The hippocampal-cortical system cerebral blood flow in schizophrenia: Primary disease versus antipsychotic medication effects.

Most of the brain-based biomarker research in schizophrenia (SZ) results from chronic medicated samples. Disambiguating contributions of "primary" disease vs. psychotropic medication effects to the neurobiology of SZ remains challenging. In this study, using 3Tesla pseudo-continuous Arterial Spin Labeling (pCASL), we examined regional cerebral blood flow (CBF) in hippocampus and its cortical projection network in SZ probands [n = 41, including antipsychotic-free (SZ-OFF, n = 14) and treated with antipsychotic(s) (SZ-ON, n = 27)], their first-degree relatives [n = 28, including relatives with lifetime psychosis-spectrum disorders (REL-P, n = 14) and without (REL-NP, n = 14)], and healthy controls (HC, n = 16) [n = 85 total]. SZ-OFF demonstrated elevated CBF in the left middle cingulate, ventromedial and dorsolateral prefrontal cortex (PFC), compared to SZ-ON (Hedges' g = 0.65-0.91). No difference in hippocampal CBF emerged in SZ-OFF vs. SZ-ON, while SZ-OFF vs. HC showed reduced CBF in the left anterior hippocampus (g = 1.09). Among relatives, REL-P had elevated CBF in the right ventrolateral PFC, compared to REL-NP (g = 0.73) - resembling the "hyperfrontality" effect in SZ-OFF. Conversely, REL-NP vs. HC showed reduced CBF throughout the right PFC (g = 0.52-0.79). Our findings demonstrate unique regional CBF-based activity signatures potentially capturing primary disease effects (SZ-OFF: elevated CBF in PFC but reduced CBF in the anterior hippocampus) vs. antipsychotic effects (SZ-ON: "normalization" of CBF). The observed PFC "hyperactivity" (evidenced by elevated CBF in both SZ-OFF and REL-P) may constitute a regionally-specific "psychosis maker". Future research targeted at granular aspects of hippocampal-PFC pathology in medicated and unmedicated samples may inform more precise, novel interventions in SZ.