Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI)
| Status: | Completed |
|---|---|
| Conditions: | Hospital, Neurology |
| Therapuetic Areas: | Neurology, Other |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 6/15/2018 |
| Start Date: | February 2007 |
| End Date: | May 2013 |
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.
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.
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.
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.
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.
We found this trial at
3
sites
Indiana University INDIANA UNIVERSITY is a major multi-campus public research institution, grounded in the liberal...
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Dartmouth Hitchcock Medical Center Dartmouth-Hitchcock is a national leader in patient-centered health care and building...
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