Dopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol)
Condition: Tourette Syndrome
MeSH terms: Tourette Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

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.
    

Intervention name(s): levodopa solution 2mg/ml for i.v. use; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 2mg/mL in normal saline; normal saline
Other intervention name(s): L-DOPA; L-3,4-dihydroxyphenylalanine; NaCl 0.9% in water
Intervention MeSH terms: Levodopa; Dihydroxyphenylalanine
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Tourette Syndrome; fMRI; levodopa; working memory; dopamine