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

[0] Shink E, Bevan MD, Bolam JP, Smith Y, The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey.Neuroscience 73:2, 335-57 (1996 Jul)

[0] Bevan MD, Magill PJ, Terman D, Bolam JP, Wilson CJ, Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network.Trends Neurosci 25:10, 525-31 (2002 Oct)[1] Bevan MD, Magill PJ, Hallworth NE, Bolam JP, Wilson CJ, Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs.J Neurophysiol 87:3, 1348-62 (2002 Mar)[2] Magill PJ, Bolam JP, Bevan MD, Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network.Neuroscience 106:2, 313-30 (2001)[3] Magill PJ, Bolam JP, Bevan MD, Relationship of activity in the subthalamic nucleus-globus pallidus network to cortical electroencephalogram.J Neurosci 20:2, 820-33 (2000 Jan 15)

[0] Isoda M, Hikosaka O, Role for subthalamic nucleus neurons in switching from automatic to controlled eye movement.J Neurosci 28:28, 7209-18 (2008 Jul 9)

[0] Beurrier C, Bezard E, Bioulac B, Gross C, Subthalamic stimulation elicits hemiballismus in normal monkey.Neuroreport 8:7, 1625-9 (1997 May 6)

[0] Carpenter MB, Jayaraman A, Subthalamic nucleus of the monkey: connections and immunocytochemical features of afferents.J Hirnforsch 31:5, 653-68 (1990)

[0] Florio T, Capozzo A, Cellini R, Pizzuti G, Staderini EM, Scarnati E, Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat.Behav Brain Res 126:1-2, 93-103 (2001 Nov 29)[1] DeLong MR, Crutcher MD, Georgopoulos AP, Primate globus pallidus and subthalamic nucleus: functional organization.J Neurophysiol 53:2, 530-43 (1985 Feb)[2] 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)[3] Monakow KH, Akert K, Kunzle H, Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey.Exp Brain Res 33:3-4, 395-403 (1978 Nov 15)[4] Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, DeLong MR, Obeso JA, The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.Brain 124:Pt 9, 1777-90 (2001 Sep)[5] Sato F, Lavallee P, Levesque 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)[6] Carpenter MB, Carleton SC, Keller JT, Conte P, Connections of the subthalamic nucleus in the monkey.Brain Res 224:1, 1-29 (1981 Nov 9)[7] Carpenter MB, Jayaraman A, Subthalamic nucleus of the monkey: connections and immunocytochemical features of afferents.J Hirnforsch 31:5, 653-68 (1990)[8] Sato F, Parent M, Levesque M, Parent A, Axonal branching pattern of neurons of the subthalamic nucleus in primates.J Comp Neurol 424:1, 142-52 (2000 Aug 14)[9] Lee HS, Kim SW, Yoo IS, Chung SP, Common causes of hemiballism.Am J Emerg Med 23:4, 576-8 (2005 Jul)[10] Klawans HL, Moses H 3rd, Nausieda PA, Bergen D, Weiner WJ, Treatment and prognosis of hemiballismus.N Engl J Med 295:24, 1348-50 (1976 Dec 9)[11] Beurrier C, Bezard E, Bioulac B, Gross C, Subthalamic stimulation elicits hemiballismus in normal monkey.Neuroreport 8:7, 1625-9 (1997 May 6)[12] Bergman H, Wichmann T, DeLong MR, Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.Science 249:4975, 1436-8 (1990 Sep 21)[13] Patil PG, Carmena JM, Nicolelis MA, Turner DA, Ensemble recordings of human subcortical neurons as a source of motor control signals for a brain-machine interface.Neurosurgery 55:1, 27-35; discussion 35-8 (2004 Jul)[14] Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL, Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons.J Neurosci 23:5, 1916-23 (2003 Mar 1)[15] Salin P, Manrique C, Forni C, Kerkerian-Le Goff L, High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.J Neurosci 22:12, 5137-48 (2002 Jun 15)[16] Meissner W, Harnack D, Hoessle N, Bezard E, Winter C, Morgenstern R, Kupsch A, High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission.Neurochem Int 44:4, 281-6 (2004 Mar)[17] 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)[18] Bevan MD, Magill PJ, Terman D, Bolam JP, Wilson CJ, Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network.Trends Neurosci 25:10, 525-31 (2002 Oct)[19] Bevan MD, Magill PJ, Hallworth NE, Bolam JP, Wilson CJ, Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs.J Neurophysiol 87:3, 1348-62 (2002 Mar)[20] Lehericy S, Benali H, Van de Moortele PF, Pelegrini-Issac M, Waechter T, Ugurbil K, Doyon J, Distinct basal ganglia territories are engaged in early and advanced motor sequence learning.Proc Natl Acad Sci U S A 102:35, 12566-71 (2005 Aug 30)[21] Foffani G, Priori A, Involvement of the human subthalamic nucleus in movement preparation.Neurology 63:1, 195-6; author reply 196 (2004 Jul 13)

[0] Elble RJ, Central mechanisms of tremor.J Clin Neurophysiol 13:2, 133-44 (1996 Mar)

[0] Pollak P, Benabid AL, Gross C, Gao DM, Laurent A, Benazzouz A, Hoffmann D, Gentil M, Perret J, [Effects of the stimulation of the subthalamic nucleus in Parkinson disease]Rev Neurol (Paris) 149:3, 175-6 (1993)

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ref: Gradinaru-2009.04 tags: Deisseroth DBS STN optical stimulation 6-OHDA optogenetics date: 05-10-2016 23:48 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

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

  • Viviana Gradinaru, Murtaza Mogri, Kimberly R. Thompson, Jaimie M. Henderson, Karl Deisseroth
  • 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 eNpHr (inhibitory) opsin vector targeting excitatory neurons (under control of the CaMKIIa receptor) to the STN as identified stereotaxically & 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 -- 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 only projection neurons Thy1::ChR2 (not excitatory cells in STN), again did optotrode (optical stim, eletrical record) recordings.
    • HFS of afferent fibers to STN shut down most of the local circuitry there, with some residual low-amplitude high frequency burstiness.
    • Observed marked effects with this treatment! Afferent 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? They should test with normal mice.

____References____

[0] Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K, Optical Deconstruction of Parkinsonian Neural Circuitry.Science no Volume no Issue no Pages (2009 Mar 19)
[1] Eusebio A, Brown P, Synchronisation in the beta frequency-band - The bad boy of parkinsonism or an innocent bystander?Exp Neurol no Volume no Issue no Pages (2009 Feb 20)
[2] Wingeier B, Tcheng T, Koop MM, Hill BC, Heit G, Bronte-Stewart HM, Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease.Exp Neurol 197:1, 244-51 (2006 Jan)

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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: Hashimoto-2003.03 tags: DBS STN subthalamic nucleus globus pallidus electrophysiology date: 03-07-2012 21:57 gmt revision:3 [2] [1] [0] [head]

PMID-12629196[0] Stimulation of the Subthalamic Nucleus Changes the Firing Pattern of Pallidal Neurons

  • why does STN stim work? investigated the effects of STN HFS on neuronal activity of GPi and GPe.
  • monkeys were treated with MPTP
  • used a scaled-down version of human DBS stimulator (cool!)
  • high frequency stimulation resulted in stimulus-synchronized regular firing pattern, plus an overall increase in pallidal firing rate.
    • they think that this synchrony may underlie the beneficial effect of HFS in the STN
  • only behavior was, apparently, what amplitude and frequency were required to alleviate parkinsonian symptoms.
  • if i do DBS in normal monkeys, is there anything to say that the effect will be similar or comparable to treatment stimulation?
  • they remind us that HFS = lesion in terms of alleviating symptoms of parkinsons.

____References____

[0] Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL, Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons.J Neurosci 23:5, 1916-23 (2003 Mar 1)

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ref: Mink-1996.11 tags: basal ganglia review parkinsons STN DBS date: 03-05-2012 23:33 gmt revision:13 [12] [11] [10] [9] [8] [7] [head]

PMID-9004351[0] The basal ganglia: focused selection and inhibition of competing motor programs.

  • Plenty of focus on diseased states, but normal function is unclear.
  • basal ganglia do not generate motor programs; that is the task of the cerebrum / cerebellum (based on timing).
  • review posits that the inhibitory output of the BG acts to seletively inhibit competing motor mechanisms in order to prevent them from interfering with voluntary movements that are generated by other CNS structures.
  • Involvement of the BG in motor control old -- dates back to Kinner Wilson describes pathology of rigidity and tremor following lenticular degeneration.
    • Thought that the pyramidal system was new and plastic, whereas the extrapyramidal system was archaic and postural / static.
    • Extrapyramidal system is actually prepyramidal, too.
  • Striatum.
    • receives excitatory input from all of the cerebrum except primary auditory and visual cortices.
    • cortical projections terminate in longitudinal bands.
    • in reciprocally connected areas of frontal, temporal, and parietal cortex terminate in adjacent or interdigitating zones in the striatum.
    • somatotopy in projections: areas receiving input from the face area of sensory or motor cortex are separate from those receiving input from the arm area.
    • The zones themselves overlap / are interdigitated, but not completely.
    • 95% of the cells are medium spiny neurons (MSN).
      • The remainder are glutamine from centromedian and parafasicular nuclei of the thalamus, cholinergic input from large aspiny neurons, GABA from neighboring MSTs, and dopamine from SNpc.
    • When Flaherty and Graybiel (1994) PMID-7507981[1] injected retrograde tracer into GPi and anterograde tracer into sensory or motor cortex they were able to demonstrate multiple striatal zones that were labeled from both injections. This suggests that information is sent from cortex to striatum in a multiply convergent and divergent pattern with reconvergence in GPi after processing in the striatum (Fig. 2).
    • Caudate projects to SNpc
    • Putamen projects to the GPi.
    • Acetylcholine: there is a patchy distribution of heavily and lightly stained regions, corresponding to striosomes and the matrix.
      • Dendrites of most MSN are restricted to a single compartment.
      • both striosomes and matrix receive input from the SNpc, but only the striosomes project back to the SNpc.
      • Striosomes can affect the matrix via large aspiny neurons, AChe, 1-2% of the total striatal population.
    • One striatal cell receives input from thousands of cortical cells.
      • Activation of a MSN appears to require concurrent excitatory input from a large number of cortical afferents.
    • MSNs have a low resting firing rate of 0.1 - 1 Hz -- strong resting potassium current.
      • Cells can switch between two stable states: hyperpolarized -80mV and moderately polarized -50mV.
      • This appears to be stabilized by large aspiny cholinergic neurons (?)
  • D1 increases cAMP, D2 usually decreases cAMP. both expressed on MSN; some suggest differentially, based on anatomical target.
  • STN
    • dendrites up to 1200um.
    • in GPi and SNpr, STN axon collaterals branch to ensheath the cell bodies and proximal dendrites of their target neurons.
    • each axon from the subthalamic nucleus ensheathes many GPi neurons.
    • Input primarily from the oculo-and somato-motor areas of the frontal lobes.
    • does not seem to have much intrinisic processing; it's more of a relay.
  • GPi:
    • About 70% send axon collaterals to both thalamus and brainstem.
    • Projects to ventrolateral (Vlo) and ventral anterior nucleus (VApc).
    • Little overlap in projections fom the basal ganglia and the cerebellum in the thalamus.
    • collaterals of most GPi axons projecting to thalamus project to an area at the junction of the midbrain and pons adjacent to the pedunculopontine nucleus (PPN). Some call it the "midbrain extrapyramical area", which projects to the reticulospinal motor system.
  • GPe:
    • Most output inhibitory to STN; most input from the striatum and STN.
    • Also output to GPi and SNr.

Electrophysiology:

  • In the striatum, cells fire in relation to both the direction of movement (25%) as well as the direction of force (50%) (Crutcher and DeLong 1984b PMID-6705862[2]).
  • More cells fire during slow "ramp" movements than during fast "ballistic" movements, possibly due to their relation to proximal muscle activity, or due to force / speed modulation.
  • Cells fire phasically relative to cue, to movement, or after movement / before the next movement ("set" neurons). .
  • In the putamen, most activity is late, though there is a distribution anterior-posterior, with anterior cells more likely to fire early; these are possibly of cognitive origin.
  • In the striatum, activity has been found to context-dependent: e.g. cells respond to touch, but only if it is within the context of a movement.
    • Romo et. a.l 1992 controlled for this wrt externally triggered movements vs. self-initiated movements.
    • Within the caudate, Hikosaka et al 1989a described cell firing in the caudate relative to delayed, cued, and remembered saccades.
      • context-dependent activity is a feature of the striatum, but not necessarily the function.
  • Cholinergic large aspiny neurons appear to have no relation to movement.
    • But they do fire in relation to sensory input or to reward.
    • Since one effect of cholinergic input to MSN is to stabilize the present state, in the situation where the current behavior results in a reward, activity of the cholinergic interneurons would tend to reinforce the ongoing pattern of striatal activity. Interesting!! memory!

STN:

  • tonically active, with a resting rate of 20 Hz.
  • somatotopic organization, lower extremity dorsal and face / eyes ventral.
  • neurons increase firing rate in relation to eye or limb movement. (Matsumura et al 1992, Wichmann et al 1994a [3]).
  • In monkeys treained to perform elbow movements, 60-75% STN neurons had activity related to movement direction (Georgopoulos et al 1983) (Wichmann et al 1994a).
    • Unclear proportion responded to passive movement: 20% former, 50% latter.
  • It is not known to what degree STN neurons discharge in relation to other movement parameters. Only 1 study, with only 7 neurons, had some correlation to velocity ( Georgopoulos 1983)
  • Onset of activity slower than M1 or EMG.
  • Ventral STN: of all task-related neurons, 23% were related to saccades, 39% related to visual fixation, 15% to visual sensory responses.
  • Matsumura 1992 shows that 52% of STN neurons had activity related to maintained eye position but not to saccades.
    • STN supresses saccades: STN excites SNr which inhibits collicular neurons involved in saccade generation.
  • in MPTP monkeys, ablation or inactivation of the STN cauyses transient diskinesia but when it resolved monkeys were able to move normally. (BErgman et al 1990; Wichmann et al 1994b).

GPi:

  • activity does not correlate with physical parameters of movement.
    • no consistent relationship between GPi activity and joint position, force production, movement amplitude, or movement velocity during wrist movement.
    • little correlation of GPi output with EMG profiles either.
  • Ramp and ballistic movements: equal amounts of control.

SNr:

  • All involved in eye movements are tonically active.
  • virtually all have been reported to decrease activity during eye movement.
    • Still yet: SNr show firing rate decreases while GPi show firing rate increases.
    • Decreased SNr discharge results in disinhibition in the superior colliculus to initiate saccades.
    • Could also be that the SC generates simultaneous eye and head movements, and the SNr helps to inhibit (?) neck muscles.
  • None in response to saccades in the dark (!)
  • Over half have sensory responses.

GPe:

  • 2 types
    • HF, 70 Hz, interrupted with long pauses.
    • LF, 10 Hz, with frequent spontaneous bursts.
  • Activity during movement remarkably similar to GPi.
  • Weak encoding of movement amplitude, velocity, and muscle length and force is weak.
    • Movement related activity is late.
  • Might effect center - surround inhibition on the GPi; unclear what it does to the STN?

SNpc:

  • Schultz and Romo 1995 - SNpc neurons respond as early as possible to stimuli that indicates the availability of reward, and to the presence of reward, but only within a context.
    • No tuning to movement.

Synthesis:

  • Author believes that the basal ganglia serve to repress motor actions / plans that compete with the present or desired movement.
    • Eg. ones that are elicited through auto-association in the cerebral cortex.
    • corrolary: if there is an inability to focally inhibit competing mechanisms generally, it might be expected that the resulting movement deficit would be compounded during a sequence of movements, as is observed.
  • Discrete lesions in experimental animals often do not produce the movement disorders associated with human basal ganglia disease.
  • If the tonically active basal ganglia output inhibits competing motor mechanisms, the tonic inhibition must be removed from desired mechanisms. This must be done in a focused manner at the right time and in the right context in order not to activate competing mechanisms. The vast machinery of the striatum with its context-specificity, plasticity and spatiotemporal filtering selects which MPGs should be allowed to turn on. Thus, when a movement is made, the basal ganglia output has two parallel actions: inhibition of a multitude of competing MPGs via STN and GPi and focused selection of desired MPGs via striatum and GPi. Dysfunction of either of these actions would cause abnormal posture and movement.

Parkinson's disease:

  • Symptoms:
    • Tremor at rest
    • bradykinesia
    • paucity of movement (akinesia)
    • muscular rigidity
    • abnormally flexed posture with postural instability.
  • Tremor possibly from abnormal bursting in the thalamus. (Pare et al 1990)
  • Highly idiopathic and progressive.
  • Symptoms may reflect involvement of other systems in addition to the nigrostriatal dopamine system.
  • Bradykinesia:
    • excessive co-contraction, insufficient agonist activity.
    • movement is more impaired when visual cues are absent.
      • self-initiated movements are slower than visually cued movements
      • more impaired when deprived of visual feedback of the ongoing movement or if they cannot see the moving body.
      • Likely they have an increased dependence on visual feedback to compansate for the deficit.
    • slower on simultaneous and sequential movements than they were on individual components (Benecke et al 1986, 1987).
      • Greater latency to begin second movement.
      • Others have found no particular sequencing deficit (Agostino et al 1994).
  • Rigidity likely due to inability to inhibit reflex mechanisms.
    • One of these is the transcortical reflex, which can (normally) be inhibited when subjects are instructed not to resist movement.
      • PD patients have abnormally increased transcortical stretch reflexes.
      • Reflex cannot be inhibited upon instruction (Berardelli et al 1983, Rothwell et al 1983, Taton and Lee 1975).
    • When normal subjects are subjected to a perturbation in the anterior-posterior dimension while standing, they have a stereotyped pattern of muscle activity in the legs and trunk that maintains upright stance. If they then sit down and are subjected to the same perturbation, this activity no longer occurs. By contrast, patients with Parkinson’s disease have an inappropriate cocontraction of leg and back muscles in response to perturbation from upright stance. When the same subjects are subjected to a perturbation in a sitting position, they continue to have the same pattern of muscle activity. (Horak et al 1992)
  • Akinesia
    • May be due to a loss of of dopamine input to the prefrontal, premotor, or motor cortex. (Gaspar et al 1991, 1992; Sawaguchi and Goldman-Rakic 1994).
      • Animals with focal lesions to dopamine input to prefrontal cortex have prolonged reaction times (Humer et al 1994); animals with basal ganglia lesion do not.
  • Microwriting / micrographia: common problem where writing size is normal initially, but within several letters the writing gets progressively smaller so that by the end of the line, it may be illegible.
    • Hypothesis: depending on the movement and mechanisms involved, the number of mechanisms competing with the desired movement may increase additively as the sequence progresses leafing to progressive slowing of the movement.

Huntingtons

  • Early stages characterized by frequent, brief, random twitch-like movements and dementia. smoe of the movements resemble normal voluntary movement.
  • Involuntary EMG bursts 50 - 300 ms in duration.
  • Marked loss of striatal neurons.
    • Specifically, MSN enkephalin-containing that project to GPe. (Reiner 1988).
    • Substance-P MSN that project to GPi and SNr are preserved until later in the disease when rigidity typically appears.
    • Experimental lesions in the striatum rarely cause chorea, which makes sense as it is the specific pattern of striatal cell loss that matters (Crossman, 1987).
    • Stroke of the striatum in humans rarely causes chorea.
  • It should be emphasized that neurons in many parts of the brain including cortex and cerebellum degenerate in Huntington's disease, hence inferences of basal ganglia function drawn from HD must be interpreted with caution.
  • In contrast to PD, the long-latency stretch reflex is absent or reduced in Huntington's disease.
    • Plus somatosensory evoked potentials are markedly reduced.
    • People with chorea not from Huntington's disease have normal long-latency reflexes.

STN / Hemiballismus

  • Damage to STN by ischemic stroke results in bizarre involuntary movement that is charaterized by large amplitude, flinging (ballistic) movement of the contralateral extremities.
    • Symptoms are immediate and improve over time.
    • Similar to chorea, but more commonly affects proximal joints, and the movements are larger.
  • Hemiballismus can be caused by injecting biculculine into STN, which is somewhat paradoxical since biculculine is a GABA antagonist and would be expected to cause disinihbition (activation) of STN. Yet the results are similar to lesion of STN. (Crossman 1987)
  • After STN lesion there is decreased activity in GPe and GPi.
  • Hemiballismus can be eliminated by lesioning GPi outputs (Carpener 1950).
  • STN is exitatory in GPi / GPe; lesioning reduces GPi's ability to inhibit competing motor programs.
    • Loss of excitatory input to GPi results in abnormal phasic or bursting activity in GPi or its targets and this bursting causes twitches or chorea.

Experimental lesions:

  • Focal inactivation of the putamen with GABA-A agonist muscimol causes decreased movement amplitude with cocontraction of agonist and antagonist muscles in visually-guided arm movements.
  • Lesions studies suggest that the striatum is functionally heterogeneous with the function of each component determined by its cortical afferents.
    • Authors suggest that the function of each component is more likely to be reflected in its outputs than inputs.
  • Caudate does seem involved in more cognitive processing; it has different connectivity despite similar construction.
  • Muscimol into the SNr results in involuntary saccades and inability to mantain fixation.
    • Thus, just as GPi inactivation results in abnormal excess limb and trunk muscle activity, SNr inactivation results in abnormal excess eye movements. (Hikosaka and Wurtz, 1985b).
  • Lesion of GPi is an old treatment for PD in humans (Cooper and Bravo, 1958). \
    • Surprisingly, the most consistent beneficial effect of pallidotomy may be the reduction of dyskinesias that are induced by L-Dopa treatment (Laitinen et al 1992).

Large papers are not dissimilar from large software projects -- they take time, iteration, and concentration. Papers, however, are harder as the feedback is not immediate and gratifying.

____References____

[0] Mink JW, The basal ganglia: focused selection and inhibition of competing motor programs.Prog Neurobiol 50:4, 381-425 (1996 Nov)
[1] Flaherty AW, Graybiel AM, Input-output organization of the sensorimotor striatum in the squirrel monkey.J Neurosci 14:2, 599-610 (1994 Feb)
[2] Crutcher MD, DeLong MR, Single cell studies of the primate putamen. II. Relations to direction of movement and pattern of muscular activity.Exp Brain Res 53:2, 244-58 (1984)
[3] Wichmann T, Bergman H, DeLong MR, The primate subthalamic nucleus. I. Functional properties in intact animals.J Neurophysiol 72:2, 494-506 (1994 Aug)

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ref: 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: -0 tags: locomotion decerebrated monkeys spinal cord section STN stimulation date: 03-01-2012 23:53 gmt revision:0 [head]

PMID-7326562 Locomotor control in macaque monkeys

  • Were not able to induce walking with in monkeys with a sectioned spinal cord
  • Were able to induce walking motion by pulsed stimulation of the STN, with varying walking speed with varying currents!
  • Detailed, informative report, more than I have time to record here today.

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ref: Litvak-2011.02 tags: DBS MEG STN synchrony oscillations london connectivity beta basal ganglia date: 02-29-2012 19:59 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-21147836[0] Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson’s disease

  • Used MEG plus LFP recordings of the STN.
  • Two spatially and spectrally separated networks were identified.
    • A temporoparietal-brainstem network was coherent with the subthalamic nucleus in the alpha (7-13 Hz) band,
    • whilst a predominantly frontal network was coherent in the beta (15-35 Hz) band.
  • Dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex.
  • Idea of characterizing connectivity based on synchronization / comodulation: (Fries 2005).
  • Synchronization is exaggerated in Parkinson's disease (Sharott et al 2005b, Mallet et al 2008).
  • Some patients had dopamine dysregulation syndrome and medication-induced hypersexuality.
  • None of the > 45 Hz STN LFP patterns had a scalp pattern consistent with a cortical source.
  • Cortical source frequency not really that different between ON and OFF medication, except at maybe tremor frequencies.
  • But cortex drives the subthalamic area robustly.
    • That said, these patients were at rest.
    • Small difference between ON and OFF states possibly because they were at rest.
  • Both healthy subjects and those with parkinson's disease show resting connectivity between basal ganglia and the SMA, temporopareital area and parts of the prefrontal cortex. (Postuma and Dagher 2006); Helmich et al 2010).
  • Beta band coupling between cerebral cortex and subthalamic nucleus drops before and during movement (Cassidy et al 2002 PMID-12023312; Lalo et al 2008)
    • During imagination of movement (Kuhn et al 2008).
    • During action observation (Alegre et al 2010).
      • Is this consistent with the conflict / reinforcement learning hypothesis?
  • A big problem is determining if the oscillations are pathological or non-pathological
    • Impossible to control, since we cannot record from healthy humans.

____References____

[0] Litvak V, Jha A, Eusebio A, Oostenveld R, Foltynie T, Limousin P, Zrinzo L, Hariz MI, Friston K, Brown P, Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease.Brain 134:Pt 2, 359-74 (2011 Feb)

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ref: -0 tags: bilateral STN lesion rats perseverence nose poke impulsivity DBS basal ganglia date: 02-29-2012 17:44 gmt revision:1 [0] [head]

PMID-9421169 Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats.

  • Excitotoxic lesion of STN alleviate motor impairment found in PD dopamine depletion model.
  • What about normal rats?
  • investigated the behavioural effects of bilateral excitotoxic lesions of the STN in rats performing a five-choice test of divided and sustained visual attention, modelled on the human continuous performance task.
  • This task required the animals to detect a brief visual stimulus presented in one of five possible locations and respond by a nose-poke in this illuminated hole within a fixed delay, for food reinforcement
  • STN lesion:
    • decreased discriminatory activity
    • increase premature responses & preservative panel pushes and nose-poke responses.
  • Subsequent D1/D2 anatagonist administration reduced premature responses but not preservative nose-pokes.
  • Consistent with action selection and inhibition.
  • Suggest that these cognitive-type effects should be examined in humand that have STN DBS.

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ref: Mallet-2008.04 tags: DBS oscillations STN beta 6-OHDA rats ECoG acute date: 02-29-2012 01:11 gmt revision:4 [3] [2] [1] [0] [head]

PMID-18448656[0] Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex.

  • STN has pronounced beta band oscillations in PD patients.
  • 6-OHDA rodent model (here) shows the same, depending on state.
    • Synchronization in both local cellular assemblies and broadly across the STN + ECoG.
    • ECoG looks causal in their studies.
    • Frequencies > 15 Hz, not lower (theta), as in other studies.
  • Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment.
  • Acute disruption of dopamine transmission in control animals with antagonists of D(1)/D(2) receptors did not exaggerate STN or cortical beta oscillations.
    • This despite the potent agonist induced catalepsy in the rats!
    • Must be neural plasticity & structural.
    • Takes > 4 days.
    • Actual striatal DA levels decrease within 1 h of midbrain 6-OHDA
  • Under normal conditions, beta synchronization may be useful for sensory-motor processing (Uhlhaas and Singer 2006).
  • Synchronized activity is preferentially transmitted due to temporal summation.

____References____

[0] Mallet N, Pogosyan A, Sharott A, Csicsvari J, Bolam JP, Brown P, Magill PJ, Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex.J Neurosci 28:18, 4795-806 (2008 Apr 30)

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ref: Bergman-1990.09 tags: parkinsons STN lesion 1990 MPTP DBS date: 02-28-2012 21:06 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-2402638[] Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.

  • MPTP monkeys.
  • Guided by the rate hypothesis (which is probably false, but no matter!)
  • The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor.
  • the study that opened up a treatment - and helped many people!!
  • wasn't the first DBS surgery done in 1983 by Benabid? No, it was 1993!

____References____

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ref: Starr-2005.06 tags: STN DBS MPTP UCSF dystonia date: 02-28-2012 17:59 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-15703229[0] Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque.

  • both dystonia and PD.
  • Several firing rate changes:
    • dystonic patients showed decreased GPI firing.
    • PD patients showed higher pallidial discharge
    • GPi discharge rate was inversely correlated with dystonia severity.
  • Control with recordings from normal monkeys.
  • GPi showed increased oscillatory activity in the 2- to 10-Hz range (theta) and increased bursting activity in both dystonia and PD as compared with the normal NHPs.

____References____

[0] Starr PA, Rau GM, Davis V, Marks WJ Jr, Ostrem JL, Simmons D, Lindsey N, Turner RS, Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque.J Neurophysiol 93:6, 3165-76 (2005 Jun)

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ref: Wichmann-1994.08 tags: STN normal physiology delong wichmann date: 02-27-2012 22:05 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-7983514[0] The Primate Subthalamic Nucleus. 1. Functional Properties in Intact Animals.

  • Lots of cells -- 301 cells in the STN, 1589 microstimulation sites, 72 cross-correlation pairs.
  • 55% modulated to passive contralateral movement, 86% of these to muscle palpitation, 25% to light touch.
  • Caudalventral STN devoid of calls responding to touch or movement.
  • Somatotopic organization: lateral arm, medial leg.
    • Representation of proximal muscles / portions much larger than distal portions, consistent with Carpenter 1950.
  • Mostly rate increases in response to step tracking tasks, usually uniphasic.
  • 40ua, 200-500 ms train duration, 400 Hz did not produce movement. Stimulation of the lateral borders often led to eye movements.
  • 11% of pairs were seen to be synchronized, separated by 100-200um.
    • Much smaller than in the cortex.
    • This strongly supports the concept of functional segregation in the basal ganglia-thalamocortical pathways.
  • Mean firing rate 23 Hz old studies, 19 Hz present study.
  • "Most hypotheses concerning the role of the basal ganglia in movement were derived from experience with diseases originating in the basal ganglia or from experiments involving the activation or inactivation of large parts of BG nuclei. These results are notoriously hard to interpret, because gross changes in motor circuit activity likely results in rather nonspecific activity changes in multiple parts of the neuraxis, unlike minute alterations in the firing patterns of individual neurons in the basal ganglia may have under physiological conditions".
  • Basal ganglia may have a role in the late phases of movement, perhaps even their termination.
  • "More is known about the role of the indirect pathway in the pathophysiology of movement disorders such as Parkinson's disease and ballism than in the control of normal movement." word, yes.

____References____

[0] Wichmann T, Bergman H, DeLong MR, The primate subthalamic nucleus. I. Functional properties in intact animals.J Neurophysiol 72:2, 494-506 (1994 Aug)

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ref: DeLong-1985.02 tags: globus pallidus subthalamic STN electrophysiology Georgopoulos DeLong DBS date: 02-24-2012 21:50 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-3981228[0] Primate globus pallidus and subthalamic nucleus: functional organization

  • cells respond to arm, leg, and orofacial movements (mostly in the arm tho)
  • ~25% of these responded to passive joint movement - the latency is in accord with proprioceptive driving.
  • arm-related neurons were found throughout the rostrocaudal extent of both globus pallidus segments
  • look @ the articles that cite this!

____References____

[0] DeLong MR, Crutcher MD, Georgopoulos AP, Primate globus pallidus and subthalamic nucleus: functional organization.J Neurophysiol 53:2, 530-43 (1985 Feb)

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ref: Hershey-2010.12 tags: DBS impulsivity STN feedback stability gonogo date: 02-22-2012 22:04 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

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 (e.g. STN controls pausing in conflict situations) 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 coefficients 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 SNr, and dorsal is closer to the ZI and thalamus.

____References____

[0] Hershey T, Campbell MC, Videen TO, Lugar HM, Weaver PM, Hartlein J, Karimi M, Tabbal SD, Perlmutter JS, Mapping Go-No-Go performance within the subthalamic nucleus region.Brain 133:Pt 12, 3625-34 (2010 Dec)

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ref: Carpenter-1981.11 tags: STN subthalamic nucleus anatomy tracing globus_pallidus PPN substantia_nigra DBS date: 02-22-2012 22:01 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-7284825[0] Connections of the subthalamic nucleus in the monkey.

  • STN projects to both segments of the globus pallidus in a laminar and organized fashion.
    • most fibers projected to the lateral pallidal segment (aka GPe).
  • also projected to specific thalamic nuclei (VAmc, VLm, DMpl).
  • the major projection of PPN is to SN.
  • striatum projects to the substantia nigra pars reticulata (SNr). interesting.
  • see also: PMID-1707079[1]
    • "Anterograde transport in fibers and terminal fields surrounded retrogradely labeled cells in the LPS (GPe), suggesting a reciprocal relationship [to the STN]"
  • These data suggest that the STN receives its major subcortical input from cell of the LPS (GPe) arranged in arrays which have a rostrocaudal organization.
  • No cells of the MPS (GPi) or SN project to the STN.
  • The output of the STN is to both segments of the GP and SNpr.
  • Major subcortical projections to PPN arise from the MPS (GPi) and SNpr (output of the BG) , but afferents also arise from other sources.
    • The major projection of PPN is to SN.
    • HRP injected into PPN produced profuse retrograde transport in cells of the MPS and SNpr and distinct label in a few cells of the zona incerta and STN.

____References____

[0] Carpenter MB, Carleton SC, Keller JT, Conte P, Connections of the subthalamic nucleus in the monkey.Brain Res 224:1, 1-29 (1981 Nov 9)
[1] Carpenter MB, Jayaraman A, Subthalamic nucleus of the monkey: connections and immunocytochemical features of afferents.J Hirnforsch 31:5, 653-68 (1990)

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

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

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

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ref: 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: Steigerwald-2008.11 tags: parkinsons disease essential tremor DBS STN VIM date: 02-22-2012 18:40 gmt revision:4 [3] [2] [1] [0] [head]

PMID-18701754[0] Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state

  • Recorded from the STN in both PD and ET patients -- with the ET patients acting as a control (sorta; as good as we'll get).
  • ET is common neuromotor condition that involves intention tremor and movement overshoot; progresses over many years.
    • Malfunction of the olivocerebellar pathways.
    • no involvement of Dopamine-dependent pathways.
  • 65 PD patients!
  • Classified single units based on ISI & the asymmetry index, the ratio of the mode to the mean of the ISI histogram.
    • bursting or burstlike firing, intermitten grouped firing separated by periods of pauses.
      • Further analyzed for burstlike features via 'burst surprise method' Salcman 1985).
    • irregular, broad ISI CV > 85.
    • Regular tonic firing, bell shaped ISI, CV < 90.
  • PD patients had more burst-like neurons; ET patients had more irregular neurons.
  • Neurons with theta and beta characteristics predominated in bursting neurons (71/81); gamma oscillationgs were commonly found in nonbursting cells (8/11).
  • Only found synchronized beta activity in SUAs recorded from PD patients.
  • Levy: emphasized the importance of tremor for beta-band oscillations because the majority of synchronous cells were recorded from five patients with resting tremor in the operating room, whereas no synchronous pairs were found in nontremulous patients.
  • aha! a limitation of our study, however, is the lack of tremor recordings during surgeries // we were therefore not able to determine the amount of tremor-locked activity within the 3-10 Hz or transient changes in response to intermittent tremor.
    • Another limitation: no movements, attention could have wandered.
  • Still, STN firing rate increased, as per MPTP model.
  • Shift toward bursting type activity in PD.
  • Did not find differences in the proportion of neurons exhibiting intrinsic oscillatory activity or interneuronal synchronization.
  • Large proportion of neurons exhibiting theta-band activity around 4Hz in PD patients; c.f. monkeys, 10 Hz activity dominates.
    • Tremor is not an accurate reporter of pathology.

____References____

[0] Steigerwald F, Pötter M, Herzog J, Pinsker M, Kopper F, Mehdorn H, Deuschl G, Volkmann J, Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state.J Neurophysiol 100:5, 2515-24 (2008 Nov)

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ref: Vitek-2008.03 tags: DBS function efferent STN date: 02-22-2012 18:39 gmt revision:2 [1] [0] [head]

PMID-18540149[0] Deep brain stimulation: how does it work?

  • MPTP monkey research suggests that activation of output and the resultant change in pattern of neuronal activity that permeates throughout the basal ganglia motor circuit is the mechanism responsible for symptom improvement.
    • Sensible network approach.
  • If pathological plasticity mechanisms are responsible for the symptoms, perhaps we should look for similarly slow treatments?

____References____

[0] Vitek JL, Deep brain stimulation: how does it work?Cleve Clin J Med 75 Suppl 2no Issue S59-65 (2008 Mar)

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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: Mirabella-2011.08 tags: DBS STN inhibition nogo Italy date: 02-22-2012 18:26 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-21810782[0] Deep Brain Stimulation of Subthalamic Nuclei Affects Arm Response Inhibition In Parkinson’s Patients

  • Inhibitory control is improved only when both DBS are active, that is, the reaction time to the stop signal is significantly shorter in the DBS-ON condition than in all the others (left, right, or neither).
    • Inhibition is probably not lateralized.
  • CF [1]
  • The STN plays a critical role in the control of movements by integrating cortical inputs from several motor areas (Mink 1996, Romanelli et al 2005) (but how -- in what role?)
    • Alteration of STN functioning leads to loss of the ability to control movements as in the case of Parkinson's disease (Obeso et al 2008).
    • This control can be partially restored by DBS (Perlmutter and Mink 2006).
    • I don't agree with this. Things are far more nuanced, and the STN likely has a different role.
  • Theri metric is the SSRT:the stop signal reaction time.
    • One study found that SSRT was longer when DBS was on.
    • Two others bilateral DBS decreased length of the SSRT.
  • This task creates conflict on all trials, as they are instructed to both move as fast as possible, but also avoid hitting the target on stop trials.
    • In healthy subjects this leads to a delay strategy.
  • SSRT is not measured, but rather estimated from a 'race condition' between Go and Stop cues.
  • They propose that DBS affects the procrastination strategy, and that this strategy was less often adopted by PD patients than normal controls.
    • Or that STN / BG affects the ability to stop currently proceeding active movements.

____References____

[0] Mirabella G, Iaconelli S, Romanelli P, Modugno N, Lena F, Manfredi M, Cantore G, Deep Brain Stimulation of Subthalamic Nuclei Affects Arm Response Inhibition In Parkinson's Patients.Cereb Cortex no Volume no Issue no Pages (2011 Aug 1)
[1] Frank MJ, Samanta J, Moustafa AA, Sherman SJ, Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism.Science 318:5854, 1309-12 (2007 Nov 23)

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ref: RodriguezOroz-2001.09 tags: STN SNr parkinsons disease single unit recording spain 2001 tremor oscillations DBS somatotopy organization date: 02-22-2012 18:24 gmt revision:12 [11] [10] [9] [8] [7] [6] [head]

PMID-11522580[0] The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics

  • Looks like they discovered exactly what we have discovered ... only in 2001. This is both good and bad.
    • From the abstract: "Neurones responding to movement were of the irregular or tonic type, and were found in the dorsolateral region of the STN. Neurones with oscillatory and low frequency activity did not respond to movement and were in the ventral one-third of the nucleus. Thirty-eight tremor-related neurones were recorded."
  • Again, from the abstract: "The findings of this study indicate that the somatotopic arrangement and electrophysiological features of the STN in Parkinson's disease patients are similar to those found in monkeys."
  • It may be that we want to test differential modulation / oscillation: look for differences between rest and activity, if there is sufficient support for both these in the files we have.
  • These people were much, much more careful about localization of their single-electrode tracks. E.g. they calculated electrode location relative the DBS electrode stereotatically, and referenced this to the postoperative MRI location of the treatment electrode.
  • Many more (32% of 350 neurons) responded to active or passive movement.
  • Of this same set, 15% (31 neurons) had a firing rate with rhythmical activity; 38 neurons had rhythmic activity associated with oscillatory EMG, but most of these were responsive to passive stimulation.
  • Autocorrelation of the neuronal bursting and tremor peaked at mean 7Hz, while autocorr. of EMG peaked at mean 5Hz.
  • This whole paragraph is highly interesting: ''The neuronal response associated with active movements was studied by simultaneous recording of neuronal EMG activity of the limbs. Five tremor-related neurons, recorded while a voluntary movement was performed, were available for analysis. Voluntary activation of a particular limb segment arrested the tremor. This was associated with a change in the discharges of the recorded neuron, which fired at a slower rate and in synchrony with the voluntary movement. On occasions, freezing of the voluntary movement ensued and tremor reappeared, changing the neuronal activity back to the typical 4-5Hz tremor-related activity. The cross-correlation analysis of two such neurons showed a peak frequency of 4.63 and 4.88 Hz for tremor-related activity, and 1.5 to 1.38 Hz during voluntary movement. Whether neuronal discharges in the STN preceded or followed EMG activity of the limbs could not be precisely established under the present conditions.
  • Somatotopic representation in the STN is expected from normal and MTPT-treated monkeys. Indeed, somatotopy is enhanced int he GPm of MTPT-treated monkeys.
    • This somatotopy is likely to result from organized afferent from the primary motor cortex (M1) to dorsolateral STN; this is the target of DBS treatment. Ventral and medial STN seems to project to associative and limbic cortical regions.
    • It seems they think the STN is generally not diseased, it is just a useful target for stimulating without evoked movement as in M1. This is consistent with optogenetic studies by Deisseroth [1].
    • Supporting this: "DBS of STN in Parkinson's disease improves executive motor functions, but aggravates conditional associative learning.
  • Interesting: In Parkinson's disease patients with tremor, Levy and colleagues found synchronization and a high firing rate (>10Hz) while recording pairs of neurons >600um apart.
  • Recordings of cortical activity through EEG and STN LFP showed significant coherence in the beta and gamma frequency bands during movement - consistent with corticosubthalamic motor projection. ... and suggest that the STN neurons involved in parkinsonian tremor are the same as the ones ativated during the performance of a voluntary movement. (! -- I agree with this.)
  • More: The reciprocal inhibitory-excitatory connections tightly linking the GPe and the STN may generate self-perpetuating oscillations.

Old notes:

  • this paper concentrates on STN electrophysiology in PD.
    • has a rather excellent list of references.
  • found a somatotopic organization in the STN, with most motor-related units more irregular and in the dorsolateral STN.
  • found a substantial fraction of tremor-synchronized neurons.
  • conclude that the somatotopic organization is about the same as in monkeys (?) (!)
  • M1 projects to STN, as verified through anterograde tracing studies. [1] These neurons increase their firing rate in response to passive movements.
  • there appears to be a relatively-complete representation of the body in the dorsolateral STN.

____References____

[0] Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, DeLong MR, Obeso JA, The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.Brain 124:Pt 9, 1777-90 (2001 Sep)
[1] Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K, Optical deconstruction of parkinsonian neural circuitry.Science 324:5925, 354-9 (2009 Apr 17)

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ref: Salin-2002.06 tags: STN HFS DBS stimulation dopamine date: 02-22-2012 18:23 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-12077209[0][] High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.

  • they wanted to measure the cellular/molecular effects of STN DBS - reasonable.
    • in-situ hybridization histochemistry and immunocytochemnistry.
  • HFS of the STN decreases the metabolic activity of STN neurons (cytochrome oxidase (CoI) levels decreased!),
    • However it did not affect the overexpression of enkephalin {1135} mRNA or the decrease in substance P in the ipsilateral striatum.
    • Decreased/corrects glutamate decarboxylase 67 (GAD67) in the substantia nigra following STN lesion, worsened in the entopeduncular (GPe-ish: see wiki) nucleus, no change in GPi.
    • HFS, however, increases c-fos activity, which seems to be involved in immediate early gene induction and stress response (as well as 8,000 other papers about this protein)
  • this stimulation may not simply cause interruption of STN outflow.
  • STN on the order of 300ua through a 200um teflon-coated stainless bipolar (twisted pair) electrode (important to consider)
  • unilateral HFS in STN in hemiparkinsonian rats can induce dyskinesias
    • buuut a higher intensity of stimulation was required to elicit dyskinesia in animals with the dopamine lesion as compared to the intact rats. Parkinsonian animals are more resistant to HFS of the STN.
    • Therefore they matched the stimulus intensity to the behavior correlates, not the absolute values of the currents.
  • STN HFS in animals with dopamine lesions on the same brain side may prevent the previously reported dopamine hyperactivity in the contralateral hemisphere.
  • note bene, the entopeduncular nucleus is probably not a good taget for surgical treatment PMID-14602091[1][] High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission.

____References____

[0] Salin P, Manrique C, Forni C, Kerkerian-Le Goff L, High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.J Neurosci 22:12, 5137-48 (2002 Jun 15)
[1] Meissner W, Harnack D, Hoessle N, Bezard E, Winter C, Morgenstern R, Kupsch A, High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission.Neurochem Int 44:4, 281-6 (2004 Mar)

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ref: Levy-2002.06 tags: DBS parkinsons STN oscillations beta date: 02-22-2012 18:17 gmt revision:4 [3] [2] [1] [0] [head]

PMID-12023310[0] Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease.

  • Key finding: Synchronized HFOs (high-frequency oscillations, 15-30Hz here) between STN neurons were observed in 28 out of 37 pairs in five patients who had tremor in the operating room and none of 45 pairs in three patients who did not.
  • Active movement suppressed synchronized HFOs in three out of five pairs of neurones, independent of changes in firing rate.
  • Dopamine treatment also supressed LFP HFOs, synchrony between STN neuron pairs, and synchrony between tremor cells.
  • They suggest that STN is diseased ... however, STN does not receive a great number of SNc projections, hence the pathology may merely bre reflective of upstream structures.

____References____

[0] Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO, Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease.Brain 125:Pt 6, 1196-209 (2002 Jun)

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ref: Heimer-2006.01 tags: STN DBS synchrony basal ganglia reinforcement learning beta date: 02-22-2012 17:07 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-17017503[0] Synchronizing activity of basal ganglia and pathophysiology of Parkinson's disease.

  • They worry that increased synchrony may be an epi-phenomena of tremor or independent oscillations with similar frequency.
  • Modeling using actor/critic models of the BG.
  • Dopamine depletion, as in PD, resultis in correlated pallidal activity, and reduced information capacity.
  • Other studies have found that DBS desynchronizes activity -- [1] or [2].
  • Biochemical and metabolic studies show that GPe activity does not change in Parkinsonism.
  • Pallidal neurons in normal monkeys do not show correlated discharge (Raz et al 2000, Bar-Gad et al 2003a).
  • Reinforcement driven dimensionality reduction (RDDR) (Bar-Gad et al 2003b).
  • DA activity, through action on D1 and D2 receptors on the 2 different types of MSN, affects the temporal difference learning scheme in which DA represents the difference between expectation and reality.
    • These neurons have a static 5-10 Hz firing rate, which can be modulated up or down. (Morris et al 2004).
  • "The model suggests that the chronic dopamine depletion in the striatum of PD patients is perceived as encoding a continuous state where reality is worse than predictions." Interesting theory.
    • Alternately, abnormal DA replacement leads to random organization of the cortico-striatal network, eventually leading to dyskinesia.
  • Recent human studies have found oscillatory neuronal correlation only in tremulous patients and raised the hypothesis that increased neuronal synchronization in parkinsonism is an epi-phenomenon of the tremor of independent oscillators with the same frequency (Levy et al 2000).
    • Hum. might be.
  • In rhesus and green monkey PD models, a major fraction of the primate pallidal cells develop both oscillatory and non-oscillatory pair-wise correlation
  • Our theoretical analysis of coherence functions revealed that small changes between oscillation frequencies results in non-significant coherence in recording sessions longer than 10 minutes.
  • Their theory: current DBS methods overcome this probably by imposing a null spatio-temporal firing in the basal ganglia enabling the thalamo-cortical circuits to ignore and compensate for the problematic BG".

____References____

[0] Heimer G, Rivlin M, Israel Z, Bergman H, Synchronizing activity of basal ganglia and pathophysiology of Parkinson's disease.J Neural Transm Suppl no Volume :70, 17-20 (2006)
[1] 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)
[2] 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: Wichmann-2011.12 tags: DBS STN basal ganglia bursts oscillation review wichmann beta date: 02-22-2012 17:05 gmt revision:13 [12] [11] [10] [9] [8] [7] [head]

PMID-21723919[0] Pathological basal ganglia activity in movement disorders.

  • The paradigm has shifted: initial idea was that firing rates changed,
  • later in detailed description of basal ganglia firing rate changes:
    • burst patterns and oscillations
  • 6-OHDA murines + MPTP monkey models so essential yada yada.
  • intraoperative microelectrode recordings yada yada.
  • Nice figure:
    • Black = inhibitory; gray = excitatory. From Galvan and Wichmann 2008.
    • note differences between D2 and D1.
  • Recall corticostriatal fibers are often (50%) collaterals from corticospinal axons.
  • Corticostriatal pathway separate from cortico-subthalamic pathway, so the two get different signals. (Parent and Parent 2006).
    • Few collaterals, and of those axons go to red nucleus and cerebral peduncle -- not pyramids.
  • Indirect (GPe, STN targets) and direct (GPi/SNr) striatal projections generally, but not completely, seem separate.
  • VA = ventroanterior; VL = ventrolateral thalamus.
  • Collaterals from GPi/SNr reach the intralaminar thalamic nuclei: the CM (centromedian) and the PF (parafascicular) nuclei.
  • One of the important additional function of the intralaminar thalamic nuclei is to provide saliency information to the striatum during procedural learning (Kimura et al 2004; Minamimoto et al 2009).
  • There is a considerable body of evidence that the absence of dopaminergic transmission may trigger changes in the density and morphology of dendritic spines on striatal projection neurons.
    • Thereby influencing corticostriatal transmission.
    • This is consistent with the progressive nature of the disease.
  • Serotonin and acetylcholine also involved in striatum, but their role in PD less well characterized.
  • Tremor and dystonia possibly due to afferents from the deep cerebellar nuclei and efferents to the cerebellar cortex.
  • Rate model failures:
    • thalamotomy procedures did not result in worsening of parkinsonism.
    • GPi lesions produced bradykinesia in normal monkeys (despite the GABA output!)
    • GPe lesions do not produce parkinsonism.
    • not all studies report changes in FR in GPi/GPe.
    • A significant factor interfering with the assessment of FR changes in PD patients is that its dependent on the state of arousal of the patients.
  • Burstiness: Increased burstiness (Fig. 2A) has emerged as one of the most reliable abnormalities of neuronal firing in the basal ganglia in parkinsonism, as shown in dopamine-depleted monkeys and in patients with PD
  • Oscillations: much in the beta band (10-35 Hz) throughout extrastriatal BG.
old redirect: see [1]
  • LFP power:
  • Brown is the purveyor of the high kinetic / low akinetic hypothesis (2003, 2005).
  • Oscillations do not occur in acute dopamine depletion.
  • GABA receptor blockade in GPe results in dyskinesias.
  • STN inactivation results in ballismus, as noted elsewhere.
  • GPi lesioning is clinically used to abolish dyskinesias in patients with treatment-resistant hyperkinetic movements.

____References____

[0] Wichmann T, Dostrovsky JO, Pathological basal ganglia activity in movement disorders.Neuroscience 198no Issue 232-44 (2011 Dec 15)
[1] Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, DeLong MR, Obeso JA, The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.Brain 124:Pt 9, 1777-90 (2001 Sep)

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ref: Cassim-2002.12 tags: DBS STN oscillations ablation france VIM amish. date: 02-22-2012 16:59 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-12495873[0] Relationship between oscillations in the basal ganglia and synchronization of cortical activity.

  • STN neurons in the rat typically fire in + phases of cortical EEG.
  • Ablation of ipsilateral cortex makes firing random
  • 6-OHDA animals the orignial busting pattern is increased;
  • ablation of the cortex makes the firing pattern tonic.
  • GP firing in parkinsonian animals become very oscillatory as opposed to movement-locked.
  • Levy et al 2000 -- STN neurons show both oscillatory behavior and tremor-locked behavior, and some both.
  • with DBS, dominant EMG frequency shifts from ~ 12 Hz to ~40 Hz piper rhythm.
  • Reiterate that Beta rhythms occur not during movement, but only during tonic or sustained forces. Oscillations could be a means of keeping a 'symbolic' movement alive.
    • Therefore, it is possible to find EEG-EEG coherence between two distant cortical entities involved in the same motor task.
      • Really need to record LFP during DBS surgeries.
  • It should be kept in mind that the VIM has no direct relationship with the basal ganglia, and is rather involved in the cerebellar system and the cortico-ponto-cerebellothalamo-cortical loop. (cortex, pontine nucleus, cerebellum / thalamic cerebellum, cortex)
  • Reiterate the importance of > 60Hz oscillations in STN and GPi.
    • the authors put forward the hypothesis of two systems within the basal ganglia: a "low-frequency system" and a "high-frequency system". The "low-frequency system" would impair movement, and would be blocked either by dopaminergic stimulation or focal destruction of GPI or STN, thus explaining the good results of pallidotomy for example. The "high-frequency system" would promote movement, and would be artificially enhanced by high frequency stimulation of either nucleus.
  • Basal ganglia oscillations within the beta band were recently demonstrated to be reduced by voluntary movement [53].

Also, random: the world's highest rate of Parkinson's disease is in the Amish in the NE US. More than twice that of anywhere else; http://www.viartis.net/parkinsons.disease/news/090801.htm

____References____

[0] Cassim F, Labyt E, Devos D, Defebvre L, Destée A, Derambure P, Relationship between oscillations in the basal ganglia and synchronization of cortical activity.Epileptic Disord 4 Suppl 3no Issue S31-45 (2002 Dec)

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ref: Parent-1995.01 tags: basal ganglia anatomy review STN GPe DBS date: 02-22-2012 15:48 gmt revision:17 [16] [15] [14] [13] [12] [11] [head]

PMID-7711769[0] Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop.

  • Pallidal and nigral neurons have wide dendritic arborizations at right angles to the unbranched incoming striatal axons, leading to (hypothetically) a confulence of information from distinct functional striatal territories on many neurons and to extreme reception convergence [242].
    • This pattern suggests that projections arising from very small areas of the cortex may extend through very large regions of the striatum, particularly along the rostrocaudal plane.
    • Individual striatal neurons receive relatively few synapses from restricted cortical areas; this makes it difficult to conceive how the cortico-striatal projection system could convey information in a highly specific manner; specificity does not exist at a cellular level.
  • Cortex to striatum:
    • Virtually all cortical functional areas contribute, at varying degrees, to the cortico-striatal projection, inputs from the sensorimotor cortex being particularly extensive and those from the visual cortex much less so.
    • Cortico-sriatal projection originates from neurons located in both supragranular (layers I-III) and infragranular (V,VI) cortical layers.
    • Cortical neurons project ipsilaterally or contralaterally, but not usually bilaterally.
    • Cortical cells arborize on restricted, topologically defined domains in the striatum.
    • Restricted cortical regions project to parasagitally elongated domains in the caudate nucleus.
      • this seems to be a general feature. see B and C below.
      • Reminds me of the cerebellum.
    • non-adjacent cortical areas (prefrontal and pareital cortices)project to adjacent striatal territories.
    • The association, sensorimotor, and limbic cortical areas project in a segregated manner onto threes distinct striatal regions referred to as the associative, sensorimotor, and limbic striatal territories.
    • In this view, cortical information is not directly transposed at striatal level, but is integrated and transformed into strict associative, sensorimotor, and limbic functional modalities.
  • Convergence and divergence:
    • There is a vast reduction in the number of neurons from the cortex to the striatum.
    • This has led many to infer overlap or convergence.
    • Actual projection is patchy -- divisions of striosomes and extrastriosomal matrix -- with the individual axons sending out further sub-patches.
      • This degree of segregation breaks down for sensorimotor territory.
    • cortico-striatal neurons in infragranular layers project principally to striosomes while those in supragranular layers send their axons to the matrix. things are tightly organized.
  • The output cells of the matrix are grouped in clusters in relation to the different projection systems that lead from the striatum to the GPe and GPi. These are called 'matrisomes'.
    • These might be a way of bringing into proximity different cortical signals so they can be recombined in novel ways.
    • That said, there was substantial topographical overlap of the frontal eye field and the supplementary eye field, and though these are closely interdigitated they do not mix.
  • Medium spiny neurons:
    • The primary projection neurons of the striatum.
    • GABA. Plus substance P, enkephalin, dynorphin and neurotensin. (!)
      • The coexistence of GABA with a given peptide in a spiny neuron is in correlation with it's target site.
      • At that time they didn't know what the peptides did.
    • Axon emits several collaterals:
      • Local axonal arborizations restricted tot he dendritic domain of its cell of origin or a nearby cell -- inluding an 'autonapse' or of nearby projection neurons.
      • Less common axonal arborization goes far beyond and often does not overlap the dendritic domain of the cell of origin.
    • Projected to by the cortex, thalamus, and the SNc.
    • Usually silent, except with cortical / thalamic input.
  • Interneurons in the striatum are non-spiny.
    • Less than 2% (of entire striatal population, not just interneurons) them are huge, cholinergic cells.
      • These form symmetric synapses on virtually all parts of MSN.
    • Medium, 1% of population, have short axons and are GABA ergic.
    • Second medium, nitrous oxide signaling interneurons.
    • SNc efferents synapes ontot the base of the spines, but only on MSN that have cortical afferents.
    • Thalamic input synapse onto morphologically distinct type of MSN.
    • Destruction of the dopaminergic nicgro-striatal pathway results in a decrease in levels of mRNA for substance P and increase in mRNA for enkephalin.
  • Striatal MSN projections:
    • Relatively discrete in cats and monkeys; highly collateralized in rats, where many neurons project to GPe, GPi, SN, or some pair.
  • Fibers from the associative territory massively invade the whole extent of SNr, without clear territorial demarcation.
    • Meanwhile, inputs from the limbic striatal territory appears to be widely distributed in the substantia nigra & VTA.
  • Most authors think that the distinction between the GPi and SNr is artificial -- they are split by the internal capsule.
    • However, GPi is mostly sensorimotor, while SNr is associative.
  • Projections from striatum to pallidus * SNr very organized and layered.
    • Pictures. read the paper. words do not do this justice.
    • For example, injections of anterograde tracers in various sectors of the striatum produce elongated, longitudinally oriented terminal fields that cover nearly the entire rostrocaudal extent of the substantia nigra.
    • "The dorsal climbing fibers and the corresponding wooly fibers from replicable modular units whose boundaries do not respect the limit between SNc and SNr compartments. ... They are distrinuted along the rostrocaudal extent of the substantia nigra according to a remarkably precise and constant sequence.
  • As in [1]: striatal and subthalamic terminals converge onto the same pallidal neurons within these regions of overlap, possibly in register with those from the striatum.
    • The striato-pallidal fibers and striato-nigral fibers arborize at least twice in the target structures, suggesting there are multiple copies of the same information to distinct subsets of pallidal/nigral populations.
      • Meanwhile, GPi/SNr axons are highly collateralized and not strictly confined to disctinct subnuclei.
      • That is, output is both convergent and divergent.
      • There are several multi-laminar models of the SNr [54] or the globus pallidus [243].
  • Regarding information funneling due to the very large dendritic fields of pallidal neurons:
    • anterograde double-labeling experiments in the squirrel monkey clearly indicate that neighboring striatal cell populations do not have overlapping terminal fields in the GP or SN.
      • Axons from adjacent striatal cell populations produce two sets of terminal fields that interdigitate but never mix.
      • cortical information is conveyed and integrated along multiple, segregated channels.
  • Output of GPi/SNr = VA, VL thalamus, both ipsi and contralateral.
    • Lesser: pedunculopontine tegmental nucleus & centromedian thalamus, superior colliculus.
    • Highly collateralized output.
    • Lamellar distribution of cells that share similar functional characteristics.
    • Synapse almost exclusively on thalamic projection neurons.
    • Centromedian nucleus: no projection to the cortex; rather projects to the striatum, hence is involved in regulation.
    • Pedunculopontine nucleus: mostly re-afferent back to the BG!
      • innervation of the SNc, subthalamic nucleus, and the pallidum. [95,149,186-188,202,207,215,263,277].
      • Acetylcholine output.
      • Deep cerebellar nuclei project to the pedunculopontine nuclei in primates.
  • GPe: efferent fibers from large terminal boutons that make synapses mostly of the symmetrical type with proximal dendrites and soma of GPi/SNr neurons. These GABA synapses may be of ultimate importance in regulating activity.
    • Also projects to the reticulothalamic region, which supplies GABA synapses to the rest of the thalamus, hence GPe can disinhibit most of the thalamus. Such complexity.

____References____

[0] Parent A, Hazrati LN, Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop.Brain Res Brain Res Rev 20:1, 91-127 (1995 Jan)
[1] Parent A, Hazrati LN, Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry.Brain Res Brain Res Rev 20:1, 128-54 (1995 Jan)

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ref: Shink-1996.07 tags: STN GPe GPi globus_pallidus anatomy retrograde tracing DBS date: 02-22-2012 15:34 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-8783253[0] The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey.

  • interconnected neurons in the subthalamic nucleus and the globus pallidus external innervate the same population of neurons in the internal segment of the globus pallidus.
    • e.g. there is a consistent functional organization between the three areas! (need to look up the organization of the striatum, too).
  • they did a similar study with injections of dextran amine into the GPi, and found that the labeled neurons in the STN and GPe were, as before, in register.
    • labeled GPe axons were not reactive to GABA & seemed to be from STN
    • labeled STN axons seemed to be from the GPe & were GABA reactive.
  • Has anyone traced out the connection in the brain of a Parkinson's patient? Does it change with the disease?

____References____

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ref: Magill-2001.01 tags: dopamine STN globus_pallidus cortex parkinsons DBS 6OHDA date: 02-22-2012 15:31 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-11566503[0] Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network

  • Compared unit activity STN / GP and EEG in rats under urethane anesthesia in control and 6OHDA rats.
  • DA depletion:
    • increased FR of STN neurons.
    • caused oscillations in GP neurons.
  • dopamine depletion causes the STN-GP circuit to become more reactive to the influence of the activity of cortical inputs. also see PMID-10632612[1]
  • oscillatory activity in the STN-GP network in anaesthetised rats is phase-locked to rhythmic cortical activity and is abolished by transient cortical activation as well as cortical ablation.
    • 15-20% of the network still oscillated following cortex removal, suggesting that intrinsic properties pattern activity when dopamine levels are reduced.
  • cool figures - nice recordings, high SNR, clear oscillations in the firing and ECoG signal

____References____

[0] Magill PJ, Bolam JP, Bevan MD, Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network.Neuroscience 106:2, 313-30 (2001)
[1] Magill PJ, Bolam JP, Bevan MD, Relationship of activity in the subthalamic nucleus-globus pallidus network to cortical electroencephalogram.J Neurosci 20:2, 820-33 (2000 Jan 15)

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ref: Guridi-2001.01 tags: STN DBS 2001 parkinsons hemiballismus Obeso date: 02-22-2012 15:14 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-11133783[0] The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma

  • Lesions of the globus pallidus, thalamus, as well as the STN can lead to hemiballismus
  • none-the-less, hemiballismus is a rather rare complication in STN DBS or lesion
  • GABA projection to the GPi is reduced in PD due to dopamine depletion
    • STN has projects glutamergic projections to GPi, so lesion would tend to worsten activity
    • STN also projects to the GPe, and lesioning it reduces hyper-activity there.
    • Therefore the balance of lesioning is to permit movements but not hemiballismus.
  • STN lesion in normal patients induces hemibalismus and chorea, but threshold for movements are raised with chronic dopamine depletion. cf {207}
  • Quality of life issues: perhaps everything has been learned already. {1124}

____References____

[0] Guridi J, Obeso JA, The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma.Brain 124:Pt 1, 5-19 (2001 Jan)

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ref: Bevan-2002.1 tags: STN GPe globus pallidus oscillations parkinsons DBS date: 02-22-2012 15:13 gmt revision:8 [7] [6] [5] [4] [3] [2] [head]

PMID-12220881[] Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network.

  • !!! autonomous oscillation of STN and GPe underlies tonic activity and is important for synaptic activity (e.g. normal??)
    • this is a review, of course.
  • during quiet wakefulness, neurons in STN and GPe fire differently without rhythm or strong correlation.
    • this is more pronounced when STN/GPe neurons are isolated from synaptic input (e.g. when prepared in a slice)-- they have inherent oscillatory characteristics. hum.
      • this may allow persistent activity or timed (gating) of planned activity (as opposed to timing of compensatory movement, which are mostly handled by the cerebellum).
      • the persistent activity must be more complicated than synchronized firing as in PD.
      • Random thought: I wonder if you 'clocked' the brain you would get discrete reaction times. Longshot; would need to review up and down states in the cortex?
  • during voluntary movement, GPe and STN neurons display a complex relationship to features of motor activity.
  • GPe and STN are reciprocally connected (STN with the Glu, GPe with the GABA)
    • as in other original papers, most of the axons from these regions have branched axons that mediate both reciprocal connections and innervation of output nuclei.
  • interesting thought: STN/GPe network could act as a 'generic' recursive pattern generator.
  • see figure 1 - single IPSP regulate the timing of spikes in the STN. large IPSP can synchronize and entrain the intrinsic high firing rate of STN neurons by prolonging the interspike interval.
    • bursts of IPSP can lead to rebound excitation, and hence a paradoxical increase in activity inn the STN. PMID-11877509[]
      • large IPSPs reset STN neurons oscillatory cycle & lead to synchronization
      • small IPSPs lead to phase-dependent delays and probably lead to desynchronization.
      • neuromodulators, like ACh, serotonin, and dopamine, can influence the polarization of STN neurons, and hence will have a profound effect on activity.
      • STN activity is more dependent one the pattern of afferent activity (of course!) than the gross magnitude of incoming spikes.
  • figure 2 - the network configuration between STN and GPe can markedly affect resulting activity. When there are possible reciprocal connections, the network produces tremor; when the network is more organized so that STN cannot recurrently activate GPe, multiple rhythms occur.
    • recall that both structures have extensive & sparsely connected dendritic fields, and are highly topographically organized.
  • figure 3 - [2,3]- oscillatory activity in the STN is a consequence of dopamine depletion and is also a feature of normal activity.
    • this is dependent on the presence of cortex. lack of cortex = regular firing.
    • GPe firing is tonic and constant in normal animals, and becomes oscillatory in 6-OHDA treated animals.
  • administration of dopamine agonists in PD patients causes higher frequency rhythms (30-70hz); without treatment, oscillations are in the 8-12 and lower range.

my notes:

  • IPSPs seem to have a very interesting and complex effect on the firing properties of tonically-active STN nenurons. who knows how this is being used, and in what representation the associated information is being processed?
  • still need to understand what dopamine is doing, and why absence leads to oscillations!
    • dopamine must modulate basal ganglia insensitivity to cortex.

____References____

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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: Isoda-2008.07 tags: STN switching motor control scaccades monkeys electrophysiology DBS date: 02-22-2012 15:02 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-18614691[0] Role for subthalamic nucleus neurons in switching from automatic to controlled eye movement.

  • we found neurons that showed a phasic change in activity specifically before volitionally controlled saccades which were switched from automatic saccades
  • A majority of switch-related neurons were considered to inhibit no-longer-valid automatic processes, and the inhibition started early enough to enable the animal to switch.
  • We suggest that the STN mediates the control signal originated from the medial frontal cortex and implements the behavioral switching function using its connections with other basal ganglia nuclei and the superior colliculus.
  • neurons have a really high rate of spiking - what we observe in DBS surgeries.
  • nice. There may be alternate explanations, but this one is plausible.

____References____

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ref: Fellows-2006.04 tags: parkinsons subthalamic nucleus thalamus DBS STN force velocity overshoot grasp date: 02-22-2012 14:51 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

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

  • Deep Brain stimulation improves 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.

____References____

[0] Fellows SJ, Kronenbürger M, Allert N, Coenen VA, Fromm C, Noth J, Weiss PH, The effect of subthalamic nucleus deep brain stimulation on precision grip abnormalities in Parkinson's disease.Parkinsonism Relat Disord 12:3, 149-54 (2006 Apr)
[1] Weiss PH, Dafotakis M, Metten L, Noth J, Distal and proximal prehension is differentially affected by Parkinson's disease. The effect of conscious and subconscious load cues.J Neurol 256:3, 450-6 (2009 Mar)

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ref: Parent-1995.01 tags: basal ganglia anatomy review STN DBS date: 02-22-2012 14:40 gmt revision:15 [14] [13] [12] [11] [10] [9] [head]

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) STN
    • pars compacta of the substantia nigra (dopamine) SNpc
    • centromedian / parafasicular thalamic complex (glutamate) CM/Pf
    • dorsal raphe nucleus (serotonin)
    • pedunculopontine tegmental nucleus. (glutamate and acetylcholine) PPN
  • 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. Symptoms gradually resolve.
  • 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, so afferents from STN is not too large.
  • 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 the STN 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).
  • The 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 -> greater rigidity.
    • 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. Important -- it is also an output structure of the BG.
    • 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 to the STN.
    • 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 (above).
  • In animals at rest, striatal neurons are quiet, whereas SNr and GPi are tonically active.

____References____

[0] Parent A, Hazrati LN, Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry.Brain Res Brain Res Rev 20:1, 128-54 (1995 Jan)

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ref: -3000 tags: DBS STN oscillations beta gamma research date: 02-21-2012 16:51 gmt revision:22 [21] [20] [19] [18] [17] [16] [head]

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. ( My personal impression, post-hoc, is that this is an epiphenomena of something else; evidence is contradictory.)

  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}. This is consistent with GPi function controlling the vigor or scaling of muscle responses
  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}, and DCS is likely to do the same PMID-21039949. 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}, as well as expedited decision making in conflict situations {1077} 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}

footnote: how much is our search for oscillations informed by our available analytical techniques?

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. Also, stroke in the STN in normal individuals causes hemiballismus, which resolves gradually; this is not consistent with oscillations, but rather connectivity and activity.)

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 of the spiking rate, 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 β\beta power relative to γ\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.

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ref: Gale-2009.03 tags: STN DBS monkey comparison electrophysiology date: 02-21-2012 16:34 gmt revision:2 [1] [0] [head]

PMID-19167367[0] Subthalamic nucleus discharge patterns during movement in the normal monkey and Parkinsonian patient.

  • Compared STN activity in normal monkeys and parkinsonian humans performing the same joystick target acquisition task.
  • PD neurons were much burstier, and had lower variance in responses.
  • Simultaneously recorded neurons in the human demonstrated consistent oscillatory synchronization at restricted frequency bands, whereas synchronized oscillatory neurons in the monkey were not restricted to distinct frequencies (this is possibly not meaningful).
  • the net effect of PD may be a reduction in the physiological degrees of freedom of BG neurons with diminished information carrying capacity.
  • PETHs look bad compared to our results.

____References____

[0] Gale JT, Shields DC, Jain FA, Amirnovin R, Eskandar EN, Subthalamic nucleus discharge patterns during movement in the normal monkey and Parkinsonian patient.Brain Res 1260no Issue 15-23 (2009 Mar 13)

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ref: Turner-2010.12 tags: STN DBS basal ganglia motor learning vigor scaling review date: 02-16-2012 21:27 gmt revision:3 [2] [1] [0] [head]

PMID-20850966[0] Basal ganglia contributions to motor control: a vigorous tutor.

  • Using single-cell recording and inactivation protocols these studies provide consistent support for two hypotheses: the BG modulates movement performance ('vigor') according to motivational factors (i.e. context-specific cost/reward functions) and the BG contributes to motor learning.
  • Most BG associated clinical conditions involve some form of striatal dysfunction -- clincal sings occur when the prinicpal input nucleus of the BG network is affected.
    • Lesions of the output nuclei are typically subtle, consistent that pallidotomy is an effective treatment for PD and dystonia.
    • It is better to block BG output completely than pervert the normal operations of motor areas that receive BG output.
    • Pathological firing patters degrade the ability of thalamic neurons to transmit information reliably.
      • Bad BG activity may block cortico-thalamic-cortico communication.
      • Hence BG treatment does not reflect negative images of normal function.
  • Years of debate have been resolved by a confirmation that the direct and indirect pathways originate from biochamically distinct and morphologically disctinct types of projection neurons [97, 105].
    • Direct: D1; indirect = D2, GPe.
  • CMPf projects back to the striatuim.
  • Movement representation in the BG: ref [36]
  • Results of GPi inactivation:
    • RT are not lengthened. These results are not consistent with the idea that the BG contributes to the selection or initiation of movement.
    • GPi inactivation does not perturb on-line error correction process or the generation of discrete corrective submovements.
      • Rapid and-path corrections are preserved in PD.
      • Challenges the idea that the BG mediates on-line correction of motor error.
    • GPi inactivation does not affect the execution of overlearned or externally cued sequences of movements.
      • contradicts claims, based on neuroimaging and clinical evidence, that the BG is involved in the long term storage of overlearned motor sequences or the ability to string together successive motor acts.
    • GPi inactivation reduces movement velocity and acceleration.
      • Very consistent finding.
      • Mirrors the bradykinesia observed in PD.
      • Common side-effect of DBS of the GPi for dystonia.
    • GPI inactivation produces marked hypometria -- unsershooting of the desired movement extent.
      • Un accompanied by changes in movement linearity or directional accuracy.
  • Conclusion: impaired gain.
    • Movement: bradykinesia and hypometria
    • hand-writing: micrographia
    • speech: hyophonia [65].
    • There is a line of evidence suggesting that movement gain is controlled independently of movement direction.
    • Motor cost terms, which scale with velocity, may link and animals' previous experience with the cost/benefit contingencies of a task [75] to its current allocation of energy to meet the demands of a specific task.
      • This is consistent with monkey rapid fatiguing following BG lesion.
      • Schmidt et al [5] showed that patients with lilateral esions of the putamen or pallidum are able to control grip forces normally in response to explicit sensory instructions, but do not increase grip force spontaneously despite full understanding that higher forces will earn more money.
    • Sensory cuse and curgent conditions increase movement speed equally in healthy subjects and PD patients.
  • BG and learning:
    • role in dopamine-mediated learning is uncontroversial and supported by a vast literature [10,14,87].
    • Seems to be involved in reward-driven acquisition, but not long-term retention or recall of well-learned motor skills.
    • Single unit recording studies have demonstrated major changes in the BG of animals as they learn procedural tasks. [88-90]
      • Learning occurs earlier in the striatum than cortex [89,90].
    • One of the sequelae associated with pallidotomy is an impaired ability to learn new motor sequences [22 92] and arbitrary stimulus-response associations [93].
    • BG is the tutor, cortex is the storage.

____References____

[0] Turner RS, Desmurget M, Basal ganglia contributions to motor control: a vigorous tutor.Curr Opin Neurobiol 20:6, 704-16 (2010 Dec)

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ref: Sato-2000.08 tags: STN anatomy DBS date: 02-15-2012 03:43 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-10888744[0] Axonal branching pattern of neurons of the subthalamic nucleus in primates

  • 5 disctinct STN projection neurons:
    • projecting to the SNr, GPi and GPe (21.3%)
    • SNr and GPe (2.7%)
    • GPI and GPe (48%)
    • GPe only (10.7%)
    • Axons toward the striatum, but whose terminal arborization could not be visualized (17.3%)
  • collaterals are highly patterned and have specific subtypes
  • ramify on the two output structures, the GPi and SNr.
  • more camera-lucida beautiful computerized drawings/tracings.

____References____

[0] Sato F, Parent M, Levesque M, Parent A, Axonal branching pattern of neurons of the subthalamic nucleus in primates.J Comp Neurol 424:1, 142-52 (2000 Aug 14)

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ref: Teagarden-2007.03 tags: STN striatum operant conditioning behavior rats 2006 DBS date: 02-15-2012 03:36 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-17182916[0] Subthalamic and Striatal Neurons Concurrently Process Motor, Limbic, and Associative Information in Rats Performing an Operant Task

  • STN encodes behavioral events (reinforcement, nose poke, correct / incorrect trials). So does the striatum.
  • This study is rather nonspecific, but it makes sense that a conserved and well connected region is active during learning & general behavior.
    • That is, while the subthalamic nucleus is considered an output relay of the basal ganglia, more likely it operates in parallel to facilitate forms of learning; as such, responses are shown to rewards, cues, etc.

____References____

[0] Teagarden MA, Rebec GV, Subthalamic and striatal neurons concurrently process motor, limbic, and associative information in rats performing an operant task.J Neurophysiol 97:3, 2042-58 (2007 Mar)

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ref: Georgopoulos-1983.08 tags: STN monkeys primate Georgopoulos globus pallidus date: 02-10-2012 18:57 gmt revision:2 [1] [0] [head]

PMID-6875658[0] Relations between parameters of step-tracking movements and single cell discharge in the globus pallidus and subthalamic nucleus of the behaving monkey.

  • Step tracking task in monkeys; wrist flexion and extension.
    • first one in monkeys, apparently.
    • 87 neurons in GP, 36 in GPi, 29 in STN.
  • Linear tuning to direction and distance, same as in motor cortex by Georgopoulos.
    • More likely to see frequency increase.
  • Earlier firing rate change in STN than GPe than GPi.
  • Two patterns of firing in the globus pallidus external:
    • more frequent: high discharge rate interrupted with pauses of varying duration
    • less frequent: low average discharge rate with very high frequency bursts.
  • GPi: high frequency with frequent bursts.
  • GPi/e generally high firing rate - 80-100 Hz, with frequent bursts.
    • But not as deep movement tuning as M1.
  • Only primates have projections from the motor cortex to the STN.
    • This seems like an evolutionarily recent development -- apparently the cortex needs the extra level of control?

See also citing articles: http://scholar.google.com/scholar?cites=16339220378239936453&as_sdt=5,34&sciodt=0,34&hl=en

____References____

[0] Georgopoulos AP, DeLong MR, Crutcher MD, Relations between parameters of step-tracking movements and single cell discharge in the globus pallidus and subthalamic nucleus of the behaving monkey.J Neurosci 3:8, 1586-98 (1983 Aug)

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ref: Zaghloul-2009.03 tags: DBS STN reinforcement learning humans unexpected reward Baltuch date: 01-26-2012 18:19 gmt revision:1 [0] [head]

PMID-19286561[0] Human Substantia Nigra Neurons Encode Unexpected Financial Rewards

  • direct, concise.
  • 15 neurons in 11 patients -- we have far more!

____References____

[0] Zaghloul KA, Blanco JA, Weidemann CT, McGill K, Jaggi JL, Baltuch GH, Kahana MJ, Human substantia nigra neurons encode unexpected financial rewards.Science 323:5920, 1496-9 (2009 Mar 13)

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ref: Nishioka-2008.12 tags: STN hemiballismus lesion stroke MRI neurosurgery date: 01-26-2012 17:31 gmt revision:3 [2] [1] [0] [head]

PMID-18842415[0] Transient hemiballism caused by a small lesion of the subthalamic nucleus.

  • Hemiballism is most commonly caused by ischemic stroke and most cases have a favorable prognosis.
  • Lesions directly involving the subthalamic nucleus (STN) are the cause of a minority of cases but are usually associated with poor prognosis.
  • We report two patients with a small STN lesion who presented with transient hemiballism.
  • This may be a useful ref in the future.
  • This reports the same result: PMID-17702635

____References____

[0] Nishioka H, Taguchi T, Nanri K, Ikeda Y, Transient hemiballism caused by a small lesion of the subthalamic nucleus.J Clin Neurosci 15:12, 1416-8 (2008 Dec)

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ref: Wiener-2008.08 tags: STN operant conditioning timing rats lesion DBS impulsivity date: 01-26-2012 17:29 gmt revision:3 [2] [1] [0] [head]

PMID-18562098[0] Accurate timing but increased impulsivity following excitotoxic lesions of the subthalamic nucleus.

  • Synopsis: Animals whose STNs were lesioned were able to maintain temporal control and response on a peak interval timing task, but they were unable to inhibit operant responses late into the trial. This suggests that STN may be used in impulse control / behavioral inhibition.

____References____

[0] Wiener M, Magaro CM, Matell MS, Accurate timing but increased impulsivity following excitotoxic lesions of the subthalamic nucleus.Neurosci Lett 440:2, 176-80 (2008 Aug 1)

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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: Wilson-2006.12 tags: parkinsons burst firing MPTP mice STN DBS date: 01-26-2012 17:25 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-16973296[0] Subthalamic nucleus neurones in slices from MPTP-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity

  • loss of dopamine in parkinson-model rats (not MPTP!) induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurons
  • MPTP mice, neurons fire slower, and more irregularly
  • only dopamine varied (increased) firing rate.
  • the STN & GP are insufficient to generate the abberant firing patterns in the STN, by itself - the disease is more than just dopamine depletion.

____References____

[0] Wilson CL, Cash D, Galley K, Chapman H, Lacey MG, Stanford IM, Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity.Neuroscience 143:2, 565-72 (2006 Dec 1)

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ref: Lee-2005.07 tags: STN subthalamic nucleus hemiballismus DBS date: 01-26-2012 17:24 gmt revision:3 [2] [1] [0] [head]

PMID-16032642[0] Common causes of hemiballism.

  • stroke of the STN results in hemiballismus - wild movements of the limbs. recall the input to the STN is inhibitory from GPe, and the output is exitatory to the GPi. chemical treatment is via dopamine blockade (1976!)
  • hemiballism is rare, but usually associated with lesion to the contralateral STN.
    • however, half the cases of hemiballismus are associated with damage to the afferent or efferent pathways to the STN.
    • diabetes type 2 also commonly causes hemiballismus (hyperglycemia in asian women!)
  • hemiballismus is absent in sleep - the thalamocortical relay must be turned off.
  • hemiballismus is generally associated with high metabolic activity in the basal ganglia.
  • does this mean that stimulation to the STN in healthy monkeys will disinhibit large, possibly conflicting movements?
  • my thought: the subthalamic nucleus must be involved in the selection and regulation of appropriate movements.

____References____

[0] Lee HS, Kim SW, Yoo IS, Chung SP, Common causes of hemiballism.Am J Emerg Med 23:4, 576-8 (2005 Jul)

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ref: Foffani-2004.07 tags: STN motor preparation human 2003 basal_ganglia DBS SMA date: 01-26-2012 17:23 gmt revision:3 [2] [1] [0] [head]

PMID-15249649 Involvement of the human subthalamic nucleus in movement preparation

  • STN receives large afferent from SMA, so it should be involved in movement planning.
  • the STN and nearby structures are active before self-paced movements in humans.
  • normal patients show a negative EEG movement-related potential (MRP) starting 1-2 seconds before the onset of self-paced movements.
  • STN also shows premovement negative MRP.
    • REquire very sensitive methods to record this MRP -- it's on the order of 1 uv.
  • the amplitude of the scalp MRP is reduced in parkinson's patients.
    • impairment of movement preparation in PD may be related to deficits in the SMA and M1, e.g. underactivity.
    • the MRP is normalized with the administration of levodopa.
  • MPTP monkeys have increased activity in the STN
  • examined the role of the STN in movement preparation and inhibition via MRP recorded from DBS electrodes in the STN + simultaneously recorded scalp electrodes.
  • their procedure has the leads externalized during the first week after surgery.

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ref: Florio-2001.11 tags: STN PPN lesions preparatory rats DBS date: 01-26-2012 17:22 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-11704255[0] Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat.

  • the title says it all ;)
  • they describe hemiballismus as "stereotyped repetitive involuntary movements of the cotralateral limbs" (might have to see this to understand it)
  • what the rat had to do:
    1. press lever 1 upon trigger 1 stimuli
    2. wait 3-4 seconds for the trigger 2 stimuli
    3. then press lever 2, upon which a pellet of food was given to the rat.
  • lesions of the STN in the rat do not induce hyperkinetic movements in overt behaviors, but cause anticipatory motor responses in delayed-reaction tasks, like a nose-poke.
    • see figure 7 for the bar-graph of this.
    • rats tended to release the lever before the reward or CS for reward was triggered
    • still - this might be a cognitive problem, not a lack of anticipation.
  • the PPN has remarkable reciprocating connections with the STN, and other basal ganglia nuclei
    • PPN lesion increases reaction time during conditioned movements, making the animals bradykinetic or akinetic
      • "the animals bearing the combined lesion were severely impaired in conditioned responding to salient stimuli involved in the paradigm and showed side-specific lengthening of reaction and movement times without global motor impairments."
      • has anybody looked at activity in the PPN of parkinsonian monkeys? hum.
    • compare to [1] - PPN lesions can restore normal activity in SNr & STN. but, if you don't have the STN to restore, then PPN doesn't matter.

____References____

[0] Florio T, Capozzo A, Cellini R, Pizzuti G, Staderini EM, Scarnati E, Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat.Behav Brain Res 126:1-2, 93-103 (2001 Nov 29)
[1] Breit S, Lessmann L, Unterbrink D, Popa RC, Gasser T, Schulz JB, Lesion of the pedunculopontine nucleus reverses hyperactivity of the subthalamic nucleus and substantia nigra pars reticulata in a 6-hydroxydopamine rat model.Eur J Neurosci 24:8, 2275-82 (2006 Oct)

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ref: Sato-2000.01 tags: globus_pallidus anatomy STN GPi GPe SNr substantia nigra tracing DBS date: 01-26-2012 17:20 gmt revision:6 [5] [4] [3] [2] [1] [0] [head]

PMID-10660885[0] Single-axon tracing study of neurons of the external segment of the globus pallidus in primate.

  • wow, check out the computerized tracing! the neurons tend to project to multiple areas, usually. I didn't realize this. I imagine that it is relatively common in the brain.
  • complicated, tree-like axon collateral projection from GPe to GPi.
    • They look like the from through some random-walk process; paths are not at all efficient.
    • I assume these axons are mylenated? unmylenated?
  • dendritic fields in the STN seem very dense.
  • study done in cyno. rhesus

____References____

[0] 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)

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ref: Beurrier-1997.05 tags: STN stimulation hemiballismus 2007 DBS date: 01-26-2012 17:20 gmt revision:4 [3] [2] [1] [0] [head]

PMID-9189903[] Subthalamic stimulation elicits hemiballismus in normal monkey.

  • the effects of stimulation on normal waking primates has never been evaluated (doh!)
  • In the normal monkey, HFS appears reversibly to incapacitate the STN and allow the emergence of involuntary proximal displacements, due to disinhibition of the thalamo-cortical pathway
  • in MPTP-treated monkey HFS buffers STN activity and alleviates akinesia and rigitity by reducing inputs to the internal segment of the globus pallidus. (STN output is excitatory) (or so the theory at the time goes)
  • perhaps i will need to buy this article ;(

____References____

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ref: Carpenter-1990.01 tags: STN afferents anatomy DBS date: 01-26-2012 17:19 gmt revision:4 [3] [2] [1] [0] [head]

PMID-1707079 Subthalamic nucleus of the monkey: connections and immunocytochemical features of afferents.

  • retrograde and anterograde transport of horseradish peroxidase injected into parts of the STN.
  • did not label any afferents from the frontal cortex or CM/Pf, possibly because they are collaterals of projections to other areas.
  • is the globus pallidus arranged in rostral-caudal dorso-ventral parallel layers? the afferents seem to be so.

____References____

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ref: Bergman-1994.08 tags: subthalamic nucleus STN basal ganglia globus pallidus electrophysiology 1994 MPTP DBS date: 01-26-2012 17:19 gmt revision:3 [2] [1] [0] [head]

PMID-7983515[0] The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism

  • idea: record from STN and GPi before and after MPTP treatment in green monkeys.
  • recorded 4-8hz periodic activity (via autocorrelograms) in significantly more neurons from the MPTP treated animals in both the STN and GPi.
  • mean firing rate was increased in STN,
  • tremor-correlated cells found in both.
  • burst activity higher in both, too.
  • modulations in firing rate due to the application of flexion and extension torque pulses were higher in MPTP animals (duration and amplitude), in both areas.
  • spikes were longer in MPTP
  • no tyrosene hydroxylase activity in the PD mks.
  • PD tremor only frequently occurs in green mks following MPTP

____References____

[0] Bergman H, Wichmann T, Karmon B, DeLong MR, The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism.J Neurophysiol 72:2, 507-20 (1994 Aug)

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ref: Monakow-1978.11 tags: motor_cortex STN subthalamic nucleus anatomy DBS date: 01-26-2012 17:17 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-83239[0] Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey.

  • this paper is old and important!
  • The ipsilateral subthalamic nucleus receives a moderately strong and somatotopic organized projection from Woolsey's precentral motor cortex (PMd, M1 i guess)
    • No projections from the postcentral gyrus! (S1) (Is this still thought to be true?)
  • The remaining nucleus is occupied by less intensive projections from premotor and prefrontal areas
  • STN is a convergence site for pallidal and cortical motor/frontal projections.
  • autoradiography slices are damn hard for me to read.

____References____

[0] Monakow KH, Akert K, Künzle H, Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey.Exp Brain Res 33:3-4, 395-403 (1978 Nov 15)

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ref: Klawans-1976.12 tags: STN DBS heminallisms date: 01-26-2012 17:17 gmt revision:3 [2] [1] [0] [head]

PMID-980081[0] Treatment and prognosis of hemiballismus.

  • Acute hemiballismus due to a cerebrovascular lesion may have a grave prognosis. In the past nine years, we have treated 11 patients who had an acute onset of hemiballismus believed to be the result of an acute vascular lesion with neuroleptic drugs (most frequently haloperidol). None of the 11 died, and the movement disorders were greatly reduced or eliminated. In eight patients the drugs were withdrawn within six months, without recurrence of the movement disorders. Spinal-fluid homovanillic acid levels were increased in three patients, suggesting that altered dopaminergic feedback mechanisms may be involved in the pathophysiology of hemiballismus. Our observations suggest that the prognosis of hemiballismus is not necessarily as grave as has been believed, and that neuroleptic therapy may alter the outcome of this disorder.

____References____

[0] Klawans HL, Moses H 3rd, Nausieda PA, Bergen D, Weiner WJ, Treatment and prognosis of hemiballismus.N Engl J Med 295:24, 1348-50 (1976 Dec 9)

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ref: neuro notes-0 tags: STN globus_pallidus striatum diagram basal_ganglia date: 01-26-2012 17:16 gmt revision:1 [0] [head]

http://www.gpnotebook.co.uk/cache/-1248198589.htm (bitrotted)

  • note that the loop around both preserves sign, more or less, provided you take into account the D2 receptor along the 'indirect' pathway
  • this has some glaring flaws: the globus pallius external projects to the globus pallidus internal, cortex projects to STN, thalamus projects to striatum, etc.

http://www.portfolio.mvm.ed.ac.uk/studentwebs/session1/group71/john.htm

  • has a good diagram of the neurotransmitters involved in the motor selection pathway. need to understand the kinetics of the dopamine receptor family

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ref: neuro synth-0 tags: STN DBS date: 01-26-2012 17:16 gmt revision:18 [17] [16] [15] [14] [13] [12] [head]

  • STN is small, 25k neurons in the rat, but much larger in the human - 500k [0]
  • It has a high degree of somatotopy both afferent and efferent, as well as at least two functional divisions dorsal/caudal.
    • Neurons in the dorsal STN respond to passive and active movements; rostral STNn receives afferents from the associative and limbic areas. [1]
    • Somatotopy in Parkinson's disease is partially destroyed - many of the cells fire synchronously - and the receptive fields are less specific, with increased bilaterality [2]
  • There are organized projections from M1/premotor [3] + FEF [2] which is a relatively complete map [4] but NOTHING from S1.
  • STN also receives proprioceptive afferents [1].
  • Inhibitory (GABA) input comes from GPe [2]
    • Most of these GPe axons co-arborize on GPi, STN, and SNc [5]
    • These inhibitory fibers synapse on the soma/proximal dendrites; cortical/thalamic Glu synapse on distal dendrites [2]
  • PPN's major efferent is to the STN [6,7].
  • Similarly, there is an organized efferent projection to Gpe/GPi, with a lot of branched axons [2]
    • In fact, most of the efferents from the STN are branched and project to more than one structure in the basal ganglia [8]
    • These efferent fibers form sheets parallel to the dorsal-ventral rostral/caudal plane of the GPe in a structure reminiscent of the cerebellum [7]
    • A few of the contralaterals project to some nuclei of the thalamus [6,7].
  • Lesions of STN in humans cause violent involuntary gesticulating movements [9] but lack-of-waiting or anticipatory movements in rats [0].
    • These lesions can be treated with dopamine antagonists [9]
    • Concomitant lesions to the adjascent PPN projections do not cause heminallismus [10]
  • DA-toxic (6-hydroxydopamine) lesions increase the connection strength (synchronization) between the GP, STN, and cortex. [8]
  • High-current stimulation in the STN of normal monkeys results in contralateral hemibalismus [11].
  • Surgical lesion of the STN in MPTP monkeys treats their tremor, bradykinesia, and akinesia (but not balance and gait problems) [12]
  • DBS of the STN can be used to treat Parkinson's disease [13]
    • Some people find that HFS increases entrained firing rate in STN [14]
    • Others find that it decreases metabolic activity [15,16]
      • In accord with this, another group finds that STN DBS restores cortical glucose metabloism [17]
  • Normal oscillations in the STN may actually be non-pathological and involved in sequence generation [18,19]
Hypothesis: The STN is involved in gating movements through the basal ganglia based on executive and motor context. Like everything else in the brain, this gating is plastic, and partially modulated by dopamergic input from the substantia nigra & other brainstem structures.
  • A high-field study found the STN to be exclusively activated upon early motor learning of a sequencing task. [20]
  • In normal patients, the STN is active before self-paced movements. My data supports this. The associated negative movement potential is attenuated in Parkinsonian patients [21]

____References____

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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: Israel-2008.01 tags: review DBS caudate putamen STN date: 01-25-2012 00:56 gmt revision:3 [2] [1] [0] [head]

PMID-17949812[0] Pathophysiology of the basal ganglia and movement disorders: From animal models to human clinical applications

  • MPTP monkeys:
    • resting tremor is not easily repeated in MPTP treated macaque monkeys, though it does occur in green (vervet) monkeys.
    • low doses of MPTP seem to first cause mild frontal cognitive deficits in monkeys without motor signs. (strange...); this acute MPTP treatment produced DA depletion that is equal or more severe in the caudate nucleus than in the putamen.
    • in comparison, lower, longer doses of the toxin, which is thought to better emulate the progression of PD, causes a greater decrease in the putamen.
    • frontal eye effects and cognitive deficits are observed before motor signs, which is in line with early cog. deficits found in human MPTP and PD.
    • MPTP treatment results in an increase in the number of neurons that fire in bursts.
    • physiological studies of the pallidum in MPTP-treated monkeys demonstrate that their pair-wise crosscorrelograms become peaked and oscillatory, suggesting that DA depletion induces an abnormal coupling of basal ganglia loops (could test this in my data).
  • tonic firing rate of STN neurons is (they claim) about 20Hz; this increases to about 25Hz after MPTP treatment. The firing rate of neurons in the GPi increase with MPTP, GPE decrease.
  • their description of the ''box and arrow' model of pathophysiology of PD is quite easy to understand, as are their critiques - that it fails to explain the dynamic manifestations of the disease, namely resting tremor and rigidity.
  • there are hyper-direct projections from the motor cortex to the STN
  • the box and arrow model does not accurately predict the result of removal of GPi: according to the direct/indirect pathway model, removal of the GPI should alleviate akinesia, bradykinesia, and rigidity. However, pallidotomy has been shown to be primarily effective in alleviating l-dopa induced dyskinesias (involuntary movements, like tic or chorea) -- exactly the opposite of what the model would predict.
  • a better (or at least more recent) model is that the striatum / pallidus / STN are involved in selection of actions & inhibition of competing actions; this is achieved via focused striatial inhibition.
    • problem: changes in pallidal activity lag behind movement initiation (!)
  • even better hypothesis: that the basal ganglia perform reinforcement driven dimensionality reduction. This has been discussed by Graybeil and others, but it's implication to PD is only lightly touched here (they mention that it is more in accord with neurons in the striatum involved in the same actions to no show an increase in correlation as would be expected from an action-selection hypothesis.
  • remind us that exposed-metal microelectrodes have a tendency to stimulate fibers, not cell bodies.
    • nevertheless, the effect of DBS in PD is remarkably similar to lesion; the exact mechanism is still under intense study. (hypotheses: depolarization block, stimulation of bypassing inhibitory pathways, induction of GABA release from GPe projection neurons. )
    • their hypothesis: DBS enforces a constant spatio-temporal firing pattern of the discharge structures of the basal ganglia. The null output of the globus pallidus is ignored by the rich thalamic & cortical circuits, which can 'take over'.
  • ( in the conclusion: quote: "These findings may call for development of future therapies that will target this abnormal synchronization (Tass, 1999 P.A. Tass, Phase Resetting in Medicine and Biology, Springer, Berlin (1999).Tass, 1999)." exactly!!

____References____

[0] Israel Z, Bergman H, Pathophysiology of the basal ganglia and movement disorders: from animal models to human clinical applications.Neurosci Biobehav Rev 32:3, 367-77 (2008)

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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: Benabid-2005.12 tags: Benabid famous DBS STN review date: 01-25-2012 00:22 gmt revision:2 [1] [0] [head]

PMID-16280671[0] Deep-brain stimulation in Parkinson's disease: long-term efficacy and safety - What happened this year?

  • 260 reports on DBS in 2004!
  • (from the abstract) There is an urgent need for the organization of research and reports, and no need to report small series replicating well-established conclusions. oopsie.
  • Clinical reports should concentrate on unobserved effects in relation to causative parameters, based on the precise location of electrodes,
  • and on clinical reports comparable between teams and on methods to optimize and facilitate the tuning of parameters and postoperative evaluations in order to make this treatment easier to provide for the neurologist

____References____

[0] Benabid AL, Chabardès S, Seigneuret E, Deep-brain stimulation in Parkinson's disease: long-term efficacy and safety - What happened this year?Curr Opin Neurol 18:6, 623-30 (2005 Dec)

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ref: Lehericy-2005.08 tags: fMRI motor_learning basal_ganglia STN subthalamic date: 01-25-2012 00:20 gmt revision:2 [1] [0] [head]

PMID-16107540[0] Distinct basal ganglia territories are engaged in early and advanced motor sequence learning

  • generally a broad, well-referenced study.
  • they used a really high-field magnet (3T) during tapping-learning task over the course of a month.
  • STN was activated early in motor learning, but not afterward, specifically the sequence learning
  • during the course of learning (an as the task became progressively more automatic) associative striatal activation shifted to motor activity.
    • STN could act by inhibiting competing motor outputs, thus building a temporally ordered sequence of movements.
  • SN was active throughout the course of the experiment.
  • during the 'fast learning' stage, there was transient activation of the ACC
  • also during the beginning portion of motor learning lobules V and VI of the cerebellum were activated.
  • rostral premotor and prefrontal cortical areas are connected to the associative territory of the striatum, which projects back to the frontal cortex the VA/VL nuclei of the thalamus.

____References____

[0] Lehéricy S, Benali H, Van de Moortele PF, Pélégrini-Issac M, Waechter T, Ugurbil K, Doyon J, Distinct basal ganglia territories are engaged in early and advanced motor sequence learning.Proc Natl Acad Sci U S A 102:35, 12566-71 (2005 Aug 30)

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ref: Elble-1996.03 tags: tremor STN VIM thalamus basal_ganglia Elble Parkinson's ET dyskinesia thalamus VIM DBS date: 01-24-2012 21:19 gmt revision:7 [6] [5] [4] [3] [2] [1] [head]

PMID-8849968[] Central Mechanisms of Tremor -- available through Duke's Ovid system. also in email.

  • focuses at first on the nonlinear aspect of all control: the systems are hard to understand because of the complexities of their interactions.
    • nonlinear systems are capable of complex interactions that are not predicted by the sum of their individual behaviors.
  • in general, there are two different types of tremor:
    • mechanical reflex oscillations (depend on sensorimotor loops), permit damped oscillations in response to pulsate perturbations.
      • is effected by the stifness and inertia of the segment involved.
    • central oscillations
      • frequencies independent of limb mechanics/segment length.
      • still subject to modulation by sensorimotor feedback.
      • if the tremor is at the same frequency as the mechanical resonance, the tremor will be worse!
  • physiologic tremor has both components of mechanical oscillations (3-5Hz) and central oscillations (8-12hz), which are usually attenuated by the low-pass property of the musculoskeletal system.
    • associated spindle and tendon organ discharge are not sufficient to produce 8 - 12 Hz oscillation - hence, this is most likely from a central source, eg. the cortex, inferior olive, and thalamus.
  • Essential tremor is also centrally generated, though it appears to be affected by somatosensory driving.
    • essential tremor frequency is strongly correlated with patient age (where the frequency decreases with increasing age).
    • the origin of ET is unknown: postmortem examinations reveal no deficits in M1/S1, thalamus, inferior olive, raphe nucleus, and reticular nuclei, globus pallidus, and spinal cord...
    • but, the inferior olive seems to be the most likely culprit:
      • tremor induced by harmaline increased inhibition-rebound properties of neurons, and this induces intention-related tremor in monkeys
      • harmaline induced olivary oscillation is similar to ET in terms of frequency, EMG, and drug-response.
      • olivary hypothesis is supported by PET scans, which show increased glucose consumption there in ET patients.
      • the ventrolateral (VL) thalamus and Ventralis intermedius (VIM) receives input from the contralateral cerebellar nuclei.
        • this is why VIM is such a good target for treatment of ET.
  • parkinsons tremor:
    • VOP is a better target for treating bradykinesia and other symptoms of PD, while VIM is the best for treating tremor
    • neurons in the globus pallidus and STN become entrained to tremor. STN lesion / HFS is effective in treating dyskinesia and other PD symptoms.
    • in MPTP monkeys, STN/ GPi neurons are also entrained to the tremor frequency.
  • other tremor:
    • neuropathic/tumorogenic tremor usually takes weeks to appear, suggesting that CNS reorganization is a cause of tremor, not intrinsic sensorimotor deafferentation
      • local lesions in the striatum, thalamus, & globus pallidus often cause dystonias, not tremor.
  • Cerebellar tremor
    • seems to be caused by an inability to properly compensate/ brake with antagonist muscles during voluntary and postural movements. movement control becomes heavily dependent on sensory feedback, which is often too slow for adequate compensation.
  • neuroleptic drugs can often cause tremor (or tardive dyskinesia). Neurolepric - calming, tranquilizer, antipsychotic.
    • lithium can cause permanent tremor due to cerebellar gliosis!
  • VOP projects to the supplementary motor area (SMA) and dorsolateral prefrontal cortex (DLPFC) PMID-21629131 ; VIM projects to M1 & contralateral cerebellum, as mentioned above.

____References____

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ref: Dorval-2010.08 tags: DBS Dorval STN irregular regular basal ganglia model date: 01-24-2012 20:24 gmt revision:1 [0] [head]

PMID-20505125[0] Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity.

  • Hypothesis: disorder in the STN leads to parkinsonian symptoms (tremor, akinesia).
  • finger tapping test.
  • Irregular DBS was less effective than regular DBS at eliminating bradykinesia.
  • computational model: this is because there are more transmission errors at thalamic output neurons.
    • computational model possibly fluffy to keep conclusion from being too short?
  • cf. [1][2] -- which includes an irregular stimulation protocol (at longer timescales).

____References____

[0] Dorval AD, Kuncel AM, Birdno MJ, Turner DA, Grill WM, Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity.J Neurophysiol 104:2, 911-21 (2010 Aug)
[1] 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)
[2] 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: 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: Eusebio-2009.05 tags: DBS STN beta gamma oscillations synchrony tremor review date: 03-23-2009 18:32 gmt revision:1 [0] [head]

PMID-19233172[0] Synchronisation in the beta frequency-band - The bad boy of parkinsonism or an innocent bystander?

  • Excessive synchronisation of basal ganglia neuronal activity in the beta frequency band has been implicated in Parkinson's disease
  • However, the extent to which beta synchrony has a mechanistic (rather than epiphenomenal) role in parkinsonism remains unclear, and the suppression of this activity by deep brain stimulation is contentious.
PMID-16289053[1] Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease.
  • Beta rhythm for them = 11-30Hz. Observed in the LFP recorded from the DBS electrode itself.
  • This study shows for the first time that STN DBS attenuates the power in the prominent beta band recorded in the STN of patients with PD.

____References____

[0] Eusebio A, Brown P, Synchronisation in the beta frequency-band - The bad boy of parkinsonism or an innocent bystander?Exp Neurol no Volume no Issue no Pages (2009 Feb 20)
[1] Wingeier B, Tcheng T, Koop MM, Hill BC, Heit G, Bronte-Stewart HM, Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease.Exp Neurol 197:1, 244-51 (2006 Jan)

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ref: Pollak-1993.01 tags: DBS STN subthalamic nucleus original 1993 Benabid date: 03-12-2007 04:58 gmt revision:2 [1] [0] [head]

PMID-8235208[] Effects of the stimulation of the subthalamic nucleus in Parkinson disease

  • the original study! (in french:)
  • even back then, they used a quadripolar medtronic stimulating electrode w/ stimulation frequency of 130Hz.
  • how far have we come? not too far.

____References____