DESCRIPTION (provided by applicant): Our ability to regulate our impulses enables us to plan for the future, to maintain our focus in th face of distractions, and to manage our emotions. Failures of self-regulation are an important component of mild traumatic brain injury (mTBI) and co-occurring disorders, including substance abuse and PTSD. Because of the importance of self-regulation in our daily lives, impairments have profound effects on the lives of Veterans with mTBI, who complain of poor decision making, diminished concentration, and difficult-to-control emotions. Due to barriers to care including the severity of these symptoms, the remoteness of their homes, and concerns about disclosing the extent of their deficits, many of these Veterans are poorly able to participate in counseling and cognitive rehabilitation to address these issues. In such circumstances, effective adjunctive medications to improve self-regulation are important to reinforce the ability of these Veterans to manage their symptoms and to engage in behavioral therapies. Unfortunately, very few medications are effective for cognitive issues in patients with mTBI, and current agents are not effective for many symptoms and for many Veterans. The purpose of this application is to develop adjunctive medication options for the treatment of impaired self-regulation. To this end, we will use functional MRI to identify relevant brain networks, and a medication, tolcapone, that our preliminary data suggests will improve brain function. Specifically, self-regulatory deficits ae thought to emerge from failures of top- down control - i.e. the ability of higher-order goals to constrain impulses, habits, and other more "stimulus-driven" responses. Convergent data from multiple fields argue that top-down control in the brain is reflected in the ability of prefrontal cortex to influence activity in other brain regions. Given the clear need for new therapeutic approaches to self-regulatory impairments, this mapping from brain to behavior identifies a potential biomarker for self-regulatory failure, and points toward a strategy for developing treatments. As we detail in our study, both our work and other reports suggest that tolcapone may improve the ability of prefrontal cortex to influence other brain areas by increasing the amount of dopamine in the frontal cortex. Thus, we propose to directly test the hypotheses that self-regulatory deficits in Veterans with mTBI result from diminished top-down control, and that administration of tolcapone will improve self-regulation. We will employ three clinically-relevant tasks within a randomized, double-blind, placebo- controlled translational functional MRI study to address behavioral, cognitive, and emotional self-regulation, respectively: a financial decision-making task that balances short-term and long-term goals, an attentional task that requires subjects to pay attention to some objects but not to others, and an emotion regulation task that addresses emotion-cognition interactions. By testing tractable hypotheses, these studies address a critical barrier to progress in the fields of cognitive rehabilitation and psychotherapy. By using brain imaging to evaluate the influence of tolcapone on brain activity related to relevant tasks, we gain insights into mechanism of action that can guide the development of treatments, whether pharmacological or otherwise. This proposal thus represents an innovative, pragmatic approach to a problem - self-regulatory difficulty after mTBI - that is widespread, under-treated, and for which Veterans desperately want new therapies.

Our ability to regulate our impulses enables us to plan for the future, to maintain our focus in th face of distractions, and to manage our emotions. Failures of self-regulation are an important component of mild traumatic brain injury (mTBI) and co-occurring disorders, including PTSD and substance abuse. Veterans with mTBI often report poor decision making, diminished concentration, and difficult-to-control emotions. Due to barriers to care including the severity of these symptoms, the remoteness of their homes, and/or concerns about disclosing the extent of their deficits, many Veterans are poorly able to participate in counseling and cognitive rehabilitation to address these issues. This proposal seeks to understand and develop adjunctive medication treatments that improve self-regulation in Veterans with mTBI and thereby improve daily function, participation in therapies, and quality of life.