Expired Study
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Saint Louis, Missouri 63110


Purpose:

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 summary:

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.


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.


Study is Available At:


Original ID:

05-0832


NCT ID:

NCT00634556


Secondary ID:

R01MH073856-01A1


Study Acronym:

TSfMRI


Brief Title:

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


Official Title:

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


Overall Status:

Completed


Study Phase:

Phase 1


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

55 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Washington University School of Medicine


Oversight Authority:

United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

49


Enrollment Type:

Actual


Overall Contact Information

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

Study Dates

Start Date:February 2006
Completion Date:October 2010
Completion Type:Actual
Primary Completion Date:October 2010
Primary Completion Type:Actual
Verification Date:February 2018
Last Changed Date:February 8, 2018
First Received Date:March 5, 2008

Study Outcomes

Outcome Type:Secondary Outcome
Measure:serum prolactin concentration
Time Frame:approximately 2 hours after infusion begins
Safety Issues:False
Outcome Type:Primary Outcome
Measure: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
Safety Issues:False

Study Interventions

Intervention Type:Drug
Name:levodopa solution 2mg/ml for i.v. use
Description:2mg/mL in normal saline
Arm Name:levodopa solution 2mg/ml for i.v. use
Other Name:L-DOPA
Intervention Type:Drug
Name:placebo
Description:normal saline
Arm Name:Placebo
Other Name:NaCl 0.9% in water

Study Arms

Study Arm Type:Placebo Comparator
Arm Name:Placebo
Description:normal saline i.v.
Study Arm Type:Experimental
Arm Name: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.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Washington University School of Medicine
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Institute of Mental Health (NIMH)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Results Reference
Citation:Siddiqi SH, Creech ML, Black KJ. Orthostatic stability with intravenous levodopa. PeerJ. 2015 Aug 27;3:e1198. doi: 10.7717/peerj.1198. eCollection 2015.
PMID:26336641
Reference Type:Results Reference
Citation:Black KJ, Campbell MC, Koller JM, Schneider B, Hershey T. Dopaminergic modulation of working-memory-related cortical activity in Tourette syndrome. Annual meeting, Society for Neuroscience, Chicago, 20 Oct 2009. http://www.sfn.org/
Reference Type:Results Reference
Citation:Campbell M, Koller J, Shipley E, Creech M, Hershey T, Black K. Dopaminergic modulation of working memory in Tourette's syndrome [abstract]. J Neuropsychiatry Clin Neurosci 20(2):232, 2008. http://neuro.psychiatryonline.org/article.aspx?articleid=103362
Reference Type:Reference
Citation:Black KJ, Carl JL, Hartlein JM, Warren SL, Hershey T, Perlmutter JS. Rapid intravenous loading of levodopa for human research: clinical results. J Neurosci Methods. 2003 Jul 15;127(1):19-29.
PMID:12865145
Reference Type:Reference
Citation:Hershey T, Black KJ, Hartlein JM, Barch DM, Braver TS, Carl JL, Perlmutter JS. Cognitive-pharmacologic functional magnetic resonance imaging in tourette syndrome: a pilot study. Biol Psychiatry. 2004 May 1;55(9):916-25.
PMID:15110735

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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