Structural brain alterations of the subcortical limbic system in schizophrenia and bipolar disorders

Schizophrenia spectrum disorders (SSD) and bipolar disorders (BD) are severe mental disorders linked to brain alterations in the limbic system. Small, anatomically complex structures remain unexplored in morphological studies of these disorders. We examined case-control differences in MRI-derived brain volumes of the fornix, nucleus accumbens, basal forebrain, septal nuclei, hypothalamus, and mammillary bodies, and their associations with clinical characteristics, sex, and cognition.

A cross-sectional sample of 1604 participants (802 healthy controls (HC), 462 patients with SSD and 340 BD patients) aged 17-65 years was included for the volumetric analysis of T1-weighted MR images using the ScLimbic segmentation tool from FreeSurfer. ANCOVA and multiple regression models, adjusted for age, age², sex, and intracranial volume, assessed for volumetric case-control differences and associations with clinical variables.

We observed smaller right nucleus accumbens volumes in SSD (Cohen's d = -0.19, p = 0.004) and smaller right fornix volumes (p = 0.008) in SSD (d = -0.16) and BD (d = -0.12) compared to HC, found specifically in schizophrenia and bipolar I disorder subgroups. Additionally, SSD patients using antipsychotic medication (AP) had smaller bilateral basal forebrain volumes than non-users (left: p = 0.003, d = -0.27; right: p = 0.005, d = -0.26). Smaller basal forebrain volumes were associated with higher anticholinergic burden of AP medication (p = 0.01, r = -0.11) and attentional deficits (p = 0.009, r = 0.19) in secondary analyses, with the latter emerging only without intracranial volume adjustment.

The findings highlight region-specific smaller volumes in subcortical limbic structures in SSD and BD relative to healthy controls. Observed basal forebrain differences suggest a potential impact of AP use, warranting further investigation.