Post-traumatic stress disorder (PTSD) is a disabling and prevalent disorder that is rapidly becoming the most common mental health problem facing Veterans returning home from Iraq and Afghanistan. In addition to the devastating effects of PTSD, secondary effects include increased risk for suicide, depression, and substance use disorders. Unfortunately, PTSD is often resistant to current therapeutic interventions and a full recovery is uncommon. The development of therapies targeted at the underlying pathophysiology is a promising avenue for the effective treatment of PTSD, but to develop these treatments, first we must better understand the underlying neurobiological mechanisms. To date, most research on the neurobiological mechanisms of PTSD has focused on an amygdala-mediated fear circuit. Compelling animal models show that a different neural circuit, mediated by the bed nucleus of the stria terminalis (BNST), is critical for anxiety. The BNST also mediates hypervigilance and responses to stress, which may explain the critical features of PTSD. Thus, we propose that combat Veterans with PTSD have alterations in a BNST-mediated anxiety circuit. We have recently characterized the BNST neural circuitry in humans and have developed novel methods to examine BNST function. Our preliminary data demonstrates that the BNST is specifically engaged in situations where a threat is unpredictable, and that individuals with PTSD show significantly heightened BNST responses to unpredictable threat relative to predictable threat. The study will focus on three specific aims: (1) Investigate BSNT function in individuals with PTSD to determine if PTSD is associated with heightened BNST responses to unpredictable threat (2) Identify patterns of PTSD-related functional dysconnectivity in the BNST-mediated anxiety circuit. A circuit-level approach is critical for identifying interactions between regions in the circuit. (3) Test for relationships between units o analysis in the RDoC Negative Valence System/Response to Potential Harm. A dimensional approach that is consistent with NIMH's RDoC objectives is employed in this project by examining a novel neurobiological mechanism of PTSD across multiple units of analysis, from neural circuit to behavior. This project will also elucidate the brain-physiology-symptom relationships within two constructs of the Negative Valence system: Response to Potential Harm (unpredictable threat, BNST) and Response to Acute Threat (predictable threat, amygdala). Ultimately we aim to elucidate the neurobiological mechanisms underlying PTSD to identify novel brain targets for treatment. Importantly, the BNST and amygdala respond differently to pharmacological agents; therefore, if we find evidence for BNST alteration in PTSD, the BNST and responses to unpredictable threat will provide novel targets for treatment.

Public Health Relevance

PTSD is a substantial public health problem and current treatments leave substantial room for improvement. This study will determine whether function of an anxiety neural circuit mediated by the bed nucleus of the stria terminalis is altered in PTSD. Such knowledge is critical for identifying novel brain targets and guiding the development of new interventions to prevent and treat trauma and stress-based disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Borja, Susan
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Theiss, Justin D; Ridgewell, Caitlin; McHugo, Maureen et al. (2017) Manual segmentation of the human bed nucleus of the stria terminalis using 3T MRI. Neuroimage 146:288-292
Avery, S N; Clauss, J A; Blackford, J U (2016) The Human BNST: Functional Role in Anxiety and Addiction. Neuropsychopharmacology 41:126-41