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.

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).

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.

Auditory and Visual Oddball Stimulus Processing Deficits in Schizophrenia and the Psychosis Risk Syndrome: Forecasting Psychosis Risk With P300.

Identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may improve clinical prediction in the psychosis risk syndrome (PRS) and help elucidate the pathogenesis of schizophrenia. Amplitude reduction of the P300 event-related potential component reflects attention-mediated processing deficits and is among the most replicated biological findings in schizophrenia, making it a candidate biomarker of psychosis risk. The relative extent to which deficits in P300 amplitudes elicited by auditory and visual oddball stimuli precede psychosis onset during the PRS and predict transition to psychosis, however, remains unclear. Forty-three individuals meeting PRS criteria, 19 schizophrenia patients, and 43 healthy control (HC) participants completed baseline electroencephalography recording during separate auditory and visual oddball tasks. Two subcomponents of P300 were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. Auditory and visual target P3b and novel P3a amplitudes were reduced in PRS and schizophrenia participants relative to HC participants. In addition, baseline auditory and visual target P3b, but not novel P3a, amplitudes were reduced in 15 PRS participants who later converted to psychosis, relative to 18 PRS non-converters who were followed for at least 22 months. Furthermore, target P3b amplitudes predicted time to psychosis onset among PRS participants. These results suggest that P300 amplitude deficits across auditory and visual modalities emerge early in the schizophrenia illness course and precede onset of full psychosis. Moreover, target P3b may represent an important neurophysiological vulnerability marker of the imminence of risk for psychosis.

Metabolic abnormalities and low dietary Omega 3 are associated with symptom severity and worse functioning prior to the onset of psychosis: Findings from the North American Prodrome Longitudinal Studies Consortium.

OBJECTIVE: Patients with schizophrenia have a high prevalence of metabolic disorders and cardiovascular mortality. It is possible that a vulnerability to metabolic abnormalities is associated with risk for psychosis, symptoms and functionality. In this study, we evaluate demographic information, cardiometabolic indices, symptoms and functioning in an antipsychotic free cohort at Clinical High Risk (CHR) for psychosis from the NAPLS Omega 3 fatty acid clinical trial. METHOD: Subjects received physical exams and metabolic monitoring prior to randomization into the Omega 3 versus Placebo trial. Anthropometrical measures, vital signs, glucose, and lipids were assessed along with symptoms, functioning, dietary Omega 3 fatty acids, erythrocyte polyunsaturated fatty acid content and a measure of lipid peroxidation (TBARS, Thiobarbituric acid-reactive substances). RESULTS: The sample included 113 CHR subjects (42.1% female; 17.5% Latino) ages 12-29. The mean BMI was 24.3 with a trend toward higher BMI and a higher incidence of metabolic syndrome in Latino subjects; 36% of the sample was obese/overweight; 37.6% met criteria for prehypertension/hypertension; 4.2% met criteria for prediabetes/diabetes; 9.6% showed evidence of insulin resistance and 44.7% had dyslipidemia. The TBARS was elevated at 9.8 µM ±â€¯6.1 (normal 1.86-3.94 µM). Metabolic parameters and a diet low in Omega 3 rich foods were significantly associated with prodromal symptoms and poor functioning. CONCLUSIONS: CHR subjects show a high percentage of metabolic abnormalities prior to exposure to antipsychotic medication. These findings reinforce that early detection of metabolic disturbances and food insecurity is crucial since these factors are modifiable with the potential for significant gains in terms of quality of life, physical and mental health.

Relation between cannabis use and subcortical volumes in people at clinical high risk of psychosis.

Among people at genetic risk of schizophrenia, those who use cannabis show smaller thalamic and hippocampal volumes. We evaluated this relationship in people at clinical high risk (CHR) of psychosis. The Alcohol and Drug Use Scale was used to identify 132 CHR cannabis users, the majority of whom were non-dependent cannabis users, 387 CHR non-users, and 204 healthy control non-users, and all participants completed magnetic resonance imaging scans. Volumes of the thalamus, hippocampus and amygdala were extracted with FreeSurfer, and compared across groups. Comparing all CHR participants with healthy control participants revealed no significant differences in volumes of any ROI. However, when comparing CHR users to CHR non-users, a significant ROI×Cannabis group effect emerged: CHR users showed significantly smaller amygdala compared to CHR non-users. However, when limiting analysis to CHR subjects who reported using alcohol at a 'use without impairment' severity level, the amygdala effect was non-significant; rather, smaller hippocampal volumes were seen in CHR cannabis users compared to non-users. Controlling statistically for effects of alcohol and tobacco use rendered all results non-significant. These results highlight the importance of controlling for residual confounding effects of other substance use when examining the relationship between cannabis use and neural structure.

Evaluating the impact of cannabis use on thalamic connectivity in youth at clinical high risk of psychosis.

BACKGROUND: Disruptions in thalamic functional connectivity have been observed in people with schizophrenia and in youth at clinical high risk (CHR) of psychosis. However, the impact of environmental risk factors for psychosis on thalamic dysconnectivity is poorly understood. We tested whether thalamic dysconnectivity is related to patterns of cannabis use in a CHR sample. METHODS: 162 CHR and 105 control participants were assessed on cannabis use severity, frequency, and age at onset of first use as part of the North American Prodrome Longitudinal Study and completed resting-state fMRI scans. Whole-brain thalamic functional connectivity maps were generated using individual subjects' anatomically defined thalamic seeds. RESULTS: Thalamic connectivity did not significantly correlate with current cannabis use severity or frequency in either CHR or controls. In CHR cannabis users, a significant correlation emerged between attenuated thalamic connectivity with left sensory/motor cortex and a younger age at onset of cannabis use. CHR who used cannabis before age 15 did not differ on thalamic connectivity as compared to CHR who used after age 15 or CHR who were cannabis naïve. No group differences in thalamic connectivity emerged when comparing CHR separated by moderate/high use frequency, low-frequency or cannabis naïve. CONCLUSIONS: Although a younger age at onset of cannabis use may be associated with disrupted thalamo-cortical coupling, cannabis use does not appear to be an identifying characteristic for thalamic connectivity in CHR with moderate/high use frequency compared to low-frequency users or CHR who are cannabis naïve.

Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk.

IMPORTANCE: Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness. OBJECTIVES: To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012. MAIN OUTCOMES AND MEASURES: Whole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging. RESULTS: Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10(-8), Spearman ρ = 0.27, P < 4.75 × 10(-5), 2-tailed). CONCLUSIONS AND RELEVANCE: Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.

Early auditory gamma-band responses in patients at clinical high risk for schizophrenia.

BACKGROUND: Gamma-band oscillations and their synchronization have been implicated in the coordination of activity between distributed neuronal assemblies in the service of sensory registration of stimuli and perceptual binding of their features. Prior electroencephalographic (EEG) studies of chronic schizophrenia patients have documented deficits in the magnitude and/or phase synchrony of stimulus-evoked gamma oscillations, findings that have been linked to neurotransmission abnormalities involving GABA and NMDA-glutamate receptors. However, it remains unclear whether these abnormalities are present at the onset of the illness, or indeed, whether they are present during the prodromal period preceding illness onset. Accordingly, we examined the magnitude and phase synchrony of the transient gamma-band response (GBR) elicited by an auditory stimulus in young patients with schizophrenia and in patients at clinical high risk for psychosis based on their manifestation of putatively prodromal symptoms. METHODS: EEG was recorded during an auditory oddball target detection task in three groups: young schizophrenia patients early in their illness (YSZ; n = 19), patients at clinical high risk for psychosis (CHR; n = 55), and healthy controls (HC; n = 42). Single-trial EEG epochs and the average event-related potential time-locked to standard tones from the oddball task were subjected to time-frequency decomposition using Morlet wavelet transformations. The GBR between 50 and 100 ms following the tone onset was quantified in terms of evoked power, total power, and the phase-locking factor (PLF) reflecting cross-trial phase synchrony. RESULTS: GBR evoked power was significantly reduced in YSZ (p < 0.01) and CHR (p < 0.05) patients, relative to HC. Similarly, GBR PLF was significantly reduced in YSZ (p < 0.01) and showed a marginal reduction in CHR patients (p = 0.057), relative to HC. GBR total power was not reduced in CHR patients (p = 0.68) and showed only a trend level reduction in YSZ (p = 0.072). Within the CHR group. there were no significant GBR differences between the patients who converted to a psychotic disorder and those who did not convert to psychosis during a 12-month follow-up period. CONCLUSION: Reductions in the transient auditory GBR, as reflected by evoked power and phase synchrony, are evident in the early stages of schizophrenia and appear to precede psychosis onset. However, the absence of total power GBR abnormalities in CHR patients, with only a trend toward reduction in YSZ patients, suggests that the magnitude of the GBR is intact early in the course

Glycine treatment of the risk syndrome for psychosis: report of two pilot studies.

Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium-to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.