Divergent cortical-subcortical intrinsic neural timescales in first-episode drug-naïve or minimally treated schizophrenia.

BACKGROUND: The neuropathological mechanisms of schizophrenia remain unclear. Intrinsic neural timescale (INT) reflects the temporal organization of neural activity. This study aimed to characterize INT alterations in patients with first-episode schizophrenia who were drug-naïve or minimally treated, while minimizing confounding effects of chronic illness and medication exposure. METHODS: Resting-state fMRI data were collected from 123 first-episode, drug-naïve or minimally treated schizophrenia patients and 102 matched healthy controls. INT values were derived from the autocorrelation function of the fMRI signal. Group differences in INT were assessed using analysis of covariance (ANCOVA), controlling for age, gender and scanner site. Additional analyses included correlation analyses, gene annotation and enrichment analyses, and spatial correlation analyses. RESULTS: Patients exhibited a divergent cortical-subcortical pattern, characterized by reduced cortical INT and prolonged subcortical INT. Compared with healthy controls, patients showed significant INT alterations in 13 regions of interest (p-fdr < 0.05), predominantly involving the default mode network (5 regions) and subcortical network (4 regions), as well as the sensorimotor network, memory retrieval network, salience network, and ventral attention network. Regions with altered INT were enriched for synapse-related genes, and their spatial distribution was correlated with cerebral blood flow. CONCLUSIONS: Our findings show that first-episode drug-naïve or minimally treated schizophrenia patients are characterized by disrupted intrinsic neural timescales with distinct cortical-subcortical alterations. These abnormalities may be related to cerebral perfusion, synaptic function and symptom severity. The distinct cortical-subcortical alterations of INTs may represent a candidate neurobiological marker of early-stage schizophrenia.