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

Alyssa R Roeckner¹, Esther R-H Lin¹, Rebecca Hinrichs¹, Nathaniel G Harnett^{2

3}, Lauren A M Lebois^{2

3}, Sanne J H van Rooij¹, Timothy D Ely¹, Tanja Jovanovic⁴, Vishnu P Murty⁵, Steven E Bruce⁶, Stacey L House⁷, Francesca L Beaudoin^{8

9}, Xinming An¹⁰, Thomas C Neylan¹¹, Gari D Clifford^{12

13}, Sarah D Linnstaedt¹⁰, Laura T Germine^{3

14

15}, Scott L Rauch^{3

14

16}, John P Haran¹⁷, Alan B Storrow¹⁸, Christopher Lewandowski¹⁹, Paul I Musey²⁰, Phyllis L Hendry²¹, Sophia Sheikh²¹, Christopher W Jones²², Brittany E Punches^{23

24}, Robert A Swor²⁵, Lauren A Hudak²⁶, Jose L Pascual^{27

28}, Mark J Seamon^{28

29}, Elizabeth M Datner^{30

31}, Claire Pearson³², David A Peak³³, Roland C Merchant³⁴, Robert M Domeier³⁵, Niels K Rathlev³⁶, Brian J O'Neil³⁷, Paulina Sergot³⁸, Leon D Sanchez^{34

39}, Jutta Joormann⁴⁰, John F Sheridan^{41

42}, Steven E Harte^{43

44}, Karestan C Koenen⁴⁵, Ronald C Kessler⁴⁶, Samuel A McLean^{47

48}, Kerry J Ressler^{2

3}, Jennifer S Stevens⁴⁹

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
² Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA.
³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
⁴ Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, USA.
⁵ Department of Psychology, Temple University, Philadelphia, PA, USA.
⁶ Department of Psychological Sciences, University of Missouri - St. Louis, St. Louis, MO, USA.
⁷ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Epidemiology, Brown University, Providence, RI, USA.
⁹ Department of Emergency Medicine, Brown University, Providence, RI, USA.
¹⁰ Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
¹⁴ Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA.
¹⁵ The Many Brains Project, Belmont, MA, USA.
¹⁶ Department of Psychiatry, McLean Hospital, Belmont, MA, USA.
¹⁷ Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹⁸ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹ Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA.
²⁰ Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
²¹ Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, USA.
²² Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA.
²³ Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, USA.
²⁴ Ohio State University College of Nursing, Columbus, OH, USA.
²⁵ Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
²⁶ Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA.
²⁷ Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁹ Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA.
³⁰ Department of Emergency Medicine, Jefferson Einstein hospital, Jefferson Health, Philadelphia, PA, USA.
³¹ Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
³² Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, USA.
³³ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁴ Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁵ Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, USA.
³⁶ Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, USA.
³⁷ Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, USA.
³⁸ Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, USA.
³⁹ Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.
⁴⁰ Department of Psychology, Yale University, New Haven, CT, USA.
⁴¹ Division of Biosciences, Ohio State University College of Dentistry, Columbus, OH, USA.
⁴² Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, USA.
⁴³ Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴⁴ Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴⁶ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴⁷ Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁸ Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. jennifer.stevens@emory.edu.

PMID: 40319171
PMCID: PMC12340031 (available on 2026-09-01)
DOI: 10.1038/s41386-025-02115-1

Multicenter Study

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

Alyssa R Roeckner et al. Neuropsychopharmacology. 2025 Sep.

. 2025 Sep;50(10):1573-1582.

doi: 10.1038/s41386-025-02115-1. Epub 2025 May 3.

Authors

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
² Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA.
³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
⁴ Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, USA.
⁵ Department of Psychology, Temple University, Philadelphia, PA, USA.
⁶ Department of Psychological Sciences, University of Missouri - St. Louis, St. Louis, MO, USA.
⁷ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Epidemiology, Brown University, Providence, RI, USA.
⁹ Department of Emergency Medicine, Brown University, Providence, RI, USA.
¹⁰ Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
¹⁴ Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA.
¹⁵ The Many Brains Project, Belmont, MA, USA.
¹⁶ Department of Psychiatry, McLean Hospital, Belmont, MA, USA.
¹⁷ Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹⁸ Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹ Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, USA.
²⁰ Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
²¹ Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, USA.
²² Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA.
²³ Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, USA.
²⁴ Ohio State University College of Nursing, Columbus, OH, USA.
²⁵ Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
²⁶ Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA.
²⁷ Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁹ Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA.
³⁰ Department of Emergency Medicine, Jefferson Einstein hospital, Jefferson Health, Philadelphia, PA, USA.
³¹ Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
³² Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, USA.
³³ Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁴ Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁵ Department of Emergency Medicine, Trinity Health-Ann Arbor, Ypsilanti, MI, USA.
³⁶ Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, USA.
³⁷ Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, USA.
³⁸ Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, USA.
³⁹ Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.
⁴⁰ Department of Psychology, Yale University, New Haven, CT, USA.
⁴¹ Division of Biosciences, Ohio State University College of Dentistry, Columbus, OH, USA.
⁴² Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, USA.
⁴³ Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴⁴ Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴⁶ Department of Health Care Policy, Harvard Medical School, Boston, MA, USA.
⁴⁷ Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁸ Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. jennifer.stevens@emory.edu.

PMID: 40319171
PMCID: PMC12340031 (available on 2026-09-01)
DOI: 10.1038/s41386-025-02115-1

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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Conflict of interest statement

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials