Altered Sex Differences in Hippocampal Subfield Volumes in Schizophrenia

Abstract

Background and hypothesis: The hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD), and healthy controls (CTL).

Study design: One thousand and five hundred and twenty-one participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; CTL, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models.

Study results: Significant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, hippocampal-amygdaloid transition area, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex CTL. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η < 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD.

Conclusions: Using a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to CTL, due to higher volumetric deficits in males.

Keywords: bipolar disorders; hippocampus; neuroimaging; schizophrenia; sex differences.

Fig. 1.

Hippocampal volumes stratified by diagnostic group and sex. ComBat-harmonized volumetric data is displayed as raincloud plots, which combines boxplots, unadjusted raw data points (scatterplot), and the distributions of the data (histogram) using split-half violins. CTL, healthy controls, BD, bipolar disorders, SZ, schizophrenia spectrum disorders; CA, cornu ammonis; GC-ML-DG, granule cells in the molecular layer of the dentate gyrus; HATA, hippocampal-amygdaloid transition area.

Fig. 2.

Estimates of total hippocampus and subfield volumes stratified by diagnostic subgroup and sex. The model is adjusted for age, age², and intracranial volume. Estimates are displayed with upper and lower confidence intervals. Stars represent significant group difference relative to healthy controls (CTL), after false discovery rate correction. Significance codes: P < .01 “*.” Abbreviation: BP, bipolar; SCZ, schizophrenia; SCZ-AF, schizoaffective disorder, OPD, other psychotic disorders; CA, cornu ammonis; GC-ML-DG, granule cells in the molecular layer of the dentate gyrus; HATA, hippocampal-amygdaloid transition area.