Hippocampal subfield activity in schizophrenia: Effects of the disease course

Alterations in hippocampal structure and function are established in schizophrenia. However, the specific patterns of hippocampal activity along the schizophrenia course remain unknown. Eighty-five study participants [34 schizophrenia probands (SZ), 32 first-degree relatives (REL), 19 healthy controls (HC)] underwent 3Tesla ultra-high resolution brain MRI (Vascular Space Occupancy); relative cerebral blood volume (rCBV)-an index of regional activity-was estimated across hippocampal subfields: dentate gyrus (DG), CA3, CA1, and subiculum (SUB). To examine effects of the schizophrenia course, SZ were stratified into SZ-Early (≤7 yrs. from psychosis onset), SZ-Mid-Course (8-14 yrs) and SZ-Advanced (≥15 yrs). REL were grouped into those with (RELP) and without (REL-NP) psychosis spectrum disorders. Medication effects were examined by contrasting SZ on- vs. off-antipsychotics. No hippocampal rCBV differences emerged in SZ vs. HC or in SZ-on vs. SZ-off antipsychotic medications. However, among the SZ course groups, SZ-Early showed elevated rCBV in CA3, CA1 and DG compared to SZ-Advanced and HC (p = .004-032). Illness duration-based cross-sectional "trajectories" demonstrated elevated hippocampal rCBV within the initial 7 yrs., followed by an intermediary plateau (8-20 yrs), and a subsequent decline in advanced (20+ yrs) SZ. Among biological relatives of SZ, REL-P vs. HC showed reduced rCBV in SUB, CA1 and DG (p = .021-0.046). Our findings demonstrate differential patterns of hippocampal rCBV along the schizophrenia course. Regional hippocampal activity may serve as a granular biomarker sensitive to the effects of the schizophrenia course and, via future work, inform SZ stage-specific interventions: e.g., reducing hippocampal hyperactivity in early-course SZ vs. enhancing this same circuit's function in advanced stages of SZ.