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

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Brief Title

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

Official Title

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

Brief 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

BOLD (blood oxygen-level dependent) fMRI (functional magnetic resonance imaging) response to a working memory task

Secondary Outcome

 serum prolactin concentration

Condition

Tourette Syndrome

Intervention

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

Study Arms / Comparison Groups

 levodopa solution 2mg/ml for i.v. use
Description:  levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

49

Start Date

February 2006

Completion Date

October 2010

Primary Completion Date

October 2010

Eligibility 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.
      

Gender

All

Ages

18 Years - 55 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Kevin J Black, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00634556

Organization ID

05-0832

Secondary IDs

R01MH073856-01A1

Responsible Party

Sponsor

Study Sponsor

Washington University School of Medicine

Collaborators

 National Institute of Mental Health (NIMH)

Study Sponsor

Kevin J Black, MD, Principal Investigator, Washington Universisty School of Medicine


Verification Date

February 2018