Forecasting prognostic trajectories with mismatch negativity in early psychosis.

BACKGROUND: Prognostic heterogeneity in early psychosis patients yields significant difficulties in determining the degree and duration of early intervention; this heterogeneity highlights the need for prognostic biomarkers. Although mismatch negativity (MMN) has been widely studied across early phases of psychotic disorders, its potential as a common prognostic biomarker in early periods, such as clinical high risk (CHR) for psychosis and first-episode psychosis (FEP), has not been fully studied. METHODS: A total of 104 FEP patients, 102 CHR individuals, and 107 healthy controls (HCs) participated in baseline MMN recording. Clinical outcomes were assessed; 17 FEP patients were treatment resistant, 73 FEP patients were nonresistant, 56 CHR individuals were nonremitters (15 transitioned to a psychotic disorder), and 22 CHR subjects were remitters. Baseline MMN amplitudes were compared across clinical outcome groups and tested for utility prognostic biomarkers using binary logistic regression. RESULTS: MMN amplitudes were greatest in HCs, intermediate in CHR subjects, and smallest in FEP patients. In the clinical outcome groups, MMN amplitudes were reduced from the baseline in both FEP and CHR patients with poor prognostic trajectories. Reduced baseline MMN amplitudes were a significant predictor of later treatment resistance in FEP patients [Exp(ß) = 2.100, 95% confidence interval (CI) 1.104-3.993, p = 0.024] and nonremission in CHR individuals [Exp(ß) = 1.898, 95% CI 1.065-3.374, p = 0.030]. CONCLUSIONS: These findings suggest that MMN could be used as a common prognostic biomarker across early psychosis periods, which will aid clinical decisions for early intervention.

Prediction of psychosis: model development and internal validation of a personalized risk calculator.

BACKGROUND: Over the past two decades, early detection and early intervention in psychosis have become essential goals of psychiatry. However, clinical impressions are insufficient for predicting psychosis outcomes in clinical high-risk (CHR) individuals; a more rigorous and objective model is needed. This study aims to develop and internally validate a model for predicting the transition to psychosis within 10 years. METHODS: Two hundred and eight help-seeking individuals who fulfilled the CHR criteria were enrolled from the prospective, naturalistic cohort program for CHR at the Seoul Youth Clinic (SYC). The least absolute shrinkage and selection operator (LASSO)-penalized Cox regression was used to develop a predictive model for a psychotic transition. We performed k-means clustering and survival analysis to stratify the risk of psychosis. RESULTS: The predictive model, which includes clinical and cognitive variables, identified the following six baseline variables as important predictors: 1-year percentage decrease in the Global Assessment of Functioning score, IQ, California Verbal Learning Test score, Strange Stories test score, and scores in two domains of the Social Functioning Scale. The predictive model showed a cross-validated Harrell's C-index of 0.78 and identified three subclusters with significantly different risk levels. CONCLUSIONS: Overall, our predictive model showed a predictive ability and could facilitate a personalized therapeutic approach to different risks in high-risk individuals.

Impaired error-related processing in patients with first-episode psychosis and subjects at clinical high risk for psychosis: An event-related potential study.

AIM: Impaired event-related potential (ERP) indices reflecting performance-monitoring systems have been consistently reported in patients with schizophrenia. However, whether these impairments exist from the beginning of the early phase of psychosis, such as in first-episode psychosis (FEP) patients and individuals at clinical high risk (CHR) for psychosis, has not yet been clearly ascertained. METHODS: Thirty-seven FEP patients, 22 CHR subjects, and 22 healthy controls (HC) performed a visual go/no-go task so that three ERP components associated with performance monitoring-error-related negativity (ERN), correct response negativity (CRN), and error positivity (Pe) -could be assessed. Repeated-measures analysis of variance (ANOVA) with age and sex as covariates was used to compare ERN, CRN, and Pe across the groups. RESULTS: Repeated-measures ANOVA with age and sex as covariates revealed that compared with HC, FEP patients and CHR subjects showed significantly smaller ERN amplitudes at the Fz (F = 4.980, P = 0.009) and FCz (F = 3.453, P = 0.037) electrode sites. Neither CRN nor Pe amplitudes showed significant differences across the FEP, CHR, and HC groups. CONCLUSION: These findings suggest that performance monitoring is already compromised during the early course of psychotic disorders, evident in FEP patients and CHR subjects, as reflected in the reduced ERN amplitude. Considering these findings, ERN could serve as a potential indicator of early-stage psychosis.

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders.

Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex.

Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/-) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/- mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/-. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/- again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/- remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/- mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.

The effects of four days of intensive mindfulness meditation training (Templestay program) on resilience to stress: a randomized controlled trial.

The interest in mindfulness meditation interventions has surged due to their beneficial effects in fostering resilience and reducing stress in both clinical and non-clinical populations. However, the relaxation benefits that may occur while practicing mindfulness meditation and long-term benefits of these interventions remain unclear. Fifty-one participants were recruited and randomized into the experimental and control groups, which underwent 4 days of Intensive Meditation (Templestay program, n = 33) and Relaxation (Control, n = 18), respectively. The self-report measures of Cognitive and Affective Mindfulness Scale-Revised (CAMS) and the modified Korean version of the Resilience Quotient Test (RQT) were administered pre-, post- and 3 months after the intervention to measure participants' levels of mindfulness and resilience. Participants in both the Templestay program and Control groups showed significant increases in their scores on CAMS and RQT after completing the program. During the 3-month follow-up, a significant interaction effect of the intervention method and time was revealed for the individuals' CAMS and RQT scores. Our findings support the hypothesis that while relaxation practices may have certain stress reduction effects, the effects are predominantly mediated by the mindfulness meditation practice. Furthermore, the long-term benefits of increased resilience observed in the Templestay program group suggest that the practice may be a possible treatment strategy in clinical populations, such as patients with depression and anxiety.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high-risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design Setting and Participants: Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. Main Outcomes and Measures: For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores. Results: CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSA showed significant but weak associations (|ß|<0.09; PFDR<0.05) with positive symptoms and IQ. Conclusions and Relevance: The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

Thalamic Connectivity System Across Psychiatric Disorders: Current Status and Clinical Implications.

The thalamic connectivity system, with the thalamus as the central node, enables transmission of the brain's neural computations via extensive connections to cortical, subcortical, and cerebellar regions. Emerging reports suggest deficits in this system across multiple psychiatric disorders, making it a unique network of high translational and transdiagnostic utility in mapping neural alterations that potentially contribute to symptoms and disturbances in psychiatric patients. However, despite considerable research effort, it is still debated how this system contributes to psychiatric disorders. This review characterizes current knowledge regarding thalamic connectivity system deficits in psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder, across multiple levels of the system. We identify the presence of common and distinct patterns of deficits in the thalamic connectivity system in major psychiatric disorders and assess their nature and characteristics. Specifically, this review assembles evidence for the hypotheses of 1) thalamic microstructure, particularly in the mediodorsal nucleus, as a state marker of psychosis; 2) thalamo-prefrontal connectivity as a trait marker of psychosis; and 3) thalamo-somatosensory/parietal connectivity as a possible marker of general psychiatric illness. Furthermore, possible mechanisms contributing to thalamocortical dysconnectivity are explored. We discuss current views on the contributions of cerebellar-thalamic connectivity to the thalamic connectivity system and propose future studies to examine its effects at multiple levels, from the molecular (e.g., glutamatergic) to the behavioral (e.g., cognition), to gain a deeper understanding of the mechanisms that underlie the disturbances observed in psychiatric disorders.

Eye movement as a biomarker of impaired organizational strategies during visual memory encoding in obsessive-compulsive disorder.

The symptoms of obsessive-compulsive disorder (OCD) are largely related to impaired executive functioning due to frontostriatal dysfunction. To better treat OCD, the development of biomarkers to bridge the gap between the symptomatic-cognitive phenotype and brain abnormalities is warranted. Therefore, we aimed to identify biomarkers of impaired organizational strategies during visual encoding processes in OCD patients by developing an eye tracking-based Rey-Osterrieth complex figure test (RCFT). In 104 OCD patients and 114 healthy controls (HCs), eye movements were recorded during memorization of the RCFT figure, and organizational scores were evaluated. Kullback-Leibler divergence (KLD) scores were calculated to evaluate the distance between a participant's eye gaze distribution and a hypothetical uniform distribution within the RCFT figure. Narrower gaze distributions within the RCFT figure, which yielded higher KLD scores, indicated that the participant was more obsessed with detail and had less organizational strategy. The OCD patients showed lower organizational scores than the HCs. Although no group differences in KLD scores were noted, KLD scores were significantly associated with organization T scores in the OCD group. The current study findings suggest that eye tracking biomarkers of visual memory encoding provide a rapidly determined index of executive functioning, such as organizational strategies, in OCD patients.

Neurophysiological Correlate of Emotion Regulation by Cognitive Reappraisal and Its Association With Psychotic Symptoms in Early Psychosis.

BACKGROUND: Emotion dysregulation is crucial to both poor social functioning and psychotic symptom formation in patients with schizophrenia. The efficient use of emotion regulation strategies, such as cognitive reappraisal, has been less frequently observed in the early phases of psychotic disorder. It is unknown whether neurophysiological responses related to emotion regulation by cognitive reappraisal are altered in early psychosis. METHODS: Fifty-four patients with first-episode psychosis (FEP), 34 subjects at clinical high risk (CHR) for psychosis, and 30 healthy controls (HCs) participated in event-related potential recordings during a validated emotion regulation paradigm to measure the effect of cognitive reappraisal on emotion regulation. Late positive potentials (LPPs), which reflect emotional arousal, were compared across the groups and the 3 conditions (negative, cognitive reappraisal, and neutral). The relationship among LPP modulation by cognitive reappraisal and social/role functioning and severity of psychotic symptoms was investigated in the early psychosis group. RESULTS: The FEP and CHR participants showed comparably larger LPP amplitudes in the negative and cognitive reappraisal conditions than in the neutral condition, whereas the HCs presented larger LPPs in the negative condition than in the cognitive reappraisal and neutral conditions. LPP modulation by cognitive reappraisal was negatively correlated with positive symptom severity in the FEP patients and with disorganization severity in the CHR subjects. CONCLUSIONS: Inefficient use of cognitive reappraisal may be related to the impaired emotion regulation and psychotic symptoms from the very beginning of psychotic disorder. This study provides the first neurophysiological evidence regarding current concepts of emotion regulation in early psychosis.

Intact thalamic microstructure in asymptomatic relatives of schizophrenia patients with high genetic loading.

BACKGROUND: Disrupted thalamic connectivity system, which encompasses the deficits in the thalamus and thalamocortical connectivity, is regarded to contribute to the pathophysiology of schizophrenia. Recent reports suggest the possible genetic contribution to the disrupted thalamo-prefrontal connectivity, however, research on elucidating thalamic connectivity system components, specifically the thalamic nuclei, associated with the genetic predisposition to schizophrenia has been limited. Here, we investigated the genetic aspects of thalamic nuclei-specific microstructural integrities in schizophrenia. METHODS: A total of 34 asymptomatic relatives of schizophrenia patients with high genetic loading and 33 healthy control subjects underwent diffusion tensor imaging, diffusion kurtosis imaging, and T1-weighted magnetic resonance imaging. The thalamus was segmented via a connectivity-based segmentation method using the region-of-interest masks. The microstructural integrity of each thalamic nucleus, measured by averages of the diffusion kurtosis values, was then compared between the groups. RESULTS: The volumetric and mean kurtosis values of the thalamic nuclei were intact in asymptomatic relatives of schizophrenia patients with high genetic loading. CONCLUSIONS: Our results revealed that, in the thalamic connectivity system, the genetics may hold different weights of effects on different components, and that more is given on the thalamo-prefrontal connectivity than on the thalamus. Further, the current results may add further evidence to the current literature that thalamic nuclei microstructural abnormalities present in psychosis may have state marker characteristics.

White Matter Correlates of Theory of Mind in Patients With First-Episode Psychosis.

Deficits in theory of mind (ToM) are considered as a distinctive feature of schizophrenia. Functional magnetic resonance imaging (fMRI) studies have suggested that aberrant activity among the regions comprising the mentalizing network is related to observed ToM deficits. However, the white matter structures underlying the ToM functional network in schizophrenia remain unclear. To investigate the relationship between white matter integrity and ToM impairment, 35 patients with first-episode psychosis (FEP) and 29 matched healthy controls (HCs) underwent diffusion tensor imaging (DTI). Using tract-based spatial statistics (TBSS), fractional anisotropy (FA) values of the two regions of interest (ROI)-the cingulum and superior longitudinal fasciculus (SLF)-were acquired, and correlational analysis with ToM task scores was performed. Among the patients with FEP, ToM strange story scores were positively correlated with the FA values of the left cingulum and left SLF. There was no significant correlation between FA and ToM task scores in HCs. These results suggest that the left cingulum and SLF constitute a possible neural basis for ToM deficits in schizophrenia. Our study is the first to demonstrate the white matter connectivity underlying the mentalizing network, as well as its relation to ToM ability in patients with FEP.

Mapping thalamocortical functional connectivity with large-scale brain networks in patients with first-episode psychosis.

Abnormal thalamocortical networks involving specific thalamic nuclei have been implicated in schizophrenia pathophysiology. While comparable topography of anatomical and functional connectivity abnormalities has been reported in patients across illness stages, previous functional studies have been confined to anatomical pathways of thalamocortical networks. To address this issue, we incorporated large-scale brain network dynamics into examining thalamocortical functional connectivity. Forty patients with first-episode psychosis and forty healthy controls underwent T1-weighted and resting-state functional magnetic resonance imaging. Independent component analysis of voxelwise thalamic functional connectivity maps parcellated the cortex into thalamus-related networks, and thalamic subdivisions associated with these networks were delineated. Functional connectivity of (1) networks with the thalamus and (2) thalamic subdivision seeds were examined. In patients, functional connectivity of the salience network with the thalamus was decreased and localized to the ventrolateral (VL) and ventroposterior (VP) thalamus, while that of a network comprising the cerebellum, temporal and parietal regions was increased and localized to the mediodorsal (MD) thalamus. In patients, thalamic subdivision encompassing the VL and VP thalamus demonstrated hypoconnectivity and that encompassing the MD and pulvinar regions demonstrated hyperconnectivity. Our results extend the implications of disrupted thalamocortical networks involving specific thalamic nuclei to dysfunctional large-scale brain network dynamics in schizophrenia pathophysiology.

Reduced cortical gyrification in the posteromedial cortex in unaffected relatives of schizophrenia patients with high genetic loading.

Although abnormal cortical gyrification has been consistently reported in patients with schizophrenia, whether gyrification abnormalities reflect a genetic risk for the disorder remains unknown. This study investigated differences in cortical gyrification between unaffected relatives (URs) with high genetic loading for schizophrenia and healthy controls (HCs) to identify potential genetic vulnerability markers. A total of 50 URs of schizophrenia patients and 50 matched HCs underwent T1-weighted magnetic resonance imaging to compare whole-brain gyrification using the local gyrification index (lGI). Then, the lGI clusters showing significant differences were compared between the UR subgroups based on the number of first-degree relatives with schizophrenia to identify the effect of genetic loading on cortical gyrification changes. The URs exhibited significantly lower cortical gyrification than the HCs in clusters including medial parieto-occipital and cingulate regions comprising the bilateral precuneus, cuneus, pericalcarine, lingual, isthmus cingulate, and posterior cingulate gyri. Moreover, URs who had two or more first-degree relatives with schizophrenia showed greater gyrification reductions in these clusters than those who had at least one first-degree relative with schizophrenia. Our findings of reduced gyrification in URs, which are consistent with accumulated evidence of hypogyria observed in regions showing patient-control differences in previous studies, highlight that such hypogyria in posteromedial regions may serve as a genetic vulnerability marker and reflect early neurodevelopmental abnormalities resulting from a genetic risk for schizophrenia.

Auditory P300 as a Neurophysiological Correlate of Symptomatic Improvement by Transcranial Direct Current Stimulation in Patients With Schizophrenia: A Pilot Study.

Background. The reduced amplitude, prolonged latency, and increased intertrial variability of auditory P300 have been consistently reported in relation to the symptomatic severity of schizophrenia. This study investigated whether auditory P300 event-related potentials can be used as an objective indicator of symptomatic improvement by transcranial direct current stimulation (tDCS) in patients with schizophrenia. Methods. Ten patients with schizophrenia received 20 minutes of 2-mA tDCS twice a day for 5 consecutive weekdays. The anode was placed over the left dorsolateral prefrontal cortex, and the cathode was placed over the left temporo-parietal cortex. The Positive and Negative Syndrome Scale (PANSS) and the auditory P300 were measured for each participant at baseline and after the completion of the tDCS applications. Results. The participants showed significant improvement in the positive and negative symptoms as indexed by change in the PANSS scores by the tDCS. The P300 amplitude, latency, and intertrial variability did not statistically significantly differ after the tDCS application. However, a significant association was observed between the reduced P300 intertrial variability and improvement in the positive symptoms by tDCS. In addition, the changes in both the P300 latency and intertrial variability were significantly correlated with reduced negative symptoms after the tDCS application. Conclusions. Although this pilot study is limited by the small sample size and lack of a sham control, the results suggest that auditory P300 may be a putative marker reflecting the effect of tDCS on the positive and negative symptoms of schizophrenia.

Progressive Impairment of Mismatch Negativity Is Reflective of Underlying Pathophysiological Changes in Patients With First-Episode Psychosis.

BACKGROUND: Although mismatch negativity (MMN) is associated with the pathophysiology of schizophrenia, whether MMN progressively worsens during the initial years of psychotic disorder has not yet been sufficiently studied. We aimed to investigate whether longitudinal reduction of MMN occurs in patients with first-episode psychosis (FEP) and whether it is reflective of change in cognitive functioning or clinical status. METHODS: MMN and the clinical status of 25 patients with FEP were measured and the Trail Making Test (TMT) was administered at baseline and reassessed after 1 year of usual treatment. The MMN of 25 matched healthy controls (HCs) was measured at baseline. Repeated-measures analysis of variance was used to compare MMNs at baseline among the groups, and paired t-test was utilized to compare the baseline and 1-year MMN amplitudes of FEP patients. To identify the association between changes in MMN and changes in cognitive, symptomatic, or functional status over 1 year, multiple regression analysis was used to control for other possible confounders. RESULTS: MMN amplitudes at baseline were significantly attenuated in FEP patients compared to those in HC. The 1-year follow-up MMN amplitude decreased significantly at the Fz electrode site in the FEP group. Additionally, the decreased MMN amplitude significantly correlated with worsened TMT part B (TMT-B) performance over 1 year but did not correlate with symptomatic or functional improvement. CONCLUSIONS: FEP patients with an MMN amplitude reduction showed worsening of cognitive functioning, which might reflect pathophysiological progression during the early years of a psychotic episode.

Relationship between resting-state theta phase-gamma amplitude coupling and neurocognitive functioning in patients with first-episode psychosis.

BACKGROUND: Although cognitive dysfunction is a core element of schizophrenia, the neurobiological underpinnings of the pathophysiology are not yet sufficiently understood. Because the resting state is crucial for cognitive functioning and electroencephalography (EEG) can reflect instantaneous neural activity, we investigated theta phase-gamma amplitude coupling (TGC) of resting-state EEG and its relationship with cognitive function in patients with first-episode psychosis (FEP) to reveal the neural correlates of cognitive dysfunction. METHODS: A total of 59 FEP patients and 50 healthy controls (HCs) underwent resting-state, eyes-closed EEG recordings and performed the Trail Making Test Part A (TMT-A) and Part B (TMT-B) and California Verbal Learning Test (CVLT). TGC from the source signal of the resting-state EEG in default mode network (DMN)-related brain regions was compared between groups. Correlation analyses were performed between TGC and cognitive function test performance in FEP patients. RESULTS: Mean resting-state TGC was larger for the FEP patients than for the HCs. Patients with FEP showed increased TGC in the left posterior cingulate cortex, which was correlated with better performance on the TMT-A and TMT-B and on immediate and delayed recall in the CVLT. CONCLUSIONS: These results suggest that patients with FEP show compensatory hyperactivation of resting-state TGC in DMN-related brain regions, which may be related to the reallocation of cognitive resources to prepare for successful cognitive execution. This study not only highlights the neural underpinnings of cognitive dysfunction in FEP patients but also provides useful background to support the development of treatments for cognitive dysfunction in schizophrenia.

Impaired Performance on the Reading the Mind in the Eyes Test in First-Episode Psychosis and Clinical High Risk for Psychosis.

OBJECTIVE: Although previous studies have reported impaired performance in the reading the mind in the eyes test (RMET), which measures complex emotion recognition abilities, in patients with schizophrenia, reports regarding individuals at clinical high risk (CHR) for psychosis have been inconsistent, mainly due to the interacting confounding effects of general cognitive abilities and age. We compared RMET performances across first-episode psychosis (FEP) patients, CHR individuals, and healthy controls (HCs) while controlling for the effects of both general cognitive abilities and age. METHODS: A total of 25 FEP, 41 CHR, and 44 HC subjects matched for age participated in this study. RMET performance scores were compared across the groups using analysis of variance with sex and intelligence quotient as covariates. Exploratory Pearson's correlation analyses were performed to reveal the potential relationships of RMET scores with clinical symptom severity in the FEP and CHR groups. RESULTS: RMET performance scores were significantly lower among FEP and CHR participants than among HCs. FEP patients and CHR subjects showed comparable RMET performance scores. RMET scores were negatively correlated with Positive and Negative Syndrome Scale (PANSS) positive symptom subscale scores in the FEP patients. No significant correlation was identified between RMET scores and other clinical scale scores. CONCLUSION: Impaired RMET performance is present from the risk stage of psychosis, which might be related to positive symptom severity in early psychosis. Longitudinal studies are necessary to confirm the stability of complex emotion recognition impairments and their relationship with social functioning in early psychosis patients.

A pilot study investigating the effect of transcranial direct current stimulation on the electrophysiological correlates of working memory in patients with schizophrenia.

Transcranial direct current stimulation (tDCS) exerts pro-cognitive effects in various populations. We evaluated the effect of tDCS on cognitive performance and its electrophysiological correlates in schizophrenia patients. Ten participants received 10 sessions of tDCS and performed cognitive performance tasks; error-related negativity and correct response negativity (CRN) were measured before and after tDCS. Verbal performance was improved by tDCS and strongly correlated with a reduced CRN amplitude. Despite the lack of sham control design and possible practice effects of cognitive tasks, we might conclude that CRN could be a modifiable electrophysiological correlate of cognitive improvement by tDCS.