Jennifer A. Sumner, Ph.D. - US grants

DESCRIPTION (provided by applicant): Overgeneral autobiographical memory (OGM) has emerged as an important phenomenon for understanding the etiology, phenomenology, and course of depression, and it indeed may represent a vulnerability factor for the onset and course of depression. However, knowledge is lacking about certain factors that influence OGM. Specifically, major questions remain unresolved regarding 1) the mechanisms that contribute to OGM and how they may interact, and 2) the possible molecular genetic influences on OGM and their pathways. Furthermore, the extent to which the mechanisms underlying OGM impact depression, either independently or through their effect on OGM, is unknown. This proposal aims to address these issues using data from an ongoing 8-year longitudinal prospective study of risk factors for anxiety and unipolar mood disorders. Although an examination of the mechanisms underlying OGM was not an aim of the larger investigation, measures of the proposed mechanisms are being administered for other reasons, and DNA is being collected. The proposed study will conduct an empirical test of the recent CaR-FA-X model that presents three mechanisms that may underlie OGM: capture and rumination, functional avoidance, and impaired executive control (Williams et al., 2007). Structural equation modeling (SEM) will be used to investigate the degree to which these proposed mechanisms contribute to both OGM (alone and in interaction) and depression (both directly and indirectly through their effect on OGM). Furthermore, the relationship between OGM and several candidate genes selected for their theoretical relevance to depression and memory processes will be investigated. If significant associations are detected, then SEM will be used to examine how the relevant genes may relate to the mechanisms of the CaR-FA-X model. Training activities include 1) the completion of course work in genetics, SEM, human memory and cognition, and human neuropsychology, 2) participation in summer workshops on SEM, molecular biology, and biomarker research, and 3) consultation with experts in the fields of OGM research, statistics, and genetics. These experiences will provide a strong foundation for the completion of both the proposed project and future cross-cutting research on risk factors for depression. The proposed research will provide empirical evidence that can inform current theoretical models and subsequent studies of this proposed risk factor for depression. The findings may also have implications for the clinical treatment of depression, as knowledge of the mechanisms that underlie OGM, and their effects on depression, could inform interventions. In addition, research on the relationship between OGM and genetic risk factors may increase understanding of how genes confer liability to depression, and further develop existing integrative profiles of biological and behavioral indicators of depression. PUBLIC HEALTH RELEVANCE: An empirical investigation of the mechanisms of overgeneral autobiographical memory (OGM) may have important implications for the study and treatment of depression. Greater knowledge of the biological and behavioral markers underlying OGM-a proposed risk factor for depression-has implications for understanding the etiology and course of depression. Additionally, such knowledge may inform existing treatments for depression by identifying additional targets for intervention.

? DESCRIPTION (provided by applicant): This K01 Career Development Award will provide Dr. Jennifer Sumner with the necessary skills to establish an independent research career focused on elucidating the psychological and biological mechanisms by which traumatic experiences contribute to cardiovascular disease (CVD) in women, the leading cause of death worldwide. Posttraumatic stress disorder (PTSD), the quintessential stress-related mental disorder, prospectively predicts increased CVD incidence. However, PTSD is a complex and heterogeneous disorder, and the aspects of PTSD that drive CVD risk are unknown. Mechanistic knowledge, particularly in women, is also lacking. These limitations impede the development of clinical applications to offset CVD risk. The overall aim of this K01 proposal is to begin to test a theoretically based biological model by which a core element of PTSD-posttraumatic fear responses (e.g., hypervigilance, re-experiencing)- relates to CVD and intermediate markers of cardiovascular health in women. Supported by a multidisciplinary team of expert mentors, Dr. Sumner will examine how posttraumatic fear responses (measured across self- report and psychophysiological levels of analysis) relate to cardiovascular health in women. The training plan will provide Dr. Sumner with required background and skills in several domains in order to become an independent investigator with an integrative research program on the mechanisms by which the psychological sequelae of trauma contribute to CVD in women. Through coursework, hands-on training, and mentored meetings, Dr. Sumner will address prior gaps in training and develop skills in 1) cardiovascular, neurological, and clinical epidemiology, 2) quantitative methods for analyzing epidemiologic and longitudinal data, 3) CVD- related physiology and biomarkers, and 4) psychophysiological measures of fear responses. The training plan also includes completion of a Master's of Science degree in Patient-Oriented Research from Columbia University. The proposed research program harnesses two richly characterized ongoing cohort studies to test how posttraumatic fear responses relate to cardiovascular risk in women. Using data from the Nurses' Health Study II (NHS II), a longitudinal epidemiologic study of women's health, Dr. Sumner will determine if self- reported posttraumatic fear symptoms relate to hypertension and CVD incidence and CVD-related biomarkers. In the REactions to Acute Care and Hospitalization (REACH) study, a study of risk for PTSD after acute coronary syndrome and its relation to recurrent cardiac events at New York-Presbyterian Hospital, Dr. Sumner will collect data to test associations between fear responses at multiple levels of analysis-self-report symptoms and psychophysiological indicators (i.e., skin conductance and heart rate)-with hospital readmission and cardiac event recurrence. These research and training activities will inform an R01 application that will comprehensively test the biological mechanisms by which posttraumatic fear symptoms across multiple levels of analysis contribute to CVD in women.

PROJECT SUMMARY Posttraumatic stress disorder (PTSD) increases risk of incident cardiovascular disease (CVD) by 25-50%. Most individuals (50-90%) experience a traumatic event in their lifetime, and PTSD is the fifth most common psychiatric disorder. Experts have now called for increased CVD surveillance after trauma and for PTSD treatment trials powered to reduce CVD risk. However, both CVD risk and PTSD are complex phenomena that likely interact in nuanced ways. Therefore, for such efforts to be successful, we must first identify the mechanisms by which PTSD influences incident CVD risk. Further, we must understand which of the dimensions underlying PTSD activate those CVD risk mechanisms. This study will determine which PTSD dimension(s) contribute to endothelial dysfunction, one of the earliest modifiable precursors to CVD. Only three studies in select trauma-exposed populations (male veterans and police officers) have tested the association of PTSD symptoms with flow-mediated dilation (FMD), a functional measure of endothelial dysfunction. This early work points to endothelial dysfunction as a potential mechanism of the PTSD-CVD link, but the limited generalizability and lack of nuanced measurement of both posttraumatic stress and endothelial dysfunction in those studies has limited their impact. Indeed, we still do not know whether PTSD and endothelial dysfunction are associated in individuals from the broader community. Knowledge of which aspects of PTSD are most ?cardiotoxic? is also lacking, so we do not know which posttraumatic stress dimensions to target. Fear responses are a core component of PTSD with direct biological relevance to cardiovascular function, whereas the dysphoria dimension of PTSD is considered more auxiliary. In this study, we will examine cross-sectional and longitudinal associations of PTSD and its underlying dimensions with functional and, secondarily, cellular measures of endothelial dysfunction (FMD and circulating endothelial cell-derived microparticles, respectively) in a community-dwelling sample of CVD-free adult men and women with a history of trauma (50% with current PTSD). In Primary Aim 1, we will test the association of PTSD diagnosis with endothelial dysfunction. In Primary Aim 2, we will examine which PTSD dimensions (objective measures of fear and dysphoria, as well as interview-assessed lower-order symptom dimensions) are most strongly associated with endothelial dysfunction. In a Secondary Aim, we will examine how these PTSD dimensions predict change in endothelial dysfunction over 2 years in a subset of the sample. Finally, we will explore the role of stress-related biological mechanisms, including autonomic imbalance, inflammation, and oxidative stress, in the associations of PTSD dimensions with endothelial dysfunction. This study will provide the strongest evidence to date for a biologically plausible mechanistic model of PTSD?s influence on incident CVD risk. If our hypotheses are supported, future interventions will be optimized to reduce posttraumatic fear or another PTSD dimension so as to reduce early endothelial damage and offset CVD risk, making CVD surveillance and intervention after trauma worthwhile.