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

February 8, 2018 updated by: Washington University School of Medicine
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 Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

49

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington Universisty School of Medicine,

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 51 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
Other Names:
  • L-DOPA
  • L-3,4-dihydroxyphenylalanine
Placebo Comparator: Placebo
normal saline i.v.
Drug: placebo
normal saline
Other Names:
  • NaCl 0.9% in water

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
From about 30 to 120 minutes after infusion begins

Secondary Outcome Measures

Outcome Measure
Time Frame
serum prolactin concentration
Time Frame: approximately 2 hours after infusion begins
approximately 2 hours after infusion begins

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Collaborators

National Institute of Mental Health (NIMH)

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2006

Primary Completion (Actual)

October 1, 2010

Study Completion (Actual)

October 1, 2010

Study Registration Dates

First Submitted

March 5, 2008

First Submitted That Met QC Criteria

March 12, 2008

First Posted (Estimate)

March 13, 2008

Study Record Updates

Last Update Posted (Actual)

February 12, 2018

Last Update Submitted That Met QC Criteria

February 8, 2018

Last Verified

February 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 05-0832
  • R01MH073856-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Vital signs IPD are shared at: Siddiqi SH, Creech ML, Black KJ. Orthostatic stability with intravenous levodopa. PeerJ. 2015 Aug 27;3:e1198. doi: 10.7717/peerj.1198. eCollection 2015. PubMed ID: 26336641 There is no plan to share other IPD.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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