Christine L. Larson - US grants

DESCRIPTION (provided by applicant): Evolutionary fitness dictates that threat must be detected quickly. Rapid identification of potential harm has resulted in a relatively rapid, automatic threat detection system with a bias toward false positives. Given its well-documented role in fear and responses to salient stimuli, the amygdala has been identified as a likely facilitator of rapid detection of potential threats. Following work indicating that specific phobics respond more rapidly to phobia-relevant stimuli, Larson and colleagues (2002) found more rapid amygdala activation among specific phobics during phobia-relevant compared to neutral and other negative stimuli, and compared to nonphobic's responses to phobia-relevant stimuli. These data underscore the need to consider the dynamic process of emotion and its neural instantiation to more fully characterize healthy and pathological affective responses. While the aforementioned data point to rapid amygdala responding as a potential characteristic defining phobic fear, it is also possible that flexibility in the time course of the amygdala response is a normal, adaptive process such that during initial presentations of salient affective stimuli the amygdala responds more rapidly to prepare for potential threat. Over time and decreasing likelihood of threat this response slows. To test the idea that the chronometry of amygdala activation is flexible with respect to stimulus salience, 15 healthy subjects will complete an fMRI investigation of the time course of amygdala responding during an aversive conditioning paradigm. It is hypothesized that amygdale responses will be more rapid early in the conditioning phase compared to late conditioning and extinction periods. In addition, the dynamic pattern of amygdala activity during two means of attenuating responses to aversively conditioned stimuli, extinction and conditioned inhibition, will be compared. Thus, the major aim of the proposed study is to further examine the dynamic process of the neural substrates of emotional experience, including both time course and magnitude of the neural instantiation of affective processes.

? DESCRIPTION (provided by applicant): Trauma exposure is extremely common and increases risk for a host of negative health outcomes, most notably posttraumatic stress disorder (PTSD). Given the potential harmful sequelae of trauma exposure, it is crucial to identify acute post-trauma risk factors that predict chronic PTSD and other poor post-trauma outcomes. While some progress has been made in this effort, attempts to identify recently traumatized individuals at risk for poor long-term post-trauma adjustment have proven difficult. In this project we aim to identify predictors of both acute and chronic posttrauma symptoms, and more importantly, identify acute post-trauma measures that predict chronic PTSD, as well as other syndromes including depression and substance use problems. We will assess the predictive utility of three processes that are 1) rooted in basic cognitive and affective neuroscience, 2) articulated in the RDoC matrix, 3) map directly onto established interventions, and 4) show promise in our preliminary data. Leveraging our unique access to the large patient population in the Level 1 trauma service at the Medical College of Wisconsin, we will conduct multi-level (neural circuits, physiology, behavior, self-report) longitudinal assessments of posttrauma and other symptoms, and RDoC-based predictors of these symptoms. Within two weeks of trauma exposure we will assess RDoC-based indices of processes hypothesized to in- crease posttraumatic stress symptoms, including extinction and retention of extinction of conditioned fear (Acute Threat/Fear, Sustained Threat), impaired filtering of threat (Attentional Control), and attentional bias to threat (Sustained Threat). At six months post-exposure we will again conduct multilevel assessments of these processes and measure symptoms of PTSD and other relevant syndromes. In addition to these two primary assessment points (both involving neuroimaging), we will also collect a battery indexing cognitive and affective functioning and symptom severity at multiple points up to 24 months post-exposure. We will scan 220 individuals, oversampled for acute posttrauma symptoms, at 2 weeks with the goal of a final six-month sample of 200, and a final 24-month sample of 150. We hypothesize that acute impairments in fear extinction, extinction- related plasticity (changes in resting state functional connectivity from before to after extinction), attentional filtering, and attentional bias will preict elevated PTSD symptoms six to twenty-four months post-exposure. This work offers several key innovations: 1) longitudinal multi-level assessment of acutely traumatized patients, 2) the use of neural measures to predict long-term outcomes, 3) the use of a novel paradigm to assess extinction-induced plasticity, and 4) the combination of extinction and attention, two core mechanisms hypothesized to increase risk for PTSD, in the same sample. We expect this project to further the NIMH mission through the use of RDoC indices grounded in basic science, translated to clinical indicators, and directly linked to empirically-determined interventions. Findings from this work will provide new knowledge aiding early identification of trauma-exposed individuals most-at risk for chronic PTSD, and potentially targets for early intervention.

Youth violence victimization is common and increases risk for a host of negative health outcomes, most notably posttraumatic stress disorder (PTSD), which is the strongest predictor of poor quality of life following trauma, even among those injured during the event. Given the potential harmful sequelae of trauma exposure, it is crucial to identify acute post-victimization risk factors that predict chronic PTSD. At this juncture relatively little data exists to aid in prediction of youth at risk for poor long-term adjustment following victimization or other types of trauma, and there are no studies measuring relevant neural systems. Thus, our team aims to 1) characterize acute post-victimization neurobehavioral predictors of risk for chronic PTSD with a focus on prefrontal-subcortical function during processing of threat processing and frontoparietal networks for cognitive control, and 2) use machine learning to identify the most robust set of predictors of chronic PTSD drawn from a comprehensive assessment of youth neuroimaging, behavior and self-report, parent and family factors, and neighborhood and community variables. Our team is well-prepared to successfully achieve these aims, as we have relevant expertise in conducting prospective longitudinal assessment of acute neurobehavioral predictors of risk for PTSD in adults (Larson), conducting longitudinal assessment of youth victims of violence (Levas), and longitudinally characterizing neurobehavioral profiles of youth PTSD (Herringa). We will recruit youth victims of violence aged 10-16 from the Emergency Department at Children?s Hospital of Wisconsin in Milwaukee, and conduct comprehensive assessments at 2 weeks, 3 months, and 12 months following victimization. To achieve a final sample of 200 youth at 12 month follow-up, we will recruit 240 youth, oversampled for risk for PTSD based on currently available brief self-report indicators. Each assessment will include measures of neural systems instantiating threat processing, including both reactivity to threat and anticipation of unpredictable and predictable threat, and cognitive control, along with measures of PTSD and other symptoms, cognitive functioning, family environment, social and school functioning, and socioenvironmental factors (e.g. neighborhood disadvantage, discrimination). We will examine how acute post- victimization variables (2 week) and early change following victimization (from 2 weeks to 3 months) predict PTSD and other outcomes twelve months later. We will use both hypothesis-driven analyses focusing on a priori specified regions and predictors, as well as comprehensive data-driven machine learning analyses. The comprehensive assessment will allow for determination of the additional utility of neural markers for predicting risk beyond previously identified self-report indicators. We expect this project to lead to identification of predictors of risk for PTSD following victimization that are linked to underlying processes (hyper-responsivity to threat, aberrant cognitive control) that can directly inform preventive interventions, ultimately improving the quality of life for youth victims of violence.