Isabelle M. Rosso - US grants

[unreadable] DESCRIPTION (provided by applicant): The principal aim of this career development plan is to provide the candidate with the training, support, and resources required to develop as an independent investigator in the field of neuropsychiatric research. The candidate's long-term goals are to advance knowledge of the developmental neuropathology of schizophrenia by establishing a multidisciplinary research program that combines epidemiologic, developmental, and neuroimaging methods. The candidate's short-term goals for the duration of this award are to develop expertise in the following areas: (1) methods, design, and analysis of magnetic resonance imaging (MRI) studies; (2) cognitive neuroscience and neuropsychology; (3) longitudinal research methods and design. These training goals will be met through a combined program of coursework, consultation with established research scientists in these fields, and completion of a research study plan at McLean Hospital's Brain Imaging Center. The design and hypotheses of the proposed study were based on a growing body of work (including the candidate's prior research) indicating that genetic and obstetric factors may disrupt brain development in a manner that predisposes to schizophrenia. There is also preliminary evidence that the characteristic timing of psychosis onset in late adolescence may relate to maturational brain changes that occur around this period in prefrontal and temporal-limbic cortices. Accordingly, the research plan proposes a longitudinal, case-control investigation of adolescents at high (HR) and low (LR) genetic risk for schizophrenia. The first major aim of the study is to examine the contributions of genetic risk status and OCs to the prediction of neuropsychological measures of cognitive function and structural MRI measures of regional brain volume. The second major aim is to assess age-related changes in brain structure and cognitive function between the baseline and 2-year follow-up assessments in the HR and LR subjects. The results of this study are expected to increase our understanding of the normative brain maturational changes of adolescence, which has been a relatively under-studied area despite its potential relevance to schizophrenia and other neuropsychiatric disorders. In addition, this study has relevance to the pathophysiology of schizophrenia and to the premorbid identification of individuals at heightened risk for the disorder. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a common and debilitating neuropsychiatric disorder in which an acute fear response to a traumatic event does not abate. This failure to recover from trauma is thought to be due at least in part to a deficit in learning not to fear situations and stimuli previously associated with the trauma. Thus, PTSD has been conceptualized as a disorder of 'fear conditioning' that involves a hyperresponsivity of neurons in brain regions mediating fear expression and a hyporesponsivity of neurons in brain regions mediating fear extinction. Moreover, converging evidence suggests that neurotransmitter alterations relate to these changes in neuron excitability, including alterations in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The proposed study will apply proton magnetic resonance spectroscopy (1H-MRS) methods to test hypotheses that PTSD is associated with altered GABA in two key brain areas: the ventromedial prefrontal cortex (VMPFC) and anterior insular cortex. We will also employ a well-validated fear conditioning paradigm to examine the hypothesis that VMPFC neurochemistry is associated with fear extinction deficits in PTSD. We will recruit 93 subjects comprised of 31 PTSD subjects, 31 trauma- exposed controls, and 31 healthy controls with no trauma history. Subjects will undergo single voxel high-field 1H-MRS using MEGAPRESS sequences that are optimized for detection and quantification of GABA, and have yielded encouraging preliminary data in these two brain regions. We will examine GABA levels in relation to PTSD diagnosis and symptoms, and in relation to behavioral indices of fear extinction recall and anxiety sensitivity. This will allow us to examine whether regional brain GABA is a marker of clinical and behavioral phenotypes of PTSD. Future research directions will include examination of whether GABA alterations in PTSD are sensitive to pharmacological treatment, and examination of their diagnostic specificity. Indeed, it is likely that GABA alterations represent biomarkers of behavioral phenotypes that are not only found in PTSD but also related psychiatric disorders. In this way, the goals of this research are relevant to priorities delineated in the NIMH strategic plan and RDoC initiative, particularly the identification of biobehavioral markers that may lead to the development of a biologically-valid psychiatric nosology. PUBLIC HEALTH RELEVANCE: The proposed study may provide the first direct, in vivo evidence that altered levels of the brain chemical GABA are markers of persistent clinical symptoms and fear responses in post- traumatic stress disorder (PTSD). In the short-term, our findings will improve our understanding of brain chemistry in PTSD and of how brain chemistry relates to certain maladaptive behaviors that cause impairment in patients. In the longer term this research may help understand how current treatments affect brain chemistry, and ultimately may lead to better diagnosis and treatment of PTSD and related disorders.

PROJECT 4 (ROSSO LAB): SUMMARY Post-Traumatic Stress Disorder (PTSD) is a leading cause of global disease burden, and it is twice as common in women as in men. In addition to female sex, genetic factors are established risk factors for PTSD. Furthermore, the diagnosis requires exposure to at least one highly traumatizing stressor, which independently and synergistically with genetic vulnerability leads to long-lasting perturbations in biological arousal systems. A number of moderators of stress responsiveness may contribute to PTSD, including the differential risk seen in women. Altered function of corticotropin releasing factor (CRF) and pituitary adenylate cyclase-activating polypeptide (PACAP) systems represent candidate mechanisms of sex-dependent moderation of PTSD liability. Higher blood PACAP levels and allelic variation in the gene (ADCYAP1R1) encoding the PAC1R receptor predict greater anxious arousal symptoms and total symptoms in women with PTSD, and greater physiological arousal during anxiety-related paradigms. Variation in CRF and its Type-I receptor have also been associated with both PTSD and depression, and sex differences may produce persistent physiological arousal in women exposed to severe stress. Importantly, the neurobiological correlates of CRF/PACAP overlap with arousal-related brain circuitry that is implicated in PTSD, including extended amygdala (extAMG) and medial prefrontal cortex (mPFC). This project is designed to identify CRF-, PACAP-, CRF+PACAP-predominant intermediate phenotypes in women and men with PTSD. Two subregions of the extAMG, the amygdala (AMG) and bed nucleus of the stria terminalis (BNST), will be independently examined, due to evidence of their partially separable roles in fear versus anxiety, and their potentially differential contributions to PTSD. The mPFC will be a focus as a region that modulates arousal responses to threat via reciprocal connections with the AMG and BNST. Using blood samples from adults with DSM-5 PTSD, we will examine CRF and PACAP variation (genetic, epigenetic, mRNA) in relation to markers of hyperarousal across levels of analysis: (1) blood levels of PACAP and hypothalamic pituitary adrenal axis hormones (ACTH and cortisol) as indices of CRF function; (2) resting state functional magnetic resonance imaging of extAMG-mPFC; (4) diffusion tensor imaging of extAMG-mPFC; (5) magnetic resonance spectroscopy of mPFC glutamate metabolism and neuronal integrity (N-acetylaspartate); (6) physiological indices of arousal during fear conditioning and dark enhanced startle paradigms; and (7) clinical symptoms of hyperarousal: anxious arousal, dysphoric arousal, and sleep disruption (using self-report and actigraphy). Project 4 will enhance our understanding of biobehavioral mechanisms of CRF/PACAP in humans, with the potential to identify new PTSD biomarkers. Neuroimaging of BNST function and glutamate metabolism is particularly innovative and may facilitate development of improved diagnostics or therapeutics for individuals with PTSD. We focus on the same peptide systems and brain regions as the other SPARED Projects, and we will use new discoveries from across the Center to continuously refine and optimize our objectives.

SUMMARY Intrusive trauma recollections are hallmark symptoms of posttraumatic stress disorder (PTSD), manifesting as flashbacks, nightmares, and reactivity to trauma reminders. These symptoms are distressing, disabling, and they predict worse illness course, above-and-beyond total symptom severity. Clinical descriptions highlight the re-experiencing of sensory-perceptual aspects of the trauma in the ?here-and-now?. It has been proposed that these psychological mechanisms represent a loss of integration between the hippocampus, which mediates contextual binding, and midline parieto-occipital cortices, which support sensory-perceptual elaboration. However, no research investigations have tested whether imaging measures of hippocampus circuitry relate to these key mechanistic features of intrusions. Most PTSD studies have assessed intrusions using instruments that are vulnerable to retrospective recall bias and that do not assess psychological characteristics of intrusions that may be most sensitive to neural variation. In addition, prior studies have not parsed trauma mechanisms relevant to hippocampus phenotypes, such as chronicity of trauma (threat) exposure, which moderates the severity of hippocampus deficits. Finally, most PTSD imaging studies considered the hippocampus as a unitary structure, whereas evidence shows that anterior (aHPC) and posterior hippocampus (pHPC) have dissociable functions and connectivity, as well as differential involvement in PTSD. The proposed study will leverage multiple lines of evidence suggesting that key psychological mechanisms of intrusions may be mediated by alterations in pHPC metabolism and connectivity with parieto-occipital cortices. We will use ecological momentary assessment (EMA) to assess intrusion characteristics in daily life (over a two-week period following the baseline imaging). We will test hypotheses that imaging measures of pHPC functional connectivity, anatomical connectivity, and neurochemistry predict sensory-perceptual vividness and out-of-context quality of intrusion symptoms, more so with increasing chronicity of trauma (threat) exposure. Finally, we will conduct multivariate modeling to identify combinations of neuroimaging metrics that best predict EMA-assessed variables. This project is innovative for its joint examination of mechanistic dimensions of intrusions and trauma exposure, both selected based on their predicted neurobiological relevance. This also will be the first study to apply multimodal imaging for the dissociation of aHPC and pHPC networks in PTSD, and to examine these hippocampus metrics in relation to real-world symptoms of PTSD. Overall our research strategy is consistent with that of the NIMH Research Domain Criteria (RDOC) with regards to identifying neurobiologically-relevant dimensions of behavior (intrusive memory) and their interactions with environmental influences (trauma, threat exposure). A major implication of segregating neural biomarkers in relation to intrusion and trauma mechanisms is the potential for identifying neural endpoints conducive to targeted treatment with novel perceptual or cognitive training programs, or targeted neuromodulation.