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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

49 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-02-28

Study Completion Date

2010-10-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Tourette Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

OTHER

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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levodopa solution 2mg/ml for i.v. use

levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.

Group Type EXPERIMENTAL

levodopa solution 2mg/ml for i.v. use

Intervention Type DRUG

2mg/mL in normal saline

Placebo

normal saline i.v.

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

normal saline

Interventions

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levodopa solution 2mg/ml for i.v. use

2mg/mL in normal saline

Intervention Type DRUG

placebo

normal saline

Intervention Type DRUG

Other Intervention Names

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L-DOPA L-3,4-dihydroxyphenylalanine NaCl 0.9% in water

Eligibility Criteria

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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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

55 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes