investigating the causal role of presma in levodopa-induced dyskinesia in parkinson's disease

Conditions: Dyskinesia, Drug-Induced; Parkinson Disease

Summary: 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.

Eligibility criteria:
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