Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

P300 in schizophrenia: Then and now.

The 1965 discovery of the P300 component of the electroencephalography (EEG)-based event-related potential (ERP), along with the subsequent identification of its alteration in people with schizophrenia, initiated over 50 years of P300 research in schizophrenia. Here, we review what we now know about P300 in schizophrenia after nearly six decades of research. We describe recent efforts to expand our understanding of P300 beyond its sensitivity to schizophrenia itself to its potential role as a biomarker of risk for psychosis or a heritable endophenotype that bridges genetic risk and psychosis phenomenology. We also highlight efforts to move beyond a syndrome-based approach to understand P300 within the context of the clinical, cognitive, and presumed pathophysiological heterogeneity among people diagnosed with schizophrenia. Finally, we describe several recent approaches that extend beyond measuring the traditional P300 ERP component in people with schizophrenia, including time-frequency analyses and pharmacological challenge studies, that may help to clarify specific cognitive mechanisms that are disrupted in schizophrenia. Moreover, we discuss several promising areas for future research, including studies of animal models that can be used for treatment development.

Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

Surgical Emergencies in the ICU.

Surgical emergencies are common in the critical care setting and require prompt diagnosis and management. Here, we discuss some of the surgical emergencies involving the gastrointestinal, hepatobiliary, and genitourinary sites. In addition, foreign body aspiration and necrotizing soft-tissue infections have been elaborated. Clinicians should be aware of the risk factors, keys examination findings, diagnostic modalities, and medical as well as surgical treatment options for these potentially fatal illnesses.

Auditory N100 amplitude deficits predict conversion to psychosis in the North American Prodrome Longitudinal Study (NAPLS-2) cohort.

BACKGROUND: The auditory N100 is an event related potential (ERP) that is reduced in schizophrenia, but its status in individuals at clinical high risk for psychosis (CHR) and its ability to predict conversion to psychosis remains unclear. We examined whether N100 amplitudes are reduced in CHR subjects relative to healthy controls (HC), and this reduction predicts conversion to psychosis in CHR. METHODS: Subjects included CHR individuals (n = 552) and demographically similar HC subjects (n = 236) from the North American Prodrome Longitudinal Study. Follow-up assessments identified CHR individuals who converted to psychosis (CHRC; n = 73) and those who did not (CHR-NC; n = 225) over 24 months. Electroencephalography data were collected during an auditory oddball task containing Standard, Novel, and Target stimuli. N100 peak amplitudes following each stimulus were measured at electrodes Cz and Fz. RESULTS: The CHR subjects had smaller N100 absolute amplitudes than HC subjects at Fz (F(1,786) = 4.00, p 0.046). A model comparing three groups (CHRC, CHR-NC, HC) was significant for Group at the Cz electrode (F(2,531) = 3.58, p = 0.029). Both Standard (p = 0.019) and Novel (p = 0.017) stimuli showed N100 absolute amplitude reductions in CHR-C relative to HC. A smaller N100 amplitude at Cz predicted conversion to psychosis in the CHR cohort (Standard: p = 0.009; Novel: p = 0.001) and predicted shorter time to conversion (Standard: p = 0.013; Novel: p = 0.001). CONCLUSION: N100 amplitudes are reduced in CHR individuals which precedes the onset of psychosis. N100 deficits in CHR individuals predict a greater likelihood of conversion to psychosis. Our results highlight N100's utility as a biomarker of psychosis risk.

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis.

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

Mismatch Negativity in Response to Auditory Deviance and Risk for Future Psychosis in Youth at Clinical High Risk for Psychosis.

Importance: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P). Objective: To examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use. Design, Setting, and Participants: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. Main Outcomes and Measures: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. Results: The CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity. Conclusions and Relevance: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Visual cortical plasticity and the risk for psychosis: An interim analysis of the North American Prodrome Longitudinal Study.

BACKGROUND: Adolescence/early adulthood coincides with accelerated pruning of cortical synapses and the onset of schizophrenia. Cortical gray matter reduction and dysconnectivity in schizophrenia are hypothesized to result from impaired synaptic plasticity mechanisms, including long-term potentiation (LTP), since deficient LTP may result in too many weak synapses that are then subject to over-pruning. Deficient plasticity has already been observed in schizophrenia. Here, we assessed whether such deficits are present in the psychosis risk syndrome (PRS), particularly those who subsequently convert to full psychosis. METHODS: An interim analysis was performed on a sub-sample from the NAPLS-3 study, including 46 healthy controls (HC) and 246 PRS participants. All participants performed an LTP-like visual cortical plasticity paradigm involving assessment of visual evoked potentials (VEPs) elicited by vertical and horizontal line gratings before and after high frequency ("tetanizing") visual stimulation with one of the gratings to induce "input-specific" neuroplasticity (i.e., VEP changes specific to the tetanized stimulus). Non-parametric, cluster-based permutation testing was used to identify electrodes and timepoints that demonstrated input-specific plasticity effects. RESULTS: Input-specific pre-post VEP changes (i.e., increased negative voltage) were found in a single spatio-temporal cluster covering multiple occipital electrodes in a 126-223 ms time window. This plasticity effect was deficient in PRS individuals who subsequently converted to psychosis, relative to PRS non-converters and HC. CONCLUSIONS: Input-specific LTP-like visual plasticity can be measured from VEPs in adolescents and young adults. Interim analyses suggest that deficient visual cortical plasticity is evident in those PRS individuals at greatest risk for transition to psychosis.

Abnormally Large Baseline P300 Amplitude Is Associated With Conversion to Psychosis in Clinical High Risk Individuals With a History of Autism: A Pilot Study.

Psychosis rates in autism spectrum disorder (ASD) are 5-35% higher than in the general population. The overlap in sensory and attentional processing abnormalities highlights the possibility of related neurobiological substrates. Previous research has shown that several electroencephalography (EEG)-derived event-related potential (ERP) components that are abnormal in schizophrenia, including P300, are also abnormal in individuals at Clinical High Risk (CHR) for psychosis and predict conversion to psychosis. Yet, it is unclear whether P300 is similarly sensitive to psychosis risk in help-seeking CHR individuals with ASD history. In this exploratory study, we leveraged data from the North American Prodrome Longitudinal Study (NAPLS2) to probe for the first time EEG markers of longitudinal psychosis profiles in ASD. Specifically, we investigated the P300 ERP component and its sensitivity to psychosis conversion across CHR groups with (ASD+) and without (ASD-) comorbid ASD. Baseline EEG data were analyzed from 304 CHR patients (14 ASD+; 290 ASD-) from the NAPLS2 cohort who were followed longitudinally over two years. We examined P300 amplitude to infrequent Target (10%; P3b) and Novel distractor (10%; P3a) stimuli from visual and auditory oddball tasks. Whereas P300 amplitude attenuation is typically characteristic of CHR and predictive of conversion to psychosis in non-ASD sample, in our sample, history of ASD moderated this relationship such that, in CHR/ASD+ individuals, enhanced - rather than attenuated - visual P300 (regardless of stimulus type) was associated with psychosis conversion. This pattern was also seen for auditory P3b amplitude to Target stimuli. Though drawn from a small sample of CHR individuals with ASD, these preliminary results point to a paradoxical effect, wherein those with both CHR and ASD history who go on to develop psychosis have a unique pattern of enhanced neural response during attention orienting to both visual and target stimuli. Such a pattern stands out from the usual finding of P300 amplitude reductions predicting psychosis in non-ASD CHR populations and warrants follow up in larger scale, targeted, longitudinal studies of those with ASD at clinical high risk for psychosis.

Forecasting Remission From the Psychosis Risk Syndrome With Mismatch Negativity and P300: Potentials and Pitfalls.

Clinical outcomes vary for individuals at clinical high risk (CHR) for psychosis, ranging from conversion to a psychotic disorder to full remission from the risk syndrome. Given that most CHR individuals do not convert to psychosis, recent research efforts have turned toward identifying specific predictors of CHR remission, a task that is conceptually and empirically dissociable from the identification of predictors of conversion to psychosis, and one that may reveal specific biological characteristics that confer resilience to psychosis and provide further insights into the mechanisms associated with the pathogenesis of schizophrenia and those underlying a transient CHR syndrome. Such biomarkers may ultimately facilitate the development of novel early interventions and support the optimization of individualized care. In this review, we focus on two event-related brain potential measures, mismatch negativity and P300, that have attracted interest as predictors of future psychosis among CHR individuals. We describe several recent studies examining whether mismatch negativity and P300 predict subsequent CHR remission and suggest that intact mismatch negativity and P300 may reflect the integrity of specific neurocognitive processes that confer resilience against the persistence of the CHR syndrome and its associated risk for future transition to psychosis. We also highlight several major methodological concerns associated with these studies that apply to the broader literature examining predictors of CHR remission. Among them is the concern that studies that predict dichotomous remission versus nonremission and/or dichotomous conversion versus nonconversion outcomes potentially confound remission and conversion effects, a phenomenon we demonstrate with a data simulation.

Reliability of mismatch negativity event-related potentials in a multisite, traveling subjects study.

OBJECTIVE: To determine the optimal methods for measuring mismatch negativity (MMN), an auditory event-related potential (ERP), and quantify sources of MMN variance in a multisite setting. METHODS: Reliability of frequency, duration, and double (frequency + duration) MMN was determined from eight traveling subjects, tested on two occasions at eight laboratory sites. Deviant-specific variance components were estimated for MMN peak amplitude and latency measures using different ERP processing methods. Generalizability (G) coefficients were calculated using two-facet (site and occasion), fully-crossed models and single-facet (occasion) models within each laboratory to assess MMN reliability. RESULTS: G-coefficients calculated from two-facet models indicated fair (0.4 < G<=0.6) duration MMN reliability at electrode Fz, but poor (G < 0.4) double and frequency MMN reliability. Single-facet G-coefficients averaged across laboratory resulted in improved reliability (G > 0.5). MMN amplitude reliability was greater than latency reliability, and reliability with mastoid referencing significantly outperformed nose-referencing. CONCLUSIONS: EEG preprocessing methods have an impact on the reliability of MMN amplitude. Within site MMN reliability can be excellent, consistent with prior single site studies. SIGNIFICANCE: With standardized data collection and ERP processing, MMN can be reliably obtained in multisite studies, providing larger samples sizeswithin rare patient groups.

Deficits in auditory predictive coding in individuals with the psychosis risk syndrome: Prediction of conversion to psychosis.

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early- to late-appearing standards within local trains of repeating standards (p < .0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p = .0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p = .0.0107) and a more prominent deficit for late-appearing standards (p = .0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p = .02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Electroencephalography and Event-Related Potential Biomarkers in Individuals at Clinical High Risk for Psychosis.

Clinical outcomes vary among youths at clinical high risk for psychosis (CHR-P), with approximately 20% progressing to full-blown psychosis over 2 to 3 years and 30% achieving remission. Recent research efforts have focused on identifying biomarkers that precede psychosis onset and enhance the accuracy of clinical outcome prediction in CHR-P individuals, with the ultimate goal of developing staged treatment approaches based on the individual's level of risk. Identifying such biomarkers may also facilitate progress toward understanding pathogenic mechanisms underlying psychosis onset, which may support the development of mechanistically informed early interventions for psychosis. In recent years, electroencephalography-based event-related potential measures with established sensitivity to schizophrenia have gained traction in the study of CHR-P and its clinical outcomes. In this review, we describe the evidence for event-related potential abnormalities in CHR-P and discuss how they inform our understanding of information processing deficits as vulnerability markers for emerging psychosis and as indicators of future outcomes. Among the measures studied, P300 and mismatch negativity are notable because deficits predict conversion to psychosis and/or CHR-P remission. However, the accuracy with which these and other measures predict outcomes in CHR-P has been obscured in the prior literature by the tendency to only report group-level differences, underscoring the need for inclusion of individual predictive accuracy metrics in future studies. Nevertheless, both P300 and mismatch negativity show promise as electrophysiological markers of risk for psychosis, as target engagement measures for clinical trials, and as potential translational bridges between human studies and animal models focused on novel drug development for early psychosis.

Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease.

The autosomal codominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria, and inflammation, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first-generation intravenously administered RNA interference (RNAi) therapeutic ARC-AAT and then with next-generation subcutaneously administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis, and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria, and autophagosomes in hepatocytes was evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation, and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in phase II/III clinical trials.

Stability of mismatch negativity event-related potentials in a multisite study.

OBJECTIVES: Mismatch negativity (MMN), an auditory event-related potential sensitive to deviance detection, is smaller in schizophrenia and psychosis risk. In a multisite study, a regression approach to account for effects of site and age (12-35 years) was evaluated alongside the one-year stability of MMN. METHODS: Stability of frequency, duration, and frequency + duration (double) deviant MMN was assessed in 167 healthy subjects, tested on two occasions, separated by 52 weeks, at one of eight sites. Linear regression models predicting MMN with age and site were validated and used to derive standardized MMN z-scores. Variance components estimated for MMN amplitude and latency measures were used to calculate Generalizability (G) coefficients within each site to assess MMN stability. Trait-like aspects of MMN were captured by averaging across occasions and correlated with subject traits. RESULTS: Age and site accounted for less than 7% of MMN variance. G-coefficients calculated at electrode Fz were stable (G = 0.63) across deviants and sites for amplitude measured in a fixed window, but not for latency (G = 0.37). Frequency deviant MMN z-scores averaged across tests negatively correlated with averaged global assessment of functioning. CONCLUSION: MMN amplitude is stable and can be standardized to facilitate longitudinal multisite studies of patients and clinical features.

Associations between physiological responses to social-evaluative stress and daily functioning in first-episode schizophrenia.

Schizophrenia (SZ) is associated with impaired adaptive functioning, including difficulties managing the demands of independent living, work, school, and interpersonal relationships. Prior studies have linked the physiological stress response with less effective coping in daily life. Differences in stress-response tendencies may also support heterogeneity in daily functioning in SZ. The present study examined two established measures of the stress response in patients with first-episode SZ. Salivary cortisol was included as an index of hypothalamic-pituitary-adrenal response. Vagal suppression (VS), a measure of stress-related reduction in heart rate variability, was used to assess parasympathetic flexibility. Greater cortisol response and VS to social-evaluative stress were predicted to be associated with better functioning in SZ over and above relationships with social cognition and neurocognition, two well-established predictors of functional outcome. Thirty-eight first-episode SZ outpatients and 29 healthy comparison subjects (HC) provided social cognitive, neurocognitive, and physiological measurements before and after the Trier Social Stress Test (TSST). Although SZ and HC did not differ on VS to the TSST, patients exhibited significant associations between VS and functioning across all four domains of the Role Functioning Scale. Furthermore, greater VS predicted more effective functioning with friends, beyond the contributions associated with social cognition and neurocognition, and strengthened the positive effects of higher levels of social cognition on independent living/self-care. VS elicited by social-evaluative stress in the laboratory may reflect stress-response tendencies in daily life that are relevant for daily functioning in first-episode SZ.

Impaired Potentiation of Theta Oscillations During a Visual Cortical Plasticity Paradigm in Individuals With Schizophrenia.

Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity mediated by glutamatergic transmission at N-methyl-D-aspartate receptors (NMDARs). Impaired neuroplasticity has been implicated in the pathophysiology of schizophrenia, possibly due to underlying NMDAR hypofunction. Analogous to the high frequency electrical stimulation used to induce LTP in vitro and in vivo in animal models, repeated high frequency presentation of a visual stimulus in humans in vivo has been shown to induce enduring LTP-like neuroplastic changes in electroencephalography (EEG)-based visual evoked potentials (VEPs) elicited by the stimulus. Using this LTP-like visual plasticity paradigm, we previously showed that visual high-frequency stimulation (VHFS) induced sustained changes in VEP amplitudes in healthy controls, but not in patients with schizophrenia. Here, we extend this prior work by re-analyzing the EEG data underlying the VEPs, focusing on neuroplastic changes in stimulus-evoked EEG oscillatory activity following VHFS. EEG data were recorded from 19 patients with schizophrenia and 21 healthy controls during the visual plasticity paradigm. Event-related EEG oscillations (total power, intertrial phase coherence; ITC) elicited by a standard black and white checkerboard stimulus (~0.83 Hz, several 2-min blocks) were assessed before and after exposure to VHFS with the same stimulus (~8.9 Hz, 2 min). A cluster-based permutation testing approach was applied to time-frequency data to examine LTP-like plasticity effects following VHFS. VHFS enhanced theta band total power and ITC in healthy controls but not in patients with schizophrenia. The magnitude and phase synchrony of theta oscillations in response to a visual stimulus were enhanced for at least 22 min following VHFS, a frequency domain manifestation of LTP-like visual cortical plasticity. These theta oscillation changes are deficient in patients with schizophrenia, consistent with hypothesized NMDA receptor dysfunction.

Association Between P300 Responses to Auditory Oddball Stimuli and Clinical Outcomes in the Psychosis Risk Syndrome.

Importance: In most patients, a prodromal period precedes the onset of schizophrenia. Although clinical criteria for identifying the psychosis risk syndrome (PRS) show promising predictive validity, assessment of neurophysiologic abnormalities in at-risk individuals may improve clinical prediction and clarify the pathogenesis of schizophrenia. Objective: To determine whether P300 event-related potential amplitude, which is deficient in schizophrenia, is reduced in the PRS and associated with clinical outcomes. Design, Setting, and Participants: Auditory P300 data were collected as part of the multisite, case-control North American Prodrome Longitudinal Study (NAPLS-2) at 8 university-based outpatient programs. Participants included 552 individuals meeting PRS criteria and 236 healthy controls with P300 data. Auditory P300 data of participants at risk who converted to psychosis (n = 73) were compared with those of nonconverters who were followed up for 24 months and continued to be symptomatic (n = 135) or remitted from the PRS (n = 90). Data were collected from May 27, 2009, to September 17, 2014, and were analyzed from December 3, 2015, to May 1, 2019. Main Outcomes and Measures: Baseline electroencephalography was recorded during an auditory oddball task. Two P300 subcomponents were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. Results: This study included 788 participants. The PRS group (n = 552) included 236 females (42.8%) (mean [SD] age, 19.21 [4.38] years), and the healthy control group (n = 236) included 111 females (47.0%) (mean [SD] age, 20.44 [4.73] years). Target P3b and novelty P3a amplitudes were reduced in at-risk individuals vs healthy controls (d = 0.37). Target P3b, but not novelty P3a, was significantly reduced in psychosis converters vs nonconverters (d = 0.26), and smaller target P3b amplitude was associated with a shorter time to psychosis onset in at-risk individuals (hazard ratio, 1.45; 95% CI, 1.04-2.00; P = .03). Participants with the PRS who remitted had baseline target P3b amplitudes that were similar to those of healthy controls and greater than those of converters (d = 0.51) and at-risk individuals who remained symptomatic (d = 0.41). Conclusions and Relevance: In this study, deficits in P300 amplitude appeared to precede psychosis onset. Target P3b amplitudes, in particular, may be sensitive to clinical outcomes in the PRS, including both conversion to psychosis and clinical remission. Auditory target P3b amplitude shows promise as a putative prognostic biomarker of clinical outcome in the PRS.