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Sequential decreases in basolateral amygdala response to threat predict failure to recover from PTSD

Neuropsychopharmacology volume 50, pages 1573–1582 (2025)Cite this article

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Abstract

Amygdala hyperreactivity early-post trauma has been a demonstrable neurobiological correlate of future posttraumautic stress disorder (PTSD). The basolateral amygdala (BLA) particularly is vital for fear memory and threat processing, but BLA functional dynamics following a traumatic event are unexplored. BLA reactivity to threat may be a trait that can predict PTSD and persist over time. Alternatively, BLA responsivity to threat cues may change over time and be related to PTSD severity. As part of a larger, multisite study, AURORA, participants 18–75 years old were enrolled in an emergency department (ED) within 72 h of a traumatic event (N = 304, 199 female). At 2-weeks and 6-months post-trauma, PTSD symptoms, BLA responses to threat (fearful>neutral faces), and functional connectivity (FC) during fMRI were assessed. Generalizability of findings was assessed in an external replication sample of ED patients (n = 33). Two weeks post-trauma right BLA reactivity positively predicted later PTSD severity. However, left BLA reactivity to threat at 6 months post-trauma was negatively associated with PTSD severity at that timepoint (ΔPseudo-R2 = 0.04, IRR = 0.38, p < 0.001). In addition, a decrease in BLA reactivity from 2-weeks to 6-months predicted greater PTSD severity at 6 months (ΔPseudo-R2 = 0.03, IRR = 0.58, p < 0.001). This replicated in the external sample. A reduction in left BLA FC with the dorsal attention network predicted increased PTSD severity over time. These findings support a shift in BLA function within the first 6 months post-trauma that predicts PTSD pathology and stand in contrast to prior conceptualizations of amygdala hyperreactivity as a trait-like PTSD risk factor.

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Fig. 1: Task-related whole-brain activation and significant associations between the BLA response to social threat cues and PTSD symptom severity in the Discovery cohort.
Fig. 2: Significant associations between changes in the left BLA response to social threat cues and 6-month PTSD symptom severity in both cohorts.
Fig. 3: Left BLA functional connectivity.

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Data availability

Data and/or research tools used in the preparation of this manuscript were obtained from the National Institute of Mental Health (NIMH) Data Archive (NDA). NDA is a collaborative informatics system created by the National Institutes of Health to provide a national resource to support and accelerate research in mental health. Dataset identifier(s): NIMH Data Archive Digital Object Identifier (DOI) https://doi.org/10.15154/5t8n-fj46. Data and analysis code are available via https://github.com/aroeckner/BLA. Any additional information required to reanalyze the data reported in this paper is available from Jennifer Stevens, PhD (jennifer.stevens@emory.edu).

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Acknowledgements

The investigators wish to thank the trauma survivors participating in the AURORA Study. Their time and effort during a challenging period of their lives make our efforts to improve recovery for future trauma survivors possible.

Funding

This research was supported by the National Institute of Mental Health K00 MH119603, K01 MH118467, U01 MH110925, and F31 MH126623, as well as the U.S. Department of Defense W81XWH-22-C-0122. This project was supported by NIMH under U01MH110925, the US Army MRMC, One Mind, and The Mayday Fund. The content is solely responsibility of the authors and does not necessarily represent the official views of any of the funders. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or of the Submitters submitting original data to NDA.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Alyssa R. Roeckner, Esther R.-H. Lin, Rebecca Hinrichs, Sanne J. H. van Rooij, Timothy D. Ely & Jennifer S. Stevens

  2. Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA

    Nathaniel G. Harnett, Lauren A. M. Lebois & Kerry J. Ressler

  3. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Nathaniel G. Harnett, Lauren A. M. Lebois, Laura T. Germine, Scott L. Rauch & Kerry J. Ressler

  4. Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, USA

    Tanja Jovanovic

  5. Department of Psychology, Temple University, Philadelphia, PA, USA

    Vishnu P. Murty

  6. Department of Psychological Sciences, University of Missouri - St. Louis, St. Louis, MO, USA

    Steven E. Bruce

  7. Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Stacey L. House

  8. Department of Epidemiology, Brown University, Providence, RI, USA

    Francesca L. Beaudoin

  9. Department of Emergency Medicine, Brown University, Providence, RI, USA

    Francesca L. Beaudoin

  10. Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Xinming An & Sarah D. Linnstaedt

  11. Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, USA

    Thomas C. Neylan

  12. Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA

    Gari D. Clifford

  13. Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA

    Gari D. Clifford

  14. Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA

    Laura T. Germine & Scott L. Rauch

  15. The Many Brains Project, Belmont, MA, USA

    Laura T. Germine

  16. Department of Psychiatry, McLean Hospital, Belmont, MA, USA

    Scott L. Rauch

  17. Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA

    John P. Haran

  18. Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Alan B. Storrow

  19. Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA

    Christopher Lewandowski

  20. Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Paul I. Musey

  21. Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, USA

    Phyllis L. Hendry & Sophia Sheikh

  22. Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA

    Christopher W. Jones

  23. Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, USA

    Brittany E. Punches

  24. Ohio State University College of Nursing, Columbus, OH, USA

    Brittany E. Punches

  25. Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA

    Robert A. Swor

  26. Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Lauren A. Hudak

  27. Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA

    Jose L. Pascual

  28. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jose L. Pascual & Mark J. Seamon

  29. Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA

    Mark J. Seamon

  30. Department of Emergency Medicine, Jefferson Einstein hospital, Jefferson Health, Philadelphia, PA, USA

    Elizabeth M. Datner

  31. Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    Elizabeth M. Datner

  32. Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, USA

    Claire Pearson

  33. Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA

    David A. Peak

  34. Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Roland C. Merchant & Leon D. Sanchez

  35. Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, USA

    Robert M. Domeier

  36. Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, USA

    Niels K. Rathlev

  37. Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, USA

    Brian J. O’Neil

  38. Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, USA

    Paulina Sergot

  39. Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA

    Leon D. Sanchez

  40. Department of Psychology, Yale University, New Haven, CT, USA

    Jutta Joormann

  41. Division of Biosciences, Ohio State University College of Dentistry, Columbus, OH, USA

    John F. Sheridan

  42. Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, USA

    John F. Sheridan

  43. Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Steven E. Harte

  44. Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA

    Steven E. Harte

  45. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA

    Karestan C. Koenen

  46. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA

    Ronald C. Kessler

  47. Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Samuel A. McLean

  48. Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Samuel A. McLean

Authors
  1. Alyssa R. Roeckner
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  2. Esther R.-H. Lin
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  3. Rebecca Hinrichs
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  4. Nathaniel G. Harnett
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  5. Lauren A. M. Lebois
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  6. Sanne J. H. van Rooij
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  7. Timothy D. Ely
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  8. Tanja Jovanovic
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  9. Vishnu P. Murty
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  10. Steven E. Bruce
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  11. Stacey L. House
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  12. Francesca L. Beaudoin
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  13. Xinming An
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  14. Thomas C. Neylan
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  15. Gari D. Clifford
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  16. Sarah D. Linnstaedt
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  17. Laura T. Germine
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  18. Scott L. Rauch
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  19. John P. Haran
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  20. Alan B. Storrow
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  21. Christopher Lewandowski
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  22. Paul I. Musey
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  23. Phyllis L. Hendry
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  24. Sophia Sheikh
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  25. Christopher W. Jones
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  26. Brittany E. Punches
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  27. Robert A. Swor
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  28. Lauren A. Hudak
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  29. Jose L. Pascual
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  30. Mark J. Seamon
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  31. Elizabeth M. Datner
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  32. Claire Pearson
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  33. David A. Peak
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  34. Roland C. Merchant
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  35. Robert M. Domeier
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  36. Niels K. Rathlev
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  37. Brian J. O’Neil
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  38. Paulina Sergot
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  39. Leon D. Sanchez
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  40. Jutta Joormann
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  41. John F. Sheridan
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  42. Steven E. Harte
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  43. Karestan C. Koenen
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  44. Ronald C. Kessler
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  45. Samuel A. McLean
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  46. Kerry J. Ressler
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  47. Jennifer S. Stevens
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Contributions

SAM, RC, KJR, KCK, ARR, JSS, RH, SJHvR, TDE, NH, VPM, LAML, TJ, SLH and SEB contributed to the conceptualization, including formulation or evolution of overarching research goals and aims, of the study. FLB, XA, TCN, GDC, SDL, LTG, SLR, JJ, DAP, JFS, SEH, SAM, RCK, KJR, KCK, SJHvR, JSS, TDE, NH, VM, LL, TJ, SLH. and SB contributed to the methodology of the study, including development or design of methodology and creation of models. ARR, JSS, SJHvR, J TDE, NH, VM, LL, TJ, SLH, SB and KJR contributed to the neuroimaging data collection, formal analyses and validation of the study. SLH, FLB, XA, JSS, TCN, GDC, TJ, SDL, LTG, SLR, JPH, ABS, CL, PIMJr, PLH, SS, CWJ, BEP, RAS, JLP, MJS, CP, DAP, RCM, RMD, NKR, BJO, LDS, SAM, RCK, KJR and KCK conducted the research and investigation process, specifically, performing the experiments or data and evidence collection. SLH, FLB, XA, JSS, TCN, GDC, TJ, SDL, LTG, SLR, JPH, ABS, CL, PIMJr, PLH, SS, CWJ, BEP, RAS, JLP, MJS, CP, DAP, RCM, RMD, NKR, BJO, LDS, SAM, RCK., KJR. and KCK provided the resources for the study, including provision of study materials, patients, laboratory samples, instrumentation, computing resources or other analysis tools. SLH, FLB, XA, JSS, TCN, GDC, TJ, SDL, LTG, SLR, SAM, RCK, KJR and KCK were responsible for data curation, including management activities to annotate, scrub data and maintain research data for initial use and later reuse. ARR, ER-HL, and JSS were responsible for writing the original draft, including preparation, creation and presentation of the published work. All authors contributed to the paper by reviewing and editing the original draft. ARR and JSS were responsible for data visualization, including preparing, creating and presenting the published work, specifically, visualization and data presentation. SAM, RCK, KJR, KCK, and JSS were responsible for supervision, including oversight and leadership for the research activity planning and execution, including mentorship external to the core team. SLH, FLB, JSS, TJ, JPH, ABS, CL PIMJr, PLH, SS, CWJ, BEP, RAS, JLP, MJS, CP, RCM, RMD, NKR, NJO, LDS and SB were responsible for project administration, including management and coordination, responsibility for the research activity planning and execution. SAM, RCK, KJR and KCK were responsible for acquisition of the financial support for the project leading to this publication. ARR was responsible for funding supporting her effort on this publication.

Corresponding author

Correspondence to Jennifer S. Stevens.

Ethics declarations

Competing interests

Dr. Harnett reports grant support from the National Institute of Mental Health, K00 MH119603. Dr. Lebois reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD) and grant support from the National Institute of Mental Health, K01 MH118467. ISSTD and NIMH were not involved in the analysis or preparation of the manuscript. Dr. van Rooij is supported by the NIMH (K01MH121653). Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Jazz Pharmaceuticals. In the last three years Dr Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, the Rett Research Foundation, and Samsung Research. Dr Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. Dr. Germine receives funding from the National Institute of Mental Health (R01 MH121617) and am on the board of the Many Brains Project. My family also has equity in Intelerad Medical Systems, Inc. Dr Rauch reported serving as secretary of the Society of Biological Psychiatry; serving as a board member of Community Psychiatry and Mindpath Health; serving as a board member of National Association of Behavioral Healthcare; serving as secretary and a board member for the Anxiety and Depression Association of America; serving as a board member of the National Network of Depression Centers; receiving royalties from Oxford University Press, American Psychiatric Publishing Inc, and Springer Publishing; and receiving personal fees from the Society of Biological Psychiatry, Community Psychiatry and Mindpath Health, and National Association of Behavioral Healthcare outside the submitted work. Dr. Sheikh has received funding from the Florida Medical Malpractice Joint Underwriter’s Association Dr. Alvin E. Smith Safety of Healthcare Services Grant; Allergan Foundation; the NIH/NIA-funded Jacksonville Aging Studies Center (JAX-ASCENT; R33AG05654); and the Substance Abuse and Mental Health Services Administration (1H79TI083101-01); and the Florida Blue Foundation. Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. Dr. Datner serves as Medical Advisor and on the Board of Directors for Cayaba Care. Dr. Joormann receives consulting payments from Janssen Pharmaceuticals. Dr. Harte has no competing interest related to this work, though in the last three years he has received research funding from Aptinyx and Arbor Medical Innovations, and consulting payments from Aptinyx. Dr. Koenen’s research has been supported by the Robert Wood Johnson Foundation, the Kaiser Family Foundation, the Harvard Center on the Developing Child, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institutes of Health, One Mind, the Anonymous Foundation, and Cohen Veterans Bioscience. She has been a paid consultant for Baker Hostetler, Discovery Vitality, and the Department of Justice. She has been a paid external reviewer for the Chan Zuckerberg Foundation, the University of Cape Town, and Capita Ireland. She has had paid speaking engagements in the last three years with the American Psychological Association, European Central Bank. Sigmund Freud University – Milan, Cambridge Health Alliance, and Coverys. She receives royalties from Guilford Press and Oxford University Press. In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. Dr. McLean served as a consultant for Walter Reed Army Institute for Research and for Arbor Medical Innovations, and BioXcel Therapeutics, Inc. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. The remaining authors declare no competing interests.

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Roeckner, A.R., Lin, E.RH., Hinrichs, R. et al. Sequential decreases in basolateral amygdala response to threat predict failure to recover from PTSD. Neuropsychopharmacol. 50, 1573–1582 (2025). https://doi.org/10.1038/s41386-025-02115-1

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