{"doi":"10.1101/2025.02.11.637551","title":"Mapping the Psychosis Spectrum – Imaging Neurosubtypes from Multi-Scale Functional Network Connectivity","abstract":"ABSTRACT This study aims to identify Psychosis Imaging Neurosubtypes (PINs)— homogeneous subgroups of individuals with psychosis characterized by distinct neurobiology derived from imaging features. Specifically, we utilized resting-state fMRI data from 2103 B-SNIP 1&2 participants (1127 with psychosis, 350 relatives, 626 controls) to compute subject-specific multiscale functional network connectivity (msFNC). We then derived a low-dimensional neurobiological subspace, termed Latent Network Connectivity (LNC), which captured system-wide interconnected multiscale information across three components (cognitive-related, typical, psychosis-related). Projections of psychosis participants’ msFNC onto this subspace revealed three PINs through unsupervised learning, each with distinct cognitive, clinical, and connectivity profiles, spanning all DSM diagnoses (Schizophrenia, Bipolar, Schizoaffective). PIN-1, the most cognitively impaired, showed Cerebellar-Subcortical and Visual-Sensorimotor hypoconnectivity, alongside Visual-Subcortical hyperconnectivity. Most cognitively preserved PIN-2 showed Visual-Subcortical, Subcortical-Sensorimotor, and Subcortical-Higher Cognition hypoconnectivity. PIN-3 exhibited intermediate cognitive function, showing Cerebellar-Subcortical hypoconnectivity alongside Cerebellar-Sensorimotor and Subcortical-Sensorimotor hyperconnectivity. Notably, 55% of relatives aligned with the same neurosubtype as their affected family members—a significantly higher rate than random chance (p-value Relatives-to-PIN-1 < 0.001, p-value Relatives-to-PIN-2 < 0.05, p-value Relatives-to-PIN-3 < 0.001) compared to a non-significant 37% DSM-based classification, supporting a biological basis of these neurosubtypes. Cognitive performance reliably aligns with distinct brain connectivity patterns, which are also evident in relatives, supporting their construct validity. Our PINs differed from original B-SNIP Biotypes, which were determined from electrophysiological, cognitive, and oculomotor data. These findings underscore the limitations of DSM-based classifications in capturing the biological complexity of psychotic disorders and highlight the potential of imaging-based neurosubtypes to enhance our understanding of the psychosis spectrum.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555427,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.7789,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1051703,"name":"Pablo Andrés-Camazón","orcid":"0000-0002-7322-1248","position":1,"is_corresponding":false},{"id":1218324,"name":"Kyle M. Jensen","orcid":"0000-0001-7896-2232","position":2,"is_corresponding":false},{"id":1454215,"name":"Prerana Bajracharya","orcid":null,"position":3,"is_corresponding":false},{"id":84132,"name":"Covadonga M. Díaz‐Caneja","orcid":"0000-0001-8538-3175","position":4,"is_corresponding":false},{"id":233025,"name":"Juan Bustillo","orcid":"0000-0001-8730-8152","position":5,"is_corresponding":false},{"id":90656,"name":"Jessica A. Turner","orcid":"0000-0003-0076-8434","position":6,"is_corresponding":false},{"id":227749,"name":"Zening Fu","orcid":"0000-0002-1591-4900","position":7,"is_corresponding":false},{"id":227757,"name":"Jiayu Chen","orcid":"0000-0001-5059-372X","position":8,"is_corresponding":false},{"id":227761,"name":"Vince D. Calhoun","orcid":"0000-0001-9058-0747","position":9,"is_corresponding":false},{"id":254824,"name":"Armin Iraji","orcid":"0000-0002-0605-593X","position":10,"is_corresponding":false},{"id":1454214,"name":"Ram Ballem","orcid":null,"position":0,"is_corresponding":true}],"reference_count":91,"raw_metadata":null,"created_at":"2026-07-19T02:54:59.329539Z","pmid":"40196606","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}