The underlying neurobiology of posttraumatic stress disorder (PTSD) has been hypothesized to involve dysfunction within neural systems that mediate fear conditioning, emotional control, and central regulation of the autonomic nervous system. However, functional neuroimaging research examining cognitive skills has also started to identify alterations within other neural systems. In a recent publication we reported preliminary results from a functional magnetic resonance imaging (fMRI) cognitive control paradigm, the Arrows Task, which was used to examine elevated posttraumatic stress symptoms (PTSS) and brain function following Operation Enduring Freedom/Operation Iraqi Freedom/New Dawn (OEF/OIF/OND) combat deployment. Those findings were consistent with a neural resource shift away from higher-level association areas and supported a conceptual model of posttraumatic stress disorder (PTSD) that emphasizes the role of hyperarousal and alterations in central catecholamines. Previous investigations using executive function fMRI paradigms to study PTSD and PTSS, including our own research, have all suffered from one or more limitations such as the enrollment of participants who did not meet full diagnostic criteria for PTSD, use of fMRI paradigms that combined both executive function and symptom provocation procedures, examination of samples without combat trauma, and the failure to screen or control adequately for co-morbid disorders such as depression and mild traumatic brain injury (mTBI). The current application proposes a well-designed functional neuroimaging study that would focus on combat-related PTSD while implementing such controls. The proposed study's primary objective would be to examine PTSD-related changes in neural function associated with cognitive control and the relationship between this activation and clinical symptoms, daily functioning (i.e., sleep, psychosocial function), and external measures of executive functions. Another important aim of this study would be to examine alterations in resting state functional connectivity and to relate these to activation during cognitive control. It would be conducted as a cross sectional study of OEF/OIF/OND veterans with a confirmed PTSD diagnosis and would include a trauma exposed comparison group and an additional comparison group to examine PSTD in combination with co-morbid mTBI. Co-morbid depression would also be addressed and all participants would complete a formal assessment for PTSD and related conditions (e.g., substance abuse), including the Clinician-Assisted PTSD Scale for DSM-5 and other PTSD common data elements as key measures. The project's duration would be three and a half years and it would acquire event-related and resting state fMRI data, anatomical imaging, and data from symptom and outcome measures to characterize the sample. We hypothesize that the engagement of cognitive control in patients with PTSD will be associated with an Arrows Task activation pattern which, relative to the comparison groups, will include decreased activation within heteromodal association cortex and increases within other structures involved in emotional regulation and primary sensory or motor functions. Image regression analyses would also be performed and these activation changes are expected to be related to abnormal connectivity, clinical symptoms, cognitive impairment, and problems with daily functioning.

An estimated 13% to 20% of post-deployment personnel eventually develop posttraumatic stress disorder (PTSD). These Veterans and Service Members are at increased risk for a variety of health, cognitive, and social problems that are related to long-term disability and mortality. The proposed study would examine neuroimaging measures that our preliminary research has found to be related to PTSD symptoms, cognitive impairment, and neural dysfunction following combat deployment. Confirmation of these early findings and further development of the imaging methods has the potential to contribute neuroimaging markers that may ultimately inform differential diagnosis and prognosis, guide treatment decisions, and serve as biological targets for use in clinical trials to assess the effectiveness of new pharmacological agents and behavioral interventions.