Efficacy of Pharmacological Treatment of Working Memory Impairment After Traumatic Brain Injury: Evaluation With fMRI

Work from our institution has shown that moderate and severe TBI subjects demonstrate an
altered cerebral representation when they attempt to process a verbal WM task. Specifically,
our data show a post-TBI pattern of activation that is dispersed and more lateralized to the
right hemisphere, as compared to healthy controls. Taken together, we interpret these
findings to mean that it is requires more cerebral resources for TBI subjects to process
tasks that were previously more automatic. In other words, their processing is less
efficient. This is consistent with TBI patients’ self-reports of needing to expend greater
cognitive effort to perform such tasks, both in the lab and in everyday life. Our
preliminary data was the first step in understanding the cerebral substrate of these
difficulties. However, simply indicating that individuals with TBI have a WM problem is not
enough. The development of targeted interventions to ameliorate these deficits is the next
step in the treatment process.

The present proposal has important implications for TBI rehabilitation. One of the major
goals of cognitive remediation is to help TBI patients learn new information more accurately
and efficiently, and to improve their performance in activities of everyday life. 123
Because WM impairments are so prevalent in TBI, the present study can help to shed light on
potential treatment alternatives for these potentially devastating problems. In spite of the
prevalence and popularity of cognitive remediation strategies and procedures, there remains
little empirical support for their efficacy, and virtually no understanding of the
underlying neurocognitive processes that facilitate intervention. The ability to develop a
potentially efficacious treatment modality, which has a solid foundation, would be immensely
beneficial.

Inclusion Criteria:

We will include only those subjects who have sustained moderate to severe initial
injuries, as defined by an initial 24-hour Glasgow Coma Scale 128 scores below 13. In the
event that a GCS score is not available, subjects will only be included if there is
sufficient medical documentation that would allow for a post-hoc estimation of initial
GCS, or if other confirmatory data (e.g., positive anatomic neuroimaging findings, focal
neurologic signs) are available. Individuals with a history of prior moderate to severe
head injury, stroke, seizures, severe psychiatric disturbances (i.e., those known to
influence memory performance, such as schizophrenia, bipolar disorder), or drug abuse will
not be included as subjects. In addition, a score of 11 or greater on the Mini Mental
Status Exam will be required to insure that subject can participate effectively in the
study protocol. Because of potential effects on cognition and hemodynamic response,
subjects currently taking benzodiazepines, narcotics, neuroleptics, anticonvulsants,
antispasticity agents or psychostimulants will not be included.

In addition, any patient that is on medications that may interact with any of the study
medications (e.g. birth control bills or cyclosporin). Psychiatric symptoms and substance
abuse history will be obtained using a structured psychiatric interview, the Diagnostic
Interview Schedule 129DIS. In addition patients with history of drug dependency,
hypertension out of control, significant cardiac disease, or inability to undergo MRI.
(e.g. metalworker, Medtronic infusion pump)