Hippocampal subfield volumes are uniquely affected in PTSD and depression: International analysis of 31 cohorts from the PGC-ENIGMA PTSD Working Group

Abstract

Background: PTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression. Methods:We used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.Results: A significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=-0.13) and CA1 (ß=-0.09) after adjusting for covariates and multiple testing (adjusted p's (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 (ß=-0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls (ß=-0.12, q=0.012), C-PTSD-only (ß=-0.17, q=0.001), and Depression-only (ß=-0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males. Conclusions:Collectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

Sex is a defining feature of neuroimaging phenotypes in major brain disorders

“…To further understand the role of the hippocampus in depression and affective disorders, recent work from the ENIGMA consortium has begun to examine volumetric abnormalities in subfields of the hippocampus. In a recent study of participants with varying levels of trauma exposure, Salminen et al [2019b] showed that depression, but not PTSD, was associated with smaller volumes in the hippocampal CA1 and hippocampal tail. Sex-stratified analyses showed this effect was specific to females.…”

“…Given the significant effect in the hippocampus from the subcortical meta-analysis, our group recently completed a prospective mega-analysis of hippocampal subfield markers of PTSD, and the effect of comorbid depression. Specifically, Salminen et al [2019b] showed that the effect of depression was stronger than the effect of PTSD in the whole sample and in females, but not in males. Females with depression showed smaller volumes in the hippocampal tail and CA1 subfield compared to those without depression and were not significantly affected by PTSD.…”

ENIGMA‐anxietyworking group: Rationale for and organization oflarge‐scaleneuroimaging studies of anxiety disorders

“…In addition to the samples that could be allocated to the four subgroups, the ENIGMA-Anxiety database contains information on samples with anxiety disorder diagnoses that are not an immediate focus of investigation; these samples concern, for example, children with separation anxiety (Calkins et al, 2015;Salum et al, 2011;Salum et al, 2015;Satterthwaite et al, 2014), children at risk for developing an anxiety disorder (Battaglia et al, 2012;Fu, Taber-Thomas, & Pérez-Edgar, 2017;Taber-Thomas, Morales, Hillary, & Pérez-Edgar, 2016), participants with anxiety-related traits and at risk phenotypes (Campbell-Sills et al, 2011;Dannlowski et al, 2015;Dannlowski et al, 2016;Mujica-Parodi et al, 2009; alterations in the microstructure of white matter tracts based on DTI data (Kochunov et al, 2015), in the connectivity of brain functional networks utilizing resting-state functional (f)MRI (Adhikari et al, 2018), and in the responsivity of brain regions to anxiety-related cues utilizing task-related functional (f)MRI paradigms (under development). Then, ENIGMA approaches that assess more subtle variations in brain morphology including investigation of regional subfields (e.g., of hippocampus and amygdala (Salminen et al, 2019;Saygin et al, 2017)), subcortical shape (Ching et al, 2020;Gutman et al, 2015;Gutman, Wang, Rajagopalan, Toga, & Thompson, 2012;Ho et al, 2019), and brain asymmetry (Kong et al, 2018), can be key next steps.…”

Variations in response to trauma and hippocampal subfield changes

“…Segmentation of hippocampal subfield volumes using lower resolution (1 mm 3 ) MRI ( Ahmed-Leitao et al, 2019 ; Chen et al, 2018 ; Hayes et al, 2017 ; Salminen et al, 2019 ), has also been performed to characterize hippocampal changes in individuals with PTSD. These studies have reported either reduced volume of the DG ( Hayes et al, 2017 ), CA1 and CA3 ( Chen et al, 2018 ), or no differences in subfield volumes in the PTSD population ( Ahmed-Leitao et al, 2019 ).…”

“…These studies have reported either reduced volume of the DG ( Hayes et al, 2017 ), CA1 and CA3 ( Chen et al, 2018 ), or no differences in subfield volumes in the PTSD population ( Ahmed-Leitao et al, 2019 ). A recent report also suggested that changes in CA1 are rooted in the interaction between comorbid depression and PTSD ( Salminen et al, 2019 ). However, given that the most important anatomical landmarks for subfield labeling (i.e., the thin band formed by the inner lamina of the CA and the outer lamina of the DG) are not visible at this lower resolution, the segmentation process is less reliable and consistent across individuals ( de Flores et al, 2015 ; Iglesias et al, 2015 ; Wisse et al, 2014 ).…”