Hippocampal subfields, daily stressors, and resting cortisol in individuals at clinical high-risk for psychosis

Introduction: The hippocampus, comprised of functionally distinct subfields, both regulates stress and is affected by it during psychosis pathogenesis. Hippocampal abnormalities are evident across psychosis spectrum and are associated with aberrant cortisol levels and greater environmental stressors exposure. These associations, particularly at the subfield-level, are poorly understood in individuals at clinical high-risk (CHR) for psychosis. This represents a significant literature gap given this critical pathogenetic period is characterized by an interplay between environmental stressors and biological susceptibility. Methods: A total of 121 participants including 51 CHR (mean age=18.61) and 70 healthy controls (HC; mean age=18.3) were enrolled in the study. Participants completed a structural scan, salivary cortisol assays, and a self-report measure assessing distress from daily stressors exposure (DSI). Hippocampal subfield segmentation was conducted using Freesurfer. Results: Smaller hippocampal subfields were associated with greater stress levels. Greater DSI was associated with lower volumes in CA1 (r = -0.38) and CA2/3 (r = -0.29), but not in CA4/DG (r = -0.28), presubiculum (r = -0.09), or subiculum (r = -0.17). Higher resting cortisol was associated with lower volumes in presubiculum (r = -0.4) but not subiculum (r = -0.22), CA1 (r = 0.08), CA2/3 (r = 0.1), or CA4/DG (r = -0.005). Regressions indicated effects for CA1 and DSI (8 = 0.57, p = .03) and presubiculum and cortisol (8 = 0.61, p = .02) are specific to CHR participants relative to HCs. Conclusions: The findings provided insights into links between stress and brain vulnerability during psychosis-risk period. Regional differences highlighted potentially different mechanisms by which stress impacts specific subfields. Presubiculum may be more susceptible to the impact of early stress on HPA-axis and cornu amonis to acute stressors.