Sustained Attention and Executive Functioning After Brain Trauma

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ABSTRACT Traumatic brain injury (TBI) affects 2 million individuals in the United States each year, ranging from mild concussions to severe trauma or, in about 50,000 cases, even death. TBI survivors endure long-lasting memory loss and cognitive impairments associated with frontal lobe disturbances, as well as psychological consequences. TBI models in the laboratory have been associated for decades with declines in long-term learning and memory, although the types of behavioral tests performed to date have not focused on the complex attention impairments related to the frontal lobe, which are common in most brain injuries. Specifically, higher-order cognitive capabilities such as sustained attention and executive functioning are significantly affected by TBI and represent sophisticated brain capacities to direct and focus cognitive activity on specific stimuli or use environmental feedback to “unlearn” a previously valid set of rules, switch gears and filter unwanted distractions, respectively. The overarching aim of this proposal is to assess clinically- relevant cognitive-behavioral dimensions sensitive to TBI, and to begin to address mechanistic questions regarding altered neurotransmission responsible for such behavioral deficits. Specifically, the aims are designed to 1) determine higher-order cognitive function capabilities, namely sustained attention via the 3-choice serial reaction time task and cognitive flexibility via the attentional set-shifting test, after moderate TBI, which are tasks that have not been assessed after experimental TBI and 2) evaluate moderate TBI-induced changes in brain markers of monoamine regulation, such as vesicular monoamine transporter 2, tryptophan hydroxylase and tyrosine hydroxylase in [discrete brain regions critical for directly or indirectly modulating] goal directed behavior and executive function. The proposed studies will be carried out in both male and normal cycling female rats, an approach that is clinically relevant. Specifically, females account for up to 45% of the TBI population and these injuries occur independent of estrous stage and therefore evaluating normal cycling females parallels the real world. Integrating animal models of higher-order cognition in the standard neurotrauma battery of behavior after TBI as well as assessing monoamine regulation in cortical regions not well studied after TBI is paramount to investigating complex cognitive problems and finding therapeutic targets more relevant to the clinic. This two-year R03 grant will generate preliminary data that will serve as proof-of-concept for an NIH R01 individual grant application, allowing future work to also evaluate potential pharmacological and rehabilitative therapies for TBI-induced cognitive dysfunction.