Investigating the Causal Role of preSMA in Levodopa-induced Dyskinesia in Parkinson's Disease
- Conditions
- Dyskinesia, Drug-InducedParkinson Disease
- Interventions
- Device: Repetitive transcranial magnetic stimulation
- Registration Number
- NCT03354455
- Lead Sponsor
- Danish Research Centre for Magnetic Resonance
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 20
- Clinical diagnosis of Parkinson's Disease (Hoehn & Yahr 1-3)
- Peak-of-dose levodopa-induced dyskinesia
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description SHAM TMS Repetitive transcranial magnetic stimulation 30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold. REAL TMS Repetitive transcranial magnetic stimulation 30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold.
- Primary Outcome Measures
Name Time Method Levodopa-induced change in task-related regional neural activity as indexed by the blood oxygen level dependent (BOLD) signal Within the first 60 minutes after levodopa intake 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.
- Secondary Outcome Measures
Name Time Method Severity of LID Within the first 60 minutes after levodopa intake 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.
Onset of LID Within the first 60 minutes after levodopa intake A single priming session of REAL rTMS over the SMA will prolong the time to onset of LID compared with SHAM.
Trial Locations
- Locations (1)
Danish Research Centre for Magnetic Resonance
🇩🇰Hvidovre, Capital Region, Denmark