The proposed study investigates the use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for levodopa-induced dyskinesia (LID) in Parkinson's Disease (PD). Specifically, the study aims to determine whether patterned stimulation of the pre-supplementary motor area (pre-SMA) can delay the onset of LID after levodopa intake and reduce LID severity in PD patients. This study will provide critical insights into potential targets for rTMS treatment, optimal rTMS parameters, and the mechanisms underlying LID in Parkinson's disease.

Long-term use of levodopa in Parkinson's Disease (PD) often leads to motor complications, such as Levodopa-Induced Dyskinesia, which significantly impacts patients' daily lives. Various brain regions have been targeted for treatment with Transcranial Magnetic Stimulation (TMS), including the supplementary motor area (SMA), primary motor cortex, cerebellum, and prefrontal cortex. Specifically, targeting the pre-SMA with 1-Hz rTMS has been shown to delay and reduce dyskinesia severity in PD patients following levodopa administration. These findings suggest that the pre-supplementary motor area is a promising target for brain stimulation therapy, as it plays a causal role in the pathophysiology of peak-of-dose dyskinesia.

The current study aims to build on previous research by optimizing the stimulation intensity and location based on individual neuroanatomy and simulated electric fields. Additionally, the study will explore the impact of rTMS delivered in short high-frequency bursts, differing from the single rTMS pulses used in previous studies. In the context of LID, Deep Brain Stimulation (DBS) typically targets the subthalamic nucleus (STN) using gamma frequencies (40-200 Hz, most commonly 130 Hz). Drawing from this principle, the study posits that delivering rTMS bursts at gamma frequencies to the pre-SMA will effectively mitigate LID symptoms. Moreover, evidence from cortical brain rhythm recordings highlights that beta frequencies (12-30 Hz), which are crucial for movement control and are disrupted in PD, may also hold therapeutic potential. Therefore, the study will investigate whether rTMS bursts at beta frequencies could similarly reduce LID symptoms. Given the absence of prior research directly comparing the effects of different burst frequencies on LID, the study will systematically apply two distinct burst frequencies, in separate patient groups, to determine which, if either, produces a meaningful reduction in LID symptoms.

Dyskinesia onset time and severity will be measured using the Unified Dyskinesia Rating Scale (UDysRS) and assessed by a clinician rater who is blinded to the treatment condition. The results will be compared between the active and sham stimulation conditions.

Inclusion Criteria:

• Clinically established or probable PD
• Clinical Diagnostic Criteria for Parkinson's Disease
• Peak-of-dose levodopa-induced dyskinesia.
• Stable antiparkinsonian medicine for at least four weeks.
• Signed informed consent.

Exclusion Criteria:

• Psychiatric disorders.
• Usage of antipsychotic medication, Donepezil, and GABAergic medications (such as pregabalin and gabapentin).
• Regular usage of benzodiazepines and opioids (more than once per week).
• History of neurological disease other than Parkinson's disease.
• History of epilepsy/conditions associated with increased risk to seizure-induction through TMS.
• Close relatives suffering from epilepsy/conditions associated with increased risk to seizure-induction through TMS.
• Contraindications for MRI scan
• Female participants of childbearing age must not be pregnant and that they must use contraception during the trial.
• Refuse to be informed about new health related information and accidental health related findings that might appear through participation in the study.

Sharing of anonymised data

After study completion

Anonymised data, reasonable request

Participants will receive sham rTMS by flipping the coil upside down. This will still provide similar sensory experience as an active stimulation that the patients will not distinguish between. Dyskinesia assessment is filmed during the visit and an experienced rater is unaware of a treatment condition of the patient.