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

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 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

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

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

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

Evidence of Slow Neural Processing, Developmental Differences and Sensitivity to Cannabis Effects in a Sample at Clinical High Risk for Psychosis From the NAPLS Consortium Assessed With the Human Startle Paradigm

Biomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals. Methods: Startle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35. Results: At 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR). Discussion: This is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants

Multiplexed suspension array platform for high-throughput protein assays

A multiplexed suspension array platform, based on SU8 disks patterned with machine-readable binary identification codes is presented. Multiple probe molecules, each attached to individual disks with different unique codes, provide multiplexed detection of targets in a small sample volume. The experimental system consists of a microfluidic chamber for arraying the particles in a manner suitable for high throughput imaging using a simple fluorescent microscope, together with custom software for automated code readout and analysis of assay response. The platform is demonstrated with a multiplexed antibody assay targeting 3 different human inflammatory cytokines. The suitability of the platform for other bio-analytical applications is discussed.<br/

Between-site reliability of startle prepulse inhibition across two early psychosis consortia

Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; however, between-site stability has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling participants studies were carried out as a part of quality assurance procedures to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) consortium, eight normal participants traveled to each of the eight NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy participants were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between-site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multisite studies, it is essential to institute quality assurance procedures early and establish between-site reliability to assure comparable data across sites

Water Penetration-Its Effect on the Strength and Toughness of Silica Glass

International audienceWhen a crack forms in silica glass, the surrounding environment flows into the crack opening, and water from the environment reacts with the glass to promote crack growth. A chemical reaction between water and the strained crack-tip bonds is commonly regarded as the cause of subcritical crack growth in glass. In silica glass, water can also have a secondary effect on crack growth. By penetrating into the glass, water generates a zone of swelling and, hence, creates a compression zone around the crack tip and on the newly formed fracture surfaces. This zone of compression acts as a fracture mechanics shield to the stresses at the crack tip, modifying both the strength and subcritical crack growth resistance of the glass. Water penetration is especially apparent in silica glass because of its low density and the fact that it contains no modifier ions. Using diffusion data from the literature, we show that the diffusion of water into silica glass can explain several significant experimental observations that have been reported on silica glass, including (1) the strengthening of silica glass by soaking the glass in water at elevated temperatures, (2) the observation of permanent crack face displacements near the crack tip of a silica specimen that had been soaked in water under load, and (3) the observation of high concentrations of water close to the fracture surfaces that had been formed in water. These effects are consistent with a model suggesting that crack growth in silica glass is modified by a physical swelling of the glass around the crack tip. An implication of water-induced swelling during fracture is that silica glass is more resistant to crack growth than it would be if swelling did not occur