Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI)

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.

Inclusion criteria

• Age: Individuals aged 18-65 who sustained a mild to severe TBI 4 months prior to study entry.
• 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.
• 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:

• a history of other neurologic disorders (such as epilepsy, cerebrovascular disease, mental retardation, neurodegenerative disorders)
• significant systemic medical illness such as clinically significant liver disease, renal disease, atherosclerotic coronary vascular disease, or hypertension requiring medication management
• 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
• women currently pregnant or lactating. Female participants will be asked to take a pregnancy test to confirm they are not currently pregnant.