What Can Alleviate Levodopa-Induced Dyskinesia in Parkinson Disease?

Low-frequency transcranial stimulation of the pre-supplementary motor area was found to delay the onset and reduce severity of levodopa-induced dyskinesia in patients with Parkinson disease (PD), according to study findings published in Brain Communications.

While considered the standard of care for PD, long-term usage of the commonly used dopamine therapy levodopa has been associated with dyskinesia, which is characterized by involuntary and uncontrollable movements. As researchers explain, prior analyses utilizing pharmacodynamic functional MRI (fMRI) exhibited that the intake of levodopa triggers an excessive activation of the pre-supplementary motor area in patients with PD with peak-of-dose dyskinesia.

They sought to examine whether the abnormal responsiveness of the pre-supplementary motor area to levodopa may signal a stimulation target for treating dyskinesia. In the pre-registered, interventional study, researchers recruited a gender-balanced group of 17 patients with PD with peak-of-dose dyskinesia who received 30 minutes of robot-assisted repetitive transcranial magnetic stimulation after they had paused their anti-Parkinson medication.

Participants were applied real-repetitive transcranial magnetic stimulation at 100% or sham-repetitive transcranial magnetic stimulation at 30% of individual resting corticomotor threshold of left first dorsal interosseous muscle on separate days in counterbalanced order.

After undergoing repetitive transcranial magnetic stimulation, patients were then administered 200 mg of oral levodopa and underwent fMRI to map brain activity, while additionally performing a visually cued go/no-go task.

“Patients were positioned in the MRI scanner and task-related brain activity was mapped with fMRI until the emergence of dyskinesia,” explain the study authors. “If patients did not develop choreiform dyskinesia within four cycles of task- and resting-state-fMRI the session was stopped.”

Prior to the stimulation and immediately after the scanning session, patients were assessed clinically for symptoms of PD, via part 3 of the Unified Parkinson Disease Rating Scale (UPDRS-III), and dyskinesia, via Unified Dyskinesia Rating Scale (UDysRS). “The assessment was video recorded for subsequent blinded scoring of the UPDRS-III (except rigidity) and the objective part of the UDysRS,” wrote the researchers.

After completion of the blinded video assessment, it was revealed that real-repetitive transcranial magnetic stimulation delayed the onset of dyskinesia and reduced its severity when compared with sham-repetitive transcranial magnetic stimulation.

Moreover, individual improvement in dyskinesia severity was indicated to scale linearly with the modulatory effect of real-repetitive transcranial magnetic stimulation on task-related activation in the pre-supplementary motor area. Stimulation-induced delay in dyskinesia onset was also found to correlate positively with the induced electric field strength in the pre-supplementary motor area.

“Our results provide converging evidence that the levodopa-triggered increase in pre-supplementary motor area activity plays a causal role in the pathophysiology of peak-of-dose dyskinesia and constitutes a promising cortical target for brain stimulation therapy,” concluded the study authors.

Reference

Lohse A, Meder D, Nielsen S, et al. Low-frequency transcranial stimulation of pre-supplementary motor area alleviates levodopa-induced dyskinesia in Parkinson disease: a randomized cross-over trial. Brain Commun. Published online September 18, 2020. doi:10.1093/braincomms/fcaa147