Neural correlates of conceptual-level fear generalization in posttraumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) may develop when mechanisms for making accurate distinctions about threat relevance have gone awry. Generalization across conceptually related objects has been hypothesized based on clinical observation in PTSD, but the neural mechanisms remain unexplored. Recent trauma-exposed military veterans (n = 46) were grouped into PTSD (n = 23) and non-PTSD (n = 23). Participants learned to generalize fear across conceptual categories (animals or tools) of semantically related items that were partially reinforced by shock during functional magnetic resonance imaging. Conditioned fear learning was quantified by shock expectancy and skin conductance response (SCR). Relative to veteran controls, PTSD subjects exhibited a stronger neural response associated with fear generalization to the reinforced object category in the striatum, anterior cingulate cortex, amygdala, occipitotemporal cortex, and insula (Z > 2.3; p < 0.05; whole-brain corrected). Based on SCR, both groups generalized the shock contingency to the reinforced conceptual category, but learning was not significantly different between groups. We found that PTSD was associated with an enhanced neural response in fronto-limbic, midline, and occipitotemporal regions to a learned representation of threat that is based on previously established conceptual knowledge of the relationship between basic-level exemplars within a semantic category. Behaviorally, veterans with PTSD were somewhat slower to differentiate threat and safety categories as compared with trauma-exposed veteran controls owing in part to an initial overgeneralized behavioral response to the safe category. These results have implications for understanding how fear spreads across semantically related concepts in PTSD.

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Fig. 1: Subjects were presented with 80 unique exemplars of animals (40) and tools (40) for 6 s each.
Fig. 2: Physiological and behavioral and indices of conceptual fear generalization.
Fig. 3: FMRI correlates of conceptual fear generalization.

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Acknowledgements

The VA Mid-Atlantic MIRECC Workgroup contributors for this paper include: Mira Brancu, PhD, Jean C. Beckham, PhD, Patrick S. Calhoun, PhD, Eric Dedert, PhD, Eric B. Elbogen, PhD, John A. Fairbank, PhD, Robin A. Hurley, MD, Jason D. Kilts, PhD, Nathan A. Kimbrel, PhD, Angela Kirby, MS, Christine E. Marx, MD, MA, Scott D. McDonald, PhD, Scott D. Moore, MD, PhD, Jennifer C. Naylor, PhD, Jared Rowland, PhD, Cindy Swinkels, PhD, Steven T. Szabo, MD, PhD, Katherine H. Taber, PhD., Larry A. Tupler, PhD, Elizabeth E. Van Voorhees, PhD, H. Ryan Wagner, Ph.D., Ruth E. Yoash-Gantz, PsyD. This research was supported by the US Department of Veterans Affairs (VA) Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) core funds of the Department of Veterans Affairs Office of Mental Health Services. Dr. Morey also received financial support from the VA Office of Research and Development (5I01CX000748-01, 5I01CX000120-02). Additional financial support was provided by the National Institute for Neurological Disorders and Stroke (R01NS086885-01A1). Writing of this manuscript was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the Durham VA Health Care System, and the Department of Veterans Affairs Mid-Atlantic MIRECC. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government.

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R.A.M. wrote the manuscript, contributed to data analysis, interpretation of the data, and acquisition of data, gave final approval for the version to be published and is accountable for all aspects of the work including accuracy and integrity. C.C.H. made substantial contributions to data analysis, interpretation of the data, acquisition of data, and gave final approval for the version to be published. D.S. contributed to data analysis, interpretation of the data, and acquisition of data, gave final approval for the version to be published. M.A.M. Workgroup contributed to the acquisition of data, gave final approval for the version to be published. J.E.D. made substantial contributions to the conception and design, contributed to the interpretation of the data, gave final approval for the version to be published. K.S.L. made substantial contributions to the conception and design, interpretation of the data, and writing the manuscript, gave final approval for the version to be published, and is accountable for all aspects of the work including accuracy and integrity.

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Correspondence to Rajendra A. Morey.

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Morey, R.A., Haswell, C.C., Stjepanović, D. et al. Neural correlates of conceptual-level fear generalization in posttraumatic stress disorder. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-0661-8

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