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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).


[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: 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.


[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: 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.


[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: 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.


[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: 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.


[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: 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.


[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".


[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.


[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: RodriguezOroz-2011.01 tags: DBS dopamine impulse control spain pamplona ventral beta date: 02-22-2012 17:02 gmt revision:9 [8] [7] [6] [5] [4] [3] [head]

PMID-21059746[0] Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson’s disease

  • recorded LFP in the STN of 28 patients.
    • of these 10 had impulse control disorders, 9 had dyskinesias, and 9 had no complications.
  • compared ON and OFF medication.
  • no difference between groups in off states.
  • large differences in ON states.
    • Impulse control problems: theta-alpha activity(4-10 Hz) 6 Hz mean.
      • Larger coherence with frontal regions 4-7.5 Hz.
    • Dyskinesias: higher frequency theta-alpha 8 Hz mean.
      • Higher coherence with motor areas, 7.5 - 10Hz.
    • No problems: no noticeable LFP oscillations (?).
  • PD patients often have side-effects of Punding and hobbyism.
    • Does meth treat PD? Selegiline does. Fascinating history there regarding combining MAOI + amphetamine --> effective PD drug.
    • Why does both meth and levodopa induce impulsivity?
    • Some of the other effects of L-DOPA treatment: hypersexuality, manic behavior or shopping.
    • Lesion of the subthalamic nucleus by infarction or tumor is associated with behavioral alterations including agitation, manic states and logorrhoea, with or without hemiballismus.
  • In some patients with ICD (impulse control disorders) induced by subthalamic nucleus deep brain stimulation, the abnormal behavior was provoked by stimulation with a ventral contact and suppressed by switching it off. (dorsal region is more motor).
    • In three patients with ICD, stimulation through the ventral contact induced a euphoric state -- PPN?
  • STN recordings from rats and monkeys modify their frequency in response to reward related tasks (Aron and Poldrack 2006); in humans the STN is active during an inhibition task (LI et al 2008).
  • LFP recordings from the treatment electrode were very low! 16uV.
  • Typical results show large differences between ON and OFF: ON show more activity > 60 Hz, OFF more < 60 Hz (Brown et al 2001; Brown 2003 Gatev et al 2006).
  • LFP recordings in PD patients from the STN showed that emotional stimulus led to a decrease in alpha power in the ventral contacts (Brucke et al 2007), whereas active movement led to a decrease in the beta power recorded in the dorsal subthalamic nucleus (Alegre et al 2005).
  • Original work on STN mediating impulsivity: Delong 1983 PMID-6422317 The neurophysiologic basis of abnormal movements in basal ganglia disorders.
    • Single cell studies in the basal ganglia of behaving animals have revealed specific relations of neuronal activity to movements of individual body parts and a relation to specific parameters of movement, particularly direction, amplitude, and velocity. (no fulltext available).


[0] Rodriguez-Oroz MC, López-Azcárate J, Garcia-Garcia D, Alegre M, Toledo J, Valencia M, Guridi J, Artieda J, Obeso JA, Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease.Brain 134:Pt 1, 36-49 (2011 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: 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.


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

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

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

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


[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: Bassett-2009.07 tags: Weinberger congnitive efficiency beta band neuroimagaing EEG task performance optimization network size effort date: 12-28-2011 20:39 gmt revision:1 [0] [head]

PMID-19564605[0] Cognitive fitness of cost-efficient brain functional networks.

  • Idea: smaller, tighter networks are correlated with better task performance
    • working memory task in normal subjects and schizophrenics.
  • Larger networks operate with higher beta frequencies (more effort?) and show less efficient task performance.
  • Not sure about the noisy data, but v. interesting theory!


[0] Bassett DS, Bullmore ET, Meyer-Lindenberg A, Apud JA, Weinberger DR, Coppola R, Cognitive fitness of cost-efficient brain functional networks.Proc Natl Acad Sci U S A 106:28, 11747-52 (2009 Jul 14)

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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.


[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)