Electroencephalography Microstate Instability and Clinical Outcomes in Individuals at Clinical High Risk of Psychosis

Importance: Clinical criteria for identifying individuals at clinical high risk of psychosis (CHR) have been established, but their predictive accuracy remains insufficient for guiding treatment decisions. Identifying reliable biomarkers associated with mechanisms of illness and treatment in individuals at CHR is therefore a central research goal. Here, we consider resting-state electroencephalography (EEG) microstates as such a potential biomarker. Objective: To determine whether EEG microstate features are associated with future conversion to psychosis and other future clinical outcomes in individuals at CHR. Design, Setting, and Participants: Baseline EEG microstate data were collected from October 2009 through August 2014 as part of the 8-site case-control North American Prodrome Longitudinal Study-2 (NAPLS-2) during eyes-open resting-state conditions with continuous auditory white noise. Data were recorded from healthy control (HC) individuals and participants at CHR, including those at CHR with conversion to psychosis (CHR-C) and those with nonconversion (CHR-NC), followed up for 24 months. Individuals with CHR-NC were further divided into those with remission (CHR-R) or those with ongoing symptomatology (CHR-S) subgroups. A total of 241 individuals at CHR (52.4%) completed the full 24-month follow-up. Data were analyzed between January and November 2025. Main Outcomes and Measures: Resting-state EEG microstate features (coverage, duration, and occurrence) across 7 distinct microstate classes, along with cognitive test battery scores. Results: Compared with HC participants (n = 183; 103 [56.3%] male; mean [SD] age, 20.2 [5.0] years), individuals at CHR (n = 460; 265 [57.6%] male; mean [SD] age, 19.2 [4.4] years) showed reduced microstate duration (Cohen d, 0.28; 95% CI, 0.07 to 0.49) and increased occurrence (Cohen d, 0.12; 95% CI, 0.03 to 0.21) across classes, reflecting reduced microstate temporal stability. Moreover, individuals with CHR-C (n = 56) exhibited greater instability than those with CHR-R (n = 70) and HC participants but not compared to those with CHR-S (n = 115). Within the CHR group, lower stability was associated with earlier conversion to psychosis and with increased positive symptoms. While individuals at CHR demonstrated cognitive deficits relative to HC participants, including attention scores, lower microstate stability was associated with better attention scores in both groups. Conclusions and Relevance: In this study, EEG microstate stability, irrespective of class, was reduced in individuals at CHR compared to HC participants and was especially diminished in future CHR converters. The association between lower stability and better attention suggests that instability may at least partly reflect a compensatory mechanism for attention deficits. EEG microstate instability shows promise as a prognostic biomarker of clinical outcome in CHR.