Brain Injury
Conditions
Keywords
TBI, Memory, Methylphenidate, Ritalin, Memory and Attention Training
Brief summary
Traumatic brain injury (TBI) is a significant public health problem, with 1.5-2.0 million Americans injured each year. Cognitive deficits, particularly in the domains of memory and attention are frequently the source of lingering disability after TBI and a source of enormous distress to the injured individuals and their family/caregivers. To date, interventions to ameliorate chronic cognitive deficits have been directed at either pharmacological interventions or cognitive rehabilitation. We propose to (1) To compare the efficacy of three interventions: memory and attention training (MAAT), methylphenidate, and memory/attention training in combination with methylphenidate and (2) use functional MRI (fMRI) to characterize changes in activation of the neural circuitry of memory and attention due to MAAT alone, methylphenidate alone, and MAAT in combination with methylphenidate. This is a two by two design with medication (methylphenidate/placebo) and cognitive therapy (Memory and Attention Training (MAAT) or an Attention control intervention) as possible interventions. Using a randomized, placebo-controlled, double-blind design, 200 individuals with persistent cognitive deficits 6-12 months after MTBI will be randomized to receive a six week trial of either (1) MAAT and placebo, (2) MAAT and methylphenidate (0.3 mg/kg BID), (3) attention control intervention and methylphenidate (0.3 mg/kg BID), or (4) attention control intervention and placebo. Symptom distress, attention and memory performance, and activation patterns of the neural circuitry of attention and memory while undergoing fMRI will be characterized at baseline, and after the four treatment conditions. This study will provide important information on three interventions for the most disabling sequelae of an enormous public health problem. Further, it will help to clarify underlying neural mechanisms and suggest additional treatment possibilities.
Detailed description
Summary and Gaps to be Addressed by the Proposed Study What is known: There are two interventions of promising efficacy in ameliorating deficits in attention and memory after mild traumatic brain injury (MTBI): (i) memory and attention training/rehabilitation, and (ii) catecholaminergic augmentation (particularly with methylphenidate - which augments both dopaminergic and adrenergic systems). fMRI and other functional imaging strategies are providing valuable insights into the underlying neural mechanisms of the cognitive enhancing effects of methylphenidate in some neuropsychiatric populations (individuals with ADHD), and the effects of cognitive rehabilitation efforts in some domains (e.g. speech and language in individuals after stroke). What is not known: To date there are no studies that apply a psychopharmacological strategy of augmenting neurotransmitter systems known to modulate memory/attention (dopaminergic and adrenergic systems) in combination with a cognitive rehabilitation intervention known to improve memory/attention (memory/attention training) in individuals with MTBI. We are aware of no published studies that use fMRI to assess the neural mechanisms of memory/attention improvement from the use of catecholaminergic agents or memory/attention training in individuals with MTBI. It is important to determine the efficacy of combined memory/attention training and methylphenidate. It is equally important to begin to understand the neural mechanisms underlying effective treatment as it may help to inform the development of the next generation of interventions and perhaps lead to individually tailored treatment interventions. This proposal will start to address these gaps in our knowledge.
Interventions
OTHERPlacebo as both treatments
Placebo capsules and Placebo Memory and Attention Training
DRUGMethylphenidate
Dosage dependent on weight
BEHAVIORALMemory and Attention Training
Weekly Memory and Attention Training with at home practice.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Dartmouth-Hitchcock Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age: Individuals aged 18-65 who sustained a mild to severe TBI 4 months prior to study entry. 2. TBI: Subjects must sustain a traumatic blow to the head, resulting in either alteration of level of consciousness (manifested by being dazed and confused or having amnesia for the event) or loss of consciousness (LOC). Duration of LOC will be estimated by using all available information including patient and witness reports, emergency personnel records and Dartmouth Hitchcock Medical Center (DHMC) medical records. Post traumatic amnesia (PTA) will be estimated by careful questioning of patients to determine the time of return of continuous memory. This will be informed by review of medical records. We plan to include individuals with intracranial or skull injuries stemming from the TBI, providing they meet the inclusion criteria. Such lesions will be catalogued, and included as a factor in the data analysis. 3. Cognitive Deficits: Subjects will have either subjective and objective evidence of persistent cognitive deficits. Subjects must report persistent memory or attention deficits as a result of their injury, which are of sufficient severity to interfere with social and/or occupational functioning. Subjects must either score more than 2 standard deviations below the age adjusted norm or estimates of baseline premorbid function on one or more tests of attention and/or memory administered as part of the baseline screening cognitive battery (see below), or score greater than 1.0 standard deviations below either age adjusted norms or estimates of premorbid function on 2 or more of the screening tests.
Exclusion criteria
The following factors will exclude otherwise eligible subjects from participation: 1. a history of other neurologic disorders (such as epilepsy, cerebrovascular disease, mental retardation, neurodegenerative disorders) 2. significant systemic medical illness such as clinically significant liver disease, renal disease, atherosclerotic coronary vascular disease, or hypertension requiring medication management 3. current Diagnostic and Statistical Manual (DSM-IV) Axis I diagnosis of psychiatric illness other than substance abuse. We have given careful consideration to the inclusion of the latter group given our use of a stimulant with potential abuse properties. Because of the potential for cross-over abuse with cocaine, amphetamines, and other stimulants, individuals with such histories will be excluded from this study. Individuals with history of otherwise uncomplicated ethanol or other non-stimulant drug abuse currently in stable remission will be eligible. The Structured Clinical Interview for DSM-IV (MINI) will be used to screen for psychiatric illness 4. women currently pregnant or lactating. Female participants will be asked to take a pregnancy test to confirm they are not currently pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment) | pre- to post-6 week treatment intervention (at least 7 weeks) | Change in performance (percent correct,adjusted for guessing) from pre-(baseline) to post-treatment (approximately 7 weeks) for in-scanner n-back working memory task (Range: 0-100). Higher scores means better performance. |
| Neuropsychological Assessment, CVLT-II | post-intervention (at least 7 weeks) | Memory measure: California Verbal Learning Test, 2nd edition (CVLT), Total, trials 1-5 (range: 0-80). Higher scores are better outcome. |
| Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time) | post-intervention (at least 7 weeks) | Continuous Performance Test, Distractibility Condition (Reaction Time in msecs) (range: 0-800). Higher score is worse performance. |
| Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | pre- to post-treatment (at least 7 weeks) | Change from pre- to post-treatment in brain activation in the right inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment. |
| Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | pre- to post-intervention (at least 7 weeks) | Change from pre- to post-treatment in brain activation in the anterior cingulate region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment. |
| Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | pre- to post-treatment (at least 7 weeks) | Change from pre- to post-treatment in brain activation in the left middle/inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self Report Questionnaire - MASQ | post-intervention (at least 7 weeks) | The Multiple Abilities Questionnaire (self rating) is a questionnaire in which participants can identify deficits/complaints in the areas of language, visual perception, verbal memory, visual memory and attention and concentration. A total score is calculated; range is 30-130. Higher scores indicate greater level of complaints (worse outcome). For the purposes of this study, a score one standard deviation above the mean (102.7) indicated significant reported cognitive complaints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Both Conditions Placebo as both treatments: Placebo capsules and Placebo Memory and Attention Training | 19 |
| Active Drug/Active Therapy Methylphenidate: Dosage dependent on weight
Memory and Attention Training: Weekly Memory and Attention Training with at home practice. | 18 |
| Active Drug/Placebo Therapy Methylphenidate: Dosage dependent on weight | 20 |
| Placebo Drug/Active Therapy Memory and Attention Training: Weekly Memory and Attention Training with at home practice. | 19 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo Both Conditions | Total | Placebo Drug/Active Therapy | Active Drug/Placebo Therapy | Active Drug/Active Therapy |
|---|---|---|---|---|---|
| Age, Continuous | 37.3 years STANDARD_DEVIATION 14.2 | 40.1 years STANDARD_DEVIATION 13.3 | 37.2 years STANDARD_DEVIATION 12 | 43.0 years STANDARD_DEVIATION 15 | 43.1 years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 73 Participants | 17 Participants | 20 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 72 Participants | 17 Participants | 19 Participants | 17 Participants |
| Region of Enrollment United States | 19 Participants | 75 Participants | 18 Participants | 20 Participants | 18 Participants |
| Sex: Female, Male Female | 6 Participants | 26 Participants | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 49 Participants | 14 Participants | 14 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 | 0 / 20 | 0 / 18 |
| other Total, other adverse events | 8 / 19 | 12 / 18 | 11 / 20 | 9 / 18 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 | 0 / 20 | 0 / 18 |
Outcome results
Primary
Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention
Change from pre- to post-treatment in brain activation in the anterior cingulate region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.
Time frame: pre- to post-intervention (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | -0.31 units on a scale | Standard Deviation 0.36 |
| Active Drug/Active Therapy | Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | 0.09 units on a scale | Standard Deviation 0.36 |
| Active Drug/Placebo Therapy | Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | 0.20 units on a scale | Standard Deviation 0.42 |
| Placebo Drug/Active Therapy | Change in Anterior Cingulate Gyrus Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | 0.05 units on a scale | Standard Deviation 0.27 |
p-value: <0.05ANCOVA
Primary
Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention
Change from pre- to post-treatment in brain activation in the left middle/inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.
Time frame: pre- to post-treatment (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | -0.16 units on a scale | Standard Deviation 0.2 |
| Active Drug/Active Therapy | Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | 0.04 units on a scale | Standard Deviation 0.15 |
| Active Drug/Placebo Therapy | Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | 0.07 units on a scale | Standard Deviation 0.24 |
| Placebo Drug/Active Therapy | Change in Left Middle/Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | .10 units on a scale | Standard Deviation 0.21 |
Primary
Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention
Change from pre- to post-treatment in brain activation in the right inferior frontal region of interest in arbitrary units provided by the SPM (statistical parametric mapping) program (range: unknown). Higher scores indicate greater increase in activation from pre- to post-treatment.
Time frame: pre- to post-treatment (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | -0.18 units on a scale | Standard Deviation 0.28 |
| Active Drug/Active Therapy | Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | 0.05 units on a scale | Standard Deviation 0.28 |
| Active Drug/Placebo Therapy | Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | .15 units on a scale | Standard Deviation 0.29 |
| Placebo Drug/Active Therapy | Change in Right Inferior Frontal Activation During Working Memory Processing (3-back > 0-back Condition) From Baseline to Post-intervention | .14 units on a scale | Standard Deviation 0.22 |
Primary
Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment)
Change in performance (percent correct,adjusted for guessing) from pre-(baseline) to post-treatment (approximately 7 weeks) for in-scanner n-back working memory task (Range: 0-100). Higher scores means better performance.
Time frame: pre- to post-6 week treatment intervention (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment) | -4.46 percentage of correct targets (adjusted) | Standard Deviation 30.8 |
| Active Drug/Active Therapy | Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment) | 4.69 percentage of correct targets (adjusted) | Standard Deviation 26.8 |
| Active Drug/Placebo Therapy | Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment) | 4.86 percentage of correct targets (adjusted) | Standard Deviation 29.5 |
| Placebo Drug/Active Therapy | Functional MRI Task Performance and Brain Activation (Change From Baseline to Post-treatment) | -0.36 percentage of correct targets (adjusted) | Standard Deviation 23.4 |
p-value: <0.05ANOVA
Primary
Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time)
Continuous Performance Test, Distractibility Condition (Reaction Time in msecs) (range: 0-800). Higher score is worse performance.
Time frame: post-intervention (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time) | 426.4 units on a scale | Standard Deviation 15.3 |
| Active Drug/Active Therapy | Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time) | 394.7 units on a scale | Standard Deviation 17.3 |
| Active Drug/Placebo Therapy | Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time) | 416.6 units on a scale | Standard Deviation 15.9 |
| Placebo Drug/Active Therapy | Neuropsychological Assessment - CPT, Distractibility Condition (Reaction Time) | 413.0 units on a scale | Standard Deviation 17.3 |
Primary
Neuropsychological Assessment, CVLT-II
Memory measure: California Verbal Learning Test, 2nd edition (CVLT), Total, trials 1-5 (range: 0-80). Higher scores are better outcome.
Time frame: post-intervention (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Neuropsychological Assessment, CVLT-II | 51.3 units on a scale | Standard Deviation 1.9 |
| Active Drug/Active Therapy | Neuropsychological Assessment, CVLT-II | 51.8 units on a scale | Standard Deviation 2.1 |
| Active Drug/Placebo Therapy | Neuropsychological Assessment, CVLT-II | 51.9 units on a scale | Standard Deviation 1.9 |
| Placebo Drug/Active Therapy | Neuropsychological Assessment, CVLT-II | 57.2 units on a scale | Standard Deviation 2 |
p-value: <0.04Kruskal-Wallis
Secondary
Self Report Questionnaire - MASQ
The Multiple Abilities Questionnaire (self rating) is a questionnaire in which participants can identify deficits/complaints in the areas of language, visual perception, verbal memory, visual memory and attention and concentration. A total score is calculated; range is 30-130. Higher scores indicate greater level of complaints (worse outcome). For the purposes of this study, a score one standard deviation above the mean (102.7) indicated significant reported cognitive complaints.
Time frame: post-intervention (at least 7 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Both Conditions | Self Report Questionnaire - MASQ | 116.4 units on a scale | Standard Deviation 4.5 |
| Active Drug/Active Therapy | Self Report Questionnaire - MASQ | 120.5 units on a scale | Standard Deviation 4.8 |
| Active Drug/Placebo Therapy | Self Report Questionnaire - MASQ | 114.1 units on a scale | Standard Deviation 4.5 |
| Placebo Drug/Active Therapy | Self Report Questionnaire - MASQ | 118.1 units on a scale | Standard Deviation 4.8 |
p-value: <0.01ANCOVA
p-value: <0.05ANCOVA