Regionally specific volume deficits along the hippocampal long axis in early and chronic psychosis

Previous studies in psychosis patients have shown hippocampal volume deficits across anterior and posterior regions or across subfields, but subfield specific changes in volume along the hippocampal long axis have not been examined. Here, we tested the hypothesis that volume changes exist across the hippocampus in chronic psychosis but only the anterior CA region is affected in early psychosis patients. We analyzed structural MRI data from 179 patients with a non-affective psychotic disorder (94 chronic psychosis; 85 early psychosis) and 167 heathy individuals demographically matched to the chronic and early psychosis samples respectively (82 matched to chronic patients; 85 matched to early patients). We measured hippocampal volumes using Freesurfer 6-derived automated segmentation of both anterior and posterior regions and the CA, dentate gyrus, and subiculum subfields. We found a hippocampal volume deficit in both anterior and posterior regions in chronic psychosis, but this deficit was limited to the anterior hippocampus in early psychosis patients. This volume change was more pronounced in the anterior CA subfield of early psychosis patients than in the dentate gyrus or subiculum. Our findings support existing models of psychosis implicating initial CA dysfunction with later progression to other hippocampal regions and suggest that the anterior hippocampus may be an important target for early interventions. Keywords: Schizophrenia, Hippocampus, First episode psychosis, Volume, Subfields

Increased hippocampal CA1 cerebral blood volume in schizophrenia

Hippocampal hyperactivity has been proposed as a biomarker in schizophrenia. However, there is a debate whether the CA1 or the CA2/3 subfield is selectively affected. We studied 15 schizophrenia patients and 15 matched healthy control subjects with 3T steady state, gadolinium-enhanced, absolute cerebral blood volume (CBV) maps, perpendicular to the long axis of the hippocampus. The subfields of the hippocampal formation (subiculum, CA1, CA2/3, and hilus/dentate gyrus) were manually segmented to establish CBV values. Comparing anterior CA1 and CA2/3 CBV between patients and controls revealed a significant subfield-by-diagnosis interaction. This interaction was due to the combined effect of a trend of increased CA1 CBV (p = .06) and non-significantly decreased CA2/3 CBV (p = 0.14) in patients relative to healthy controls. These results support the emerging hypothesis of increased hippocampal activity as a biomarker of schizophrenia and highlight the importance of subfield-level investigations

Dentate gyrus microstructure is associated with resilience after exposure to maternal stress across two human cohorts

Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we test across two independent cohorts whether MS is associated with depressive symptoms and with DG micro- and macro-structural alterations in offspring. Methods: We analyzed DG DTI mean diffusivity (DG-MD) and volume in a 3-Generation Family Risk for Depression study (TGS; n=69, mean age 35.0) and the Adolescent Brain Cognitive Development Study (ABCD; n=5196, mean age 9.9) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (in TGS) and a measure compiled from the Adult Response Survey (ABCD). PHQ-9 and rumination scales (TGS) and Child Behavior Checklist (ABCD) measured offspring depressive symptoms at follow-up. Schedule for Affective Disorders and Schizophrenia–Lifetime interview measured depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (TGS) and 1-year (ABCD) after MRI. In ABCD, DG-MD is increased in high-MS offspring who have depressive symptoms at follow-up, but not in offspring who remain resilient or whose mother had low MS. Conclusions: Converging results across two independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression