Motor cortex stimulation: mild transient benefit in a primate model of Parkinson disease

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The authors sought to examine the therapeutic efficacy of motor cortex stimulation (MCS) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–treated macaques and to characterize therapeutic differences with varying modes, frequencies, and durations of stimulation.


Motor cortex stimulation was delivered at currents below motor threshold and at frequencies between 5 and 150 Hz through epidural electrodes over the primary motor cortex. The animals were studied during and without MCS using video analysis, activity logging, and food retrieval tasks. Animals were examined using two different stimulation protocols. The first protocol consisted of 1 hour of MCS therapy daily. The second protocol exposed the animal to continuous MCS for more than 24 hours with at least 2 weeks between MCS treatments.


Daily MCS yielded no consistent change in symptoms, but MCS at 2-week intervals resulted in significant increases in activity. Effects of biweekly MCS disappeared, however, within 24 hours of the onset of continuous MCS. In this study, MCS only temporarily reduced the severity of MPTP-induced parkinsonism.

Abbreviations used in this paper:GP = globus pallidus; MCS = motor cortex stimulation; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine; PD = Parkinson disease; rTMS = repetitive transcranial magnetic stimulation; SEM = standard error of the mean; TH = tyrosine hydroxylase.

Article Information

Address reprint requests to: Robert S. Turner, Ph.D., Department of Neurobiology, University of Pittsburgh, 4074 BST-3, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261-0001. email:

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    Graphs representing the schedule for daily 1-hour MCS testing (A) and showing that daily MCS failed to improve general akinesia or Klüver task performance (B–D). A: Upper timeline illustrates the course of a typical 1-hour observation period during which MCS (black bar) was delivered continuously and the Klüver task (K) was administered four times. Lower timeline illustrates how these observation sessions were administered at the same time every day with active MCS at different frequencies and polarities, and sham stimulation (Stim) sessions (hatched vertical bars) delivered in random order. B: Mean whole-body activity levels for different MCS polarities (data collapsed across frequencies; 33, eight, and 19 sessions for anodal, bipolar, and cathodal MCS, respectively), and for off-MCS (No Stim, 21 sessions) and levodopa (L-dopa, five sessions) control conditions. C: Mean whole-body activity levels for different MCS frequencies (data collapsed across polarities; 23, 13, seven, and 17 sessions for 5-, 30-, 75-, and 150-Hz MCS, respectively), and for off-MCS (21 sessions) and levodopa (five sessions) control conditions. D: Effects of MCS on Klüver task performance for different MCS polarities and frequencies. Error bars = SEMs. *p < 0.05, **p < 0.01, ***p < 0.001 (relative to the off-MCS control condition).

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    Graphs showing organization of biweekly continuous MCS schedule (A) and that MCS yielded a transient context-dependent improvement in akinesia and Klüver task performance (B–D). A: After 1 week of observations during and following sham stimulation, MCS was delivered continuously for approximately 25 hours. One-hour observation periods were performed twice on the 1st day of sham/MCS and then daily for 4 days. B: Effects of continuous MCS on mean activity levels as a function of time since the onset of stimulation. Activity averaged across whole 1-hour observation periods (center line) showed a significant increase during the 1st day of MCS. That effect returned almost to baseline by the 24th hour of testing, which was almost completely accounted for by increased activity during the 5-minute epochs around presentations of the Klüver task (top line). The MCS did not affect spontaneous activity during the 10-minute epochs between Klüver task presentations (bottom line). C: Minute-by-minute averages of activity level aligned on presentations of the Klüver task illustrate the strong enhancement of activity restricted to the period during the Klüver task (shaded region). The MCS-induced enhancement was large during the 1st hour of MCS but attenuated by the 24th hour of MCS. D: Klüver task performance as a function of MCS duration. Each plotted point is an average of three sessions. Error bars = SEMs. *p < 0.005, **p < 0.001 (relative to the matching pre-MCS conditions).

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    Bar graph demonstrating the minimal effects of daily MCS on clinically relevant behavioral measures. An observer blinded to the stimulation condition quantified the prevalence of nine different behaviors during each hour-long observation session by using videotapes. Representative results are presented comparing sessions off MCS (five sessions) and 30-Hz MCS (four sessions). Error bars = SEMs. *p < 0.05.



Bankiewicz KSOldfield EHChiueh CCDoppman JLJacobowitz DMKopin IJ: Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Life Sci 39:7161986


Bankiewicz KSSanchez-Pernaute ROiwa YKohutnicka MCummins AEberling J: Preclinical models of Parkinson's disease. Curr Protoc Neurosci 9:Suppl1321999


Canavero SPaolotti RBonicalzi VCastellano GGreco-Crasto SRizzo L: Extradural motor cortex stimulation for advanced Parkinson disease. Report of two cases. J Neurosurg 97:120812112002


Chen XYCarp JSChen LChen YPillai SWang Y: Effects of sensorimotor cortex stimulation on soleus H-reflex in rats: initial results. Society for Neuroscience Abstract Viewer/Itinerary Planner 2005


Czernecki VPillon BHoueto JLPochon JBLevy RDubois B: Motivation, reward, and Parkinson's disease: influence of dopatherapy. Neuropsychologia 40:225722672002


David HNAnsseau MAbraini JH: Dopamine-glutamate reciprocal modulation of release and motor responses in the rat caudate-putamen and nucleus accumbens of “intact” animals. Brain Res Brain Res Rev 50:3363602005


Drouot XOshino SJarraya BBesret LKishima HRemy P: Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation. Neuron 44:7697782004


German DCDubach MAskari SSpeciale SGBowden DM: 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced parkinsonian syndrome in Macaca fascicularis: which midbrain dopaminergic neurons are lost?. Neuroscience 24:1611741988


Ghabra MBHallett MWassermann EM: Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology 52:7687701999


Goldberg JABoraud TMaraton SHaber SNVaadia EBergman 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 22:463946532002


Grabli DMcCairn KHirsch ECAgid YFeger JFrancois C: Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study. Brain 127:203920542004


Houeto JLMesnage VMallet LPillon BGargiulo Mdu Moncel ST: Behavioural disorders, Parkinson's disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 72:7017072002


Kaneoke YVitek JL: Burst and oscillation as disparate neuronal properties. J Neurosci Methods 68:2112231996


Kumar RLozano AMMontgomery ELang AE: Pallidotomy and deep brain stimulation of the pallidum and subthalamic nucleus in advanced Parkinson's disease. Mov Disord 13:1 Suppl73821998


Limousin PKrack PPollak PBenazzouz AArdouin CHoffmann D: Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 339:110511111998


Nini AFeingold ASlovin HBergman H: Neurons in the globus pallidus do not show correlated activity in the normal monkey, but phase-locked oscillations appear in the MPTP model of parkinsonism. J Neurophysiol 74:180018051995


Ohnishi THayashi TOkabe SNonaka IMatsuda HIida H: Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C] raclopride positron emission tomography study in anesthetized macaque monkeys. Biol Psychiatry 55:4844892004


Oiwa YEberling JLNagy DPivirotto PEmborg MEBankiewicz KS: Overlesioned hemiparkinsonian non human primate model: correlation between clinical, neurochemical and histochemical changes. Front Biosci 8:a155a1662003


Pagni CAAltibrandi MGBentivoglio ACaruso GCioni BFiorella C: Extradural motor cortex stimulation (EMCS) for Parkinson's disease. History and first results by the study group of the Italian neurosurgical society. Acta Neurochir 93:Suppl1131192005


Pagni CAZeme SZenga F: Further experience with extradural motor cortex stimulation for treatment of advanced Parkinson's disease. Report of 3 new cases. J Neurosurg Sci 47:1891932003


Pascual-Leone AValls-Sole JBrasil-Neto JPCammarota AGrafman JHallett M: Akinesia in Parkinson's disease. II. Effects of subthreshold repetitive transcranial motor cortex stimulation. Neurology 44:8928981994


Pessiglione MGuehl DJan CFrancois CHirsch ECFeger J: Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism: II. Effects of reward preference. Eur J Neurosci 19:4374462004


Rothblat DSSchroeder JASchneider JS: Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: potential contributors to spontaneous recovery from experimental Parkinsonism. J Neurosci Res 65:2542662001


Schneider JSGonczi HDecamp E: Development of levodopa-induced dyskinesias in parkinsonian monkeys may depend upon rate of symptom onset and/or duration of symptoms. Brain Res 990:38442003


Schrag AQuinn N: Dyskinesias and motor fluctuations in Parkinson's disease. A community-based study. Brain 123:229723052000


Silberstein PPogosyan AKuhn AAHotton GTisch SKupsch A: Corticocortical coupling in Parkinson's disease and its modulation by therapy. Brain 128:127712912005


Starr PARau GMDavis VMarks WJ JrOstrem JLSimmons D: Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque. J Neurophysiol 93:316531762005


Strafella APPaus TBarrett JDagher A: Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 21:RC1572001


Strafella APPaus TFraraccio MDagher A: Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126:260926152003


Szabo JCowan WM: A stereotaxic atlas of the brain of the cynomolgus monkey (Macaca fascicularis). J Comp Neurol 222:2653001984


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