Search

BackgroundAdolescence/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.MethodsAn 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.ResultsInput-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.ConclusionsInput-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.

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.

ObjectiveTo 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.MethodsReliability 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.ResultsG-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.ConclusionsEEG preprocessing methods have an impact on the reliability of MMN amplitude. Within site MMN reliability can be excellent, consistent with prior single site studies.SignificanceWith standardized data collection and ERP processing, MMN can be reliably obtained in multisite studies, providing larger samples sizeswithin rare patient groups.

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).

ObjectivesMismatch 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.MethodsStability 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.ResultsAge 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.ConclusionMMN amplitude is stable and can be standardized to facilitate longitudinal multisite studies of patients and clinical features.

Abstract: Background: Clinical outcomes vary among young people with the psychosis risk syndrome (PRS), with approximately 20% of individuals progressing to a psychotic disorder over 2–3 years and 30% achieving clinical remission. The identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may enhance the accuracy of clinical outcome prediction in the PRS and help elucidate the pathogenic mechanisms of psychosis onset. Auditory P300 event-related potential (ERP) component amplitude reductions are well established in schizophrenia and reflect early attention-mediated information processing deficits. Recent studies employing auditory oddball tasks have shown that P300 amplitude deficits in PRS individuals are associated with later clinical outcomes, including both conversion to full-blown psychosis and remission from the at-risk state. The present study examined whether these effects extend to P300 in the visual modality using visual oddball task data collected as part of the North American Prodrome Longitudinal Study. Specifically, we evaluated whether visual P300 amplitudes are reduced in the PRS and predict future clinical outcomes. Methods: 540 individuals meeting PRS criteria and 229 healthy individuals completed baseline EEG recording during a visual oddball task. Visual P300 subcomponents were measured in response to two stimulus types: (1) infrequent target stimuli, reflecting top-down allocation of attention (target P3b), and (2) infrequent non-target novel distractor stimuli, reflecting bottom-up orienting of attention (novelty P3a). P300 amplitudes of PRS participants who converted to psychosis (n=70) were compared with those of PRS non-converters who were followed clinically for 24 months and continued to be symptomatic (n=131) or fully remitted from the PRS (n=87). Results: Group comparison effects did not differ by stimulus type. Visual P300 amplitudes were not significantly reduced in the PRS group relative to healthy individuals (p=.25). However, baseline target P3b and novelty P3a amplitudes were reduced in PRS individuals who later converted to psychosis relative to all PRS non-converters, including those who remitted (p=.006, d=.44) and those who remained symptomatic (p=.015, d=.37), as well as healthy individuals (p=.001, d=.44). Baseline P300 amplitudes were similar among healthy controls, PRS remitters, and PRS individuals who remained symptomatic (ps>.45). Moreover, visual P300 amplitudes differentiated future psychosis converters after accounting for PRS symptom severity. Finally, both target P3b and novelty P3a amplitudes predicted the time to psychosis onset in PRS participants (p=.03 and p=.02, respectively), such that more deficient P300 amplitudes were associated with shorter time to conversion. Discussion: Baseline visual P300 amplitudes were reduced in future PRS converters relative to non-converters, with effect sizes comparable to those reported in previous auditory P300 studies of the PRS. Results implicate visual P300 as a neurophysiological vulnerability marker that predicts clinical outcomes among PRS individuals, including future transition to psychosis. Accordingly, together with prior auditory P300 studies, results suggest that P300 may have the potential to contribute to personalized early intervention in the PRS by distinguishing individuals with the greatest risk for psychotic illness, who require the most aggressive treatment, from those who may need minimal intervention.

AbstractBiomarkers 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.MethodsStartle 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.ResultsAt 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).DiscussionThis 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.

Abstract Background Individuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-). Methods Clinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality. Results In line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p

Abstract Background: Reductions in the auditory P300 event-related potential (ERP) component are well established in schizophrenia and reflect early attention-mediated auditory processing deficits. Two subcomponents of P300 are evident depending on oddball task conditions; P3b is elicited by infrequent target stimuli and reflects top-down attention allocation, whereas P3a is elicited by infrequent non-target novel distractor stimuli and reflects bottom-up orienting of attention. The present study examined whether auditory P300 abnormalities precede illness onset and are associated with future clinical status by assessing both target P3b and novel P3a in individuals at clinical high risk for psychosis (CHR) and healthy controls (HC) collected as part of the North American Prodrome Longitudinal Study. Methods: CHR (n = 552) and HC (n = 235) participants completed baseline EEG recording during an auditory oddball task. CHR participants were further categorized by clinical status after 24 months of study participation (n = 298) and included a subgroup who transitioned to psychosis (CHR-Transition; n = 73), a subgroup who did not transition but remained symptomatic (CHR-Symptomatic; n = 135), and a subgroup who did not transition and was in symptom remission (CHR-Remission; n = 90). Results: CHR participants had reduced target P3b and novel P3a amplitudes relative to HC (Ps < .001). There was also an effect of 24-month clinical status group on both P3b and P3a amplitudes (P < .001 and P = .006, respectively). Planned contrasts revealed that compared to HC, CHR participants had smaller target P3b amplitudes at baseline (P < .001). In addition, CHR-Transition participants had attenuated P3b amplitudes at baseline relative to all CHR participants who did not transition to psychosis (P = .037). Furthermore, both CHR-Transition and CHR-Symptomatic had smaller P3b amplitudes than both HC (Ps < .001) and CHR-Remission (P = .003 and P = .005, respectively), while P3b of CHR-Remission did not differ from HC at baseline (P > .05). In contrast, although CHR participants also had smaller novel P3a amplitudes than HC at baseline (P < .001), P3a did not differentiate CHR-Transition participants from CHR participants who did not transition within 24 months (P > .05). Despite CHR-Transition and CHR-Symptomatic having smaller P3a amplitudes than HC (P = .028 and P = .002, respectively), they did not differ from CHR-Remission (Ps > .05) at baseline. Moreover, target P3b predicted the time to psychosis onset in CHR participants over and above novel P3a amplitude (P = .024). Conclusion: Both target P3b and novel P3a are reduced in individuals identified to be at risk for developing a psychotic disorder, and P3b in particular appears sensitive to future transition to psychosis. Given this association with clinical outcomes, results implicate target P3b as a neurophysiological vulnerability marker for psychosis.

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.