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

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ClinicalTrials.gov Identifier: NCT03354455
Recruitment Status : Recruiting
First Posted : November 28, 2017
Last Update Posted : November 28, 2017
Sponsor:
Collaborators:
Copenhagen University Hospital Bispebjerg
Danish Movement Disorder Society (DANMODIS)
Danish Parkinson Association
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Dyskinesia, Drug-Induced Parkinson Disease Device: Repetitive transcranial magnetic stimulation Not Applicable

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Masking Description: Sham stimulation
Primary Purpose: Basic Science
Official Title: Targeting the Pre-supplementary Motor Area With Repetitive Transcranial Magnetic Stimulation to Alleviate Levodopa-induced Dyskinesia in Parkinson´s Disease
Actual Study Start Date : August 1, 2017
Estimated Primary Completion Date : July 1, 2019
Estimated Study Completion Date : July 1, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Levodopa
U.S. FDA Resources

Arm Intervention/treatment
Experimental: REAL TMS
30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold.
Device: 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.

Sham Comparator: SHAM TMS
30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold.
Device: 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.




Primary Outcome Measures :
  1. Levodopa-induced change in task-related regional neural activity as indexed by the blood oxygen level dependent (BOLD) signal [ Time Frame: 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 :
  1. Onset of LID [ Time Frame: 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.

  2. Severity of LID [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03354455


Contacts
Contact: Hartwig R Siebner, MD, DMSci 38626541 ext +45 h.siebner@drcmr.dk

Locations
Denmark
Danish Research Centre for Magnetic Resonance Recruiting
Hvidovre, Capital Region, Denmark, 2650
Contact: Karam Sidaros, PhD    38623330 ext +45    karams@drcmr.dk   
Contact: Hartwig R Siebner, MD, DMSci    38626541 ext +45    h.siebner@drcmr.dk   
Principal Investigator: Hartwig R Siebner, MD, DMSci         
Principal Investigator: Annemette Løkkegaard, MD, PhD         
Sub-Investigator: David Meder, PhD         
Sub-Investigator: Damian M Herz, MD, PhD         
Sub-Investigator: Allan Lohse, MD         
Sponsors and Collaborators
Danish Research Centre for Magnetic Resonance
Copenhagen University Hospital Bispebjerg
Danish Movement Disorder Society (DANMODIS)
Danish Parkinson Association
Investigators
Principal Investigator: Hartwig R Siebner, MD, DMSci Danish Research Centre for Magnetic Resonance

Responsible Party: Danish Research Centre for Magnetic Resonance
ClinicalTrials.gov Identifier: NCT03354455     History of Changes
Other Study ID Numbers: H-15017863
First Posted: November 28, 2017    Key Record Dates
Last Update Posted: November 28, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Parkinson Disease
Dyskinesias
Dyskinesia, Drug-Induced
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Neurologic Manifestations
Signs and Symptoms
Neurotoxicity Syndromes
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Poisoning
Levodopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs