This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-MH-101: Biomarkers in Mental Disorders. The application takes a construct-oriented approach to the identification of biomarkers for prevalent forms of mental illness. Specifically, the proposed work focuses on physiological response indicators of two key dispositional constructs that have direct referents in neurobiology as well as behavior: (1) fear/fearlessness, and (2) inhibitory control. Variations in fear and fearlessness are posited to reflect individual differences in the sensitivity of the brain's defensive motivational system. Variations in inhibitory control are posited to reflect individual differences in the functioning of brain systems that modulate affective and behavioral response in the service of distal goals. The current proposal builds on extensive preliminary research directed at developing sensitive and precise psychometric measures of dispositional fear and disinhibitory (externalizing) tendencies and identifying brain correlates of these constructs. We propose that these constructs, because they provide a concrete basis for linking neurobiological systems to measurable deviations in behavior, can serve as important referents for a physiologically based science of individual differences relevant to psychopathology. A two-year program of work is proposed involving collection of psychometric, diagnostic, and physiological (including EEG/ERP) data from a large sample of incarcerated offenders. Analyses will be performed to establish how constructs of dispositional fear and disinhibition, operationalized psychometrically, relate to varying forms of psychopathology (including impulse control disorders, affiliated personality disorders, and psychopathy as assessed by clinical interview) and to varying physiological indicators. In addition, advanced electrocortical analysis techniques including EEG time-frequency decomposition, neural source imaging, and phase coherence analysis will be applied to the brain response data to elucidate neural circuits that underlie individual variations in fear/fearlessness and disinhibition and to clarify how deviations in the functioning of these circuits contribute to varying mental disorders. This work promises to advance our understanding of overlapping and distinctive aspects of varying mental disorders by studying these disorders in relation to unifying constructs with clear neurobiological referents. Work of this kind can provide the basis for direct neurophysiological assessment of individual difference constructs relevant to psychopathology as well as improved identification of individuals at biological risk for the development of mental illness. PUBLIC HEALTH RELEVANCE: Research on the biological bases of impulse control ('externalizing') disorders is essential to an understanding of the causes of such disorders and to developing effective methods for preventing and treating them. The proposed work seeks to bridge clinical-diagnostic entities with underlying biological systems by studying two key dispositional constructs that have direct referents in neurobiology as well as behavior: (1) fear/fearlessness, and (2) inhibitory control. The current work will contribute to an understanding of brain circuits that give rise to individual differences relevant to psychopathology, and provide information that can help to reshape disorder definitions in ways that make them more amenable to biological analysis.