Investigating the Causal Role of preSMA in Levodopa-induced Dyskinesia in Parkinson's Disease

Targeting the Pre-supplementary Motor Area With Repetitive Transcranial Magnetic Stimulation to Alleviate Levodopa-induced Dyskinesia in Parkinson´s Disease

University Hospital Bispebjerg and Frederiksberg, Danish Movement Disorder Society (DANMODIS), Danish Parkinson Association

Using a within-subject cross-over design, we will include 20 patients with Parkinson disease (PD) and peak-of-dose dyskinesia. Patients will be studied after withdrawal from their normal dopaminergic medication. On two separate days, each patient will receive off-line, effective (high-intensity) or ineffective (low-intensity) 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the presupplementary motor area (preSMA) before functional magnetic resonance (fMRI). Immediately after the patient will perform a Go/No-Go task during fMRI in the the OFF state for 9 minutes. Then the scan is paused and the patient will receive 200 mg fast-acting oral levodopa and undergo whole-brain task-related fMRI at 3 Tesla until peak-of-dose dyskinesia will emerge. During task-related fMRI, patients has to click on a mouse with their right hand (Right-Go), left hand (Left-Go), or no action (No-Go) in response to arbitrary visual cues. The patients will also be tested for different aspects of impulsivity using neuropsychological questionnaires and computerized tests.

The most common form of levodopa-induced dyskinesias (LID) manifests when levodopa levels are highest and is referred to as peak-of-dose dyskinesia. 50% of patients experience LID after 4-6 years of treatment, reaching a frequency of 40% after 4-6 years. The main risk factors for developing LID are disease duration, levodopa dose and age-at-onset, but none of these factors alone can predict whether and when an individual patient with PD will develop LID. There is converging evidence that exogenously administered levodopa induces non-physiological release and reuptake of dopamine in the striatum. This non-physiological dopaminergic stimulation gives rise to aberrant plasticity in the striatum that causes a sensitization of the cortico-basal ganglia system to levodopa. Dyskinesia often severely affects patients' quality of life requiring advanced treatment. Adopting a novel pharmacological fMRI (ph-fMRI) approach, our group recently identified a functional signature of LID in the human brain: To bypass any problems due to movement artefacts, fMRI was performed in the time-span between the administration of levodopa and the onset of dyskinesia. Ph-fMRI revealed that a single oral dose of levodopa caused an abnormal cortico-striatal activation and connectivity pattern in pre-SMA and putamen in LID patients relative to PD patients without LID. We predict that 1 Hz rTMS of pre-SMA will attenuate the levo-dopa-induced overactivity in the pre-SMA and putamen and normalise the pre-SMA-putamen connectivity pattern. This may possibly involve an altered interaction with the right inferior frontal gyrus (rIFG).On two separate days, each patient will receive effective (high-intensity) or ineffective (low-intensity) 1 Hz rTMS (i.e. control rTMS session) of the pre-SMA before fMRI (Off-line rTMS). Pharmacological fMRI (ph-fMRI): Immediately after rTMS the patient will perform a Go/No-Go task during fMRI in the the OFF state for 9 minutes. Then the scan is paused and the patient will receive 200 mg fast-acting oral levodopa and undergo whole-brain task-related fMRI at 3 Tesla until peak-of-dose dyskinesia will emerge. During task-related fMRI, patients press a computer mouse with the right hand (Right-Go), left hand (Left-Go), or no action (No-Go) in response to arbitrary visual cues. We want to include 20 patients in the final analysis of the study. In a previous comparable study we experienced a drop-out rate around a third. We therefore aim to enrol 30 patients.

30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold.

30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold.

Frequency: 1 Hz., Pulse shape: biphasic, Duration: 30 minutes (1800 pulses). Neuronavigation: MRI-guided and robot-assisted neuronavigation using Localite software and an Axilum robot.

Levodopa-induced change in task-related regional neural activity as indexed by the blood oxygen level dependent (BOLD) signal

A single priming session of REAL rTMS over the preSMA will attenuate the abnormal pharmacodynamic BOLD response (which is an index of regional neural activity) in the cortico-basal ganglia loop after levodopa challenge compared with SHAM rTMS.

A single priming session of REAL rTMS over the SMA will prolong the time to onset of LID compared with SHAM.

A single priming session of REAL rTMS over the SMA will lower the the severity of LID measured on the Unified Dyskinesia Rating Scale (UDysRS) compared with SHAM.

Inclusion Criteria: Clinical diagnosis of Parkinson's Disease (Hoehn & Yahr 1-3) Peak-of-dose levodopa-induced dyskinesia Exclusion Criteria: Insufficient Danish language skills Neurological disease other than Parkinson's Disease Major psychiatric illness Sedatives or serotonergic medication in their current treatment. Severe tremor Montreal Cognitive Assessment score < 26 Contraindication for transcranial magnetic stimulation: Epilepsy or epilepsy in 1st degree relatives Contraindications for MRI-scanning: Pacemaker Pregnancy Metallic foreign objects inside the body Severe claustrophobia