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Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors

Molecular Psychiatry volume 28, pages 657–667 (2023)Cite this article

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Abstract

The hippocampus and the amygdala play a central role in post-traumatic stress disorder (PTSD) pathogenesis. While alternations in volumes of both regions have been consistently observed in individuals with PTSD, it remains unknown whether these reflect pre-trauma vulnerability traits or acquired post-trauma consequences of the disorder. Here, we conducted a longitudinal panel study of adult civilian trauma survivors admitted to a general hospital emergency department (ED). One hundred eligible participants (mean age = 32.97 ± 10.97, n = 56 females) completed both clinical interviews and structural MRI scans at 1-, 6-, and 14-months after ED admission (alias T1, T2, and T3). While all participants met PTSD diagnosis at T1, only n = 29 still met PTSD diagnosis at T3 (a “non-Remission” Group), while n = 71 did not (a “Remission” Group). Bayesian multilevel modeling analysis showed robust evidence for smaller right hippocampus volume (P+ of ~0.014) and moderate evidence for larger left amygdala volume (P+ of ~0.870) at T1 in the “non-Remission” group, compared to the “Remission” group. Subregion analysis further demonstrated robust evidence for smaller volume in the subiculum and right CA1 hippocampal subregions (P+ of ~0.021–0.046) in the “non-Remission” group. No time-dependent volumetric changes (T1 to T2 to T3) were observed across all participants or between groups. Results support the “vulnerability trait” hypothesis, suggesting that lower initial volumes of specific hippocampus subregions are associated with non-remitting PTSD. The stable volume of all hippocampal and amygdala subregions does not support the idea of consequential, progressive, stress-related atrophy during the first critical year following trauma exposure.

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Fig. 1: Segmentation of hippocampus and amygdala subfields.
Fig. 2: Consort diagram.
Fig. 3: Posterior distributions of the main effect of group at 1-month post-trauma (T1).
Fig. 4: Posterior distributions of the main effect of time (T3–T1) and group-by-time interaction (T3–T1).

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Data availability

The dataset and materials used in this work is available by contacting the study PIs on a reasonable request.

Code availability

Scripts to reproduce data analysis associated with the current manuscript can be found at: https://github.com/KoremNSN/longitudinal_anatomy.

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Acknowledgements

The authors would like to thank our wonderful research team at Tel-Aviv Sourasky Medical Center—including Naomi Fine, Nili Green, Mor Halevi, Sheli Luvton, Yael Shavit, Olga Nevenchannaya, Iris Rashap, Efrat Routledge, and Ophir Leshets—for their significant contributions to participants, screening, enrollment, assessments, and follow-up. We extend our gratitude to all the participants of this study, who completed all the assessments at three different time points after experiencing a traumatic event, thus contributing to scientific research on post-traumatic psychopathology.

Funding

This work was supported by award number R01-MH-103287 from the National Institute of Mental Health (NIMH) given to AYS (PI), IL, and TH (co-Investigators, subcontractors), and had undergone critical review by the NIMH Adult Psychopathology and Disorders of Aging study section.

Author information

Author notes

  1. These authors contributed equally: Arieh Y. Shalev, Talma Hendler.

Authors and Affiliations

  1. Yale School of Medicine, Yale University, New Haven, CT, USA

    Ziv Ben-Zion, Nachshon Korem, Tobias R. Spiller, Or Duek & Ilan Harpaz-Rotem

  2. US Department of Veterans Affairs National Center for PTSD, Clinical Neuroscience Division, VA Connecticut Healthcare System, West Haven, CT, USA

    Ziv Ben-Zion, Nachshon Korem, Tobias R. Spiller, Or Duek & Ilan Harpaz-Rotem

  3. Sagol Brain Institute Tel Aviv, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ziv Ben-Zion & Talma Hendler

  4. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Ziv Ben-Zion & Talma Hendler

  5. Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Tobias R. Spiller

  6. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Jackob Nimrod Keynan

  7. School of Psychological Sciences, University of Haifa, Haifa, Israel

    Roee Admon

  8. The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa, Israel

    Roee Admon

  9. Wu Tsai Institute, Yale University, New Haven, CT, USA

    Ilan Harpaz-Rotem

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

    Ilan Harpaz-Rotem

  11. Department of Psychiatry, College of Medicine, Texas A&M, College Station, TX, USA

    Israel Liberzon

  12. Department of Psychiatry, NYU Grossman School of Medicine, New York City, NY, USA

    Arieh Y. Shalev

  13. Faculty of Social Sciences and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Talma Hendler

Authors
  1. Ziv Ben-Zion
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  2. Nachshon Korem
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  3. Tobias R. Spiller
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  4. Or Duek
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  5. Jackob Nimrod Keynan
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  6. Roee Admon
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  7. Ilan Harpaz-Rotem
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  8. Israel Liberzon
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  9. Arieh Y. Shalev
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  10. Talma Hendler
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Contributions

TH, IL, and AYS designed, obtained funding, supervised, and oversaw the implementation of the study. ZB-Z, AYS, and TH had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. ZB-Z, JNK, and RA carried out the procedural aspects of the study, the research assistants’ training, guidance and monitoring, management of participants, and QA of data. ZB-Z, NK, OD, and TRS analyzed the results and drafted the initial manuscript together with IH-R, AYS, and TH. Critical revisions of the manuscript were conducted by NK, OD, TRS, JNK, RA, IH-R, IL, AYS, and TH, until finalizing it. All authors have read and approved the final manuscript and its submission to “Molecular Psychiatry”.

Corresponding author

Correspondence to Ziv Ben-Zion.

Ethics declarations

Competing interests

TH is the chief medical officer of “GrayMatters Health Co” (Haifa, Israel). All other authors report no potential conflicts of interest to declare.

Ethical approval

The research study met all ethical regulations as required by the ethics committee at Tel-Aviv Sourasky Medical Center (Reference number 0207/14). All subjects gave written informed consent in accordance with the Declaration of Helsinki and received financial remuneration at the end of each time-point (1-, 6-, and 14-months post-trauma). The study’s ClinicalTrials.gov registration ID is NCT03756545 (clinicaltrials.gov/ct2/show/NCT03756545).

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Ben-Zion, Z., Korem, N., Spiller, T.R. et al. Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors. Mol Psychiatry 28, 657–667 (2023). https://doi.org/10.1038/s41380-022-01842-x

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