Dopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol) (TSfMRI)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Kevin J. Black, MD, Washington University
ClinicalTrials.gov Identifier:
NCT00634556
First received: March 5, 2008
Last updated: June 11, 2013
Last verified: June 2013
  Purpose

Dr. Kevin J. Black at Washington University is conducting a study to learn whether we can use MRI scans to test dopamine function in the brain and to determine whether the brain performs memory tasks differently in Tourette Syndrome (TS). TS is a movement disorder characterized by vocal tics (sounds) and motor tics (movements). We will measure how and where brain activity changes using magnetic resonance imaging (MRI) scans during memory tasks and after taking levodopa. Levodopa is a drug commonly used for the treatment of Parkinson's disease (PD), a very different movement disorder.


Condition Intervention
Tourette Syndrome
Drug: levodopa solution 2mg/ml for i.v. use
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: Dopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol)

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • BOLD (blood oxygen-level dependent) fMRI (functional magnetic resonance imaging) response to a working memory task [ Time Frame: From about 30 to 120 minutes after infusion begins ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • serum prolactin concentration [ Time Frame: approximately 2 hours after infusion begins ] [ Designated as safety issue: No ]

Enrollment: 49
Study Start Date: February 2006
Study Completion Date: October 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: levodopa solution 2mg/ml for i.v. use
levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.
Drug: levodopa solution 2mg/ml for i.v. use
2mg/mL in normal saline
Other Names:
  • L-DOPA
  • L-3,4-dihydroxyphenylalanine
Placebo Comparator: Placebo
normal saline i.v.
Drug: placebo
normal saline
Other Name: NaCl 0.9% in water

Detailed Description:

Clinical observations suggest that in TS there is abnormal function in the brain's motor system that can be modified by manipulating dopamine. My colleagues and I have hypothesized that nonmotor brain systems may also show dopamine-sensitive functional abnormalities. Recently we tested this hypothesis using functional magnetic resonance imaging (fMRI). A cognitive task involving working memory (WM) produced excessive activation of several brain regions in TS subjects compared to controls, but this excessive activation normalized after administering the dopamine precursor levodopa (Hershey et al, 2004).

We can state the following focused hypotheses and corresponding specific aims:

(1) In TS, normal performance during a working memory (WM) task requires greater activation of specific brain regions (parietal cortex, medial frontal cortex and thalamus) than in control subjects, and this excess fMRI response is reduced (improved) by exogenous levodopa. (2) These fMRI results in TS relate specifically to WM, to TS, and to dopamine receptor activation, rather than to non-WM components of the cognitive task, comorbidity, placebo effects, or other confounds.

Specific Aim 1. Test whether the preliminary fMRI results generalize to a larger and more representative sample of adults with TS.

Specific Aim 2. Clarify the variables that interact to produce the differential fMRI responses to a WM task and levodopa observed in TS subjects vs controls.

2a. Task components. Control for non-WM components of the task and delineate a "dose-response" curve for effects of WM load on fMRI responses.

2b. Clinical variables. Test whether the fMRI results in our preliminary data are associated with TS itself rather than with comorbid conditions, treatment history, demographic variables, or state variables such as current tic severity / tic suppression.

2c. Pharmacology. Test whether the post-levodopa changes in WM-related fMRI signal relate specifically to levodopa plasma concentration (rather than practice effects, placebo effects, or passage of time) and are replicated by a nonselective dopamine receptor agonist or by a dopamine D2/D3/D4 agonist.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18-55.
  • Tic subjects must meet DSM-IV-TR criteria for a chronic tic disorder.
  • Controls are matched for age (within 4 years), sex, handedness (right-handed, non-right-handed), and education (within 2 years), and if possible for race and ethnicity

Exclusion Criteria:

  • Inability to give competent informed consent.
  • Lactation, pregnancy or possibility of pregnancy.
  • Contraindication to MRI (pacemaker; nontrivial metallic foreign bodies; significant claustrophobia).
  • Contraindication to levodopa or carbidopa (known allergy).
  • Significant neurological disease (not counting the tic disorder).
  • Current renal, cardiac or hepatic disease that would make study participation less safe.
  • Head injury with loss of consciousness for more than 5 minutes or with neurological sequelae.
  • Lifetime history of serious lifetime psychopathology or substance abuse. (Specific exclusions are: lifetime diagnosis of mental retardation, autism, psychosis, mania, somatization disorder, panic disorder, social phobia [excludes symptoms present only when treated with a neuroleptic], anorexia nervosa or bulimia, drug or alcohol dependence, antisocial personality disorder, or dementia, or current major depression.)
  • Depot neuroleptics in the past 6 months.
  • Other antipsychotics within the past 2 weeks.
  • Behavioral therapy for Tics of OCD sx in the past 2 weeks.
  • For one half of the subjects in each diagnostic group: any brain-active medications within the past 2 weeks. For the remaining subjects: neuroactive medications in the past 2 weeks other than SSRIs, alpha-2 agonists, norepinephrine reuptake inhibitors, or clonazepam.
  • Additional exclusions for controls: No history of tic disorder, OCD or ADHD. If under age 25, no first-degree relative with a tic disorder. No exposure to neuroleptics in the past year and none ever for a period exceeding a week.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00634556

Locations
United States, Missouri
Washington Universisty School of Medicine,
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Kevin J. Black, MD
Investigators
Principal Investigator: Kevin J Black, MD Washington Universisty School of Medicine
  More Information

Additional Information:
Publications:
Responsible Party: Kevin J. Black, MD, Professor, Washington University
ClinicalTrials.gov Identifier: NCT00634556     History of Changes
Other Study ID Numbers: 05-0832, R01MH073856-01A1
Study First Received: March 5, 2008
Last Updated: June 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:
Tourette Syndrome
fMRI
levodopa
working memory
dopamine

Additional relevant MeSH terms:
Tourette Syndrome
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tic Disorders
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Mental Disorders Diagnosed in Childhood
Mental Disorders
Dihydroxyphenylalanine
Dopamine
Dopamine Agents
Levodopa
Dopamine Agonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Cardiotonic Agents
Cardiovascular Agents
Therapeutic Uses
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Protective Agents
Antiparkinson Agents
Anti-Dyskinesia Agents

ClinicalTrials.gov processed this record on April 20, 2014