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

Primary Purpose

Dyskinesia, Drug-Induced, Parkinson Disease

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
Repetitive transcranial magnetic stimulation
Sponsored by
Danish Research Centre for Magnetic Resonance
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Dyskinesia, Drug-Induced

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Danish Research Centre for Magnetic Resonance

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

REAL TMS

SHAM TMS

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
June 1, 2017
Last Updated
August 3, 2019
Sponsor
Danish Research Centre for Magnetic Resonance
Collaborators
University Hospital Bispebjerg and Frederiksberg, Danish Movement Disorder Society (DANMODIS), Danish Parkinson Association
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1. Study Identification

Unique Protocol Identification Number
NCT03354455
Brief Title
Investigating the Causal Role of preSMA in Levodopa-induced Dyskinesia in Parkinson's Disease
Official Title
Targeting the Pre-supplementary Motor Area With Repetitive Transcranial Magnetic Stimulation to Alleviate Levodopa-induced Dyskinesia in Parkinson´s Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
August 1, 2017 (Actual)
Primary Completion Date
September 16, 2018 (Actual)
Study Completion Date
September 16, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Danish Research Centre for Magnetic Resonance
Collaborators
University Hospital Bispebjerg and Frederiksberg, Danish Movement Disorder Society (DANMODIS), Danish Parkinson Association

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dyskinesia, Drug-Induced, Parkinson Disease

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
Participant
Masking Description
Sham stimulation
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
REAL TMS
Arm Type
Experimental
Arm Description
30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold.
Arm Title
SHAM TMS
Arm Type
Sham Comparator
Arm Description
30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold.
Intervention Type
Device
Intervention Name(s)
Repetitive transcranial magnetic stimulation
Intervention Description
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.
Primary Outcome Measure Information:
Title
Levodopa-induced change in task-related regional neural activity as indexed by the blood oxygen level dependent (BOLD) signal
Description
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.
Time Frame
Within the first 60 minutes after levodopa intake
Secondary Outcome Measure Information:
Title
Onset of LID
Description
A single priming session of REAL rTMS over the SMA will prolong the time to onset of LID compared with SHAM.
Time Frame
Within the first 60 minutes after levodopa intake
Title
Severity of LID
Description
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.
Time Frame
Within the first 60 minutes after levodopa intake

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hartwig R Siebner, MD, DMSci
Organizational Affiliation
Danish Research Centre for Magnetic Resonance
Official's Role
Principal Investigator
Facility Information:
Facility Name
Danish Research Centre for Magnetic Resonance
City
Hvidovre
State/Province
Capital Region
ZIP/Postal Code
2650
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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