From Resting-State Functional Hippocampal Centrality to Functional Outcome: An Extended Neurocognitive Model of Psychosis

Background. We previously proposed a neurocognitive model of psychosis in which reduced morphometric hippocampal-cortical connectivity precedes impaired episodic memory, social cognition, negative symptoms, and functional outcome. We provided support for this model in a patient subtype, and aimed to extend these findings in the modality of resting-state functional MRI to potentially explain the progression for a broader range of patients. Methods. We used a subsample of our previous analysis consisting of 54 patients with first-episode psychosis and 52 controls and applied the machine-learning algorithm Subtype and Stage Inference, which combines clustering and disease progression modeling, to the patient data for rs-functional hippocampal connectivity, episodic memory, social cognition, negative symptoms and functional outcome. Results. We identified three subtypes, with Subtype 0 being unimpaired on the markers, Subtype 1 showing impaired hippocampal connectivity and episodic memory, and Subtype 2 showing impaired memory and a trend for impaired functional outcome. We identified similar progression patterns to the morphometric results in functional MRI data (functional hippocampal dysconnectivity preceded cognition, symptoms, and functioning in one subtype and followed these alterations in another subtype). We further show that the impairments in morphometric and rs-functional hippocampal connectivity do not necessarily overlap in patients, hinting towards an additive effect of each MRI modality in explaining the neurocognitive underpinnings of this model. Conclusion. Our results provide an extension of our previous work and build the foundation for a multimodal neurocognitive model of psychosis, potentially elucidating this important aspect of disease progression in psychosis for a broader range of patients.