Neuroimaging studies have documented brain structural changes in schizophrenia at different stages of the illness, including clinical high-risk (cHR), genetic high-risk (gHR), first-episode schizophrenia (FES), and chronic schizophrenia (ChS). There is growing awareness that neuropathological processes associated with a disease fail to map to a specific brain region but do map to a specific brain network. We sought to investigate brain structural damage networks across different stages of schizophrenia.

We initially identified gray matter alterations in 523 cHR, 855 gHR, 2162 FES, and 2640 ChS individuals relative to 6963 healthy controls. By applying novel functional connectivity network mapping to large-scale discovery and validation resting-state functional magnetic resonance imaging datasets, we mapped these affected brain locations to four specific networks.

Brain structural damage networks of cHR and gHR had limited and non-overlapping spatial distributions, with the former mainly involving the frontoparietal network and the latter principally implicating the subcortical network, indicative of distinct neuropathological mechanisms underlying cHR and gHR. By contrast, brain structural damage networks of FES and ChS manifested as similar patterns of widespread brain areas predominantly involving the somatomotor, ventral attention, and subcortical networks, suggesting an emergence of more prominent brain structural abnormalities with illness onset that have trait-like stability over time.

Our findings may not only provide a refined picture of schizophrenia neuropathology from a network perspective, but also potentially contribute to more targeted and effective intervention strategies for individuals at different schizophrenia stages.

Cognitive impairment is a core feature of schizophrenia and has been observed in both familial (FHR) and clinical high-risk (CHR) samples. Nonetheless, there is a paucity of research directly contrasting cognitive profiles in these two high-risk states and first-episode schizophrenia. This study aimed to compare cognitive functions in patients with first-episode schizophrenia-spectrum disorder (FES), their unaffected siblings (FHR), CHR individuals and healthy controls.

A standardized battery of cognitive assessments was administered to 69 FES patients, 71 help-seeking CHR individuals without family history of psychotic disorder, 50 FHR participants and 68 controls. FES and CHR participants were recruited from territory-wide early intervention service for psychosis in Hong Kong. CHR status was ascertained using Comprehensive Assessment of At-Risk Mental State.

Among four groups, FES patients displayed the largest global cognitive impairment and had medium-to-large deficits across all cognitive tests relative to controls. CHR and FHR participants significantly underperformed in most cognitive tests than controls. Among various cognitive tests, digit symbol coding demonstrated the greatest magnitude of impairment in FES and CHR groups compared with controls. No significant difference between two high-risk groups was observed in global cognition and all individual cognitive tests except digit symbol coding which showed greater deficits in CHR than in FHR participants.

Clinical and familial risk groups experienced largely comparable cognitive impairment that was intermediate between FES and controls. Digit symbol coding may have the greatest discriminant capacity in distinguishing FES and CHR from healthy controls, and between two high-risk samples.