Subtyping psychotic disorders using a data-driven approach reveals divergent cortical and cellular signatures
4 affiliations
- 1Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN USA
- 2Department of Psychology, Yale University, New Haven, CT USA
- 3Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, TN USA
- 4Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ USA
Abstract
Structural brain abnormalities in psychosis are well-replicated but heterogenous posing a barrier to uncovering the pathophysiology, etiology, and treatment of psychosis. To parse neurostructural heterogeneity and assess for the presence of anatomically-derived subtypes, we applied a data-driven method, similarity network fusion (SNF), to structural neuroimaging data in a broad cohort of individuals with psychosis (schizophrenia spectrum disorders (SSD) n = 280; bipolar disorder with psychotic features (BD) n = 101). SNF identified two transdiagnostic subtypes in psychosis (subtype 1: n = 158 SSD, n = 75 BD; subtype 2: n = 122 SSD, n = 26 BD) that exhibited divergent patterns of abnormal cortical surface area and subcortical volumes. Compared to controls (n = 243), subtype 1 showed moderate enlargement of surface area in frontal and parietal areas and larger dorsal striatal volumes, whereas subtype 2 demonstrated markedly smaller surface areas in frontal and temporal areas and subcortical volumes, including hippocampus, amygdala, thalamus and ventral striatum. When comparing subtypes on clinical characteristics, subtype 2 demonstrated more severe negative symptoms, greater neuropsychological impairment, and lower estimated premorbid intellectual functioning. Integrating cell-type data imputed from gene expression in the Allen Human Brain Atlas revealed an association between interregional glial cell and parvalbumin-expressing interneuron abundance and surface area expansion in subtype 1, yet cortical thinning in subtype 2. The largest deviations from controls were present in subtype 2 surface area that spatially coupled with layer 5 glutamatergic neuron abundance, critical for corticostriatal connectivity. These outcomes indicate early diverging neurodevelopmental trajectories of psychosis subtypes, as evidenced by opposing patterns in surface area, cellular fingerprints, and subcortical volumes.
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BibTeX
@article{hill2026subtyping,
title = {{Subtyping psychotic disorders using a data-driven approach reveals divergent cortical and cellular signatures}},
author = {Lauren D. Hill and Xi-Han Zhang and Baxter P. Rogers and Anna S. Huang and Victoria Fox and Brandee Feola and Stephan Heckers and Avram J. Holmes and Neil D. Woodward},
journal = {Molecular Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41380-026-03774-2},
url = {https://doi.org/10.1038/s41380-026-03774-2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Subtyping psychotic disorders using a data-driven approach reveals divergent cortical and cellular signatures
AU - Lauren D. Hill
AU - Xi-Han Zhang
AU - Baxter P. Rogers
AU - Anna S. Huang
AU - Victoria Fox
AU - Brandee Feola
AU - Stephan Heckers
AU - Avram J. Holmes
AU - Neil D. Woodward
PY - 2026
DA - 2026/07/23
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03774-2
UR - https://doi.org/10.1038/s41380-026-03774-2
AB - Structural brain abnormalities in psychosis are well-replicated but heterogenous posing a barrier to uncovering the pathophysiology, etiology, and treatment of psychosis. To parse neurostructural heterogeneity and assess for the presence of anatomically-derived subtypes, we applied a data-driven method, similarity network fusion (SNF), to structural neuroimaging data in a broad cohort of individuals with psychosis (schizophrenia spectrum disorders (SSD) n = 280; bipolar disorder with psychotic features (BD) n = 101). SNF identified two transdiagnostic subtypes in psychosis (subtype 1: n = 158 SSD, n = 75 BD; subtype 2: n = 122 SSD, n = 26 BD) that exhibited divergent patterns of abnormal cortical surface area and subcortical volumes. Compared to controls (n = 243), subtype 1 showed moderate enlargement of surface area in frontal and parietal areas and larger dorsal striatal volumes, whereas subtype 2 demonstrated markedly smaller surface areas in frontal and temporal areas and subcortical volumes, including hippocampus, amygdala, thalamus and ventral striatum. When comparing subtypes on clinical characteristics, subtype 2 demonstrated more severe negative symptoms, greater neuropsychological impairment, and lower estimated premorbid intellectual functioning. Integrating cell-type data imputed from gene expression in the Allen Human Brain Atlas revealed an association between interregional glial cell and parvalbumin-expressing interneuron abundance and surface area expansion in subtype 1, yet cortical thinning in subtype 2. The largest deviations from controls were present in subtype 2 surface area that spatially coupled with layer 5 glutamatergic neuron abundance, critical for corticostriatal connectivity. These outcomes indicate early diverging neurodevelopmental trajectories of psychosis subtypes, as evidenced by opposing patterns in surface area, cellular fingerprints, and subcortical volumes.
SN - 1359-4184
SN - 1476-5578
ER -