Fitness is positively associated with hippocampal formation subfield volumes in schizophrenia: a multiparametric magnetic resonance imaging study

Abstract

Hippocampal formation (HF) volume loss is a well-established finding in schizophrenia, with select subfields, such as the cornu ammonis and dentate gyrus, being particularly vulnerable. These morphologic alterations are related to functional abnormalities and cognitive deficits, which are at the core of the insufficient recovery frequently seen in this illness. To counteract HF volume decline, exercise to improve aerobic fitness is considered as a promising intervention. However, the effects of aerobic fitness levels on HF subfields are not yet established in individuals with schizophrenia. Therefore, our study investigated potential associations between aerobic fitness and HF subfield structure, functional connectivity, and related cognitive impact in a multiparametric research design. In this cross-sectional study, 53 participants diagnosed with schizophrenia (33 men, 20 women; mean [SD] age, 37.4 [11.8] years) underwent brain structural and functional magnetic resonance imaging and assessments of aerobic fitness and verbal memory. Multivariate multiple linear regressions were performed to determine whether aerobic fitness was associated with HF subfield volumes and functional connections. In addition, we explored whether identified associations mediated verbal memory functioning. Significant positive associations between aerobic fitness levels and volumes were demonstrated for most HF subfields, with the strongest associations for the cornu ammonis, dentate gyrus, and subiculum. No significant associations were found for HF functional connectivity or mediation effects on verbal memory. Aerobic fitness may mitigate HF volume loss, especially in the subfields most affected in schizophrenia. This finding should be further investigated in longitudinal studies.Clinical Trials Registration: The study on which the manuscript is based was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112 ) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Fig. 1. Hippocampal formation subfields.

The hippocampal formation subfields segmented with Freesurfer v7.2 shown in different views. The table is based on Iglesias et al. [53] ML molecular layer, HATA hippocampal amygdala transition area, GCMLDG granule cell and molecular layer of the dentate gyrus, CA cornu ammonis.

Fig. 2. β-coefficients of aerobic fitness and the covariates predicting volumes of the hippocampal formation subfields.

The x-axis shows the predictors of the multivariate multiple linear regression, and the y-axis, the 38 hippocampal formation subfields from both hemispheres. The heatmap is filled with the β-coefficients. Blue indicates a positive effect, red a negative effect. The darker the color, the stronger is the effect in the corresponding direction. BMI body mass index, CA cornu ammonis, CPZ chlorpromazine equivalents, DD disorder duration, EY education years, GCMLDG granule cell and molecular layer of the dentate gyrus HATA hippocampal amygdala transition area, l left hemisphere, ML molecular layer, r right hemisphere.