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

NCT ID: NCT03354455

Last Updated: 2019-08-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-01
• Study Completion Date: 2018-09-16

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.

Conditions

Dyskinesia, Drug-Induced; Parkinson Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

REAL TMS

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

Group Type: EXPERIMENTAL

Repetitive transcranial magnetic stimulation

Intervention Type: DEVICE

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.

SHAM TMS

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

Group Type: SHAM_COMPARATOR

Repetitive transcranial magnetic stimulation

Intervention Type: DEVICE

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.

Interventions

Repetitive transcranial magnetic stimulation

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.

Intervention Type: DEVICE

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Bispebjerg and Frederiksberg

OTHER

Sponsor Role: collaborator

Danish Movement Disorder Society (DANMODIS)

UNKNOWN

Sponsor Role: collaborator

Danish Parkinson Association

OTHER

Sponsor Role: collaborator

Danish Research Centre for Magnetic Resonance

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hartwig R Siebner, MD, DMSci

Role: PRINCIPAL_INVESTIGATOR

Danish Research Centre for Magnetic Resonance

Locations

Danish Research Centre for Magnetic Resonance

Hvidovre, Capital Region, Denmark

Countries

Denmark

Other Identifiers

H-15017863

Identifier Type: -

Identifier Source: org_study_id