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[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] Bar-Gad I, Morris G, Bergman H, Information processing, dimensionality reduction and reinforcement learning in the basal ganglia.Prog Neurobiol 71:6, 439-73 (2003 Dec)

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ref: -0 tags: DBS dystonia globus pallidus witt date: 10-05-2013 23:42 gmt revision:2 [1] [0] [head]

PMID-23549056 Use of pallidal deep brain stimulation in postinfarct hemidystonia.

  • Witt J, Starr PA, Ostrem JL. 2013
  • Result: GPi DBS generates subjective improvements in movement after surgery;
  • However, one year after implantation, no effect could be measured.
  • See also: {1263}

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ref: -0 tags: DBS dystonia trial globus pallidus GPI witt date: 10-05-2013 23:41 gmt revision:1 [0] [head]

PMID-23787946 Predictive factors of outcome in primary cervical dystonia following pallidal deep brain stimulation.

  • Witt JL, Moro E, Ash RS, Hamani C, Starr PA, Lozano AM, Hodaie M, Poon YY, Markun LC, Ostrem JL. 2013
  • Some of the treatments do work, but the authors were unsuccessful in determining criteria to suggest proper candidates.

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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: -0 tags: Hutchison oscillations basal ganglia beta gamma globus pallidus date: 03-26-2012 16:21 gmt revision:2 [1] [0] [head]

PMID-15496658 Neuronal oscillations in the basal ganglia and movement disorders: evidence from whole animal and human recordings.

  • This is a review / mini-symposium (only 3 pages)
    • Cites other Hutchison papers: 1997, 1998.
  • Critique classical hypothesis in that GPi firing does not increase that much, 10-22% in animal models. IT explains akinesia and bradykinesia, but not rigidity or tremor. (This was 8 years ago, remember!)
    • Plus, most neurons have intrinsic pacemaker-like properties that sets the rate of firing in the absence of synaptic input. (Bevan et al 2002).
  • Oscillations:
    • Alpha band enhanced after MPTP treatment in green monkeys and in the STN of some PD patients with tremor at rest.
    • Higher frequency oscillations (beta, 15-25Hz) can be observed in some patients without resting tremor.
    • Much slower oscillations discovered by Judith Walters, 6 OHDA rat (0.3 - 2Hz).
    • Also ultralow, multisecond oscillations, which appear in dopamine stimulated rats. (Ruskin et al 1999a,,b, 2003).
      • Lesion of the STN was not found to change these ultralow oscillations, but did modify the connectivity between GP and SNr.
    • Courtemanche et al 2003 studied the possible normal physiological function for oscillations in basal ganglia networks.
      • Beta band decreased during saccadic eye movements.
      • LFP syncronization showed task-related decrease, but only in sites engaged in the task, as evicenced by saccade-related activity.
  • Boraud tested gradual small-dose administration of MPTP toxin:
    • Minimal changes in the average firing rate of GPi neurons
    • Oscillatory activity between 4-9 and 11-14 Hz, with differences between monkeys.
      • Oscillations increased with symptom presentation.
  • Goldberg et al 2004: analyzed coherence between EEG and BG LFP; surmise that in the PD condition the basal ganglia and cortex become more closely entrained by global brain dynamics, which are reflected in the widespread local field potentials.
  • Peter Brown: oscillations in the beta band are enhanced to such an extent in Parkinson's disease that voluntary movements are not generated because motor command for initiation cannot override the enhanced oscillatory state.
    • That is, movement initiation corresponds to beta-band desynchronization, and movement command cannot 'break through'.

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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: Iansek-1980.04 tags: globus pallidus GPe GPi electrophysiology 1980 date: 02-29-2012 18:17 gmt revision:2 [1] [0] [head]

PMID-7411442 The monkey globus pallidus: neuronal discharge properties in relation to movement.

  • motor units are generally inactive during inactivity. the relationship to movement of the discharges of such neurons was found to be very specific
    • This is in comparison to other results, which report a sustained firing, esp in GPi.
  • the discharges (as analyzed through histograms) of many neurones were related to only a particular direction of movement about one joint in the right limb.
  • some discharges were related to multijoint movements -> probably due to control of contraction of particular muscles.
    • nonetheless, this relationship was a loose one; there is not a tight coupling between pallidal activity and muscle contraction.
  • some responded to ipsilateral as well as contralateral movements.
    • PMID-7925805 Unilateral leasions in the GP results in bilateral increase in reaction time. hence, GP is involved in initiation. RT speed eventually recovered.
  • only the posterior globus pallidus - well posterior to the maximum expansion - contained movement related cells.
    • the a-p stereotaxic coordinates were less useful than the location of the maximum mediolateral width of the structure.
    • cells occurred in clusters, separated by regoins of non-movement related.
  • cells in the internal segment had no such organization.
  • many of the non-movement related neurons were tonically active.
  • this was before there was A/D recording, apparently!

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ref: -0 tags: distrupted oscillations Mallet 2008 6-OHDA globus pallidus date: 02-29-2012 01:15 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-19109506 Parkinsonian beta oscillations in the external globus pallidus and their relationship with subthalamic nucleus activity.

  • Rat 6-OHDA.
  • On rate model: Although synchronization of GP unit activity increased by almost 100-fold during beta oscillations, the mean firing rate of GP neurons decreased compared with controls.
  • Synchronized firing persisted across different brain states, suggesting hardwiring.
  • GP and STN are frequency aligned but phase skewed.
    • Lateral inhibition in GP seems essential / see model.
  • Suggest that GPe / STN could generate oscillations that propagate to the rest of the BG.
    • But then why is the cortex required?

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ref: -0 tags: oscillations DBS globus pallidus parkinsons date: 02-28-2012 17:24 gmt revision:1 [0] [head]

PMID-17880401 Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism.

  • In monkeys, progressive dopamine depetion process, recording changes during disease progression -- good!
  • No big change in firing rates, makes sense as this is likely controlled by other network or cellular homeostatic mechanisms.
  • Early in intoxication inhibitory responses to movement disappeared.
    • Yet synchrony did not appear at this time -- it is a sequelae?
    • Correlated activity appeared later, once the animals became severly akinetic.
  • Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely.
  • Probably it's movement related activity, not overall states. YES.

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ref: 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: -0 tags: globus pallidus delong response tuning date: 02-24-2012 21:41 gmt revision:1 [0] [head]

PMID-4997823 Activity of Pallidal Neurons During Movement

  • GPe activity notably different from GPi.
    • "So characteristic were the discharge patterns of units in each segment that early in the course of the experiment ti be came apparent when the electrode entered and left each segment.
  • Two types of cells in GPe:
    • High frequency with periods of quiet (85%)
    • Low frequency with bursts.
  • Only one type in GPi: continuous HF discharge, 10-100 Hz, mean 63 Hz.
  • Mostly contralateral, ~ 15% ipsilateral related discharge.
  • Leg and arm responding units intermixed.
  • Conclusion: pallidus not involved in reflexes.
  • Substantia innominata = region posterior the pallidus, contains the nucleus basalis.
  • I'd really like to get recordings of this quality!

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ref: 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: Bergman-1998.01 tags: basal ganglia globus pallidus electrophysiology parkinsons 2001 DBS date: 02-22-2012 18:52 gmt revision:5 [4] [3] [2] [1] [0] [head]

PMID-9464684[0] Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.

  • The firing of neurons in the globus pallidus of normal monkeys is almost always uncorrelated.
  • after MPTP treatment, the firing patterns of GP became correlated and oscillatory (see the figures!!)
  • dopamine must support normal segregation of the informational channels in the basal ganglia, and breakdown of this causes the pathology of PD.
  • has a decent diagram of the basal ganglia-thalamo-cortical circuits.
  • two different hypotheses of BG function: segregated and convergent. data support the former.

____References____

[0] Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, Vaadia E, Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.Trends Neurosci 21:1, 32-8 (1998 Jan)

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ref: Holgado-2010.09 tags: DBS oscillations beta globus pallidus simulation computational model date: 02-22-2012 18:36 gmt revision:4 [3] [2] [1] [0] [head]

PMID-20844130[0] Conditions for the Generation of Beta Oscillations in the Subthalamic Nucleus–Globus Pallidus Network

  • Modeled the globus pallidus external & STN; arrived at criteria in which the system shows beta-band oscillations.
    • STN is primarily glutamergic and projects to GPe (along with many other areas..)
      • STN gets lots of cortical afferent, too.
    • GPe is GABAergic and projects profusely back to STN.
    • This inhibition leads to more accurate choices.
      • (Frank, 2006 PMID:,
        • The present [neural network] model incorporates the STN and shows that by modulating when a response is executed, the STN reduces premature responding and therefore has substantial effects on which response is ultimately selected, particularly when there are multiple competing responses.
        • Increased cortical response conflict leads to dynamic adjustments in response thresholds via cortico-subthalamic-pallidal pathways.
        • the model accounts for the beneficial effects of STN lesions on these oscillations, but suggests that this benefit may come at the expense of impaired decision making.
        • Not totally convinced -- impulsivity is due to larger network effects. Delay in conflict situations is an emergent property, not localized to STN.
      • Frank 2007 {1077}.
  • Beta band: cite Boraud et al 2005.
  • Huh parameters drawn from Misha's work, among others + Kita 2004, 2005.
    • Striatum has a low spike rate but high modulation? Schultz and Romo 1988.
  • In their model there are a wide range of parameters (bidirectional weights) which lead to oscillation
  • In PD the siatum is hyperactive in the indirect path (Obeso et al 2000); their model duplicates this.

____References____

[0] Holgado AJ, Terry JR, Bogacz R, Conditions for the generation of beta oscillations in the subthalamic nucleus-globus pallidus network.J Neurosci 30:37, 12340-52 (2010 Sep 15)

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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: 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: 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: 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: 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: 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: BarGad-2003.12 tags: information dimensionality reduction reinforcement learning basal_ganglia RDDR SNR globus pallidus date: 01-16-2012 19:18 gmt revision:3 [2] [1] [0] [head]

PMID-15013228[] Information processing, dimensionality reduction, and reinforcement learning in the basal ganglia (2003)

  • long paper! looks like they used latex.
  • they focus on a 'new model' for the basal ganglia: reinforcement driven dimensionality reduction (RDDR)
  • in order to make sense of the system - according to them - any model must ingore huge ammounts of information about the studied areas.
  • ventral striatum = nucelus accumbens!
  • striatum is broken into two, rough, parts: ventral and dorsal
    • dorsal striatum: the caudate and putamen are a part of the
    • ventral striatum: the nucelus accumbens, medial and ventral portions of the caudate and putamen, and striatal cells of the olifactory tubercle (!) and anterior perforated substance.
  • ~90 of neurons in the striatum are medium spiny neurons
    • dendrites fill 0.5mm^3
    • cells have up and down states.
      • the states are controlled by intrinsic connections
      • project to GPe GPi & SNr (primarily), using GABA.
  • 1-2% of neurons in the striatum are tonically active neurons (TANs)
    • use acetylcholine (among others)
    • fewer spines
    • more sensitive to input
    • TANs encode information relevant to reinforcement or incentive behavior

____References____

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ref: Hallworth-2005.07 tags: globus pallidus subthalamic nucelus parkinsons date: 12-07-2011 04:04 gmt revision:1 [0] [head]

PMID-16000620[0] Globus Pallidus Neurons Dynamically Regulate the Activity Pattern of Subthalamic Nucleus Neurons through the Frequency-Dependent Activation of Postsynaptic GABAA and GABAB Receptors

  • in normal animals, STN neurons are spontaneously active, with a resting rate between 10hz and 30hz.
  • during movement, STN neurons display somatotopic, spatiotemporally related changes in activity.
  • in parkinsonian animals, precise sonatotopy is lost, and there is an emergence of correlated, rhythmic activity. STN activity phase-related to tremor has been found in PD patients.
    • this study wants to try to explain why the rhythmic burst activity occurs.
  • one idea: synchronous barages of inhibitory activity results in hyperpolarization-induced high-frequency firing.
  • alternate: GABA_a receptors an mediate a tonic current that profoundly influences postsynaptic excitability. problem: GABA_a receptor antagonists have no effect on STN activity.
  • tonic GABA current was not observed, while there was plenty of GABA mediated IPSPs.
  • strong tetanic simulation of the internal capsule results in STN hyperpolarization followed by bursts of APs. (well then, why do we target the STN in DBS if the oscillations are not it's fault?)

____References____

[0] Hallworth NE, Bevan MD, Globus pallidus neurons dynamically regulate the activity pattern of subthalamic nucleus neurons through the frequency-dependent activation of postsynaptic GABAA and GABAB receptors.J Neurosci 25:27, 6304-15 (2005 Jul 6)

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ref: Kemp-1971.09 tags: globus pallidus striatum 1971 neuroanatomy date: 12-07-2011 04:03 gmt revision:1 [0] [head]

PMID-4399123[0] The connexions of the striatum and globus pallidus: synthesis and speculation. !! great figures, great synthesis !!

  • a striking feature of the striatum (caudate and putamen, functionally the same is the dense axonal plexus - this receives a major contribution from the contralateral branches the short axon terminals (interneurons) as well as afferent projections. perhaps the most important characteristic of the axonal plexus is that all the component fibers cross dendrites rather than lie parallel to them -- just like the cerebellum''.
  • the cerebellum also has excitatory input and inhibitory output. similar structure to do a similar thing? ++ plenty of interneurons ++plenty of dendritic spines.
  • all of the cerebral cortex projects to the cerebellum, even the visual cortex has projections to the pontine nuclei. however, there is an exceptionallly small projection from the visual cortex to both the cerebellum and striatum.

____References____

[0] Kemp JM, Powell TP, The connexions of the striatum and globus pallidus: synthesis and speculation.Philos Trans R Soc Lond B Biol Sci 262:845, 441-57 (1971 Sep 30)

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ref: Kimura-1996.12 tags: putamen globus pallidus learning basal ganglia electrophysiology projection date: 10-03-2008 17:05 gmt revision:1 [0] [head]

PMID-8985875 Neural information transferred from the putamen to the globus pallidus during learned movement in the monkey.

  • study of the physiology of the projection from the striatum to the external and internal segments of the globus pallidus.
  • Identified neurons which project from the striatum to pallidus via antridromic activation after stim to the GPe / GPi.
  • there were two classes of striatal neurons:
    • tonically active neurons (TANs, rate: 4-8hz)
      • TANs were never activated by antidromic stimulation. therefore, they probably do not project to the pallidus.
    • phasically active neurons (very low basal rate, high frequency discharge in relation to behavioral tasks
      • All PANs found projected to the globus pallidus.
      • PANs were responsive to movement or movement preparation. (or not responsive to the particular behaviors investigated)
        • the PANns that showed activity before movement initiation more frequently projected to GPi and not GPE (or both - need to look at the anatomy more).
      • PANs also show bursts of activity time-locked to the initiation of movement (e.g. time locked to a particular part of the movement).
      • no neurons with sensory response!
  • when they microstimulated in the putamen, a few pallidal neurons showed exitatory response; most showed inhibitory/supressive response.

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ref: Grabli-2004.09 tags: basal_ganglia gobus_pallidus pathology GPe date: 03-11-2007 04:22 gmt revision:0 [head]

PMID-15292053 Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study.

  • there is a functional map within the basal ganglia according to its cortical projections.
  • reversible and focal dysfunction induced by microinjections if bicuculline in the sensorimotor territory of the external globus pallidus can generate abnormal movements. They wanted to test this in the other parts.
  • We found that bicuculline microinjections induced stereotypy when performed in the limbic part of the GPe, and attention deficit and/or hyperactivity when performed in the associative part
  • the behavioural effects shared similar features with symptoms observed in Tourette's syndrome, attention deficit/hyperactivity and compulsive disorders

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ref: Kita-1999.05 tags: globus pallidus GPe caudate putamen anatomy projection date: 03-11-2007 04:09 gmt revision:0 [head]

PMID-10380964 Monkey globus pallidus external segment neurons projecting to the neostriatum.

  • horseradish-peroxidase study in rhesus monkeys.
  • 30% of GPe neurons project to the neostriatum (caudate and putamen)

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ref: Di-1994.06 tags: dopamine NMDA striatum globus_pallidus ion_channels neurotransmitters date: 0-0-2007 0:0 revision:0 [head]

PMID-7521083 Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions.

  • in striatum, 2 basic classes of neural transmission:
    • fast neural transmission:
      • glutamate response in striatum to cortical/thalamic input via AMPA on medium spiny neurons
      • GABA output of the striatum
    • modulatory neural transmission:
      • NMDA
      • DA dopamine
      • substance P
      • ACh acetylecholine (large aspiny neurons, 30um soma! 1-2% of the population)
  • input to the cholinergic large aspiny neurons
    • GABA/substance P medium-spiny neurons which project to SNr + GPi
    • DA neurons from tegmentum, a8 a9 a10 groups
    • Glu neurons in the thalamus, and, to a lesser extent, from the cortex
  • DA D2 autoreceptors inhibit/regulate the release of DA, and it can also modulate the release of ACh + glu
    • specifically D2 has been demonstrated to inhibit ACh release, but not D1 (accourse)
  • figure 2 is kinda nice for the neurotransmitters in the basal ganglia
  • not really all that clear of an article

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ref: Cooper-2000.09 tags: globus pallidus electrophysiology current clamp channel date: 0-0-2007 0:0 revision:0 [head]

PMID-10970430 Electrophysiological and morphological characteristics of three subtypes of rat globus pallidus neurone in vitro

  • there are 3 morphological types of neurons.
    • A: inward rectfier + low-threshold calcium current = anode break depolarizations.
    • B: no inward rectifier, just fast monophasic AHP. small.
    • C: big! (...)

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ref: Gdowski-2001.02 tags: globus pallidus reward electrophysiology 2001 date: 0-0-2007 0:0 revision:0 [head]

PMID-11160530 Context Dependency in the Globus Pallidus Internal Segment During Targeted Arm Movements

  • most of the movement-responsive neurons had modulations in the cued segment of the task, not in the subsequent relaxed, self-paced phase.
  • this constitutes a reward or context-dependence.
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ref: Wannier-2002.01 tags: globus_pallidus electrophysiology caudate putamen basal_ganglia date: 0-0-2007 0:0 revision:0 [head]

PMID-11924876 Neuronal activity in primate striatum and pallidum related to bimanual motor actions

  • monkeys had to pull on a spring-loaded drawer and grab food with other hand.
  • half the recorded neurons were responsive to this task.
  • targeted: 20.1 to 14.v mm anterior to the interaural plane of the rhesus monkey brain.
    • 19.2 mm looks good for GPe
    • 17.4 for putamen and caudate (right below area 24 in the cortex - Ventral cingulate cortex)
    • 15.6 for putamen, GPe, and GPi.
  • can these be modulated by imagined movement? e.g. in a BMI?