Tanja Jovanovic, PhD - US grants

emotions; vocalization; child abuse; animal communication behavior; animal developmental psychology; amygdala; maternal behavior; hippocampus; behavioral /social science research tag; Macaca mulatta; infant animal;

DESCRIPTION (provided by applicant): Patients with posttraumatic stress disorder (PTSD) have persistent fear despite the presence of safety signals. Although the inability to inhibit fear is a central problem in PTSD, it has not been well studied. One of the goals of the present study is to assess fear potentiation and fear inhibition as independent processes in humans. This study will use fear potentiation of the acoustic startle response as a measure of fear, given that it has been observed across many different species and its neural correlates are well known. The first part of the study will translate a conditional discrimination procedure (AX+/BX-), validated in animals, in order to quantify fear inhibition in PTSD. Furthermore, we will test whether the subjects are cognitively aware of the contingencies between the experimental stimuli. Previous research has found that contingency awareness plays a key factor in developing fear-potentiated startle. The present study will investigate how awareness interacts with startle in PTSD subjects. Finally, the present study will examine the relationship between contingency awareness and fear inhibition.

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large urban centers in the U.S. increases the likelihood of exposure to traumatizing events. Of those who survive such events, approximately 10% will develop this debilitating disorder that affects both the individual and their family. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a "one size fits all" treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorder or impede treatment. While both genes and environment interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. Moreover, amygdala projections modulate neuroendocrine systems, namely the hypothalamic-pituitary-adrenal (HPA) axis, which is the common pathway of the stress response. Cortisol performs important regulatory functions in these brain structures, and participates in the formation, processing, and retrieval of memories, particularly fearful ones. Furthermore, another neurobiological finding in PTSD is hyper-sensitive feedback of dexamethasone, a cortisol analogue, on the HPA axis. Although amygdala and cortisol feedback function have been studied separately in PTSD, the interaction of these two systems has not been studied in the same patients. The proposed study will provide innovative tools to tease apart the relationship between the amygdala and the HPA axis in a human clinical population. Our recent discovery of HPA axis suppression and fear dysregulation coupled with the development of new fear conditioning paradigms provides a unique opportunity to interrogate the amygdala-HPA interactions to determine aspects of the neurobiological underpinnings of the pathology related to PTSD. PUBLIC HEALTH RELEVANCE: Posttraumatic stress disorder (PTSD) is a highly debilitating and complex disorder frequently comorbid with many medical and psychiatric illnesses. Understanding the neurobiological mechanisms underlying this disorder will provide improved tools for targeting symptoms that are specific to PTSD. The ultimate goal of this proposal is to combine basic psychopathology research and basic neuroscience research to inform the development of novel and effective approaches for treating PTSD, particularly in high-risk populations such as low-income, African-Americans.

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large urban centers in the U.S. increases the likelihood of exposure to traumatizing events. Of those who survive such events, approximately 10% will develop this debilitating disorder that affects both the individual and their family. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a one size fits all treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorder or impede treatment. While both genes and environment interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. Moreover, amygdala projections modulate neuroendocrine systems, namely the hypothalamic-pituitary-adrenal (HPA) axis, which is the common pathway of the stress response. Cortisol performs important regulatory functions in these brain structures, and participates in the formation, processing, and retrieval of memories, particularly fearful ones. Furthermore, another neurobiological finding in PTSD is hyper-sensitive feedback of dexamethasone, a cortisol analogue, on the HPA axis. Although amygdala and cortisol feedback function have been studied separately in PTSD, the interaction of these two systems has not been studied in the same patients. The proposed study will provide innovative tools to tease apart the relationship between the amygdala and the HPA axis in a human clinical population. Our recent discovery of HPA axis suppression and fear dysregulation coupled with the development of new fear conditioning paradigms provides a unique opportunity to interrogate the amygdala-HPA interactions to determine aspects of the neurobiological underpinnings of the pathology related to PTSD.

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) occurs in some people after exposure to events that cause extreme fear or helplessness. The incidence of war zones worldwide and the prevalence of violence in large urban centers in the U.S., increases the likelihood of exposure to traumatizing events. Of those who survive such events, approximately 10% will develop this debilitating disorder that affects both the individual and thei family. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a one size fits all treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorde or impede treatment. While both genes and environment interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. We have found that one of the hallmark physiological markers associated with PTSD symptom severity is the inability to inhibit the fear response under safe conditions. This phenotype appears to be a robust marker regardless of trauma type, as it is observed in both civilian and combat PTSD populations. The proposed study will capitalize on this observable marker and individual variability among traumatized individuals to investigate the structural and functional neural underpinnings of impaired fear inhibition. By comparing analyses of this physiological phenotype to the DSM defined disorder, the study will use an innovative approach to understand the pathophysiology of PTSD. The use of state-of-the art imaging tools to fine- tune the measurements of size, shape, and function of the brain areas involved in fear inhibition will offer much-needed insight into individual differences in vulnerability to trauma.

DESCRIPTION (provided by applicant): High rates of trauma exposure and post-traumatic stress disorder (PTSD) in low-income, urban populations underscore the urgent need for research in this under-represented group. In such samples, exposure to trauma may begin early in life; studies of children and young adults from similar samples suggest that initial trauma exposure during childhood or adolescence is common. In addition, women are at higher risk for anxiety than men; although some new research indicates specific genetic and endocrine factors that play a role in this difference, the timeline of emergence of these sex differences are still unclear. Of particular concern is the perpetuation of the cycle mental health disorders, in that children of depressed or anxious mothers are at higher risk of developing anxiety and depression themselves. Risk factors include biological factors such as genetics as well as environmental factors, such as increased risk of child trauma exposure. Our recent study identified a gene polymorphism of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor as a risk genotype for PTSD in women. The proposed study will target the same candidate gene in children at risk for trauma and PTSD, using psychophysiological biomarkers of anxiety. The proposed study will investigate these biomarkers in children at high risk for trauma exposure prior to puberty and will re-test them again after puberty in order to examine the emergence of sex differences in PTSD. We have developed several physiological, startle-based phenotypes that are related to PTSD. Specifically, we have found that impaired inhibition of fear-potentiated startle is a robust biomarker of PTSD in survivors of combat and civilian trauma. Furthermore, dark-enhanced startle is associated with PTSD specifically in women, providing a physiological index for measuring sex differences in anxiety. Preliminary data from a low-income, primarily African American urban population collected from school-age children indicate that these same startle-based phenotypes are sensitive to developmental as well as pubertal changes.

? DESCRIPTION (provided by applicant): Trauma exposure is high in HIV-infected individuals both prior and subsequent to infection. The incidence of post-traumatic stress disorder (PTSD) has been reported to be between approximately 5% - 15% among the 30 million people living with HIV (PLWH). PTSD is a severely debilitating, stress-related psychiatric illness associated with intrusive and fearful memories as well as flashbacks, and nightmares of the traumatic event(s) for much of the victims' lives, and significant impairment in routine daily activities. Th challenges presented by PTSD are magnified in PLWH because PTSD leads to poor adherence to antiretroviral (ART) medications, increasing the odds of virologic failure. PTSD also increases sexual risk behaviors, increasing the risk of transmission. The neurobiology of PTSD has been a topic of intense study over the past two decades; however, there is minimal understanding of the neurobiology of PTSD within the context of HIV. Two systems that have been repeatedly documented to drive PTSD symptoms are the neural circuitry that underlies the startle response and the endocrine axis that controls the body's response to stress. Therefore, the current application will test the central hypothesis that HIV exacerbates PTSD symptoms and augments underlying neurobiological correlates of PTSD in women. One limitation to studying the interaction of trauma and PTSD with HIV is the high likelihood of trauma exposure within PLWH, making it difficult to identify a control group for rigorous experimental analysis. In order to address this previous limitation, the current work will compare the impact of similar levels of trauma exposure between PLWH and individuals at high risk for HIV. The population selected for this study will be recruited from the Atlanta site of the NIH-funded Women's Interagency HIV Study (WIHS) which recruits from a population with overlapping recruitment for the NIH-funded Grady Trauma Project (GTP). The GTP has studied the impact of trauma exposure in a predominantly African American population for nearly 10 years focusing the proposed work on one of the most at-risk populations of PLWH, southern African-American women. The current project leverages the expertise in these two established studies and synergistically combines their individual areas of expertise positioning the generated body of work for maximum impact in the shortest amount of time possible. In the proposed project, we will examine the clinical, physiological, and neuroendocrine correlates of fear extinction as an intermediate phenotype of trauma-related symptoms. We will use dimensional approaches to symptom analyses (Aim 1), innovative biobehavioral assessments (Aim 2), and cutting-edge biomolecular techniques (Aim 3) in order to better understand the pathophysiology of PTSD co-morbid with HIV. The identification of the biological correlates of interactions among trauma processes and HIV infection has the potential to lead to better treatment approaches in terms of both pharmacological and behavioral interventions ultimately leading to improved ART adherence, reduced risk behaviors, and an enriched quality of life.

SUMMARY Childhood trauma exposure constitutes a major risk factor for subsequent psychopathology, including depression, posttraumatic stress disorder, substance abuse, personality disorders, and schizophrenia. Violence exposure in low-income, urban populations can occur early in life, increasing risk for trauma exposure in children living in inner-city areas. While it is shown that early adverse experiences affect brain activation and connectivity as well as fear physiology during development in children, the mechanisms of these effects on the brain are not clearly understood. Very few studies have captured the effects of ongoing trauma during development, as most are based on retrospective data. The proposed longitudinal study is well-positioned to address this gap in knowledge given our recruitment from a high trauma risk population. The proposed research will combine neuroimaging and fear physiology methods to examine critical periods for trauma-related correlates of brain development. Recruitment of male and female children will allow for exploratory analyses of sex differences during development. Retrospective research on trauma exposure and neural development suggest that ages 9 through 11 represent particularly sensitive periods for fear-relevant neurobiology. In order to target this critical period, 9-year-old children will be recruited from the Grady Trauma Project in inner-city Atlanta, composed primarily of low-income, African American families and followed prospectively for two years. Trauma exposure and startle will be assessed every six months between ages 9 and 11, in order to assess the critical period for trauma exposure. Brain structure and function will be assessed every year, at years 9, 10, and 11. In our previous studies, we have found that the degree of trauma exposure significantly increases between 9 and 11 years of age. The unique prospective longitudinal design will allow for analysis of the effects of both pre-existing trauma and new trauma exposure on the neurobiological phenotypes.

? DESCRIPTION (provided by applicant): Epidemiological studies worldwide have documented a high rate of exposure to traumatic events, including life-threatening accidents, rape, combat, physical violence, witnessing the death or injury of others and natural disasters. Such traumatic experiences significantly increase the likelihood of having a mental illness, including posttraumatic stress disorder (PTSD), depression or substance abuse. Although more than 80% of the population will experience a traumatic event, only a fraction of those will develop a mental illness, suggesting a large role for biological risk factors. However, there are currently no biological factors that can be used to prospectively monitor vulnerable individuals. Recent epigenetic studies report extensive DNA methylation differences in those who have experienced trauma that associate with psychopathology. Because changes in DNA methylation accumulate over time, the molecular signature of trauma exposure may be evident substantially before trauma-related symptoms develop. However, the timeline and permanence of epigenetic changes are still unclear. This study will address this question by leveraging infrastructure from an ongoing investigation (R01 MH094757; PI Ressler) that is prospectively characterizing trauma victims from Atlanta's inner-city Level 1 trauma center. To evaluate how DNA methylation changes over time, we will prospectively collect DNA samples for the first 3 months after a traumatic event and characterize the DNA methylation changes that occur acutely (within the first weeks up to 1 month) and stably (through 3 months). We will also evaluate changes in 4 specific stress-response genes (FKBP5, SLC6A4, BDNF and COMT). Finally, we will evaluate whether acute changes in DNA methylation predict psychiatric symptoms and fear-potentiated startle response, a physiological phenotype that has been associated with PTSD, at 3 months after the trauma. This study is highly novel in its focus on acute epigenetic mechanisms; furthermore, it focuses on psychophysiological phenotypes of trauma exposure rather than DSM diagnoses as advocated in the NIMH Research Domains Criteria. The units of analyses will include molecular (DNA methylation), physiological (fear-potentiated startle), and self-report (PTSD Symptom Scale, Beck Depression inventory) measures as dimensional measures of trauma response. This research will provide much needed insight into the pathophysiology of trauma on a molecular level and lay a foundation for early intervention studies. Identification of how the epigenome responds to a traumatic event will provide preliminary data for larger prospective studies that facilitate early detection of trauma-related psychopathology.