N400 event-related brain potential index of semantic processing and two-year clinical outcomes in persons at high risk for psychosis: A longitudinal study.

The N400 event-related brain potential (ERP) semantic priming effect reflects greater activation of contextually related versus unrelated concepts in long-term semantic memory. Deficits in this measure have been found in persons with schizophrenia and those at clinical high risk (CHR) for this disorder. In CHR patients, we previously found that these deficits predict poorer social functional outcomes after 1 year. In the present study, we tested whether these deficits predicted greater psychosis-spectrum symptom severity and functional impairment over 2 years. We measured N400 semantic priming effects at baseline in CHR patients (n = 47) who viewed prime words each followed by a related/unrelated target word at stimulus-onset asynchronies (SOAs) of 300 or 750 ms. We measured psychosis-spectrum symptoms using the Structured Interview for Prodromal Symptoms and role and social functioning with the Global Functioning: Role and Social scales, at baseline, 1 (n = 29) and 2 years (n = 25). There was a significant interaction between the N400 semantic priming effect at the 300-ms SOA and time on GF:Role scores, indicating that, contrary to expectations, smaller baseline N400 semantic priming effects were associated with more improvement in role functioning from baseline to Year 1, but baseline N400 priming effects did not predict role functioning at Year 2. N400 priming effects were not significantly associated with different trajectories in psychosis-spectrum symptoms or social functioning. Thus, CHR patients' N400 semantic priming effects did not predict clinical outcomes over 2 years, suggesting that this ERP measure may have greater value as a state or short-term prognostic neurophysiological biomarker.

N400 event-related brain potential and functional outcome in persons at clinical high risk for psychosis: A longitudinal study.

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' psychosis-like 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 follow-up (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.

Effects of anxiety state on N400 event-related brain potential response to unexpected semantic stimuli.

Emotional states can influence how people use meaningful context to make predictions about what comes next. To measure whether state anxiety influences such prediction, we used the N400 event-related brain potential (ERP) response to semantic stimuli, whose amplitude is smaller (less negative) when the stimulus is more predicted based on preceding context. Participants (n = 28) were randomized to one of two groups, who underwent either an "anxious-uncertainty" procedure previously shown to increase anxiety, or a control procedure. Both before and after this procedure, participants' ERPs were recorded while they viewed category definitions (e.g., "a type of fruit"), each followed by a target word that was either a high-typicality category exemplar ("apple"), low-typicality exemplar ("cherry"), or non-exemplar ("clamp") of the category. Participants' task was to respond by pressing one of two buttons to indicate whether the target represented a member of the category. As expected, based on previous work, overall, N400 amplitudes were largest (most negative) in response to non-exemplars, intermediate to low-typicality exemplars, and smallest to high-typicality exemplars. N400 amplitudes were larger to non-exemplars after the anxious-uncertainty procedure than after the control procedure. N400 amplitudes to both types of exemplars did not differ after the anxious-uncertainty procedure versus the control procedure. The results are consistent with participants devoting more neural resources to processing contextually unexpected items under anxious states, rather than anxiety facilitating processing of expected items.

Atypical prediction error learning is associated with prodromal symptoms in individuals at clinical high risk for psychosis.

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.

N400 event-related brain potential as an index of real-world and neurocognitive function in patients at clinical high risk for schizophrenia.

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.

Decreased Gamma Auditory Steady-State Response Is Associated With Impaired Real-World Functioning in Unmedicated Patients at Clinical High Risk for Psychosis.

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.

Religiosity is associated with less prediction of the typical: An event-related brain potential study.

Why are some people more religious than others? According to one hypothesis, people who strongly seek definitive explanations for situations with incomplete information are more likely to be religious. According to a different hypothesis, individuals with smaller "prediction error" responses to unexpected stimuli are more likely to discount evidence contradicting religious beliefs, predisposing them to maintain such beliefs. We sought neurophysiological evidence for these hypotheses using the N400 event-related potential (ERP), which is smaller to more contextually expected stimuli, reflecting prediction of probable completions for meaningful situations. We recorded ERPs from participants viewing category definitions followed by high-typicality category exemplar (HTE), low-typicality exemplar (LTE), or non-exemplar (NE) words. As expected, N400s were largest for NEs, intermediate for LTEs, and smallest for HTEs. Religiosity correlated with smaller N400 amplitude differences between HTEs and both LTEs and NEs. Less strong prediction of probable stimuli based on prior information may predispose to religiosity.

Relationships between cognitive event-related brain potential measures in patients at clinical high risk for psychosis.

Neurophysiological measures of cognitive functioning that are abnormal in patients with schizophrenia are promising candidate biomarkers for predicting development of psychosis in individuals at clinical high risk (CHR). We examined the relationships among event-related brain potential (ERP) measures of early sensory, pre-attentional, and attention-dependent cognition, in antipsychotic-naïve help-seeking CHR patients (n = 36) and healthy control participants (n = 22). These measures included the gamma auditory steady-state response (ASSR; early sensory); mismatch negativity (MMN) and P3a (pre-attentional); and N400 semantic priming effects - a measure of using meaningful context to predict related items - over a shorter and a longer time interval (attention-dependent). Compared to controls, CHR patients had significantly smaller P3a amplitudes (d = 0.62, p = 0.03) and N400 priming effects over the long interval (d = 0.64, p = 0.02). In CHR patients, gamma ASSR evoked power and phase-locking factor were correlated (r = 0.41, p = 0.03). Reductions in mismatch negativity (MMN) and P3a amplitudes were also correlated (r = -0.36, p = 0.04). Moreover, lower gamma ASSR evoked power correlated with smaller MMN amplitudes (r = -0.45, p = 0.02). MMN amplitude reduction was also associated with reduced N400 semantic priming over the shorter but not the longer interval (r = 0.52, p < 0.002). This pattern of results suggests that, in a subset of CHR patients, impairment in pre-attentional measures of early information processing may contribute to deficits in attention-dependent cognition involving rapid, more automatic processing, but may be independent from pathological processes affecting more controlled or strategic processing. Thus, combining neurophysiological indices of cognitive deficits in different domains offers promise for improving their predictive power as prognostic biomarkers of clinical outcome.

Event-Related Potentials in the Clinical High-Risk (CHR) State for Psychosis: A Systematic Review.

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.