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

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Object

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.

Methods

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.

Conclusions

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: rturner@pitt.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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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.

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