Layla Banihashemi - US grants

DESCRIPTION (provided by applicant): In response to an acute stressor, the autonomic nervous system orchestrates a number of cardiovascular adjustments, including increases in blood pressure and heart rate, which support an adaptive stress response (i.e., "fight or flight"). However, some individuals display "exaggerated" cardiovascular reactions to acute psychological stressors (e.g., large stressor-evoked changes in blood pressure). These individuals are at greater risk for coronary heart disease, the leading cause of death in the United States for the last century. Circuits within the brain control autonomic responses to stress. These circuits begin in hypothalamic and limbic forebrain regions that project to preganglionic neurons that ultimately innervate body organs. The paraventricular nucleus of the hypothalamus (PVN) is particularly important in controlling stress responses in that it not only controls autonomic responses to stress, but also controls stressor-evoked hormone release. The animal literature demonstrates that PVN activity is modulated by cortical and limbic regions also involved in modulating cardiovascular function, particularly the prefrontal cortex (PFC) and the bed nucleus of the stria terminalis (BNST). Further, the animal literature has shown that the PFC exerts an inhibitory influence over the PVN via its projection to the BNST and that the BNST activates the PVN through a direct, dense projection. Together, these regions form a functional circuit that modulates cardiovascular responses to stress. Our goal is to investigate the role of the subgenual cingulate cortex (SCC, the human homologue of the rat medial PFC), BNST, and PVN in human cardiovascular responses to stress using functional magnetic resonance imaging (fMRI) techniques. Thus, we hypothesize that individual differences in cardiovascular stress reactivity will be associated with corresponding individual differences in the SCC-BNST-PVN circuit. Specific Aim 1 tests the hypothesis that individual differences in cardiovascular stress reactivity covary with stressor- evoked activation of the SCC, BNST, and PVN. Stressor-evoked changes in blood pressure and heart rate will be used to assess cardiovascular stress reactivity. Stressor-evoked activation of our regions of interest will be examined using fMRI blood oxygen level-dependent (BOLD) responses. Specific Aim 2 tests the hypothesis that individual differences in cardiovascular stress reactivity covary with functional connectivity between these regions. Functional connectivity analyses measure the correlated activation of distinct brain regions and are the best techniques available for examining a system of circuits in human brain imaging. Our proposed experiments will enhance our understanding of the neural circuitry underlying risk for coronary heart disease. PUBLIC HEALTH RELEVANCE: Coronary heart disease (CHD) has been the leading cause of death in the United States for the last century. Some individuals display "exaggerated" cardiovascular reactions to acute psychological stressors (e.g., large changes in blood pressure) and these individuals are at greater risk for developing CHD. Thus, to better understand neural mechanisms underlying CHD risk, it is important to understand individual differences in the function of neural circuits that control cardiovascular responses to stress.

DESCRIPTION (provided by applicant): Childhood adversity is a risk factor for developing recurrent and chronic mood and anxiety disorders. Further, childhood adversity is associated with dysregulated stress reactivity, which also underlies mood and anxiety disorders. However, the mechanisms by which childhood adversity shapes stress reactivity and confers vulnerability to stress-related affective disorders are unclear. Central visceral circuits (CVCs) comprise a candidate neural mechanism that may underlie both dysregulated stress reactivity and affective disorders. These circuits are the neural basis of brain-body connections, and are responsible for the reciprocal relationship between affect and physiology and the control of stress responses. CVCs encompass descending preautonomic circuits that orchestrate physiological outflow, and ascending viscerosensory circuits that relay information regarding body state from the brainstem to higher order brain areas. Early life experience differentially influences the structure and function of CVCs, as evidenced by studies in rat. While childhood adversity is associated with gross variations (e.g., in volume) within emotion-related brain regions and tracts in humans, littl is known regarding how childhood adversity specifically influences CVCs. To test the central hypothesis that childhood adversity influences later stress reactivity and vulnerability to affectie disorders via changes in the structure and function of CVCs, three aims will be evaluated in a representative community sample of 120 young adults. These participants will be well characterized for childhood adversity (e.g., emotional and physical abuse or neglect, parental arguing) and affective disorder symptoms (i.e., depressive and anxious symptoms). Participants will complete one MRI scanner session in order to gain multimodal neuroimaging data, including: 1. High-resolution structural connectivity (measures derived from a diffusion spectrum imaging sequence and subsequent detailed tractography), 2. Structural integrity (measures derived from a diffusion tensor imaging sequence), and 3. Stressor-evoked functional connectivity (psychophysiological interaction analyses performed with blood-oxygen-level dependent time-series data). Aim 1 tests the hypothesis that childhood adversity will be associated with the structural and functional connectivity of CVCs. Aim 2 tests the hypothesis that childhood adversity will be associated with both stress reactivity (derived from psychophysiological data acquired within the MRI scanner) and affective disorder symptoms. Aim 3 (Exploratory) tests the extent to which CVC structure/function represents a part of the path between childhood adversity and stress reactivity or affective disorder symptoms. Significance: Uncovering adversity-related changes in the structure and function of CVCs has the potential to provide methods of early detection of risk for affective disorders and of assessing the effectiveness of interventions in treating affective disorders.

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.