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Potential sensitive period effects of maltreatment on amygdala, hippocampal and cortical response to threat

Molecular Psychiatry volume 28, pages 5128–5139 (2023)Cite this article

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Abstract

Childhood maltreatment is a leading risk factor for psychopathology, though it is unclear why some develop risk averse disorders, such as anxiety and depression, and others risk-taking disorders including substance abuse. A critical question is whether the consequences of maltreatment depend on the number of different types of maltreatment experienced at any time during childhood or whether there are sensitive periods when exposure to particular types of maltreatment at specific ages exert maximal effects. Retrospective information on severity of exposure to ten types of maltreatment during each year of childhood was collected using the Maltreatment and Abuse Chronology of Exposure scale. Artificial Intelligence predictive analytics were used to delineate the most important type/time risk factors. BOLD activation fMRI response to threatening versus neutral facial images was assessed in key components of the threat detection system (i.e., amygdala, hippocampus, anterior cingulate, inferior frontal gyrus and ventromedial and dorsomedial prefrontal cortices) in 202 healthy, unmedicated, participants (84 M/118 F, 23.2 ± 1.7 years old). Emotional maltreatment during teenage years was associated with hyperactive response to threat whereas early childhood exposure, primarily to witnessing violence and peer physical bullying, was associated with an opposite pattern of greater activation to neutral than fearful faces in all regions. These findings strongly suggest that corticolimbic regions have two different sensitive period windows of enhanced plasticity when maltreatment can exert opposite effects on function. Maltreatment needs to be viewed from a developmental perspective in order to fully comprehend its enduring neurobiological and clinical consequences.

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Fig. 1: The seven anatomically predefined regions of interest (ROIs) and their interconnections.
Fig. 2: Sensitive period analyses.
Fig. 3: Dose–response relation between statistically significant risk factors and scaled fMRI BOLD response.
Fig. 4: Differential time courses of fMRI-BOLD activation to negative faces minus neutral faces.
Fig. 5: Time courses of fMRI-BOLD activation to negative faces and neutral faces.

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Data availability

All anonymized data used in these analyses have been deposited on Zenodo (https://doi.org/10.5281/zenodo. 5271714 and zenodo.7340449) and are open source.

Code availability

The R code for determining significant type/time risk factors using random forest regression with conditional inference trees has been deposited on Zenodo (https://doi.org/10.5281/zenodo.5273055) and made open source as has the R code used to generate the supplementary tables (https://doi.org/10.5281/zenodo.7340449). The remaining code is included in the supplement as R Markdown files.

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Acknowledgements

This work was supported by the National Institutes of Health grants (Grant Nos. MH-091391, MH-113077, DA-017846, HD-0794841 [to MHT]), ANS Research Foundation ([to MHT]), National Natural Science Foundation of China (Grant No. 32000755 [to JZ]) and Natural Science Foundation of Zhejiang Province (Grant No. LQ21C090008 [to JZ]). Cynthia E. McGreenery and Elizabeth Bolger, MA, Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, Massachusetts, assisted with recruitment and assessment of study participants and Michael Rohan, Ph.D., and Gordana Vitaliano, MD, Ph.D., Brain Imaging Center, McLean Hospital, Belmont, Massachusetts, provided technical and clinical support. All of these individuals received compensation for their help.

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Authors and Affiliations

  1. Department of Psychology, Guangzhou University, Guangzhou, 510000, China

    Jianjun Zhu

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, 02115, USA

    Carl M. Anderson, Kyoko Ohashi, Alaptagin Khan & Martin H. Teicher

  3. Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, 02478, USA

    Carl M. Anderson, Kyoko Ohashi, Alaptagin Khan & Martin H. Teicher

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  1. Jianjun Zhu
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Contributions

MHT conceived the idea and was responsible for funding acquisition and project administration. MHT, JZ, K0, and AK were responsible for the methodology. Data were collected by AK, CMA, and KO and were curated by CMA, KO, and JZ. Formal analyses and visualizations were performed by JZ and MHT, and software was written by MHT, JZ, and KO. The original draft was written by MHT and JZ. All the other authors reviewed and edited the final drafts.

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Correspondence to Jianjun Zhu or Martin H. Teicher.

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Competing interests

MHT created the MACE scale used to collect data on type and timing of exposure to maltreatment used in this study. However, there is no financial conflict as this scale was placed into the public domain and it is fully available and free to use. The other authors declare that they have no competing interests.

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Zhu, J., Anderson, C.M., Ohashi, K. et al. Potential sensitive period effects of maltreatment on amygdala, hippocampal and cortical response to threat. Mol Psychiatry 28, 5128–5139 (2023). https://doi.org/10.1038/s41380-023-02002-5

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