Connectivity within the Hippocampus as a Neural Marker of Early Clinical Trajectories in the Psychosis Risk State

Psychotic disorders lack treatment-informative biomarkers, especially during the earliest illness stages when interventions are most effective. Integrating etiological theories on hippocampal pathology and whole-brain neural dysconnectivity, we studied connectivity changes within the hippocampus as a neuroimaging marker of emerging symptomatic and functional trajectories in the psychosis risk state. We analyzed multicenter longitudinal clinical and functional neuroimaging data across an eight-month period from 434 participants (356 individuals at clinical high risk for psychosis and 78 healthy controls) using latent variable regressions. Decreases of intra-hippocampal connectivity over time tracked worsening negative symptoms, depressive symptoms, and psychosocial functioning in at-risk subjects. This finding was not observed for attenuated positive symptoms and cognition, was specific to high-risk individuals relative to healthy controls, and was not obtained for connectivity within other brain areas. Unveiling the temporal sequence of these associations, we found that an early decrease in connectivity within the hippocampus preceded a subsequent worsening of negative symptoms, but not vice versa. These findings position intra-hippocampal connectivity changes as a neuroimaging marker of early affective-motivational and functional trajectories in the psychosis risk state. They further indicate that changes of connectivity within the hippocampus hold prognostic value specifically for emerging negative symptoms. This informs future risk stratification approaches and neurostimulation therapies in the psychosis risk state: Intra-hippocampal connectivity decline could be a valuable predictive marker to improve risk stratification. Ameliorating connectivity reduction within the hippocampus may represent a promising neurostimulation target to prevent unfavorable clinical trajectories. One Sentence SummaryDecreasing connectivity within the hippocampus is a neural prognostic marker of worsening negative symptoms in the psychosis risk state