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[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] Williams JC, Rennaker RL, Kipke DR, Long-term neural recording characteristics of wire microelectrode arrays implanted in cerebral cortex.Brain Res Brain Res Protoc 4:3, 303-13 (1999 Dec)

[0] Jackson A, Mavoori J, Fetz EE, Long-term motor cortex plasticity induced by an electronic neural implant.Nature 444:7115, 56-60 (2006 Nov 2)

[0] Isoda M, Hikosaka O, Switching from automatic to controlled action by monkey medial frontal cortex.Nat Neurosci 10:2, 240-8 (2007 Feb)

{1384}
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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.

{1010}
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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)

{1236}
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ref: -0 tags: optogenetics micro LED flexible electrodes PET rogers date: 12-28-2017 03:24 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

PMID-23580530 Injectable, cellular-scale optoelectronics with applications for wireless optogenetics.

  • Supplementary materials
  • 21 authors, University Illinois at Urbana-Champaign, Tufts, China, Northwestern, Miami ..
  • GaN blue and green LEDs fabricated on a flexible substrate with stiff inserter.
    • Inserter is released in 15 min with a dissolving silk fibrin.
    • made of 250um thick SU-8 epoxy, reverse photocured on a glass slide.
  • GaN LEDS fabricated on a sapphire substrate & transfer printed via modified Karl-Suss mask aligner.
    • See supplemental materials for the intricate steps.
    • LEDs are 50um x 50um x 6.75um
  • Have integrated:
    • Temperature sensor (Pt serpentine resistor) / heater.
    • inorganic photodetector (IPD)
      • ultrathin silicon photodiode 1.25um thick, 200 x 200um^2, made on a SOI wafer
    • Pt extracellular recording electrode.
        • This insulated via 2um thick more SU-8.
  • Layers are precisely aligned and assembled via 500nm layer of epoxy.
    • Layers made of 6um or 2.5um thick mylar (polyethylene terephthalate (PET))
    • Layers joined with SU-8.
    • Wiring patterned via lift-off.
  • Powered via RF scavenging at 910 Mhz.
    • appeared to be simple, power in = light out; no data connection.
  • Tested vs control and fiber optic stimulation, staining for:
    • Tyrosine hydroxylase (makes l-DOPA)
    • c-fos, a neural activity marker
    • u-LEDs show significant activation.
  • Also tested for GFAP (astrocytes) and Iba1 (activated microglia); flexible & smaller devices had lower gliosis.
  • Next tested for behavior using a self-stimulation protocol; mice learned to self-stimulate to release DA.
  • Devices are somewhat reliable to 250 days!

{1356}
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ref: -2016 tags: Kozai carbon fiber microelectrodes JNE PEDOT PSS pTS date: 04-27-2017 01:42 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-27705958 Chronic in vivo stability assessment of carbon fiber microelectrode arrays.

  • showed excellent recording characteristics and nearly zero glial scarring.
  • 6.4um carbon fiber + 800nm parylene-C = 8.4um.
    • Cytec Thoronel T-650 CF, Youngs modulus = 255 GPa, tensile strength = 4.28 GPa, PAN-based.
  • Everything protected with our wonderful phenol epoxy 353NDT, heat-cure.
  • Used two coating solutions:
    • Solution of 0.01 M 3,4-ethylenedioxythiophene (483028, Sigma-Aldrich, St. Louis, MO): 0.1 M sodium p-toluenesulfonate (152536, Sigma-Aldrich, St. Louis, MO).
      • pTS is not that dissimilar from it's alkyl cousin, SPS, {1353}. Likely a soapy chemical due to the opposed methyl and sulfonic acid group; benzine will take up less room in the polymer c.f. SDS & may lower the oxidation potential of EDOT.
      • Tosylates have been explored as a EDOT counterion : PMID-22383043 Characterization of poly(3,4-ethylenedioxythiophene):tosylate conductive polymer microelectrodes for transmitter detection. and PEDOT-TMA
    • Solution was composed of 0.01 M 3,4-ethylene-dioxythiophene (483028, Sigma-Aldrich, St. Louis, MO):0.1 M polystyrene sulfonate (m.w. 70.000, 222271000, Acros, NJ).
    • For each solution the electrodeposition was carried out by applying 100 pA/channel for 600 s to form a layer of poly(3,4-ethylenedioxythiophene):sodium p-toluenesulfonate (PEDOT:pTS) or poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS).
      • Weird, would use voltage control here..
  • According to works by Green et al [45] and Hukins et al [46], equation (1) can be used to determine the aging time that
the fibers have undergone: t 37=t TQ10 T37)/10 where t 37 is the simulated aging time at 37 °C, t T is the amount of real time that the samples have been kept at the elevated temperature, T , and Q10 is an aging factor that is equal to 2, according to ASTM guidelines for polymer aging [47].
  • Show > 2MOhm impedance of the small-area electrodes. At the aging endpoint, PEDOT:pTS had about half the impedance of PEDOT:PSS.
    • 4M PSS, 7M pTS, both plated down to ~ 130k initial, went up to 2M pSS, 840k pTS.
  • Recording capability quite stellar
  • Likewise for the glial response.

{1381}
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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)

{1367}
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ref: -0 tags: microstimulation rat cortex measurement ICMS spread date: 01-26-2017 02:52 gmt revision:0 [head]

PMID-12878710 Spatiotemporal effects of microstimulation in rat neocortex: a parametric study using multielectrode recordings.

  • Measure using extracellular ephys a spread of ~ 1.3mm from near-threshold microstimulation.
  • Study seems thorough despite limited techniques.

{1362}
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ref: -0 tags: serial electron microscopy Lichtman reconstruction nervous tissue date: 01-17-2017 23:32 gmt revision:0 [head]

PMID-26232230 Saturated Reconstruction of a Volume of Neocortex.

  • Data presented at Cell "Big Questions in Neuroscience", perhaps the most impressive of the talks.

{1360}
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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.

{1270}
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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)

{1327}
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ref: -0 tags: ice charles lieber silicon nanowire probes su-8 microwire extracellular date: 10-14-2016 23:28 gmt revision:2 [1] [0] [head]

PMID-26436341 Three-dimensional macroporous nanoelectronic networks as minimally invasive brain probes.

  • Xie C1, Liu J1, Fu TM1, Dai X1, Zhou W1, Lieber CM1,2.
  • Again, use silicon nanowire transistors as sensing elements. These seem rather good; can increase the signal, and do not suffer from shunt resistance / capacitance like wires.
    • They're getting a lot of mileage out of the technology; initial pub back in 2006.
  • Su-8, Cr/Pd/Cr (stress elements) and Cr/Au/Cr (conductor) spontaneously rolled into a ball, then the froze in LN2. Devices seemed robust to freezing in LN2.
  • 300-500nm Su-8 passivation layers, as with the syringe injectable electrodes.
  • 3um trace / 7um insulation (better than us!)
  • Used 100nm Ni release layer; thin / stiff enough Su-8 with rigid Si support chip permitted wirebonding a connector (!!)
    • Might want to use this as well for our electrodes -- of course, then we'd have to use the dicing saw, and free-etch away a Ni (or Al?) polyimide adhesion layer -- or use Su-8 like them. See figure S-4
  • See also {1352}

{1334}
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ref: -0 tags: micro LEDS Buzaki silicon neural probes optogenetics date: 04-18-2016 18:00 gmt revision:0 [head]

PMID-26627311 Monolithically Integrated μLEDs on Silicon Neural Probes for High-Resolution Optogenetic Studies in Behaving Animals.

  • 12 uLEDs and 32 rec sites integrated into one probe.
  • InGaN monolithically integrated LEDs.
    • Si has ~ 5x higher thermal conductivity than sapphire, allowing better heat dissipation.
    • Use quantum-well epitaxial layers, 460nm emission, 5nm Ni / 5nm Au current injection w/ 75% transmittance @ design wavelength.
      • Think the n/p GaN epitaxy is done by an outside company, NOVAGAN.
    • Efficiency near 80% -- small LEDs have fewer defects!
    • SiO2 + ALD Al2O3 passivation.
    • 70um wide, 30um thick shanks.

{1251}
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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.

{1298}
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ref: -0 tags: RF microstimulation cats threshold date: 09-04-2014 18:43 gmt revision:1 [0] [head]

PMID-13539663 Subcortical threshold voltages as a function of sine wave frequencies Brown and Brackett

  • 22 GA insulated stainless steel electrodes, both bipolar and monopolar.
    • This happens to be near spike recording passband, unfortunately.
  • Square wave stimulation (8) Mihailovic and Delgado 1956 "Electrical stimulation of monkey brain with various frequencies and pulse durations".
  • Hines (6)(1940) , stimulating the monkey cortex with [a] sine wave, reported jerky uncompleted movements from 1260 Hz to 1440 Hz.
    • Monopolar surface stimulation, though.

{1297}
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ref: -0 tags: RF microstimulation UCSF date: 09-04-2014 18:42 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-4550167[1] Sensory responses elicited by subcortical high frequency electrical stimulation in man. -- everything innovative has already been done in the 70s!

  • "A radiofrequency current of 100 kHz sine wave was applied to therapeutic targets in the human brain and produced unpleasant sensory responses. Increasing the applied frequency to 250 kHz eliminated these responses.
  • Targets:
    • Near the junctions between the ventral lateral and the posteroventral lateral thalamic nuclei in patients with dyskinesias
    • Medial lemniscus in patients with intractable pain.
  • Frequently the patients reported that hte 100kHz radiofrequency current produced a severe unpleasant tingling or burning sensation.
    • The sensation was similar in quality and site to that elicited by 60 pps fstimulation, but tended to be much more intense and could not be tolerated by the patients.
  • The current necessary to produce sensory responses could produce a temperature change of less than 0.5 deg C as measured by our thermistor monitor.
  • Brown and Brackett {1298} have shown that motor responses are obtained when stimulating subcortical structures in the cat with frequencies as high as 100 kHz.
    • From 50 Hz to 25 kHz, they found the response to be smooth and definite.
    • Above 25 kHz the responses from most areas consisted of quick transient jerks at the onset of stimulus.
  • Other workers dealing with a variety of structures have reported stimulus responses to quite high frequencies.
    • As the frequency is raised, the current required for excitation increases.
    • Ultimately I 2R heating and tissue destruction provide the upper frequency limit for excitation.

{875}
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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)

{1281}
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ref: -0 tags: microelectrode patents date: 05-02-2014 00:07 gmt revision:1 [0] [head]

Various microelectrode patents:

Microelectronics:

{1278}
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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. (!!)

{1246}
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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.

{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)

{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.

{999}
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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 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____

' ''' ()

{1227}
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ref: Ledochowitsch-2011.01 tags: Ledochowitsch transparent micro ECoG Peter date: 01-30-2013 07:01 gmt revision:2 [1] [0] [head]

PMID-22254956[0] A transparent μECoG array for simultaneous recording and optogenetic stimulation.

  • We present a 49-channel μECoG array with an electrode pitch of 800 μm and a 16-channel linear μECoG array with an electrode pitch of 200 μm.
  • The backing material was Parylene C. Transparent, sputtered indium tin oxide (ITO) was used in conjunction with e-beam evaporated gold to fabricate the electrodes

____References____

[0] Ledochowitsch P, Olivero E, Blanche T, Maharbiz MM, A transparent μECoG array for simultaneous recording and optogenetic stimulation.Conf Proc IEEE Eng Med Biol Soc 2011no Issue 2937-40 (2011)

{823}
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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)

{781}
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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)

{946}
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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 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=0.9g ; 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)

{748}
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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)

{1201}
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ref: Kato-2006.01 tags: bioactive neural probes flexible parylene japan Kato microspheres date: 01-28-2013 03:57 gmt revision:1 [0] [head]

PMID-17946847[0] Preliminary study of multichannel flexible neural probes coated with hybrid biodegradable polymer.

  • Conference proceedings. a little light.
  • :-)
  • probes made of parylene-C

____References____

[0] Kato Y, Saito I, Hoshino T, Suzuki T, Mabuchi K, Preliminary study of multichannel flexible neural probes coated with hybrid biodegradable polymer.Conf Proc IEEE Eng Med Biol Soc 1no Issue 660-3 (2006)

{1217}
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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)

{1216}
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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)

{898}
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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)

{1214}
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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.

{311}
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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____

{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)

{750}
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ref: Menei-1994.09 tags: microspheres beads polycaprolactone biocompatible drug delivery histology date: 01-27-2013 20:54 gmt revision:3 [2] [1] [0] [head]

PMID-7814435 Fate and biocompatibility of three types of microspheres implanted into the brain.

  • microspheres ( 24μm ) appear to be engulfed or surrounded by histocytic cells.
  • poly(e-caprolactone), which is supposed to be biodegradable, did not dissolve in the brain. The polymer is hydrophobic.
  • 20um spheres could be engulfed by macrophages; their microspheres were too large, and were encapsulated in a thin coallagen layer and astrocytic process.
  • no scale bars - annoying - but we can estimate the size of the coating to be about the same size as the beads themselves.

{737}
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ref: Biran-2005.09 tags: microelectrode Michigan probe glia tissue response electrode immune histology MEA Biran date: 01-24-2013 20:49 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-16045910[0] Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays.

  • See also {1190} (wow, I'm redundant!)
  • Important point: ED1 up-regulation and neuronal loss were not observed in microelectrode stab controls, indicating that the phenotype did not result from the initial mechanical trauma of electrode implantation, but was associated with the foreign body response.
    • CD68 = ED1 is a marker for microglia and other macrophages. (wikipedia article is informative).
    • GFAP = glial fibrillary acidic protein, marker for astrocytes.
  • Recording failure is caused by chronic inflammation (mostly activated microglia) at the microelectrode brain tissue interface.
  • Only tested response 2 and 4 weeks after implantation. Makes sense for stab wound, but didn't the want to see a longer term response? Or do their electrodes just not last that long?
  • What did they coat the silicon probes in?
  • Used silastic to shock-mount their floating electrodes, but this apparently made no difference compared to conventional dental cement and bone screw mounting.
  • Suggest that chronic inflammatory response may be related to the absorption of fibrogen and complement to the surface of the device (device should not be porous?), the subsequent release of pro-inflammatory and cytotoxic cytokines by activated microphages, and the persistence of activated macrophages around materials which cannot be broken down.
    • Well then, how do you make the electrodes biochemically / biologically 'invisible'?
    • Persistently activated microglia are found around insoluble plaques in AD (plaques that cannot be / are not removed from the brain via proteolysis. Microglia form 'glitter cells' when they engulf undigestible stubstances). This has been termed 'frustrated phagocytosis', which results in increased secretion of proinflamatory cytokines that directly or indirectly cause neuronal death.
  • Significant reductions in neurofiliament reactivity was seen up to 230um from the microelectrode interface; this was not seen for stab wounds. Maximum recording distance is about 130um; 100um more reasonable in normal conditions.
  • Accumulating evidence from postmortem analysis of patients implanted with DBS electrodes reveals that chronic neuroinflamation is part of the response to such (duller, larger) implants as well. They have seen cell loss up to 1mm fromt the electrode surface here.

____References____

[0] 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)

{1024}
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ref: COLLIAS-1957.05 tags: histology microelectrode vasulature date: 01-23-2013 23:56 gmt revision:4 [3] [2] [1] [0] [head]

PMID-13429398[0] Histopathological changes produced by implanted electrodes in cat brains; comparison with histopathological changes in human and experimental puncture wounds.

  • Quite a good and overcomplete / long article -- fully describes their result of implanting bundles of 0.005" varnished steel wires into the brains of cats.
    • Saw hemorrhagic necrosis, necrosis from edema, and eventual encapsulation and collapse of capilaries around the chronic implant. All things that we still have to contend with.
  • From [1]: ... For single penetrating electrodes into cat cortex, Collias and Manuelidis noted and increase in hemorrhagic damage near electrode tracks of the cortex nearest the point of electrode entry into the pia.
  • They also reported that the damage appeared to be randomly distributed among the implants, which they attributed to differences in local vasculature.
  • The toxicity of certain metals, namely, platinum, platinum-8% tungsten, platinum-10% rhodium, platinum-10% iridium, platinum-10% nickel, platinized platinum, a gold-nickel-chromium alloy, a gold-palladium-rhodium alloy, a chromium-nickel-molybdenum alloy (Vitallium), stainless steel, silver, rhenium, and gold, was evaluated histologically following chronic implantation for 2 months in the brains of cats. Of the above metals, all but silver were found to be nontoxic. Boron was also evaluated and found to be nontoxic.

____References____

[0] COLLIAS JC, MANUELIDIS EE, Histopathological changes produced by implanted electrodes in cat brains; comparison with histopathological changes in human and experimental puncture wounds.J Neurosurg 14:3, 302-28 (1957 May)
[1] 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)

{1102}
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ref: Gilletti-2006.09 tags: electrode micromotion histology GFAP variable reluctance date: 01-04-2013 02:28 gmt revision:2 [1] [0] [head]

PMID-16921202[0] Brain micromotion around implants in the rodent somatosensory cortex.

  • Used a differential variable reluctance transducer (DVRT) in adult rats (n = 6) to monitor micromotion normal to the somatosensory cortex surface
    • Reluctance e.g. AC inductance varied with a floating bobbin (or so -- they do not list the details of this COTS device).
  • Pulsatile surface micromotion was observed to be in the order of 10-30 um due to pressure changes during respiration and 2-4 um due to vascular pulsatility.
  • Large inward displacements of brain tissue between 10-60 um were observed in n = 3 animals immediately following the administration of anesthesia

____References____

[0] Gilletti A, Muthuswamy J, Brain micromotion around implants in the rodent somatosensory cortex.J Neural Eng 3:3, 189-95 (2006 Sep)

{1190}
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ref: Biran-2005.09 tags: Tresco histology chronic implantation astrocytes microglia date: 01-04-2013 02:28 gmt revision:3 [2] [1] [0] [head]

PMID-16045910[0] Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays.

  • We observed persistent ED1 immunoreactivity around implanted silicon microelectrode arrays implanted in adult rat cortex that was accompanied by a significant reduction in nerve fiber density and nerve cell bodies in the tissue immediately surrounding the implanted silicon microelectrode arrays.
  • We found that explanted electrodes were covered with ED1/MAC-1 immunoreactive cells and that the cells released MCP-1 and TNF-a under serum-free conditions in vitro.
  • See also [1] and [2]
  • Electrodes: Michigan type, 5mm long, 200um wide tapering to 30um, 15um thick at the shank tapering to 2um.
    • Show that the chronic response is markedly different than acute stab wounds.
    • "Stab wounds resulted in comparatively minimal neurofilament loss at 2 weeks (A) and no apparent loss by 4 weeks".
    • "The number of neuronal bodies is reduced in the area adjacent to microelectrodes (B, D) but appears unaltered surrounding stab wound lesions (A, C; lesion site in center of each image)."
  • Includes details of immunostaining, which could be useful.

____References____

[0] 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)
[1] Szarowski DH, Andersen MD, Retterer S, Spence AJ, Isaacson M, Craighead HG, Turner JN, Shain W, Brain responses to micro-machined silicon devices.Brain Res 983:1-2, 23-35 (2003 Sep 5)
[2] Gilletti A, Muthuswamy J, Brain micromotion around implants in the rodent somatosensory cortex.J Neural Eng 3:3, 189-95 (2006 Sep)

{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.

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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.

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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: Gubellini-2009.09 tags: DBS PD 2009 review historical microstimulation ICMS chronaxie rheobase date: 02-22-2012 14:33 gmt revision:11 [10] [9] [8] [7] [6] [5] [head]

PMID-19559747[0] Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior.

  • Wow, DBS has been used since the 1950s for localization of lesion targets; in the 1960's was discovered to alleviate tremor; 70s and 80s targeted at the cerebellum for treatimng movement disorders or epilepsy.
  • Extensive list of all the other studies & their stimulation protocols.
  • Large mylenated fibers have chronaxies ranging aruond 30-200 us, while cell bodies and dendrites this value is around 1-10ms. (Rank, 1975).
    • Lapique: minimum energy is a/b, where b is the rhreobase (the minimal electric current of infinite duration that results in an action potential), and chronaxie is the minimum time over which an electric current double the strength of the rheobase needs to be applied in order ti stimulate a nerve cell.
    • Q(t)t=U rh(1+t cht) where U rh is the rheobase and t ch is the chronaxie.
    • you can simplify this to: I th=I rh(1+t cht) where I rh is the rheobase current and I th is the threshold current (Irnich, 2002).
  • Measurements of chronaxie in VIM and GPi found values of 60-75us, hence DBS effects are likely mediated through the activation of afferent and efferent axons. (Holsheimer et al 2000a, 2000b)
    • In line with these findings, cortical stimulation also results in the activation of afferent and efferent axons (Nowak and Bullier, 1998a, 1998b PMID-9504844).
    • Ustim can result in cell body hyperpolarization coupled with action potential initiation in the axon (McIntyre and Grill, 1999; Nowak and Bullier 1998a b).
  • Stimulation depends on the direction of the electric field, obviously. When the axons and E are ||.
  • Acute stimulation is different from chronic DBS (as used in patients); it may be a mistake to extrapolate conclusions.
    • DBS electrodes become encapsulated, and current delivered hence decreases.
  • Strong placebo effect of just the DBS surgery.
    • Implantation of electrodes alone had therapeutic benefit in 6-mo trial. (Mann et al 2009).
  • mean lead impedance is 400-120 ohms in clinical DBS leads, PT-IR.
    • platinum is relatively non-toxic to the brain when compared to metals such as gold or rhodium.
  • If stimulation exceeds 30 uC/cm^2/phase, there is a risk of tissue damage. This equates to 30ma.
  • Stainless steel electrodes are damadged by days of in vivo stimulation -- metal ions are lost.
  • STN neurons spontaneously oscillate due to leak Ca currents and C-activated K channels.
  • STN DBS seems to disrupt abnormal synchronized activity recorded in the BG-thalamocortical loops in PD. (meta-analysis of several studies).
  • STN DBS seems to reduce FR in the SNr.
  • STN excitotoxic leasion in rats causes increased impulsivity, impaired accuracy, premature responses, and more attention to food reward location in rats.
    • There is a hyperdirect pathway from the medial prefrontal cortex to the STN; breaking this decreases attention and perseverance.
    • STN HFS sometimes induces impulsive behavior in humans, with which this is consistent. (This may be sequelae from levodopa treatment).
    • STN HFS often causes weight gain in patients. But it might be because they can eat more or are more 'motivated at life'.
    • Controlled studies in rats show that STN lesion does not effect quantity consumed, either food, ehanol, or cocaine.
      • Differential effect when the reward was food vs. cocaine -- the STN may modulate the reward system based on the nature of the reward.
  • Huh: HFS of the ZI (zona incerta) has been reported to be superior to STN HFS for improving contralateral parkinsonism in PD patients.
    • Could be current diffusion into the STN, however, as lesioning this structure in rats has less effect than lesioning STN.
    • See also {1098}.
  • Chronic GPi DBS does not allow reducing L-DOPA dosage, unlike STN stimulation, but it is a good treatment for dyskinesia.
  • VIM treatment is very effective for tremor, but it does not treat the other motor symptoms of PD. Furthermore, it wears off after a few years.
    • CM/Pf seems like an even better target (Center median / parafasicular complex of the thalamus -- see {1119}.
  • DBS in the PPN (pedunculo pontine nucleus, brainstem target of the BG) at 10 HZ induces a feeling of well-being , concomitant with a modest improvement in motor function; no effect at 80 Hz.
  • Dystonia: GPi is a efficacious target for DBS.
    • Full effect takes a year (!), suggesting that the effect is through reorganization of the BG / neuroplascticity.
  • ET : lesions of the VIM, STN, or cerebellum can reduce symptoms. DBS of the VIM, STN, or ZI all have been found effective.
  • Huntington's disease involves degeneration of the projection neurons from the caudate and putamen.
    • HD affects motor, cognitive, and psychiatric functioning.
  • Drug addiction: inactivating the Nucelus accumbens (NAc) may reduce motivation to obtain the drug, but it may also reduce the motivation to do anything (apathy).
  • GPi DBS also a target for reducing chorea.
  • STN DBS may worsen treatment-resistant-depression; this seen in an animal model, and anecdotally in humans with PD.
  • OCD can be treated with DBS through the internal capsule extending toward the NAc / ventral striatum.
    • side effects include hypomania or anxiety.
    • Alas there is no satisfactory animal model of OCD, which hampers research.

____References____

[0] Gubellini P, Salin P, Kerkerian-Le Goff L, Baunez C, Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior.Prog Neurobiol 89:1, 79-123 (2009 Sep)

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ref: -0 tags: microstim ICMS axons soma Nowak NMDA date: 01-27-2012 23:30 gmt revision:1 [0] [head]

PMID-9504843 Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. I. Evidence from chronaxie measurements.

  • Slice experiments / in vitro.
  • The chronaxie for orthodromic activation was similar to that for axonal activation, but was 40 times smaller than the chronaxie for direct cell body activation. This suggests that, whenever a postsynaptic response is elicited after electrical stimulation of the cortical gray matter, axons (either axonal branches or axon initial segments), but not cell bodies, are the neuronal elements activated.

PMID-9504844 Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. II. Evidence from selective inactivation of cell bodies and axon initial segments.

  • Blocked soma and proximal axons / dendrites from firing AP through iontophoresis of NMDA.
  • When the NMDA-induced depolarization block was performed at the site of electrical stimulation, an unexpected increase in the amplitude of the orthodromic (backwards, into the white matter) responses was observed.
    • Possibly due to an increase in axonal excitability (?)
    • Superexitability eventually washed out, leading to responses that was 15-20% lower than before NMDA soma / proximal axon block.
  • "Since the neocortex is organised as a network of local and long-range reciprocal connections, great attention must be paid to the interpretation of data obtained with electrical stimulation."

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ref: -0 tags: micromotion electrode FEA model date: 01-27-2012 19:19 gmt revision:1 [0] [head]

PMID-16317234 A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex.

  • Postulate that mechanical strains induced around the implant site may be one of the leading factors responsible for the sustained tissue response in chronic implants
  • A tangential tethering force results in 94% reduction in the strain value at the tip of the polyimide probe track in the tissue,
  • Simulated 'soft' probe induced two orders of magnitude smaller values of strain compared to a simulated silicon probe.
  • Shows some insertion forces:
  • As well as mechanical properties of the brain.

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ref: work-2009 tags: bipolar opamp design current control microstimulation date: 01-06-2012 20:13 gmt revision:15 [14] [13] [12] [11] [10] [9] [head]

Recently I've been working on a current-controlled microstimulator for the lab, and have not been at all satisfied with the performance - hence, I decided to redesign it.

Since it is a digitally current-controlled stimulator, and the current is set with a DAC (MCP4822), we need a voltage controlled current source. Here is one design:

  • Because the output of the DAC is ground-referenced, and there is no negative supply in the design, the input buffers must be PNP transistors. These level-shift the input (0-2V, corresponding to 0-400uA) + 0.65V ( V be ), and increase the current. Both are biased with 1uA here, though 10uA would also work (lazily, through 1M resistors - I've checked that these work well too). This sets the base current at about 10nA for Q2 and Q1.
  • Q3 and Q4 are a current-mirror pair. If Q1 Vb increases, Ie for Q3 will decrease, increasing Ib for Q4 and hence its Ic. This will decrease the base current in Q6 and Q5, as desired. On the other hand, increasing Q2 Vb will decrease Q4 Ic, increasing Ib in Q6 and Q5. The current mirror effects the needed negative feedback in the circuit. This mirror could also be implemented with PNP transistors, but it doesn't work as well as then the collector (which has voltage gain) is tied to the emitter of the input PNP transistors. Voltage gain is needed to drive Q5 / Q6.
  • Q5 & Q6 are Darlington cascaded NPN transistors for current gain. If Q6 is omitted, Ib in Q5 increases -> Ib in Q1 decreases -> Ic in Q3 decreases -> Ib in Q4 increases. This results in a set-point of Ib = 100nA in Q5 -> Ic ~10uA. (unacceptable for our task).

What I really need is a high-side regulated current source; after some fiddling, here is what I came up with:

  • V2 is from the DAC; for the testing, I just simulate with a votlage ramp. This circuit, due to the 5V biasing (I have 5V available for the DAC, hence might as well use it) works well up to about 4V input voltage - exactly what the DAC can produce.
  • Q1 and Q2 are biased through 1M resistors R6 and R8; their emitters are coupled to a common-emitter amplifier Q3 and Q4.
  • As the voltage across R1 increases, Ib in Q1 decreases. This puts more current through the base of Q4, increasing the emitter voltage on both Q3 and Q4. This reduces the current in Q3, hence reducing the current in Q5 -> the voltage across R1. feedback ;-)
  • I tried using a current mirror on the high-side, but according to spice, this actually works *worse*. Q5 & Q3 / Q4 have more than enough gain as it stands.
  • Yes, that's 100V - the electrodes we use have high impedance, so need a good bit of voltage to get the desired current.
  • Now, will need to build this circuit to verify that it actually works.

  • (click for the full image)
  • This simulates OK, but shows some bad transients related to switching - I'll have to inspect this more closely, and possibly tune the differential stage (e.g. remove the fast transient response - Q6 and Q12 seem to turn off before Q5 and Q11 do, which pulls the output to +50v briefly)

  • This is the biphasic, bipolar stimulator's response to a rising ramp command voltage, as measured by the current through R17. Note how clean the signal is :-) But, I'm sure that it won't look quite this nice in real life! Will try one half out on a breadboard to see how it looks.
  • Note I switched from NMOS switching transistors to NPN - Q15 and Q16 shunt the bias current from Q3/Q2 and Q8/Q9, keeping the output PNPs (Q5 and Q11). These transistors are in saturation, so they take 100-200ns to turn off, which should be fine for this application where pulse width is typically 100us.
  • I've fed the pull-down NPN base current from the positive supply here, so that as long as Q5 and Q11 are on, Q6 and Q12 are also on. The storage time here (not that it is much, the transistors are kept out of saturation via D1-4) helps to keep the mean difference in voltage between animal or stimulee's ground and isolated stimulator ground low. In previous stimulators the high-side was a near-saturation PNP, which pulled the voltage all the way to the positive supply when stimulation started. This meant that any stray capacitance had to be charged through the brain - bad!
    • Note this means that the emitter current through Q6 and Q12 is more than the current through R17 by that passed through Q14 and Q13. By design, this is 1/50th that through Q5 and Q11. This means that the actual stimulated current will be 95% of the commanded current, something which is easily corrected in software.

  • Larger view of the schematic. Still worried about stability - perhaps will need to add something to limit slew rate.
  • V2 on the right is the command voltage from the DAC.

  • The amplifier in figure 5 suffered from low bandwidth, primarily because the large resistors effected slow timeconstants, and because there was no short path to +50V from the high-side PNP transistors. This led to very slow turn-off times. To remedy this:
    • Bias current to Q3 & Q4 was increased (R6 & R8 decreased) -> more current to charge / discharge capacitance.
    • Common emitter resistor concomitantly decreased to 22k. This increases the collector current.
    • Pull-up resistors changed to a current mirror. This allows the current through Q4 to pull up the bases of Q5 and Q6, letting them turn off more quickly. If Q1 is off (e.g. voltage across R1 is high), Q4 will be on, and Q6 will source this current. etc.
  • With this done, I tested it on the breadboard & it oscillated. bad! Hence, I put a 1nf (10nf in the schematic) capacitor from the collector of Q3 to ground - hence limiting the slew rate. This abolished oscillations and led to a very pretty linear turn-on waveform.
  • However, the turn-off waveform was an ugly exponential. Why? With Q2 or Q10 fully on, Q3 will be off. Q4 will effectively recharge C1 through R7. As the voltage across R7 goes to zero, so does the charging current. Since I don't want to add in a negative supply, I simply shifted the base voltage of Q3 and Q4 using a diode, about as simple as you can get!
  • Eventually, I replaced R7 with a current source ... but this did not change the fall waveform that much; it is still (partially) exponential. Possibly this is from the emitter resistors on the high-side.

  • As of now, the final version - tested using surface mount devices; seems to work ok!
  • Note added transistor Q11 - this discharges / removes minority carriers from the base of Q8. Even though D1 and D2 guarantee a current-starved Q8 in previous designs, they leave no path to ground from the base, so this transistor was taking forever to turn off. This was especially the case when switching (recall this is one half of a H-bridge, and Q9 would actually be on the other side of the h-bridge), since the other sides' Q9 would push current, while Q8 would continue to conduct & sink current. This current through R1 would increase Q8 emitter voltage, reverse-biasing its' base-emitter junction, making the transistor take 100us of us to turn off. Bad, since the amplifier is intended to replicate 100us pulses! Anyway, Q11 neatly solves the problem (albeit with 100ns or so of saturated-switching storage time - something that Q10 has anyway).
  • D1 and D2 are no longer really necessary, but I've left them in this diagram for illustrative purposes. (and they improve storage time a bit).

  • Update as the result of testing. Changes:
    • Added emitter resistors on the two current mirrors (Q6, Q7; Q12, Q13). This eliminated stability problems
    • Changed the anti-saturation diodes to a resistor. This is needed as it takes some time for Q9 to turn off, and to avoid unbalanced currents through the electrode pairs, this charge should be pulled to ground through Q8. In the actual circuit, Q11 is driven with a 4-8us delayed version of the control signal V4 so that Q8 remains on longer than current source Q9.
    • Decreased C1 to 100pf; because the amplifier is more stable now, the slew rate can be increased.

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ref: Nicolelis-1997 tags: nicolelis microwire array electrophysiology rats date: 01-05-2012 03:35 gmt revision:2 [1] [0] [head]

PMID-9136763[0] Reconstructing the engram: simultaneous, multisite, many single neuron recordings.

  • descibes Miguel's microwire arrays.
  • 100 units from 48 microwires in rats.
  • 2.3 units / microwire.
  • stable for weeks -- c.f. 2011. [1]

____References____

[0] Nicolelis MA, Ghazanfar AA, Faggin BM, Votaw S, Oliveira LM, Reconstructing the engram: simultaneous, multisite, many single neuron recordings.Neuron 18:4, 529-37 (1997 Apr)
[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: Goldstein-1973.07 tags: Salcman microelectrodes bucking analysis stiffness youngs modulus mechanical MEA date: 01-04-2012 01:22 gmt revision:4 [3] [2] [1] [0] [head]

IEEE-4120642 (pdf) Mechanical Factors in the Design of Chronic Recording Intracortical Microelectrodes

____References____

Goldstein, Seth R. and Salcman, Michael Mechanical Factors in the Design of Chronic Recording Intracortical Microelectrodes Biomedical Engineering, IEEE Transactions on BME-20 4 260 -269 (1973)

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ref: MolinaLuna-2007.03 tags: ICMS microstimulation cortical thin-film electrodes histology MEA date: 01-03-2012 22:54 gmt revision:2 [1] [0] [head]

PMID-17178423[0] Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays.

  • they claim that thin-film electrodes are better than microelectrode arrays, as they show less evidence of cortical damage.
    • thin-film electrodes show higher reproducability
    • more accurate spatial arrangement.
  • epidural stimulation (they were implanted between the dura and skull)

____References____

[0] Molina-Luna K, Buitrago MM, Hertler B, Schubring M, Haiss F, Nisch W, Schulz JB, Luft AR, Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays.J Neurosci Methods 161:1, 118-25 (2007 Mar 30)

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ref: GULD-1964.07 tags: platinum iridium microelectrode eltrolytic etching original date: 01-03-2012 19:05 gmt revision:2 [1] [0] [head]

PMID-14199966[0] A Glass-covered platinum microelectrode

  • Details the manufacture and testing of PT-IR (70/30) etched solder glass-coated microelectrodes.
  • Melt a bead of the glass on the top and gradually draw the bead downward, surrounded by the heater of a pipette drawing machine.

____References____

[0] GULD C, A GLASS-COVERED PLATINUM MICROELECTRODE.Med Electron Biol Eng 2no Issue 317-27 (1964 Jul)

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ref: Pearce-2004.01 tags: neural recording microfluidics in-vitro MEA date: 01-03-2012 06:53 gmt revision:4 [3] [2] [1] [0] [head]

PMID-17271187[0] Dynamic control of extracellular environment in in vitro neural recording systems.

  • they show how to create microfluidic channels on top of in-vitro microfluidic arrays.
  • used dorsal root ganglion cells.
  • key aspect:
    • make a thin cavity/space between two polycarbonate panes.
    • fill the cavity with liquid-phase isobornyl acrylate
    • cover the panes with a high-resolution mask
    • upon exposure to UV light the isobornyl polymerizes.
    • did this on top of a MEA-60
  • looks like they can very accurately deliver pulses and streams of fluid.

____References____

[0] Pearce T, Oakes S, Pope R, Williams J, Dynamic control of extracellular environment in in vitro neural recording systems.Conf Proc IEEE Eng Med Biol Soc 6no Issue 4045-8 (2004)

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ref: Blum-2004.01 tags: microstimulator MEA Georgia Blum integrated circuit date: 01-03-2012 06:53 gmt revision:3 [2] [1] [0] [head]

PMID-17271195[0] Models of stimulation artifacts applied to integrated circuit design.

  • for MEAs.
  • Idea: develop a model of the stimulation artifact so they can optimize removal in SPICE.
  • reference documents that say that biphasic stimulation + active artifact suppression (by discharging the electrodes after stimulation, [1]) are acknowledged means of reducing stimulus artifact.
  • artifact appears to be 1ms saturating, 6ms non-saturating pulse.
  • a little light on details.

____References____

[0] Blum R, Ross J, Das S, Brown E, Deweerth S, Models of stimulation artifacts applied to integrated circuit design.Conf Proc IEEE Eng Med Biol Soc 6no Issue 4075-8 (2004)
[1] Jimbo Y, Kasai N, Torimitsu K, Tateno T, Robinson HP, A system for MEA-based multisite stimulation.IEEE Trans Biomed Eng 50:2, 241-8 (2003 Feb)

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ref: Williams-1999.12 tags: recording microwire guinea kipke MEA Michigan date: 01-03-2012 03:18 gmt revision:2 [1] [0] [head]

PMID-10592339[0] Long term neural recording characteristics of wire microelectrode arrays implanted in cerebral cortex

  • details the williams microwire array assembly protocol - basically the same as what gary does here in the nicolelis lab, only written up nicely and for guinea pigs not rhesus macaques.
  • references miguel's book on multielectrode recordings

____References____

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ref: Ghovanloo-2005.01 tags: Najafi microstimulation Ghovanloo date: 01-02-2012 03:06 gmt revision:2 [1] [0] [head]

PMID-15651568[0] A compact large voltage-compliance high output-impedance programmable current source for implantable microstimulators.

  • from NCSU - reprazent!
  • (from abtract:) "A new CMOS current source is described for biomedical implantable microstimulator applications, which utilizes MOS transistors in deep triode region as linearized voltage controlled resistors (VCR)."

____References____

[0] Ghovanloo M, Najafi K, A compact large voltage-compliance high output-impedance programmable current source for implantable microstimulators.IEEE Trans Biomed Eng 52:1, 97-105 (2005 Jan)

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ref: Akin-1995.06 tags: Najafi neural recording technology micromachined digital TETS 1995 PNS schematics date: 01-01-2012 20:23 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

IEEE-717081 (pdf) An Implantable Multichannel Digital neural recording system for a micromachined sieve electrode

  • Later pub: IEEE-654942 (pdf) -- apparently putting on-chip isolated diodes is a difficult task.
  • 90mw of power @ 5V, 4x4mm of area (!!)
  • targeted for regenerated peripheral neurons grown through a micromachined silicon sieve electrode.
    • PNS nerves are deliberately severed and allowed to regrow through the sieve.
  • 8bit low-power current-mode ADC. seems like a clever design to me - though I can't really follow the operation from the description written there.
  • class e transmitter amplifier.
  • 3um BiCMOS process. (you get vertical BJTs and Zener diodes)
  • has excellent schematics. - including the voltage regulator, envelop detector & ADC.
  • most of the power is dissipated in the voltage regulator (!!) - 80mW of 90mW.
  • tiny!
  • rather than using pseudoresistors, they use diode-capacitor input filter which avoids the need for chopping or off-chip hybrid components.
  • can record from any two of 32 input channels. I think the multiplexer is after the preamp - right?

____References____

Akin, T. and Najafi, K. and Bradley, R.M. Solid-State Sensors and Actuators, 1995 and Eurosensors IX.. Transducers '95. The 8th International Conference on 1 51 -54 (1995)

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ref: Doty-1969.01 tags: Doty microstimulation brain behavior macaque conditioned stimulus attention motivation 1969 date: 12-29-2011 23:28 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-4888623[0] Electrical stimulation of the brain in behavioral context.

  • Excellent review.
  • Focal stimulation of macaques can induce insect-grabbing responses, after which they will carefully examine their hands to see what was caught!
    • Same thing has been observed in humans -- the patient reported that he wanted to catch 'that butterfly'.
  • Such complicated action must be the effect of downstream / upstream targets of the stimulated site, as the actual stimulation carries no information other than it's spatial locality within the brain.
  • Stimulation of the rostral thalamus in the language hemisphere can elicit phrases: "Now one goes home", "Thank you", "I see something".
    • These are muttered involuntarily and without recollection of having been spoken.
  • Doty stimulated macaques at 20ua for 500us as a CS in postcentral gyrus (S1?) for a lever press CR, which should (he says)only activate a few dozen neurons.
  • Can elicit mating behaviors in oposums with electrical stimulation of the hypothalamus, but only if another opossum or furry object is present.
  • Stimulation of the caudate nucleus in humans causes an arrest reaction: they may speak, smile, or laught inappropriately, but appropriate voluntary responses are brought to a halt.
  • Stimulation of the basolateral amygdala can cause:
    • Hungry cats to immediately stop eating
    • Stop stalking prey
    • Non-hunting animals to stalk prey, and indeed will solve problems to gain access to rats which can be attacked.
  • Prolonged stimulation of almost every place in the brain of a cat at 3-8Hz can put it to sleep, though since lab cats normally sleep 17/24hours, this result may not be significant.
  • Stimulation at most sites in the limbic system has the still mysterious ability to organize motor activity in any fashion required to produce more of the activity or to avoid it, as the case may be.
  • Rats that are stimulated in the periaqueductal gray will self-administer stimulation, but will squeal and otherwise indicate pain and fright during the stimulation. Increasing the duration of stimulation from 0.5 to 1 second makes self-administration of this apparently fearful stimulation stop in both rats and cats.
  • Certain patterns of activity within systems responsible for fearful or aggressive behavior, rather than being aversive are perversely gratifying. This is clearly recognized in the sociology of man...
  • Rats will self-stimulate with the same stimulus trains that will cause them to eat and drink, and under some conditions the self-stimulation occurs only if food or water is available.
  • On the other hand, rats will choose self-stimulation of the lateral hypothalamus instead of food, even when they are starving.
    • Electrically induced hunger is its own reward.
  • The work of Loucks (124, 125) forms the major point of origin for the concept that motivation is essential to learning. with careful and thorough training, Loucks was unable to form CRs to an auditory CS using stimulation of the motor cortex as the US. With this paradigm, the limb movements elicited by the US never appeared to the CS alone; but movements were readily established when each CS-US combination was immediately followed by the presentation of food.
    • However: Kupalov independently proved that stimulation of the motor cortex could be used as the US, at the same time using stimulation at other loci as the CS.
    • Why the difference? Attention -- failures are commonly obtained with animals that consistenly fidget or fight restraint, as most of them do.
    • Cortical stimulation itself is not rewarding or aversive; animals neither seek nor avoid stimulation of most neocortical areas.
  • On classical conditioning: [Bures and colleagues (20, 65) bibtex:Bures-1968 bibtex:Gerbrandt-1968] found that if an anticedent stimulus, which might or might not effect a neuron, were consistently followed by effective intracellular electrical stimulation of that individual neuron, in roughly 10 percent of the cells of the neocortex, hippocampus, thalamus, or mesencephalic reticular formation a change in the response of that cell to the antecedent stimulus could be observed.
  • With an apparent exception of the cerebellum it is possible to electrical excitation any place in the brain as a CS in chickens, rats, rabbits ...
  • Stimulation of group 1 proprioceptive muscle-afferent fibers in cats is ineffective as a CS.
    • Muscle spindles lack clear access to the systems subserving conditioned reflexes. (These instead go to the cerebellum)
  • Macaques can also discriminate between two stimulation sites 1-3 mm apart apparently over the entirety of the cortex, at frequencies between 2 and 100Hz, and over a 4-10fold range of currents.
  • In human cases where electrical stimulation or the cortex elicits specific memories, extirpation of the stimulated area does not effect recall of this memory (156) {973}.

____References____

[0] Doty RW, Electrical stimulation of the brain in behavioral context.Annu Rev Psychol 20no Issue 289-320 (1969)

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ref: Douglas-1991.01 tags: functional microcircuit cat visual cortex microstimulation date: 12-29-2011 05:12 gmt revision:3 [2] [1] [0] [head]

PMID-1666655[0] A functional microcircuit for cat visual cortex

  • Using in vivo stim and record, They describe what may be a 'cannonical' circuit for the cortex.
  • Not dominated by excitation / inhibition, but rather cell dynamics.
  • Thalamus weaker than poysynaptic inupt from the cortex for excitation.
  • Focuses on Hubel and Wiesel style stuffs. Cats, SUA.
  • Stimulated the geniculate body & observed the response using intracellular electrodes from 102 neurons.
  • Their traces show lots of long-duration inhibition.
  • Probably not relevant to my purposes.

____References____

[0] Douglas RJ, Martin KA, A functional microcircuit for cat visual cortex.J Physiol 440no Issue 735-69 (1991)

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ref: Tehovnik-1996.03 tags: ICMS technique Tehovnik MIT 1996 current density microstimulation date: 12-29-2011 05:11 gmt revision:2 [1] [0] [head]

PMID-8815302[0] Electrical stimulation of neural tissue to evoke behavioral responses

  • reference to justify our current levels.
  • radial dispersion of current, inverse square falloff of excitability.
  • low currents (10 ua) can activate 10-1000 of neurons in cat M1 (allegedly).

____References____

[0] Tehovnik EJ, Electrical stimulation of neural tissue to evoke behavioral responses.J Neurosci Methods 65:1, 1-17 (1996 Mar)

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ref: Brown-2008.03 tags: microstimulation recording artifact supression MEA ICMS date: 12-28-2011 20:43 gmt revision:3 [2] [1] [0] [head]

IEEE-4464125 (pdf) Stimulus-Artifact Elimination in a Multi-Electrode System

  • Stimulate and record on the same electrode within 3ms; record on adjacent electrodes within 500us.
  • Target at MEAs, again.
  • Notes that very small charge mismatches of 1% or less, which is common and acceptable in traditional analog circuit designs, generates an artifact that saturates the neural amp signal chain.
  • for stimulating & recording on the same electrode, the the residual charge must be brought down to 1/1e5 the stimulating charge (or less).
  • paper follows upon {833} -- shared author, Blum -- especially in the idea of using active feedback to cancel artifact charge & associated voltage.
  • target the active feedback for keeping all amplifier out of saturation.
  • vary highpass filter poles during artifact supression (!)
  • bias currents of 1fA on the feedback highpass stage. yikes.

Brown EA, Ross JD, Blum RA, Yoonkey N, Wheeler BC, and DeWeerth SP (2008) Stimulus-Artifact Elimination in a Multi-Electrode System. IEEE TRans. Biomed. Circuit Sys. 2. 10-21

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ref: Nicolelis-1998.11 tags: spatiotemporal spiking nicolelis somatosensory tactile S1 3b microwire array rate temporal coding code date: 12-28-2011 20:42 gmt revision:3 [2] [1] [0] [head]

PMID-10196571[0] Simultaneous encoding of tactile information by three primate cortical areas

  • owl monkeys.
  • used microwires arrays to decode the location of tactile stimuli; location was encoded through te population, not within single units.
  • areas 3b, S1 & S2.
  • used LVQ (learning vector quantization) backprop, LDA to predict/ classify touch trials; all yielded about the same ~60% accuracy. Chance level 33%.
  • Interesting: "the spatiotemporal character of neuronal responses in the SII cortex was shown to contain the requisite information for the encoding of stimulus location using temporally patterned spike sequences, whereas the simultaneously recorded neuronal responses in areas 3b and 2 contained the requisite information for rate coding."
    • They support this result by varying bin widths and looking at the % of correctly classivied trials. in SII, increasing bin width decreases (slightly but significantly) the prediction accuracy.

____References____

[0] Nicolelis MA, Ghazanfar AA, Stambaugh CR, Oliveira LM, Laubach M, Chapin JK, Nelson RJ, Kaas JH, Simultaneous encoding of tactile information by three primate cortical areas.Nat Neurosci 1:7, 621-30 (1998 Nov)

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ref: Hassell-2007.08 tags: microstimulator ICMS ASIC Hassel date: 12-20-2011 06:17 gmt revision:1 [0] [head]

IEEE-4352820 (pdf) Constant-Current Adjustable-Waveform Microstimulator for an Implantable Hybrid Neural Prosthesis

  • Focus on hybrid electro-chemical prosthesis: electrical release of glutamate. For "native output modality".
    • For use in neuronal culture, at least initially.
  • Talk about constant-current sources, typically current-mirrors. Want the following:
    • Linearity
    • High output impedance.
    • voltage compliance.
    • Are these things necessarily well motivated? constant power may be better. eh.
  • WAnt to cascode current output for greater output impedance.
  • They appear not to have completed the ASIC (at time of publication).

____References____

Hassell, T.J. and Jedlicka, S.S. and Rickus, J.L. and Irazoqui, P.P. Engineering in Medicine and Biology Society, 2007. EMBS 2007. 29th Annual International Conference of the IEEE 2436 -2439 (2007)

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ref: Tehovnik-2006.08 tags: ICMS cortical microstimulation pyramidal neurons date: 12-20-2011 06:08 gmt revision:1 [0] [head]

PMID-16835359[0] Direct and indirect activation of cortical neurons by electrical microstimulation.

  • looked at ICMS via single-cell recording, behavior, and fMRI.
  • These properties suggested that microstimulation activates the most excitable elements in cortex, that is, by and large the fibers of the pyramidal cells.
    • this is a useful result to perhaps reference..

____References____

[0] Tehovnik EJ, Tolias AS, Sultan F, Slocum WM, Logothetis NK, Direct and indirect activation of cortical neurons by electrical microstimulation.J Neurophysiol 96:2, 512-21 (2006 Aug)

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ref: Jimbo-2003.02 tags: MEA microstimulation artifact supression date: 12-17-2011 01:41 gmt revision:2 [1] [0] [head]

PMID-12665038[0] A system for MEA-based multisite stimulation.

  • stimulate and record the same MEA channel.
  • used voltage-control stimulation.
  • very low leakage current switches, DG202CSE, 100Gohm, Maxim, above. non-mechanical = low vibration.
  • switches switch between stimulator and preamp. obvious.
  • uses active shorting post-stimulation to remove residual charge,
  • uses active sample/hold of the preamplifier while the stimulator is connected to the electrodes.
  • adds stimulation pulse to the initial electrode offset (interesting!)

____References____

[0] Jimbo Y, Kasai N, Torimitsu K, Tateno T, Robinson HP, A system for MEA-based multisite stimulation.IEEE Trans Biomed Eng 50:2, 241-8 (2003 Feb)

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ref: Laubach-2003.03 tags: cluster matlab linux neurophysiology recording on-line data_analysis microstimulation nicolelis laubach date: 12-17-2011 00:38 gmt revision:4 [3] [2] [1] [0] [head]

IEEE-1215970 (pdf)

  • 2003
  • M. Laubach
  • Random Forests - what are these?
  • was this ever used??

follow up paper: http://spikelab.jbpierce.org/Publications/LaubachEMBS2003.pdf

  • discriminant pusuit algorithm & local regression basis (again what are these? lead me to find the lazy learning package: http://iridia.ulb.ac.be/~lazy/

____References____

Laubach, M. and Arieh, Y. and Luczak, A. and Oh, J. and Xu, Y. Bioengineering Conference, 2003 IEEE 29th Annual, Proceedings of 17 - 18 (2003.03)

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ref: Jackson-2006.11 tags: Fetz Andrew Jackson BMI motor learning microstimulation date: 12-16-2011 04:20 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-17057705 Long-term motor cortex plasticity induced by an electronic neural implant.

  • used an implanted neurochip.
  • record from site A in motor cortex (encodes movement A)
  • stimulate site B of motor cortex (encodes movement B)
  • after a few days of learning, stimulate A and generate mixure of AB then B-type movements.
  • changes only occurred when stimuli were delivered within 50ms of recorded spikes.
  • quantified with measurement of (to) radial/ulnar deviation and flexion/extension of the wrist.
  • stimulation in target (site B) was completely sub-threshold (40ua)
  • distance between recording and stimulation site did not matter.
  • they claim this is from Hebb's rule: if one neuron fires just before another (e.g. it contributes to the second's firing), then the connection between the two is strengthened. However, i originally thought this was because site A was controlling the betz cells in B, therefore for consistency A's map was modified to agree with its /function/.
  • repetitive high-frequency stimulation has been shown to expand movement representations in the motor cortex of rats (hmm.. interesting)
  • motor cortex is highly active in REM

____References____

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ref: -0 tags: circular polarized antenna microstrip ultrawideband date: 02-03-2010 21:30 gmt revision:1 [0] [head]

excellent! Ultra-wideband circular polarized microstrip archimedean spiral

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ref: -0 tags: reynolds number microorganisms engineering math fluid mechanics date: 01-25-2010 19:17 gmt revision:0 [head]

http://jilawww.colorado.edu/perkinsgroup/Purcell_life_at_low_reynolds_number.pdf - great! Never thought about this before.

  • On being a microorganism in water with an abundant food source: "It's like driving a datsun in Saudi Arabia"

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ref: -0 tags: xmos microcontroller microporcessor threading date: 08-11-2009 16:15 gmt revision:0 [head]

http://www.xmos.com/

  • Looks nice! They even publish their board designs and schematics - makes sense given they want their chips to be incorporated into products.
  • Their processors are 'event-driven', which seems to mean that they have 8 sets of registers, one set per thread, with presumably rapid switching between the threads. I did not investigate how excatly their processor works, whether this means they don't need DMA, etc.
  • -- an example with dual LAN8700 ethernet interfaces.

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ref: Isoda-2007.02 tags: SMA saccade basal_forebrain executive function 2007 microstimulation SUA cortex sclin date: 10-03-2008 17:12 gmt revision:2 [1] [0] [head]

PMID-17237780[0] Switching from automatic to controlled action by monkey medial frontal cortex.

  • SCLIN's blog entry
  • task: two monkeys were trained to saccade to one of two targets, left/right pink/yellow. the choice was cued by the color of the central fixation target; when it changed, they should saccade to the same-colored target.
    • usually, the saccade direction remained the same; sometimes, it switched.
    • the switch could either occur to the same side as the SUA recording (ipsilateral) or to the opposite (contralateral).
  • found cells in the pre-SMA that would fire when the monkey had to change his adapted behavior
    • both cells that increased firing upon an ipsi-switch and contra-switch
  • microstimulated in SMA, and increased the number of correct trials!
    • 60ua, 0.2ms, cathodal only,
    • design: stimulation simulated adaptive-response related activity in a slightly advanced manner
    • don't actually have that many trials of this. humm?
  • they also did some go-nogo (no saccade) work, in which there were neurons responsive to inhibiting as well as facilitating saccades on both sides.
    • not a hell of a lot of neurons here nor trials, either - but i guess proper statistical design obviates the need for this.
  • I think if you recast this in tems of reward expectation it will make more sense and be less magical.
  • would like to do shadlen-similar type stuff in the STN
questions
  1. how long did it take to train the monkeys to do this?
  2. what part of the nervous system looked at the planned action with visual context, and realized that the normal habitual basal-ganglia output would be wrong?
    1. probably the whole brain is involved in this.
    2. hypothetical path of error trials: visual system -> cortico-cortico projections + context activation -> preparatory motor activity -> basal ganglia + visual context (is there anatomical basis for this?) -> activation of some region that detects the motor plan is unlikely to result in reward -> SMA?

____References____

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ref: bookmark-0 tags: Delgado Bulls microstimulation ICMS control implant date: 01-06-2008 18:05 gmt revision:2 [1] [0] [head]

http://www.biotele.com/Delgado.htm

  • stimulated the caudate to stop the charging bull.
  • interesting account of the later part of his life spent in Spain, when his popularity wained
  • Delgado still appears to have some quite radical tendencies, such as belief in the inexorable advance of technology, even if it is immoral/unethical.

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ref: notes-0 tags: low-power microprocessor design techniques ieee DSP date: 05-29-2007 03:30 gmt revision:2 [1] [0] [head]

http://hardm.ath.cx:88/pdf/lowpowermicrocontrollers.pdf

also see IBM's eLite DSP project.

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ref: bookmark-0 tags: microdrilling surgery craniotomy impedance date: 0-0-2006 0:0 revision:0 [head]

http://www.pathscientific.com/products.html

Pathformer is an electrosurgical hand-held meidcal device that cuts holes in nails and skin. It operates on mesoscissioning technology, cutting the nail/skin with a microcutting tool, using skin impedance as a feedback for stopping the cutting intervention. Pathformer is approved by FDA for creating holes in nails for treating subungual hematoma (black toe).