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 COMT inhibitor tolcapone impacts memory and self regulation, as measured both behaviorally (via cognitive testing) and neurophysiologically (via functional MRI). A new study arm that does not include use of tolcapone, nominally equivalent to the placebo arm only, is now also included to address performance on cognitive testing alone.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Not Applicable

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: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

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 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 (not required for subjects who participate only in the study arm that does not include study medication);
• 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 TBI event or seizures requiring active treatment;
• History of brain tumor, stroke, Alzheimer's disease, aneurysm rupture, or multiple sclerosis;
• History of schizophrenia, ADHD or psychiatric diagnosis EXCEPT depression or 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

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Functional MRI Arm; 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	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	BOLD signal provides an indirect measure of brain activity during cognitive testing	Approximately 60-240 minutes following tolcapone/placebo administration
Performance on Cognitive Testing	Tasks to assess cognition will be performed while subjects are in the MRI scanner	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.

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 (Estimate): October 9, 2014

Study Record Updates

• Last Update Posted (Actual): March 11, 2022
• Last Update Submitted That Met QC Criteria: February 23, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: MRI; memory; traumatic brain injury; concussion; tolcapone
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds, Nonpenetrating; Brain Injuries; Brain Injuries, Traumatic; Brain Concussion; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors; 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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No