Pulvinar-cortical connectomic deviations identify symptom-relevant biotypes in schizophrenia

Schizophrenia exhibits profound clinical heterogeneity, yet biologically interpretable imaging markers capturing symptom-specific variance remain elusive. Although the pulvinar is a critical higher-order thalamic hub for cortico-cortical coordination, whether its individualized abnormalities can define clinically meaningful biotypes remains unexplored. The present study implemented a symptom-guided normative modeling framework using multisite resting-state functional MRI data from 746 healthy controls and 387 patients with schizophrenia. Individualized pulvinar-cortical deviation profiles were estimated relative to a healthy reference model and integrated with symptom-guided feature selection and unsupervised clustering. Two partially separable biotypes were identified within a clinically enriched low-dimensional feature space. The biotypes were clinically anchored primarily in negative symptom severity, with a significant between-biotype difference that remained after adjustment for site and other available covariates. Symptom-relevant connections showed a structured cortical distribution concentrated predominantly in somatomotor, visual, and ventral attention networks. Imaging-transcriptomic analyses provided exploratory spatial molecular context, with Biotype 1 showing enrichment profiles involving translation, protein targeting, and synaptic organization, and Biotype 2 showing profiles involving neurodevelopment, synaptic remodeling, and metal-ion homeostasis. Site-exclusion analyses indicated partial stability of the biotype solution, although clinical separation varied across sites. Projection into an independent repetitive transcranial magnetic stimulation cohort showed nominal, uncorrected differences in 2-week negative symptom improvement that were not sustained at 4 weeks and should therefore be considered hypothesis-generating. These findings support a symptom-guided pulvinar-cortical framework for characterizing schizophrenia heterogeneity, while independent replication using prespecified models is required to establish clinical and biological validity.