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Post-traumatic stress disorder (PTSD) is a common, disabling disorder that significantly impacts many combat Veterans. Research estimates that 15-23% of the soldiers returning from deployment in Afghanistan have PTSD (Fulton et al., 2015). The rate of PTSD in Veterans is at least twice the rate of lifetime PTSD in the general population (Kessler et al., 2005). With the high prevalence of PTSD in Veterans, the identification of more effective treatments is crucial. The current first line treatments for PTSD, including selective serotonin reuptake inhibitors (SSRIs) and exposure-based therapies (Bisson et al., 2013), both target brain networks involved in fear processing (Felmingham et al., 2007; Hauner et al., 2012). However, the neurocircuitry of PTSD may extend beyond fear networks and include additional anxiety networks. Fear is a response to an immediate, predictable threat, while anxiety involves responses to uncertain, unpredictable threats. Although overlapping, fear and anxiety have distinct neural networks mediated by the amygdala and bed nucleus of the stria terminalis (BNST) respectively (Avery et al., 2016; Lebow & Chen, 2016). Most PTSD research has focused on the fear network, while the BNST-mediated anxiety network has been understudied in Veterans with PTSD. Such knowledge is critical for identifying brain targets and guiding the development of new interventions to treat PTSD. The current study examined amygdala-mediated fear and BNST-mediated anxiety responses to threat in 32 Veterans with combat PTSD and 13 Veterans with combat exposure without PTSD. Individuals completed a threat anticipation task in a magnetic resonance imaging (MRI) scanner where participants viewed predictable threat cues followed by threat images, predictable neutral cues followed by neutral images, and unpredictable threat cues followed by either a threat or neutral image. The study examined amygdala and BNST responses (activation, connectivity) to unpredictable and predictable threats. First, we found that Veterans with PTSD had heightened BNST activation to all the cues and images, regardless of the type of image, which suggests Veterans have an overall hyperarousal to all images. Second, Veterans with PTSD showed stronger BNST and amygdala connectivity with multiple regions in the fear and anxiety networks including the hippocampus, hypothalamus, insula, and ventromedial prefrontal cortex. The connectivity findings suggest that the Veterans with PTSD have increased communication within both the fear and anxiety networks during threat processing relative to controls. Third, we also discovered that the combat-exposed control group (those without PTSD) had different BNST and amygdala connectivity during the neutral conditions. These findings may reflect post-combat response or even a pre-trauma resilient response in combat-exposed individuals who do not go on to develop PTSD, potentially suggesting a brain basis of resilience to PTSD. Thus, we found that in combat PTSD there are alterations in both amygdala/fear and BNST/anxiety brain networks. These findings extend the historic and current understanding of the neurocircuitry of PTSD from a fear-based model to now also include BNST-mediated anxiety networks. This new knowledge is crucial for improving our understanding of the brain basis of PTSD and improving treatments that now may aim to target the BNST-mediated anxiety network. Importantly, novel treatments based on a neurobiological model of PTSD that includes both the fear and anxiety networks may increase effectiveness of treatments for PTSD in the hope of eliminating some of the burden of PTSD. 

Target Article

Feola, B., Flook, E. A., Gardner, H., Phan, K. L., Gwirtsman, H., Olatunji, B., & Blackford, J. U. (2023). Altered bed nucleus of the stria terminalis and amygdala responses to threat in combat veterans with posttraumatic stress disorder. Journal of Traumatic Stress, 00, 1–14.

Discussion Questions

  1. How does the anxiety network differ from the fear network in PTSD? 
  2. How does the current study extend our current understanding of PTSD?
  3. Would treatment approaches differ if providers knew that both fear and anxiety networks were altered in individuals with PTSD? 

About the Authors

Brandee Feola, PhD
: Dr. Feola is a Research Assistant Professor in the Department of Psychiatry and Behavioral Sciences at Vanderbilt University Medical Center. Dr. Feola’s research program examines stress and anxiety throughout development and across psychiatric disorders including PTSD and schizophrenia. She can be contacted at brandee.feola@vumc.org. 
Jennifer Blackford, PhD
: Dr. Blackford is the Director of Research and Hattie B. Munroe Professor at the Munroe-Meyer Institute, Professor of Neurological Sciences at University of Nebraska Medical Center, and Professor of Psychology at University of Nebraska-Omaha. Dr. Blackford's research program aims to identify and characterize the neurobiological basis of anxiety across the lifespan and the role of anxiety neurocircuitry in people with psychiatric disorders including PTSD, alcohol use disorders, and schizophrenia. She can be contacted at jblackford@unmc.edu.

References Cited

Avery, S. N., Clauss, J. A., & Blackford, J. U. (2016). The Human BNST: Functional Role in Anxiety and Addiction. In Neuropsychopharmacology (Vol. 41, Issue 1, pp. 126–141). Nature Publishing Group. https://doi.org/10.1038/npp.2015.185

Bisson, J. I., Roberts, N. P., Andrew, M., Cooper, R., & Lewis, C. (2013). Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults. Cochrane Database of Systematic Reviews, 12. https://doi.org/10.1002/14651858.CD003388.pub4.

Felmingham, K., Kemp, A., Williams, L., Das, P., Hughes, G., Peduto, A., & Bryant, R. (2007). Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder. Psychological Science, 18(2), 127–129. https://doi.org/10.1111/j.1467-9280.2007.01860.x

Fulton, J. J., Calhoun, P. S., Wagner, H. R., Schry, A. R., Hair, L. P., Feeling, N., Elbogen, E., & Beckham, J. C. (2015). The prevalence of posttraumatic stress disorder in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans: A meta-analysis. Journal of Anxiety Disorders, 31, 98–107. https://doi.org/10.1016/j.janxdis.2015.02.003

Hauner, K. K., Mineka, S., Voss, J. L., & Paller, K. a. (2012). Exposure therapy triggers lasting reorganization of neural fear processing. Proceedings of the National Academy of Sciences of the United States of America, 109(23), 9203–9208. https://doi.org/10.1073/pnas.1205242109

Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62(6), 593–602. https://doi.org/10.1001/archpsyc.62.6.593

Lebow, M. A., & Chen, A. (2016). Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Molecular Psychiatry, 21, 450–463. https://doi.org/10.1038/mp.2016.1