Posttraumatic stress disorder (PTSD) is an extreme and sustained maladaptive response to traumatic events. PTSD is a major cause of mental health morbidity and loss of function in affected individuals. Two symptom clusters - re-experiencing symptoms, which include intrusive memories and thoughts, sometimes triggered by environmental cues, and hyperarousal symptoms, characterized by a tonic state of concern and active monitoring of the environment for threat - are particularly debilitating for maintaining effective occupational and social functioning. Individuals with PTSD are prone to re-experience the trauma in a variety of settings and in response to a variety of cues that often differ from the initial traumatic event. Fear generalization and contextualization paradigms provide models to test hypothesized alterations in functional brain regions and connectivity in PTSD that is biased to interpreting cues in the environment as trauma relevant, thus maintaining re-experiencing symptoms. Hyperarousal symptoms are characterized by constant threat monitoring. A predator stress model, which examines vigilance and active coping responses to imminent threats, is useful to test changes in systems that manage multiple, competing demands created by a threatening environment. We propose to test a neural circuit model that forms the basis of re-experiencing and hyperarousal symptoms of PTSD. The functional components of the network model include a threat-alerting system that consists of the amygdala, extended amygdala/ventral striatum, insula, and ventromedial PFC, and a threat-assessing system that consists of hippocampus, anterior cingulate, dorsal striatum, dorsomedial PFC, precuneus, and ventrolateral PFC. To gain insight into the pathogenesis of the re-experiencing and hyperarousal symptoms of PTSD, we have developed a series of interactive paradigms of fear learning and threat-based arousal for the fMRI setting that contain features of computer gaming and virtual reality to identify the relevant dysfunction in connectivity patterns within the proposed brain network. These tasks will be conducted in Veterans with PTSD returning from post-9/11 operations in the Middle East and combat-exposed controls, and brain network relationships will be correlated with current PTSD symptoms. The insights gained into the pathogenesis of PTSD will lay the groundwork for developing future therapeutic interventions that are targeted to symptoms.

Public Health Relevance

TO VETERANS HEALTH Re-experiencing (frequent memories and thoughts of traumatic events) and hyperarousal (being on-guard and jumpy) symptoms of posttraumatic stress disorder (PTSD) are particularly debilitating for maintaining effective occupational and social functioning. Our goal is to understand the pathogenesis of PTSD specific to these symptoms with experimental models of fear learning, and threat-based vigilance in conjunction with functional brain imaging. The insights gained into the pathogenesis of PTSD will lay the groundwork for developing future therapeutic interventions that are targeted to reduce the most debilitating symptoms of PTSD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Mental Health and Behavioral Science A (MHBA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Durham VA Medical Center
United States
Zip Code
Chen, Lyon W; Sun, Delin; Davis, Sarah L et al. (2018) Smaller hippocampal CA1 subfield volume in posttraumatic stress disorder. Depress Anxiety 35:1018-1029
Logue, Mark W; van Rooij, Sanne J H; Dennis, Emily L et al. (2018) Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia. Biol Psychiatry 83:244-253
Sun, Delin; Davis, Sarah L; Haswell, Courtney C et al. (2018) Brain Structural Covariance Network Topology in Remitted Posttraumatic Stress Disorder. Front Psychiatry 9:90
Morey, Rajendra A; Haswell, Courtney C; Hooper, Stephen R et al. (2016) Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder. Neuropsychopharmacology 41:791-801
Gold, Andrea L; Morey, Rajendra A; McCarthy, Gregory (2015) Amygdala-prefrontal cortex functional connectivity during threat-induced anxiety and goal distraction. Biol Psychiatry 77:394-403
Morey, Rajendra A; Lancaster, Sarah C; Haswell, Courtney C (2015) Trauma re-experiencing symptoms modulate topology of intrinsic functional networks. Biol Psychiatry 78:156-8
Morey, R A; Dunsmoor, J E; Haswell, C C et al. (2015) Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder. Transl Psychiatry 5:e700