Two structural alteration patterns of the thalamus in patients with schizophrenia

The thalamus has been reported as structurally impaired in individuals with schizophrenia. Previous studies have demonstrated structural heterogeneity within the thalamus in schizophrenia. However, the alteration patterns among patient subtypes defined by thalamic nuclei remain unclear.

This study included 124 drug-naïve individuals with first-episode schizophrenia (FES) as the discovery cohort for thalamic subtype identification. Volumes of thalamic nuclei were used as inputs for k-means + + cluster analysis to identify patient subtypes. Subsequently, a machine learning classifier was developed in the discovery cohort, and was validated in an independent cohort with FES (N = 68), and applied in two cohorts with long-term schizophrenia, containing 95 treated individuals with long-term illness and 30 never-treated individuals with long-term illness, respectively. Additionally, the respective groups of controls were recruited as normative references for cognitive and brain structural characteristics.

We identified two highly replicable thalamic subtypes in individuals with FES: one with widespread volumetric reductions (subtype 1) and another with widespread volumetric increases (subtype 2). A classifier trained on this distinction validated the subtypes in an independent FES cohort. In long-term illness, the reduced-volume pattern of subtype 1 was consistent but more severe, with treated patients exhibiting greater volumetric deficits and cognitive abnormalities than their FES counterparts. Conversely, the increased-volume pattern of subtype 2 was attenuated in long-term illness, manifesting as selected increases in certain nuclei in treated patients and showing no significant alterations in never-treated patients.

Our findings demonstrate two neuroanatomical thalamic subtypes in schizophrenia. Subtype 1, characterized by severe and progressive thalamocortical deficits, represents a critical subgroup that may benefit from early detection and cognitive-focused interventions. The attenuation of subtype 2 in chronic illness suggests its pathophysiology may be distinct and associated with treatment or disease course. Future longitudinal studies tracking thalamic heterogeneity from the first-episode drug-naïve stage are essential to clarify the progression of these subtypes and their impact on cognitive decline.