Ryan J. Herringa, Ph.D. - US grants

DESCRIPTION (provided by applicant): Anxiety disorders and depression are among the most common psychiatric disorders. The etiology of these conditions is unknown, but exposure to stress and an inability to cope with stress likely contribute to the development of these disorders. Dysregulation of the corticotropin-releasing hormone (CRH) system is associated with depression and certain anxiety disorders, making it a likely candidate for linking stress to these disorders. CRH and its receptors are known to play a role in mediating the stress response. Recent work suggests that CRH-binding protein (CRH-BP) may also play a role in stress. Evidence suggests that CRH-BP binds locally released CRH and prevents its action at CRH receptors. CRH-BP may thus serve to maintain homeostasis in the CRH system, thereby limiting the stress response. Despite this, CRH-BP remains a poorly understood component of the CRH system. The proposed research will focus on the nature of the interactions of CRH-BP with CRH and CRH receptors within the brain during stress. An examination of the stress-induced regulation and function of CRH-BP may prove useful in understanding mechanisms underlying stress-related psychopathology and may lead to new treatment approaches for disorders involving dysregulation of the CRH system.

DESCRIPTION (provided by applicant): The goal of this career development award is to provide the candidate with additional knowledge and skills in the implementation and analysis of event-related fMRI and brain connectivity. This knowledge and skill set will be used to explore the neural basis of emotion regulation in healthy adolescents with and without trauma exposure, and its dysfunction in adolescent post-traumatic stress disorder (PTSD). PTSD is a debilitating illness for youth and their families, and is often comorbid with other anxiety disorders and depression. Adult PTSD related to childhood trauma carries additional risk for depression, anxiety, substance abuse, and suicide. Treatment of pediatric PTSD is largely limited to psychotherapy, which shows moderate effect sizes, leaving many youth with persistent illness even when such treatment is accessible. While evidence is limited, medications have shown little benefit for pediatric PTSD. In light of these factors, it is of great importance to understad how PTSD may alter neurodevelopmental trajectories, with the aim of instituting biologically informed, early interventions that may avert negative outcomes in childhood and subsequent adulthood. Pediatric PTSD is characterized clinically and behaviorally by abnormal emotion regulation, but few studies have examined the neural basis of emotion regulation in this illness. Functional brain studies in adult PTSD offer a testable model of limbic and prefrontal changes that that may underlie impaired emotion regulation. This includes increased activation of the amygdala and the dorsal anterior cingulate (dACC) cortex, which promote fear responses. At the same time, there is impaired engagement of the ventromedial prefrontal cortex (vmPFC), which normally suppresses fear and anxiety responses. Adolescence is a particularly sensitive period of prefrontal cortical development, with the potential for even greater prefrontal-limbic imbalance associated with PTSD. This could be reflected, for example, by diminished age-related activity in the prefrontal cortex. In contrast, healthy trauma-exposed adolescents may show even greater age-related ventral prefrontal recruitment. Successful treatment, in turn, for youth with PTSD may engage compensatory or resilient mechanisms seen in healthy trauma-exposed youth. However, these models remain largely untested. The proposed research plan will examine the functional neural correlates of implicit emotion regulation in healthy youth with and without trauma exposure, and youth with PTSD, with an emphasis on amygdala and prefrontal cortical regions. This research will focus on initially on baseline (pre-treatment) brai differences compared to healthy youth, with a longitudinal one-year follow up as an exploratory aim. Forty youth, ages 12- 18, will be recruited for each group. Validated fMRI paradigms and behavioral measures will be employed. The fMRI tasks include two complementary paradigms to explore implicit emotion regulation, using emotional faces and emotional pictures, respectively. In Aim 1, we predict that healthy youth will engage both amygdala and prefrontal areas during emotion regulation, and that prefrontal-amygdala connectivity will increase with age. Healthy trauma-exposed youth will show greater amygdala activation, but greater vmPFC activation and connectivity in compensation. In Aim 2, we predict that pediatric PTSD and healthy trauma youth, compared to healthy non-trauma youth, will show increased amygdala and dACC activation. However pediatric PTSD will be differentiated from both comparison groups by impaired vmPFC activation and connectivity during emotion regulation. This will be reflected by diminished age-associated increases in vmPFC function in PTSD. Exploratory analyses will examine longitudinal changes in amygdala and prefrontal function in healthy and PTSD adolescents, and how PTSD symptom changes correlate with brain function change over time. The candidate is a pediatric psychiatrist and affective neuroscientist, with a long-standing interest in stress- induced changes in brain and behavior. His clinical specialization includes the use of trauma-focused cognitive behavioral therapy to treat traumatized youth. The candidate has conducted initial fMRI studies of emotion regulation in a traumatized, young adult population, with experience in the analysis of block design tasks. Immediate career development goals during the award period include additional training in conducting fMRI in youth, analysis of event related fMRI and functional/effective connectivity, and training in clinicl trials for a future R01 fMRI treatment study. Acquisition of these skills and knowledge will allow the candidate to become an independent investigator in the affective neuroscience of pediatric PTSD. Long-term career goals include the development of expertise in delineating neurodevelopmental trajectories of trauma-resilient vs. trauma- vulnerable emotion regulation as related to pediatric PTSD, and pioneering research exploring treatment- induced changes in emotion regulation circuitry in pediatric PTSD. The proposed program of training and research will be conducted at the University of Wisconsin-Madison, which is a leading institution in the neuroscientific study of emotion, featuring state-of-the art neuroimaging facilities and distinguished faculty. These include Drs. Richard Davidson (mentor) and Ned Kalin (co-mentor), both of whom are pioneers in the study of the neural circuitry underlying emotion regulation in health and psychopathology. This cross- disciplinary research plan therefore allows for a stepwise approach to a career in the affective neuroscience of pediatric PTSD.

Project Summary The overarching goal of this proposal is to map neurodevelopmental trajectories of emotion regulation in healthy adolescents and adolescents with affective disorders. The ability to regulate emotion is a critical developmental task and predicts numerous social and emotional outcomes into adulthood. Conversely, emotion regulation development is compromised in affective disorders, particularly in youth with a history of maltreatment. Crucially, maltreatment not only increases risk for affective disorders, but is also associated with greater illness severity, suicide attempts, and treatment resistance in both youth and adults. However, no studies have comprehensively and longitudinally examined neurodevelopmental trajectories of cognitive- emotional control in typical development, nor how these trajectories are disrupted in affective disordered youth with and without maltreatment. Notably, preliminary data suggest that maltreatment may represent a unique subtype of affective disorders, characterized by declining emotion regulation capacity over adolescence. This innovative research program will 1) map trajectories of cognitive-emotional neurodevelopment in typically developing (TD) adolescents, 2) characterize divergence in these trajectories in non-maltreated and maltreated adolescents with affective disorders (AD, AD+M, respectively), and 3) determine to what extent neurodevelopmental trajectories of emotion regulation contribute to recovery vs. illness persistence over time. This interdisciplinary research team will recruit 210 youth (70/group TD, AD, AD+M), ages 10-16, to be followed over 3 annual assessments. At each assessment, behavioral and neural indices of cognitive- emotional control will be captured during fMRI. Here, youth will complete a comprehensive battery of validated tasks probing multiple levels of cognitive-emotional function including emotional reactivity, implicit (automatic) emotion regulation, explicit (voluntary) emotion regulation, and general executive function. Simultaneous with fMRI, physiological markers of emotional arousal will be measured including skin conductance, corrugator EMG, and pupillary response. Primary analyses will 1) examine neurobehavioral trajectories of emotion regulation in TD youth, 2) elucidate divergence in neurobehavioral trajectories of emotion regulation in AD and AD+M youth, and 3) map neurodevelopmental trajectories of illness recovery vs. persistence in affective disordered youth. This ambitious program of neurodevelopmental research promises to yield the first longitudinal and comprehensive set of behavioral and neural markers of cognitive-emotional control in pediatric affective disorders. Furthermore, it will explore the potential for maltreatment to represent a deleterious subtype of affective disorders. In total, this research addresses key areas of the NIMH Strategic Plan including (1) characterizing neurodevelopmental trajectories and biomarkers of illness trajectories, and (2) identifying biomarkers which may be utilized for tailoring treatments and developing novel interventions.

Project Summary The goal of this proposal is to elucidate neurobehavioral mechanisms of parent-child extinction learning in early adolescent PTSD. Notably, deficits in directly learned fear extinction are implicated in adult PTSD. However, youth with PTSD live within the family system, which could impact their ability to extinguish trauma memories. Indeed, abnormal parent-child transmission of fear following trauma is a potent risk factor for youth PTSD. Furthermore, trauma-focused cognitive behavioral therapy (TF-CBT), the gold-standard treatment for pediatric PTSD, uses exposure therapy of the child's trauma narrative for both youth and their caregiver. Here, TF-CBT aims to promote extinction of trauma-related fear both directly in the child and vicariously through parent modeling. However, no reported studies have examined the cumulative impact of direct and vicarious fear extinction in pediatric PTSD. Finally, the diagnosis of PTSD in youth continues to rely on DSM syndromal criteria, creating a great need to establish objective, biologically based diagnoses. This innovative research program will (1) identify physiological impairments in direct/vicarious fear extinction and their unique contributions to adolescent PTSD, (2) identify the neural substrates of fear acquisition and direct/vicarious extinction learning in adolescent PTSD, and (3) use machine learning on biomarkers of fear acquisition and direct/vicarious extinction to classify trauma exposure and PTSD diagnosis in adolescents. This interdisciplinary research team will recruit 40 non-traumatized typically developing (TD) youth, 40 trauma- exposed comparison (TEC) youth without mental illness, and 80 medication-free youth with PTSD, ages 10-14, along with their primary caregiving parent. Youth and parents will undergo fear acquisition followed by a novel fear extinction paradigm. Here, youth will undergo two extinction training conditions: 1) direct extinction and 2) vicarious extinction by observing their parent complete extinction training. Parent/child skin conductance and corrugator EMG will be measured during all fear protocol phases. Additionally, youth will complete all fear phases during fMRI to probe neural substrates of fear acquisition, and direct and vicarious extinction. Following physiological and fMRI analyses, a deep evolutionary machine learning approach will be applied to youth neurophysiological fear indices to classify trauma and PTSD status. Primary analyses will 1) examine physiological markers of direct and vicarious extinction in youth and their relative contribution to PTSD, 2) examine neural abnormalities during direct and vicarious extinction in adolescent PTSD, and 3) determine whether adding vicarious extinction markers enhances machine learning classification of youth trauma and PTSD status. This ambitious program of parent-child extinction learning promises to yield the first comprehensive set of neurophysiological markers of pediatric PTSD that will allow for objective, rational targeting of treatment in the parent-child dyad to improve outcomes for afflicted youth.