Remediation of Impaired Self-Regulation in Patients With Mild TBI

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.

Study Overview

• Status: Completed
• Conditions: Mild Traumatic Brain Injury
• Intervention / Treatment: Drug: Tolcapone; Drug: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95655
      • VA Northern California Health Care System, Mather, CA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Functional MRI Arm 1: Tolcapone first, then 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.	Drug: Tolcapone; COMT Inhibitor; Other Names: Tasmar; Drug: Placebo; A pill that contains no active ingredient
Experimental: Functional MRI Arm 2: Placebo first, then 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.	Drug: Tolcapone; COMT Inhibitor; Other Names: Tasmar; Drug: Placebo; A pill that contains no active ingredient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI.	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.	Approximately 60-240 minutes following tolcapone/placebo administration
Performance on Cognitive Testing	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.	Approximately 60-240 minutes following tolcapone/placebo administration

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: University of California, Berkeley; University of California, San Francisco
• Investigators: Principal Investigator: Andrew S Kayser, MD PhD, VA Northern California Health Care System, Mather, CA

Publications and helpful links

General Publications

• Westphal AJ, Ballard ME, Rodriguez N, Vega TA, D'Esposito M, Kayser AS. Working memory, cortical dopamine tone, and frontoparietal brain recruitment in post-traumatic stress disorder: a randomized controlled trial. Transl Psychiatry. 2021 Jul 12;11(1):389. doi: 10.1038/s41398-021-01512-6.

Helpful Links

• Reference + link to the published open-access manuscript

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): June 30, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: October 6, 2014
• First Submitted That Met QC Criteria: October 6, 2014
• First Posted (Estimated): October 9, 2014

Study Record Updates

• Last Update Posted (Estimated): September 22, 2025
• Last Update Submitted That Met QC Criteria: September 17, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: MRI; memory; post-traumatic stress disorder; concussion; tolcapone
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Brain Injuries, Traumatic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds, Nonpenetrating; Brain Injuries; Stress Disorders, Traumatic; Brain Concussion; Stress Disorders, Post-Traumatic; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Nitro Compounds; Ketones; Benzophenones; Nitrophenols; Tolcapone
• Other Study ID Numbers: D0825-I; 1I01RX000825-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No