Mild Traumatic Brain Injury
Conditions
Keywords
concussion, MRI, memory, tolcapone, post-traumatic stress disorder
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).
Interventions
DRUGTolcapone
COMT Inhibitor
DRUGPlacebo
A pill that contains no active ingredient
Sponsors
University of California, Berkeley
University of California, San Francisco
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Intervention model description
In this study, subjects received either tolcapone or placebo in randomized, double-blind, counterbalanced fashion. The study is a single arm study in which all subjects receive both tolcapone and placebo, but to comply with clinical trial reporting requirements, it is listed here as a two arm study: one arm for subjects who received tolcapone first, and one arm for subjects who received placebo first. 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. The alternative (grouping by tolcapone or placebo) loses this within-subject information.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
All subjects participated in a single-arm study in which all subjects received tolcapone and placebo in randomized, counterbalanced, crossover fashion. Because baseline dopamine levels can differ substantially between individuals, each subject serves as their own control. As a result, compiling data for a tolcapone arm and a placebo arm is not preferred, as such a grouping ignores the within-subject comparison. Instead, subjects are grouped per sequence.
Pre-assignment details
Subjects were screened based on inclusion and exclusion criteria. Only eligible subjects were assigned to a study arm. 55 subjects provided informed consent to participate in screening and study procedures, but after the screening visit, only 35 subjects were determined to be eligible to proceed to study arm assignment.
Participants by arm
| Arm | Count |
|---|---|
| Baseline Data for All Subjects 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. Baseline information was obtained across the entire group, not per arm
Tolcapone: COMT Inhibitor
Placebo: A pill that contains no active ingredient | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Baseline Data for All Subjects |
|---|---|
| Age, Continuous | 35.5 years STANDARD_DEVIATION 8.3 |
| Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) | 25.4 units on a scale STANDARD_DEVIATION 19.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
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
Population: Using the Analysis of Functional Neuroimaging (AFNI) package, we implemented a 3-way ANOVA for the interaction between drug (tolcapone minus placebo), stimulus emotion (neutral versus anxious), and CAPS score. In the summary analysis below, the number of suprathreshold voxels below represents 2.65mm3 isotropic voxels in the left frontal pole and right inferior gyrus, respectively. It is a count, not a mean, and the fMRI package does \*not\* provide bootstrapped ranges for suprathreshold voxels.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tolcapone | Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI. | 270 voxels |
| Placebo | Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI. | 111 voxels |
p-value: <0.0001ANOVA
Primary
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.
Time frame: Approximately 60-240 minutes following tolcapone/placebo administration
Population: The population of 30 subjects evaluated in this single arm study is described elsewhere in this record. Here we used a 2-way ANOVA to evaluate the interaction between drug (tolcapone minus placebo) and CAPS-score with respect to the working memory performance measure d', taken from signal detection theory and based upon the hit rate and false alarm rate.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tolcapone | Performance on Cognitive Testing | 25.4 units on a scale |
| Placebo | Performance on Cognitive Testing | 25.4 units on a scale |
p-value: 0.0184ANOVA