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There is emerging evidence that identification and treatment of individuals in the prodromal or clinical high-risk (CHR) state for psychosis can reduce the probability that they will develop a psychotic disorder. Event-related brain potentials (ERPs) are a noninvasive neurophysiological technique that holds promise for improving our understanding of neurocognitive processes underlying the CHR state. We aimed to systematically review the current literature on cognitive ERP studies of the CHR population, in order to summarize and synthesize the results, and their implications for our understanding of the CHR state. Across studies, amplitudes of the auditory P300 and duration mismatch negativity (MMN) ERPs appear reliably reduced in CHR individuals, suggesting that underlying impairments in detecting changes in auditory stimuli are a sensitive early marker of the psychotic disease process. There are more limited data indicating that an earlier-latency auditory ERP response, the N100, is also reduced in amplitude, and in the degree to which it is modulated by stimulus characteristics, in the CHR population. There is also evidence that a number of auditory ERP measures (including P300, MMN and N100 amplitudes, and N100 gating in response to repeated stimuli) can further refine our ability to detect which CHR individuals are most at risk for developing psychosis. Thus, further research is warranted to optimize the predictive power of algorithms incorporating these measures, which could help efforts to target psychosis prevention interventions toward those most in need.

Aim The N400 event‐related potential is a neurophysiological index of cognitive processing of real‐world knowledge. In healthy populations, N400 amplitude is smaller in response to stimuli that are more related to preceding context. This ‘N400 semantic priming effect’ is thought to reflect activation of contextually related information in semantic memory (SM). N400 semantic priming deficits have been found in schizophrenia, and in patients at clinical high risk (CHR) for this disorder. Because this abnormality in processing relationships between meaningful stimuli could affect ability to navigate everyday situations, we hypothesized it would be associated with real‐world functional impairment in CHR patients. Second, we hypothesized it would correlate with global neurocognitive impairment in this group. Methods We measured N400 semantic priming in 35 CHR patients who viewed prime words each followed by a related or unrelated target word, at stimulus‐onset asynchrony (SOA) of 300 or 750 ms. We measured academic/occupational and social function with the global function (GF): Role and Social scales, and cognitive function with the MATRICS Consensus Cognitive Battery (MCCB). Results Decreased N400 semantic priming at the 300‐ms SOA correlated with lower GF:Role scores. Decreased N400 semantic priming at the 750‐ms SOA correlated with lower MCCB composite scores. Conclusions Deficits in activating contextually related concepts in SM over short time intervals may contribute to functional impairment in CHR patients. Furthermore, N400 priming deficits over longer intervals may be a biomarker of global cognitive dysfunction in this population. Longitudinal studies are needed to determine whether these deficits are associated with schizophrenia risk within this population.

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Aim Deficits in synchronous, gamma-frequency neural oscillations may contribute to schizophrenia patients’ real-world functional impairment and can be measured electroencephalographically using the auditory steady-state response (ASSR). Gamma ASSR deficits have been reported in schizophrenia patients and individuals at clinical high risk (CHR) for developing psychosis. We hypothesized that, in CHR patients, gamma ASSR would correlate with real-world functioning, consistent with a role for gamma synchrony deficits in functional impairment. Methods A total of 35 CHR patients rated on Global Functioning: Social and Role scales had EEG recorded while listening to 1-ms, 93-dB clicks presented at 40 Hz in 500-ms trains, in response to which 40-Hz evoked power and intertrial phase-locking factor (PLF) were measured. Results In CHR patients, lower 40-Hz PLF correlated with lower social functioning. Conclusions Gamma synchrony deficits may be a biomarker of real-world impairment at early stages of the schizophrenia disease trajectory.

Reductions in the auditory mismatch negativity (MMN) have been well-demonstrated in schizophrenia rendering it a promising biomarker for understanding the emergence of psychosis. According to the predictive coding theory of psychosis, MMN impairments may reflect disturbances in hierarchical information processing driven by maladaptive precision-weighted prediction errors (pwPEs) and enhanced belief updating. We applied a hierarchical Bayesian model of learning to single-trial EEG data from an auditory oddball paradigm in 31 help-seeking antipsychotic-naive high-risk individuals and 23 healthy controls to understand the computational mechanisms underlying the auditory MMN. We found that low-level sensory and high-level volatility pwPE expression correlated with EEG amplitudes, coinciding with the timing of the MMN. Furthermore, we found that prodromal positive symptom severity was associated with increased expression of sensory pwPEs and higher-level belief uncertainty. Our findings provide support for the role of pwPEs in auditory MMN generation, and suggest that increased sensory pwPEs driven by changes in belief uncertainty may render the environment seemingly unpredictable. This may predispose high-risk individuals to delusion-like ideation to explain this experience. These results highlight the value of computational models for understanding the pathophysiological mechanisms of psychosis.

Background: The N400 event-related brain potential (ERP) semantic priming effect is thought to reflect activation by meaningful stimuli of related concepts in semantic memory and has been found to be deficient in schizophrenia. We tested the hypothesis that, among individuals at clinical high risk (CHR) for psychosis, N400 semantic priming deficits predict worse symptomatic and functional outcomes after one year.Methods: We measured N400 semantic priming at baseline in CHR patients (n = 47) and healthy control participants (n = 25) who viewed prime words each followed by a related or unrelated target word, at stimulus-onset asynchronies (SOAs) of 300 or 750 ms. We measured patients' psychosislike symptoms with the Scale of Prodromal Symptoms (SOPS) Positive subscale, and academic/occupational and social functioning with the Global Functioning (GF):Role and Social scales, respectively, at baseline and one-year followup (n = 29).Results: CHR patients exhibited less N400 semantic priming than controls across SOAs; planned contrasts indicated this difference was significant at the 750-ms but not the 300-ms SOA. In patients, reduced N400 semantic priming at the 750-ms SOA was associated with lower GF:Social scores at follow-up, and greater GF:Social decrements from baseline to follow-up. Patients' N400 semantic priming was not associated with SOPS Positive or GF:Role scores at follow-up, or change in these from baseline to follow-up. Conclusions:In CHR patients, reduced N400 semantic priming at baseline predicted worse social functioning after one year, and greater decline in social functioning over this period. Thus, the N400 may be a useful prognostic biomarker of real-world functional outcome in CHR patients.

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