PTSD and depression show unique trauma-related signatures in the hippocampal subfields:

International analysis from the PGC-ENIGMA PTSD Working Group

Lauren E. Salminen, Mark W. Logue, Yuanchao Zheng, Philipp Saemann, Emily L. Dennis,

Emily C. Clark, Neda Jahanshad, Juan E. Iglesias, Christopher D. Whelan, Steven E. Bruce, Jasmeet Hayes, Soraya Seedat, Paul M. Thompson, Rajendra A. Morey


Subregions of the hippocampus are cytoarchitecturally and functionally distinct and may be differentially impacted by trauma-related mental health conditions. Here we used a harmonized neuroimaging protocol based on FreeSurfer 6.0 to identify sub-structural markers of PTSD and depression across 30 cohorts worldwide (N=3,118; Mage=38.9±13.9 years). We used a mega-analytic design to test main effects of PTSD without covarying for depression, effects of depression without covarying for PTSD, and the interaction between these conditions. Random effects models revealed a significant negative main effect of depression (n=976, vs. no depression n=1862) on the hippocampal tail (b=-0.12) and CA1 (b=-0.09) after adjusting for covariates and multiple testing (FDR-p’s=0.028). We did not observe main effects of PTSD (n=1288 vs. control, n=1830). An interaction between PTSD and depression was significant in the CA1 (b=-0.25, FDR-p=0.033), with larger volumes in the PTSD-only group compared to those with PTSD+depression. The PTSD-only group also showed larger volumes in the CA3, CA4, molecular layer, and tail compared to the PTSD+depression group, despite the lack of significant interaction main effect. Individuals with PTSD-only showed larger CA3 volumes compared to controls, but main effects were not observed in the depression-only group. Collectively these results align with earlier work suggesting that PTSD with and without depression represents unique biological phenotypes. Future prospective studies should consider these differences for developing adequate recruitment strategies that capture this variance in trauma-exposed samples.

Key Words: PTSD, depression, hippocampal subfields, trauma

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