Visceral neural circuits linking childhood threat and deprivation with stress physiology and affective symptoms in a transdiagnostic sample using high-field personalized brain mapping

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Project Summary/Abstract Childhood adversity was recently posited to be psychiatry's greatest public health challenge, as it is a major predictor of mood, anxiety and trauma-related (i.e., affective) disorders. Childhood adversity is also associated with dysregulated physiological stress reactivity, which individuals with affective disorders also display. While stress is thought to be a mechanism by which childhood adversity influences physical and mental health, few studies have considered stress-related brain regions beyond corticoamygdalar and hippocampal structures and little is known regarding how childhood adversity impacts specific, proximally stress-responsive neural circuits. Central visceral circuits (CVCs) are implicated in affective psychopathology and are critical in the control of stress responses. CVCs comprise visceromotor and viscerosensory pathways that reciprocally connect hypothalamic and limbic forebrain regions to brainstem nuclei. Preliminary data show significant links between: 1) childhood adversity and CVCs and 2) CVCs and affective symptoms. These results also suggest opposing influences of childhood “threat” vs. “deprivation” on CVCs. “Threat” experiences include abuse and other traumatic events, while “deprivation” comprises diminished environmental stimuli, such as low childhood socioeconomic status or neighborhood deprivation. Interestingly, evidence suggests that threat blunts, while deprivation heightens physiological stress reactivity (e.g., cortisol reactivity). Thus, we propose that threat and deprivation may have different effects on the CVCs most proximal to the control of stress responses, including understudied regions such as the brainstem nucleus of the solitary tract (NST), paraventricular nucleus of the hypothalamus (PVN) and bed nucleus of the stria terminalis (BST). In the proposed, limitations of lower field strength MRI are overcome with the improved signal-to-noise and unprecedented resolution of high-field MRI at 7 Tesla. Multimodal neuroimaging will acquire specialized structurals, and resting-state, mental stress and emotion-evoked, and white matter connectivity. Stress physiology measures will also be collected. Consistent with the RDoC initiative, we will recruit a continuous and transdiagnostic community sample of 220 young adults (ages 18-35) with a full range of childhood threat, deprivation and affective symptoms to examine: 1) the effects of childhood threat and deprivation on CVC connectivity, 2) the effects of childhood threat and deprivation on stress physiology and affective symptoms, and 3) the extent to which CVC connectivity mediates the relationship between threat and deprivation, and physiological and affective outcomes. Significance. Our proposal is congruent with NIMH Strategy 1.3, Map the connectomes for mental illnesses, focusing on CVCs as the “connectome” of interest. Elucidating how CVCs may link childhood threat and deprivation to stress physiology and affective symptoms using high-field personalized brain mapping may enhance our ability to translate findings from preclinical models and may guide clinical thinking by providing novel proximally stress-responsive targets and/or novel or integrative approaches for intervention.