Objective: To prove the causal role of pre-supplementary motor area (preSMA) in levodopa-induced dyskinesia using an interventional brain stimulation approach that targets abnormal preSMA activity.

Background: Levodopa-induced dyskinesia (LID) is a major complication of chronic dopamine replacement therapy. Our group has previously shown that pre-supplementary motor area (preSMA) is involved in the development of dyskinesia [1]. Using pharmaco-functional magnetic resonance imaging (p-fMRI), we showed that a single dosage of levodopa elicited abnormal activation of preSMA during “No-Go trials” in PD patients suffering from peak-of-dose LID compared with non-dyskinetic patients. Yet this finding is correlational in nature and does not prove causality which requires an interventional approach.

Method: Nineteen dyskinetic PD patients with peak-of-dose LID were included in the study. Two patients dropped out. While being OFF their usual dopamine replacement therapy, patients were stimulated over the preSMA for 30 minutes with robot-guided, neuro-navigated 1 Hz repetitive transcranial magnetic stimulation (rTMS). Patients were subsequently administered 200 mg of fast-acting soluble levodopa. The patients were stimulated twice in a counter-balanced cross-over-design with sessions spaced by a minimum of two weeks: one session with an effective stimulation (100 % resting motor threshold (rMT) of the first dorsal interosseous [FDI] muscle) and one control session (30 % of rMT in FDI). Hypotheses were pre-registered ahead of data collection.

Results: A single priming session of effective rTMS over the preSMA increased the time from intake of levodopa to the onset of peak-of-dose LID compared with control rTMS (mean difference: 8 minutes, p = 0.019, Wilcoxon signed rank, one-tailed). Real-rTMS also lowered dyskinesia severity (mean difference = -2.6 points; p = 0.03, Wilcoxon signed rank, one-tailed). Larger improvements were associated with higher stimulation intensities both in terms of the transition time from OFF to dyskinetic ON (r = 0.70, p = 0.001) and severity (r= -0.44, p = 0.0695).

Conclusion: Our experiment suggests that the increased preSMA sensitivity to levodopa seen in dyskinetic PD patients in previous studies promotes dyskinesia.

References: 1. Herz, D. M. et al. The acute brain response to levodopa heralds dyskinesias in Parkinson disease. Annals of Neurology 75, 829–836 (2014).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibitory-repetitive-transcranial-magnetic-stimulation-of-pre-supplementary-motor-area-improves-levodopa-induced-dyskinesia-in-parkinsons-disease/