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Development of Pharmaco fMRI Challenge in Healthy Control and Aggressive Subjects

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In this R21 application, we propose to develop S-Citalopram (S-CIT) as a Psychopharmacologic Challenge (PPC) agent used in conjunction with the fMRI examination of social-emotional processing. PPC studies have been in use in biological psychiatry for more than 30 years. Optimally, PPC studies involve the use of an agent that selectively activates a central neurotransmitter synapse or that acts at a known receptor (or receptors) of a specific neurotransmitter system. While behavioral and/or peripheral hormonal responses were useful as outcome measures both lack the ability to localize brain areas of differences between patient subjects and controls. With the advent of brain imaging there is an opportunity to use central outcome measures in the context of PPC. Some studies have used PET imaging with PPC and have begun to localize the source of patient-control differences. However, PET has limited temporal resolution and is not typically used in conjunction with behaviorally relevant tasks. In contrast, fMRI has excellent temporal resolution and is always used in the context of behaviorally relevant tasks. We propose to develop this method, first, in impulsive aggressive subjects because: a) aggression and impulsivity are inversely correlated with 5-HT function in human subjects, b) social-emotional information processing is partly mediated by 5-HT and, c) social-emotional information processing is altered in impulsive aggressive subjects and patient control differences regarding impulsivity and socio-emotional information processing are localized to relevant regions of the brain (e.g., Orbitomedial Prefrontal Cortex, Anterior Cingulate Cortex and Amygdala). Ultimately, this study will examine both Impulsive Aggressive subjects and Healthy Controls to determine if S-CIT/fMRI Challenge can be developed as a new procedure to examine 5-HT function in the context of relevant behavioral tasks that are simultaneously located to specific brain regions. PUBLIC HEALTH RELEVANCE Recurrent, impulsive aggressive behavior poses a significant concern for our society both from the viewpoint of the individual who engages in these behaviors and of the people and property that these behaviors target. Emerging epidemiological data suggest that "recurrent, problematic, impulsive aggressive behavior" is far from rare and is present in at least 5.4% of the general population lifetime (~ 16 million). This study will examine the neurotransmitter function correlates of impulsivity and social-emotional information processing in impulsive aggressive subjects to determine whether or not 5-HT is relevant to impulsivity and social-emotional information processing in these subjects and if there are subjects-control differences in this regard. In addition, this work has the potential to advance the field of neuropsychopharmacology so that we can examine neurotransmitter function underlying behavioral tasks in specific brain regions. Unlike outcome measures such as behavior and neuroendocrine responsiveness, we can now look directly into the brain to assess the role of specific neurotransmitters.

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