Soldiers in the war zone are at high risk for potentially significant repercussions resulting from combat experiences. Combat stress can lead to a number of highly impactful emotional and cognitive conditions, most notably Posttraumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD), and mild Traumatic Brain Injury (mTBI). The primary goal of affective neuroscience is to effectively identify the neural substrates that define mental disorders. While cross-sectional brain imaging research has provided enormous insight into the mechanisms of major mental disorders, these conditions are by nature dynamic and a snapshot of the turbulence of these conditions provides a limited methodology for understanding how changes in symptoms are reflected in the underlying brain mechanisms. Our application attempts to use an approach that maps these dynamic conditions over time using 3 sessions spaced 9 month apart to measure the dynamics in brain processing in Veterans with significant combat exposure. This approach will enable a better understanding of the fluctuation and dynamics of the neural systems involved in PTSD, in the context of MDD and mTBI. Functional magnetic resonance imaging (fMRI) allows for measurement of the hemodynamic brain response during specific processes, such as anticipation of aversive stimuli, which are relevant to the pathophysiology of PTSD. The goal of this application is to determine the brain mechanisms that delineate PTSD and determine how these mechanisms can predict poor clinical course. We posit that measurement of the dynamic change in brain response to anticipatory stress can incorporate the fluctuations clinical course of PTSD, MDD, and mTBI. Conversely, these fluctuations often obscure understanding of brain processing when assessed cross-sectionally. We will examine this hypothesis by pursuing the following three specific aims: (1) Identify cross- sectionally neural biomarkers of combat-related PTSD and determine if these biomarkers are sufficiently sensitive and specific;(2) Determine the extent to which brain activation to anticipatory stress at baseline predicts changes in PTSD symptom severity at follow-up and (3) Determine the extent to which specific candidate neural biomarkers reflect the clinical course of PTSD and key comorbid disorders and how these regions differentially recruit modulatory networks. In the short term, this research may contribute to the development of well-developed neural models of these disorders in our Veteran population. In the long term, this research will lay the foundation for studies aimed at determining candidate neural biomarkers that can provide an objective neural representation of disease course for therapeutic intervention studies.

Public Health Relevance

In the proposed merit we aim to collect longitudinal brain imaging data on those who acquired PTSD following combat exposure, in contrast to those with similar combat experience without PTSD. This proposal has the specific aims of separating those neural substrates that are pertinent to PTSD from those better characterized by common comorbidities, such as depression and mild traumatic brain injury. In addition, through a longitudinal approach, we aim to understand the predictors of dynamic change in PTSD in the context of combat stress, as well as examining the validity of cross-sectional neural biomarkers. Determination of successful treatment outcome depends on appropriate diagnosis which is difficult as these conditions share numerous clinical and behavioral manifestations. In this way advancements in our understanding on neural mechanisms of change can lead directly to better quality of care. This line of investigation provides unique and complimentary information to elucidate the overall project regarding stress response.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science A (MHBA)
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VA San Diego Healthcare System
San Diego
United States
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Stout, Daniel M; Buchsbaum, Monte S; Spadoni, Andrea D et al. (2018) Multimodal canonical correlation reveals converging neural circuitry across trauma-related disorders of affect and cognition. Neurobiol Stress 9:241-250
Bomyea, J; Matthews, S C; Buchsbaum, M S et al. (2017) Neural differences underlying face processing in veterans with TBI and co-occurring TBI and PTSD. J Affect Disord 223:130-138
Connolly, Colm G; Ho, Tiffany C; Blom, Eva Henje et al. (2017) Resting-state functional connectivity of the amygdala and longitudinal changes in depression severity in adolescent depression. J Affect Disord 207:86-94
Buchsbaum, Monte S; Simmons, Alan N; DeCastro, Alex et al. (2015) Clusters of Low (18)F-Fluorodeoxyglucose Uptake Voxels in Combat Veterans with Traumatic Brain Injury and Post-Traumatic Stress Disorder. J Neurotrauma 32:1736-50
Spadoni, Andrea D; Kosheleva, Elena; Buchsbaum, Monte S et al. (2015) Neural correlates of malingering in mild traumatic brain injury: A positron emission tomography study. Psychiatry Res 233:367-72