Abstract Background: Social skills develop along with metacognitive abilities from early childhood through young adulthood. Impairment in metacognitive and other social cognitive abilities may contribute to poorer social function in clinical high risk for psychosis (CHR) adolescents. However, it is unclear whether social cognitive impairment represents developmental delay in skill acquisition or, rather, a consequence of emerging symptoms. Furthermore, it is unknown how early pharmacotherapy could influence this developmental trajectory. This study examined the hypotheses that (1) age-related trajectories of social cognition differ between CHR and normally developing youth and (2) age-related trajectories are partially explained by history of symptoms and psychotropic medication. Methods: Emotion perception, social perception, and theory of mind abilities were assessed in 675 CHR and 264 age-matched healthy comparison (HC) participants aged 12–35 (average = 19.0 ± 4.5 years). Linear and nonlinear curves were fit to relationships between social cognitive variables and age. Differences in age effects between CHR and HC were modeled as interaction terms. Duration of a prodromal syndrome prior to baseline and medication history were tested for interactions with age effects. Results: Emotion perception and social perception age trajectories did not differ by group. Theory of mind age trajectory, particularly for sarcasm items, had a lower slope for CHR than HC. CHR diverged from HC from mid-adolescence onward (starting to differ between approximately ages 15 and 17.5), with a minimum observation window of 4 years required to detect correlations with age. Age trajectory for theory of mind was unrelated to the presence or duration of a prior prodromal syndrome but did interact with medication history, wherein participants with an antipsychotic or antidepressant medication history did not differ from HCs. Only antipsychotic- and antidepressant-naive CHR participants showed a smaller slope for theory of mind, with differences from HC increasing with advanced age. Conclusion: In the current study, all social cognitive abilities increased during adolescence, but development of theory of mind appeared blunted for CHR participants starting in mid-adolescence. This difference, however, was only true for participants without an antipsychotic or antidepressant medication history, which could suggest benefits of early treatment or subgroups within CHR for whom social cognition is affected differently. These cross-sectional results require longitudinal replication and further inquiry into the relationships between treatment history and social cognitive development. Current results suggest that factors related to risk for psychosis may moderate adolescent social development, and that interventions targeting social cognition may be particularly helpful at this stage.

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.

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.

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.

Background

Clinical high risk (CHR) status is characterized by impairments in social cognition, but questions remain concerning their stability over development. In cross-sectional analysis of a large naturalistic sample, the current study examined whether those at CHR status show deviant trajectories for age-related change in social cognitive ability, and whether these trajectories are influenced by treatment history.

Method

Emotion perception (EP) and theory of mind (ToM) were assessed in 675 CHR and 263 healthy comparison (HC) participants aged 12-35. Age effects in CHR were modeled against HC age-expected performance. Prior medication status was tested for interactions with age.

Results

CHR exhibited normal age trajectory for EP, but significantly lower slopes for ToM from age 17 onward. This effect was specific to stimuli exhibiting sarcasm and not to detection of lies. When treatment history was included in the model, age-trajectory appeared normal in CHR subjects previously prescribed both antipsychotics and antidepressant medication, although the blunted trajectory still characterized 80% of the sample.

Discussion

Cross-sectional analyses suggested that blunting of ToM in CHR develops in adolescence, while EP abilities were diminished evenly across the age range. Exploratory analyses of treatment history suggested that ToM was not affected, however, in CHRs with lifetime histories of both antipsychotic and antidepressant medications. Reduction in age-expected ToM ability may impair the ability of individuals at CHR to meet social developmental challenges in adolescence. Medication effects on social cognition deserve further study.

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.

More than 20 years after the clinical high risk syndrome for psychosis (CHR) was first articulated, it remains controversial whether the CHR syndrome predicts onset of psychosis with diagnostic specificity or predicts pluripotential diagnostic outcomes. Recently, analyses of observational studies, however, have suggested that the CHR syndrome is not pluripotential for emergent diagnostic outcomes. The present report conducted additional analyses in previously reported samples to determine (1) whether comorbid disorders were more likely to persist in CHR patients compared to a comparison group of patients who responded to CHR recruitment efforts but did not meet criteria, termed help-seeking comparison subjects (HSC); and (2) whether clinically defined pluripotential CHR subgroups could be identified. All data were derived from 2 multisite studies in which DSM-IV structured diagnostic interviews were conducted at baseline and at 6-month intervals. Across samples we observed persistence of any nonpsychotic disorder in 80/147 CHR cases (54.4%) and in 48/84 HSC cases (57.1%, n.s.). Findings with persistence of anxiety, depressive, and bipolar disorders considered separately were similar. Efforts to discover pluripotential CHR subgroups were unsuccessful. These findings add additional support to the view that the CHR syndrome is not pluripotential for predicting various diagnostic outcomes but rather is specific for predicting emergent psychosis.

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.

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.