Longitudinal Inference of Hippocampal Volume and Morphometric Hippocampal-Cortical Connectivity in Psychosis

Schizophrenia and related psychoses are characterized by significant reductions in hippocampal volume and morphometric hippocampal-cortical connectivity. No study to date has addressed the temporal relationship between deviations in volume and connectivity across the heterogeneous spectrum of psychosis. To explore this relationship, we sampled cross-sectional neuroimaging data from 174 patients and 120 non-clinical controls from two studies on first- and multi-episode psychosis. We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm combining clustering and disease progression modeling, to eight measures of hippocampal volume and morphometric hippocampal-cortical connectivity (subfields and adjacent white matter regions per hemisphere) combined. We then performed in-depth SuStaIn analyses for 18 volumes (five subfields and four white matter regions per hemisphere) and 18 connectivity measures (graph-theory-based participation coefficient) separately. Some individuals showed no deviations (no increase or decrease) from control means in volume and connectivity. For individuals who did show deviations, we identified an overall progression pattern from deviations in volume toward connectivity. In-depth SuStaIn analyses revealed three distinct volume patterns (intact volume, subfield-dominant, whiter matter-dominant) which were followed by one of four possible connectivity patterns (intact connectivity, whiter matter-dominant, subfield-dominant, subiculum-dominant). These subtypes further showed significant differences in illness duration, age, and a trend for episodic memory. Considering that hippocampal volume and morphometric connectivity distinctively precede cognitive and clinical symptoms of psychosis, our findings contribute to disentangling the relationship between both hippocampal metrics, potentially elucidating distinct hippocampal pathways toward the heterogeneous manifestations of psychosis.