Dopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol) (TSfMRI)
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.
|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 ]
|Study Start Date:||February 2006|
|Study Completion Date:||October 2010|
|Primary Completion Date:||October 2010 (Final data collection date for primary outcome measure)|
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
Placebo Comparator: Placebo
normal saline i.v.
Other Name: NaCl 0.9% in water
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.
|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|