellular nanoelectrodes (SCINEs).

  • <300 nm diameter W fibers, several um long, fabricated via FIB.
  • Functionalized with a hydrophobic silane on the oxide.
    • Quite complete & custom methods here.
  • Not quite whole cell recording, but excellent SNR; 4mv APs.
    • Slice, rat hippocampus organotypic.
    • Expected much larger recorded APs; suspect partial membrane penetration.
    • Only lasted a few seconds to minutes.
  • Needed custom recording setup for interfacing with 100Gohm electrodes; stray capacitance < 4 pf.
  • Intracellular electrodes must be designed to not shunt the membrane open upon insertion.
    • In a study where whole-cell recordings were established prior sharp microelectrode penetration, all neurons showed significant depolarization following impalement.
    • Here there was no change in membrane voltage in 10% of insertions of the silane-functionalized SCINEs. only in the functionalized electrodes).
    • Minor distortion of the AP was observed.
  • In whole-cell patch clamping, diffusion from the pipette to the cytosol interrupts biochemical processes necessary for normal cellular function (e.g. respiration!).
  • The hardness of the tungsten ensures that SCINEs can be repeatedly inserted millimeter-deep into brain tissue without noticeable damage to the tip.
    • E.g. 300 nm tungsten will not easily navigate vasculature...

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ref: -0 tags: bone marrow transplant chimera immune response to indwelling electrode implant capadona inflammation date: 02-02-2017 23:24 gmt revision:1 [0] [head]

PMID-24973296 The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted intracortical microelectrodes.

  • Quite good introductory review on current understanding of immune / inflammatory / BBB breakdown response to indwelling neural implants.
  • Used chimera mice with marrow from CFP mice transplanted into irradiated hosts, so myeloid cells were labeled (including macrophages and monocytes).
    • Details of this process are properly fascinating ... there are clever ways of isolating and selecting the right marrow cells.
  • Implanted with a dummy Michigan style probe, 2mm x 123 um x 15um.
  • Histological processes and cell sorting / labeling also highly detailed.
  • 60% of the infiltrating cells (CFP+) are macrophages.
    • Within the total IBA1+ population (macrophages + microglia), we saw that only 20% of the total IBA1+ population was comprised of microglia at two weeks post implantation (Fig. 9G).
    • Additionally, at chronic time points (four, eight and sixteen weeks), we observed that less than 40% of the total IBA1+ population was comprised of microglia (Fig. 9G).
    • On the other hand, no significant differences were observed in microglia populations over time (Fig. 9G, Table 4). Together, our results suggest a predominant role of infiltrating macrophages surrounding implanted microelectrodes over time.
  • IBA1 = marker for ionized calcium binding adapter molecule, to label the total population of microglia/ macrophages (both resting and activated)
  • CD68 = activated microglia / macrophage.
    • Hard to discriminate microglia and infiltrating macrophages.
  • Interestingly, fluctuations in GFAP+ immunoreactivity correlated well with neuronal density and CFP+ immunoreactivty, suggesting a possible role of astrocytes in facilitating trafficking of blood-derived cells.
  • Contrary to what has been suggested by many intracortical microelectrode studies, a consistent connection was not found between activated microglia/macrophages and neuron density in our chimera models

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ref: -0 tags: nanotube tracking extracellular space fluorescent date: 02-02-2017 22:13 gmt revision:0 [head]

PMID-27870840 Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain

  • Extracellular space (ECS) takes up nearly a quarter the volume of the brain (!!!)
  • Used the intrinsic fluorescence of single-walled carbon nanotubes @ 1um, 845nm excitation, with super-resolution tracking of diffusion.
    • Were coated in phospholipid-polyethylene glycol (PL-PEG), which display low cytotoxicity compared to other encapsulants.
  • 5ul, 3ug/ml injected into the ventricles of young rats; allowed to diffuse for 30 minutes post-injection.
  • No apparent response of the microglia.
  • Diffusion tracking revealed substantial dead-space domains in the ECS.
    • As compared to patch-clamp loaded SWCNTs
  • Estimate from parallel and perpendicular diffusion rates that the characteristic scale of ECS dimension is 80 to 270nm, or 150 +- 40nm.
  • The ECS nanoscale dimensions as visualized by tracking similar in dimension and tortuosity to electron microscopy.
  • Viscosity of the extracellular matrix from 1 to 50 mPa S, up to two orders of magnitude higher than the CSF.
  • Positive control through hyalurinase + several hours to digest the hyaluronic acid.
    • But no observed changes in morphology of the neurons via confocal .. interesting.
    • Enzyme digestion normalized the spatial heterogenaity of diffusion.

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ref: -0 tags: juxtacellular recording gold mushroom cultured hippocampal neurons Spira date: 02-01-2017 02:44 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

Large-Scale Juxtacellular Recordings from Cultured Hippocampal Neurons by an Array of Gold-Mushroom Shaped Microelectrodes

  • Micrometer sized Au mushroom MEA electrodes.
  • Functionalized by poly-ethylene-imine (PEI, positively charged)/laminin (extracellular matrix protein) undergo a process to form juxtacellular junctions between the neurons and the gMµEs.
  • No figures, but:
    • Whereas substrate integrated planar MEA record FPs dominated by negative-peak or biphasic-signals with amplitudes typically ranging between 40-100 µV and a signal to noise ratio of ≤ 5,
    • The gMµE-MEA recordings were dominated by positive monophasic action potentials.
    • It is important to note that monophasic high peak amplitudes ≥ 100 µV are rarely obtained using planar electrodes arrays, whereas when using the gMµE-MEA, 34.48 % of the gMµEs recorded potentials ≥ 200 µV and 10.64 % recorded potentials in the range of 300-5,085 µV.
  • So, there is a distribution of coupling, approximately 10% "good".

PMID-27256971 Multisite electrophysiological recordings by self-assembled loose-patch-like junctions between cultured hippocampal neurons and mushroom-shaped microelectrodes.

  • Note 300uV - 1mV extracellular 'juxtacellular' action potentials from these mushroom recordings. This is 2 - 5x better than microwire extacellular in-vivo ephys; coupling is imperfect.
    • Sharp glass-insulated W electrodes, ~ 10Mohm, might achieve better SNR if driven carefully.
  • 2um mushroom cap Au electrodes, 1um diameter 1um long shaft
    • No coating, other than the rough one left by electroplating process.
    • Impedance 10 - 25 Mohm.
  • APs decline within a burst of up to 35% -- electrostatic reasons?
  • Most electrodes record more than one neuron, similar to in-vivo ephys, with less LFP coupling.

PMID-23380931 Multi-electrode array technologies for neuroscience and cardiology

  • The key to the multi-electrode-array ‘in-cell recording’ approach developed by us is the outcome of three converging cell biological principals:
    • (a) the activation of endocytotic-like mechanisms in which cultured Aplysia neurons are induced to actively engulf gold mushroom-shaped microelectrodes (gMμE) that protrude from a flat substrate,
    • (b) the generation of high Rseal between the cell’s membrane and the engulfed gMμE, and
    • (c) the increased junctional membrane conductance.
  • Functionalized the Au mushrooms with an RGD-based peptide
    • RGD is an extracellular matrix binding site on fibronectin, which mediates it's interaction with integrin, a cell surface receptor; it is thought that other elements of fibronectin regulate specificity with its receptor. PMID-2418980

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ref: -0 tags: vertical nanowire juxtacellular recording date: 02-01-2017 00:50 gmt revision:2 [1] [0] [head]

PMID-22231664 Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits.

  • Note actual coupling is low, 0.002, compared to patch-clamp (400uV vs 200mV). Signal is rather noisy.
  • Dissociated cultures of rat cortical neurons
  • Stimulation current 200 pa enough to change membrane potential, but not initiate a spike.
    • This is 200e-12 / 20e-6 = 5 orders of magnitude lower current than typical ICMS.

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ref: -0 tags: direct electrical stimulation neural mapping review date: 01-26-2017 02:28 gmt revision:0 [head]

PMID-22127300 Direct electrical stimulation of human cortex -- the gold standard for mapping brain functions?

  • Fairly straightforward review, shows the strengths and weaknesses / caveats of cortical surface stimulation.
  • Axon initial segment and nodes of Ranvier (which has a high concentration of Na channels) are the most excitable.
  • Stimulation of a site in the LGN of the thalamus increased the BOLD signal in the regions of V1 that received input from that site, but strongly suppressed it in the retinotopicaly matched regions of extrastriate cortex.
  • To test the hypothesis that the deactivation of extrastriate cortex might be due to synaptic inhibition of V1 projection neurons, GABA antagonists were microinjected into V1 in monkeys in experiments that combined fMRI, ephys, and microstim.
    • Ref 25. PMID-20818384
    • These findings suggest that the stimulation of cortical neurons disrupts the propagation of cortico-cortico signals after the first synapse.
    • Likely due to feedforward and recurrent inhibition.
  • Revisit the hypothesis of tight control of excitation and inhibition (e.g. in-vivo patch clamping + drugs). "The interactions between excitation and inhibition within cortical microcircuits as well as between inter-regional connections haper the predicability of stimulation."
  • The average size of a fMRI voxel:
    • 55ul, 55mm^2
    • 5.5e6 neurons,
    • 22 - 55e9 billion synapses,
    • 22km dendrites (??)
    • 220km axons.
  • In the 1970s, Daniel Pollen conducted a series of studies stimulating the visual cortex of cats and humans.
    • Observed long intra-stim responses, and post-stim afterdischarges.
    • Importantly, he also observed inhibitory effects of DES on cortical responses at the stimulation site.
      • The inhibitory effect depended on the state of the neuron before stimulation.
      • High spontaneous activity + low stim strengths = inhibition;
      • low spontaneous activity + high stim strengths = excitation.
  • In the author's opinion, there is an equal or greater number of inhibitory responses to electrical microstimulation as excitatory. Only, there is a reporting bias toward the positive.
  • Many locations for paresthesias:
    • postcentral sulcus (duh)
    • opercular area inferior postcentral gyrus (e.g. superior to and facing the temporal lobe)[60]
    • posterior cingulate gyrus
    • supramarginal gyrus
    • temporal lobe, limbic and isocortical structures.

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ref: -0 tags: Kleinfeld vasculature cortex review ischemia perfusion date: 01-22-2017 19:40 gmt revision:3 [2] [1] [0] [head]

PMID-25705966 Robust and fragile aspects of cortical blood flow in relation to the underlying angioarchitecture.

  • "The penetrating arterioles that connect the pial network to the subsurface network are bottlenecks to flow; occlusion of even a single penetrating arteriole results in the death of a 500 μm diameter cylinder of cortical tissue despite the potential for collateral flow through microvessels."
  • The pioneering work of Fox and Raichle [7] suggest that there is simply not enough blood to go around if all areas of the cortex were activated at once.
  • There is strong if only partially understood coupling between neuronal and vascular dysfunction [15]. In particular, vascular disease leads to neurological decline and diminished cognition and memory [16].
  • A single microliter of cortex holds nearly one meter of total vasculature length wow! PMID-23749145
  • Subsurface micro vasculature (not arterioles or venules) is relatively robust to occlusion; figure 4.

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ref: Bartels-2008.09 tags: neurotrophic kennedy speech FM transmitter wireless Georga recording electrophysiology electrode date: 01-19-2017 02:18 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-18672003[0] Neurotrophic electrode: method of assembly and implantation into human motor speech cortex.

  • Glass electrode with 3-4 2mil Teflon insulated Au wires within it to record spiking.
  • Induce neurites (e.g. dendrites, axons, blood vessels, oligodendrocytes) to grow up into it using autologous sciatic nerve, and stay for the lifetime of the patient (Kennedy 1989) [1].
    • Histology has revealed axons, but not neurons, within the tissue inside the tip. (Kennedy 1989, 1992a.)
    • No glia in rat and monkey tests; PMID-1421115
    • Inserted 5-6mm into the cortex at an angle of 45 deg. far!?
  • Bipolar amplification on pairs of the Au wires.
  • patients damaged their electrodes due to spasms; same for monkeys, presumably. Seems the electronice and gold wires are also highly fragile. I'm quite familiar with this.
  • Includes a sine wave source for calibration. good idea!
  • Inductively powered @ 1Mhz.
  • FM modulation at 39.2Mz and 43.9Mhz. COTS?
    • The implantable electronics are bulky as can be seen in Figs. 14 and ​and 19. (what a mess?!)
  • 3 patients, 4 years in 2 patients that dies from unrelated causes, over 3 years in a third.
  • describe construction of electrode -- not complicated.

____References____

[0] Bartels J, Andreasen D, Ehirim P, Mao H, Seibert S, Wright EJ, Kennedy P, Neurotrophic electrode: method of assembly and implantation into human motor speech cortex.J Neurosci Methods 174:2, 168-76 (2008 Sep 30)
[1] Kennedy PR, The cone electrode: a long-term electrode that records from neurites grown onto its recording surface.J Neurosci Methods 29:3, 181-93 (1989 Sep)

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ref: -0 tags: neural coding rats binary permutation retrosplenial basolateral amygdala tetrode date: 12-19-2016 07:39 gmt revision:1 [0] [head]

PMID-27895562 Brain Computation Is Organized via Power-of-Two-Based Permutation Logic.

  • Nice and interesting data, sort of kitchen sink of experiments but ...
  • At first blush it seems they have re-discovered Haar wavelets / the utility of binary decompositions.
  • Figures 9 and 10, however, suggest a discriminable difference in representation in layers 2/3 and 5/6, supporting their binary hypothesis.
    • The former targeted the mouse's large retrosplenial cortex; the latter, the hamster's prelimbic cortex.

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ref: -0 tags: L1 cell adhesion neural implants microglia DRG spinal cord dorsal root inflammation date: 11-19-2016 22:55 gmt revision:1 [0] [head]

PMID-22750248 In vivo effects of L1 coating on inflammation and neuronal health at the electrode-tissue interface in rat spinal cord and dorsal root ganglion.

  • Kolarcik CL1, Bourbeau D, Azemi E, Rost E, Zhang L, Lagenaur CF, Weber DJ, Cui XT.
  • Quote: With L1, neurofilament staining was significantly increased while neuronal cell death decreased.
  • These results indicate that L1-modified electrodes may result in an improved chronic neural interface and will be evaluated in recording and stimulation studies.
  • Ok, so this CAM seems to mitigate against microglia / inflammation, but how was it selected vs any of the other CAMs and surface proteins? (This domain is almost completely unknown by me..)
  • Ultimate strategy likely to be a broad combination of mechanical (size, flexibility), biochemical (inflammation, cell migration), electrochamical (surface coatings) and vasculature-avoiding approaches.

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ref: -0 tags: china trustwothiness social engineering communism date: 10-31-2016 05:42 gmt revision:1 [0] [head]

China 'social credit': Beijing sets up huge system

So long as it purports to measure just one social variable -- 'trustworthiness' -- it might be a good idea. Many commerce websites (.. ebay ..) have these sort of rating systems already, and they are useful. When humans live in smaller communities something like this is in the shared consciousness.

Peering into everyone's purchasing habits and hobbies, however, seems like it will be grossly myopic and, as the article says, Orwellian. Likely they will train a deep-belief network on past data of weakly and communist party defined success, with all purchasing and social media as the input data, and use that in the proprietary algorithm for giving people their scalars to optimize. This would be the ultimate party control tool -- a great new handle for controlling people's minds, even 'better' than capitalism.

Surprising that the article only hints at this, and that the Chinese themselves seem rather clueless that it's a power play. In this sense, it's a very clever play to link it to reproduction.


Other comments:

These sorts of systems may be necessary in highly populated countries, where freedom and individuality are less valued and social cohesion is requisite.

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ref: -0 tags: PEDOT electropolymerization electroplating gold TFB borate counterion acetonitrile date: 10-18-2016 07:49 gmt revision:3 [2] [1] [0] [head]

Electrochemical and Optical Properties of the Poly(3,4-ethylenedioxythiophene) Film Electropolymerized in an Aqueous Sodium Dodecyl Sulfate and Lithium Tetrafluoroborate Medium

  • EDOT has a higher oxidation potential than water, which makes polymers electropolymerized from water "poorly defined".
  • Addition of SDS lowers the oxidation potential to 0.76V, below that of EDOT in acetonitrile at 1.1V.
  • " The potential was first switched from open circuit potential to 0.5 V for 100 s before polarizing the electrode to the desired potential. This initial step was to allow double-layer charging of the Au electrode|solution interface, which minimizes the distortion of the polymerization current transient by double-layer capacitance charging.17,18 "
    • Huh, interesting.
  • Plated at 0.82 - 0.84V, 0.03M EDOT conc.
  • 0.1M LiBF4 anion / electrolyte; 0.07M SDS sufactant.
    • This SDS is incorporated into the film, and affects redox reactions as shown in the cyclic voltammagram (fig 4)
      • Doping level 0.36
    • BF4-, in comparison, can be driven out of the film.

Improvement of the Electrosynthesis and Physicochemical Properties of Poly(3,4-ethylenedioxythiophene) Using a Sodium Dodecyl Sulfate Micellar Aqueous Medium

  • "The oxidation potential of thiopene = 1.8V; water = 1.23V.
  • Claim: "The polymer films prepared in micellar medium [SDS] are more stable than those obtained in organic solution as demonstrated by the fact that, when submitted to a great number of redox cycles (n ≈ 50), there is no significant loss of their electroactivity (<10%). These electrochemical properties are accompanied by color changes of the film which turns from blue-black to red-purple upon reduction."
  • Estimate that there is about 21% DS- anions in the PEDOT - SDS films.
    • Cl - was at ~ 7%.
  • I'm still not sure about incorporating soap into the electroplating solution.. !

Electrochemical Synthesis of Poly(3,4-ethylenedioxythiophene) on Steel Electrodes: Properties and Characterization

  • 0.01M EDOT and 0.1M LiClO4 in acetonitrile.
  • Claim excellent adhesion & film properties to 316 SS.
  • Oxidation / electrodeposition at 1.20V; voltages higher than 1.7V resulted in flaky films.

PMID-20715789 Investigation of near ohmic behavior for poly(3,4-ethylenedioxythiophene): a model consistent with systematic variations in polymerization conditions.

  • Again use acetonitrile.
  • 1.3V vs Ag/AgCl electrode.
  • Perchlorate and tetraflouroborate both seemed the best counterions (figure 4).
  • Figure 5: Film was difficult to remove from surface.
    • They did use a polycrystaline Au layer:
    • "The plating process was allowed to run for 1 min (until approximately 100 mC had passed) at a constant potential of 0.3 V versus Ag/AgCl in 50 mM HAuCl4 prepared in 0.1 M NaCl."
  • Claim that the counterions are trapped; not in agreement with the SDS study above.
  • "Conditions for the consistent production of conducting polymer films employing potentiostatic deposition at 1.3 V for 60-90 s have been determined. The optimal concentration of the monomer is 0.0125 M, and that of the counterion is 0.05 M. "

PMID-24576579 '''Improving the performance of poly(3,4-ethylenedioxythiophene) for brain–machine interface applications"

  • Show that TFB (BF4-) is a suitable counterion for EDOT electropolymerization.
  • Comparison is between PEDOT:TFB deposited in an anhydrous acetronitrile solution, and PEDOT:PSS deposited in an aqueous solution.
    • Presumably the PSS brings the EDOT into solution (??).
  • figure 3 is compelling, but long-term, electrodes are not that much better than Au!
    • Maybe we should just palate with that.

PEDOT-modified integrated microelectrodes for the detection of ascorbic acid, dopamine and uric acid

  • Direct comparison of acetonitrile and water solvents for electropolymerization of EDOT.
  • "PEDOT adhesion is best on gold surface due to the strong interactions between gold and sulphur atoms.
  • images/1353_2.pdf
    • Au plating is essential!

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ref: -0 tags: David Kleinfeld penetrating arterioles perfusion cortex vasculature date: 10-17-2016 23:24 gmt revision:1 [0] [head]

PMID-17190804 Penetrating arterioles are a bottleneck in the perfusion of neocortex.

  • Focal photothrombosis was used to occlude single penetrating arterioles in rat parietal cortex, and the resultant changes in flow of red blood cells were measured with two-photon laser-scanning microscopy in individual subsurface microvessels that surround the occlusion.
  • We observed that the average flow of red blood cells nearly stalls adjacent to the occlusion and remains within 30% of its baseline value in vessels as far as 10 branch points downstream from the occlusion.
  • Preservation of average flow emerges 350 mum away; this length scale is consistent with the spatial distribution of penetrating arterioles
  • Rose bengal photosensitizer.
  • 2p laser scanning microscopy.
  • Downstream and connected arterioles show a dramatic reduction in blood flow, even 1-4 branches in; there is little reduncancy (figure 2)
  • Measured a good number of vessels (and look at their density!); results are satisfactorily quantitative.
  • Vessel leakiness extends up to 1.1mm away (!) (figure 5).

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ref: -0 tags: gold micrograin recording electrodes electroplating impedance date: 10-17-2016 20:28 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-23071004 Gold nanograin microelectrodes for neuroelectronic interfaces.

  • We report a single-cell sized microelectrode, which has unique gold nanograin structures, using a simple electrochemical deposition method.
  • Fabricated microelectrode had a sunflower shape with 1-5 (um of micropetals along the circumference of the microelectrode and 500 nm nanograins at the center.
  • The nanograin electrodes had 69-fold decrease of impedance and 10-fold increase in electrical stimulation capability compared to unmodified flat gold microelectrodes.
  • images/1270_1.pdf pdf
  • The deposition was conducted with an aqueous solution containing 25 mM HAuCl (HAuCl · 3H O, Sigma-Aldrich, MO, 4 4 2USA) and 20 g/L polyvinylpyrrolidone (surfactant, stabilizing agent)

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ref: -0 tags: Charles Lieber syringe-injectable electronics SU-8 chronic flexible date: 10-14-2016 23:30 gmt revision:1 [0] [head]

PMID-27571550 Stable long-term chronic brain mapping at the single-neuron level.

  • Fu TM, Hong G1, Zhou T1, Schuhmann TG, Viveros RD2, Lieber CM.
  • 8 months with only 800nm of Su-8 (400nm of insulation!!). This is both surprising and very impressive; we have to step up our game!
  • In a mouse, too - their surgical technique must be very good. Mice only live ~ 2 years anyway.
  • Figure 3 -- stability -- incredible.
  • Recording sites were bare platinum, 20um diameter; stimulation sites were also bare Pt, 150um dia.
    • No plating or mircowire-fets, so far as I can see; electrode impedances were stable at 200 - 600k (supplementary figure 12).

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ref: -0 tags: ultrasonic BMI monkey LFP intan nordic Ozturk UCSD date: 09-30-2016 19:38 gmt revision:2 [1] [0] [head]

A Wireless 32-Channel Implantable Bidirectional Brain Machine Interface

  • Yi Su 1,2,*, Sudhamayee Routhu 2, Kee S. Moon 3, Sung Q. Lee 4, WooSub Youm 4 and Yusuf Ozturk 2,
  • Only LFP from a utah array, but solid work none-the-less.
  • 20V unipolar stimulation.
    • Through separate recording and stimulation electrodes.
  • 35mm x 10mm.
  • LFP due to limited bandwidth.
    • Less RF bw & compression that the wireless system I designed 6 years ago.
    • Reason: "Further, in order to analyze the integrative synaptic processes, LFP is the signal of interest instead of spikes, because synaptic processes cannot be captured by spike activity of a small number of neurons"
captured by spike activity of a small number of neurons.
  • Reference use of DuraGen followed by silicone elastomer.
  • Didn't cite us.

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ref: -0 tags: bone regrowth hyperelastic 3d print implant hydroxyapatite polycaptolactone date: 09-30-2016 18:27 gmt revision:0 [head]

Hyperelastic “bone”: A highly versatile, growth factor–free, osteoregenerative, scalable, and surgically friendly biomaterial

  • (From the abstract): hyperelastic “bone” is composed of 90 weight % (wt %) hydroxyapatite and 10 wt % polycaprolactone or poly(lactic-co-glycolic acid),
  • Can be rapidly three-dimensionally (3D) printed (up to 275 cm3/hour) from room temperature extruded liquid inks.
  • Mechanical properties: ~32 to 67% strain to failure, ~4 to 11 MPa elastic modulus & was highly absorbent (50% material porosity)
  • Supported cell viability and proliferation, and induced osteogenic differentiation of bone marrow–derived human mesenchymal stem cells cultured in vitro over 4 weeks without any osteo-inducing factors in the medium.
  • HB did not elicit a negative immune response, became vascularized, quickly integrated with surrounding tissues, and rapidly ossified and supported new bone growth without the need for added biological factors.

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ref: -0 tags: David Kleinfeld cortical vasculature laser surgery network occlusion flow date: 09-23-2016 06:35 gmt revision:1 [0] [head]

Heller Lecture - Prof. David Kleinfeld

  • Also mentions the use of LIBS + q-switched laser for precisely drilling holes in the scull. Seems to work!
    • Use 20ns delay .. seems like there is still spectral broadening.
    • "Turn neuroscience into an industrial process, not an art form" After doing many surgeries, agreed!
  • Vasodiliation & vasoconstriction is very highly regulated; there is not enough blood to go around.
    • Vessels distant from a energetic / stimulated site will (net) constrict.
  • Vascular network is most entirely closed-loop, and not tree-like at all -- you can occlude one artery, or one capillary, and the network will route around the occlusion.
    • The density of the angio-architecture in the brain is unique in this.
  • Tested micro-occlusions by injecting rose bengal, which releases free radicals on light exposure (532nm, 0.5mw), causing coagulation.
  • "Blood flow on the surface arteriole network is insensitive to single occlusions"
  • Penetrating arterioles and venules are largely stubs -- single unbranching vessels, which again renders some immunity to blockage.
  • However! Occlusion of a penetrating arteriole retards flow within a 400 - 600um cylinder (larger than a cortical column!)
  • Occulsion of many penetrating vessels, unsurprisingly, leads to large swaths of dead cortex, "UBOS" in MRI parlance (unidentified bright objects).
  • Death and depolarizing depression can be effectively prevented by excitotoxicity inhibitors -- MK801 in the slides (NMDA blocker, systemically)

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ref: -0 tags: laser induced breakdown spectroscopy for surgery tissue differentiation date: 09-22-2016 19:26 gmt revision:0 [head]

PMID-25426327 Laser induced breakdown spectroscopy for bone and cartilage differentiation - ex vivo study as a prospect for a laser surgery feedback mechanism.

  • Mehari F1, Rohde M2, Knipfer C2, Kanawade R1, Klämpfl F1, Adler W3, Stelzle F4, Schmidt M1.
  • Tested on pig ear cartilage & cortical bone.
  • 532nm, Q-switched, flashlamp-pumped Nd:YAG, 80mJ pulse energy, 10ns, 1Hz.
  • Commercial spectrogram; light collected with 50um fiber optic connector.
    • We could probably put this in line with the laser mirrors, probably..
  • Super clean results: see any of the figures.
    • AUC = 1.00 !!

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ref: -0 tags: super resolution imaging PALM STORM fluorescence date: 09-21-2016 05:57 gmt revision:0 [head]

PMID-23900251 Parallel super-resolution imaging

  • Christopher J Rowlands, Elijah Y S Yew, and Peter T C So
  • Though this is a brief Nature intro article, I found it to be more usefully clear than the wikipedia articles on super-resolution techniques.
  • STORM and PALM seek to stochastically switch fluorophores between emission and dark states, and are parallel but stochastic; STED and RESOLFT use high-intensity donut beams to stimulate emission (STED) or photobleach (RESOLFT) fluorophores outside of an arbitrarily-small location.
    • All need gaussian-fitting to estimate emitter location from the point-spread function.
  • This article comments on a clever way of making 1e5 donuts for parallel (as opposed to rastered) STED / RESOLFT.
  • I doubt stetting up a STED microscope is at all easy; to get these resolutions, everything must be still to a few nm!

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ref: -0 tags: nucleus accumbens caudate stimulation learning enhancement MIT date: 09-20-2016 23:51 gmt revision:1 [0] [head]

Temporally Coordinated Deep Brain Stimulation in the Dorsal and Ventral Striatum Synergistically Enhances Associative Learning

  • Monkeys had to learn to associate an image with one of 4 reward targets.
    • Fixation period, movement period, reward period -- more or less standard task.
    • Blocked trial structure with randomized associations + control novel images + control familiar images.
  • Timed stimulation:
    • Nucleus Accumbens during fixation period
      • Shell not core; non-hedonic in separate test.
    • Caudate (which part -- targeting?) during feedback on correct trials.
  • Performance on stimulated images improved in reaction time, learning rate, and ultimate % correct.
  • Small non-significant improvement in non-stimulated novel image.
  • Wonder how many stim protocols they had to try to get this correct?

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ref: -0 tags: image registration optimization camera calibration sewing machine date: 07-15-2016 05:04 gmt revision:20 [19] [18] [17] [16] [15] [14] [head]

Recently I was tasked with converting from image coordinates to real world coordinates from stereoscopic cameras mounted to the end-effector of a robot. The end goal was to let the user (me!) click on points in the image, and have the robot record that position & ultimately move to it.

The overall strategy is to get a set of points in both image and RW coordinates, then fit some sort of model to the measured data. I began by printing out a grid of (hopefully evenly-spaced and perpendicular) lines via a laserprinter; spacing was ~1.1 mm. This grid was manually aligned to the axes of robot motion by moving the robot along one axis & checking that the lines did not jog.

The images were modeled as a grating with quadratic phase in u,vu,v texture coordinates:

p h(u,v)=sin((a hu/1000+b hv/1000+c h)v+d hu+e hv+f h)+0.97 p_h(u,v) = sin((a_h u/1000 + b_h v/1000 + c_h)v + d_h u + e_h v + f_h) + 0.97 (1)

p v(u,v)=sin((a vu/1000+b vv/1000+c v)u+d vu+e vv+f v)+0.97 p_v(u,v) = sin((a_v u/1000 + b_v v/1000 + c_v)u + d_v u + e_v v + f_v) + 0.97 (2)

I(u,v)=16p hp v/(2+16p h 2+16p v 2) I(u,v) = 16 p_h p_v / ( \sqrt{ 2 + 16 p_h^2 + 16 p_v^2}) (3)

The 1000 was used to make the parameter search distribution more spherical; c h,c vc_h,c_v were bias terms to seed the solver; 0.97 was a duty-cycle term fit by inspection to the image data; (3) is a modified sigmoid.

I I was then optimized over the parameters using a GPU-accelerated (CUDA) nonlinear stochastic optimization:

(a h,b h,d h,e h,f h|a v,b v,d v,e v,f v)=Argmin u v(I(u,v)Img(u,v)) 2 (a_h,b_h,d_h,e_h,f_h | a_v,b_v,d_v,e_v,f_v) = Argmin \sum_u \sum_v (I(u,v) - Img(u,v))^2 (4)

Optimization was carried out by drawing parameters from a normal distribution with a diagonal covariance matrix, set by inspection, and mean iteratively set to the best solution; horizontal and vertical optimization steps were separable and carried out independently. The equation (4) was sampled 18k times, and equation (3) 34 billion times per frame. Hence the need for GPU acceleration.

This yielded a set of 10 parameters (again, c hc_h and c vc_v were bias terms and kept constant) which modeled the data (e.g. grid lines) for each of the two cameras. This process was repeated every 0.1 mm from 0 - 20 mm height (z) from the target grid, resulting in a sampled function for each of the parameters, e.g. a h(z)a_h(z) . This required 13 trillion evaluations of equation (3).

Now, the task was to use this model to generate the forward and reverse transform from image to world coordinates; I approached this by generating a data set of the grid intersections in both image and world coordinates. To start this process, the known image origin u origin| z=0,v origin| z=0u_{origin}|_{z=0},v_{origin}|_{z=0} was used to find the corresponding roots of the periodic axillary functions p h,p vp_h,p_v :

3π2+2πn h=a huv/1000+b hv 2/1000+(c h+e h)v+d hu+f h \frac{3 \pi}{ 2} + 2 \pi n_h = a_h u v/1000 + b_h v^2/1000 + (c_h + e_h)v + d_h u + f_h (5)

3π2+2πn h=a vu 2/1000+b vuv/1000+(c v+d v)u+e vv+f v \frac{3 \pi}{ 2} + 2 \pi n_h = a_v u^2/1000 + b_v u v/1000 + (c_v + d_v)u + e_v v + f_v (6)

Or ..

n h=round((a huv/1000+b hv 2/1000+(c h+e h)v+d hu+f h3π2)/(2π) n_h = round( (a_h u v/1000 + b_h v^2/1000 + (c_h + e_h)v + d_h u + f_h - \frac{3 \pi}{ 2} ) / (2 \pi ) (7)

n v=round((a vu 2/1000+b vuv/1000+(c v+d v)u+e vv+f v3π2)/(2π) n_v = round( (a_v u^2/1000 + b_v u v/1000 + (c_v + d_v)u + e_v v + f_v - \frac{3 \pi}{ 2} ) / (2 \pi) (8)

From this, we get variables n h,origin| z=0andn v,origin| z=0n_{h,origin}|_{z=0} and n_{v,origin}|_{z=0} which are the offsets to align the sine functions p h,p vp_h,p_v with the physical origin. Now, the reverse (world to image) transform was needed, for which a two-stage newton scheme was used to solve equations (7) and (8) for u,vu,v . Note that this is an equation of phase, not image intensity -- otherwise this direct method would not work!

First, the equations were linearized with three steps of (9-11) to get in the right ballpark:

u 0=640,v 0=360 u_0 = 640, v_0 = 360

n h=n h,origin| z+[30..30],n v=n v,origin| z+[20..20] n_h = n_{h,origin}|_{z} + [-30 .. 30] , n_v = n_{v,origin}|_{z} + [-20 .. 20] (9)

B i=[3π2+2πn ha hu iv i/1000b hv i 2f h 3π2+2πn va vu i 2/1000b vu iv if v] B_i = {\left[ \begin{matrix} \frac{3 \pi}{ 2} + 2 \pi n_h - a_h u_i v_i / 1000 - b_h v_i^2 - f_h \\ \frac{3 \pi}{ 2} + 2 \pi n_v - a_v u_i^2 / 1000 - b_v u_i v_i - f_v \end{matrix} \right]} (10)

A i=[d h c h+e h c v+d v e v] A_i = {\left[ \begin{matrix} d_h && c_h + e_h \\ c_v + d_v && e_v \end{matrix} \right]} and

[u i+1 v i+1]=mldivide(A i,B i) {\left[ \begin{matrix} u_{i+1} \\ v_{i+1} \end{matrix} \right]} = mldivide(A_i,B_i) (11) where mldivide is the Matlab operator.

Then three steps with the full Jacobian were made to attain accuracy:

J i=[a hv i/1000+d h a hu i/1000+2b hv i/1000+c h+e h 2a vu i/1000+b vv i/1000+c v+d v b vu i/1000+e v] J_i = {\left[ \begin{matrix} a_h v_i / 1000 + d_h && a_h u_i / 1000 + 2 b_h v_i / 1000 + c_h + e_h \\ 2 a_v u_i / 1000 + b_v v_i / 1000 + c_v + d_v && b_v u_i / 1000 + e_v \end{matrix} \right]} (12)

K i=[a hu iv i/1000+b hv i 2/1000+(c h+e h)v i+d hu i+f h3π22πn h a vu i 2/1000+b vu iv i/1000+(c v+d v)u i+e vv+f v3π22πn v] K_i = {\left[ \begin{matrix} a_h u_i v_i/1000 + b_h v_i^2/1000 + (c_h+e_h) v_i + d_h u_i + f_h - \frac{3 \pi}{ 2} - 2 \pi n_h \\ a_v u_i^2/1000 + b_v u_i v_i/1000 + (c_v+d_v) u_i + e_v v + f_v - \frac{3 \pi}{ 2} - 2 \pi n_v \end{matrix} \right]} (13)

[u i+1 v i+1]=[u i v i]J i 1K i {\left[ \begin{matrix} u_{i+1} \\ v_{i+1} \end{matrix} \right]} = {\left[ \begin{matrix} u_i \\ v_i \end{matrix} \right]} - J^{-1}_i K_i (14)

Solutions (u,v)(u,v) were verified by plugging back into equations (7) and (8) & verifying n h,n vn_h, n_v were the same. Inconsistent solutions were discarded; solutions outside the image space [0,1280),[0,720)[0, 1280),[0, 720) were also discarded. The process (10) - (14) was repeated to tile the image space with gird intersections, as indicated in (9), and this was repeated for all zz in (0..0.1..20)(0 .. 0.1 .. 20) , resulting in a large (74k points) dataset of (u,v,n h,n v,z)(u,v,n_h,n_v,z) , which was converted to full real-world coordinates based on the measured spacing of the grid lines, (u,v,x,y,z)(u,v,x,y,z) . Between individual z steps, n h,originn v,originn_{h,origin} n_{v,origin} was re-estimated to minimize (for a current zz' ):

(u origin| z+0.1u origin| z+0.1) 2+(v origin| z+0.1+v origin| z) 2 (u_{origin}|_{z' + 0.1} - u_{origin}|_{z' + 0.1})^2 + (v_{origin}|_{z' + 0.1} + v_{origin}|_{z'})^2 (15)

with grid-search, and the method of equations (9-14). This was required as the stochastic method used to find original image model parameters was agnostic to phase, and so phase (via parameter f f_{-} ) could jump between individual zz measurements (the origin did not move much between successive measurements, hence (15) fixed the jumps.)

To this dataset, a model was fit:

[u v]=A[1 x y z x 2 y 2 z 2 w 2 xy xz yz xw yw zw] {\left[ \begin{matrix} u \\ v \end{matrix} \right]} = A {\left[ \begin{matrix} 1 && x && y && z && x'^2 && y'^2 && \prime z'^2 && w^2 && x' y' && x' z' && y' z' && x' w && y' w && z' w \end{matrix} \right]} (16)

Where x=x10x' = \frac{x}{ 10} , y=y10y' = \frac{y}{ 10} , z=z10z' = \frac{z}{ 10} , and w=2020zw = \frac{ 20}{20 - z} . ww was introduced as an axillary variable to assist in perspective mapping, ala computer graphics. Likewise, x,y,zx,y,z were scaled so the quadratic nonlinearity better matched the data.

The model (16) was fit using regular linear regression over all rows of the validated dataset. This resulted in a second set of coefficients AA for a model of world coordinates to image coordinates; again, the model was inverted using Newton's method (Jacobian omitted here!). These coefficients, one set per camera, were then integrated into the C++ program for displaying video, and the inverse mapping (using closed-form matrix inversion) was used to convert mouse clicks to real-world coordinates for robot motor control. Even with the relatively poor wide-FOV cameras employed, the method is accurate to ±50μm\pm 50\mu m , and precise to ±120μm \pm 120\mu m .

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ref: -2016 tags: 6-OHDA parkinsons model warren grill simulation date: 05-10-2016 23:30 gmt revision:4 [3] [2] [1] [0] [head]

PMID-26867734 A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson’s disease

  • Kumaravelu K1, Brocker DT1, Grill WM
  • Background: Although animal models (6-OHDA rats, MPTP mk) are rendered parkinsonian by a common mechanism (loss of dopaminergic neurons), there is considerable variation in the neuronal activity underlying the pathophysiology, including differences in firing rates, firing patterns, responses to cortical stimulation, and neuronal synchronization across different basal ganglia (BG) structures (Kita and Kita 2011;Nambu et al. 2000).
    • Yep. Highly idiopathic disease.
    • Claim there are good models of the MPTP monkey:
      • PMID-20309620 Modeling shifts in the rate and pattern of subthalamopallidal network activity during deep brain stimulation.
      • PMID-22805068 Network effects of subthalamic deep brain stimulation drive a unique mixture of responses in basal ganglia output.
  • Biophysical model of the cortex - basal ganglia - thalamus circuit
    • Hodgkin-Huxley type.
      • Single compartment neurons.
    • Validated by comparing responses of the BG to CTX stimulation.
    • Details, should they be important:
      • Each rCortex (regularly spiking) neuron
        • excitatory input from one TH neuron
        • inhibitory input from four randomly selected iCortex neurons.
        • Izhikevich model.
      • Each iCortex (fast inhibitory) neuron
        • excitatory input from four randomly selected rCortex neurons.
      • Each dStr (direct, D1/D5, ex) neuron
        • excitatory input from one rCortex neuron
        • inhibitory axonal collaterals from three randomly selected dStr neurons.
      • Each idStr (indirect, D2, inhib) neuron
        • excitatory input from one rCortex neuron
        • inhibitory axonal collaterals from four randomly selected idStr neurons.
      • Each STN neuron
        • inhibitory input from two GPe neurons
        • excitatory input from two rCortex neurons.
        • DBS modeled as a somatic current.
      • Each GPe neuron
        • inhibitory axonal collaterals from any two other GPe neurons
        • inhibitory input from all idStr neurons.
      • Each GPi neuron
        • inhibitory input from two GPe neurons
        • inhibitory input from all dStr neurons.
      • Some GPe/GPi neurons receive
        • excitatory input from two STN neurons,
        • while others do not.
      • Each TH neuron receives inhibitory input from one GPi neuron.
  • Diseased state:
    • Loss of striatal dopamine is accompanied by an increase in acetylcholine levels (Ach) in the Str (Ikarashi et al. 1997)
      • This results in a reduction of M-type potassium current in both the direct and indirect MSNs. (2.6 -> 1.5)
    • Dopamine loss results in reduced sensitivity of direct Str MSN to cortical stimulation (Mallet et al. 2006)
      • corticostriatal synaptic conductance from 0.07 to 0.026
    • Striatal dopamine depletion causes an increase in the synaptic strength of intra-GPe axonal collaterals resulting in aberrant GPe firing (Miguelez et al. 2012)
      • Increase from 0.125 to 0.5.
  • Good match to experimental rats:
  • Ok, so this is a complicated model (they aim to be the most complete to-date). How sensitive is it to parameter perturbations?
    • Noticeable ~20 Hz oscillations in BG in PD condition
    • ~9 Hz in STN & GPi.
  • And how well do the firing rates match experiment?
    • Not very. Look at the error bars.
  • What does DBS (direct current injection into STN neurons) do?
    • Se d,e,f: stochastic parameter; g,h,i: (semi) stochastic wiring.
  • Another check: NMDA antagonist into STN suppressed STN beta band oscillations in 6-OHDA lesioned rats (Pan et al. 2014).
    • Analysis of model GPi neurons revealed that episodes of beta band oscillatory activity interrupted alpha oscillatory activity in the PD state (Fig. 9a, b), consistent with experimental evidence that episodes of tremor-related oscillations desynchronized beta activity in PD patients (Levy et al. 2002).
  • What does DBS, at variable frequencies, do oscillations in the circuit?
  • How might this underly a mechanism of action?

Overall, not a bad paper. Not very well organized, which is not assisted by the large amount of information presented, but having slogged through the figures, I'm somewhat convinced that the model is good. This despite my general reservations of these models: the true validation would be to have it generate actual behavior (and learning)!

Lacking this, the approximations employed seem like a step forward in understanding how PD and DBS work. The results and discussion are consistent with {1255}, but not {711}, which found that STN projections from M1 (not the modulation of M1 projections to GPi, via efferents from STN) truly matter.

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ref: -2012 tags: Emo Todorov contact invariant animation optimization complex motor behavior date: 05-04-2016 17:34 gmt revision:3 [2] [1] [0] [head]

* Watch the [http://homes.cs.washington.edu/~todorov/index.php?video=MordatchSIGGRAPH12&paper=Mordatch,%20SIGGRAPH%202012 movies! Discovery of complex behaviors through contact-invariant optimization]

  • Complex movements tend to have phases within which the set of active contacts (hands, feet) remains invariant (hence can exert forces on the objects they are contacting, or vice versa).
  • Discovering suitable contact sets is the central goal of optimization in our approach.
    • Once this is done, optimizing the remaining aspects of the movement tends to be relatively straightforward.
    • They do this through axillary scalar variables which indicate whether the a contact is active or not, hence whether to enable contact forces.
      • Allows the optimizer to 'realize' that movements should have phases.
      • Also "shapes the energy landscape to be smoother and better behaved"
  • Initial attempts to make these contact axillary variables discrete -- when and where -- which was easy for humans to specify, but made optimization intractable.
    • Motion between contacts was modeled as a continuous feedback system.
  • Instead, the contact variables c ic_i have to be continuous.
  • Contact forces are active only when c ic_i is 'large'.
    • Hence all potential contacts have to be enumerated in advance.
  • Then, parameterize the end effector (position) and use inverse kinematics to figure out joint angles.
  • Optimization:
    • Break the movement up into a predefined number of phases, equal duration.
    • Interpolate end-effector with splines
    • Physics constraints are 'soft' -- helps the optimizer : 'powerful continuation methods'
      • That is, weight different terms differently in phases of the optimization process.
      • Likewise, appendages are allowed to stretch and intersect, with a smooth cost.
    • Contact-invariant cost penalizes distortion and slip (difference between endpoint and surface, measured normal, and velocity relative to contact point)
      • Contact point is also 'soft' and smooth via distance-normalized weighting.
    • All contact forces are merged into a f 6f \in \mathbb{R}^6 vector, which includes both forces and torques. Hence contact force origin can move within the contact patch, which again makes the optimization smoother.
    • Set τ(q,q˙,q¨)=J(q) Tf+Bu\tau(q, \dot{q}, \ddot{q}) = J(q)^T f + B u where J(q) T J(q)^T maps generalize (endpoint) velocities to contact-point velocities, and f above are the contact-forces. BB is to map control forces uu to the full space.
    • τ(q,q˙,q¨)=M(q)q˙+C(q,q˙)q˙+G(q)\tau(q, \dot{q}, \ddot{q}) = M(q)\dot{q} + C(q, \dot{q})\dot{q} + G(q) -- M is inertia matrix, C is Coriolis matrix, g is gravity.
      • This means: forces need to add to zero. (friction ff + control uu = inertia + coriolis + gravity)
    • Hence need to optimize ff and uu .
      • Use friction-cone approximation for non-grab (feet) contact forces.
    • These are optimized within a quadratic programming framework.
      • LBFGS algo.
      • Squared terms for friction and control, squared penalization for penetrating and slipping on a surface.
    • Phases of optimization (continuation method):
      • L(s)=L CI(s)+L physics(s)+L task(s)+L hint(s)L(s) = L_{CI}(s) + L_{physics}(s) + L_{task}(s) + L_{hint}(s)
      • task term only: wishful thinking.
      • all 4 terms, physcics lessened -- gradually add constraints.
      • all terms, no hint, full physics.
  • Total time to simulate 2-10 minutes per clip (only!)
  • The equations of the paper seem incomplete -- not clear how QP eq fits in with the L(s)L(s) , and how c ic_i fits in with J(q) Tf+BuJ(q)^T f + B u

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ref: -0 tags: ZeroMQ messaging sockets multithreading date: 05-03-2016 06:10 gmt revision:0 [head]

ZeroMQ -- much better sockets framework than native TCP/UDP sockets.

  • Bindings for Ocaml, too.
  • Supports Erlang-like concurrency.

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ref: -0 tags: google glucose sensing contact lens date: 04-28-2016 19:41 gmt revision:2 [1] [0] [head]

A contact lens with embedded sensor for monitoring tear glucose level

  • PMID-21257302
  • Metal stack: Ti 10nM / Pd 10nM / Pt 100nm.
  • on a 100um thick PET film.
  • A 30 µL glucose oxidase solution (10 mg/mL) was dropped onto the sensor area.
  • Then the sensor was suspended vertically above a titanium isopropoxide solution in a sealed dish for 6 h to create a GOD/titania sol-gel membrane, just as reported (Yu et al., 2003).
  • After forming the sol-gel membrane, a 30 µL aliquot of Nafion® solution was dropped onto the same area of the sensor, and allowed to dry in air for about 20 min.
  • Yet, the interference rejection from Nafion is imperfect; at 100uM concentrations, glucose is indistinguishable from ascorbic acid + lactate + urea.
  • Sensor drifts to 55% original performance after 4 days: figure 6
    • sensor was stored in a buffer @ 4C.
    • Probably OK for contact lenses, though.

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ref: -0 tags: concentation of monoamine dopamine serotonin and norepinephrine in the brain date: 04-28-2016 19:38 gmt revision:3 [2] [1] [0] [head]

What are the concentrations of the monoamines in the brain? (Purpose: estimate the required electrochemical sensing area & efficiency)

  • Dopamine: 100 uM - 1 mM local, extracellular.
    • PMID-17709119 The Yin and Yang of dopamine release: a new perspective.
  • Serotonin (5-HT): 100 ng/g, 0.5 uM, whole brain (not extracellular!).
  • Norepinephrine / noradrenaline: 400 nm/g, 2.4 uM, again whole brain.
    • PMID-11744005 An enriched environment increases noradrenaline concentration in the mouse brain.
    • Also has whole-brain extracts for DA and 5HT, roughly:
      • 1200 ng/g DA
      • 400 ng/g NE
      • 350 ng/g 5-HT
  • So, one could imagine ~100 uM transient concentrations for all 3 monoamines.

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ref: -0 tags: deep reinforcement learning date: 04-12-2016 17:19 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

Prioritized experience replay

  • In general, experience replay can reduce the amount of experience required to learn, and replace it with more computation and more memory – which are often cheaper resources than the RL agent’s interactions with its environment.
  • Transitions (between states) may be more or less
    • surprising (does the system in question have a model of the environment? It does have a model of the state & action expected reward, as it's Q-learning.
    • redundant, or
    • task-relevant
  • Some sundry neuroscience links:
    • Sequences associated with rewards appear to be replayed more frequently (Atherton et al., 2015; Ólafsdóttir et al., 2015; Foster & Wilson, 2006). Experiences with high magnitude TD error also appear to be replayed more often (Singer & Frank, 2009 PMID-20064396 ; McNamara et al., 2014).
  • Pose a useful example where the task is to learn (effectively) a random series of bits -- 'Blind Cliffwalk'. By choosing the replayed experiences properly (via an oracle), you can get an exponential speedup in learning.
  • Prioritized replay introduces bias because it changes [the sampled state-action] distribution in an uncontrolled fashion, and therefore changes the solution that the estimates will converge to (even if the policy and state distribution are fixed). We can correct this bias by using importance-sampling (IS) weights.
    • These weights are the inverse of the priority weights, but don't matter so much at the beginning, when things are more stochastic; they anneal the controlling exponent.
  • There are two ways of selecting (weighting) the priority weights:
    • Direct, proportional to the TD-error encountered when visiting a sequence.
    • Ranked, where errors and sequences are stored in a data structure ordered based on error and sampled 1/rank\propto 1 / rank .
  • Somewhat illuminating is how the deep TD or Q learning is unable to even scratch the surface of Tetris or Montezuma's Revenge.

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ref: -0 tags: meta compilation self-hostying ACM date: 12-30-2015 07:52 gmt revision:2 [1] [0] [head]

META II: Digital Vellum in the Digital Scriptorium: Revisiting Schorre's 1962 compiler-compiler

  • Provides high-level commentary about re-implementing the META-II self-reproducing compiler, using Python as a backend, and mountain climbing as an analogy. Good read.
  • Original paper
  • What it means to be self-reproducing: The original compiler was written in assembly (in this case, a bytecode assembly). When this compiler is run and fed the language description (figure 5 in the paper), it outputs bytecode which is identical (or almost nearly so) to the hand-coded compiler. When this automatically-generated compiler is run and fed the language description (again!) it reproduces itself (same bytecode) perfectly.
    • See section "How the Meta II compiler was written"

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ref: Linsmeier-2011.01 tags: histology lund electrodes immune response fine flexible review Thelin date: 12-08-2015 23:57 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-21867803[0] Can histology solve the riddle of the nonfunctioning electrode? Factors influencing the biocompatibility of brain machine interfaces.

  • We show results from an ultrathin multichannel wire electrode that has been implanted in the rat cerebral cortex for 1 year.
    • 12um Pt-Ir wires in a 200um bundle coated with gelatin. See PMID-20551508[1]
    • Electrode was left in the rat cortex for 354 days
    • no clear GFAP staining or ED1 positive cells at the electrode tips.
  • To improve biocompatibility of implanted electrodes, we would like to suggest that free-floating, very small, flexible, and, in time, wireless electrodes would elicit a diminished cell encapsulation.
  • Suggest standardized methods for the electrode design, the electrode implantation method, and the analyses of cell reactions after implantation
  • somewhat of a review -- Stice, Biran 2005 [2] 2007 [3].
  • 50um is the recording distance Purcell 2009.
  • See also [4]
  • Study of neuronal density and ED1 reactivity / GFAP:
    • Even at 12 weeks the correlation between NeuN density and GFAP / ED1 was small -- r 2=0.12r^2 = 0.12
    • Note that DAPI labels many unknown cells in the vicinity of the electrode.

____References____

[0] Linsmeier CE, Thelin J, Danielsen N, Can histology solve the riddle of the nonfunctioning electrode? Factors influencing the biocompatibility of brain machine interfaces.Prog Brain Res 194no Issue 181-9 (2011)
[1] Lind G, Linsmeier CE, Thelin J, Schouenborg J, Gelatine-embedded electrodes--a novel biocompatible vehicle allowing implantation of highly flexible microelectrodes.J Neural Eng 7:4, 046005 (2010 Aug)
[2] Biran R, Martin DC, Tresco PA, Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays.Exp Neurol 195:1, 115-26 (2005 Sep)
[3] Biran R, Martin DC, Tresco PA, The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull.J Biomed Mater Res A 82:1, 169-78 (2007 Jul)
[4] Thelin J, Jörntell H, Psouni E, Garwicz M, Schouenborg J, Danielsen N, Linsmeier CE, Implant size and fixation mode strongly influence tissue reactions in the CNS.PLoS One 6:1, e16267 (2011 Jan 26)

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ref: -0 tags: alumina utah array electrode parylene encapsulation date: 10-23-2015 21:28 gmt revision:1 [0] [head]

Utah/blackrock group has been working on improving the longevity of their parlyene encapsulation with the addition of ~50nm Al2O3.

  • PMID-24771981 '''Self-aligned tip deinsulation of atomic layer deposited Al2O3 and parylene C coated Utah electrode array based neural interfaces
    • Process:
      • Normal Utah array dicing saw / glass frit / thinning and etch fabrication for the Utah probe.
      • Sputtered Ti, Sputtered Pt. (not sure how they mask this?)
      • Sputtered iridium oxide (SIROF, sputtered in an Ar + O2 plasma) electrode tips (again, not sure about the mask..)
      • ALD Al2O3 passivation, 50nm. Cambridge Fiji system, same as nanolab. Must take a long time!
      • A-174, aka 3-Methacryloxypropyltrimethoxysilane adhesion promoter (which presumably acts by pulling hydroxy groups off the alumina substrate; Al-O bonds have higher energy than Si-O)
      • 6um parylene.
      • Laser ablation of tips with 1000 pulses from KrF 5ns 100Hz excimer laser. Works much better than poking the electrode tips through thin aluminum foil.
      • O2 plasma descum / removal of carbon residues.
      • BOE removal of Al2O3 above the SIROF
    • Of note, ALD Al2O3 has included hydroxy bonds, which means that it gradually etches in PBS. (Pure Al2O3, as passivates aluminum parts exposed to seawater, does not?)
    • PBS also etches Si3N4, and crystaline Si.
  • IEEE-6627006 (pdf) Bi-layer encapsulation of utah array based neural interfaces by atomic layer deposited Al2O3 and parylene C
    • Atomic layer deposited (ALD) alumina is an excellent moisture barrier with WVTR at the order of ~ 10e-10 g·mm/m2·day [10-13]. But alumina alone is not suitable for encapsulation since it dissolves in water [14].
    • Demonstrated stable power-up of RF encapsulated devices for up to 600 equivalent days in 37C PBS.
      • Actual testing carried out at 57C, 4x accelerated.
  • PMID-24658358 Long-term reliability of Al2O3 and Parylene C bilayer encapsulated Utah electrode array based neural interfaces for chronic implantation.
    • Demonstrated good barrier longevity with wired Utah probes, active probes with flip-chip (Au/Sn eutectic reflow) record/stimulate circuits, and ones with bonded RF stimulation chips, INIR-6. (6th version!)
    • PBS etching of Si lead to undercutting & eventual flake-off of the SIROF, leading to dramatic impedance increase. (Figure 5 and 7).
      • no Pt under the SIROF?

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ref: -0 tags: reactive oxygen accelerated aging neural implants date: 10-07-2015 18:45 gmt revision:1 [0] [head]

PMID-25627426 Rapid evaluation of the durability of cortical neural implants using accelerated aging with reactive oxygen species.

  • Takmakov P1, Ruda K, Scott Phillips K, Isayeva IS, Krauthamer V, Welle CG.
  • TDT W / PI implants completely failed (W etched and PI completely flaked off) after 1 week in 87C H2O2 / PBS solution. Not surprising.
    • In the Au plated W, the Au remained, the PI flaked off, while thin fragile gold tubes were left. Interesting.
  • Pt/Ii + Parylene-C microprobes seemed to fare better; one was unaffected, others experienced a drop in impedance.
  • NeuralNexus (Si3N4 insulated, probably, plus Ir recording pads) showed no change in H2O2 RAA, strong impedance drop (thicker oxide layer?)
  • Same for blackrock / utah probe (Parylene-C), though there the parylene peeled from the Si substrate a bit.

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ref: -0 tags: street fighting mathematics Sanjoy Mahajan date: 10-04-2015 23:09 gmt revision:0 [head]

https://mitpress.mit.edu/sites/default/files/titles/free_download/9780262514293_Street_Fighting_Mathematics.pdf

https://mitpress.mit.edu/sites/default/files/titles/free_download/9780262526548_Art_of_Insight.pdf

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ref: -0 tags: polyimide adhesion delamination Stieglitz date: 08-18-2015 22:19 gmt revision:1 [0] [head]

Thin films and microelectrode arrays for neuroprosthetics

  • Juan Ordonez, Martin Schuettler, Christian Boehler, Tim Boretius and Thomas Stieglitz
  • Discussion of adhesion & ideas of using siliconcarbides as opposed to adhesion promoters (Silane A-174) to maintain good metal-polymer adhesion even with an equilibrium water vapor pressure.
  • Transition metals form carbide bonds with polyimide, but noble metals do not.
  • A one-metal (preferably noble) system is advantageous, as two metals will form a galvanic cell and eventually corrode.
  • Therefore it's best to develop non-metallic non-toxic adhesion promotion technologies.

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ref: -0 tags: berkeley airbears2 configuration linux debian 8.1 date: 08-13-2015 23:42 gmt revision:1 [0] [head]

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ref: -0 tags: adhesion polymer metal FTIR epoxy eponol paint date: 05-01-2015 19:20 gmt revision:0 [head]

Degradation of polymer/substrate interfaces – an attenuated total reflection Fourier transform infrared spectroscopy approach

  • Suggests why eponol is used as an additive to paint.
  • In this thesis, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy has been used to detect changes at the interfaces between poly (vinyl butyral-co-vinyl alcohol-co-vinyl acetate) (PVB) and ZnSe upon exposure to ozone, humidity and UV-B light.
  • Also, the response of PVB-aluminum interfaces to liquid water has been studied and compared with the same for eponol (epoxy resin, diglycidyl ether of bisphenol A)-aluminum interfaces.
  • In the presence of ozone, humidity and UV-B radiation, an increase in carbonyl group intensity was observed at the PVB-ZnSe interface indicating structural degradation of the polymer near the interface. However, such changes were not observed when PVB coated ZnSe samples were exposed to moisture and UV-B light in the absence of ozone showing that ozone is responsible for the observed structural deterioration. Liquid water uptake kinetics for the degraded PVB monitored using ATR-FTIR indicated a degradation of the physical structural organization of the polymer film.
  • Exposure of PVB coated aluminum thin film to de-ionized water showed water incorporation at the interface. There were evidences for polymer swelling, delamination and corrosion of the aluminum film under the polymer layer.
    • On the contrary, delamination/swelling of the polymer was not observed at the eponol-aluminum interface, although water was still found to be incorporated at the interface. Al-O species were also observed to form beneath the polymer layer.
    • A decrease of the C-H intensities was detected at the PVB-aluminum interface during the water uptake of the polymer, whereas an increase of the C-H intensities was observed for the eponol polymer under these conditions.
    • This is assigned to rearrangement of the macromolecular polymer chains upon interaction with water.

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ref: -0 tags: Kewame carbon nanotube yarn wet spinning CNT date: 03-26-2015 18:29 gmt revision:0 [head]

Neural Stimulation and Recording with Bidirectional, Soft Carbon Nanotube Fiber Microelectrodes

  • 43um diameter CTN yarn
  • Shows superior charge injection / surface area.
  • polystyrene-polybutadiene co-polymer insulation (like ABS, without the acrylonitrile)
  • https://chemistry.beloit.edu/classes/nanotech/CNT/nanotoday3_5_24.pdf -- details on the process of spinning these CNT yarns.
    • Tensile strength still far below commercial carbon fibers or high-strength polymers.

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ref: -0 tags: microflex interconnect polyimide Stieglitz date: 03-03-2015 00:33 gmt revision:1 [0] [head]

IEEE-938305 (pdf) High Density Interconnects and flexible hybrid assemblies for active biomedical implants

  • Idea: make vias in your metallized PI film. Bump-bond through these vias to a chip below.
  • Achieve center-to -center distances of 100um.
  • No longer using this? See {1250}, which uses thermosonic bonding.

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ref: -2000 tags: polyimide acrylic aluminum electro deposition imide insulation ultra thin date: 02-27-2015 19:42 gmt revision:0 [head]

Ultrathin, Layered Polyamide and Polyimide Coatings on Aluminum

  • Alternating polyelectrolyte deposition of layered poly(acrylic acid)/poly(allylamine hydrochloride) (PAA/PAH) films on Al produces ultrathin coatings that protect Al from Cl--induced corrosion.
  • Resistance goes from 5 MOhm/cm^2 at 10nm thickness to ~50MOhm/cm^2 following imidization of the monolayer-applied polymer films.

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ref: -0 tags: gold carbon nanotube electroplating impedance PEG date: 10-24-2014 22:25 gmt revision:1 [0] [head]

PMID-21379404 Creating low-impedance tetrodes by electroplating with additives

  • Electroplated tetrodes to 30-70 kΩ by adding polyethylene glycol (PEG) or multi-walled carbon nanotube (MWCNT) solutions to a commercial gold-plating solution.
  • Cui and Martin [12] showed that altering the concentration of gold-plating solution and electroplating current can change the morphology of a gold-plated microelectrode coating.
  • Additionally, Keefer et al. [13] found that adding multi-walled carbon nanotubes (MWCNTs) to a gold-plating solution created microelectrode coatings with a “rice-like” texture and very low impedances.
  • Au electroplating solution made of non-cyanide, gold-plating solution (5355, SIFCO Selective Plating, Cleveland, OH).
  • A one-second, reversed-polarity pulse helped to clean the surface of the tetrode tip and lowered the impedances to 2MΩ to 3 MΩ before electroplating.
  • Electroplating pulses were one to five seconds long and were repeated until the tetrodes reached the desired impedances. After electroplating, the tetrodes were soaked in DI, air dried, and checked for shorts.

Conclusion: 75% PEG, commercial electropating solution, 0.1ua current pluses to 250K or less.

  • Though the Caswell Au plating solution will likely behave differently ..

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ref: -0 tags: wirebonding finishes gold nickel palladium electroless electrolytic date: 09-21-2014 02:53 gmt revision:3 [2] [1] [0] [head]

Why palladium?


To prevent black nickel: http://tayloredge.com/reference/Electronics/PWB/BlackPad_ITRI_Round1.PD

Introduction The use of electroless nickel / immersion gold (E.Ni/I.Au) as a circuit board finish has grown significantly in the last few years. It provides a flat board finish, is very solderable, provides a precious metal contact surface and the nickel strengthens the plated holes. However, as the usage of E.Ni/I.Au increased, a problem was found on BGA (Ball Grid Array) components. An open or fractured solder joint sometimes appears after board assembly on the occasional BGA pad. The solder had wet and dissolved the gold and formed a weak intermetallic bond to the nickel. This weak bond to the nickel readily fractures under stress or shock, leaving an open circuit. The incidence of this problem appears to be very sporadic and a low ppm level problem, but it is very unpredictable. A BGA solder joint cannot be touched-up without the component being removed. After the BGA component is removed, a black pad is observed at the affected pad site. This black pad is not readily solderable, but it can be repaired.


From: http://www.smtnet.com/Forums/index.cfm?fuseaction=view_thread&Thread_ID=4430

You don't have enough gold. Your 2uin is too porous and is allowing the nickel to corrode. Prove that this by hand soldering to these pads with a more active flux, like a water soluble solder paste, than you are using.

You must have at least 3uin of immersion gold. Seriously consider >5uin.

Your nickel thickness is fine. Although if you wanted to trade costs, consider giving-up nickel to 150uin thickness, while increasing the gold thickness. Gold over electroless nickel creates brittle joints because of phosphorous in the nickel plating bath. The phosphorous migrates into the over-plating. Electrolytic nickel and gold plating should not be a problem.

If you stay with the electroless nickel, keep the phosphorous at a mid [7 - 9%] level. Just as important, don't let the immersion gold get too aggressive. The immersion gold works by corroding the nickel. If it is too aggressive it takes away the nickel and leave phosphorous behind. This makes it look like the phosphorous level is too high in the nickel bath.

Gold purity is very important for any type of wire bonding process. For aluminum wedge bonding, gold should have a purity of 99. 99% [no thalium] and the nickel becomes critical. No contaminates and the nickel wants to be plated a soft as possible. This requires good control of Ph and plating chemicals in the nickel-plating bath.

Harman "Wire Bonding In Microelectronics" McGraw-Hill is a good resource for troubleshooting wire bonding. I reviewed it in the SMTnet Newsletter a couple of months ago.


That said, electrolytic nickel + electrolytic gold does work well -- perhaps even better than ENEPIG:

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ref: Cosman-2005.12 tags: microstimulation RF pain neural tissue ICMS date: 09-04-2014 18:10 gmt revision:14 [13] [12] [11] [10] [9] [8] [head]

One of the goals/needs of the lab is to be able to stimluate and record nervous tissue at the same time. We do not have immediate access to optogenetic methods, but what about lower frequency EM stimulation? The idea: if you put the stimulation frequency outside the recording system bandwidth, there is no need to switch, and indeed no reason you can't stimulate and record at the same time.

Hence, I very briefly checked for the effects of RF stimulation on nervous tissue.

  • PMID-16336478[0] Electric and Thermal Field Effects in Tissue Around Radiofrequency Electrodes
    • Most clinical response to pulsed RF is heat ablation - the RF pulses can generate 'hot spots' c.f. continuous RF.
    • Secondary effect may be electroporation; this is not extensively investigation.
    • Suggests that 500kHz pulses can be 'rectified' by the membrane, and hence induce sodium influx, hence neuron activation.
    • They propose that some of the clinical effects of pulsed RF stimulation is mediated through LTD response.
  • {1297} -- original!
  • PMID-14206843[2] Electrical Stimulation of Excitable Tissue by Radio-Frequency Transmission
    • Actually not so interesting -- deals with RF powered pacemakers and bladder stimulators; both which include rectification.
  • Pulsed and Continous Radiofrequency Current Adjacent to the Cervical Dorsal Root Ganglion of the Rat Induces Late Cellular Activity in the Dorsal Horn
    • shows that neurons are activated by pulsed RF, albeit through c-Fos staining. Electrodes were much larger in this study.
    • Also see PMID-15618777[3] associated editorial which calls for more extensive clinical, controlled testing. The editorial gives some very interesting personal details - scientists from the former Soviet bloc!
  • PMID-16310722[4] Pulsed radiofrequency applied to dorsal root ganglia causes a selective increase in ATF3 in small neurons.
    • used 20ms pulses of 500kHz.
    • Small diameter fibers are differentially activated.
    • Pulsed RF induces activating transcription factor 3 (ATF3), which has been used as an indicator of cellular stress in a variety of tissues.
    • However, there were no particular signs of axonal damage; hence the clinically effective analgesia may be reflective of a decrease in cell activity, synaptic release (or general cell health?)
    • Implies that RF may be dangerous below levels that cause tissue heating.
  • Cellphone Radiation Increases Brain Activity
    • Implies that Rf energy - here presumably in 800-900Mhz or 1800-1900Mhz - is capable of exciting nervous tissue without electroporation.
  • Random idea: I wonder if it is possible to get a more active signal out of an electrode by stimulating with RF? (simultaneously?)
  • Human auditory perception of pulsed radiofrequency energy
    • Evicence seems to support the theory that it is local slight heating -- 6e-5 C -- that creates pressure waves which can be heard by humans, guinea pigs, etc.
    • Unlikely to be direct neural stimulation.
    • High frequency hearing is required for this
      • Perhaps because it is lower harmonics of thead resonance that are heard (??).

Conclusion: worth a shot, especially given the paper by Alberts et al 1972.

  • There should be a frequency that sodium channels react to, without inducing cellular stress.
  • Must be very careful to not heat the tissue - need a power controlled RF stimulator
    • The studies above seem to work with voltage-control (?!)

____References____

[0] Cosman ER Jr, Cosman ER Sr, Electric and thermal field effects in tissue around radiofrequency electrodes.Pain Med 6:6, 405-24 (2005 Nov-Dec)
[1] Alberts WW, Wright EW Jr, Feinstein B, Gleason CA, Sensory responses elicited by subcortical high frequency electrical stimulation in man.J Neurosurg 36:1, 80-2 (1972 Jan)
[2] GLENN WW, HAGEMAN JH, MAURO A, EISENBERG L, FLANIGAN S, HARVARD M, ELECTRICAL STIMULATION OF EXCITABLE TISSUE BY RADIO-FREQUENCY TRANSMISSION.Ann Surg 160no Issue 338-50 (1964 Sep)
[3] Richebé P, Rathmell JP, Brennan TJ, Immediate early genes after pulsed radiofrequency treatment: neurobiology in need of clinical trials.Anesthesiology 102:1, 1-3 (2005 Jan)
[4] Hamann W, Abou-Sherif S, Thompson S, Hall S, Pulsed radiofrequency applied to dorsal root ganglia causes a selective increase in ATF3 in small neurons.Eur J Pain 10:2, 171-6 (2006 Feb)

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ref: -0 tags: physical principles of scalable neural recording marblestone date: 08-25-2014 20:21 gmt revision:0 [head]

PMID-24187539 Physical principles for scalable neural recording.

  • Marblestone AH1, Zamft BM, Maguire YG, Shapiro MG, Cybulski TR, Glaser JI, Amodei D, Stranges PB, Kalhor R, Dalrymple DA, Seo D, Alon E, Maharbiz MM, Carmena JM, Rabaey JM, Boyden ES, Church GM, Kording KP.

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ref: -0 tags: intracortical utah array fabrication MEMS Normann date: 08-14-2014 01:35 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-1937509 A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array.

  • Campbell PK1, Jones KE, Huber RJ, Horch KW, Normann RA. (1991)
  • One of (but not the) first papers describing their methods / idea (I think).
  • First conf paper: {1294} (1988)
  • later adopted glass frit insulator --

{1291}
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ref: -0 tags: tungsten welding CVD arc braze 1971 date: 08-12-2014 20:56 gmt revision:0 [head]

Weldability of Tungsten and Its Alloys

  • tried relatively exotic brazing methods:
    • Niobium,
    • Tantalum
    • W - 26% Re
    • Mo
      • No mention of what we'll be doing (NiCr resistance wire -- only easily available fine wire)
  • Note that the ductile-to-brittle transition is low for their samples, 150-250C.
  • Samples made via arc-melting or WF + H2 CVD.

{1112}
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ref: Seymour-2011.06 tags: PEDOT Seymour electrode recording parylene date: 08-06-2014 22:39 gmt revision:3 [2] [1] [0] [head]

PMID-21301965[0] Novel multi-sided, microelectrode arrays for implantable neural applications.

  • There are problems with parylene multielectrode arrays:
    • water and salts will rapidly diffuse into the various interfacial boundaries
    • Interfacial delamination due to poor wet adhesion of parylene on metal
      • This possibly due to mechanical stress
      • causes excessive cross-talk or noise.
    • Parylene-C devices are prone to poor adhesion at either the dielectric to dielectric interface or at the dielectric to metal interface *** (Sharma and Yasuda 1982; Yasuda et al 2001)
  • solution: PPXCH 2NH 2PPX-CH_2NH_2 and PPXCHOPPX-CHO -- reactive parylene (amine bonds?!)
  • PEDOT is absolutely essential for attaining reasonable performance / impedance from the 85um^2 gold electrodes.
    • Thermal noise on 280um^2 and 170um^2 Au electrodes was too high to record neurons.
    • AU thickness 0.5um.
  • Performed soak tests on their electrodes; the reactive parylene is good, but not sure if it's a worthy improvement.

____References____

[0] Seymour JP, Langhals NB, Anderson DJ, Kipke DR, Novel multi-sided, microelectrode arrays for implantable neural applications.Biomed Microdevices 13:3, 441-51 (2011 Jun)

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ref: -0 tags: debugging reinvented java CMU code profiling instrumentation date: 08-02-2014 06:32 gmt revision:3 [2] [1] [0] [head]

images/1289_1.pdf -- Debugging reinvented: Asking and Answering Why and Why not Questions about Program Behavior.

  • Smart approach to allow users to quickly find the causes of bugs (or more generically, any program actions).

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ref: -0 tags: automatic programming inductive functional igor date: 07-29-2014 02:07 gmt revision:0 [head]

Inductive Rule Learning on the Knowledge Level.

  • 2011.
  • v2 of their IGOR inductive-synthesis program.
  • Quote: The general idea of learning domain specific problem solving strategies is that first some small sample problems are solved by means of some planning or problem solving algorithm and that then a set of generalized rules are learned from this sample experience. This set of rules represents the competence to solve arbitrary problems in this domain.
  • My take is that, rather than using heuristic search to discover programs by testing specifications, they use memories of the output to select programs directly (?)
    • This is allegedly a compromise between the generate-and-test and analytic strategies.
  • Description is couched in CS-lingo which I am inexperienced in, and is perhaps too high-level, a sin I too am at times guilty of.
  • It seems like a good idea, though the examples are rather unimpressive as compared to MagicHaskeller.

{1276}
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ref: -0 tags: polyimide silicon oxide aluminum adhesion pressure cooker date: 06-16-2014 21:28 gmt revision:2 [1] [0] [head]

Interfacial adhesion of polymeric coatings for microelectronic encapsulation

  • Find that, after a pressure-cooker test, adhesion of polyimide PI-2610 (what we use) to SiO2 was weaker than to Al, SiN, and copper.
  • Aluminum adhesion is quite good, at least to (only) 15 days @ 85C / 85% RH. Reference studies that find the adhesion to be 'acceptable' for the microelectronics industry.
    • Should we use an aluminum adhesion layer? Less biocompatible metal than Ti, and more likely to degrade in saline.
  • Found that copper adhesion actually went up with water exposure!
  • Polyimide adheres more strongly to glass than epoxy following accelerated aging.

{1287}
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ref: -0 tags: maleimide azobenzine glutamate photoswitch optogenetics date: 06-16-2014 21:19 gmt revision:0 [head]

PMID-16408092 Allosteric control of an ionotropic glutamate receptor with an optical switch

  • 2006
  • Use an azobenzene (benzine linked by two double-bonded nitrogens) as a photo-switchable allosteric activator that reversibly presents glutamate to an ion channel.
  • PIMD:17521567 Remote control of neuronal activity with a light-gated glutamate receptor.
    • The molecule, in use.
  • Likely the molecule is harder to produce than channelrhodopsin or halorhodopsin, hence less used. Still, it's quite a technology.

{1286}
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ref: -0 tags: ovipositor wasp fig needle insertion SEM date: 05-29-2014 19:58 gmt revision:0 [head]

Biomechanics of substrate boring by fig wasps

  • Lakshminath Kundanati and Namrata Gundiah 2014

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ref: -0 tags: automatic programming date: 05-18-2014 07:02 gmt revision:1 [0] [head]

various:

  • http://www.lighttable.com/2014/05/16/pain-we-forgot/ -- approaching the problem by making better tools / interfaces.
  • http://pchiusano.blogspot.com/2013/05/the-future-of-software-end-of-apps-and.html -- approaching the problem by making the web one giant functional & typed language, distributed over all clients.
    • Strongly advocates the utility and need for typed languages to provide contexts for actions.
    • Interesting, but altogether dreamy and unlikely.
  • Bloom language
    • "the standard data structures in Bloom are disorderly collections, rather than scalar variables and structures. These data structures reflect the realities of non-deterministic ordering inherent in distributed systems. Bloom provides simple, familiar syntax for manipulating these structures. In the Bud prototype, much of this syntax comes straight from Ruby, with a taste of MapReduce and SQL." perfect.
    • From Berkeley.
    • Based on Daedalus data language, which specifies temporal ordering?
      • "The basic idea is that Time (meaning both the sequentiality of program steps in a single “thread”, and coordination of steps across threads/machines) is needed for only one purpose: to prevent multiple possible states from co-occurring. I.e. the purpose of time is to seal fate at each instantaneous moment." src

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ref: -0 tags: optogenetics glutamate azobenzine date: 05-07-2014 19:51 gmt revision:0 [head]

PMID-17521567 Remote control of neuronal activity with a light-gated glutamate receptor.

  • Neuron 2007.
  • azobenzines undergo a cis to trans confirmational change via illumination with one wavelength, and trans to cis via another. (neat!!)
  • This was used to create photo-controlled (on and off) glutamate channels.

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ref: -0 tags: polyimide adhesion aluminum integrated circuit date: 05-07-2014 19:29 gmt revision:0 [head]

Polyimide insulators for multilevel interconnections Arthur M. Wilson

  • Old article (1981), but has useful historical information on the development of various PI insulators and their adhesion to aluminum, SiOx, etc.
  • Suggests that a higher-temperature cure (400C) is needed to fully drive water from the PI & cause a glass-transition. Might want to do this for the second PI layer.

{1280}
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ref: -0 tags: kevlar polyamide orientation thin-films date: 04-07-2014 19:08 gmt revision:1 [0] [head]

Preparation of uniaxially oriented polyamide films by vacuum deposition polymerization

  • Jiro Sakata, Midori Mochizuki
  • Grew polyamide (PPTA, kevlar) films using VDP (vacuum deposition polymerization).
    • Two precursors were heated in a vacuum to yield a stoichiometric polymer.
  • Polymer chains were oriented with rubbing with different polymers, e.g. cotton (!)

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ref: -0 tags: parylene plasma ALD insulation long-term saline PBS testing date: 04-02-2014 21:32 gmt revision:0 [head]

PMID-23024377 Plasma-assisted atomic layer deposition of Al(2)O(3) and parylene C bi-layer encapsulation for chronic implantable electronics.

  • This report presents an encapsulation scheme that combines Al(2)O(3) by atomic layer deposition with parylene C.
  • Al2O3 layer deposited using PAALD process-500 cycles of TMA + O2 gas.
  • Alumina and parylene coating lasted at least 3 times longer than parylene coated samples tested at 80 °C
    • That's it?
  • The consistency of leakage current suggests that no obvious corrosion was occurring to the Al2O3 film. The extremely low leakage current (≤20 pA) was excellent for IDEs after roughly three years of equivalent soaking time at 37 °C.
    • Still, they warn that it may not work as well for in-vivo devices, which are subject to tethering forces and micromotion.

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ref: -0 tags: carbon fiber electrode array parylene fire sharpening microthread date: 03-20-2014 19:57 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-23860226 A carbon-fiber electrode array for long-term neural recording.

  • Guitchounts G1, Markowitz JE, Liberti WA, Gardner TJ.
  • We describe an assembly method for a 16-channel electrode array consisting of carbon fibers (<5 µm diameter) individually insulated with Parylene-C and fire-sharpened. The diameter of the array is approximately 26 µm along the full extent of the implant.
  • Fibers from http://www.goodfellowusa.com/
    • young's modulus of 380GPa vs. tungsten 400GPa.
    • Data available from Toho Tenax
  • The absence of any report of single neuron isolation in HVC with a fixed chronic electrode implant underscores the difficulty of recording small cells (8-15um soma) with an implant whose damage length scale is large relative to the target neurons. (!!)

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ref: -0 tags: spectroscopy frequency domain PMT avalanche diode laser Tufts date: 02-25-2014 19:02 gmt revision:0 [head]

Frequency-domain techniques for tissue spectroscopy and imaging

  • 52 pages, book chapter
  • Good detail on bandwidth, tissue absorption, various technologies.

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ref: -0 tags: San Francisco community links date: 02-22-2014 22:36 gmt revision:3 [2] [1] [0] [head]

Community & housing links for San Francisco.

  1. http://c4a.me/CodeAcrossSF -- google drive location.
  2. http://localwiki.net/sf
  3. http://propertymap.sfplanning.org/
  4. http://www.sf-planning.org/
  5. http://www.sftreasurer.org/index.aspx?page=65
  6. http://us-city.census.okfn.org/
  7. https://data.sfgov.org/
  8. http://www.tenantstogether.org/
  9. http://www.flickr.com/photos/daver6/ -- graffiti!

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ref: -0 tags: hinton convolutional deep networks image recognition 2012 date: 01-11-2014 20:14 gmt revision:0 [head]

ImageNet Classification with Deep Convolutional Networks

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ref: -0 tags: shape memory polymers neural interface thiolene date: 12-06-2013 22:55 gmt revision:0 [head]

PMID-23852172 A comparison of polymer substrates for photolithographic processing of flexible bioelectronics

  • Describe the deployment of shape-memory polymers for a neural interface
    • Thiol-ene/acrrylate network (see figures)
    • Noble metals react strongly to the thiols, yielding good adhesion.
  • Cr/Au thin films.
  • Devices change modulus as they absorb water; clever!
  • Transfer by polymerization patterning of electrodes (rather than direct sputtering).
    • This + thiol adhesion still might not be sufficient to prevent micro-cracks.
  • "Neural interfaces fabricated on thiol-ene/acrylate substrates demonstrate long-term fidelity through both in vitro impedance spectroscopy and the recording of driven local field potentials for 8 weeks in the auditory cortex of laboratory rats. "
  • Impedance decreases from 1M @ 1kHz to ~ 100k over the course of 8 weeks. Is this acceptable? Seems like the insulator is degrading (increased capacitance; they do not show phase of impedance)
  • PBS uptake @ 37C:
    • PI seems to have substantial PBS uptake -- 2%
    • PDMS the lowest -- 0.22%
    • PEN (polyethelene napathalate) -- 0.36%
    • Thiol-ene/acrylate 2.19%
  • Big problem is that during photolithographic processing all the shape-memory polymers go through Tg, and become soft/rubbery, making thin metal film adhesion difficult.
    • Wonder if you could pattern more flexible materials, e.g. carbon nanotubes (?)
  • Good paper, many useful references!

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ref: -0 tags: DBS parkinsons dystonia review neurosurgery date: 10-05-2013 22:33 gmt revision:0 [head]

PMID-17848864 Deep brain stimulation

  • Kern DS, Kumar R. 2007
  • extensive review!

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ref: -0 tags: polyimide platinum electrodes Spain longitudinal intrafasicular adhesion delamination date: 10-05-2013 22:24 gmt revision:4 [3] [2] [1] [0] [head]

PMID-17278585 Assessment of biocompatibility of chronically implanted polyimide and platinum intrafascicular electrodes. 2007

  • Designed platinum/polyimide longitudinal intrafasicular electrodes (LIFEs)
    • 25um PT/Ir, insulated to 60-75um diameter. PT/IR has a young's modulus of 202 Gpa.
      • Plated with platinum black under sonication, as this forms a tougher surface than without sonication.
      • See also: PMID-20485478 Improving impedance of implantable microwire multi-electrode arrays by ultrasonic electroplating of durable platinum black. Desai SA, Rolston JD, Guo L, Potter SM. 2010
    • Polyimide PI2611, 10um thick, 50mm long, 220um wide in the electrode segment.
  • Implanted into rat sciatic nerve for 3 months.
  • These electrodes have been tested in people for two days:
    • Electrical stimulation through the implanted electrodes elicited graded sensations of touch, joint movement, and position, referring to the missing limb. This suggested that peripheral nerve interfaces could be used to provide amputees with prosthetic limbs with sensory feedback and volitional control that is more natural than what is possible with current myoelectric and body-powered prostheses.
  • CMAPs = compound muscle action potentials.
  • CNAPs = compound nerve action potentials.
  • Platinum wire LIFE performed very similarly to the thin-film polyimide LIFE in most all tests, with slightly higher potentials recorded by the larger polyimide probe.
  • 'Higher encapsulation with the polyimide probes! Geometry?
  • However, the polyimide LIFEs induced less functional decline than the wire LIFEs.
  • Other polyimide studies [14] [16] [24] -- one of which they observed a 70% reduction of tensile strength after 11 months of implantation.
    • [14] F. J. Rodríguez, D. Ceballos, M. Schüttler, E. Valderrama, T. Stieglitz, and X. Navarro, “Polyimide cuff electrodes for peripheral nerve stimulation,” J. Neurosci. Meth., vol. 98, pp. 105–118, 2000.
    • [16] N. Lago, D. Ceballos, F. J. Rodríguez, T. Stieglitz, and X. Navarro, “Long term assessment of axonal regeneration through polyimide regenerative electrodes to interface the peripheral nerve,” Biomaterials, vol. 26, pp. 2021–2031, 2005.
    • [24] M. Schuettler, K. P. Koch, and T. Stieglitz, “Investigations on explanted micromachined nerve electrodes,” in Proc. 8th Annu. Int. Conf. Int. Functional Electrical Stimulation Soc., Maroochydore, Australia, 2003, pp. 306–310.
      • The technology of sandwiching a metallization layer between two layers of polyimide seems to be suitable, because no delamination of the polyimide layers was observed even after 11 months. The right choice of metals for building the electrical conductive elements of the microelectrodes is crucial. Ti/Au/Ti/Pt layers tend to flake off from polyimide while delamination of Ti/Pt layers was not observed. However, adhesion of Ti/Pt layers was investigated after 2.5 months of implantation while Ti/Au/Ti/Pt layers were exposed after 11 months to the biological system. In previous research projects, surgeons also reported on delamination of Ti/Au layers from polyimide substrate after three months. Unfortunately, we had no possibility of inspecting these microelectrodes in our laboratory.
      • See also {1250}

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ref: -0 tags: polyimide adhesion silver surface treatment adhesion delamination date: 10-04-2013 01:30 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

Improved polyimide/metal adhesion by chemical modification approaches

  • Suggest fuming sulfuric acid (H2S04) + Ag2SO4 for 30s as the most effective treatment.
  • 1 minute in 1M KOH also effective.
  • Silver was magnetron-sputtered on; peel test performed with tape.

IEEE-4936772 (pdf) Studies of adhesion of metal films to polyimide

  • Suggest Ar / O2 plasma treatment of surface to increase Cr/Cu adhesion (mechanical effect?)
  • Used two different polyimides: one derived from (BPDA‐PDA) polyamic acid, and pyromellitic dianhydride‐4,4’‐oxydianiline (PMDA‐ODA).

IEEE-670747 (pdf) Adhesion evaluation of adhesiveless metal/polyimide substrate for MCM and high density packaging

  • Adhesion of Cr / polyimide interface is degraded significantly upon exposure to high temperature and humidity environment due to the hydrolysis of polyimide.
  • There is also some worry of Cu diffusion into the polyimide.
  • All used a Cr tie layer, 200A thick (20nm).
  • Deposited photoresist, electroplated copper, then etched to define pattern.
  • Testing performed at 121C 100% RH, +15psi. (tough!)

On polyimide-polyimide interlayer adhesion: Diffusion and self-adhesion of the polyimide PMDA-ODA (1987)

  • Diffusion occurred during the curing process of the second layer and was controlled by the cure schedule.
  • It was found that a large diffusion distance, at least 200 nm, was required to obtain a bond whose strength was equal to that of bulk material.
  • Good protocol:
    • Dry first layer at 80C for 30 minutes.
    • 150C (or lower?) bake of first layer. "as the polyamic acid imidizes (and the solvent is lost) its diffusive mobility decreases rapidly; very little diffusion occurs after the first few minutes of the second bake.
    • Spin coat second layer.
    • 400C second bake.
  • Ductility is increased for polyimide that has experienced a series of increasing cure temperatures.
  • In this context it is worth noting that the contour length of a PMDA-ODA of 30,000 molecular weight is about 130nm, a value very similar to the diffusion distances measured when T1 (first layer bake) was 150C.

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ref: -0 tags: Anna Roe optogenetics artificial dura monkeys intrinisic imaging date: 09-30-2013 19:08 gmt revision:3 [2] [1] [0] [head]

PMID-23761700 Optogenetics through windows on the brain in nonhuman primates

  • technique paper.
  • placed over the visual cortex.
  • Injected virus through the artificial dura -- micropipette, not CVD.
  • Strong expression:
  • See also: PMID-19409264 (Boyden, 2009)

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ref: -0 tags: Disseroth Kreitzer parkinsons optogenetics D1 D2 6OHDA date: 09-30-2013 18:15 gmt revision:0 [head]

PMID-20613723 Regulation of parkinsonian motor behaviors by optogenetic control of basal ganglia circuitry

  • Kravitz AV, Freeze BS, Parker PR, Kay K, Thwin MT, Deisseroth K, Kreitzer AC.
  • Generated mouse lines with channelrhodopsin2, with Cre recombinase under control of regulatory elements for the dopamine D1 (direct) or D2 (indirect) receptor.
  • optogenetic exitation of the indirect pathway elicited a parkinsonian state: increased freezing, bradykinesia and decreased locomotor initiations;
  • Activation of the direct pathway decreased freezing and increased locomotion.
  • Then: 6OHDA depletion of striatal dopamine neurons.
  • Optogenetic activation of direct pathway (D1 Cre/loxp) neurons restored behavior to pre-lesion levels.
    • Hence, this seems like a good target for therapy.

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ref: -0 tags: Kozai carbon nanotube electrode rcording histology date: 08-02-2013 05:42 gmt revision:1 [0] [head]

PMID-23142839 Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces.

  • Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad.
  • 7um diameter carbon nanotubes slide easily into cortex & yield good recording.
  • only 0.8um of parlyene-N coating.
    • Does it stick well? Does it crack?
  • Functionalized the parylene with 50nm of bromine / oxygen complex, bromoisobutyrate.
  • PEDOT recording surface drastically lowered impedance.
  • Difficult to assemble these little buggers!

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ref: -0 tags: retinal ganglion cells neural encoding Farrow date: 07-31-2013 16:21 gmt revision:0 [head]

PMID-21273316 Physiological clustering of visual channels in the mouse retina

  • Anatomy predicts that mammalian retinas should have in excess of 12 physiological channels, each encoding a specific aspect of the visual scene.
  • Although several channels have been correlated with morphological cell types, the number of morphological types generally exceeds the known physiological types.
  • Here, we attempted to sort the ganglion cells of the mouse retina purely on a physiological basis.
  • Result: The optimal partition was the 12-cluster solution of the Fuzzy Gustafson-Kessel algorithm.
    • This might be useful elsewhere ...
  • Farrow Lab is responsible for the 11,011 electrode array.

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ref: -0 tags: ACF chip bonding parylene field's metal polyimide date: 07-10-2013 18:34 gmt revision:10 [9] [8] [7] [6] [5] [4] [head]

We're making parylene electrodes for neural recording, and one critical step is connecting them to recording electronics.

Currently Berkeley uses ACF (anisotropic conductive film) for connection, which is widely used for connecting flex tape to LCD panels, or for connecting driver chips to LCD glass. According to the internet, pitches can be as low as 20um, with pad areas as low as 800um^2. source

However, this does not seem to be a very reliable nor compact process with platinum films on parylene, possibly because ACF bonding relies on raised areas between mated conductors (current design has the Pt recessed into the parylene), and on rigid substrates. ACF consists of springy polymer balls coated in Ni and Au and embedded in a thermoset epoxy resin. The ACF film is put under moderate temperature (180C) and pressure (3mpa, 430psi), which causes the epoxy to cure in a state that leaves the gold/nickel/polymer balls to be compressed between the two conductors. Hence, even if the conductors move slightly due to thermal cycling, the small balls maintain good mechanical and electrical contact. The balls are dispersed sufficiently in the epoxy matrix that there is little to no chance of conduction between adjacent pads.

(Or so I have learned from the internet.) Now, as mentioned, this is an imperfect method for joining Pt on parylene films, possibly because the parylene is so flexible, and the platinum foil is very thin (200-300 nm). Indeed, platinum does not bond very strongly to parylene, hence care must be taken to allow sufficient overlap to prevent water ingress. My proposed solution -- to be tested shortly -- is to use a low-melting temperature metal with strong wetting ability -- such as Field's metal (bismuth, tin, indium, melting point 149F, see http://www.gizmology.net/fusiblemetals.htm) to low-temperature solder the platinum to a carrier board (initially) or to a custom amplifier ASIC (later!). Parylene is stable to 200C (392F), so this should be safe. One worry is that the indium/bismuth will wet the parylene or polyimide, too; however I consider this unlikely due to the difficulty in attaching parylene to any metal.

That said, there must be good reason why ACF is so popular, so perhaps a better ultimate solution is to stiffen the parylene (or ultimately polyimide) substrate so that it can support both the temperature/pressure of ACF bonding and the stress of a continued electrical/mechanical bond to polyimide fan-out board or ASIC. It may also be possible to gold or nickel electroplate the connector pads to be slightly raised instead of recessed.


Update: ACF bond to rigid 1/2 oz copper, 4mil trace / space connector (3mil trace/space board):

Note that the copper traces are raised, and the parylene is stretched over the uneven surface (this is much easier to see with the stereo microscope). To the left of the image, the ACF paste has been sqeezed out from between the FR4 and parylene. Also note that the platinum can make potential contact with vias in the PCB.


Update 7/2: Fields metal (mentioned above) does stick to platinum reasonably well, but it also sticks to parylene (somewhat), and glass (exceptionally well!). In fact, I had a difficult time removing traces of field's metal from the Pyrex beakers that I was melting the metal with. These beakers were filled with boiling water, which may have been the problem.

When I added flux (Kester flux-pen 951 No-clean MSDS), the metal became noticeably more shiny, and the contact angle increased on the borosilicate glass (e.g. looked more like mercury); this leads me to believe that it is not the metal itself that attaches to glass, but rather oxides of indium and bismuth. Kester 951 flux consists of:

  • 2-propanol 15% (as a denaturing agent) boiling point 82.6C
  • Ethanol 73% (solvent) boiling point 78.3C
  • Butyl Acetate 7% boiling point 127C, flash point 27C
  • Methanol <3% b.p. 64.7C
  • Carboxylic acids < 3% -- proton donors? formic or oxalic acid?
  • Surfacants < 1% -- ?
Total boiling point is 173F.

After coating the parylene/platinum sample with flux, I raised the field's metal to the flux activation point, which released some smoke and left brown organic residues on the bottom of the glass dish. Then I dipped the parylene probe into the molten metal, causing the flux again to be activated, and partially wetting the platinum contacts. The figure below shows the result:

Note the incomplete wetting, all the white solids left from the process, and how the field's metal caused the platinum to delaminate from the parylene when the cable was (accidentally) flexed. Tests with platinum foil revealed that the metal bond was not actually that strong, significantly weaker than that made with a flux-core SnPb solder. also, I'm not sure of the activation temperature of this flux, and think I may have overheated the parylene.


Update 7/10:

Am considering electrodeless Ni / Pt / Au deposition, which occurs in aqueous solution, hence at much lower temperatures than e-beam evaporation Electrodeless Ni ref. On polyimide substrates, there is extensive literature describing how to activate the surface for plating: Polyimides and Other High Temperature Polymers: Synthesis ..., Volume 4. Parylene would likely need a different possibly more aggressive treatment, as it does not have imide bonds to open.

Furthermore, if the parylene / polyimide surface is *not* activated, the electrodeless plating could be specific to the exposed electrode and contact sites, which could help to solve the connector issue by strengthening & thickening the contact areas. The second fairly obvious solution is to planarize the contact site on the PCB, too, as seen above. ACF bonds can be quite reliable; last night I took apart (and successfully re-assembled) my 32" Samsung LCD monitor, and none of the flex-on-glass or chip-on-flex binds failed (despite my clumsy hands!).

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ref: -0 tags: Utah parylene cracking encapsulation electrode date: 06-28-2013 18:26 gmt revision:4 [3] [2] [1] [0] [head]

Characterization of parylene-C film as an encapsulation material for neural interface devices

  • Hsu, Jui-Meia; Kammer, Saschab; Jung, Erikc; Rieth, Lorend; Normann,A. Richarde; Solzbacher, Florianade (Utah)
  • lists Tg 35-80C for parylene-C;
  • 3um films applied.
  • Parylene samples were subjected to accelerated lifetime testing (85 % relative humidity (RH) and 85 ̊C) for 20 days, and the film did not show appearance changes as observed by optical microscopy. However, X-ray diffractograms show that the film crystallinity increased during this test.
  • 120C 100%RH for 2 hours released parylene from the silicon.
  • Soldering @ 350C backside of Utah array caused parylene to crack.
  • X-ray diffraction shows that heat causes parylene to crystalize:

___Low Dielectric Constant Materials for Ic Applications___ edited by Paul Shin Ho, Jihperng Leu, Wei William Lee

  • Aging and annealing increase crystalinity and thus lower the elongation to break and increase the modulus and mechanical strength of the films.
  • parylene-N is considerably more crystaline (57%), Tg 13C. (low!)
  • Bulk barrier properties are among the best of the organic polymeric coatings.

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ref: -0 tags: parylene microchannel micromolding glass transition temperature microfluidics date: 06-28-2013 17:34 gmt revision:3 [2] [1] [0] [head]

Parylene micromolding, a rapid low-cost fabrication method for parylene microchannel

  • doi:10.1016/j.snb.2003.09.038
  • Hong-Seok Noha∗ , Yong Huangb, Peter J. Hesketha Clemson
  • Parylene properties:
    • Glass transition temperature <90C; c.f. {1247}
    • Melting point 290C
    • Oxidation in air at 120C
    • Thermal bonding here at 200C in a vacuum oven @ 24MPa.

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ref: -0 tags: polyimide aging deadhesion humidity water absorption date: 06-28-2013 02:07 gmt revision:1 [0] [head]

Environmental Aging and Deadhesion of Polyimide Dielectric films

  • At 35C, 85% RH (not immersion!) there was little degradation in the polyimide to 2000 hours.
  • Suggest chromium or titanium as an adhesion promoter & to prevent copper from diffusing into the polyimide.
  • Plasma treatment of polyimide is commonly used prior to metal deposition in order to improve adhesion of polyimide to metallization [20].
    • Clearfield, Furman, Callegari 1994 "The Role of Physical and Chemical Structure in the Long-term Durability of Metal/Polyimide Interfaces" International Journal of Microcircuits and electronic Packaging 17(3), pp. 228-35.

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ref: -0 tags: polyimide platinum nanowire recording electrode plating date: 06-28-2013 00:46 gmt revision:2 [1] [0] [head]

IEEE-5734597 (pdf) A novel platinum nanowire-coated neural electrode and its electrochemical and biological characterization

  • Young-Hyun Jin ; IMTEK, Univ. of Freiburg, Freiburg, Germany ; Daubinger, P. ; Fiebich, B.L. ; Stieglitz, T.
  • 10um thick RIE etched polyimide and platinum electrodes.
  • polyimide was spin coated onto wafers.
  • Used relatively simple wet chemistry to plate platinum onto electrodes:
    • 0.14 M-% chloroplatin acid hexahydrate (H2PtCl6·6H2O, Sigma-Aldrich) and 7.4 M-% formic acid (HCOOH, Sigma-Aldrich) were mixed in de-ionized (DI) water. The fabricated device was floated upside down on the solution.
  • Let this plate for 7 days & effective site was enlarged by 617 times!

{1193}
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ref: Prasad-2012.1 tags: tungsten microwire electrodes histology insulation failure sanchez microwire tungsten date: 06-27-2013 22:40 gmt revision:12 [11] [10] [9] [8] [7] [6] [head]

PMID-23010756[0] Comprehensive characterization and failure modes of tungsten microwire arrays in chronic neural implants.

  • c.f. [1]
  • microwire implant, durations that ranged from acute to up to 9 months in 25 rats.
  • First 2-3 weeks electrode impedance + recording quality fluctuated the most widely.
  • Electrode recording site deterioration continued for the long-term animals as insulation damage occurred and recording surface became more recessed over time.
  • Activated microglia were found near electrode tracts in all chronic animals.
    • High ferritin expression, intraparenchymal bleeding, microglial degeneration suggesting presence of excessive oxidative stress via Fenton chemistry.
      • Wikipedia: Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species via the Fenton Reaction.[11] Hence vertebrates use an elaborate set of protective mechanisms to bind iron in various tissue compartments.
  • Ferritin expression sometimes associated with blebbing / cytorrhexis. (in figures 7-8)
    • Interestingly, during the first few hours after implantation many microglial cells are undergoing cytoplasmic fragmentation (cytorrhexis) which indicates ongoing degeneration of these cells as their cytoplasm literally breaks apart. Cytorrhexis has been previously observed in the aged human brain where it becomes particular prominent in subjects with Alzheimer’s disease.
  • Could not discriminate abiotic (insulation, recording site size) and biotic (inflammatory response) causes of failure.
    • Microglial response not correlated with prolonged performance.
  • Tungsten TDT microwire arrays. 50um diameter, 10um polyimide insulation.
  • SEM imaging pre and prior implantation.
  • Antibodies marking microglia:
    • Iba1 marks all microglia.
    • ED1 stain against CD68 to identify active macrophages [80], but not necessarily all activated microglia since many activated cells are not engaged in phagocytosis and thus are ED1-negative.
    • Anti-ferritin staining to identify those microglia involved in the sequestration of free iron that may leak as a result of BBB compromize.
      • Issue: ferritin is expressed in all tissues ..
    • OX-6 to identify antigen-presenting MHC-II (immune) cells, e.g. microglia or blood-borne immune cells.
  • Found the immunohistoheamistry not terribly convincing.
    • Above, arrows show withdrawn electrode tips.
  • Working with the FDA to promote good laboratory practice (GLP) and good manufacturing practice (GMP). Can mention the same.
  • No evidence of infection in rats.
    • Not true in monkeys..

____References____

[0] Prasad A, Xue QS, Sankar V, Nishida T, Shaw G, Streit WJ, Sanchez JC, Comprehensive characterization and failure modes of tungsten microwire arrays in chronic neural implants.J Neural Eng 9:5, 056015 (2012 Oct)
[1] Freire MA, Morya E, Faber J, Santos JR, Guimaraes JS, Lemos NA, Sameshima K, Pereira A, Ribeiro S, Nicolelis MA, Comprehensive analysis of tissue preservation and recording quality from chronic multielectrode implants.PLoS One 6:11, e27554 (2011)

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ref: -0 tags: parylene silicon neural recording probes date: 06-07-2013 00:15 gmt revision:4 [3] [2] [1] [0] [head]

http://thesis.library.caltech.edu/4671/1/PhDThesisFinalChanglinPang.pdf

  • Notes: Michigan probes suffer from thickness limited to <15um, hence are often not stiff enough to penetrate the pia & arachnoid.
  • Likewise, utach arrays are fabricated through a substrate, so cannot be made longer than 1.5-2mm. Plus, they are connected with 25um gold wires, which is both rigid and requires a fair bit of work. (Perhaps with a wirebond machine?)
  • SiO2 suffers from high internal stress (formed at high temperature) and tends to hydrate over time, both making it a less than ideal insulator for biological applications.
    • Silicon is slowly attacked in saline.
  • Use Cr/Au traces, and Ti/Pt electrode sites on his probes.
    • 2.5um minimum trace width.
  • Importantly, they solve the problem of parylene to silicon interconnect by simply fabricating the wires on parylene -- like ours -- and only use silicon as a structural support.
    • Silicon is roughened via XeF2 for good parylene adhesion.
      • Alas, does not survive a long-term soak -- but maybe this is useful? (page 102)
        • This too can be solved via bringing the parylene in vacuum up to melting temperature to better bond with Si.
  • Metal pads on parylene are destroyed by wedge bonding -- heat and pressure are too high!
  • Their solution is to use conductive epoxy & fan the wires out to omnetics pitch (635um) in what they call parylene-PCB-omnetics connector (PPO).
  • Plated a 5um x 5um electrode with platinum black to reduce the impedance from 1.1M to 9.2k (!!)
    • Problem is that Pt black is fragile, and may be scraped off during insertion -- see figure on page 95.
  • Probe shanks are ~ 170um x 150um, tip spade-type patterned via DRIE.
  • To be able to sustain soaking and lifetime testing, thick parylene layers are needed for the flexible parylene cable. The total parylene thickness of our neural probes is about 13 μm which results in a long etching time. We use photoresist as a mask when etching parylene using RIE O2 plasma etching; the etching rate of parylene and photoresist in RIE is roughly 1:1. Thick photoresist (> 20 μm) with high resolution is needed. AZ 9260 thick-film photoresist is designed for the more-demanding higher-resolution thick-resist requirements. It provides high resolution with superior aspect ratios, as well as wide focus and exposure latitude and good sidewall profiles. A process of two spinning coats using AZ 9260 has been developed to make a high-resolution thick photoresist mask of about 30 μm. Figure 4-11 shows the thick photoresist on the probe tip to guarantee a sharp tip after plasma etching. The photoresist is hard baked in oven at 120 oC for 30 min; the thick photoresist needs to be carefully handled during baking to avoid thermal cracking.
  • Otline electrolysis-based actuators ... interesting but hopefully not needed.

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ref: -0 tags: histology immune response otto indiana electrodes gfap inflamation transparent clearing vimentin date: 04-19-2013 23:59 gmt revision:4 [3] [2] [1] [0] [head]

PMID-23428842 Chronic intracortical microelectrode arrays induce non-uniform, depth-related tissue responses.

  • Woolley AJ, Desai HA, Otto KJ.
  • One timepoint, 4 weeks.
  • Laser confocal microscopy
    • after tissue clearing (optical index of refraction matching) in a 60% sucrose solution.
  • Single-shank iridium contact silicon substrate MEA.
    • Device cut level with surface of brain after insertion.
  • Intact MEAs via device-capture histology, DHhist (Woolley et al 2011)
    • 350-450um tissue explanted with device.
    • They promote their technique.
  • Tissue surrounding microdevices exhibited two major depth-related phenomena:
    • a non-uniform microglial coating along the device length and
    • a dense mass of cells surrounding the implant in cerebral cortical layers I and II.
      • The dense mass of cells contained vimentin, a protein not typically expressed highly in CNS cells, evidence that non-CNS cells likely descended down the face of the penetrating devices from the pial surface.
        • But no Iba1 (activated microglia) per se in the tissue mass.
    • Hoe342 -- cell marker.
    • This mass was apparently consistent across animals!
    • Cells in the mass were VIM positive -- fibroblasts -- meninges?
  • low GFAP = not an astrocytic scar.
  • This study provides further evidence that a progressive invasion of non-CNS cells contributes substantially to the chronic phase of the tissue response around intracortical MEAs.
    • Again, might be from BBB distruption {1237}


This result is supported by previous papers:
  • {1193} -- microglia response not correlated to electrode failure, but correlated to ferritin immunoresponse
  • {781} -- also note that menigeal fibroblasts migrate down electrode tracts.
  • {1028} -- measured vimentin, GFAP, and ED1 (not Iba1). Found Vim+ and GFAP+, suggesting reactive astrocytes and not meningeal cells. ED1 aka CD68 is specific to macrophages and not microglia, so these may be blood-derived cells.
  • {1200} -- chronic contact with the meninges v.s intraparenchymal correlated with Vim+ encapsulation.
  • {1210} -- old paper showing the same result near surface of implant.
  • {1196} -- more against GFAP & pro BBB disruption
  • {1204} -- GFAP uncorrelated (!) with NeuN intensity
  • {307} -- all initial tests of utah arrays showed fibrous encapsulation; one array was completely explanted. This is why now they put gore-tex over the implant -- to prevent fibroblast migration (i guess).

{1237}
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ref: -0 tags: winslow Tresco 2010 BBB histology immune response microelectrodes date: 04-19-2013 23:25 gmt revision:0 [head]

PMID-19963267 Quantitative analysis of the tissue response to chronically implanted microwire electrodes in rat cortex.

  • Winslow BD, Tresco PA.
  • The spatial distribution of biomarkers associated with the foreign body response to insulated microwires placed in rat cerebral cortex was analyzed 2, 4, and 12 weeks after implantation using quantitative methods.
  • We found no evidence that reactive gliosis increases over time or that neuronal loss is progressive, we did find evidence of persistent inflammation and enhanced BBB permeability at the electrode brain tissue interface that extended over the 3 month indwelling period and that exhibited more animal to animal variability at 3 months than at 2 and 4 weeks.

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ref: -0 tags: brain mapping recording Yuste date: 04-10-2013 19:31 gmt revision:1 [0] [head]

PMID-22726828 The Brain Activity Map Project and the Challenge of Functional Connectomics

  • They are more interested in every neuron within a local circuit, e.g. cortical column.
  • Referenced papers, optical:
    • Yuste et al 2011 -- referenced several times.
    • Helmchen 2011
    • Yuste and Katz 1991 (calcium)
    • Grienberger and Konnerth 2012 (1000 recorded neurons)
    • Peterka 2011 -- voltage imaging
    • Mochalin 2012 -- nanodiamonds.
  • The optical techniques only gets you .. 400um? 2mm?
    • Suggest GRIn objectives for invasive recording of the e.g. hippocampus.
  • Interesting: DNA polymerases could be used as spike sensors since their error rates are dependent on cation concentration.
    • use synthetic cells, then sequence the molecular recording.
  • The Drosophila connectome is currently 20% complete at the mesoscale (Chiang et al 2011)
    • Drosophila has 135,000 neurons
  • Bock et al 2011 have reconstructed 1,500 cell bodies with 1e13 pixels.
  • In the human genome project, every dollar invested generated $141 in the economy. (Battelle 2011).

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ref: -0 tags: brain mapping Deisseroth Donoghue widescale recording date: 04-10-2013 19:31 gmt revision:1 [0] [head]

PMID-23514423 Nanotools for Neuroscience and Brain Activity Mapping

  • human brain has roughly 85e9 neurons, 1e14 synapses, 100 neurotransmitters.
  • focus on novel nanoprobes.
  • Assuming a uniform connaction probability, the lielihood of finding synaptically coupled cells increases quadratically with N.
  • pretty high-level article.
  • Multiferroic antennas (?) -- must look this up!
  • Look up ref 146 -- microendoscope. Did they design the camera module?

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ref: -0 tags: dissertation interconnect parylene flexible electrodes date: 02-26-2013 00:30 gmt revision:2 [1] [0] [head]

http://docs.lib.purdue.edu/dissertations/AAI3444877/

  • Several different projects --
    • Stretchable PDMS electrodes
    • PDMS-parylene ECoG
    • Transmitting parallel neural data via free-space optical link
    • semi-flexible hydrogel-parylene neural electrode.
    • The parylene electrodes with selectively patterned hydrogel provide stiff mechanical properties for easy penetration into the brain tissues and subsequent flexibility after insertion upon swelling of the hydrogel.
    • advanced packaging system with using a composite inorganic parylene combination.
      • Atomic layer deposited alumina-zirconia (Al2O3–ZrO2) composite layer can provide a conformal and nano-laminated coating on parylene surface in neural packaging systems in order to improve the hermeticity for long term implantations
  • Can't get the entire PDF. annoying.

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ref: -0 tags: parylene interconnect monolithic integration silicon DRIE date: 02-26-2013 00:29 gmt revision:1 [0] [head]

A New Multi-Site Probe Array with Monolithically Integrated Parylene Flexible Cable for Neural Prostheses

    • Use DRIE to etch the back of the wafer after patterning the front. Clever!

{597}
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ref: Suner-2005.12 tags: Suner Utah probe electrophysiology reliability chronic electrode recording longevity histology MEA date: 01-31-2013 22:27 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-16425835Reliability of signals from a chronically implanted, silicon-based electrode array in non-human primate primary motor cortex

  • claim that they have done a logitudinal development series that included 39 array implants in 18 monkeys.
  • can get reliable recordings out to 3 months (only? probably the array was forced out of the brain?)
    • however, it seems that their recording quality did not decrease dramatically over those 3 months.
  • excellent methods section.
  • also {1027}

____References____

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ref: -0 tags: microelectrodes original metal pipette glass recording MEA date: 01-31-2013 19:46 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

IEEE-4065599 (pdf) Comments on Microelectrodes

  • The amplifiers themselves, even back in 1950's, posed no problems -- low bandwidth. All that is required is low noise and high input impedance.
  • KCl Glass electrodes are LPF (10M resistive + 10pf parasitic capacitance); metal HPF (capacitive).
    • The fluid tip will not see external triphasic spikes of vertebrate axons above the noise level.
  • Metal probe the most useful.
  • Pt electrode in CSF behaves like a capacitor at low voltage across a broad frequency range. CSF has compounds that retard oxidation; impedance is more resistive with physiological saline.
  • Noise voltage generated by a metal electrode best specified by equivalent noise resistance at room temperature, E rmsnoise=4kTR nδF E_{rms noise} = \sqrt{4 k T R_{n} \delta F} R_n should equal the real part of the electrode impedance at the same frequency.
  • Much of electrochemistry: solid AgCl diffuses away from an electrode tip with great speed and can hardly be continuously formed with an imposed current. Silver forms extremely stable complexes with organic molecules having attached amino and sulfhydril groups which occur in plenty where the electrode damages the tissue. Finally, the reduction-oxidation potential of axoplasm is low enough to reduce methylene blue, which places it below hydrogen. AgCl and HgCl are reduced.
  • The external current of nerve fibers is the second derivative of the traveling spike, the familiar triphasic (??) transient.
  • Svaetichin [1] and Dowben and Rose [3] plated with Platinum black. This increases the surface area.
    • Very quickly it burns onto itself a shell of very adherent stuff. It is kept from intimate contact with the tissue around it by a shell.
    • We found that if we add gelatin to the chloroplatinic acid bath from which we plate the Pt, the ball is not only made adherent to the tip but is, in a sense, prepoisoned and does not burn a shell into itself.
  • glass insulation using woods metal (which melts at a very low temperature). Platinum ball was plated onto 2-3um pipette tip. 3um gelatinized platinum black ball, impedance 100kOhm at 1kHz.
    • Highly capacitive probe: can be biased to 1 volt by a polarizing current of 1e-10 amp. (0.1nA).
  • Getting KCl solution into 1um pipettes is quite hard! They advise vacuum boiling to remove the air bubbles.
  • Humble authors, informative paper.

____References____

' ''' ()

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ref: -0 tags: polymide flexible electrode Rousche incision needle assist date: 01-30-2013 06:38 gmt revision:3 [2] [1] [0] [head]

PMID-11327505 Flexible Polyimide-Based Intracortical Electrode Arrays with Bioactive Capability

  • Use gold / polymide fabrication; electrode is 20um thick, 160um wide.
  • Still quite flexible -- buckles at 0.003 N.
  • Successfully recorded by inserting it in an incision in rat barrel cortex -- needle assist.
    • Well, not too successfully.
  • Suggest that bioactive components can be applied to the permeable polymide surface.

____References____

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ref: Kruger-2010.05 tags: microelectrode array nichrome 7 years rhesus electrophysiology MEA Kruger oblique inverted date: 01-29-2013 07:54 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-20577628[0] Seven years of recording from monkey cortex with a chronically implanted multiple electrode.

  • Seven years!! good recordings the whole time, too. As they say, this is a clinically realistic time period. Have they solved the problem?
  • Used 12.5um Ni-Cr-Al wire insulated with 3um of polymide.
    • Wires were then glued to an 8x8 connector block using conductive epoxy.
    • Glued the bundle together with a solution of plexiglas in dichloroethane.
    • Then introduced the 0.3mm bundle into a j-shaped cannula. This allowed them to approach the gray matter inverted, from below (the white matter).
    • implanted 64 ch array into ventral premotor cortex (arm representation?).
  • No apparent degradation of recording quality over that time.
  • Had some serious problems with the quality of their connector.
    • They recommend: "Rather, the contacts on the head should be made from noble metals and be flat or shallowly hollow, so that they can be easily cleaned, and no male contacts can break."
    • Really need to amplify and multiplex prior connector (imho).
  • Claim that them managed to record from two neurons on one channel for nearly 7 years (ch 54).
  • They cite us, but only to indicate that we recommend slow penetration of the brain. They agree with our results that lowering of individual electrodes is better than all at once.

____References____

[0] Kruger J, Caruana F, Volta RD, Rizzolatti G, Seven years of recording from monkey cortex with a chronically implanted multiple microelectrode.Front Neuroengineering 3 Issue 6 (2010 May 28)

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ref: Polikov-2005.1 tags: neural response glia histology immune electrodes recording 2005 Tresco Michigan microglia date: 01-29-2013 00:34 gmt revision:10 [9] [8] [7] [6] [5] [4] [head]

PMID-16198003[0] Response of brain tissue to chronically implanted neural electrodes

  • Good review (the kind where figures are taken from other papers). Nothing terribly new (upon a very cursory inspection)
  • When CNS damage severs blood vessels, microglia are indistinguishable from the blood borne, monocyte-derived macrophages that are recruited by the degranulation of platelets and the cellular release of cytokines.
  • Furthermore, microglia are known to secrete, either constitutively, or in response to pathological stimuli, neurotrophic factors that aid in neuronal survival and growth.
    • Also release cytotoxic and neurotoxic factors that can lead to neuronal death in vitro.
    • It has been suggested that the presence of insoluble materials in the brain may lead to a state of 'frustrated phagocytosis' or inability of the macrophages to remove the foreign body, resulting in persistent release of neurotoxic substances.
  • When a 10x10 array of silicon probes was implanted in feline cortex, 60% of the needle tracks showed evidence of hemorrhage and 25% showed edema upon explantation of the probes after one day (Schmidt et al 1993) {1163}
    • Although a large number of the tracks were affected, only 3-5% of the area was actually covered by hemorrhages and edema, suggesting the actual damage to blood vessels may have been relatively minor. (!!)
  • Excess fluid and cellular debris diminishes 6-8 days due to the action of activated microglia and re-absorption.
  • As testament to the transitory nature of this mechanically induced wound healing response, electrode tracks could not be found in animals after several months when the electrode was inerted and quickly removed (Yuen and Agnew 1995, Rousche et al 2001; Csicsvari et al 2003, Biran et al 2005).
  • Biran et al 2005: observed persistent ED-1 immunoreactivity around silicon microelectrode arrays implanted in rat cortex at 2 and 4 weeks following implantation; not seen in microelectrode stab wound controls.
  • On the glial scar:
    • observed in the CNS of all vertebrates, presumably to isolate damaged parts of the nervous system and maintain the integrity of the blood-brain barrier.
    • mostly composed of reactive astrocytes.
    • presumably the glial scar insulates electrodes from nearby neurons, hindering diffusion and increasing impedance.
  • On the meninges:
    • Meningeal fibroblasts, which also stain for vimentin, but not for GFAP, may migrate down the electrode shaft from the brain surface and form the early basis for the glial scar.
  • On recording quality:
    • Histological examination upon explantation revealed that every electrode with stable unit recordings had at least one large neuron near the electrode tip, while every electrode that was not able to record resolvable action potentials was explanted from a site with no large neurons nearby.
  • Perhaps the clearest example of this variability was observed in the in vivo response to plastic “mock electrodes” implanted in rabbit brain by Stensaas and Stensaas (1976) {1210} and explanted over the course of 2 years. They separated the response into three types: Type 1 was characterized by little to no gliosis with neurons adjacent to the implant, Type 2 had a reactive astrocyte zone, and Type 3 exhibited a layer of connective tissue between the reactive astrocyte layer and the implant, with neurons pushed more than 100 um away. All three responses are well documented in the literature; however this study found that the model electrodes produced all three types of reactions simultaneously,depending on where along the electrode one looked.

____References____

[0] Polikov VS, Tresco PA, Reichert WM, Response of brain tissue to chronically implanted neural electrodes.J Neurosci Methods 148:1, 1-18 (2005 Oct 15)

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ref: Salcman-1976.01 tags: Salcman electrodes recording chronic microelectrode array MEA original parylene date: 01-28-2013 22:18 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-1256090[0] A new chronic recording intracortical microelectrode

  • maintain that tethering is the rational way to go: it "re-establishes the normal biomechanics of the intact cranial vault". (Salcman 1972, 1973) {1010}
    • have model of electrode tip motion in response to brain-skull displacements (Goldstein and Salcman 1973) {1011}
      • Electrode would have a tip displacement of about 5um in response to a 1mm displacement of the electrode's point of entry into the skull.
      • Exponential dependence on recording amplitude and distance (Rall, 1962). Gradient: 7.5uv/um; movements of more than 1-2um can radically alter the recordnig shape.
      • Probably our electrodes work because the dura & gliosis becomes firmly attached to the electrode shafts.
    • not really an array so much as a number (10-12) of single-unit electrodes.
  • Details the process of parylene-C deposition, electrode microwelding, etc. Pretty cool stuff -- what has happened to this technology?
  • Each bubble is glued with cyanocrylate to the pia. (they too question the safety of this).
  • arrays can be manually inserted via forceps.
  • 25um iridium wire electroplated in 1-2um of gold
    • then electo-etched until the desired tip geometry is achieved, 1-3um diameter
    • and vacuum coated in 3um of parylene-C.
    • Impedance 1-2M with a 1kHz sine wave at 10nA. Impedance is inversely related to the frequency of the test current, phase angle of 70-80deg.
      • Ref Robinson, 1968.
    • We must emphasize the extreme sensitivity of electrode measurements to the test conditions. Measured values of Z eZ_e are usually increased 1-3M when the electrode has been stored away for a few days. Removing the electrode from the test bath for a few minutes in air can lead to equally large increases when the electrode is tested upon remersion. [...] might be oxide.
    • Pinholes are the usual failure mechanism (KD Wise 2004), {149}; parylene is 'pinhole-free'.
  • The connecting 25um Au lead is very flexible and imposes little stress on the iridium electrode.
    • Connecting wire coated in 12um of parylene C
    • Would prefer even finer wire, 12um.
  • Perspex window over the craniotomy; had a vent in this window which they could open.
  • Opening the vent would cause the brain to pulse, moving the electrodes through the cortex and changing neural activity.
  • Size of an electrode is limited by ability to introduce it into the brain.
    • Electrode must be introduced through the pia; as the pial vessels supply the cortex (or drain the cortex).
    • For their electrodes, P crit=0.9gP_{crit} = 0.9 g ; the force necessary to penetrate the pia is 0.05 - 0.2g.
  • pure iridium is stiffer than Pt-Ir by a factor of 3 or so. (521 G N/m^2 = 521 GPa, higher than tungsten, which is 400 Gpa)
    • Pure iridium is apparently the stiffest metallic element ref
  • Interesting: "Once again we are impressed by the fact that passive recording electrodes exhibit drops in impedance in the living system which they never show on in vitro testing in protein solutions at 37C.
    • Between 40 and 50 days, a slow downward trend becomes noticeable; this trend continues for the life of the animal and asymptotically approaches values below 500k. Electrodes still record.
    • See {999}
    • Surmise that pure iridium electrodes have a different metal-electrolyte interface than more conventional metals (Pl and W).
  • Mention that the ultimate purpose is for a neural prosthesis.
    • Their then use was for recordings from M1 in monkeys and V1 from cats. (Schmidt, Bak, McIntosh 1974)
  • Ref Wise et al {1012}.

____References____

[0] Salcman M, Bak MJ, A new chronic recording intracortical microelectrode.Med Biol Eng 14:1, 42-50 (1976 Jan)

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ref: Leung-2008.08 tags: biocompatibility alginate tissue response immunochemistry microglia insulation spin coating Tresco recording histology MEA date: 01-28-2013 21:19 gmt revision:4 [3] [2] [1] [0] [head]

PMID-18485471[0] Characterization of microglial attachment and cytokine release on biomaterials of differing surface chemistry

  • The important result is that materials with low protein-binding (e.g. alginate) have fewer bound microglia, hence better biocompatibility. It also seems to help if the material is highly hydrophilic.
    • Yes alginate is made from algae.
  • Used Michigan probes for implantation.
  • ED1 = pan-macrophage marker.
    • (quote:) Quantification of cells on the surface indicated that the number of adherent microglia appeared higher on the smooth side of the electrode compared to the grooved, recording site side (Fig. 2B), and declined with time. However, at no point were electrodes completely free of attached and activated microglial cells nor did these cells disappear from the interfacial zone along the electrode tract.
    • but these were not coated with anything new .. ???

____References____

[0] Leung BK, Biran R, Underwood CJ, Tresco PA, Characterization of microglial attachment and cytokine release on biomaterials of differing surface chemistry.Biomaterials 29:23, 3289-97 (2008 Aug)

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ref: Chestek-2011.08 tags: shenoy Utah array reliability recording BMI date: 01-28-2013 20:54 gmt revision:2 [1] [0] [head]

PMID-21775782[0] Long-term stability of neural prosthetic control signals from silicon cortical arrays in rhesus macaque motor cortex (Shenoy)

  • Overall, this study suggests that action potential amplitude declines more slowly than previously supposed, and performance can be maintained over the course of multiple years when decoding from threshold-crossing events rather than isolated action potentials.
  • During most time periods, decoder performance was not well correlated with action potential amplitude (p > 0.05 for three of four arrays)
    • Perhaps we are chasing the wrong dragon?
    • Still, minimal invasiveness / more channels is useful.

____References____

[0] Chestek CA, Gilja V, Nuyujukian P, Foster JD, Fan JM, Kaufman MT, Churchland MM, Rivera-Alvidrez Z, Cunningham JP, Ryu SI, Shenoy KV, Long-term stability of neural prosthetic control signals from silicon cortical arrays in rhesus macaque motor cortex.J Neural Eng 8:4, 045005 (2011 Aug)

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ref: -0 tags: decoding recording todo read biocompatibility histology electrodes future date: 01-28-2013 20:52 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

Things to read!

decoding:

  • PMID-20359500 Population decoding of motor cortical activity using a generalized linear model with hidden states
  • Robust satisficing linear regression: Performance/robustness trade-off and consistency criterion
  • PMID-15813408 Closed-loop cortical control of direction using support vector machines
  • Efficient Decoding With Steady-State Kalman Filter in Neural Interface Systems
    • Fixed gain: We analyze a low-complexity Kalman filter implementation in which the filter gain is approximated by its steady-state form, computed offline before real-time decoding commences.
    • We also find that the steady-state Kalman filter reduces the computational load (algorithm execution time) for decoding the firing rates of 25±3 single units by a factor of 7.0±0.9.

electrodes:

other random scribblings: Vascularization {1027} histology {736},{737} and size {1028},{747},{1026}, insulation {1033}. How very very important -- as important or moreso than the recording technology. What has happened to {149} ?

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ref: -0 tags: histology review electrode response bioactive coatings date: 01-28-2013 20:16 gmt revision:0 [head]

PMID-20577634 Biocompatibility of intracortical microelectrodes: current status and future prospects.

  • ... but the most widely used method to enhance biocompatibility is the chemical modification of neural probe surfaces with anti-inflammatory compounds, adhesion proteins, or bioactive molecules (Heiduschka and Thanos, 1998; He et al., 2006; Ludwig et al., 2006; Moxon et al., 2007; Rennaker et al., 2007; Seymour and Kipke, 2007; Zhong and Bellamkonda, 2007; Leung et al., 2008; Williams, 2008; Grill et al., 2009)
    • Have any of these achieved success?
    • Many other polymers are basically biocompatible, provided they still insulate after equilibriating with the surrounding vapor pressure.
    • Personally I don't think biocoatings wil lmatter much if there is persistent shear at the interface.
  • Does make sense to have the electrode surface attractive to neurons (Kennedy..). For a later date.

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ref: -0 tags: magnetic flexible insertion japan neural recording electrodes date: 01-28-2013 03:54 gmt revision:2 [1] [0] [head]

IEEE-1196780 (pdf) 3D flexible multichannel neural probe array

  • Shoji Takeuchi1, Takafumi Suzuki2, Kunihiko Mabuchi2 and Hiroyuki Fujita
  • wild -- they use a magnetic field to make the electrodes stand up!
  • Electrodes released with DRIE, as with Michigan probes.
  • As with many other electrodes, pretty high electrical impedance - 1.5M @ 1kHz.
    • 20x20um recording sites on 10um parylene.
  • Could push these into a rat and record extracellular APs, but nothing quantitative, no histology either.
  • Used a PEG coating to make them stiff enough to insert into the ctx (phantom in IEEE conference proceedings.)

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ref: Bjornsson-2006.09 tags: micro vasculature histology insertion speed tissue shear date: 01-28-2013 03:38 gmt revision:3 [2] [1] [0] [head]

PMID-16921203[0] Effects of insertion conditions on tissue strain and vascular damage during neuroprosthetic device insertion.

  • We have developed an ex vivo preparation to capture real-time images of tissue deformation during device insertion using thick tissue slices from rat brains prepared with fluorescently labeled vasculature.
  • Direct damage to the vasculature included severing, rupturing and dragging, and was often observed several hundred micrometers from the insertion site. (yikes!)
  • Advocate faster insertion of sharp devices. (tatoo needle?).
  • Cortical surface features greatly affected insertion success; insertions attempted through pial blood vessels resulted in severe tissue compression.
    • Thus, avoiding vasculature is useful not only for avoiding hemorrhaging, but also to prevent excessive tissue compression.
  • High degree of variability
    • Indicates that this should be measured! Scientifically interesting!
  • Insertion speeds:
    • Fast 2 mm/sec
    • Medium 500 um/sec
    • Slow 125 um/sec
  • Perhaps there is no need to experiment with multiple insertion speeds?

____References____

[0] Bjornsson CS, Oh SJ, Al-Kofahi YA, Lim YJ, Smith KL, Turner JN, De S, Roysam B, Shain W, Kim SJ, Effects of insertion conditions on tissue strain and vascular damage during neuroprosthetic device insertion.J Neural Eng 3:3, 196-207 (2006 Sep)

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ref: Lee-2005.12 tags: micromotion silicon michigan array simulation strain date: 01-28-2013 03:13 gmt revision:1 [0] [head]

PMID-16317231[0] Biomechanical analysis of silicon microelectrode-induced strain in the brain.

  • Simulation.
  • Our analysis demonstrates that when physical coupling between the electrode and the brain increases, the micromotion-induced strain of tissue around the electrode decreases as does the relative slip between the electrode and the brain.
  • Argue that micromotion and shear cause lost recording sensitivity due to inflammation and astroglial scarring around the electrode.
    • This seems to be the scientific consensus ATM.

____References____

[0] Lee H, Bellamkonda RV, Sun W, Levenston ME, Biomechanical analysis of silicon microelectrode-induced strain in the brain.J Neural Eng 2:4, 81-9 (2005 Dec)

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ref: Kim-2004.05 tags: histology electrode immune response Tresco hollow fiber membranes GFAP vimentin ED1 date: 01-28-2013 03:08 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-14741588[0] Chronic response of adult rat brain tissue to implants anchored to the skull.

  • The increase in tissue reactivity observed with transcranially implanted HFMs may be influenced by several mechanisms including chronic contact with the meninges and possibly motion of the device within brain tissue.
  • Broadly speaking, our results suggest that any biomaterial, biosensor or device that is anchored to the skull and in chronic contact with meningeal tissue will have a higher level of tissue reactivity than the same material completely implanted within brain tissue.
  • See also [1]
  • Could slice through the hollow fiber membrane for histology. (as we shall).
  • Good list of references.

____References____

[0] Kim YT, Hitchcock RW, Bridge MJ, Tresco PA, Chronic response of adult rat brain tissue to implants anchored to the skull.Biomaterials 25:12, 2229-37 (2004 May)
[1] Biran R, Martin DC, Tresco PA, The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull.J Biomed Mater Res A 82:1, 169-78 (2007 Jul)

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ref: XindongLiu-2006.03 tags: neural recording electrodes stability cat parlene McCreery MEA date: 01-28-2013 02:50 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

IEEE-1605268 (pdf) Evaluation of the Stability of Intracortical Microelectrode Arrays

  • 35-50um IR electrodes, electrolytically sharpened at a 10 deg angle, with a 5um blunted tip.
  • Electrodes coated in parylene, and exposed at the tip with an eximer laser. Surface area of tip ~500um^2.
  • Sorted based on features (duration, pk-pk, ratio of + to -, ratio of + time to - time), followed by a demixing matrix (PCA?)
  • Did experiments in 25 cats with some task (for another paper?); got recordings for up to 800 days. Seems consistent with our results.
  • Neurons were stable (by their metrics) for up to 60 days.
  • sparse arrays showed stable recordings sooner than dense arrays, perhaps because they are larger and more qucikly become attached to the dura.
  • Electrodes were always unstable for the first 2-3 months. Stability index is as high as 30-40 days.
  • Average electrode yield was ~ 25%.
  • no histology.

____References____

Xindong Liu and McCreery, D.B. and Bullara, L.A. and Agnew, W.F. Evaluation of the stability of intracortical microelectrode arrays Neural Systems and Rehabilitation Engineering, IEEE Transactions on 14 1 91 -100 (2006)

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ref: Feingold-2012.04 tags: Feingold Graybeil electrode moveable recording date: 01-28-2013 02:13 gmt revision:1 [0] [head]

PMID-22170970[0] A system for recording neural activity chronically and simultaneously from multiple cortical and subcortical regions in non-human primates.

  • Up to 127 electrodes in 14 brain areas for up to a year at a time.

____References____

[0] Feingold J, Desrochers TM, Fujii N, Harlan R, Tierney PL, Shimazu H, Amemori K, Graybiel AM, A system for recording neural activity chronically and simultaneously from multiple cortical and subcortical regions in nonhuman primates.J Neurophysiol 107:7, 1979-95 (2012 Apr)

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ref: Ward-2009.07 tags: microelectrode arrays immune response recording MEA Purdue date: 01-28-2013 01:52 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-19486899[0] Toward a comparison of microelectrodes for acute and chronic recordings.

  • Good research, paper well written.
  • Results suggest significant variability within and between microelectrode types with no clearly superior array (from the abstract).
  • As Miguel mantains, "Much of the new technology, however, does not supersede traditional microwire technology in its ability to evade a host immune response".
  • Initial implantation wound initiates a cascade of immune responses which culminates in a sheath of microglia, astrocytes, various ectracellular matrix constituents, and macrophages.
    • Decent citation list -- many people have been working on MEAs.
  • Fibrous encapusulation of the electrode is much less conductive than healthy nervous tissue, hence impedance measurements can be used to track tissue response.
  • Used Osort to sort the recorded neurons.
  • "Despite differing implant locations, and thus potentially differing levels of background neural activity, and differing scarring responses, which relates to the level of thermal noise in the observed signal (Ludwig et al., 2006), no significant SNR differences were observed among the MEA types for the duration of the study."
  • SNR trends did not seem to relate to site impedance trends over the 31-day period, and by inference, the extent of tissue encapsulation and neuronal density loss.
    • SNR is likely controlled by background neural noise, not thermal noise (which would be linked to impedance).
  • Electrodes with lower impedance generally recorded units from more sites than arrays with higher impedance.

____References____

[0] Ward MP, Rajdev P, Ellison C, Irazoqui PP, Toward a comparison of microelectrodes for acute and chronic recordings.Brain Res 1282no Issue 183-200 (2009 Jul 28)

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ref: -0 tags: brain micromotion magnetic resonance imaging date: 01-28-2013 01:38 gmt revision:0 [head]

PMID-7972766 Brain and cerebrospinal fluid motion: real-time quantification with M-mode MR imaging.

  • Measured brain motion via a clever MR protocol. (beyond my present understanding...)
  • ventricles move at up to 1mm/sec
  • In the Valsava maneuver the brainstem can move 2-3mm.
  • Coughing causes upswing of the CSF.

{1213}
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ref: Chhatbar-2010.05 tags: Lee von Kraus Francis SUNY downstate electrode floating headpost date: 01-28-2013 01:06 gmt revision:1 [0] [head]

PMID-20153370[0] A bio-friendly and economical technique for chronic implantation of multiple microelectrode arrays

  • Nesting design -- the headpost is the only transcutaneous object.

____References____

[0] Chhatbar PY, von Kraus LM, Semework M, Francis JT, A bio-friendly and economical technique for chronic implantation of multiple microelectrode arrays.J Neurosci Methods 188:2, 187-94 (2010 May 15)

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ref: Musallam-2007.02 tags: Musallam MEA floating rats electrodes date: 01-28-2013 00:42 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-17067683[0] A floating metal microelectrode array for chronic implantation

  • Cite Gualtierotti and Bailey (1968) for a neutral-boyancy electrode w/ rigid shaft.
  • Alumina ceramic base, laser drilled.
  • insulated with silane follwed by parylene-C, 3um.
  • Tips exposed by eximer laser. (Schmidt et al, 1995)
  • Electrophysiology, but not histology.
  • Earlier conference proceedings: PMID-17946982[1] Active floating micro electrode arrays (AFMA).

____References____

[0] Musallam S, Bak MJ, Troyk PR, Andersen RA, A floating metal microelectrode array for chronic implantation.J Neurosci Methods 160:1, 122-7 (2007 Feb 15)
[1] Kim T, Troyk PR, Bak M, Active floating micro electrode arrays (AFMA).Conf Proc IEEE Eng Med Biol Soc 1no Issue 2807-10 (2006)

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ref: Westby-1997.1 tags: recording microwire electrode MEA sweet sucrose saliva dissolving FET floating date: 01-28-2013 00:28 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-9350963 A floating microwire technique for multichannel neural recording and stimulation in the awake rat

  • sweet electrodes -- attached to glass micropipette with sucrose or saliva.
    • Chorover and DeLuca 1972 "A sweet new multiple electrode for chronic single unit recording". {1019}
  • 42 implanted rats, 252 implanted wires, 79% yield. 62% of electrodes still working at 5 weeks.
    • Targeting an area with really large somas (50um).
  • fully-floating 25um microwire ellectrodes.
  • platinum iridium, 25um, teflon coated, handled only with silastic-protected pliers & tweezers to prevent damage to the insulation.
  • electrode impdance range 200-900kOhms; check insulation by applying -3V to each electrode & looking for hydrogen bubbles.
  • soldering hardens platinum iridium alloy (huh).
  • (!!!) wires are stiffened for implantation by temporarily attaching them to a micropipette guide with sucrose which subsequently dissolves in the brain!
  • the smooth sucrose (40 grams in 50ml of water heated to 118C) coating requires about a week of desiccation to become hard enough for insertion into the brain without premature softening. Sucrose becomes clear like glass once fully desiccated.
  • the air above the craniotomy is sufficiently humid to dissolve the sucrose if left there for more than a few seconds.
  • used a miniature single-channel FET amplifier as a headstage - only one channel out of 6 could be recorded at once :( Thus their reults only apply to the best of the microwires implanted - not to all of them.
  • recorded onto a mac quadra (hahah) 20khz 12 bit
  • applying 160ua microstimulation pulses can restore low (200kohm) electrode impedance. Recording quality was generally improved for a few days following stimulation but then returned to an asymptotic level with the impedance at approximately 900kOhm.
  • electrodes only seemed to last 5 weeks, whence they declined to about 27% yeild - see figure 8.
  • good review of microelectrode recording up to that point (1997).

____References____

{1105}
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ref: Bullara-1983.09 tags: electrode grinding insulation stimulation date: 01-28-2013 00:27 gmt revision:1 [0] [head]

PMID-6632958[0] A microelectrode for delivery of defined charge densities.

  • Details the diamond impregnated lead grinding and epoxy insulation of 75um Pt-Ir wires;
  • Encapsulate the whole thing in Dacron mesh;
  • Electrodes are good for stimulating up to 300 uC / cm^2 * phase;
  • Charge balanced pulses 5-20ua in amplitude, 200us/phase, 20Hz repetition are sufficient to activate nearby cortical neurons.

____References____

[0] Bullara LA, McCreery DB, Yuen TG, Agnew WF, A microelectrode for delivery of defined charge densities.J Neurosci Methods 9:1, 15-21 (1983 Sep)

{736}
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ref: Liu-1999.09 tags: electrodes recording tissue response MEA histology date: 01-28-2013 00:24 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-10498377[0] Stability of the interface between neural tissue and chronically implanted intracortical microelectrodes.

  • implanted 7-shaft 35um iridium electrodes into the pericruciate gyrus of cats & measured the stability of recordings over several months.
  • electrodes were floating, under the dura; they note that connective tissue can force these floating arrays out of the brain, in further, or can encapsulate the electrodes.
    • electrodes activated by 'potentiodynamic cycling' to remove the insulation from the tip, I guess.
    • Insulation is epoxylite epoxy (5-10um thick) which is baked for curing and degassing at 100 and 170C each for 30 minutes.
    • more information on their fabrication in {1105}
  • Used the now-standard techniques for recording & analysis - amazing that this was all very new 10 years ago!
  • Measure stability not only on waveform shape (which will change as the position of the electrode relative to the neuron changes) but also neural tuning.
  • Lymphocytes were found to accumulate around the tips of the microstimulated sites.
  • Electrode sites that yielded recordings ('active') were all clean, with large neurons near the end, and with minimal connective tissue sheath (2-8 um; distance to nearby neurons was 30-50um).
    • Longest period for an active electrode was 242 days.
    • Electrode impedance was usually between 50 and 75 kOhm; there was no insulation failure.
  • Electrodes were stable even when the cat vigorously shook it's head in response to water placed on the head (!).
  • Electrodes were very unstable the first 2 weeks - 1 month ; rather stable thereafter.
    • Active electrodes tended to remain active ; inactive electrodes tended to remain inactive.

____References____

[0] Liu X, McCreery DB, Carter RR, Bullara LA, Yuen TG, Agnew WF, Stability of the interface between neural tissue and chronically implanted intracortical microelectrodes.IEEE Trans Rehabil Eng 7:3, 315-26 (1999 Sep)
[1] Bullara LA, McCreery DB, Yuen TG, Agnew WF, A microelectrode for delivery of defined charge densities.J Neurosci Methods 9:1, 15-21 (1983 Sep)

{1195}
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ref: Stevenson-2011.02 tags: Kording neural recording doubling northwestern chicago date: 01-28-2013 00:12 gmt revision:1 [0] [head]

PMID-21270781[0] How advances in neural recording affect data analysis.

  • Number of recorded channels doubles about every 7 years (slowish).
  • "Emerging data analysis techniques should consider both the computational costs and the potential for more accurate models associated with this exponential growth of the number of recorded neurons."

____References____

[0] Stevenson IH, Kording KP, How advances in neural recording affect data analysis.Nat Neurosci 14:2, 139-42 (2011 Feb)

{746}
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ref: Sanders-2000.1 tags: polymer fiber immune reaction biocompatibility rats polycaprolactone recording electrodes histology MEA date: 01-28-2013 00:01 gmt revision:11 [10] [9] [8] [7] [6] [5] [head]

PMID-10906696[0] Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density.

  • Fibers smaller than 6μm6 \mu m show reduced immune response.
    • Fibers implanted in the subcutaneous dorsum (below the skin in the back of rats).
    • Polypropylene. (like rope).
    • Wish the result extended to small beads & small electrodes. 7μm7 \mu m is tiny, but possible with insulated Au wires.
      • Beads: try PMID-1913150 -- shows that the 600um - 50um beads ('microspheres') are well tolerated.
      • Also {750}.
  • Macrophage density in tissue with fiber diameters 2.1-5.9um comparable to that of unoperated contralateral control.

"

fiber diametercapsule thickness
2.1-5.90.6
6.5-10.611.7
11.1-15.820.3
16.7-26.725.5

____References____

[0] Sanders JE, Stiles CE, Hayes CL, Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density.J Biomed Mater Res 52:1, 231-7 (2000 Oct)

{1211}
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ref: Harris-1998.08 tags: noise wolpert harris motor planning Fitt velocity variance control theory date: 01-27-2013 22:33 gmt revision:1 [0] [head]

PMID-9723616[0] Signal-dependent noise determines motor planning.

  • We present a unifying theory of eye and arm movements based on the single physiological assumption that the neural control signals are corrupted by noise whose variance increases with the size of the control signal
    • Poisson noise? (I have not read the article -- storing here for future reference.)
  • This minimum-variance theory accurately predicts the trajectories of both saccades and arm movements and the speed-accuracy trade-off described by Fitt's law.

____References____

[0] Harris CM, Wolpert DM, Signal-dependent noise determines motor planning.Nature 394:6695, 780-4 (1998 Aug 20)

{54}
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ref: bookmark-0 tags: intrinsic evolution FPGA GPU optimization algorithm genetic date: 01-27-2013 22:27 gmt revision:1 [0] [head]

!:

  • http://evolutioninmaterio.com/ - using FPGAs in intrinsic evolution, e.g. the device is actually programmed and tested.
  • - Adrian Thompson's homepage. There are many PDFs of his work on his homepage.
  • Parallel genetic algorithms on programmable graphics hardware
    • basically deals with optimizing mutation and fitness evaluation using the parallel arcitecture of a GPU: larger populations can be evaluated at one time.
    • does not concern the intrinsic evolution of algorithms to the GPU, as in the Adrian's work.
    • uses a linear conguent generator to produce random numbers.
    • used a really simple problem: Colville minimization problem which need only search through a four-dimensional space.
  • Cellular genetic algoritms and local search for 3-SAT problem on Graphic Hardware
    • concerning SAT: satisfiabillity technique: " many practical problems, such as graph coloring, job-shop scheduling, and real-world scheduling can be represented as a SAT problem.
    • SAT-3 refers to the length of the search clause. length 3 is apparently very hard..
    • they use a combination of greedy search (flip the bit that increases the fitness the largest ammount) and random-walk via point mutations to keep the algorithm away from local minima.
    • also use cellular genetic algorithm which works better on a GPU): select the optimal neignbor, not global, individual.
    • only used a GeForce 6200 gpu, but it was still 5x faster than a p4 2.4ghz.
  • Evolution of a robot controller using cartesian genetic programming
    • cartesian programming has many advantages over traditional tree based methods - e.g. blot-free evolution & faster evolution through neutral search.
    • cartesian programming is characterized by its encoding of a graph as a string of integers that represent the functions and connections between graph nodes, and program inputs and outputs.
      • this encoding was developed in the course of evolving electronic circuits, e.g. above ?
      • can encode a non-connected graph. the genetic material that is not utilized is analogous to biological junk DNA.
    • even in converged populations, small mutations can produce large changes in phenotypic behavior.
    • in this work he only uses directed graphs - there are no cycles & an organized flow of information.
    • mentions automatically defined functions - what is this??
    • used diffusion to define the fitness values of particular locations in the map. the fewer particles there eventually were in a grid location, the higher the fitness value of the robot that managed to get there.
  • Hardware evolution: on the nature of artifically evolved circuits - doctoral dissertation.
    • because evolved circuits utilize the parasitic properties of devices, they have little tolerance of the value of components. Reverse engineering of the circuits evolved to improve tolerance is not easy.

{897}
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ref: Harris-2011.08 tags: microelectrodes nanocomposite immune response glia recording MEA date: 01-27-2013 22:19 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-21654037[0] In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes

  • J P Harris, A E Hess, S J Rowan, C Weder, C A Zorman, D J Tyler and J R Capadona Case Western University.
  • Simple idea: electrodes should be rigid enough to penetrate the brain, yet soft enough to not damage it once implanted.
  • Many studies have shown that shear stress around a microelectrode shaft causes neural die-off and glial response.
  • You can only record from neurons if they are < 100um from the electrode tip.
  • Nanocomposite material is inspired by sea cucumber skin.
    • Our materials exhibit this behaviour by mimicking the architecture and proposed switching mechanism at play in the sea cucumber dermis by utilizing a polymer NC consisting of a controllable structural scaffold of rigid cellulose nanofibres embedded within a soft polymeric matrix. When the nanofibres percolate, they interact with each other through hydrogen bonding and form a nanofibre network that becomes the load-bearing element, leading to a high overall stiffness of the NC. When combined with a polymer system which additionally undergoes a phase transition at physiologically relevant temperatures, a contrast of over two orders of magnitude for the tensile elastic modulus is exhibited.
  • Probes were 200um wide, 100um thick, and had a point sharpened to 45deg.
  • Buckle force testing was done on 53um thick, 125um wide probes sharpened to a 30deg point.
  • Penetration stress through the rat pia is 1.2e7 dynes/cm^2 for a Si probe 40um thick and 80um wide.
  • See also {1198}

____References____

[0] Harris JP, Hess AE, Rowan SJ, Weder C, Zorman CA, Tyler DJ, Capadona JR, In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes.J Neural Eng 8:4, 046010 (2011 Aug)

{1198}
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ref: Harris-2011.12 tags: mechanically adaptive electrodes implants case western dissolving flexible histology Harris date: 01-25-2013 01:39 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-22049097[0] Mechanically adaptive intracortical implants improve the proximity of neuronal cell bodies.

  • See also [1]
  • Initial tensile modulus of 5GPa dropped to 12MPa. (almost 500-fold!)
    • Their polymer nanocomposite (NC) still swells 65-70% (with water?)
    • Implant size 100 x 200um.
  • Controlled with tungsten of identical size and coating.
  • Tethered to skull.
  • Interesting:
    • The neuronal nuclei density within 100 µm of the device at four weeks post-implantation was greater for the compliant nanocomposite compared to the stiff wire.
    • At eight weeks post-implantation, the neuronal nuclei density around the nanocomposite was maintained, but the density around the wire recovered to match that of the nanocomposite.
    • Hypothesis, in discussion: softer implants are affecting the time-course of the response rather that final results
  • The glial scar response to the compliant nanocomposite was less vigorous than it was to the stiffer wire
  • Cultured astrocytes have been shown to respond to mechanical stimuli via calcium signaling (Ostrow and Sachs, 2005).
  • Substrate stiffness is also known to shift cell differentiation in mesenchymal stem cells to be neurogenic, myogenic, or osteogenic (Engler et al., 2006).
  • In vivo studies which focus on the effects of electrode tethering have shown that untethered implants reduce the extent of the glial scar (Biran et al., 2007; Kim et al., 2004; Subbaroyan, 2007)
  • Parylene, polymide, and PDMS still each have moduli 6 orders of mangitude larger than that of the brain.
  • In some of their plots, immune response is higher around the nanocomposites!
    • Could be that their implant is still too large / stiff?
  • Note that recent research shows that vitemin may have neuroprotective effects --
    • Research has linked vimentin expression to rapid neurite extension in response to damage (Levin et al., 2009)
    • NG2+ cells that express vimentin have been proposed to support repair of central nervous system (CNS) damage, and stabilize axons in response to dieback from ED1+ cells (Alonso, 2005; Nishiyama, 2007; Busch et al., 2010)
  • Prior work (Frampton et al., 2010 PMID-20336824[2]) hypothesizes that a more compact GFAP response increases the impedance of an electrode which may decrease the quality of electrode recordings.

____References____

[0] Harris JP, Capadona JR, Miller RH, Healy BC, Shanmuganathan K, Rowan SJ, Weder C, Tyler DJ, Mechanically adaptive intracortical implants improve the proximity of neuronal cell bodies.J Neural Eng 8:6, 066011 (2011 Dec)
[1] Harris JP, Hess AE, Rowan SJ, Weder C, Zorman CA, Tyler DJ, Capadona JR, In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes.J Neural Eng 8:4, 046010 (2011 Aug)
[2] Frampton JP, Hynd MR, Shuler ML, Shain W, Effects of glial cells on electrode impedance recorded from neuralprosthetic devices in vitro.Ann Biomed Eng 38:3, 1031-47 (2010 Mar)

{1208}
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ref: Lewitus-2011.08 tags: dissolving polymer electrodes histology degrading date: 01-25-2013 01:31 gmt revision:2 [1] [0] [head]

PMID-21609850[0] The fate of ultrafast degrading polymeric implants in the brain.

  • Tyrosene-derived terpolymer (protein?) dissolves within hours & was re-absorbed.
  • Second terpolymer degrades quickly but is not resorbed.
    • This type resulted in continuous glial activation and loss of neural tissue compared to first.
  • Makes sense, not unexpected.

____References____

[0] Lewitus DY, Smith KL, Shain W, Bolikal D, Kohn J, The fate of ultrafast degrading polymeric implants in the brain.Biomaterials 32:24, 5543-50 (2011 Aug)

{1205}
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ref: Rennaker-2005.03 tags: electrode recording longevity mechanical insertion Oklahoma MEA date: 01-25-2013 01:21 gmt revision:3 [2] [1] [0] [head]

PMID-15698656[0] A comparison of chronic multi-channel cortical implantation techniques: manual versus mechanical insertion.

  • Over 60% of the animals implanted with the mechanical insertion device had driven activity at week 6
    • whereas none of the animals with manually inserted arrays exhibited functional responses after 3 weeks.
      • Roughly identical responses immediately following surgery.
      • Could be that the manual inserter had horizontal movement / shear. (This is solveable with a stereotax).
      • Other research showed little difference in tissue response at 10um/s or 100um/s PMID-21896383[1]
  • Multi-wire electrodes.
  • Mechanical insertion device was capable of rapidly inserting the electrode without visible compression of the brain.
  • Response measured relative to auditory stimulus.
  • Their insertion device looks like a pen.

____References____

[0] Rennaker RL, Street S, Ruyle AM, Sloan AM, A comparison of chronic multi-channel cortical implantation techniques: manual versus mechanical insertion.J Neurosci Methods 142:2, 169-76 (2005 Mar 30)
[1] Welkenhuysen M, Andrei A, Ameye L, Eberle W, Nuttin B, Effect of insertion speed on tissue response and insertion mechanics of a chronically implanted silicon-based neural probe.IEEE Trans Biomed Eng 58:11, 3250-9 (2011 Nov)

{1033}
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ref: Seymour-2009.1 tags: Parylene MEA biocompatibility pin hole water saturation PPX date: 01-25-2013 01:19 gmt revision:2 [1] [0] [head]

PMID-19703712[0] The insulation performance of reactive parylene films in implantable electronic devices.

  • Describe the development and testing of a superior form of parylene: poly(p-xylylene) functionalized with reactive group X (PPX-X)
  • Heat-treated PPX-X device impedance was 800% greater at 10kHz and 70% greater at 1Hz relative to heated parylene-C controls after 60 days (in saline).
  • Better wet attachment to the metal.

____References____

[0] Seymour JP, Elkasabi YM, Chen HY, Lahann J, Kipke DR, The insulation performance of reactive parylene films in implantable electronic devices.Biomaterials 30:31, 6158-67 (2009 Oct)

{1207}
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ref: -0 tags: Shenoy eye position BMI performance monitoring date: 01-25-2013 00:41 gmt revision:1 [0] [head]

PMID-18303802 Cortical neural prosthesis performance improves when eye position is monitored.

  • This proposal stems from recent discoveries that the direction of gaze influences neural activity in several areas that are commonly targeted for electrode implantation in neural prosthetics.
  • Can estimate eye position directly from neural activity & subtract it when performing BMI predictions.

{1206}
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ref: -0 tags: flexible polymer electrode recording polypyrrole Bizzi date: 01-25-2013 00:39 gmt revision:0 [head]

PMID-19164034 Cortical recording with polypyrrole microwire electrodes.

  • http://web.mit.edu/bcs/bizzilab/publications/bae2008.pdf
  • Electropolymerization of PPy on a glassy carbon electrode in solution.
  • Polypyrrole microwires were prepared by mounting a PPy film perpendicular to the stage of a cryo-microtome and slicing it in 20um sections.
  • Electrode mounted inside a glass capillary tube.
  • Impedance: 1e5 @ 1kHz.

{1111}
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ref: Stice-2007.06 tags: electrodes recording small rats S1 PGA histology GFAP date: 01-24-2013 21:07 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

PMID-17409479[0] Thin microelectrodes reduce GFAP expression in the implant site in rodent somatosensory cortex.

  • Implanted 12 um and 25 um polymide coated stainless steel
    • Wires coated with poly-glycolic acid (PGA) to facilitate implantation.
  • Only looked to 4 weeks.
  • 12 um implants significantly less GFAP (astrocyte) reactivity at 4 weeks, no difference at 2 weeks (figure 9 & 10).
    • B = bare, P = PGA coated.
  • Can use to bolster the idea that smaller implants are less irritating.

____References____

[0] Stice P, Gilletti A, Panitch A, Muthuswamy J, Thin microelectrodes reduce GFAP expression in the implant site in rodent somatosensory cortex.J Neural Eng 4:2, 42-53 (2007 Jun)

{749}
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ref: Biran-2007.07 tags: tresco biocompatibility tether skull electrodes Michigan probe recording Tresco date: 01-24-2013 20:11 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-17266019[0] The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull.

  • Good, convincing, figures.

____References____

[0] Biran R, Martin DC, Tresco PA, The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull.J Biomed Mater Res A 82:1, 169-78 (2007 Jul)

{913}
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ref: Ganguly-2011.05 tags: Carmena 2011 reversible cortical networks learning indirect BMI date: 01-23-2013 18:54 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-21499255[0] Reversible large-scale modification of cortical networks during neuroprosthetic control.

  • Split the group of recorded motor neurons into direct (decoded and controls the BMI) and indirect (passive) neurons.
  • Both groups showed changes in neuronal tuning / PD.
    • More PD. Is there no better metric?
  • Monkeys performed manual control before (MC1) and after (MC2) BMI training.
    • The majority of neurons reverted back to original tuning after BC; c.f. [1]
  • Monkeys were trained to rapidly switch between manual and brain control; still showed substantial changes in PD.
  • 'Near' (on same electrode as direct neurons) and 'far' neurons (different electrode) showed similar changes in PD.
    • Modulation Depth in indirect neurons was less in BC than manual control.
  • Prove (pretty well) that motor cortex neuronal spiking can be dissociated from movement.
  • Indirect neurons showed decreased modulation depth (MD) -> perhaps this is to decrease interference with direct neurons.
  • Quote "Studies of operant conditioning of single neurons found that conconditioned adjacent neurons were largely correlated with the conditioned neurons".
    • Well, also: Fetz and Baker showed that you can condition neurons recorded on the same electrode to covary or inversely vary.
  • Contrast with studies of motor learning in different force fields, where there is a dramatic memory trace.
    • Possibly this is from proprioception activating the cerebellum?

Other notes:

  • Scale bars on the waveforms are incorrect for figure 1.
  • Same monkeys as [2]

____References____

[0] Ganguly K, Dimitrov DF, Wallis JD, Carmena JM, Reversible large-scale modification of cortical networks during neuroprosthetic control.Nat Neurosci 14:5, 662-7 (2011 May)
[1] Gandolfo F, Li C, Benda BJ, Schioppa CP, Bizzi E, Cortical correlates of learning in monkeys adapting to a new dynamical environment.Proc Natl Acad Sci U S A 97:5, 2259-63 (2000 Feb 29)
[2] Ganguly K, Carmena JM, Emergence of a stable cortical map for neuroprosthetic control.PLoS Biol 7:7, e1000153 (2009 Jul)

{1052}
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ref: Chestek-2009.09 tags: BMI problems address critique spike sorting Shenoy date: 01-23-2013 02:23 gmt revision:3 [2] [1] [0] [head]

IEEE-5332822 (pdf) Neural prosthetic systems: Current problems and future directions

  • Where there is unlikely to be improvements: spike sorting and spiking models.
  • Where there are likely to be dramatic improvements: non-stationarity of recorded waveforms, limitations of a linear mappings between neural activity and movement kinematics, and the low signal to noise ratio of the neural data.
  • Compare different sorting methods: threshold, single unit, multiunit, relative to decoding.
  • Plot waveform changes over an hour -- this contrasts with earlier work (?) {1032}
  • Figure 5: there is no obvious linear transform between neural activity and the kinematic parameters.
  • Suggest that linear models need to be replaced by the literature of how primates actually make reaches.
  • Discuss that offline performance is not at all the same as online; in the latter the user can learn and adapt on the fly!

____References____

Chestek, C.A. and Cunningham, J.P. and Gilja, V. and Nuyujukian, P. and Ryu, S.I. and Shenoy, K.V. Engineering in Medicine and Biology Society, 2009. EMBC 2009. Annual International Conference of the IEEE 3369 -3375 (2009)

{1192}
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ref: -2002 tags: sea slugs flexible electrodes polymide Washington date: 01-04-2013 18:46 gmt revision:0 [head]

IEEE-1002325 (pdf) Silicon micro-needles with flexible interconnections

  • Implanted their isolated needles (see also {219}) in sea slugs Tritonia diomedea
    • Sea slug neurons are large -- up to 400um -- makes recording easier.
  • Silicon needles fabricated via reactive ion etching and SF6 sharpening.
  • 'intracellular recording!
  • Pretty advanced fabrication, I guess.

{1040}
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ref: Du-2011.01 tags: Harrison recording electrode MEA Blanche date: 01-04-2013 02:43 gmt revision:3 [2] [1] [0] [head]

PMID-22022568[0] Multiplexed, High Density Electrophysiology with Nanofabricated Neural Probes

  • The number of single-units possible to record doubles every 7 years [5].
  • Electrodes must be within 100um of soma to relaibly detect extracellular action potentials.
  • Existing Michigan arrays have trace features around >=1 um; here they use E-beam lithography to decrease the probe width dramatically.
    • Their wire widths are 290 nm. Still bigger than 40nm process (?)
  • Seem to use Reid Harrison's ASIC RHA22132 design.
  • noise of electrodes progressively decreased with consecutive gold electroplating cycles. Plating makes the electrodes rough, and decreases their impedance to around 1 M.
    • Electrode contacts are around 10 x 10 um square, 108 um^2 area.
  • Intrinsic noise of the amplifier 1.7 uV RMS.
  • 290 nm wire had an impedance of 9.2 k -- corresponding to 1.0 uV rms noise.
  • able to record from the same neuron from several adjacent electrodes. Spacing ~ 28 um.
  • Detail their process extensively -- 40% of probes survived the process with <= 5 defective channels. THey propose further optimization to the e-beam lithography. Probes took 7 hours to pattern on the lithography machine (!).

____References____

[0] Du J, Blanche TJ, Harrison RR, Lester HA, Masmanidis SC, Multiplexed, high density electrophysiology with nanofabricated neural probes.PLoS One 6:10, e26204 (2011)

{1189}
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ref: -0 tags: microelectrode array flexible PDMS via interconnect Georgia date: 01-04-2013 00:33 gmt revision:0 [head]

IEEE-6197244 (pdf) A PDMS-Based Integrated Stretchable Microelectrode Array (isMEA) for Neural and Muscular Surface Interfacing

  • Targeted at e.g. ECoG; in this paper, they look at cat muscle (epimyscial recording).
  • MEA is directly fabricated with a stretchable substrate, such as a thin PCB or ASIC, through via bonding for built-in packaging.

{1188}
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ref: -0 tags: flexible micxrowire arrays electrode recording Georgia polymide date: 01-04-2013 00:13 gmt revision:1 [0] [head]

IEEE-906517 (pdf) Flexible microelectrode arrays with integrated insertion devices

  • 2001 MEMS Conference.
  • FMA = flexible microelectrode arrays.
  • Both for nerves (pass-through needle) and cortex (removeable needle).
    • Primarily tested in tissue proxies.
  • Anticipated the utility of photolithography for patterning the electrodes + rigid insertion devices.
  • The elastic modulus of polymers like polymide are two orders of magnitude less than metals, but still six orders of magnitude higher than brain tissue (46kPa).
  • Pass-through needle very similar to the threaded wire idea.
  • removable needle simply stops the thread & drives the needle a bit further to break the attachment site.
    • Did not test removable needle technique (?)
  • Defined electroplating with a thick photoresist mask, as Michel says.
  • Tested FMAs with movement and acceleration vs. rigid arrays. FMAs faired much better, of course!

____References____

' ''' ()

{1178}
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ref: -0 tags: parylene flexible neural recording drug delivery microfluidics 2012 inserter needle release date: 01-02-2013 22:41 gmt revision:1 [0] [head]

PMID-23160191 Novel flexible Parylene neural probe with 3D sheath structure for enhancing tissue integration

  • They seem to think that drugs are critical for success: "These features will enhance tissue integration and improve recording quality towards realizing reliable chronic neural interfaces."
  • Similar to Kennedy: "The sheath structure allows for ingrowth of neural processes leading to improved tissue/probe integration post implantation." 8 electrodes, 4 on the cone interior, 4 on the exterior.
    • opening is 50um at tip, 300 um at base.
  • Used a PEEK-stiffened parylene ZIF connection.
  • Only tested in agarose, but it did properly release from the inserter needle.
  • I wonder if we could use a similar technique..
  • "Lab on a chip" journal (Royal society of Chemistry). nice.

{1187}
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ref: -0 tags: neural recording topologies circuits operational transconductance amplifiers date: 01-02-2013 20:00 gmt revision:0 [head]

PMID-22163863 Recent advances in neural recording microsystems.

  • Decent review. Has some depth on the critical first step of amplification.

{1186}
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ref: -0 tags: voltage sensitive dyes fluorescent protein date: 01-02-2013 05:08 gmt revision:0 [head]

PMID-20622860 Imaging brain electric signals with genetically targeted voltage-sensitive fluorescent proteins.

  • Interesting: Most fluorescent fusion proteins form intracellular aggregates during long-term expression in mammalian neurons, although this effect appears to be minimal in Aequorea victoria–derived fluorescent proteins.
  • See also {1185}

{1184}
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ref: -0 tags: optical neural recording photon induced electron transfer date: 01-02-2013 04:25 gmt revision:2 [1] [0] [head]

PMID-22308458 Optically monitoring voltage in neurons by photo-induced electron transfer through molecular wires.

  • Photoinduced electron transfer.
    • About what you would think -- a photon bumps an electron into a higher orbital, and this electron can be donated to another group or drop back down & fluoresce a photon.
  • Good sensitivity: ΔF/F\Delta F/F of 20-27% per 100mV, fast kinetics.
  • Not presently genetically targetable.
  • Makes sense in terms of energy: "A 100-mV depolarization changes the PeT driving force by 0.05 eV (one electron × half of 100-mV potential, or 0.05 V). Because PeT is a thermally controlled process, the value of 0.05 eV is large relative to the value of kT at 300 K (0.026 eV), yielding a large dynamic range between the rates of PeT at resting and depolarized potentials.
  • Why electrochromic dyes have plateaued:
    • "In contrast, electrochromic dyes have smaller delta G values, 0.003 (46) to 0.02 (47) eV, and larger comparison energies. Because the interaction is a photochemically controlled process, the energy of the exciting photon is the comparison energy, which is 1.5–2 eV for dyes in the blue-to-green region of the spectrum. Therefore, PeT and FRET dyes have large changes in energy versus their comparison energy (0.05 eV vs. 0.026 eV), giving high sensitivities; electrochromic dyes have small changes compared with the excitation photon (0.003–0.02 eV vs. 2 eV), producing low voltage sensitivity."

{1183}
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ref: -0 tags: optical imaging neural recording diamond magnetic date: 01-02-2013 03:44 gmt revision:0 [head]

PMID-22574249 High spatial and temporal resolution wide-field imaging of neuron activity using quantum NV-diamond.

  • yikes: In this work we consider a fundamentally new form of wide-field imaging for neuronal networks based on the nanoscale magnetic field sensing properties of optically active spins in a diamond substrate.
  • Cultured neurons.
  • NV = nitrogen-vacancy defect centers.
    • "The NV centre is a remarkable optical defect in diamond which allows discrimination of its magnetic sublevels through its fluorescence under illumination. "
    • We show that the NV detection system is able to non-invasively capture the transmembrane potential activity in a series of near real-time images, with spatial resolution at the level of the individual neural compartments.
  • Did not actually perform neural measurements -- used a 10um microwire with mA of current running through it.
    • I would imagine that actual neurons have far less current!

{1182}
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ref: -0 tags: optical recording voltage sensitive dyes redshirt date: 01-02-2013 03:17 gmt revision:3 [2] [1] [0] [head]

PMID-16050036 Imaging brain activity with voltage- and calcium-sensitive dyes.

  • Voltage-sensitive dyes are well suited for measuring synaptic integration, as:
    • Electrodes are too blunt to effectively record these fine, < 1um diameter structures.
    • The surface area to volume ratio is highest in the dendrites
    • Voltage-sensitive dyes also permeate internal membranes not subject to voltage gradients, hence this does not contribute to the signal, leading to a decreased ΔF/F\Delta F / F .
  • Dominant experimental noise is shot noise, statistical -- see {1181}.
  • modern dyes and imagers can reliably record single action potentials; spatial averaging yields similar resolution as electrical recording.
  • They performed optical recording of Aplysia sensory ganglia, and discovered following light tail touch: "It is almost as if the Aplysia nervous system is designed such that every cell in the abdominal ganglion cares about this (and perhaps every) sensory stimulus. In addition, more than 1000 neurons in other ganglia are activated by this touch..."
      • These results force a more pessimistic view of the present understanding of the neuronal basis of apparently simple behaviors in relatively simple nervous systems.
  • Used calcium imaging on olfactory glomeruli of mice and turtles; measurements were limited by either shot-noise or heart/breathing artifacts.
  • Confocal and two-photon microscopes, due to their exchange of spatial resolution for sensitivity, are not useful with voltage-sensitive dyes.
    • The generation of fluorescent photons in the 2-photon confocal microscope is not efficient. We compared the signals from Calcium Green-1 in the mouse olfactory bulb using 2-photon and ordinary microscopy. In this comparison the number of photons contributing to the intensity measurement in the 2-photon confocal microscope was about 1000 times smaller than the number measured with the conventional microscope and a CCD camera.
  • By the numbers, quote: Because only a small fraction of the 10e16 photons/ms emitted by a tungsten filament source will be measured, a signal-to-noise ratio of 10e8 (see above) cannot be achieved. A partial listing of the light losses follows. A 0.9-NA lamp collector lens would collect 0.1 of the light emitted by the source. Only 0.2 of that light is in the visible wavelength range; the remainder is infrared (heat). Limiting the incident wavelengths to those, which have the signal means, that only 0.1 of the visible light is used. Thus, the light reaching the
preparation might typically be reduced to 1013 photons/ms. If the light-collecting system that forms the image has high efficiency e.g., in an absorption measurement, about 1013 photons/ms will reach the image plane. (In a fluorescence measurement there will be much less light measured because 1. only a fraction of the incident photons are absorbed by the fluorophores, 2. only a fraction of the absorbed photons appear as emitted photons, and 3. only a fraction of the emitted photons are collected by the objective.) If the camera has a quantum efficiency of 1.0, then, in absorption, a total of 10e13 photoelectrons/ms will be measured. With a camera of 1000 pixels, there will be 10e10 photoelectrons/ms/pixel. The shot noise will be 10e5 photoelectrons/ms/pixel; thus the very best that can be expected is a noise that is 10e−5 of the resting light (a signal-to-noise ratio of 100 db). The extra light losses in a fluorescence measurement will further reduce the maximum obtainable signal-to-noise ratio.

{1181}
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ref: -0 tags: neural imaging recording shot noise redshirt date: 01-02-2013 02:20 gmt revision:0 [head]

http://www.redshirtimaging.com/redshirt_neuro/neuro_lib_2.htm

  • Shot Noise: The limit of accuracy with which light can be measured is set by the shot noise arising from the statistical nature of photon emission and detection.
    • If an ideal light source emits an average of N photons/ms, the RMS deviation in the number emitted is N\sqrt N .
    • At high intensities this ratio NN\frac{N}{\sqrt N} is large and thus small changes in intensity can be detected. For example, at 10^10 photons/ms a fractional intensity change of 0.1% can be measured with a signal-to-noise ratio of 100.
    • On the other hand, at low intensities this ratio of intensity divided by noise is small and only large signals can be detected. For example, at 10^4 photons/msec the same fractional change of 0.1% can be measured with a signal-to-noise ratio of 1 only after averaging 100 trials.

{1179}
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ref: -0 tags: optical coherence tomography neural recording squid voltage sensitive dyes review date: 12-23-2012 21:00 gmt revision:4 [3] [2] [1] [0] [head]

PMID-20844600 Detection of Neural Action Potentials Using Optical Coherence Tomography: Intensity and Phase Measurements with and without Dyes.

  • Optical methods of recording have been investigated since the 1940's:
    • During action potential (AP) propagation in neural tissue light scattering, absorption, birefringence, fluorescence, and volume changes have been reported (Cohen, 1973).
  • OCT is reflection-based, not transmission: illuminate and measure from the same side.
    • Here they use spectral domain OCT, where the mirror is not scanned; rather SD-OCT uses a spectrometer to record interference of back-scattered light from all depth points simultaneously (Fercher et al., 1995).
    • Use of a spectrometer allows imaging of an axial line within 10-50us, sufficient for imaging action potentials.
    • SD-OCT, due to some underlying mathematics which I can't quite grok atm, can resolve/annul common-mode phase noise for high temporal and Δphase\Delta phase measurement (high sensitivity).
      • This equates to "microsecond temporal resolution and sub-nanometer optical path length resolution".
  • OCT is generally (intially?) used for in-vivo imaging of retinas, in humans and other animals.
  • They present new data for depth-localization of neural activity in squid giant axons (SGA) stained with a voltage-sensitive near-infrared dye.
    • Note: averaged over 250 sweeps.
  • ΔPhase>>ΔIntensity\Delta Phase &gt;&gt; \Delta Intensity -- figure 4 in the paper.
  • Use of voltage-sensitive dyes improves the resolution of ΔI\Delta I , but not dramatically --
    • And Δphase\Delta phase is still a bit delayed.
    • Electrical recording is the control.
      • It will take significant technology development before optical methods exceed electrical methods...
  • Looks pretty preliminary. However, OCT can image 1-2mm deep in transparent tissue, which is exceptional.
  • Will have to read their explanation of OCT.
  • Used in a squid giant axon prep. 2010, wonder if anything new has been done (in vivo?).
  • Claim that progress is hampered by limited understanding of how these Δphase\Delta phase signals arise.

{1180}
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ref: -0 tags: optical coherence tomography neural recording aplysia date: 12-23-2012 09:12 gmt revision:2 [1] [0] [head]

PMID-19654752 Detecting intrinsic scattering changes correlated to neuron action potentials using optical coherence imaging.

  • Aplysia, intrinsic imaging of scattering change following electrical stimulation.
    • Why did it take so long for them to get this paper out.. ?
  • Nicolelis first cited author.
  • Quality of recording not necessarily high.
  • quote: "Typical transverse resolutions in OCT (10-20um) are likely insufficient to identify smaller mamallian neurons that are often studied in neuroscience."
    • Solution: optical coherence microscopy (OCM), where a higher NA lens focuses the light to a smaller spot.
    • Expense: shorter depth-of-field.
  • Why does this work? "One mechanism of these optical signals is believed to be a realignment of charged membrane proteins in response to voltage change [6].
  • A delay of roughly 70ms was observed between the change in membrane voltage and the change in scattering intensity.
    • That's slow! Might be due to conduction velocity in Aplysia.
  • SNR of scattering measurement not too high -- the neurons are alive, afterall, and their normal biological processes cause scattering changes.
    • Killing the neurons with KCl dramatically decreased the variance of scattering, consistent with this hpothesis.
  • Birefringence: "Changes in the birefringence of nerves due to electrical activity have been shown to be an order of magnitude larger than scattering intensity changes" PMID-5649693

{1173}
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ref: -0 tags: Moshe looks automatic programming google tech talk links date: 11-07-2012 07:38 gmt revision:3 [2] [1] [0] [head]

List of links from Moshe Looks google tech talk:

{1172}
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ref: -0 tags: matlab STL boost programming C++ date: 11-06-2012 21:58 gmt revision:2 [1] [0] [head]

Recently decided to move myopen's sorting program from sqlite-based persistent state to matlab persistent state, for better interoperability with lab rigs & easier introspection. For this I wrote a class for serializing STL / boost based one, two, and three dimensional resizeable containers to and from matlab files.

The code has been tested (albeit not extensively), and therefore may be of use to someone else, even if as an example. See: http://code.google.com/p/myopen/source/browse/trunk/common_host/matStor.cpp

As you can see from the header (below), the interface is nice and concise!

#ifndef __MATSTOR_H__
#define __MATSTOR_H__

class MatStor{
        typedef boost::multi_array<float, 3> array3; 
        typedef boost::multi_array<float, 2> array2; 
        
        std::string m_name; //name of the file.
        std::map<std::string, std::vector<float> > m_dat1; //one dimensional
        std::map<std::string, array2> m_dat2; //two dimensions
        std::map<std::string, array3> m_dat3; //three!
public:
        MatStor(const char* fname); 
        ~MatStor(); 
        void save(); 
        void setValue(int ch, const char* name, float val);
        void setValue2(int ch, int un, const char* name, float val);
        void setValue3(int ch, int un, const char* name, float* val, int siz);
        float getValue(int ch, const char* name, float def);
        float getValue2(int ch, int un, const char* name, float def);
        void getValue3(int ch, int un, const char* name, float* val, int siz);
}; 
#endif

{1171}
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ref: -0 tags: Zador Peikon cold spring plos date: 11-06-2012 19:46 gmt revision:1 [0] [head]

Sequencing the Connectome

  • Quote: "Interestingly, the utility of the connectome in C. elegans is somewhat limited because function is highly multiplexed, with different neurons performing different roles depending on the state of neuromodulation [7], possibly as a mechanism for compensating for the small number of neurons."
  • In comparison, the authors argue that the role of neurons in mammalian brains is much more highly determined by connectivity / physical location, and support this with examples from the visual system (area MT; how layer in V1 determines simple vs. complex tuning).
  • Only have started work on this highly ambitious project -- current plan is to use PRV amplicons for permuting the neuronal barcodes -- and offer no results, just the general framework of the idea.
    • Given that Ian spoke of the idea when he first started at CSH, I wonder just how practical this idea is?

{1169}
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ref: -0 tags: artificial intelligence projection episodic memory reinforcement learning date: 08-15-2012 19:16 gmt revision:0 [head]

Projective simulation for artificial intelligence

  • Agent learns based on memory 'clips' which are combined using some pseudo-bayesian method to trigger actions.
    • These clips are learned from experience / observation.
    • Quote: "..more complex behavior seems to arise when an agent is able to “think for a while” before it “decides what to do next.” This means the agent somehow evaluates a given situation in the light of previous experience, whereby the type of evaluation is different from the execution of a simple reflex circuit"
    • Quote: "Learning is achieved by evaluating past experience, for example by simple reinforcement learning".
  • The forward exploration of learned action-stimulus patterns is seemingly a general problem-solving strategy (my generalization).
  • Pretty simple task:
    • Robot can only move left / right; shows a symbol to indicate which way it (might?) be going.

{1155}
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ref: -0 tags: filtering spike sorting AUC ROC r date: 08-08-2012 23:35 gmt revision:12 [11] [10] [9] [8] [7] [6] [head]

A frequent task in the lab is to sort spikes (extracellular neural action potentials) from background noise. In the lab we are working on doing this wirelessly; to minimize power consumption, spike sorting is done before the radio. In this way only times of spikes need be transmitted, saving bandwidth and power. (This necessitates a bidirectional radio protocol, but this is a worthy sacrifice).

In most sorting programs (e.g. Plexon), the raw signal is first thresholded, then waveform snippets (typically 32 samples long) are compared to a template to accept/reject them, or to sort them into different units. The comparison metric is usually the mean-squared error, MSE, aka the L2 norm. This makes sense, as the spike shapes are assumed to be stereotyped (they may very well not be), and the noise white / uncorrelated (another debatable assumption).

On the headstage we are working with for wireless neural recording, jumps and memory moves are expensive operations, hence we've elected to do no waveform extraction, and instead match continuously match. By using the built-in MPEG compression opcodes, we can compute the L1 norm at a rate of 4 samples / clock -- very efficient. However, this was more motivated by hardware considerations an not actual spike sorting practice. Literature suggests that for isolating a fixed-pattern signal embedded in noise, the best solution is instead a matched filter.

Hence, a careful study of spike-sorting was attempted in matlab, given the following assumptions: fixed spike shape (this was extracted from real data), and uncorrelated band-limited noise. The later was just white noise passed through a bandpass filter, e.g.

cheby1(3, 2, [500/15e3 7.5/15])

Where the passband edges are 500 Hz and 15kHz, at a sampling rate of 30kHz. (Actual rate is 31.25kHz). Since the spike times are known, we can rigorously compare the Receiver Operating Characteristic (ROC) and the area under curve (AUC) for different sorting algorithms. Four were tried: L1 (as mentioned above, motivated by the MPEG opcodes), L2 (Plexon), FIR matched filter, and IIR matched filter.

The latter was very much an experiment -- IIR filters are efficiently implemented on the blackfin processor, and they generally require fewer taps than their equivalent FIR implementation. To find an IIR equivalent to a given FIR matched filter (whose impulse response closely looks like the actual waveshape, just time-reversed), the filter parameters were simply optimized to match the two impulse responses. To facilitate the search, the denominator was specified in terms of complex conjugate pole locations (thereby constraining the form of the filter), while the numerator coefficients were individually optimized. Note that this is not optimizing given the objective to maximize sorting quality -- rather, it is to make the IIR filter impulse response as close as possible to the FIR matched filter, hence computationally light.

And yet: the IIR filter outperforms the FIR matched filter, even though the IIR filter has 1/3 the coefficients (10 vs 32)! Below is the AUC quality metric for the four methods.

And here are representative ROC curves at varying spike SNR ratios.

The remarkable thing is that even at very low SNR, the matched IIR filter can reliably sort cells from noise. (Note that the acceptable false positive here should be weighted more highly; in the present analysis true positive and false positive are weighted equally, which is decidedly non-Bayesian given most of the time there is no spike.) The matched IIR filter is far superior to the normal MSE to template / L2 norm method -- seems we've been doing it wrong all along?

As for reliably finding spikes / templates / filters when the SNR < 0, the tests above - which assume an equal number of spike samples and non-spike samples -- are highly biased; spikes are not normally sortable when the SNR < 0.


Upon looking at the code again, I realized three important things:

  1. The false positive rate need to be integrated over all time where there is no spike, just the same as the true positive is over all time where there is a spike.
  2. All methods need to be tested with 'distractors', or other spikes with a different shape.
  3. The FIR matched filter was backwards!

Including #1 above, as expected, dramatically increased the false positive rate, which is to be expected and how the filters will be used in the real world. #2 did not dramatically impact any of the discriminators, which is good. #3 alleviated the gap between the IIR and FIR filters, and indeed the FIR matched filter performance now slightly exceeds the IIR matched filer.

Below, AUC metric for 4 methods.

And corresponding ROC for 6 different SNR ratios (note the SNRs sampled are slightly different, due to the higher false positive rate).

One thing to note: as implemented, the IIR filter requires careful matching of poles and zeros, and is may not work with 1.15 fixed-point math on the Blackfin. The method really deserves to be tested in vivo, which I shall do shortly.


More updates:

See www.aicit.org/jcit/ppl/JCIT0509_05.pdf -- they add an 'adjustment' function to the matched filter due to variance in the amplitude of spikes, which adds a little performance at low SNRs.

F(t)=[x(t)kσe˙ 1x(t)kσ] n F(t) = \left[ \frac{x(t)}{k \sigma} \dot e^{1-\frac{x(t)}{k \sigma}} \right]^n

Sigma is the standard deviation of x(t), n and k determine 'zoom intensity and zoom center'. The paper is not particularly well written - there are some typos, and their idea seems unjustified. Still the references are interesting:

  • IEEE-238472 (pdf) Optimal detection, classification, and superposition resolution in neural waveform recordings.
    • Their innovation: whitening filter before template matching, still use L2 norm.
  • IEEE-568916 (pdf) Detection, classification, and superposition resolution of action potentials in multiunit single-channel recordings by an on-line real-time neural network
    • Still uses thresholding / spike extraction and L2 norm. Inferior!
  • IEEE-991160 (pdf) Parameter estimation of human nerve C-fibers using matched filtering and multiple hypothesis tracking
    • They use a real matched filter to detect extracellular action potentials.


Update: It is not to difficult to convert FIR filters to IIR filters using simple numerical optimization. Within my client program, this is done using simulated annealing; have tested this using fminsearch in matlab. To investigate the IIR-filter fitting problem more fully, I sliced the 10-dimensional optimization space along pairs of dimensions about the optimum point as found using fminsearch.

The parameters are as follows:

  1. Two poles, stored as four values (a real and imaginary part for each pole pair). These are expanded to denominator coefficients before evaluating the IIR filter.
  2. Five numerator coeficients.
  3. One delay coefficient (to match the left/right shift).

The figure below plots the +-1 beyond the optimum for each axis pair. Click for full resolution image. Note that the last parameter is discrete, hence steps in the objective function. Also note that the problem is perfectly quadratic for the numerator, as expected, which is why LMS works so well.

Note that for the denominator pole locations, the volume of the optimum is small, and there are interesting features beyond this. Some spaces have multiple optima.

The next figure plots +-0.1 beyond the optimum for each axis vs. every other one. It shows that, at least on a small scale, the problem becomes very quadratic in all axes hence amenable to line or conjugate gradient search.

Moving away from planes that pass through a found optima, what does the space look like? E.g. From a naive start, how hard is it to find at least one workable solution? To test this, I perturbed the found optimum with white noise in the parameters std 0.2, and plotted the objective function as before, albeit at higher resolution (600 x 600 points for each slice).

These figures show that there can be several optima in the denominator, but again it appears that a very rough exploration followed by gradient descent should arrive at an optima.

{1168}
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ref: -0 tags: debian linux github persistent ssh authentication date: 07-27-2012 01:40 gmt revision:1 [0] [head]

If you don't want to repeatedly enter in your username/password for github when commiting, you'll want to enable an RSA authetication key.

-- http://www.debian.org/devel/passwordlessssh run

 ssh-keygen 
(with no options).

-- then https://help.github.com/articles/working-with-ssh-key-passphrases

 ssh-keygen -p 
with your github passphrase (I'm not totally sure this is essential).

For me, pull and push aftwerard worked without needing to supply my password. Easy!

{253}
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ref: Mehring-2003.12 tags: BMI LFP MUA SUA Mehring Vaadia date: 07-24-2012 15:54 gmt revision:3 [2] [1] [0] [head]

PMID-14634657[0]Inference of hand movements from local field potentials in monkey motor cortex

  • idea: you get equally good predictions from SUA, LFP, or MUA in decoding a 8-target center-out task.
  • c.f. {1167}

____References____

{1167}
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ref: -0 tags: SUA LFP BMI decoding Donoghue date: 07-24-2012 15:54 gmt revision:0 [head]

PMID-22157115 Decoding 3D reach and grasp from hybrid signals in motor and premotor cortices: spikes, multiunit activity, and local field potentials.

  • Idea: you get more information from SUA (what they call SA) activity than broadband LFPS for predicting reach direction / position for a freely moving monkey.
  • C.F. {253}

{1166}
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ref: Chen-2004.08 tags: brain phantoms agar agarose proxy date: 07-13-2012 01:39 gmt revision:3 [2] [1] [0] [head]

Regarding brain phantoms:

Pia:

Also, both hydrophilic and hydrophobic cleaning appears to be superior to bare tungsten, with the hydrophillic surface treatment slightly superior -- PMID-16686416[2]

____References____

[0] Chen ZJ, Gillies GT, Broaddus WC, Prabhu SS, Fillmore H, Mitchell RM, Corwin FD, Fatouros PP, A realistic brain tissue phantom for intraparenchymal infusion studies.J Neurosurg 101:2, 314-22 (2004 Aug)
[1] Ritter RC, Quate EG, Gillies GT, Grady MS, Howard MA 3rd, Broaddus WC, Measurement of friction on straight catheters in in vitro brain and phantom material.IEEE Trans Biomed Eng 45:4, 476-85 (1998 Apr)
[2] Jensen W, Yoshida K, Hofmann UG, In-vivo implant mechanics of flexible, silicon-based ACREO microelectrode arrays in rat cerebral cortex.IEEE Trans Biomed Eng 53:5, 934-40 (2006 May)

{1164}
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ref: -0 tags: neural recording McGill Musallam electrodes date: 07-12-2012 22:53 gmt revision:0 [head]

http://www.mdpi.com/1424-8220/8/10/6704/pdf NeuroMEMS: Neuro Probe Microtechnologies

  • Good review (as of 2008) of the many different approaches for nervous system recording.

{307}
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ref: Rousche-1998.07 tags: BMI Utah cat Normann recording electrode MEA histology date: 06-29-2012 01:12 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

PMID-10223510 Chronic recording capability of the Utah Intracortical Electrode Array in cat sensory cortex.

  • Focus on (surprisingly) chronic recording from the utah array: they want to demonstrate that it works.
  • Platinum coating.
  • insulated with 2-3um polymide.
  • 10 cats, 12 arrays: 2 in S1, 8 in auditory ctx, 2 V1.
  • 11 electrodes connected in each array.
  • After a 6-month implant period, 60% of implanted arrays could still record 'some type of activity'.
  • They were completely targeting neuroprostheses.
    • But acknowledge that 'the presence of fibrous encapsulation and chronic astrogliosis suggests that more research is necessary before the UIEA can be uses as a cornerstone of a neuroprosthetic device for human use.
      • And yet they went through with the human trials?
  • Electrode impedance gave no hint as to the ability of a given electrode to record neural units: many electrodes with average impedance could not record neural activity.
  • Impedances generally decreased , which is not unusual (Schmidt and Bak, 1976).
    • Likely that the polymide had become permeated with water vapor to and equilibrium point. (rather than pinhole leaks or water permeation).
  • Quiet amplifiers: 2uv pk-pk.
  • No significant trend in background activity was noted over the implant durations.
  • In nearly every cat, the dura above the electrode array adhered to the bone flap, and the electrode array adhered to the dura. Therefore, when the bone flap was removed, the UIEA was concurrently explanted from the cortex.
    • Similar to Hoogerwerf and Wise 1994 {1025}
    • The explanted UIEAs typically had become encapsulated, the encapsulation was the cause of the cortical depression.
    • Only 1 did not become encapsulated in dura.
    • This encapsulation explains the gradually varying recording properties -- the electrodes were moving out of the brain.
    • "The capsule which formed around the substrate of the UIEA was usually continuous with the dura, which was enmeshed directly to the overlying skull. The encapsulated array therefore had no freedom of movement with respect to the skull, and this may have caused local trauma which reduced the possibility of recording neural activity. This relative micromovement between the fixed array and the ‘floating’ cortical tissue may also be responsible for sustaining continued growth of the encapsulation as described above."
    • Have tried putting teflon on the top of the Utah array -- did this work?
  • Two UIEAs were not found near the cortical surface -- these two arrays were totally removed from the leptomeningeal space. although originally implanted into the cortex beneath the dura, at the time of sacrafice these arrays were found above the repaired dura, and the implanted cortex showed no evicence of cortical implant.
  • Some electrodes healthy; other showed chronic inflammation.
  • General and intense inflamation in the upper layers of cortex even on their best-performing array; no guarantee that this ctx was working properly, as it is heavily compressed with fibroblasts.
  • Regarding vascluature, see {1024}.
  • Say that the largest impediment is the formation of a capsule around the implant. (Do not mention issue of infection; I guess cats have strong immune systems as well?)
  • Rather good biological discussion and conclusion. worth a re-read. "We currently recommend that the UIEA be used for acute and short-term applications."
    • Not too many follow-ups re teflon or fixing the encapsulation problem: See {1026}
      • Indeed, {1027} doesn't even cite this! Too disastrous?

____References____

{1161}
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ref: -0 tags: springfield downtown library health society date: 05-27-2012 00:44 gmt revision:0 [head]

Just to my left, a woman in a walker rolled into the library, and promptly complained to the police officer on duty about chest pains. The library faces a square in the middle of Springfield where teenagers, shirtless hippies, skateboarders, and other non-mainstream people kill time in the warm afternoon. The library as such is a cool haven to read and access the internet -- several teenagers were playing WoW on the library computers, and I too am tapping into the resource. A possibly adrift artsy-type man of about my age similarly came to conduct his wayward business, having 'just ended up in Springfield', saying it as both and excuse and a badge of pride evincing his free spirit.

The woman is one of the classic types of hypochondriac, and though I'm only listening to them the EMT and police men know this, but they also know that on the off chance of being wrong, not taking the situation seriously could be a disaster. And so they administered simple blood pressure and pulse rate tests, both which seemed normal, then went about convincing her that she needed to be taken to the hospital to be completely checked out, thereby shifting the burden of liability to a place better protected by the standard operating procedure of a battery of tests.

The woman immediately protested, worried about the heavy cost of a ambulance ride, coupled with a paranoia that she would lose her walker. To this the EMT -- a short woman with her practical ponytail shoved through a baseball cap, as often they do -- let glints of irritation show through, asking her repeatedly to decide which hospital she wished to go to, and then asking her to arrange another means to the hospital. The woman protested, but the EMT could scarecly be blamed -- she is stuck in a system not of her design -- and somehow the smooth-souled librarian, who before had been placating library customers by putting holds on books, convinced both parties to go to the nearest hopsital. How exactly this was done I'll forever remain in ignorance, for another ambulance spun through the downtown circle at that instant, scattering sports cars, stopping sedans, and causing the skaters to pause their idling and look.

The incident vaguely reminds me when I had similar issues in Brooklyn, when i was sufficiently pained to drive my ass through the dirty orange-lit streets to a hospital in Williamsburg. They proceeded to do drug tests on me, despite my insistences, but everything checked out fine. In retrospect, the pain was likely heartburn antagonized by psychological isolation; this was before I really learned to listen to myself, and take care of the social and more basic physiological needs. The walker woman fell through these same cracks in a likely preventable but now very expensive way.

Meanwhile, a large black transsexual and a wrinkly white guy walk hurriedly past the plate glass windows of the library, talking animatedly. They may be in a fissure of sorts, but i doubt they consider it a fall...

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ref: -0 tags: loops feedback arcs video game programming date: 04-30-2012 15:12 gmt revision:0 [head]

I highly agree with this philosophy / this deconstruction of the flow of information in human structures: http://www.lostgarden.com/2012/04/loops-and-arcs.html

On criticism as a meta-arc game:

"In the past I've discussed criticism as a game that attempts to revisit an arc repeatedly and embellish it with additional meaning. The game is to generate essays superficially based on some piece of existing art. In turn, other players generate additional essays based off the first essays. This acts as both a referee mechanism and judge. Score is accumulated via reference counts and by rising through an organization hierarchy. It is a deliciously political game of wit that is both impenetrable to outsiders and nearly independent of the actual source arcs. Here creating an arc becomes a move in the larger game. "

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ref: -0 tags: bees energy harvesting honey date: 04-11-2012 06:02 gmt revision:2 [1] [0] [head]

This morning hundreds of bees were swarming outside my front door -- a fact is not without reason, as my roommate makes honey, and her hive just today outgrew the apiary. Hence the hive split this morning, and one queen be left to wait on a branch outside while scouts searched for good places to build a new colony; meanwhile hundreds of non-scout workers were swarming around her.

Bees are amazing. Anyway, a friend sent a link to an article describing how to generate microwatts of energy off a flying insect, which led me to wonder how much energy those bees could have been producing instead of milling protectively about their queen.

  • number of bees : 1000
  • power, with direct connection to flight muscles: 400 uW
  • total possible power: 400mW
  • kCal in a tablespoon (21g) of honey: 64
    • in joules: 270kJ
  • Length of time it would take for 500 madly flapping bees (1) to generate the energy within a tablespoon of honey: 375 hours (15.6 days)
  • Yield of honey from a large, productive hive: 150 lbs / year (2)
    • in watts: 27.8 W
    • number of bees: 20000 (2)
    • factor better than energy harvesting: 3.5

Conclusion: let them make honey :-)


(1) Half the bees visible were resting on leaves, not madly flapping.

(2) Rough wiki-google estimate.

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ref: -0 tags: spike sorting variational bayes PCA Japan date: 04-04-2012 20:16 gmt revision:1 [0] [head]

PMID-22448159 Spike sorting of heterogeneous neuron types by multimodality-weighted PCA and explicit robust variational Bayes.

  • Cutting edge windowing-then-sorting method.
  • projection multimodality-weighted principal component analysis (mPCA, novel).
    • Multimodality of a feature is by checking the informativeness using the KS test of a given feature.
  • Also investigate graph laplacian features (GLF), which projects high-dimensional data onto a low-dimensional space while preserving topological structure.
  • Clustering based on variational Bayes for Student's T mixture model (SVB).
    • Does not rely on MAP inference and works reliably over difficult-to sort data, e.g. bursting neurons and sparsely firing neurons.
  • Wavelet preprocessing improves spike separation.
  • open-source, available at http://etos.sourceforge.net/

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ref: -0 tags: impedance digital transmission line date: 03-14-2012 22:20 gmt revision:0 [head]

http://web.cecs.pdx.edu/~greenwd/xmsnLine_notes.pdf -- Series termination will work, provided the impedance of the driver + series resistor is matched to the impedance of the transmission line being driven.

School has been so long ago, I've forgotten these essentials!

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ref: Jarosiewicz-2008.12 tags: Schwartz BMI learning perturbation date: 03-07-2012 17:11 gmt revision:2 [1] [0] [head]

PMID-19047633[0] Functional network reorganization during learning in a brain-computer interface paradigm.

  • quote: For example, the tuning functions of neurons in the motor cortex can change when monkeys adapt to perturbations that interfere with the execution (5–7) or visual feedback (8–10) of their movements. Check these refs - have to be good!
  • point out that only the BMI lets you see how the changes reflect changes in behavior.
  • BMI also allows pertubactions to target a subset of neurons. apparently, they had the same idea as me.
  • used the PV algorithm. yeck.
  • perturbed a select subset of neurons by rotating their tuning by 90deg. about the Z-axis. pre - perturb - washout series of experiments.
  • 3D BMI, center-out task, 8 targets at the corners of a cube.
  • looked for the following strategies for compensating to the perturbation:
    • re-aiming: to compensate for the deflected trajectory, aim at a rotated target.
    • re-waiting: decrease the strength of the rotated neurons.
    • re-mapping: use the new units based on their rotated tuning.
  • modulation depths for the rotated neurons did in fact decrease.
  • PD for the neurons that were perturbed rotated more than the control neurons.
  • rotated neurons contributed to error parallel to perturbation, unrotated compensated for this, and contributed to 'errors' in the opposite direction.
  • typical recording sessions of 3 hours - thus, the adaptation had to proceed quickly and only online. pre-perturb-washout each had about 8 * 20 trials.
  • interesting conjecture: "Another possibility is that these neurons solve the “credit-assignment problem” described in the artificial intelligence literature (25–26). By using a form of Hebbian learning (27), each neuron could reduce its contribution to error independently of other neurons via noise-driven synaptic updating rules (28–30). "
    • ref 25: Minsky - 1961;
    • ref 26: Cohen PR, Feigenbaum EA (1982) The Handbook of Artificial Intelligence; 27 references Hebb driectly - 1949 ;
    • ref 28: ALOPEX {695} ;
    • ref 29: PMID-1903542[1] A more biologically plausible learning rule for neural networks.
    • ref 30: PMID-17652414[2] Model of birdsong learning based on gradient estimation by dynamic perturbation of neural conductances. Fiete IR, Fee MS, Seung HS.

____References____

[0] Jarosiewicz B, Chase SM, Fraser GW, Velliste M, Kass RE, Schwartz AB, Functional network reorganization during learning in a brain-computer interface paradigm.Proc Natl Acad Sci U S A 105:49, 19486-91 (2008 Dec 9)
[1] Mazzoni P, Andersen RA, Jordan MI, A more biologically plausible learning rule for neural networks.Proc Natl Acad Sci U S A 88:10, 4433-7 (1991 May 15)
[2] Fiete IR, Fee MS, Seung HS, Model of birdsong learning based on gradient estimation by dynamic perturbation of neural conductances.J Neurophysiol 98:4, 2038-57 (2007 Oct)

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ref: -0 tags: implicit motor sequence learning basal ganglia parkinson's disease date: 03-06-2012 22:47 gmt revision:2 [1] [0] [head]

PMID-19744484 What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease.

  • Unilateral lesion of both STN and GPi in one patient. Hence, the patient was his own control.
    • DRastically reduced the need for medication, indicating that it had a profound effect on BG output.
  • Arm contralateral lesion showed faster reaction times and normal movement speeds; ipsilateral arm parkinsonian.
  • Implicit sequence learning in a task was absent.
  • In a go / no-go task when the percent of no-go trials increased, the RT speriority of contralateral hand was lost.
  • " THe risk of persistent dyskinesias need not be viewed as a contraindication to subthalamotomy in PD patients since they can be eliminated if necessary by a subsequent pallidotomy without producting deficits that impair daily life.
  • Subthalamotomy incurs persistent hemiballismus / chorea in 8% of patients; in many others chorea spontaneously disappears.
    • This can be treated by a subsequent pallidotomy.
  • Patient had Parkinsonian symptoms largely restricted to right side.
  • Measured TMS ability to stimulate motor cortex -- which appears to be a common treatment. STN / GPi lesion appears to have limited effect on motor cortex exitability 9other things redulate it?).
  • conclusion: interrupting BG output removes such abnormal signaling and allows the motor system to operate more normally.
    • Bath DA presumably calms hyperactive SNr neurons.
    • Yuo cannot distrupt output of the BG with compete imuntiy; the associated abnormalities may be too subtle to be detected in normal behaviors, explaniing the overall clinical improbement seen in PD patients after surgery and the scarcity fo clinical manifestations in people with focal BG lesions (Bhatia and Marsden, 1994; Marsden and Obeso 1994).
      • Our results support the prediction that surgical lesions of the BG in PD would be associated with inflexibility or reduced capability for motor learning. (Marsden and Obeso, 1994).
  • It is better to dispense with faulty BG output than to have a faulty one.

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ref: bookmark-0 tags: basal ganglia dopamine reinforcement learning Graybeil date: 03-06-2012 18:14 gmt revision:4 [3] [2] [1] [0] [head]

PMID-16271465 The basal ganglia: learning new tricks and loving it

  • BG analogous to the anterior forebrain pathway (AFP), which is necessary for song learning in young birds. Requires lots of practice and feedback. Studies suggest e.g. that neural activity in the AFP is correlated with song variability, and that the AFP can adjust ongoing activity in effector motor pathways.
    • LMAN = presumed homolog of cortex that receives basal ganglia outflow. Blockade of outflow from LMAN to RA creates stereotyped singing.
  • To see accurately what is happening, it's necessary to record simultaneously, or in close temporal contiguity, striatal and cortical neurons during learning.
    • Pasupathy and biller showed that changes occur in the striatum than cortex during learning.
  • She cites lots of papers -- there has been a good bit of work on this, and the theories are coming together. I should be careful not to dismiss or negatively weight things.
  • Person and Perkel [48] reports that in songbirds, the analogous GPi to thalamus pathway induces IPSPs as well as rebound spikes with highly selective timing.
  • Reference Levenesque and Parent PMID-16087877 who find elaborate column-like arrays of striatonigral terminations in the SNr, not in the dopamine-containing SNpc.

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ref: Rouse-2011.06 tags: BMI chronic DBS bidirectional stimulator Washington Medtronic ASIC translational date: 03-05-2012 23:56 gmt revision:3 [2] [1] [0] [head]

PMID-21543839[0] A chronic generalized bi-directional brain-machine interface.

  • Using a commercial neurostimulator package & battery etc.
  • "A key goal of this research prototype is to help broaden the clinical scope and acceptance of NI techniques, particularly real-time brain state detection" Good purpose! good work!
  • Augments the stimulator with 4 channels of ECoG/LFP + accelerometer + wireless telemetry.
    • Can be used to detect parkinsons state or pre-epileptiform behavior.
      • Much of this has been though of before, it just took the technology to catch up & a group to make it.
    • Chronic data is needed from humans -- animal models are often inadequate.
  • Tested in a primate for brain control of a cursor: 1D control using ECoG.
    • Good Left/right ROC, actually.
    • A large cost is simply the clinical testing; hence they piggy-back on an existing design.
    • There should be more research-industry collaborations like this.
  • impressive specs.
  • SVM classification algorithm (only consumed 10uW!) for data compression.
  • short-time Fourier transform for extracting the power over a given band. This using a modified chopper-amplification scheme. Output data has a bandwidth of less than 5Hz, which greatly reduces processing requirements.
  • Lots of processing on the BASIC chip, much like here.
  • Also see the press release

____References____

[0] Rouse AG, Stanslaski SR, Cong P, Jensen RM, Afshar P, Ullestad D, Gupta R, Molnar GF, Moran DW, Denison TJ, A chronic generalized bi-directional brain-machine interface.J Neural Eng 8:3, 036018 (2011 Jun)

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ref: Mink-1996.11 tags: basal ganglia review parkinsons STN DBS date: 03-05-2012 23:33 gmt revision:13 [12] [11] [10] [9] [8] [7] [head]

PMID-9004351[0] The basal ganglia: focused selection and inhibition of competing motor programs.

  • Plenty of focus on diseased states, but normal function is unclear.
  • basal ganglia do not generate motor programs; that is the task of the cerebrum / cerebellum (based on timing).
  • review posits that the inhibitory output of the BG acts to seletively inhibit competing motor mechanisms in order to prevent them from interfering with voluntary movements that are generated by other CNS structures.
  • Involvement of the BG in motor control old -- dates back to Kinner Wilson describes pathology of rigidity and tremor following lenticular degeneration.
    • Thought that the pyramidal system was new and plastic, whereas the extrapyramidal system was archaic and postural / static.
    • Extrapyramidal system is actually prepyramidal, too.
  • Striatum.
    • receives excitatory input from all of the cerebrum except primary auditory and visual cortices.
    • cortical projections terminate in longitudinal bands.
    • in reciprocally connected areas of frontal, temporal, and parietal cortex terminate in adjacent or interdigitating zones in the striatum.
    • somatotopy in projections: areas receiving input from the face area of sensory or motor cortex are separate from those receiving input from the arm area.
    • The zones themselves overlap / are interdigitated, but not completely.
    • 95% of the cells are medium spiny neurons (MSN).
      • The remainder are glutamine from centromedian and parafasicular nuclei of the thalamus, cholinergic input from large aspiny neurons, GABA from neighboring MSTs, and dopamine from SNpc.
    • When Flaherty and Graybiel (1994) PMID-7507981[1] injected retrograde tracer into GPi and anterograde tracer into sensory or motor cortex they were able to demonstrate multiple striatal zones that were labeled from both injections. This suggests that information is sent from cortex to striatum in a multiply convergent and divergent pattern with reconvergence in GPi after processing in the striatum (Fig. 2).
    • Caudate projects to SNpc
    • Putamen projects to the GPi.
    • Acetylcholine: there is a patchy distribution of heavily and lightly stained regions, corresponding to striosomes and the matrix.
      • Dendrites of most MSN are restricted to a single compartment.
      • both striosomes and matrix receive input from the SNpc, but only the striosomes project back to the SNpc.
      • Striosomes can affect the matrix via large aspiny neurons, AChe, 1-2% of the total striatal population.
    • One striatal cell receives input from thousands of cortical cells.
      • Activation of a MSN appears to require concurrent excitatory input from a large number of cortical afferents.
    • MSNs have a low resting firing rate of 0.1 - 1 Hz -- strong resting potassium current.
      • Cells can switch between two stable states: hyperpolarized -80mV and moderately polarized -50mV.
      • This appears to be stabilized by large aspiny cholinergic neurons (?)
  • D1 increases cAMP, D2 usually decreases cAMP. both expressed on MSN; some suggest differentially, based on anatomical target.
  • STN
    • dendrites up to 1200um.
    • in GPi and SNpr, STN axon collaterals branch to ensheath the cell bodies and proximal dendrites of their target neurons.
    • each axon from the subthalamic nucleus ensheathes many GPi neurons.
    • Input primarily from the oculo-and somato-motor areas of the frontal lobes.
    • does not seem to have much intrinisic processing; it's more of a relay.
  • GPi:
    • About 70% send axon collaterals to both thalamus and brainstem.
    • Projects to ventrolateral (Vlo) and ventral anterior nucleus (VApc).
    • Little overlap in projections fom the basal ganglia and the cerebellum in the thalamus.
    • collaterals of most GPi axons projecting to thalamus project to an area at the junction of the midbrain and pons adjacent to the pedunculopontine nucleus (PPN). Some call it the "midbrain extrapyramical area", which projects to the reticulospinal motor system.
  • GPe:
    • Most output inhibitory to STN; most input from the striatum and STN.
    • Also output to GPi and SNr.

Electrophysiology:

  • In the striatum, cells fire in relation to both the direction of movement (25%) as well as the direction of force (50%) (Crutcher and DeLong 1984b PMID-6705862[2]).
  • More cells fire during slow "ramp" movements than during fast "ballistic" movements, possibly due to their relation to proximal muscle activity, or due to force / speed modulation.
  • Cells fire phasically relative to cue, to movement, or after movement / before the next movement ("set" neurons). .
  • In the putamen, most activity is late, though there is a distribution anterior-posterior, with anterior cells more likely to fire early; these are possibly of cognitive origin.
  • In the striatum, activity has been found to context-dependent: e.g. cells respond to touch, but only if it is within the context of a movement.
    • Romo et. a.l 1992 controlled for this wrt externally triggered movements vs. self-initiated movements.
    • Within the caudate, Hikosaka et al 1989a described cell firing in the caudate relative to delayed, cued, and remembered saccades.
      • context-dependent activity is a feature of the striatum, but not necessarily the function.
  • Cholinergic large aspiny neurons appear to have no relation to movement.
    • But they do fire in relation to sensory input or to reward.
    • Since one effect of cholinergic input to MSN is to stabilize the present state, in the situation where the current behavior results in a reward, activity of the cholinergic interneurons would tend to reinforce the ongoing pattern of striatal activity. Interesting!! memory!

STN:

  • tonically active, with a resting rate of 20 Hz.
  • somatotopic organization, lower extremity dorsal and face / eyes ventral.
  • neurons increase firing rate in relation to eye or limb movement. (Matsumura et al 1992, Wichmann et al 1994a [3]).
  • In monkeys treained to perform elbow movements, 60-75% STN neurons had activity related to movement direction (Georgopoulos et al 1983) (Wichmann et al 1994a).
    • Unclear proportion responded to passive movement: 20% former, 50% latter.
  • It is not known to what degree STN neurons discharge in relation to other movement parameters. Only 1 study, with only 7 neurons, had some correlation to velocity ( Georgopoulos 1983)
  • Onset of activity slower than M1 or EMG.
  • Ventral STN: of all task-related neurons, 23% were related to saccades, 39% related to visual fixation, 15% to visual sensory responses.
  • Matsumura 1992 shows that 52% of STN neurons had activity related to maintained eye position but not to saccades.
    • STN supresses saccades: STN excites SNr which inhibits collicular neurons involved in saccade generation.
  • in MPTP monkeys, ablation or inactivation of the STN cauyses transient diskinesia but when it resolved monkeys were able to move normally. (BErgman et al 1990; Wichmann et al 1994b).

GPi:

  • activity does not correlate with physical parameters of movement.
    • no consistent relationship between GPi activity and joint position, force production, movement amplitude, or movement velocity during wrist movement.
    • little correlation of GPi output with EMG profiles either.
  • Ramp and ballistic movements: equal amounts of control.

SNr:

  • All involved in eye movements are tonically active.
  • virtually all have been reported to decrease activity during eye movement.
    • Still yet: SNr show firing rate decreases while GPi show firing rate increases.
    • Decreased SNr discharge results in disinhibition in the superior colliculus to initiate saccades.
    • Could also be that the SC generates simultaneous eye and head movements, and the SNr helps to inhibit (?) neck muscles.
  • None in response to saccades in the dark (!)
  • Over half have sensory responses.

GPe:

  • 2 types
    • HF, 70 Hz, interrupted with long pauses.
    • LF, 10 Hz, with frequent spontaneous bursts.
  • Activity during movement remarkably similar to GPi.
  • Weak encoding of movement amplitude, velocity, and muscle length and force is weak.
    • Movement related activity is late.
  • Might effect center - surround inhibition on the GPi; unclear what it does to the STN?

SNpc:

  • Schultz and Romo 1995 - SNpc neurons respond as early as possible to stimuli that indicates the availability of reward, and to the presence of reward, but only within a context.
    • No tuning to movement.

Synthesis:

  • Author believes that the basal ganglia serve to repress motor actions / plans that compete with the present or desired movement.
    • Eg. ones that are elicited through auto-association in the cerebral cortex.
    • corrolary: if there is an inability to focally inhibit competing mechanisms generally, it might be expected that the resulting movement deficit would be compounded during a sequence of movements, as is observed.
  • Discrete lesions in experimental animals often do not produce the movement disorders associated with human basal ganglia disease.
  • If the tonically active basal ganglia output inhibits competing motor mechanisms, the tonic inhibition must be removed from desired mechanisms. This must be done in a focused manner at the right time and in the right context in order not to activate competing mechanisms. The vast machinery of the striatum with its context-specificity, plasticity and spatiotemporal filtering selects which MPGs should be allowed to turn on. Thus, when a movement is made, the basal ganglia output has two parallel actions: inhibition of a multitude of competing MPGs via STN and GPi and focused selection of desired MPGs via striatum and GPi. Dysfunction of either of these actions would cause abnormal posture and movement.

Parkinson's disease:

  • Symptoms:
    • Tremor at rest
    • bradykinesia
    • paucity of movement (akinesia)
    • muscular rigidity
    • abnormally flexed posture with postural instability.
  • Tremor possibly from abnormal bursting in the thalamus. (Pare et al 1990)
  • Highly idiopathic and progressive.
  • Symptoms may reflect involvement of other systems in addition to the nigrostriatal dopamine system.
  • Bradykinesia:
    • excessive co-contraction, insufficient agonist activity.
    • movement is more impaired when visual cues are absent.
      • self-initiated movements are slower than visually cued movements
      • more impaired when deprived of visual feedback of the ongoing movement or if they cannot see the moving body.
      • Likely they have an increased dependence on visual feedback to compansate for the deficit.
    • slower on simultaneous and sequential movements than they were on individual components (Benecke et al 1986, 1987).
      • Greater latency to begin second movement.
      • Others have found no particular sequencing deficit (Agostino et al 1994).
  • Rigidity likely due to inability to inhibit reflex mechanisms.
    • One of these is the transcortical reflex, which can (normally) be inhibited when subjects are instructed not to resist movement.
      • PD patients have abnormally increased transcortical stretch reflexes.
      • Reflex cannot be inhibited upon instruction (Berardelli et al 1983, Rothwell et al 1983, Taton and Lee 1975).
    • When normal subjects are subjected to a perturbation in the anterior-posterior dimension while standing, they have a stereotyped pattern of muscle activity in the legs and trunk that maintains upright stance. If they then sit down and are subjected to the same perturbation, this activity no longer occurs. By contrast, patients with Parkinson’s disease have an inappropriate cocontraction of leg and back muscles in response to perturbation from upright stance. When the same subjects are subjected to a perturbation in a sitting position, they continue to have the same pattern of muscle activity. (Horak et al 1992)
  • Akinesia
    • May be due to a loss of of dopamine input to the prefrontal, premotor, or motor cortex. (Gaspar et al 1991, 1992; Sawaguchi and Goldman-Rakic 1994).
      • Animals with focal lesions to dopamine input to prefrontal cortex have prolonged reaction times (Humer et al 1994); animals with basal ganglia lesion do not.
  • Microwriting / micrographia: common problem where writing size is normal initially, but within several letters the writing gets progressively smaller so that by the end of the line, it may be illegible.
    • Hypothesis: depending on the movement and mechanisms involved, the number of mechanisms competing with the desired movement may increase additively as the sequence progresses leafing to progressive slowing of the movement.

Huntingtons

  • Early stages characterized by frequent, brief, random twitch-like movements and dementia. smoe of the movements resemble normal voluntary movement.
  • Involuntary EMG bursts 50 - 300 ms in duration.
  • Marked loss of striatal neurons.
    • Specifically, MSN enkephalin-containing that project to GPe. (Reiner 1988).
    • Substance-P MSN that project to GPi and SNr are preserved until later in the disease when rigidity typically appears.
    • Experimental lesions in the striatum rarely cause chorea, which makes sense as it is the specific pattern of striatal cell loss that matters (Crossman, 1987).
    • Stroke of the striatum in humans rarely causes chorea.
  • It should be emphasized that neurons in many parts of the brain including cortex and cerebellum degenerate in Huntington's disease, hence inferences of basal ganglia function drawn from HD must be interpreted with caution.
  • In contrast to PD, the long-latency stretch reflex is absent or reduced in Huntington's disease.
    • Plus somatosensory evoked potentials are markedly reduced.
    • People with chorea not from Huntington's disease have normal long-latency reflexes.

STN / Hemiballismus

  • Damage to STN by ischemic stroke results in bizarre involuntary movement that is charaterized by large amplitude, flinging (ballistic) movement of the contralateral extremities.
    • Symptoms are immediate and improve over time.
    • Similar to chorea, but more commonly affects proximal joints, and the movements are larger.
  • Hemiballismus can be caused by injecting biculculine into STN, which is somewhat paradoxical since biculculine is a GABA antagonist and would be expected to cause disinihbition (activation) of STN. Yet the results are similar to lesion of STN. (Crossman 1987)
  • After STN lesion there is decreased activity in GPe and GPi.
  • Hemiballismus can be eliminated by lesioning GPi outputs (Carpener 1950).
  • STN is exitatory in GPi / GPe; lesioning reduces GPi's ability to inhibit competing motor programs.
    • Loss of excitatory input to GPi results in abnormal phasic or bursting activity in GPi or its targets and this bursting causes twitches or chorea.

Experimental lesions:

  • Focal inactivation of the putamen with GABA-A agonist muscimol causes decreased movement amplitude with cocontraction of agonist and antagonist muscles in visually-guided arm movements.
  • Lesions studies suggest that the striatum is functionally heterogeneous with the function of each component determined by its cortical afferents.
    • Authors suggest that the function of each component is more likely to be reflected in its outputs than inputs.
  • Caudate does seem involved in more cognitive processing; it has different connectivity despite similar construction.
  • Muscimol into the SNr results in involuntary saccades and inability to mantain fixation.
    • Thus, just as GPi inactivation results in abnormal excess limb and trunk muscle activity, SNr inactivation results in abnormal excess eye movements. (Hikosaka and Wurtz, 1985b).
  • Lesion of GPi is an old treatment for PD in humans (Cooper and Bravo, 1958). \
    • Surprisingly, the most consistent beneficial effect of pallidotomy may be the reduction of dyskinesias that are induced by L-Dopa treatment (Laitinen et al 1992).

Large papers are not dissimilar from large software projects -- they take time, iteration, and concentration. Papers, however, are harder as the feedback is not immediate and gratifying.

____References____

[0] Mink JW, The basal ganglia: focused selection and inhibition of competing motor programs.Prog Neurobiol 50:4, 381-425 (1996 Nov)
[1] Flaherty AW, Graybiel AM, Input-output organization of the sensorimotor striatum in the squirrel monkey.J Neurosci 14:2, 599-610 (1994 Feb)
[2] Crutcher MD, DeLong MR, Single cell studies of the primate putamen. II. Relations to direction of movement and pattern of muscular activity.Exp Brain Res 53:2, 244-58 (1984)
[3] Wichmann T, Bergman H, DeLong MR, The primate subthalamic nucleus. I. Functional properties in intact animals.J Neurophysiol 72:2, 494-506 (1994 Aug)

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ref: Fuentes-2009.03 tags: Nicoelis DCS spinal cord stimulation PD Fuentes Petersson 6-OHDA date: 03-03-2012 02:46 gmt revision:3 [2] [1] [0] [head]

PMID-19299613[0] Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.

  • Motivation: different levels of cortical oscillation during movement and rest (LFO decreased, medium-high freq increased); PD associated with abnormal synchronous corticostriatal oscillations.
  • In epilepsy patients, stimulation of peripheral nerve afferents is effective in desychronizing low-frequency neural activity, reducing the frequency and duration of seizures (8,9,10) PMID-11050139[1] PMID-16886985[2] PMID-18188148[3]
  • DCS (dorsal column stimulation)
    • Epidural, longitudal electrodes, horizontal electrical field.
    • Upper thoracic, mice.
    • 300Hz.
    • simpler and safer than brain surgery.
    • [24] DCS induces no increase in arousal. (Wall, PD. Brain 1970; 93:505.
  • used the tyrosine hydroxyalse inhibitor AMPT
  • M1 LFP: Osc around 1.5-4Hz and 10-15Hz enhanced; osc > 25Hz subdued.
  • DCS increased locomotion by 29x in depleted animals, and 4.9x in normal animals.
  • Also titrated L-DOPA with DAT-KO mice. Without dopamine, there is no movement.
    • DCS increased L-DOPA effectiveness by 5x (1/5 the dose was required)
  • Verified in a 6-OHDA lesion model in rats.
    • Lesioned animals moved more, sham moved less.
  • Activation of locomotion is via striatal medium spiny neurons projecting to the output nuclei of the basal ganglia [26 PMID-8402406[4] ,27 PMID-1695404[5]].
  • In PD, with reduced striatal dopamine levels, the activation threshold of the projection neurons from the striatum is significantly increased [25] PMID-17916382[6].

____References____

[0] Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA, Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.Science 323:5921, 1578-82 (2009 Mar 20)
[1] Fanselow EE, Reid AP, Nicolelis MA, Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation.J Neurosci 20:21, 8160-8 (2000 Nov 1)
[2] DeGiorgio CM, Shewmon A, Murray D, Whitehurst T, Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial.Epilepsia 47:7, 1213-5 (2006 Jul)
[3] George MS, Nahas Z, Bohning DE, Lomarev M, Denslow S, Osenbach R, Ballenger JC, Vagus nerve stimulation: a new form of therapeutic brain stimulation.CNS Spectr 5:11, 43-52 (2000 Nov)
[4] Brudzynski SM, Wu M, Mogenson GJ, Decreases in rat locomotor activity as a result of changes in synaptic transmission to neurons within the mesencephalic locomotor region.Can J Physiol Pharmacol 71:5-6, 394-406 (1993 May-Jun)
[5] DeLong MR, Primate models of movement disorders of basal ganglia origin.Trends Neurosci 13:7, 281-5 (1990 Jul)
[6] Grillner S, Wallén P, Saitoh K, Kozlov A, Robertson B, Neural bases of goal-directed locomotion in vertebrates--an overview.Brain Res Rev 57:1, 2-12 (2008 Jan)

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ref: Plaha-2008.05 tags: zona incerta DBS date: 03-03-2012 01:45 gmt revision:4 [3] [2] [1] [0] [head]

PMID-18037630[0] Bilateral stimulation in the caudal zona incerta nucleus for tremor control

  • VL DBS does not always work, and patients may develop tolerance; tried instead the caudal Zona Incerta (cZI).
    • VL ~= VIM (?) -- differing thalamic naming nomenclatures -- see {1100}.
    • VL does not always work for proximal tremor.
  • nice results! Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET
    • Works for both distal and proximal tremor.
  • Original finding: PMID-18671648
  • nice figure therein.

____References____

[0] Plaha P, Khan S, Gill SS, Bilateral stimulation of the caudal zona incerta nucleus for tremor control.J Neurol Neurosurg Psychiatry 79:5, 504-13 (2008 May)

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ref: Penney-1983.01 tags: DBS parkinsons model review chorea review date: 03-02-2012 21:22 gmt revision:2 [1] [0] [head]

PMID-6838141[0] Speculations on the Functional Anatomy of Basal Ganglia Disorders

  • "We present a model based on the accumulating evidence that suggests the importance of a cortico-striato-pallido-thalamocortical feedback circuit as the major extrapyramidal influcence on the motor system in man.
    • Behaviors generated from the cerebral cortex are focused and facilitated by projections through the basal ganglia.
    • The chorea of Huntington's disease and the bradykineasia of PD are opposite extremes of the dysfunction of this system.
      • Huntington's: inability to supress unwanted movements.
      • Inadequate inhibitory modulation of ongoing movement by the nigrostriatal dopamine pathway.
  • Anatomy already described in Kemp & Powell 1971. More details have accrued in the subsequent 4 decades.
  • Kinner Wilson 1929 -- astute observations on the nature of chorea, in Huntington's and others: how they appear to be purposeful, but are objectviely not. He infers that it may be a disorder of the premotor cortex, since the primary cortex seems to control individual muscle contractions. Much data supports this now.
  • All dopamine agonists result in choreiform dyskinesias.
  • Tardive dyskinesia seems to result from drug-induced striatal dopamine receptor supersensitivity after long-term high-dose neuroleptic therapy also manifests choreaform movements.
  • In huntington's disease, supersensitive GABA receptors develop in the globus pallidus following striatal deinnervation.
    • Likewise for PD: supersensitive dopamine receptors develop in the striatum (Lee at al 1978).
  • mention neuromodulators (substance P, angiotensin II, cholecystokinin, leucine-enkephalin) which have been largely ignored in later work -- why?
  • Tremor is very responsive to muscarinic cholinergic agonists, hence striatal cholinergic neurons may play a role in the etiology of tremor.
    • Or the effect could be mediated through the cortex (my observation).
    • But then again this is inconsistent with the fact that pallidotomy is effective at mediating tremor in PD patients.
    • Tremor is unusual in diseases like Hallervorden-Spatz and other pallidal degenerations presumably because pallidothalamic pathways are necessary for the manifestation of PD tremor.
  • THe descending SNr pathways to the tectum and midbrain tegmentum appear to be responsible for the rotatory behavior seen in models of parkinsonism in the rat (Morelli et al 1981).
    • Rotatory behavior exhibited by rats after lesioning of nigral dopamine neurons continues even in the absence of the telencephalon and thalamus (Papadopolous and Huston 1981).

Got some things completely wrong:

  • Say that the cells of the subthalamic nucleus are inhibitory on the cells of MGP (GPi)/SNr

____References____

[0] Penney JB Jr, Young AB, Speculations on the functional anatomy of basal ganglia disorders.Annu Rev Neurosci 6no Issue 73-94 (1983)

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ref: Costa-2006.1 tags: Rui Costa Miguel Nicolelis Dopamine depletion excess cortex striatum hyperkinesia akinesia parkinsons DAT-KO date: 03-02-2012 01:03 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-17046697 Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction.

  • used rats where they could rapidly switch between dopamine depletion (0.2%) and overexpression (500%)
  • most cortical and striatal neurons ( approximately 70%) changed firing rate during the transition between dopamine-related hyperkinesia and akinesia,
    • buuut the overall cortical firing rate remained unchanged
  • repeated dopamine depletion is accompanied by the loss of glutamergic synapses in striatopallidal neurons (Day et al 2006) PMID-16415865 (Kaneda et al 2005). PMID-16367790
  • with Marc Caron
  • Dopamine is believed to modulate positively the direct striatal pathway that contains predominantly D1-type receptors and disinhibits cortical neurons to modulate negatively the indirect pathway that predominantly contains D2-type receptors and increased crotical inhibition (Albin et al 1989 {1050}, Filion and Tremblay 1991; Gerfen 1992, Parr-Brownlie and Hyland, 2005).
  • According to the classical view (Albin et al 1989), lack of DA release should lead to inhibition of cortical activity and an inability to produce movement, while an excess of Dopamine should lead to increased cortical activity and hyperactivity (Gerfen, 1992).
    • mouse model: DDD PMID-17030735[] (dopamine transporter knockout)

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ref: -0 tags: Albin basal ganglia dopamine 1989 parkinsons huntingtons hemiballismus date: 03-02-2012 00:28 gmt revision:1 [0] [head]

PMID-2479133 The functional anatomy of basal ganglia disorders.

  • Matrix neurons mainly containing substance P mainly project upon the GPi or SNr
    • while those containing enkephalins project on the GPe.
  • Striosome neurons projecting to the SNc contain mainly substance P.
  • Classical hypothesis:
  • Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus.
    • These are suppressed by D2 receptor antagonists & exacerbated by dopamine agonists.
    • Chorea is a primary example.
    • Despite Huntingtons, traumatic, ischemic, or ablative lesions of the striatum in man or animals rarely produces chorea or atheosis (writhing movements).
    • In HD, cholinergic agonists will alleviate choreoatheosis, while anti-cholinergic drugs exacerbate it.
  • Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output.
    • opposite of HD, exacerbated by D2 antagonists and ameliorated by DA agonists, as well as anti-cholinergics.
  • Dystonia = the spontaneous assumption of unusual fixed postures lasting from seconds to minutes.

  • Standard model suggests that striatal lesions should result in spontaneous movements, while this is not the case in man or other mammals. (less inhibition on GPi / SNr -> greater susceptibility of the thalamus to competing programs (?))
  • hyperkinetic movements can be produced by infusing bicululline, a GABA receptor antagonist, into GPe -- silencing it.
  • In early HD, when chorea is most prominent, there is a selective loss of striatal neurons projecting to the LGP (enkephalin staining).
    • Substance P containing neurons are lost later in the disease.
  • Administration of D2 antagonists increases the synthesis of enkephalins and pre-proenkephalin mRNA in the striatum.
    • This presumably represents increases in neuronal activity.
    • Inhibition of GPe neurons decreases hyperkinetic movements? But STN is excitatory? This does not add up.
  • Hemiballismus may be caused by disinhibition of SNr (?) and the VA/VL/MD/CM-Pf thalamocortical projections.

Saccades:

  • In both PD and HD, there are both increases in the latency of initiation of saccades, slowing of saccadic velocity, and interruption of saccades.
    • In HD, there is an early loss of substance-P containing striatal terminals in the SNr, possibly resulting in over-inhibition of tectal neurons.
    • HD patients cannot supress saccades to flashed stimulus.
    • No abnormalities in saccadic control in tourette's syndrome.
  • Hikosaka: suggest that caudate neurons involved in the initiation of saccades are part of a mechanism in which sensory data are evaluated in the context of learned behaviors and anticipated actions, and then used to initiate behavior.

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ref: -0 tags: locomotion decerebrated monkeys spinal cord section STN stimulation date: 03-01-2012 23:53 gmt revision:0 [head]

PMID-7326562 Locomotor control in macaque monkeys

  • Were not able to induce walking with in monkeys with a sectioned spinal cord
  • Were able to induce walking motion by pulsed stimulation of the STN, with varying walking speed with varying currents!
  • Detailed, informative report, more than I have time to record here today.

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ref: Timmermann-2003.01 tags: DBS double tremor oscillations DICS beamforming parkinsons date: 02-29-2012 00:39 gmt revision:4 [3] [2] [1] [0] [head]

PMID-12477707[0] The cerebral oscillatory network of parkinsonian resting tremor.

  • Patients had idiopathic unliateral tremor-dominated PD.
  • MEG + EMG -> coherence analysis. (+ DICS for deep MEG recording).
  • M1 correlated to EMG at tremor and double-tremor frequency following medication withdrawal overnight.
    • M1 leads by 15 - 25 ms, consistent with conduction delay.
  • Unlike other studies, they find that many cortical areas are also coherent / oscillating with M1, including:
    • Cingulate and supplementary motor area (CMA / SMA)
    • Lateral premotor cortex (PM).
    • SII
    • Posterior pareital cortex PPC
    • contralateral cerebellum - strongest at double frequency.
  • In contrast, the cerebellum, SMA/CMA and PM show little evidence for direct coupling with the peripheral EMG but seem to be connected with the periphery via other cerebral areas (e.g. M1)
  • Power spectral analysis of activity in all central areas indicated the strongest frequency coherence at double tremor frequency.
    • Especially cerebro-cerebro coupling.
  • These open-ended observation studies are useful!

____References____

[0] Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A, The cerebral oscillatory network of parkinsonian resting tremor.Brain 126:Pt 1, 199-212 (2003 Jan)

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ref: Bergman-1990.09 tags: parkinsons STN lesion 1990 MPTP DBS date: 02-28-2012 21:06 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-2402638[] Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.

  • MPTP monkeys.
  • Guided by the rate hypothesis (which is probably false, but no matter!)
  • The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor.
  • the study that opened up a treatment - and helped many people!!
  • wasn't the first DBS surgery done in 1983 by Benabid? No, it was 1993!

____References____

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ref: -0 tags: oscillations DBS globus pallidus parkinsons date: 02-28-2012 17:24 gmt revision:1 [0] [head]

PMID-17880401 Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism.

  • In monkeys, progressive dopamine depetion process, recording changes during disease progression -- good!
  • No big change in firing rates, makes sense as this is likely controlled by other network or cellular homeostatic mechanisms.
  • Early in intoxication inhibitory responses to movement disappeared.
    • Yet synchrony did not appear at this time -- it is a sequelae?
    • Correlated activity appeared later, once the animals became severly akinetic.
  • Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely.
  • Probably it's movement related activity, not overall states. YES.

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ref: -0 tags: dopamine reinforcement learning funneling reduction basal ganglia striatum DBS date: 02-28-2012 01:29 gmt revision:2 [1] [0] [head]

PMID-15242667 Anatomical funneling, sparse connectivity and redundancy reduction in the neural networks of the basal ganglia

  • Major attributes of the BG:
    • Numerical reduction in the number of neurons across layers of the 'feed forward' (wrong!) network,
    • lateral inhibitory connections within the layers
    • modulatory effects of dopamine and acetylcholine.
  • Stochastic decision making task in monkeys.
  • Dopamine and ACh deliver different messages. DA much more specific.
  • Output nuclei of BG show uncorrelated activity.
    • THey see this as a means of compression -- more likely it is a training signal.
  • Striatum:
    • each striatal projection neuron receives 5300 cortico-striatal synapses; the dendritic fields of same contains 4e5 axons.
    • Say that a typical striatal neuron is spherical (?).
    • Striatal dendritic tree is very dense, whereas pallidal dendritic tree is sparse, with 4 main and 13 tips.
    • A striatal axon provides 240 synapses in the pallidum and makes 10 contacts with one pallidal neuron on average.
  • I don't necessarily disagree with the information-compression hypothesis, but I don't disagree either.
    • Learning seems a more likely hypothesis; could be that we fail to see many effects due to the transient nature of the signals, but I cannot do a thorough literature search on this.

PMID-15233923 Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons.

  • Same task as above.
  • both ACh (putatively, TANs in this study) and DA neurons respond to reward related events.
  • dopamine neurons' response reflects mismatch between expectation and outcome in the positive domain
  • TANs are invariant to reward predictability.
  • TANs are synchronized; most DA neurons are not.
  • Striatum displays the densest staining in the CNS for dopamine (Lavoie et al 1989) and ACh (Holt et al 1997)
    • Depression of striatal acetylcholine can be used to treat PD (Pisani et al 2003).
    • Might be a DA/ ACh balance problem (Barbeau 1962).
  • Deficit of either DA or ACh has been shown to disrupt reward-related learning processes. (Kitabatake et al 2003, Matsumoto 1999, Knowlton et al 1996).
  • Upon reward, dopaminergic neurons increase firing rate, whereas ACh neurons pause.
  • Primates show overshoot -- for a probabalistic relative reward, they saturate anything above 0.8 probability to 1. Rats and pigeons do not show this effect (figure 2 F).

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ref: -0 tags: DBS dopamine synaptic plasticity striatum date: 02-27-2012 21:57 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-11285003 Dopaminergic control of synaptic plasticity in the dorsal striatum.

  • Repetitive stimulation of corticostriatal fibers causes a massive release of glutamate and DA in the striatum, and depending on the glutamate receptor subtype preferentially activated, produces either long-term depression (LTD) or long-term potentiation (LTP) of excitatory synaptic transmission.
  • D1 and D2 (like) receptors interact synergistically to allow LTD formation, and in opposition while inducing LTP.
  • Stimulation of DA receptors has been shown to modulate voltage-dependent conductances in striatal spiny neurons, but it does not cause depolarization or hyperpolarization (Calabresi et al 2000a PMID-11052221; Nicola et al 2000)
  • Striatal spiny neurons present a high degree of colocalization of subtypes of DA and glutamate receptors. PMID-9215599
  • Striatal cells have up and down states. Wilson and Kawaguchi 1996 PMID-8601819
  • Both LTD and LTP are induced in the striatum by the repetitive stimulation of corticostriatal fibers.
    • Repetition is associated with the dramatic increase of both glutamate and DA in the striatum. (presynaptic?)
  • LTP is enhanced by blocking or removing D2 receptors.
  • More complexity here - in terms of receptors and blocking. (sure magnesium blocks NMDA receptors, but there are many other drugs used...)

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ref: -0 tags: globus pallidus delong response tuning date: 02-24-2012 21:41 gmt revision:1 [0] [head]

PMID-4997823 Activity of Pallidal Neurons During Movement

  • GPe activity notably different from GPi.
    • "So characteristic were the discharge patterns of units in each segment that early in the course of the experiment ti be came apparent when the electrode entered and left each segment.
  • Two types of cells in GPe:
    • High frequency with periods of quiet (85%)
    • Low frequency with bursts.
  • Only one type in GPi: continuous HF discharge, 10-100 Hz, mean 63 Hz.
  • Mostly contralateral, ~ 15% ipsilateral related discharge.
  • Leg and arm responding units intermixed.
  • Conclusion: pallidus not involved in reflexes.
  • Substantia innominata = region posterior the pallidus, contains the nucleus basalis.
  • I'd really like to get recordings of this quality!

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ref: -0 tags: dopamine reward prediction striatum error striatum orbitofrontal reward date: 02-24-2012 21:26 gmt revision:1 [0] [head]

PMID-11105648 Involvement of basal ganglia and orbitofrontal cortex in goal-directed behavior.

  • Many regions have a complex set of activations, but dopamine neurons appear more homogenous: they report the error in reward prediction.
    • "The homogeneity of responsiveness across the population of dopamine neurons indicates that this error signal is widely broadcast to dopamine terminal regions where it could provide a teaching signal for synaptic modifications underlying the learning of goal-directed appetitive behaviors."
    • Signals are not contingent on the type of behavior needed to obtain the reward, and hence represent a relatively 'pure' reward prediction error.
  • Unlike dopamine neurons, many striatal neurons respond to predicted rewards, although at least some may reflect the relative degree of predictability in the magnitude of the responses to reward.
  • Neuronal activations in the orbitofrontal cortex appear to involve less integration of behavioral and reward-related information, but rather incorporate another aspect of reward, the relative motivational significance of different rewards.
  • Processing is hierarchical (or supposed to be so):
    • Dopamine neurons provide a relatively pure signal of an error in reward prediction,
    • Striatal neurons signal not only reward, but also behavioral contingencies,
    • Orbitofrontal neurons signal reward and incorporate relative reward preference.

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ref: -0 tags: striatum microstimulation abnormal myclonus dyskinesia date: 02-24-2012 19:44 gmt revision:0 [head]

PMID-21508304 Discontinuous Long-Train Stimulation in the Anterior Striatum in Monkeys Induces Abnormal Behavioral States

  • Long-train microstimulation induces complex, abnormal behavior: finger licking and biting, dyskinesias, grooming; more anterior (associative) resulted in hyper, hypo manic or stereotyped behaviors.
  • Short-train stimulation induces myoclonic-like movements.

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ref: Carpenter-1981.11 tags: STN subthalamic nucleus anatomy tracing globus_pallidus PPN substantia_nigra DBS date: 02-22-2012 22:01 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-7284825[0] Connections of the subthalamic nucleus in the monkey.

  • STN projects to both segments of the globus pallidus in a laminar and organized fashion.
    • most fibers projected to the lateral pallidal segment (aka GPe).
  • also projected to specific thalamic nuclei (VAmc, VLm, DMpl).
  • the major projection of PPN is to SN.
  • striatum projects to the substantia nigra pars reticulata (SNr). interesting.
  • see also: PMID-1707079[1]
    • "Anterograde transport in fibers and terminal fields surrounded retrogradely labeled cells in the LPS (GPe), suggesting a reciprocal relationship [to the STN]"
  • These data suggest that the STN receives its major subcortical input from cell of the LPS (GPe) arranged in arrays which have a rostrocaudal organization.
  • No cells of the MPS (GPi) or SN project to the STN.
  • The output of the STN is to both segments of the GP and SNpr.
  • Major subcortical projections to PPN arise from the MPS (GPi) and SNpr (output of the BG) , but afferents also arise from other sources.
    • The major projection of PPN is to SN.
    • HRP injected into PPN produced profuse retrograde transport in cells of the MPS and SNpr and distinct label in a few cells of the zona incerta and STN.

____References____

[0] Carpenter MB, Carleton SC, Keller JT, Conte P, Connections of the subthalamic nucleus in the monkey.Brain Res 224:1, 1-29 (1981 Nov 9)
[1] Carpenter MB, Jayaraman A, Subthalamic nucleus of the monkey: connections and immunocytochemical features of afferents.J Hirnforsch 31:5, 653-68 (1990)

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ref: Boulet-2006.1 tags: hemiballismus PD parkinsons STN subtalamic DBS dyskinesia rats 2006 glutamate date: 02-22-2012 18:58 gmt revision:1 [0] [head]

PMID-17050715 Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

  • STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr.
    • Well, that just makes sense. STN is excitatory, GPi is an output structure of the BG, and stimulation should activate the area.

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ref: Bergman-1998.01 tags: basal ganglia globus pallidus electrophysiology parkinsons 2001 DBS date: 02-22-2012 18:52 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-9464684[0] Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.

  • The firing of neurons in the globus pallidus of normal monkeys is almost always uncorrelated.
  • after MPTP treatment, the firing patterns of GP became correlated and oscillatory (see the figures!!)
  • dopamine must support normal segregation of the informational channels in the basal ganglia, and breakdown of this causes the pathology of PD.
  • has a decent diagram of the basal ganglia-thalamo-cortical circuits.
  • two different hypotheses of BG function: segregated and convergent. data support the former.

____References____

[0] Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, Vaadia E, Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.Trends Neurosci 21:1, 32-8 (1998 Jan)

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ref: Steigerwald-2008.11 tags: parkinsons disease essential tremor DBS STN VIM date: 02-22-2012 18:40 gmt revision:4 [3] [2] [1] [0] [head]

PMID-18701754[0] Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state

  • Recorded from the STN in both PD and ET patients -- with the ET patients acting as a control (sorta; as good as we'll get).
  • ET is common neuromotor condition that involves intention tremor and movement overshoot; progresses over many years.
    • Malfunction of the olivocerebellar pathways.
    • no involvement of Dopamine-dependent pathways.
  • 65 PD patients!
  • Classified single units based on ISI & the asymmetry index, the ratio of the mode to the mean of the ISI histogram.
    • bursting or burstlike firing, intermitten grouped firing separated by periods of pauses.
      • Further analyzed for burstlike features via 'burst surprise method' Salcman 1985).
    • irregular, broad ISI CV > 85.
    • Regular tonic firing, bell shaped ISI, CV < 90.
  • PD patients had more burst-like neurons; ET patients had more irregular neurons.
  • Neurons with theta and beta characteristics predominated in bursting neurons (71/81); gamma oscillationgs were commonly found in nonbursting cells (8/11).
  • Only found synchronized beta activity in SUAs recorded from PD patients.
  • Levy: emphasized the importance of tremor for beta-band oscillations because the majority of synchronous cells were recorded from five patients with resting tremor in the operating room, whereas no synchronous pairs were found in nontremulous patients.
  • aha! a limitation of our study, however, is the lack of tremor recordings during surgeries // we were therefore not able to determine the amount of tremor-locked activity within the 3-10 Hz or transient changes in response to intermittent tremor.
    • Another limitation: no movements, attention could have wandered.
  • Still, STN firing rate increased, as per MPTP model.
  • Shift toward bursting type activity in PD.
  • Did not find differences in the proportion of neurons exhibiting intrinsic oscillatory activity or interneuronal synchronization.
  • Large proportion of neurons exhibiting theta-band activity around 4Hz in PD patients; c.f. monkeys, 10 Hz activity dominates.
    • Tremor is not an accurate reporter of pathology.

____References____

[0] Steigerwald F, Pötter M, Herzog J, Pinsker M, Kopper F, Mehdorn H, Deuschl G, Volkmann J, Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state.J Neurophysiol 100:5, 2515-24 (2008 Nov)

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ref: Mirabella-2011.08 tags: DBS STN inhibition nogo Italy date: 02-22-2012 18:26 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-21810782[0] Deep Brain Stimulation of Subthalamic Nuclei Affects Arm Response Inhibition In Parkinson’s Patients

  • Inhibitory control is improved only when both DBS are active, that is, the reaction time to the stop signal is significantly shorter in the DBS-ON condition than in all the others (left, right, or neither).
    • Inhibition is probably not lateralized.
  • CF [1]
  • The STN plays a critical role in the control of movements by integrating cortical inputs from several motor areas (Mink 1996, Romanelli et al 2005) (but how -- in what role?)
    • Alteration of STN functioning leads to loss of the ability to control movements as in the case of Parkinson's disease (Obeso et al 2008).
    • This control can be partially restored by DBS (Perlmutter and Mink 2006).
    • I don't agree with this. Things are far more nuanced, and the STN likely has a different role.
  • Theri metric is the SSRT:the stop signal reaction time.
    • One study found that SSRT was longer when DBS was on.
    • Two others bilateral DBS decreased length of the SSRT.
  • This task creates conflict on all trials, as they are instructed to both move as fast as possible, but also avoid hitting the target on stop trials.
    • In healthy subjects this leads to a delay strategy.
  • SSRT is not measured, but rather estimated from a 'race condition' between Go and Stop cues.
  • They propose that DBS affects the procrastination strategy, and that this strategy was less often adopted by PD patients than normal controls.
    • Or that STN / BG affects the ability to stop currently proceeding active movements.

____References____

[0] Mirabella G, Iaconelli S, Romanelli P, Modugno N, Lena F, Manfredi M, Cantore G, Deep Brain Stimulation of Subthalamic Nuclei Affects Arm Response Inhibition In Parkinson's Patients.Cereb Cortex no Volume no Issue no Pages (2011 Aug 1)
[1] Frank MJ, Samanta J, Moustafa AA, Sherman SJ, Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism.Science 318:5854, 1309-12 (2007 Nov 23)

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ref: RodriguezOroz-2001.09 tags: STN SNr parkinsons disease single unit recording spain 2001 tremor oscillations DBS somatotopy organization date: 02-22-2012 18:24 gmt revision:12 [11] [10] [9] [8] [7] [6] [head]

PMID-11522580[0] The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics

  • Looks like they discovered exactly what we have discovered ... only in 2001. This is both good and bad.
    • From the abstract: "Neurones responding to movement were of the irregular or tonic type, and were found in the dorsolateral region of the STN. Neurones with oscillatory and low frequency activity did not respond to movement and were in the ventral one-third of the nucleus. Thirty-eight tremor-related neurones were recorded."
  • Again, from the abstract: "The findings of this study indicate that the somatotopic arrangement and electrophysiological features of the STN in Parkinson's disease patients are similar to those found in monkeys."
  • It may be that we want to test differential modulation / oscillation: look for differences between rest and activity, if there is sufficient support for both these in the files we have.
  • These people were much, much more careful about localization of their single-electrode tracks. E.g. they calculated electrode location relative the DBS electrode stereotatically, and referenced this to the postoperative MRI location of the treatment electrode.
  • Many more (32% of 350 neurons) responded to active or passive movement.
  • Of this same set, 15% (31 neurons) had a firing rate with rhythmical activity; 38 neurons had rhythmic activity associated with oscillatory EMG, but most of these were responsive to passive stimulation.
  • Autocorrelation of the neuronal bursting and tremor peaked at mean 7Hz, while autocorr. of EMG peaked at mean 5Hz.
  • This whole paragraph is highly interesting: ''The neuronal response associated with active movements was studied by simultaneous recording of neuronal EMG activity of the limbs. Five tremor-related neurons, recorded while a voluntary movement was performed, were available for analysis. Voluntary activation of a particular limb segment arrested the tremor. This was associated with a change in the discharges of the recorded neuron, which fired at a slower rate and in synchrony with the voluntary movement. On occasions, freezing of the voluntary movement ensued and tremor reappeared, changing the neuronal activity back to the typical 4-5Hz tremor-related activity. The cross-correlation analysis of two such neurons showed a peak frequency of 4.63 and 4.88 Hz for tremor-related activity, and 1.5 to 1.38 Hz during voluntary movement. Whether neuronal discharges in the STN preceded or followed EMG activity of the limbs could not be precisely established under the present conditions.
  • Somatotopic representation in the STN is expected from normal and MTPT-treated monkeys. Indeed, somatotopy is enhanced int he GPm of MTPT-treated monkeys.
    • This somatotopy is likely to result from organized afferent from the primary motor cortex (M1) to dorsolateral STN; this is the target of DBS treatment. Ventral and medial STN seems to project to associative and limbic cortical regions.
    • It seems they think the STN is generally not diseased, it is just a useful target for stimulating without evoked movement as in M1. This is consistent with optogenetic studies by Deisseroth [1].
    • Supporting this: "DBS of STN in Parkinson's disease improves executive motor functions, but aggravates conditional associative learning.
  • Interesting: In Parkinson's disease patients with tremor, Levy and colleagues found synchronization and a high firing rate (>10Hz) while recording pairs of neurons >600um apart.
  • Recordings of cortical activity through EEG and STN LFP showed significant coherence in the beta and gamma frequency bands during movement - consistent with corticosubthalamic motor projection. ... and suggest that the STN neurons involved in parkinsonian tremor are the same as the ones ativated during the performance of a voluntary movement. (! -- I agree with this.)
  • More: The reciprocal inhibitory-excitatory connections tightly linking the GPe and the STN may generate self-perpetuating oscillations.

Old notes:

  • this paper concentrates on STN electrophysiology in PD.
    • has a rather excellent list of references.
  • found a somatotopic organization in the STN, with most motor-related units more irregular and in the dorsolateral STN.
  • found a substantial fraction of tremor-synchronized neurons.
  • conclude that the somatotopic organization is about the same as in monkeys (?) (!)
  • M1 projects to STN, as verified through anterograde tracing studies. [1] These neurons increase their firing rate in response to passive movements.
  • there appears to be a relatively-complete representation of the body in the dorsolateral STN.

____References____

[0] Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, DeLong MR, Obeso JA, The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.Brain 124:Pt 9, 1777-90 (2001 Sep)
[1] Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K, Optical deconstruction of parkinsonian neural circuitry.Science 324:5925, 354-9 (2009 Apr 17)

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ref: Salin-2002.06 tags: STN HFS DBS stimulation dopamine date: 02-22-2012 18:23 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-12077209[0][] High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.

  • they wanted to measure the cellular/molecular effects of STN DBS - reasonable.
    • in-situ hybridization histochemistry and immunocytochemnistry.
  • HFS of the STN decreases the metabolic activity of STN neurons (cytochrome oxidase (CoI) levels decreased!),
    • However it did not affect the overexpression of enkephalin {1135} mRNA or the decrease in substance P in the ipsilateral striatum.
    • Decreased/corrects glutamate decarboxylase 67 (GAD67) in the substantia nigra following STN lesion, worsened in the entopeduncular (GPe-ish: see wiki) nucleus, no change in GPi.
    • HFS, however, increases c-fos activity, which seems to be involved in immediate early gene induction and stress response (as well as 8,000 other papers about this protein)
  • this stimulation may not simply cause interruption of STN outflow.
  • STN on the order of 300ua through a 200um teflon-coated stainless bipolar (twisted pair) electrode (important to consider)
  • unilateral HFS in STN in hemiparkinsonian rats can induce dyskinesias
    • buuut a higher intensity of stimulation was required to elicit dyskinesia in animals with the dopamine lesion as compared to the intact rats. Parkinsonian animals are more resistant to HFS of the STN.
    • Therefore they matched the stimulus intensity to the behavior correlates, not the absolute values of