Dopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol) (TSfMRI)
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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 for i.v. administration 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) |
- 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 ]
- 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
levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.
|
Drug: levodopa solution for i.v. administration
2mg/mL in normal saline
Other Names:
|
|
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 |
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| United States, Missouri | |
| Washington Universisty School of Medicine, | |
| St. Louis, Missouri, United States, 63110 | |
| Principal Investigator: | Kevin J Black, MD | Washington Universisty School of Medicine |
More Information
Additional Information:
Publications:
| Responsible Party: | Kevin J. Black, MD, Washington University School of Medicine |
| ClinicalTrials.gov Identifier: | NCT00634556 History of Changes |
| Other Study ID Numbers: | 05-0832, R01MH073856-01A1 |
| Study First Received: | March 5, 2008 |
| Last Updated: | March 2, 2011 |
| 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:
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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 May 16, 2013