Trait, staging, and state markers of psychosis based on functional alteration of salience-related networks in the high-risk, first episode, and chronic stages

Background and hypothesisSalience is a critical mechanism for animal survival. Aberrant salience is essentially implicated in psychosis, involving the midbrain-striatum-hippocampus and the anterior cingulate cortex (ACC)-insula salience network (SN) systems. However, whether these two systems jointly or independently contribute to psychosis traits, staging, and state remains unknown. Study designEight scanners at seven institutions recruited 209 subjects with psychosis at the ultra-high-risk (UHR), first-episode (FEP), and chronic (ChrP) stages and 279 matched healthy controls (HC). Resting-state functional MRI data, which were intensively denoised and scanner effect-removed, revealed the two systems comprising five networks: midbrain-thalamic and striatal parts of the basal ganglia network (BGN-MbThal and BGN-Str), the medial temporal lobe network (MTLN), and the ACC and insular parts of the SN (SN-ACC and SN-Ins). Group differences, correlations with positive symptoms, and effects of medication/psychosis type of the networks were investigated in each psychosis stage. Study resultsConnectivity within the SN-ACC was reduced in UHR compared to HC (p<0.05, family-wise-error [FWE] corrected) and in the FEP and ChrP stages at liberal thresholds, with effect sizes of UHR>FEP>ChrP. FEP showed reduced connectivity within the BGN-MbThal, increased brain-state instability among the five networks, and positive correlations between positive symptoms and connectivity within and between the MTLN (all p<0.05, FWE). The correlation was stronger in unmedicated than in medicated, and in affective than in non-affective psychosis patients (p<0.05, FWE). ConclusionsThe results provide a novel concept that the two salience mechanisms work in an integrated and separate manner in psychosis.