Remediation of Impaired Self-Regulation in Patients With Mild TBI

Not Applicable

Completed

Conditions: Mild Traumatic Brain Injury

Interventions: Drug: Tolcapone
Drug: Placebo

Registration Number: NCT02260570

Lead Sponsor: VA Office of Research and Development

Brief Summary: The ability to regulate impulses enables us to plan for the future, to maintain focus in the face of distractions (i.e. to encode memories), and to manage emotions. This self regulation can be compromised in individuals who have a history of mild traumatic brain injury and co-occurring disorders. In this study the investigators are using functional MRI scanning to understand how memory and self regulation are expressed in the brains of people with a history of mild traumatic brain injury. The investigators are also testing whether the medication tolcapone may improve memory and self regulation.

Detailed Description: In this randomized, double-blind, placebo-controlled, crossover cognitive neuroscience study, the investigators are evaluating whether the catechol-O-methyltransferase (COMT) inhibitor tolcapone impacts memory and self regulation, as measured both behaviorally (via cognitive testing) and neurophysiologically (via functional MRI).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

Veteran ages 18-50 and in general good health;
Able to read English at a 6th grade level;
Able to provide written informed consent;
Normal or corrected to normal visual acuity;
Stable doses of all medications (2 weeks or greater);
History of mild traumatic brain injury greater than 6 months prior to participation

Exclusion Criteria

Contraindications to magnetic resonance imaging (MRI) scanning;
Inability to complete basic fMRI requirements;
History of brain surgery or penetrating brain injury;
Uncontrolled blood pressure (low or high);
Contraindications to tolcapone use;
Use of medications or drugs with dopamine-related actions within 30 days;
Active substance abuse or dependence;
Clinically severe medical illness requiring treatment;
History of psychiatric hospitalization (past 1 year) or suicide attempt (past 5 years);
Seizures greater than 4 weeks after traumatic brain injury (TBI) event or seizures requiring active treatment;
History of brain tumor, stroke, Alzheimer's disease, aneurysm rupture, or multiple sclerosis;
History of schizophrenia, attention deficit hyperactivity disorder (ADHD) or psychiatric diagnosis EXCEPT depression or post-traumatic stress disorder (PTSD)

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Functional MRI Arm 1: Tolcapone first, then placebo	Tolcapone	This cognitive science study consists of a single "arm" in which all subjects receive both tolcapone and placebo in randomized, double-blind, counterbalanced, crossover fashion. Subjects have been divided into two arms based on the order in which they received the drug intervention. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses.
Functional MRI Arm 1: Tolcapone first, then placebo	Placebo	This cognitive science study consists of a single "arm" in which all subjects receive both tolcapone and placebo in randomized, double-blind, counterbalanced, crossover fashion. Subjects have been divided into two arms based on the order in which they received the drug intervention. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses.
Functional MRI Arm 2: Placebo first, then tolcapone	Tolcapone	This cognitive science study consists of a single "arm" in which all subjects receive both tolcapone and placebo in randomized, double-blind, counterbalanced, crossover fashion. Subjects have been divided into two arms based on the order in which they received the drug intervention. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses.
Functional MRI Arm 2: Placebo first, then tolcapone	Placebo	This cognitive science study consists of a single "arm" in which all subjects receive both tolcapone and placebo in randomized, double-blind, counterbalanced, crossover fashion. Subjects have been divided into two arms based on the order in which they received the drug intervention. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses.

Primary Outcome Measures

Name	Time	Method
Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI.	Approximately 60-240 minutes following tolcapone/placebo administration	Functional MRI measures blood flow changes. Blood Oxygen Level Dependent (BOLD) signals provide an indirect unitless measure of brain activity typically described as a percentage. However, because fMRI data sets are large (\> 10,000 comparisons), analysis packages present results as F statistics or similar measures for individual voxels across the brain. Thus, no single mean or median value describes the 3-way interaction between drug (tolcapone minus placebo), stimulus emotion (neutral versus anxious), and CAPS-score with degrees of freedom = \[1,1,60\]. Because each subject serves as his/her own control, drug results are also intrinsically paired -- i.e. data are presented for participants as tolcapone minus placebo results within subject. The data values below represent the number of above-threshold, neighboring voxels in the largest clusters of voxels in the brain for the patient group as a whole, not separately for each participant.
Performance on Cognitive Testing	Approximately 60-240 minutes following tolcapone/placebo administration	Tasks to assess cognition were performed while subjects are scanned. Signal detection theory (SDT) assesses the ability of subjects to accurately recall working memory memoranda. In SDT, the sensitivity index d' results from subtracting the normalized false alarm rate from the normalized hit rate; thus, higher values of d' indicate better working memory performance. Here we evaluate the interaction with respect to d' between drug condition (tolcapone minus placebo) and Post-Traumatic Stress Disorder severity as measured by the total score on the \Clinician Administered PTSD Scale\, or CAPS. Total CAPS scores range from 0 to 80, with higher scores indicating greater PTSD severity. Because each subject serves as his/her own control, drug results for behavior are intrinsically paired -- i.e. data are presented for participants as tolcapone minus placebo results, as prespecified in the statistical analysis plan.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (1): VA Northern California Health Care System, Mather, CA
🇺🇸
Sacramento, California, United States
VA Northern California Health Care System, Mather, CA
🇺🇸Sacramento, California, United States