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."

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.
• $\frac{Q(t)}{t}=U_{\mathrm{rh}}(1+\frac{t_{\mathrm{ch}}}{t})$ where $U_{\mathrm{rh}}$ is the rheobase and $t_{\mathrm{ch}}$ is the chronaxie.
• you can simplify this to: $I_{\mathrm{th}}=I_{\mathrm{rh}}(1+\frac{t_{\mathrm{ch}}}{t})$ where $I_{\mathrm{rh}}$ is the rheobase current and $I_{\mathrm{th}}$ 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 $\stackrel{\rightharpoonup }{E}$ 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.
• 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.
• Chronic GPi DBS does not allow reducing L-DOPA dosage, unline 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.
• DBS in the PPN (pedunculo pontine nucleus) at 10 HZ induces a feeling of well-being , concommitant 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.
• 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____

PMID-19299587[0] Optical Deconstruction of Parkinsonian Neural Circuitry.

• DA depletion of the SN leads to abnormal activity in the BG ; HFS (>90Hz) of the STN has been found to be therapeutic, but the mechanism is imperfectly understood.
• lesions of the BG can also be therapeutic.
• Used chanelrhodopsin (light activated cation channel (+)) which are expressed by cell type specific promoters. (transgenic animals). Also used halorhodopsins, which are light activated chloride pumps (inhibition).
• optogenetics allows simultaneous optical stimulation and electrical recording without artifact.
• Made PD rats by 6-hydroxydopamine unilaterally into the medial forebrain bundle of rats.
• Then they injected opsin vector targeting excitatory neurons (under control of the CaMKIIa receptor) to the STN as identified stereotatically & by firing pattern.
• Electrical stimulation of this area alleviated rotational behavior (they were hemiparkinsonian rats), but not optical inhibition of STN.
• Alternately, the glia in STN may be secreting molecules that modulate local circuit activity; it has been shown that glial-derived factor adenosine accumulates during DBS & seems to help with attenuation of tremor.
• Tested this by activating glia with ChR2, which can pass small Ca+2 currents.
• This worked: blue light halted firing in the STN; but, again, no behavioral trace of the silencing was found.
• PD is characterized by pathological levels of beta oscillations in the BG, and synchronizing STN with the BG at gamma frequencies may ameliorate PD symptoms while sync. at beta will worsen. (!! could use this for my paper !!) -- see [1][2]
• Therefore, they tried excitatory optical stimulation of excitatory STN neurons at the high frequencies used in DBS (90-130Hz).
• HFS to STN failed, again, to produce any therapeutic effect!
• Next expressed channel rhodopsin in projection neurons (Thy1::ChR2), again did optotrode (optical stim eletrical record) recordings.
• HFS of afferent fibers to STN shut down most of the local circuitry there, with som residule low-amplitude high frequency burstiness.
• Observed marked effets with this treatment!! The HFS alleviated parkinsonian symptoms, profoundly, with immediate reversal once the laser was turned off.
• LFS worsened PD symptoms, in accord with electrical stimulation.
• The Thy1::ChR2 only affected excitatory projections; GABAergic projections from GPe were absent. Dopamine projections from SNr were not affected by the virus either. However, M1 layer V projection neurons were strongly labeled by the retrovirus.
• M1 layer V neurons could be antidromically recruited by optical stimulation in the STN.
• Selective M1 layer V HFS also alleviated PD symptoms ; LFS had no effect; M2 (Pmd/Pmv?) LFS causes motor behavior.
• Remind us that DBS can treat tremor, rigidity, and bradykinesia, but is ineffective at treating speech impairment, depression, and dementia.
• Suggest that axon tract modulation could be a common theme in DBS (all the different types..), as activity in white matter represents the activity of larger regions compactly.
• The result that the excitatory fibers of projections, mainly from the motor cortex, matter most in producing therapeutic effects of DBS is counterintuitive but important.
• What do these neurons do normally, anyway? give a 'copy' of an action plan to the STN? What is their role in M1 / the BG? Should test with normal mice.
• 

____References____

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

• 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____

PMID-10498377[0] Stability of the interface between neural tissue and chronically implanted intracortical microelectrodes.

• implanted 7-shaft 35um iridium electrodes into the pericruciate gyrus of cats & measured the stability of recordings over several months.
• 
• electrodes were floating, under the dura; they note that connective tissue can force these floating arrays out of the brain, in further, or can encapsulate the electrodes.
• electrodes activated by 'potentiodynamic cycling' to remove the insulation from the tip, I guess.
• Insulation is epoxylite epoxy which is apparently baked for curing and degassing at 100 and 170C each for 30 minutes.
• more information on their fabrication in {1105}
• Used the now-standard techniques for recording & analysis - amazing that this was all very new 10 years ago!
• Measure stability not only on waveform shape (which will change as the position of the electrode relative to the neuron changes) but also neural tuning.
• Lymphocytes were found to accumulate around the tips of the microstimulated sites.
• Electrode sites that yielded recordings ('active') were all clean, with large neurons near the end, and with minimal connective tissue sheath (2-8 um; distance to nearby neurons was 30-50um).
• Longest period for an active electrode was 242 days.
• Electrode impedance was usually between 50 and 75 kOhm; there was no insulation failure.
• Electrodes were stable even when the cat vigorously shook it's head in response to water placed on the head (!).
• Electrodes were very unstable the first 2 weeks - 1 month ; rather stable thereafter.
• Active electrodes tended to remain active ; inactive electrodes tended to remain inactive.

____References____

PMID-6632958 A microelectrode for delivery of defined charge densities.

• Details the diamond impregnated lead grinding and epoxy insulation of 75um Pt-Ir wires;
• Encapsulate the whole thing in Dacron mesh;
• Electrodes are good for stimulating up to 300 uC / cm^2 * phase;
• Charge balanced pulses 5-20ua in amplitude, 200us/phase, 20Hz repetition are sufficient to activate nearby cortical neurons.

PMID-19596378 Magnetic insertion system for flexible electrode implantation.

• Probes constructed from a sharp magnetic tip attached to a flexible tether.
• Cite Polikov et al 2005. {781}.
• Re micromotion: (Gilletti and Muthuswamy, 2006 {1102}; Lee et al., 2004; Subbaroyan et al., 2005 {1103}).
• 0.6 mm (600 um!) diameter steel bullet, 4mm long, on the end of 38 gauge magnet wire. Mass 7.2 +- 0.4 mg.
• Peak current 520 A froman 800V, 900uF capacitor which produces a maximum force of 10 N on the electrode, driving it at 126.25 m/s.
• Did manage to get neural data.
• Experimental evidence suggests that macrophages have difficulty adhering to and spreading on polymer fibers ranging between 2.1 and 5.9 um in diameter. PMID-8902241 Bernatchez et al. 1996 and {746}.
• Shot through the dura.
• Also reference magnetic stereotaxis for use in manipulating magnetic 'seeds' through cancers for hyperthremic destruction.
• 

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.

PMID-16921202 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

PMID-11571334 Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions

• 
• So hard to find a good sagittal diagram of the human thalamus!

PMID-11948749 Surgery of the motor thalamus: problems with the present nomenclatures.

PMID-11929926 Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cerebellar disease.

• VIM (ventral intermediate) is a cerebellar relay nucleus; VOP (ventralis oral posterior) is a pallidal relay.
• Used pain controls. clever.
• Observations:
• VIM cells have a phase lag to EMG.
• VIM firing rate decreased relative to pain controls.
• ET patients show intention tremor -- usually under visual guidance.
• This leads them to think that cells have been de-afferented by cerebellar injury, e.g. they get their input from basal ganglia / motor cortex / visual feedback, which has less forward phase margin (not a smith predictor), hence oscillations.

DBS refs (for translating from word to my latex-based build system):

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3. PMID-15601936 Amirnovin R, Williams ZM, Cosgrove GR, Eskandar EN (2004) Visually guided movements suppress subthalamic oscillations in Parkinson's disease patients. The Journal of neuroscience : the official journal of the Society for Neuroscience 24:11302-11306.
4. PMID-18634849 Amtage F, Henschel K, Schelter B, Vesper J, Timmer J, Lucking CH, Hellwig B (2008) Tremor-correlated neuronal activity in the subthalamic nucleus of Parkinsonian patients. Neuroscience letters 442:195-199.
5. PMID-9219885 Awiszus F (1997) Spike train analysis. Journal of neuroscience methods 74:155-166.
6. PMID-11948769 Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL (2002) Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 17 Suppl 3:S145-149.
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8. PMID-11863600 Davidsen J, Schuster HG (2002) Simple model for 1/f(alpha) noise. Physical review E, Statistical, nonlinear, and soft matter physics 65:026120.
9. PMID-9827589 Deuschl G, Bain P, Brin M (1998) Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Movement disorders : official journal of the Movement Disorder Society 13 Suppl 3:2-23.
10. PMID-16943402 Deuschl G et al. (2006) A randomized trial of deep-brain stimulation for Parkinson's disease. The New England journal of medicine 355:896-908.
11. PMID-11685413 Ghazanfar AA, Krupa DJ, Nicolelis MA (2001) Role of cortical feedback in the receptive field structure and nonlinear response properties of somatosensory thalamic neurons. Experimental brain research Experimentelle Hirnforschung Experimentation cerebrale 141:88-100.
12. PMID-12626014 Guillery RW, Sherman SM (2002) The thalamus as a monitor of motor outputs. Philosophical transactions of the Royal Society of London Series B, Biological sciences 357:1809-1821.
13. PMID-16120664 Gutierrez R, Carmena JM, Nicolelis MA, Simon SA (2006) Orbitofrontal ensemble activity monitors licking and distinguishes among natural rewards. Journal of neurophysiology 95:119-133.
14. PMID-15317839 Hua SE, Lenz FA (2005) Posture-related oscillations in human cerebellar thalamus in essential tremor are enabled by voluntary motor circuits. Journal of neurophysiology 93:117-127.
15. PMID-9665587 {1020} Kennedy PR, Bakay RA (1998) Restoration of neural output from a paralyzed patient by a direct brain connection. Neuroreport 9:1707-1711.
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17. PMID-11391740 Koller WC, Lyons KE, Wilkinson SB, Troster AI, Pahwa R (2001) Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Movement disorders : official journal of the Movement Disorder Society 16:464-468.
18. PMID-14663050 Kumar R, Lozano AM, Sime E, Lang AE (2003) Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor. Neurology 61:1601-1604.
19. PMID-7823093 Lebedev MA, Denton JM, Nelson RJ (1994) Vibration-entrained and premovement activity in monkey primary somatosensory cortex. Journal of neurophysiology 72:1654-1673.
20. PMID-21779720 Lebedev MA, Tate AJ, Hanson TL, Li Z, O'Doherty JE, Winans JA, Ifft PJ, Zhuang KZ, Fitzsimmons NA, Schwarz DA, Fuller AM, An JH, Nicolelis MA (2011) Future developments in brain-machine interface research. Clinics (Sao Paulo) 66 Suppl 1:25-32.
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22. PMID-2276045 Lenz FA, Kwan HC, Dostrovsky JO, Tasker RR, Murphy JT, Lenz YE (1990) Single unit analysis of the human ventral thalamic nuclear group. Activity correlated with movement. Brain : a journal of neurology 113 ( Pt 6):1795-1821.
23. PMID-8032863 Lenz FA, Kwan HC, Martin RL, Tasker RR, Dostrovsky JO, Lenz YE (1994) Single unit analysis of the human ventral thalamic nuclear group. Tremor-related activity in functionally identified cells. Brain : a journal of neurology 117 ( Pt 3):531-543.
24. PMID-3346719 Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murayama Y, Dostrovsky JO, Murphy JT (1988) Single unit analysis of the human ventral thalamic nuclear group: correlation of thalamic "tremor cells" with the 3-6 Hz component of parkinsonian tremor. The Journal of neuroscience : the official journal of the Society for Neuroscience 8:754-764.
25. PMID-11027240 Levy R, Hutchison WD, Lozano AM, Dostrovsky JO (2000) High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor. The Journal of neuroscience : the official journal of the Society for Neuroscience 20:7766-7775.
26. PMID-12023310 Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO (2002) Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease. Brain : a journal of neurology 125:1196-1209.
27. PMID-10947834 Magarinos-Ascone CM, Figueiras-Mendez R, Riva-Meana C, Cordoba-Fernandez A (2000) Subthalamic neuron activity related to tremor and movement in Parkinson's disease. The European journal of neuroscience 12:2597-2607.
28. PMID-10717435 Magnin M, Morel A, Jeanmonod D (2000) Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience 96:549-564.
29. PMID-11157565 Marsden JF, Limousin-Dowsey P, Ashby P, Pollak P, Brown P (2001) Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson's disease. Brain : a journal of neurology 124:378-388.
30. PMID-11201755 Nicolelis MA (2001) Actions from thoughts. Nature 409:403-407.
31. PMID-19543222 Nicolelis MA, Lebedev MA (2009) Principles of neural ensemble physiology underlying the operation of brain-machine interfaces. Nature reviews Neuroscience 10:530-540.
32. PMID-9781530 Ondo W, Jankovic J, Schwartz K, Almaguer M, Simpson RK (1998) Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor. Neurology 51:1063-1069.
33. PMID-7711765 Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain research Brain research reviews 20:128-154.
34. PMID-18164493 Patil PG, Turner DA (2008) The development of brain-machine interface neuroprosthetic devices. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 5:137-146.
35. PMID-15214971 Patil PG, Carmena JM, Nicolelis MA, Turner DA (2004) Ensemble recordings of human subcortical neurons as a source of motor control signals for a brain-machine interface. Neurosurgery 55:27-35; discussion 35-28.
36. PMID-15973409 Quiroga RQ, Reddy L, Kreiman G, Koch C, Fried I (2005) Invariant visual representation by single neurons in the human brain. Nature 435:1102-1107.
37. PMID-10197761 Raeva S, Vainberg N, Tikhonov Y, Tsetlin I (1999) Analysis of evoked activity patterns of human thalamic ventrolateral neurons during verbally ordered voluntary movements. Neuroscience 88:377-392.
38. PMID-11522580 Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, DeLong MR, Obeso JA (2001) The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics. Brain : a journal of neurology 124:1777-1790.
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40. PMID-12815658 Theodosopoulos PV, Marks WJ, Jr., Christine C, Starr PA (2003) Locations of movement-related cells in the human subthalamic nucleus in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 18:791-798.
41. PMID-16160097 Ventura V, Cai C, Kass RE (2005a) Statistical assessment of time-varying dependency between two neurons. Journal of neurophysiology 94:2940-2947.
42. PMID-16160096 Ventura V, Cai C, Kass RE (2005b) Trial-to-trial variability and its effect on time-varying dependency between two neurons. Journal of neurophysiology 94:2928-2939.
43. PMID-15563555 Wiest MC, Bentley N, Nicolelis MA (2005) Heterogeneous integration of bilateral whisker signals by neurons in primary somatosensory cortex of awake rats. Journal of neurophysiology 93:2966-2973.
44. PMID-15635456 Williams ZM, Neimat JS, Cosgrove GR, Eskandar EN (2005) Timing and direction selectivity of subthalamic and pallidal neurons in patients with Parkinson disease. Experimental brain research Experimentelle Hirnforschung Experimentation cerebrale 162:407-416.
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1. bibtex:Batschelet Batschelet E (1981) Circular statistics in biology. London ; New York: Academic Press.
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3. {690} Chapin JK, Moxon KA, Markowitz RS, Nicolelis MA (1999) Real-time control of a robot arm using simultaneously recorded neurons in the motor cortex. Nature neuroscience 2:664-670.
4. {329} Fetz EE (2007) Volitional control of neural activity: implications for brain-computer interfaces. The Journal of physiology 579:571-579.
5. {943} Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA (2009) Spinal cord stimulation restores locomotion in animal models of Parkinson's disease. Science 323:1578-1582.
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8. bibtex:Kuiper Kuiper NH (1962) Tests concerning random points on a circle. Proc Kon Ned Akad Wetensch 63:38-47.
9. {934} Lebedev MA, Nicolelis MA (2006) Brain-machine interfaces: past, present and future. Trends in neurosciences 29:536-546.
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12. bibtex:Zar Zar JH (1999) Biostatistical analysis, 4th Edition. Upper Saddle River, N.J.: Prentice Hall.

PMID-18037630 Bilateral stimulation in the caudal zona incerta nucleus for tremor control

• VL DBS does not always work, and patients may develop tolerance; tried instead the caudal Zona Incerta (cZI).
• VL ~= VIM (?) -- differing thalamic naming nomenclatures.
• VL does not always work for proximal tremor.
• nice results! Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET
• Works for both distal and proximal tremor.
• nice figure therein.
• 

PMID-7711765[0] Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry.

• 5 'sideways control structures' :
• subthalamic nucleus (glutamate)
• pars compacta of the substantia nigra (dopamine)
• centromedian / parafasicular thalamic complex (glutamate)
• dorsal raphe nucleus (serotonin)
• pedunculopontine tegmental nucleus. (glutamate and acetylcholine)
• STN exitatory on the GPi and SNr. Which are basically the same thing.
• Largest target is the GPe, to which it is reciprocally connected.
• STN lesions produce ballism, violent, involuntary, wild, flinging movements usually limited to the side of the body contralateral to the lesion.
• STN densely packed with soma, dendrites, and long axons.
• But no (or few) interneurons.
• Projects to:
• GPe & GPi, SN, striatum, cerebral cortex, substantia innominata, pedunculopontine tegmental nucleus and the mesencephalic and pontine reticular formation.
• These projections are topologically organized. Lateral -> dorsal pallidium, medial -> ventral pallidium (GPv).
• Projections are often collaterals to GPe, GPi, and SNr in rodents; in primates, subsytems are separate.
• Dorsolateral STN = sensorimotor, ventromedial = 'association'
• STN projections lie parallel to GP neurons, arranged in lamina along the rostral-caudal axis.
• These, like in the striatum, are arranged perpendicular to the afferent fibers.
• Subthalamic and striatal neurons converge upon the same pallidal neurons.
• "Subthalamic axons arborize throughout large caudorostral portions of the pallidum and appear to influence in a rather uniform manner large subpopulations of pallidal neurons in both pallidal segments."
• 
• Above: gray cells = pallidal neurons.
• Suggests that STN cells can excite a rather large / diffuse population of pallidal cells, whereas striatum exerts a more specific inhibitory action.
• STN neurons project somewhat diffusely and less topographically to SNr, with 'patchy' regions, very similar to other striatal-nigral projections.
• Still, 90% of synapses in SN are GABA-ergic, < 10% are glutamatergic.
• electrophysiological studies in the rat have suggested that efferent projections of the subthalamic nucleus control the inhibition of movement by setting the physiological conditions of pallidal and nigral neurons to the appropriate level prior the arrival of striatal signals.
• STN projection to striatum diffuse, weak, unbranched and 'en passant'.
• Afferent projections:
• direct projection from the cerebral cortex. Might be collaterals from the pyramidal tract.
• In rodents: 40% from the prefrontal cortex, 15% from the ACC, 9% M1.
• In primates: Mostly M1, somatotopic organization (page 9), monosynaptic.
• also S1, somatotopic, respond to sensory stimuli.
• Dorsolateral sector of the subthalamic nucleus appears to be more involved in skeletomotor behavior, whereas the ventromedial sector appears more concerned with occulomotor and associative aspects of behavior [107].
• Electrical stimulation of the cortex results in a short-latency EPSP (monosynaptic) followed by brief inhibition IPSP (from the GP), then further EPSP.
• Electrical stimulation of the STN does not elicit movements; stimulation within microzones of the striatum does.
• more is known about the role of STN in eye movements through the SNr than skeletal motor control.
• Venrtomedial sector of STN receives afferents from the frontal eye fields & supplementary eye fields.
• SNr is known to exert a tonic GABAergic inhibition on neurons in the superior colliculus.
• Inibition is suppressed by transient GABA inhibition originating from the caudate nucleus (disinhibition).
• STN, in comparison, seems to suppress eye movements through the SNr -- perhaps to maintain attention on an object of interest, under control of the cortex (FEF). .
• CF {169} : activation of the STN drives SNr activity, which inhibits the superior colliculus, allowing maintainance of eye position on an object of interest.
• GPe projects directly to the STN, GABAergic, strong on proximal dendrites (less soma /distal),
• Collaterals to both the STN and SNr, and to the greater striatum and entopeduncular nucleus.
• Strong inhibitory effect on STN firing which appears to be chronic:
• STN firing should only be elicited by strongly coherent or synchronized arrival of information from multiple extrinsic sources.
• Recall there are two negations through the Striatum (GABA) & GPe (GABA).
• Then hypothesis behind Huntington's disease & PD:
• PD: pallido-subthalamic pathway activity is decreased, leading to an increase in excitatory activity of STN on BG output structures -> greater GPi /SNr GABA ergic activity.
• Huntingtons: pallido-subthalamic activity increased (striatal neurons lost), decreased excitation of STN -> less GPi/SNr GABAergic activity on VA/VL.
• "leaving thalamocortical neurons to respond undiscriminatingly to all sorts of inputs and hence to hyperkinesia". Makes sense.
• 
• Above, classical direct and indirect pathway.
• Re direct / indirect pathway: the evidence to support this is weak; inputs from the GPe seem to spare the area containing subthalamic cells projecting to the GPi/SNr.
• Another way: pallidal control of the subthalamic nucleus in primates is exerted principally upon cells projecting back to the GPe and not upon cells projecting to GPi/SNr.
• Only the centromedian / parafasicular complex of the thalamus projects to the STN.
• These might be collaterals of the thalamo-striatal projection system.
• Projections are topographic.
• Respects boundaries: centromedian projects to sensorimotor laterodorsal STN; parafasicular nucleus innervates the associative / limbic portion of this structure. The associative projection is much stronger than the sensorimotor.
• Glutamate.
• Direct projections from the SNc; STN projects back to the SNr.
• Dopamine, excitatory; much more present in rats than primates.
• Marked increase in metabolism following dopamine agonist treatments.
• Both D1 and D2 present (at least in rats).
• Direct projections from the pedunculopontine tegmental nucleus
• Cholinergic.
• Reciprocal -- relays BG information to the brainstem and spinal cord. Locomotion? cardiovascular changes?
• Dorsal rahpe nucleus
• Serotonin, obvi.
• GPe:
• Originally thought to project to STN to mediate it's glutamate projections
• now realized to have many outputs, including to the GPi/SNr.
• Strong afferents to the reticular thalamic nucleus (with bunched arborizations), GPi/SNr ('massive arborizations'), STN, and less to striatum.
• 
• Fibers from a small striatal cell group arborize twice in each pallidal segments in a rostrocaudal sequence manner.
• GPe projections to GPI/SNr cell-to-cell.
• These two together implies that the two striatal terminal fields in the GPe would effect two rostrally located sets of GPI/SNr cells 1 & 2 that are distinct from those innervated by the striatum more caudally than GPi/SNR cells 3 & 4.
• In animals at rest, striatal neurons are quiet, whereas SNr and GPi are tonically active.

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PMID-16549385[0] The effect of subthalamic nucleus deep brain stimulation on precision grip abnormalities in Parkinson's disease

• Deep Brain stimulation improves that mobility/dexterity and dyskinesia of patients in general, via an increase in rate and decrease in reaction time, but it does not let the patient match force output to the object being manipulated (that is, the force is too large).
• The excessive levels of grip force present in the stimulation 'off' state, and present from the early stages of the disease, however, were even more marked with STN stimulation on.
• STN DBS may worsen the ability to match force characteristics to task requirements. (position control is improved?).
• quite fascinating.

See also PMID-19266149[1] Distal and proximal prehension is differentially affected by Parkinson‘s disease The effect of conscious and subconscious load cues

• asked PD and control patients to lift heavy and light objects.
• While controls were able to normalize lift velocity with the help of both conscious and subconscious load cues, the PD patients could use neither form of cue, and retained a pathological overshoot in lift velocity.
• Hence force control is remarkably affected in PD, which is consistent with the piper rhythm being absent / usually present for isometric contraction.

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PMID-10854347 The pathophysiology of essential tremor

• http://www.medscape.com/viewarticle/461397_7 (you need to register to read more than 1 page)
• Not on Neurology website :-(
• Elevated blood concentrations of harmane and harmine were noted in essential tremor cases compared with non-essential tremor controls [30]
• Suggest that this may be dietary or endogenous synthesis.
• 50% hereditary.
• Tremor is severe and debilitating; use of hands may become dangerous, eating difficult.
• Unilateral thaladectomy is recommend in some cases; targets VIM, as does DBS.
• Generally higher frequency than PD (resting) tremor.
• TRemor can be Postural, Kinetic or Isometric; first two associated with ET. (or lithium cerebellar damage)

There seems to be an interesting connection between excessive grip force, isometric muscle contraction causing coherence between motor cortex and EMG, lack of inhibition on delayed response and go-no-go task, and experiments with STN lesioned rats, and the high/low oscillation hypothesis. Rather tenuous, I suppose, but let me spell it out.

1. PD patients, STN DBS impairs ability to match force characteristics to task requirements both in terms of grip force {88}, and when lifting heavy and light objects {88-2}.
2. Isometric force creation frequently engages the piper rhythm between cortex and muscles {1066}, which may be a means of preserving motor state {1066-4}.
3. In PD patients there is marked increase in beta oscillation and synchronization {1064}, which decreases during movement {829}. Some suggest that it may be a non-coding resting state {969}, though beta-band energy is correlated with PD motor symptoms PMID-17005611, and STN DBS attenuates the power in the beta band {710-2},{753},{1073}. Alternatively synchrony limits the ability to encode meaningful information. The beta band activity does not seem associated with rest tremor {1075}. Furthermore, beta band decreases prior and during movement, and with the administration of levodopa oscillation shifts to higher frequency -- the same frequency as the piper rhythm {1075}. Closed-loop stimulation with a delay (80ms) designed to null the beta oscillations is more effective than continuous high frequency DBS {967}.
4. PD patients have deficits in inhibition on go-no-go and delayed response tasks that is exacerbated by STN DBS {1077-3}. Lesioning the STN in rats has similar effect on delayed reward task performance, though it's somewhat more complicated. (and their basal ganglia is quite a bit different). {677}.
5. The <30 Hz and >30Hz bands are inversely affected by both movement and dopamine treatment. {1069}

Hypothesis: Impulsivity may be the cognitive equivalent of excess grip force; maintenance of consistent 'force' or delayed decision making benefits from Piper-band rhythms, something which PD abolishes (gradually, through brain adaptation). DBS disrupts the beta (resting, all synchronized) rhythm, and thereby permits movement. However it also effectively 'lesions' the STN, which leads to cognitive deficits and poor force control. (Wait .. DBS plus levodopa improves 40-60Hz energy -- this would argue against the hypothesis).

Testing this hypothesis: well, first of all, is there beta-band oscillations in our data? what about piper band? We did not ask the patients to delay response, so any tests thereof will be implicit. Can look at relative energy 10Hz-30Hz and 30Hz-60Hz in the spike traces & see if this is modulated by hand position. (PETH as usual).

So. I made PETHs for beta / gamma power ratio, controlled by shuffling the PETH triggers. Beta power was between 12 and 30 Hz; gamma between 30 and 75 Hz, as set by a noncausal IIR bandpass filter. The following is a non-normalized heatmap of all significant PETHs over all sessions triggered when the hand crossed the midpoint between targets. (A z-scored heatmap was made as well; it looked worse).

X is session number, Y time, 0 = -1 sec. sampling rate = 200 Hz. In one file (the band) there seems to be selective gamma inhibition about 0.5 sec before peak movement. Likely it is an outlier. 65 neurons of 973 (single and multiunits together) were significantly 'tuned' = 6.6%; marginally significant by binomial test (p=0.02). Below is an example PETH, with the shuffled distribution represented by mean +- 1 STD in blue.

The following heatmap is created from the significant PETHs triggered on target appearance.

80 of the 204 significant PETHs are from PLEX092606005_a. The total number of significant responses (204/1674, single units and multiunits) is significant by the binomial test p < 0.001, with and without Sept. 26 removed. Below is an example plot (092606005). Looks pretty damn good, actually.

Let's see how stable this relationship is by doing a leave-half out cross-validation, 10 plies, in red below (all triggers plotted in black)

Looks excellent! Problem is we are working with a ratio, which is prone to spikes. Fix: work in log space.

Aggregate response remains about the same. 192 / 1674 significant (11.5%)

In the above figure, positive indicates increased $\beta$ power relative to $\gamma$ power. The square shape is likely relative to (negative lags) hold time and (positive lags) reaction time, though the squareness is somewhat concerning. Recording is from VIM.

PMID-20855421[0] Mapping Go-No-Go performance within the subthalamic nucleus region.

• Support the dorsal / ventral motor / cognitive model.
• Only ventral subthalamic stimulation effected Go-No-Go accuracy.
• Both ventral and dorsal stimulation showed positive motor effects.
• On inhibition in the STN: (Aron and Poldrack 2006; Frank et al 2007).
• Thought: if methamphetamine and L-Dopa have similar impulsivity / punding / hobbyism effects, why do they think that the function is localized exclusively in the STN? These behaviors seem a more general problem of dopamine disregulation. Meth heads presumably have intact STN. The pausing hypothesis seems better to me (maybe); have to check rat results.
• Such is the problem with taking one thing out of a feedback loop and assuming the resultant deficit corresponds with the original 'function' insofar as one can be assigned. Think if you adjust the coeficients on a filter -- it gets all F'ed, with minor projection onto the frequency response.
• Low-order systems are less sensitive to drastic parameter adjustment, but still purpose is obscured in feedback systems.
• See {1082}
• STN DBS can lead to impaired withholding strong prepotent responses with strong response conflict
• Such as the Stroop task (Jahanshahi et al 2000; Schroeder et al 2002; Witt et al 2004)
• Stop signal task (Ray et al 2009)
• Go-nogo tasks (Hershey et al 2004; Ballanger et al 2009).
• Rats show the same deficit in inhibiting responses in strong conflict cases (Baunex et al 1995, 2001; Baunez and Robbins 1997).
• Suggest that significant variability in treatment responses could be from the exact location of stimulation.
• Ventral STN closer to SNRc, and dorsal is closer to the ZI and thalamus.

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