DESCRIPTION (provided by applicant): At present, the ability to apply or develop neurocircuitry-based treatments founded on cognitive neuroscience is still extremely limited for two fundamental reasons: 1) conventional neuroimaging studies provide information on correlations between brain and behavior, but not how activity in one brain region directly drives activation or inhibition in another. To understand the causal relationships between different brain regions or networks, it is necessary to exert direct experimental control over specific brain regions and simultaneously image the consequences on other brain regions or networks. We refer to this as a "causal circuit map." Consequently, 2) it is unknown which specific neural pathways within these causal circuit maps are abnormal and which are intact in patients, and how particular clinical factors such as trauma exposure impact these brain pathways. It would be of fundamental theoretical and practical importance for implementing a future circuit-targeting neuromodulatory intervention to know, for example, whether stimulation should be directed to intact pathways or to abnormal ones (with a goal of normalizing dysfunction). Without causal circuit mapping, target identification and validation for future neuromodulatory treatments, such as repetitive transcranial magnetic stimulation (rTMS), will remain as trial-and-error guesswork. An additional limitation of prior studies on mood/anxiety-related disorders is that the DSM does not capture the full spectrum of clinically-significant negative affect symptomatology, including the role of trauma in clinical syndromes beyond post-traumatic stress. Our primary focus in this proposal is therefore to delineate for the first time the causal circuit maps relevant for impairments in emotion regulation (ER) and executive function (EF) in a broad range of chronically ill patients with high negative affect symptoms, consistent with the aims of the Research Domain Criteria Project (RDoC). Prior work on high negative affect disorders with correlational imaging has found abnormalities across multiple nodes in several well-defined large-scale neuronal networks. However, unlike these prior correlational studies, we propose to employ a causal circuit mapping neuroimaging approach to achieve an unprecedented level of specificity with regard to which causal brain pathways are intact and which are abnormal. Here we provide this casual map by direct brain activation using non-invasive single pulse excitatory TMS (spTMS), combined with visualization of network effects using concurrent functional magnetic resonance imaging (fMRI). The targets for spTMS/fMRI are cortical regions within well-defined large-scale networks relevant to ER/EF (eight bilateral prefrontal sites as well as one control site), thus systematically linking causal maps to circuit-level models of the illnesses A successful outcome from this study would be directly useful in guiding how and where to target existing long-term neuromodulatory interventions, and lay the groundwork for the development of novel methods.

PUBLIC HEALTH RELEVANCE: Neurocircuitry underlying emotion regulation and executive functioning has been found to be perturbed across a range of anxiety, depression and trauma-related disorders, and yet current treatments do not directly target, nor are informed by, these cognitive neuroscience insights. The proposed study will tie an innovative approach for direct circuit manipulation and mapping to an understanding of the neural mechanisms a broad range of high negative affect symptomatology, consistent with the aims of the Research Domain Criteria Project (RDoC). Thus, the overall goal of this research program is to provide the necessary evidence base, across high negative affect states and with respect to the specific impact of trauma, for the application and development of future neuromodulatory interventions.