Remediation of Impaired Self-Regulation in Patients With Mild TBI

Early Phase 1CompletedNCT02260570

VA Office of Research and Development55 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Mild Traumatic Brain Injury

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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.

Time frame: 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.