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

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

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

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

Materials and technologies for soft implantable neuroprostheses

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

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ref: -0 tags: standard enthalpy chemicals list pdf date: 06-25-2015 00:09 gmt revision:1 [0] [head]

Standard thermodynamic properties of chemical substances

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ref: -0 tags: parylene PDMS material properties gold compliant date: 02-08-2013 22:38 gmt revision:2 [1] [0] [head]

PMID-21240559 Highly-compliant, microcable neuroelectrodes fabricated from thin-film gold and PDMS

  • he microcable electrodes were also electromechanically tested, with measurable conductivity (220 kΩ) at an average 8% strain (n = 2) after the application of 200% strain.

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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: Rosin-2011.1 tags: PD closed loop DBS globus pallidus oscillations STN Vaadia heterodyne beta date: 03-26-2012 16:23 gmt revision:16 [15] [14] [13] [12] [11] [10] [head]

PMID-22017994[0] Closed-loop deep brain stimulation is superior in ameliorating parkinsonism.

  • Also reviewed by Rui Costa: PMID-22017983[1]
    • Good, brief review -- with appropriate minimal references.
  • Partial goal of the work: parameter determination and optimization can take a long time, and are typically only done every 3-6 months initially. But the actually changes of activity / responsiveness occur on a faster timescale in the disease, even instantaneous; other studies have shown that updating the stimulation parameters more frequently helps patients. (of course, this is a different form of closed-loop).
  • Pathology: intermittent neuronal oscillations in the basal ganglia and motor cortex commonly observed.
    • In MPTP treated primates these oscillations occur in the tremor band (theta, 4-7Hz), and double-tremor band (9-15Hz, alpha) (Bergman et al 1994 {120}, Ras et al 2000 PMID-11069964 ).
    • Actual pathology still inconclusive; talk about disruption of pathological patterns and 'focal inhibition', but this is no thorough review by any estimate.
  • "In recent years, the role of pathological discharge patterns in the parkinsonian brain has emerged as pivotal in the disease pathology
    • Eusebio and Brown, 2007;
    • Hammond et al., 2007;
    • Kuhn et al., 2009;
    • Tass et al., 2010;
    • Vitek, 2008;
    • Weinberger et al., 2009;
    • Wichmann and DeLong, 2006;
    • Zaidel et al., 2009.
    • Automatic systems should disrupt this pattern of discharge (Feng 2006, Tass 2003).
      • However, the role of these oscillations as the neuronal correlate of PD motor symptoms is still debated (Hammond et al., 2007; Leblois et al., 2007; Lozano and Eltahawy, 2004; McIntyre et al., 2004; Tass et al., 2010; Vitek, 2002; Weinberger et al., 2009 {1089}).
  • 2 african green monkeys, MPTP treatment.
  • Recorded from GPi & M1 (127 and 210 neurons); stimulated GPi, 7 pulses at 130Hz, 80ms after spike from reference area (M1 or GPi).
    • 80ms delay coincided with the next double-tremor oscillatory burst (12.5Hz)
    • State of neuronal oscillatory discharge of cortico-BG loops often accompanied by synchronization btw cortex and BG (see also quote below)
    • GPi following M1 activity superior (GP|M1 in their notation).
    • single pulses did not work.
    • Stimulation: 80uA 200us bipolar biphasic (small and short!).
  • Stimiulus protocol (M1 trigger) abolishes oscillatory activity in recorded GPi neurons.
  • Also reduced akinesia as measured with an accelerometer & decreased firing rate in the GPi.
    • Both work better than constant 130Hz DBS.
    • Also much more irregular: fewer stimulation pulses at longer latency.
  • Open loop control (the control) did much less regarding FR oscillations & bursts and reduction in firing rate.
    • Dorval et al 2010: increasing the stimulus irregularity of open-loop DBS decreases its beneficial clinical effectcs. (also Baker et. al 2011).
  • GP train stimulation triggered on GP firing significantly worsened akinesia, despite the fact that the pallidial FR decreased.
    • Treatment increased spike oscillation at double-tremor frequency in M1.
  • Oscillations more important than firing rate changes (new vs. old hypothesis).
    • pallidal oscillatory activity was not correlated to the pallidal discharge rate either before or during the application of standard DBS or GP|M1.
  • In our data, may have double-frequency tremor effects. Heterodyne should detect this.
    • "Studies on the dynamics of the entire cortico-basal ganglia loops have frequently reported the emergence of intra-and interloop component synchrony and oscillatory activity."
    • "Nevertheless, the somewhat intuitive connection between neuronal oscillations and parkinsonian motor symptoms, which include rest and action tremors, has been challenged (Hammond et al., 2007 PMID-17532060 ; Leblois et al., 2007 {1146}; Lozano and Eltahawy, 2004; Tass et al., 2010 {1147}; Vitek, 2002; Weinberger et al., 2009). For instance, while the parkinsonian rest tremor occurs mainly at the 4–7 Hz frequency band, the oscillatory neuronal activity is observed in several characteristic frequency bands in both human PD patients (Hutchison et al., 2004) {1156} and animal models (Bergman et al 1994, Gubellini et al 2009) {1074}"
      • This also has import to our heterodyne results!
    • Synchrony between globus pallidus and M1 is dynamic and state-dependent (whatever that means -- have to check the refs, Levy et al 2002 {829}, Timmerman et al 2003 {1087})
  • Quote: "... it suggests that reduction of the abnormal parkinsonian oscillatory activity could in fact be the underlying mechanism by which DBS exerts its action and brings about the associated clinical improvement."
  • Neuronal oscillatory activity occurs as high as the beta-band, 15-35Hz, hence clinical app. would need a tuned antiphase lag.
  • Suggest that the closed-loop treatment may be applicable to other diseases with characteristic firing patterns, like schizophrenia.
  • Since synchonization and oscillations hend to coincide, .. we found this too.
    • Heimer et al 2006 {1076}: oscillations and synchrony can exist independently.
  • Figure suck. Text inconsistent and frequently too small.
    • Wavelet spectrograms are nice tho.

Other thoughts:

  • Somebody should measure the transfer function of the BG / cortical loop. H(z).
  • This seems like adding a comb-filter or zero at a particular frequency: GP|GP stimluation exacerbated the effect, GP|M1 minimized the effect as there is a negation in there. (e.g. GP actviity decreases firing of M1, and vice versa).

____References____

[0] Rosin B, Slovik M, Mitelman R, Rivlin-Etzion M, Haber SN, Israel Z, Vaadia E, Bergman H, Closed-loop deep brain stimulation is superior in ameliorating parkinsonism.Neuron 72:2, 370-84 (2011 Oct 20)
[1] Santos FJ, Costa RM, Tecuapetla F, Stimulation on demand: closing the loop on deep brain stimulation.Neuron 72:2, 197-8 (2011 Oct 20)

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ref: Weinberger-2009.09 tags: STN DBS PD oscillations beta band review date: 03-05-2012 16:32 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-19460368[0] Pathological subthalamic nucleus oscillations in PD: can they be the cause of bradykinesia and akinesia?

  • Review of {1075}
  • Suppression of beta-band is correlated with the improvement in combined measures of bradykinesia and rigidity.
    • This does not mean that the oscillations cause rigidity! only that L-DOPA affects both. Focused entirely on Beta band.
  • Previously shown that the degree of beta oscillatory activity in the STN of PD patients correlates with the patients' benefit from dopaminergic medications, but not with baseline motor deficits. (the treatment but not the symptoms)
  • Levy 2000, 2001 for the existence of oscillatory activity in the STN & globus pallidus.
  • Prominent beta band activity in GPi & STN LFP. [Levy 2000, Levy 2001 , Brown 2001]
  • Short train HFS of the STN has been shown to decrease STN-cortex coherence for up to 25s after application. [Wingeier 2006] [Kuhn 2008]
    • Others disagree. [Foffani et al., 2006] and [Rossi et al., 2008] ).
  • In a response task, decrease in beta-band activity negatively correlates with reaction time. [Kuhn 2004]
    • Beta suppression is also correlated with increased motor planning [Williams 2005]
  • Beta band activity also present in healthy monkey striatum, human putamen, and cortex. (I wonder how? many references.)
  • Yet, to date there is no clear evidence that the degree of synchronization in the beta band directly accounts for the motor deficits in PD.
  • It has been recently shown that the percentage of neurons exhibiting oscillatory firing in the beta range correlates well (r squared = 0.62) with the degree by which PD motor symptoms improved after dopamine replacement therapy (Weinberger et al. 2006 PMID-17005611)
  • It should be noted that decrease in beta-band activity may be caused by -- rather than causal of -- decreased akinesia and rigidity.
    • That said, in rats treated with 6-OHDA, an increase in beta band activity took several days to appear after drug administration, and appeared at the same time as clinical symptoms.
  • Interesting! Activity-dependent plasticity was remarkably enhanced with a low dose of levodopa in the basal ganglia output of SNr and that there was a surprisingly good correlation (r squared = 0.81) between symptoms and the level of synaptic plasticity (Prescott et al., 2009) [2].
  • Other theory: exaggerated synchrony in the basal ganglia limits the ability to encode meaningful information, as all neurons are entrained to the same frequency hence undifferentiated.
    • Thought beta band may just be a non-coding resting state. Synaptic plasticity goes awry, and all neurons become entrained. Explains bradykinesia but not rigidity.

____References____

[0] Weinberger M, Hutchison WD, Dostrovsky JO, Pathological subthalamic nucleus oscillations in PD: can they be the cause of bradykinesia and akinesia?Exp Neurol 219:1, 58-61 (2009 Sep)
[1] Kühn AA, Tsui A, Aziz T, Ray N, Brücke C, Kupsch A, Schneider GH, Brown P, Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity.Exp Neurol 215:2, 380-7 (2009 Feb)
[2] Prescott IA, Dostrovsky JO, Moro E, Hodaie M, Lozano AM, Hutchison WD, Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients.Brain 132:Pt 2, 309-18 (2009 Feb)

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ref: Fuentes-2009.03 tags: Nicoelis DCS spinal cord stimulation PD Fuentes Petersson 6-OHDA date: 03-03-2012 02:46 gmt revision:3 [2] [1] [0] [head]

PMID-19299613[0] Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.

  • Motivation: different levels of cortical oscillation during movement and rest (LFO decreased, medium-high freq increased); PD associated with abnormal synchronous corticostriatal oscillations.
  • In epilepsy patients, stimulation of peripheral nerve afferents is effective in desychronizing low-frequency neural activity, reducing the frequency and duration of seizures (8,9,10) PMID-11050139[1] PMID-16886985[2] PMID-18188148[3]
  • DCS (dorsal column stimulation)
    • Epidural, longitudal electrodes, horizontal electrical field.
    • Upper thoracic, mice.
    • 300Hz.
    • simpler and safer than brain surgery.
    • [24] DCS induces no increase in arousal. (Wall, PD. Brain 1970; 93:505.
  • used the tyrosine hydroxyalse inhibitor AMPT
  • M1 LFP: Osc around 1.5-4Hz and 10-15Hz enhanced; osc > 25Hz subdued.
  • DCS increased locomotion by 29x in depleted animals, and 4.9x in normal animals.
  • Also titrated L-DOPA with DAT-KO mice. Without dopamine, there is no movement.
    • DCS increased L-DOPA effectiveness by 5x (1/5 the dose was required)
  • Verified in a 6-OHDA lesion model in rats.
    • Lesioned animals moved more, sham moved less.
  • Activation of locomotion is via striatal medium spiny neurons projecting to the output nuclei of the basal ganglia [26 PMID-8402406[4] ,27 PMID-1695404[5]].
  • In PD, with reduced striatal dopamine levels, the activation threshold of the projection neurons from the striatum is significantly increased [25] PMID-17916382[6].

____References____

[0] Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA, Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.Science 323:5921, 1578-82 (2009 Mar 20)
[1] Fanselow EE, Reid AP, Nicolelis MA, Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation.J Neurosci 20:21, 8160-8 (2000 Nov 1)
[2] DeGiorgio CM, Shewmon A, Murray D, Whitehurst T, Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial.Epilepsia 47:7, 1213-5 (2006 Jul)
[3] George MS, Nahas Z, Bohning DE, Lomarev M, Denslow S, Osenbach R, Ballenger JC, Vagus nerve stimulation: a new form of therapeutic brain stimulation.CNS Spectr 5:11, 43-52 (2000 Nov)
[4] Brudzynski SM, Wu M, Mogenson GJ, Decreases in rat locomotor activity as a result of changes in synaptic transmission to neurons within the mesencephalic locomotor region.Can J Physiol Pharmacol 71:5-6, 394-406 (1993 May-Jun)
[5] DeLong MR, Primate models of movement disorders of basal ganglia origin.Trends Neurosci 13:7, 281-5 (1990 Jul)
[6] Grillner S, Wallén P, Saitoh K, Kozlov A, Robertson B, Neural bases of goal-directed locomotion in vertebrates--an overview.Brain Res Rev 57:1, 2-12 (2008 Jan)

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ref: Boulet-2006.1 tags: hemiballismus PD parkinsons STN subtalamic DBS dyskinesia rats 2006 glutamate date: 02-22-2012 18:58 gmt revision:1 [0] [head]

PMID-17050715 Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

  • STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr.
    • Well, that just makes sense. STN is excitatory, GPi is an output structure of the BG, and stimulation should activate the area.

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ref: Carlson-2010.02 tags: DBS PD STN lesion date: 02-22-2012 18:44 gmt revision:4 [3] [2] [1] [0] [head]

PMID-19955287[0] Deep brain stimulation does not silence neurons in subthalamic nucleus in Parkinson's patients.

  • word to that. not a functional lesion!
  • Record SUA during DBS of the STN. good idea.
  • Saw postpulse inhibition of 1-2 us 6 us after stim in 10 of the 14 analyzed
    • might be pulse locked spikes .. but could not see them.
  • predominant shift toward random firing.
  • DBS parameters: 3-5V, 80-200 Hz, 90-200us pulses, 33 neurons 11 patients.
  • DBS likely functions through white-matter activation to effect changes in neuronal activity throughout the BG - thalamus-cortex network.
  • Looked at the spaces between stimulus artifact.
  • nice figures.
  • DBS did not change mean firing rate.
  • Modeling studies suggest that DBS depolarizes myelinated fibers, without evoking or inhibiting discharges in local cell bodies (McIntyre et al 2004 ab PMID-14668299, Miocinovic et al 2006).
    • From the former: Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon.

____References____

[0] Carlson JD, Cleary DR, Cetas JS, Heinricher MM, Burchiel KJ, Deep brain stimulation does not silence neurons in subthalamic nucleus in Parkinson's patients.J Neurophysiol 103:2, 962-7 (2010 Feb)

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ref: Prescott-2009.02 tags: PD levodopa synaptic plasticity SNr STN DBS date: 02-22-2012 18:28 gmt revision:2 [1] [0] [head]

PMID-19050033[0] Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients

  • In the SNpc -> SNr.
  • High frequency stimulation (HFS--four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau).
  • Aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.

____References____

[0] Prescott IA, Dostrovsky JO, Moro E, Hodaie M, Lozano AM, Hutchison WD, Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients.Brain 132:Pt 2, 309-18 (2009 Feb)

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ref: Lempka-2010.12 tags: DBS current control PD date: 02-22-2012 18:25 gmt revision:2 [1] [0] [head]

PMID-20493764[0] Current-controlled deep brain stimulation reduces in vivo voltage fluctuations observed during voltage-controlled stimulation.

  • Obervation: DBS electrodes show impedance whcih varies with time and stimulation.
  • Current control may reduce the need for physicians to carefully adjust the stimulation parameters in the clinic.
  • Why did this take so long? It is a relatively obvious improvement. Perhaps efficiency -- voltage control allows longer battery life?

____References____

[0] Lempka SF, Johnson MD, Miocinovic S, Vitek JL, McIntyre CC, Current-controlled deep brain stimulation reduces in vivo voltage fluctuations observed during voltage-controlled stimulation.Clin Neurophysiol 121:12, 2128-33 (2010 Dec)

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ref: Goldberg-2002.06 tags: DBS PD MPTP synchrony date: 02-22-2012 18:25 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-12040070[0] Enhanced synchrony among primary motor cortex neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease.

  • In the (MPTP) parkinsonian state, MI neurons discharged in long bursts (sometimes >2 sec long). These bursts were synchronized across many cells but failed to elicit detectable movement, indicating that even robust synchronous MI discharge need not result in movement.
    • These synchronized population bursts were absent from the GP and were on a larger timescale than oscillatory synchrony found in the GP of tremulous MPTP primates, suggesting that MI parkinsonian synchrony arises independently of basal ganglia dynamics.
  • Specificity of M1 neurons decreased to passive movement; GP showed no decrease in specificity.
    • Might be because of decreased specificity in the first place.
  • Again suggests that it's not rates but dynamics that underly pathophysiology.
  • Evarts 1965, Porter and Lemon 1993: the normal execution of voluntary movement is correlated with an increase in the synchronous discharge of primary motor cortex neurons.
  • No decrease in M1 activity w/ single unit discharge in M1 in MPTP monkeys & metabolic studies.
  • PD corresponds to a loss in specificity in the globus pallidus in response to passive joint manipulation (Filion et all 1988; Boraud et al 2000).
  • Nissl stain stains both neurons and glia (figure 2)
  • ISI plots (here called auto-associative index) markedly different before / after MPTP.
  • M1 can commonly be micro-excited with as little as 5ua (Murthy and Fetz, 1996; Tokuno and Nambu 2000).
  • Temporal width of pathological synchornization on the order of tens to hundreds of milliseconds.
  • Hypothesize loss of functional segregation along parallel corticobasal ganglia circuits (Alexander et al 1986, DeLong 1990)

____References____

[0] Goldberg JA, Boraud T, Maraton S, Haber SN, Vaadia E, Bergman H, Enhanced synchrony among primary motor cortex neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease.J Neurosci 22:11, 4639-53 (2002 Jun 1)

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ref: Brown-2003.04 tags: PD oscillations DBS date: 02-22-2012 16:06 gmt revision:4 [3] [2] [1] [0] [head]

PMID-12671940[0] Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson's disease.

  • Break oscillations into > 30 Hz and < 60 Hz bands.
    • these two are inversely affected by movement, and inversely affected by dopamine treatment.
    • This seems inconsistent with the other literature. (?)
  • Lesions of the GPi improve dyskinesias, without deleterout effects on motor function.
  • The tact assumption from the MPTP monkey research is that synchronization and bursting is an abnormal phenomena.
    • Also suggest that synchronization may be a means of 'binding' or increasing the salience of input.
  • The degree of synchronization increases during non-oscillating periods in PD patients treated with the dopamine agonist apomorphine.
  • [27] PMID-11431506 and there is one report of locking in patients without tremor.
    • In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson "surprise" analysis), and a greater proportion of cells with an irregular discharge pattern was observed.
    • During the OFF state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26).
    • Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration.
  • [31] PMID-9990083 there is evidence that human STN and GPi units firing at tremor frequency show only transient periods of locking to peripheral tremor
    • We found that GPi tremor-related activity at a given site could fluctuate between states of synchronization and independence with respect to upper limb tremor. Consistent with this finding, some paired recording sites within GPi showed periods of transient synchronization. These observations support the hypothesis of independent tremor-generating circuits whose coupling can fluctuate over time.
  • Monkeys treated with MPTP show pronounced increases in synchrony at < 30 Hz.
  • Levodopa markedly increases > 60 Hz coherence between GP & midline EEG.
    • "The synchronization of single units in STN or GPi at high frequencies has not been demonstrated in microelectrode studies to date. (2002).
    • HF coherence is found between SNT and GPi, and these structures w SMA.
  • Stimulation of the pallidium and enteopeduncular nucleus in cats at 3-10Hz leds to synchronization of the EEG and gradual slowing and eventual cessation of spontaneous movements.
    • Could this abnormal, low-frequency, synchronous oscillatory activity in GPi and its input STN act, by means of the thalamus, to hold the motor cortex in a low-frequency antikinetic state in Parkinson’s disease? [7].
  • There is a disappearance of > 60 Hz oscillations in the STN with drowsiness [29].
  • Complex movements are particuarly difficult for PD patients.
  • Human GPi neurons normally fire at 85 to 140 Hz -- so 130 Hz stimulation may entrain them.

Conclusion: he really thinks that there is a strong dichotomy between HF, pro-kinetic, and MF, anti-kinetic oscillations.

____References____

[0] Brown P, Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson's disease.Mov Disord 18:4, 357-63 (2003 Apr)

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ref: Hamani-2004.01 tags: STN subthalamic nucleus movement disorders PD parkinsons basal_ganglia globus_pallidus anatomy DBS date: 02-22-2012 15:03 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-14607789[0] The subthalamic nucleus in the context of movement disorders

  • this is a good anatomy article, very descriptive -- almost too much information to grapple with.
  • STN = important structure for the modulation of activity of basal ganglia structures
  • STN is anterior-adjacent to the red nucleus
  • The average number of neurons in each STN nucleus varies from species to species and has been estimated to be ~25 000 in rats, 35 000 in marmosets, 155 000 in macaques, 230 000 in baboons and 560 000 in humans
  • The volume of the STN is ~0.8 mm3 in rats, 2.7 mm3 in marmosets, 34 mm3 in macaques, 50 mm3 in baboons and 240 mm3 in humans.
    • Number of neurons does not scale with volume, uncertain why not.
  • STN is divided into three functional units: motor, associative, and limbic cortical regions innervate, respectively motor, associative, and limbic regions of the striatum, pallidium SNr.
    • they give a complete list of these 3 in 'intrinsic organization of the STN'
    • STN is divided into 2 rostral thirds and one cauldal third.
      • medial rostral = limbic and associative
      • lateral rostral = associative
      • dorsal = motor circuits. (the largest part, see figure 2)
        • hence, the anterodorsal is thought to be the most effective target for DBS.
  • STN is populated primarily by projection neurons
  • the dendritic field of a single STN neurons can cover up to one-half of the nucleus of rodents
  • efferent projections (per neuron, branched axons)
    • GPe, GPi, SNr 21.3%
    • GPe and SNr 2.7%
      • in both segments of the pallidum, projections are uniformly arborized & affect an extensive number of cells.
    • GPe and GPi 48%
    • GPe only 10.7%
    • 17.3% remaining toward the striatum
  • most of the cortical afferents to the STN arise from the primary motor cortex, supplementary motor area, pre-SMA, and PMd and PMv; these target the dorsal aspects of the STN.
    • afferents consist of collaterals from the pyramidal tract (layer 5) & cortical fibers that also innervate the striatum (latter more prevalent). afferents are glutamergic.
  • ventromedial STN recieves afferents from the FEF (area 8) and suppl.FEF (9)
  • GPe projects extensively to STN with GABA. see figure 3 [1]
    • almost every cell in the STN resonds to pallidal GABAergic stimulation.
    • 13.2% of GPe neurons project to GPi, STN, and SNr
    • 18.4% to GPI and STN,
    • 52.6% to only the STN and SNr
    • 15.8% remaining to the striatum.
  • DA afferents from the SNc
  • ACh from the tegmentum
  • Glutamergic afferents from the centromedian thalamus (CM)
  • Serotonin from the raphe nucleus
  • fibers from the tegmentum, SNc, motor cortex, VM.pf of the thalamus, and dorsal raphe synapse on distal dendrites
    • pallidal inhibitory fibers innervate mostly proximal dendrites and soma.
firing properties:
  • about half of STN neurons fire irregularly, 15-25% regularly, 15-50% burst.
    • bursting is related to a hyperpolarization of the cell.
  • movement-related neurons are in the dorsal portion of STN and are activated by either/both active/passive movements of single contralateral joints
  • there is a somatotopic organizaton, but it is loose.
  • many units are responsive to eye fixation, saccadic movements, or visual stim. these are in the ventral portion.
    • activation of the STN drives SNr activity, which inhibits the superior colliculus, allowing maintainance of eye position on an object of interest.
  • ahh fuck: if high currents are delivered to STN or high concentrations of GABAergic antagonists are applied abnormal movements such as dyskinesias can be elicited
    • low concentrationns of GABA antagonists induces postural asymmetry and abnormal movements, but no excessive locomotion.
  • dyskinesias result from high-frequency or high-current stimulation to the STN! low frequency stimulation induces no behavioral effects. [2]
  • small (<4% !!) lesions cause focal dystonias
  • in parkinsonian patients, activity in the STN is characterized by increased synchrony and loss of specificity in receptive fields + mildly increased mean firing rate.
    • 55% of STN units in PD patients respond to passive movements, and 24% to ipsilateral movements (really?) - indicative of the increase in receptive field size caused by the disease.

____References____

[0] Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM, The subthalamic nucleus in the context of movement disorders.Brain 127:Pt 1, 4-20 (2004 Jan)
[1] Sato F, Lavallée P, Lévesque M, Parent A, Single-axon tracing study of neurons of the external segment of the globus pallidus in primate.J Comp Neurol 417:1, 17-31 (2000 Jan 31)
[2] Beurrier C, Bezard E, Bioulac B, Gross C, Subthalamic stimulation elicits hemiballismus in normal monkey.Neuroreport 8:7, 1625-9 (1997 May 6)

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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) \frac{Q(t)}{t} = U_{rh}(1 + \frac{t_ch}{t}) where U rhU_{rh} is the rheobase and t cht_{ch} is the chronaxie.
    • you can simplify this to: I th=I rh(1+t cht) I_{th} = I_{rh} (1 + \frac{t_{ch}}{t}) where I rhI_{rh} is the rheobase current and I thI_{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\vec{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: Kuhn-2004.04 tags: STN LFP syncronization movement motor planning parkinsons PD DBS beta date: 01-26-2012 17:28 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-14960502[0] Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.

  • Asked 6 PD patients to play a game where they were warned to move / not to move.
  • Beta-frequency (20hz) power decreased prior to movement, with a time course correlated to reaction time.
    • This was followed by a late post-movement increase in beta power.
  • No-go trials showed a brief dip in beta power, with quick resumption.
  • conclude that:
    • the subthalamic nucleus is involved in the preparation of externally paced voluntary movements in humans
    • the degree of synchronization of subthalamic nucleus activity in the beta band may be an important determinant of whether motor programming and movement initiation is favored or suppressed. (hum, maybe).
  • found via Romulo's references; see the list of papers that cite it.

____References____

[0] Kühn AA, Williams D, Kupsch A, Limousin P, Hariz M, Schneider GH, Yarrow K, Brown P, Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.Brain 127:Pt 4, 735-46 (2004 Apr)

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ref: KA/4hn-2009.02 tags: DBS synchrony STN PD bradykinesia rigidity berlin oxford beta date: 01-25-2012 03:47 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-19070616[0] Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity.

  • Synchronization prominent in PD 8-35 Hz, (Engel et al., 2005; Schnitzler and Gross, 2005; Uhlhaas and Singer, 2006; Hammond et al., 2007).
  • levodopa treatment suppressed LFP activity in the STN at 8 - 35 Hz.
  • Data suggests that levodopa-induced improvements in both rigidity and bradykinesia scale with the degree of suppression of oscillatory power in the STN LFP.
    • This is irrespective of the frequency that synchronization occurs.
    • consistent with the hypothesis that excessive synchronization in the cortico-BG system limits information coding capacity, as this would be the case irrespective of frequency.
  • In the MPTP primate, synchronization tends to occur at frequencies below 15 Hz. (Galvan and Wichmann, 2008).
  • Synchonization at higher frequencies (> 40 Hz) was associated with better motor improvement (Kuhn et al 2006)
    • Enchanced movement-induced gamma activity occurs with levodopa treatment (Androulidakis et al 2007).
  • Contrary to an early report (Levt et al 2000), there was relatively little evidence for an associateion between LFP activity in the beta band and rest tremor (Amiroving et al 2004, Kuhn et al 2006, Ray et al 2008, Weinberger et al 2006).
    • This does not refute an association between rest tremor and oscillatory frequencies below 8 Hz. CF EMG studies.
  • LFS at 10-20 Hz to the STN exacerbates Parkinson's disease, though this is somewhat unqualified (Timmerman et al 2004; Chen et al 2007; Eusebio et al 2007).
    • In some patients there was an increase in LFP energy in the ON state vs the OFF state at higher frequency.

____References____

[0] Kühn AA, Tsui A, Aziz T, Ray N, Brücke C, Kupsch A, Schneider GH, Brown P, Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity.Exp Neurol 215:2, 380-7 (2009 Feb)

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ref: Frank-2007.11 tags: horses PD STN DBS levodopa decision learning science date: 01-25-2012 00:50 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-17962524[0] Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism.

  • While on DBS, patients actually sped up their decisions under high-conflict conditions. Wow!
    • This impulsivity was not effected by dopaminergic medication status.
    • Impulsivity may be the cognitive equivalent of excess grip force {88}.
  • Mathematical models of decision making suggest that individuals only execute a choice once the 'evidence' in its favor crosses a critical decision threshold.
    • people can adjust decision thresholds to meet current task demands
    • One theory is that the STN modulates decision thresholds (6) and delays decision-making when faced with a conflict. Wanted to test this in a conflict situation.
    • Record from the STN in conflict task to see ??
  • Second wanted to test negative learning.
    • Dopamine replacement therapy impairs patient's ability to learn from the negative outcomes of their decisions (11 - 13), which may account for pathological gambling behavior (14).
    • PD patients did indeed score worse on avoidance, slightly less accurate on AB choice, and about the same for the rest.
  • Made a network model.
    • Found that preSMA and STN coactivation is associated with slowed reaction times under decision conflict (25).
    • And that STN-DBS reduces coupling between cingulate and basal ganglia output (27).
    • Their model they either lesioned STN or overloaded it with high frequency regular firing.
      • either one showed the same faster response in high-conflict decisions.
  • STN dysfunction does not lead to impulsivity in all behavioral situations.
    • STN lesioned rats show enhanced preference for choices that lead to large delayed rewards compared to those that yield small immediate rewards (32,33). (This is not conflict, though -- rather reward -- but nonetheless illuminating)
  • Dopaminergic medication, by tonically elevating dopamine levels and stimulating D2 receptors, prevents learning from negative decision outcomes (11, 13, 18). Hence pathological gambling behavior (14).
  • Other studies show DBS-induced impairments in cognitive control (27 PMID-17119543, 36 PMID-15079009).

____References____

[0] Frank MJ, Samanta J, Moustafa AA, Sherman SJ, Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism.Science 318:5854, 1309-12 (2007 Nov 23)

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ref: Krack-2001.09 tags: STN subthalamic nucleus stimulation PD parkinsons DBS date: 01-24-2012 05:48 gmt revision:1 [0] [head]

PMID-11746616[0] Mirthful laughter induced by subthalamic nucleus stimulation.

  • high stimulation parameters induces mirthful laughter
  • prescribed parameters induced hypomanic behavior with marked improvement in akinesia.
  • STN must be involved in psychomotor as well as motor regulation.

____References____

[0] Krack P, Kumar R, Ardouin C, Dowsey PL, McVicker JM, Benabid AL, Pollak P, Mirthful laughter induced by subthalamic nucleus stimulation.Mov Disord 16:5, 867-75 (2001 Sep)

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ref: Hilker-2004.01 tags: STN subthalamic DBS stimulation cortex cerebellum PET PD parkinsons date: 01-24-2012 05:38 gmt revision:1 [0] [head]

PMID-14688612[0] Subthalamic Nucleus Stimulation Restores Glucose Metabolism in Associative and Limbic Cortices and in Cerebellum: Evidence from a FDG-PET Study in Advanced Parkinson's Disease

  • cortical depression of glucose metabolism
  • hypermetabolic state in the left rostral cerebellum (?!)
  • DBS generally remedies this imbalance, restoring glucose metabolism to the cortex associative/motor/frontal as well as to the thalamus distant from the stimulation site.

____References____

[0] Hilker R, Voges J, Weisenbach S, Kalbe E, Burghaus L, Ghaemi M, Lehrke R, Koulousakis A, Herholz K, Sturm V, Heiss WD, Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in advanced Parkinson's disease.J Cereb Blood Flow Metab 24:1, 7-16 (2004 Jan)

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ref: Thevathasan-2010.04 tags: DCS DBS spinal cord stimulation PD date: 12-28-2011 20:43 gmt revision:4 [3] [2] [1] [0] [head]

PMID-20404313[0] Spinal cord stimulation failed to relieve akinesia or restore locomotion in Parkinson disease.

  • motivated by [1]
  • Implanted two PD patients with commercial DBS stimulators and electrodes; observed no therapeutic effect.
  • Electric field was axial rather than transverse, hence likely did not activate the same way or same ammount as in the Nicolelis study.
  • Not sure if anyone has tried with other eletrodes... spinal cord stimulation would be great for inductive powering.

____References____

[0] Thevathasan W, Mazzone P, Jha A, Djamshidian A, Dileone M, Di Lazzaro V, Brown P, Spinal cord stimulation failed to relieve akinesia or restore locomotion in Parkinson disease.Neurology 74:16, 1325-7 (2010 Apr 20)
[1] Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA, Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.Science 323:5921, 1578-82 (2009 Mar 20)

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ref: Kapogiannis-2008.04 tags: clinical trials PD DBS TMS date: 09-18-2008 02:20 gmt revision:2 [1] [0] [head]

http://www.clinicaltrials.gov/ct2/show/NCT00558766?cond=Parkinson+Disease&rank=4 Salient points:

  • Neurons in the mesencephalon : "Their role in reward processing is thought to be dual: i) they show sustained activity with the expectation of a future reward and ii) a phasic response after reward."
  • Synapse on interneurons and cortical cells (e.g. from the substantia nigra), where they produce primary inhibition.
    • That's interesting .. why would reward cause inhibition?? what models suggest this?
    • Our hypothesis has been that a dopamine reward-related signal would increase the evocable inhibition in primary motor cortex and our findings support this.
  • Check the first exclusion criteria: Pre-menopausal status in women: Preliminary data in healthy, cycling women suggests that the variation in paired-pulse inhibition caused by the menstrual cycle may obscure the change in the response induced by the behavioral task. What? Why?
  • Others have found the same effect: PMID-18371077

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ref: bookmark-0 tags: los_angeles california map pdf date: 0-0-2006 0:0 revision:0 [head]

http://gocalif.ca.gov/tourism/pdfs/LA_OC_Map.pdf