Israel Liberzon, M.D. - US grants

DESCRIPTION (provided by applicant): Stress-related psychiatric disorders in general, and post-operative depression in particular, constitute a major challenge. Depression, anxiety and post-traumatic stress disorder (PTSD) often develop after various stressors like surgery, serious illnesses, motor vehicle accidents, and natural disasters, and vulnerability factors are likely shared by these disorders. Distinct profiles of hypothalamo-pituitary - adrenal (HPA) abnormalities, are well-established in depression and PTSD, but those alterations which are pre-existing, those which are a response to stress/trauma, and those which are a component of the active illness, remain to be identified. Only prospective study of markers prior to a predictable stressful event will be able to address this question effectively and clarify the role of a neuroendocrine response to stress in the this process prospectively. Studying candidate markers of susceptibility in subjects who undergo a predictable stressful event, such as major surgery, will be important not only for study of post-operative depression but also for study of stress-related disorders in general. Our hypothesis is that postoperative depression develops in patients with pre-stress alteration of neuroendocrine function in concert with specific premorbid risk factors. Our pilot findings suggest that major abdominal surgery constitutes a predictable stressful event leading to a de novo depression in a subgroup of postoperative patients. Therefore, we will test the hypothesis that pre-stress markers of HPA axis and catecholaminergic system will predict the development of depressive disorder following predictable stress of abdominal surgery. We predict that hypercortisolemia and DST non-suppression will predict depression. A cohort of 2lO patients undergoing elective endovascular or abdominal aortic operation for aneurysmal or occlusive disease and 70 "control" patients with aortic disease treated conservatively will be studied (4 groups). Surgical patients will be assessed preoperatively, and at three times postoperatively (3, 9, and 18 mo.) to document preoperative and postoperative neuroendocrine function and psychiatric morbidity. Control patients will be assessed to determine frequency of spontaneous onset of psychiatric abnormalities. Using mixed model regression, we will examine the role of psychological and neuroendocrine abnormalities in post-operative depression and determine the stability of specific factors (neuroendocrine measures, psychiatric symptoms and diagnoses) and whether they reliably predict the development of comorbid disorders postoperatively. We will also determine if the ability to terminate neuroendocrine stress response after surgery or in response to dexamethasone predicts outcome, and if this is linked to pre-stress abnormalities. Identification of pre-stress markers of vulnerability clearly has profound implications for our understanding of stress-related dysfunction, the pathophysiology of psychiatric disorders.

[unreadable] DESCRIPTION (provided by applicant): Emotional and cognitive processes are complementary ways to process information. Emotions provide rapid "gestalt" assessments, and cognition provides deliberative, sequential, and analytic control. Traditionally, these phenomena were examined in isolation and the somatic/neuroendocrine states that accompany emotions have been seen as mere peripheral markers of brain activity. However, neuroendocrine activity actually affects the brain, modulating cognitive and emotional processing. We propose that cognitive, emotional, and somatic (CES) processes in fact constantly interact in reciprocally interconnected feedback loops and that ineffective CES interaction can lead to dysfunctional behavior and psychopathology. A comprehensive account of CES interplay, and its contribution to the development of psychiatric disorders, has yet to emerge. We propose to create a network of cognitive/affective neuroscientists, behavioral endocrinologists and clinical researchers to develop experimental tools to directly examine CES interactions and their role in psychopathology. [unreadable] Six researchers (3 from Michigan and 3 from Columbia) will work together to (1) establish a translational network of clinical and basic behavioral scientists, (2) develop paradigms to study CES interactions, (3) collect pilot data to map the neurocircuitry of CES interaction, and (4) translate this approach to the study of psychopathology. To pursue these aims we propose specific steps towards network building (to create a multidisciplinary team and context for training translational scientists), paradigm development (to create novel experimental approaches), pilot experiments (to begin mapping the CES neurocircuitry), and translation to clinical relevance (by applying the models to psychiatric disorders, starting with PTSD). Three pilot experiments will utilize emotional (social stress), somatic (elevating cortisol) and cognitive manipulations, evaluating impacts in the domains of stimulus appraisal and decision making using neuroanatomical (fMRI), behavioral, and neuroendocrine outcome measures. These experiments will begin mapping CES neurocircuitry, probing interactions between and within prefrontal cortical regions (like cingulate and dorsomedial gyri, insula) and limbic structures (like amygdala, hippocampus, ventral caudate), and facilitate further paradigm development. [unreadable] The collaborative environment and multidisciplinary team will foster translational behavioral science mental health research, developing new paradigms and collecting preliminary data on CES interaction that shape behavior and contribute to psychopathology. It will provide a foundation for larger translational science projects and a context for training the translational scientists of the future. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is a competing renewal application for the University of Michigan's NIMH Research Education Grant, awarded 2001-2006, for partial support of an innovative Residency Research Track in the Department of Psychiatry and the Molecular and Behavioral Neuroscience Institute. This program attracts psychiatry residents into research careers by providing longitudinal research training throughout residency training and prepares graduates to become the next generation of clinician-scientists. This innovative program recruits residents before or early into residency training and provides extensive research experience as part of an extended period of postdoctoral training rather than postponing it to a post-residency fellowship. The Research Track (RT) provides the equivalent of 18 months of research training as part of a five or, for those integrating residency with fellowship training, six to seven-year training program. The research effort is spent by working approximately half-time on the research component of the training program over a period of slightly longer than three years. The goals of the RT program are to provide 1) the flexibility to effectively integrate clinical and research training, 2) a sequenced educational experience for both clinical and research training, and 3) a mentored structured research experience with established mental health investigators. This program strives to foster the development of mental health researchers by providing the training, structure, and resources that are necessary to begin an academic, research-focused career in psychiatry.

DESCRIPTION (provided by applicant): One fifth of America's children grow up in poverty. While there is good evidence that this is harmful to health, achievement, and socio-emotional adjustment, very little is known about the brain basis that mediates the detrimental effects of poverty. We address two related primary questions with this research project: (1) How does childhood poverty influence adult brain structure and function? (2). What underlying mechanisms might account for childhood poverty - brain relationships? We hypothesize chronic physiological stress dysregulation as well as harsh, unresponsive parenting during childhood will account for some of the expected linkages between childhood poverty - adult brain structure and function - particularly in the hippocampus, amygdala, and the anterior cingulate/medial prefrontal cortex. This work will piggyback onto a 14 year, ongoing longitudinal research program of low and middle-income individuals focused on childhood poverty, physiological stress, and socio-emotional development conducted by Evans, a developmental psychologist at Cornell. Half of this sample (now age 22) grew up below the poverty line and half middle income. The sample is well characterized over their life course in terms of SES and other demographic variables, as well as both physical and psychosocial risk exposures. Primary outcome variables for this longitudinal cohort include multiple methodological indicators of physiological stress (neuroendocrine, cardiovascular, and metabolic) along with parental, self, and teacher ratings of socioemotional development (internalization, externalization, self regulation. In depth data on parenting are also included. The neuroimaging work will be conducted in the Department of Psychiatry, University of Michigan by Liberzon, with expertise in the neuroimaging of stress in health and mental illness, and by Swain a child psychiatrist studying the brain basis of parenting. Brain scanning will be divided into 3 sessions: the first will acquire high resolution images for volumetric and cortical thickness analyses. In addition, a selective emotional attention task as well as an emotion appraisal/re- appraisal task will probe the functionality of amygdala-prefrontal circuits. With scan two, parenting stimuli consisting of baby cries and pictures will be used to activate circuits believed to relate to parenting behavior and social interactions. Furthermore, working memory, delayed discounting and behavioral inhibition tasks will test cortical inhibition, decision-making, in cortico-cortical and cortico-hippocampal circuitry. Finally, immediately prior to the third fMRI scan, a Trier Social Stress Test that reliably generates elevated cortisol levels in laboratory environment will be performed. The subsequent scans will directly assess brain function following acute stress induction, and allow comparison with the baseline brain function in these same subjects, including a repetition of the selective emotional attention task, the parenting task and the emotional face assessment task to re-examine amygdala, hippocampus and prefrontal cortex performance. These experiments utilize a uniquely well-characterized longitudinal sample of low- and middle-income individuals in combination with a comprehensive set of conceptually derived, innovative but also validated neuroimaging paradigms. The aim of this project is to examine the potential impacts of childhood poverty on the brain. We will examine areas of the brain well studied in relation to chronic stress and parent-child interactions.

? DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 40-70% heritability of differential vulnerability or resilience. In fact, recent studies have suggeste that the heritability for PTSD may be twice that of Major Depressive Disorder. Due to increasing collaborations across the field of PTSD genomics, it is a very exciting time for discovering the underlying genetic risk factors contributing to PTSD. The purpose of this application is to facilitate meta- analyses of genome-wide association study (GWAS) data for symptoms and diagnosis of PTSD. We propose to conduct this first large-scale meta-analysis through the PTSD group of the Psychiatric Genomics Consortium (PGC). The PGC was created in 2007 to conduct field-wide mega-analyses of individual data for five major psychiatric disorders. It united the field for the first time, and it is the largest consortium (>500 scientists from >80 institutios in 25 countries) in the history of psychiatry. The PGC has already produced three major findings with regard to the genetic architecture of psychiatric disorders. First, reliable associations can be identified with extremely large sample sizes. A meta-analysis of GWAS in SCZ has produced over 100 loci at the genome-wide significance threshold in a sample of 36,000 cases and 43,000 controls. Second, the polygenic architecture inferred from family studies was confirmed with molecular evidence, and refined via demonstration of substantial effects of both common and rare variants. Third, confirming findings from twin studies, there are shared genetic contributions among psychiatric disorders. The PGC-PTSD group was launched in May 2013 and since then has been enormously successful, with over 25 investigators contributing genotype data from over 20 studies with a total N of over 76,000 combined cases and trauma-exposed controls. We also have commitments of collaborations using ~ 77,000 additional cases and controls from banked samples from over 20 studies, and our progress thus far demonstrates feasibility of the proposed work. We hypothesize that with well-powered, large sample-size studies, along with a deeply phenotyped set of cohorts, the PGC-PTSD group can identify the genetic architecture of PTSD. We will test this hypothesis through our Primary Aim focusing on detecting novel genetic variation associated with risk for PTSD. The primary aim of this study is to detect novel genetic variants (SNPs and CNVs) that predict the development of PTSD following trauma. We will conduct the study in three stages - discovery, biological annotation, and replication. This aim will be supplemented by Exploratory Aims which will expand the genomic approaches to include GxE analyses, meta-analyses of intermediate phenotypes, and cross disorder polygenic risk score analyses. Identifying the genetic pathways underlying PTSD will lead to an improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.

Project Summary/Abstract Fifty to 90% of Americans are exposed to trauma that can lead to Post-traumatic Stress Disorder (PTSD). Only a few develop PTSD. Identifying the vulnerable and modifying the processes that translate risk into illness could reduce the public health burden of this serious disease. Risk factors and neurobiological mechanism are being identified, but much remains unknown. Emerging models identify relevant genes, environments, brain circuits and behavior, expanding our focus beyond simple fear learning to incorporate more complex neural circuits that modulate responses to threat. Studying these circuits and their functions has generated a novel model of PTSD pathophysiology that focuses on deficits in context processing (CP) and on the hippocampal- prefrontal circuitry that subserves CP functions. This model is supported by growing evidence, explains much of PTSD's phenomenology, and integrates much of its neurobiology. The aim of this project is to further develop and test this model, and explore implications for treatment and, potentially, for prevention. PTSD patients respond fearfully to ambiguous cues (e.g., loud noise) even when in safe contexts (e.g., home backyard). Difficulty linking cues to contexts may be a core problem for them, undermining access to contextual information that should modulate adaptive responses. The hippocampus (Hpc) plays a key role in this process, mediating core CP functions like pattern separation (PS) and pattern completion (PC). PS/PC deficits may underlie CP difficulties in PTSD, contributing to an inability to remember that something once threatening is now safe (extinction recall) or to recognize potential danger when danger signals are contextual (fear renewal). Glucocorticoid (GC) signaling in Hpc can impair CP functions, so evidence of increased GC receptor sensitivity in PTSD is consistent with the CP model. Genetic and developmental factors known to shape GC sensitivity may contribute to PTSD risk through impact on CP functions like PS/PC, perhaps mediated by activity/connectivity within Hpc-prefrontal (PFC) circuits. This project will test the CP model, examining links between CP functions like PS/PC and the Hpc-PFC neural pathways subserving these functions, the role of glucocorticoid signaling in moderating these pathways and functions, and the ability of GCs to improve or undermine CP functions. It will do so by studying 120 healthy subjects performing PS/PC and fear learning tasks in fMRI, under low cortisol, physiological cortisol, and elevated (moderate and high) cortisol levels. ?Baseline? levels of GC signaling will be assessed via integrated cortisol secretion (hair cortisol) and GC receptor sensitivity (in vitro lysozyme inhibition). The project will also study 150 PTSD patients in the same paradigm, to determine whether PS/PC processes are core deficits in PTSD, linked to symptom severity and extinction recall/fear renewal deficits via Hpc-PFC dysfunction, and to test the ability of GCs to ?rescue? CP deficits in PTSD, via impact on Hpc-PFC pathways.

Project Summary/Abstract Fifty to 90% of Americans are exposed to trauma that can lead to Post-traumatic Stress Disorder (PTSD). Only a few develop PTSD. Identifying the vulnerable and modifying the processes that translate risk into illness could reduce the public health burden of this serious disease. Risk factors and neurobiological mechanism are being identified, but much remains unknown. Emerging models identify relevant genes, environments, brain circuits and behavior, expanding our focus beyond simple fear learning to incorporate more complex neural circuits that modulate responses to threat. Studying these circuits and their functions has generated a novel model of PTSD pathophysiology that focuses on deficits in context processing (CP) and on the hippocampal- prefrontal circuitry that subserves CP functions. This model is supported by growing evidence, explains much of PTSD's phenomenology, and integrates much of its neurobiology. The aim of this project is to further develop and test this model, and explore implications for treatment and, potentially, for prevention. PTSD patients respond fearfully to ambiguous cues (e.g., loud noise) even when in safe contexts (e.g., home backyard). Difficulty linking cues to contexts may be a core problem for them, undermining access to contextual information that should modulate adaptive responses. The hippocampus (Hpc) plays a key role in this process, mediating core CP functions like pattern separation (PS) and pattern completion (PC). PS/PC deficits may underlie CP difficulties in PTSD, contributing to an inability to remember that something once threatening is now safe (extinction recall) or to recognize potential danger when danger signals are contextual (fear renewal). Glucocorticoid (GC) signaling in Hpc can impair CP functions, so evidence of increased GC receptor sensitivity in PTSD is consistent with the CP model. Genetic and developmental factors known to shape GC sensitivity may contribute to PTSD risk through impact on CP functions like PS/PC, perhaps mediated by activity/connectivity within Hpc-prefrontal (PFC) circuits. This project will test the CP model, examining links between CP functions like PS/PC and the Hpc-PFC neural pathways subserving these functions, the role of glucocorticoid signaling in moderating these pathways and functions, and the ability of GCs to improve or undermine CP functions. It will do so by studying 120 healthy subjects performing PS/PC and fear learning tasks in fMRI, under low cortisol, physiological cortisol, and elevated (moderate and high) cortisol levels. ?Baseline? levels of GC signaling will be assessed via integrated cortisol secretion (hair cortisol) and GC receptor sensitivity (in vitro lysozyme inhibition). The project will also study 150 PTSD patients in the same paradigm, to determine whether PS/PC processes are core deficits in PTSD, linked to symptom severity and extinction recall/fear renewal deficits via Hpc-PFC dysfunction, and to test the ability of GCs to ?rescue? CP deficits in PTSD, via impact on Hpc-PFC pathways.