Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

An event-related potential study of prepotent motor activity and response inhibition deficits in schizophrenia.

Response inhibition deficits in schizophrenia (SZ) are accompanied by reduced neural activities using event-related potential (ERP) measurements. However, it remains unclear whether the reduction in inhibition-related ERPs in SZ is contingent upon prepotent motor tendencies. This study aimed to examine the relationship between ERP markers of prepotent motor activity (lateralised readiness potential, LRP) and response inhibition (P3) by collecting behavioural and EEG data from healthy control (HC) subjects and SZ patients during a modified Go/No-Go task. A trial-averaged analysis revealed that SZ patients made more commission errors in No-Go trials compared with HC subjects, although there was no significant difference in the inhibition-related P3 effect (i.e. larger P3 amplitudes in No-Go compared with Go trials) between the two groups. Subsequently, No-Go trials were sorted and median-split into bins of stronger and weaker motor tendencies. Both HC and SZ participants made more commission errors when faced with stronger motor tendencies. The LRP-sorted P3 data indicated that HC subjects exhibited larger P3 effects in response to stronger motor tendencies, whereas this trial-by-trial association between P3 and motor tendencies was absent in SZ patients. Furthermore, SZ patients displayed diminished P3 effects in No-Go trials with stronger motor tendencies but not in trials with weaker motor tendencies, relative to HC subjects. Taken together, these findings suggest that SZ patients are unable to dynamically adjust inhibition-related neural activities in response to changing inhibitory control demands and emphasise the importance of considering prepotent motor activity when investigating the neural mechanisms underlying response inhibition deficits in SZ.

Models of mild cognitive deficits in risk assessment in early psychosis.

BACKGROUND: Mild cognitive deficits (MCD) emerge before the first episode of psychosis (FEP) and persist in the clinical high-risk (CHR) stage. This study aims to refine risk prediction by developing MCD models optimized for specific early psychosis stages and target populations. METHODS: A comprehensive neuropsychological battery assessed 1059 individuals with FEP, 794 CHR, and 774 matched healthy controls (HCs). CHR subjects, followed up for 2 years, were categorized into converters (CHR-C) and non-converters (CHR-NC). The MATRICS Consensus Cognitive Battery standardized neurocognitive tests were employed. RESULTS: Both the CHR and FEP groups exhibited significantly poorer performance compared to the HC group across all neurocognitive tests (all p < 0.001). The CHR-C group demonstrated poorer performance compared to the CHR-NC group on three sub-tests: visuospatial memory (p < 0.001), mazes (p = 0.005), and symbol coding (p = 0.023) tests. Upon adjusting for sex and age, the performance of the MCD model was excellent in differentiating FEP from HC, as evidenced by an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.895 (p < 0.001). However, when applied in the CHR group for predicting CHR-C (AUC = 0.581, p = 0.008), the performance was not satisfactory. To optimize the efficiency of psychotic risk assessment, three distinct MCD models were developed to distinguish FEP from HC, predict CHR-C from CHR-NC, and identify CHR from HC, achieving accuracies of 89.3%, 65.6%, and 80.2%, respectively. CONCLUSIONS: The MCD exhibits variations in domains, patterns, and weights across different stages of early psychosis and diverse target populations. Emphasizing precise risk assessment, our findings highlight the importance of tailored MCD models for different stages and risk levels.

Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for adolescent and adult Tlymphoblastic leukemia /lymphoma: a large cohort multicenter study in China.

T lymphoblastic leukemia /lymphoma (T-ALL/LBL) is a rare and highly aggressive neoplasm of lymphoblasts. We evaluated 195 T-ALL/LBL adolescent and adult patients who received ALL-type chemotherapy alone (chemo,n = 72) or in combination with autologous hematopoietic stem cell transplantation(auto-HSCT,n = 23) or allogeneic hematopoietic stem cell transplantation(allo-HSCT,n = 100) from January 2006 to September 2020 in three Chinese medical centers. 167 (85.6%) patients achieved overall response (ORR) with 138 complete response (CR) patients (70.8%) and 29 partial response (PR) patients (14.8%). Until October 1, 2023, no difference was found in 5-year overall survival (5-OS) and 5-year progression free survival(5-PFS) between allo-HSCT and auto-HSCT (5-OS 57.9% vs. 36.7%, P = 0.139, 5-year PFS 49.4% vs. 28.6%, P = 0.078) for patients who achieved CR, for patients who achieved PR, allo-HSCT recipients had higher 5-OS compared with chemo alone recipients (5-OS 23.8% vs. 0, P = 0.042). For patients undergoing allo-HSCT, minimal residual disease (MRD) negative population showed better 5-OS survival compared with MRD positive patients (67.8% vs. 19.6%, p = 0.000). There were no significant differences between early T-cell precursor (ETP), NON-ETP patients with or without expression of one or more myeloid-associated or stem cell-associated (M/S+) markers (NON-ETP with M/S+, NON-ETP without M/S+) groups in allo-HSCT population for 5-OS. (62.9% vs. 54.5% vs.48.4%, P > 0.05). Notch mutations were more common in patients with non-relapsed/refractory disease than relapsed/refractory disease (χ² =4.293, P = 0.038). In conclusion, Allo-HSCT could be an effective consolidation therapy not just for patients with CR, but also for those who achieved PR. The prognosis is significantly improved by obtaining MRD negative prior to allogeneic transplantation.

Correlative relationship between body mass index and heart rate variability in psychiatric disorders.

OBJECTIVE: Indicators of heart rate variability (HRV) have been used to assess the autonomic activity. However, the influence of obesity on HRV in these patients remains to be determined. This study aimed to examine how obesity (measured with the body mass index [BMI]) affects HRV and determine whether the effect varies among different psychiatric disorders. We recruited 3159 consecutive patients, including 1744 with schizophrenia, 966 with mood disorders, and 449 with anxiety disorders. Patients were divided into four groups based on BMI: underweight (< 18.5), normal weight (18.5-23.9), overweight (24-27.9), and obese (≥ 28). The cardiovascular status was assessed using several time- and frequency-based HRV indicators, measured via electrocardiogram signals recorded for 5 min. The mean BMI of the participants was 23.6 ± 4.0. The patients in the overweight and obese groups were 29.4% and 13.6% of the total, respectively. The HRV indicators were higher in underweight and normal-weight patients than in the overweight and obese ones. After stratification based on the psychiatric diagnosis, the patients with mood disorders showed lower HRV than those with schizophrenia or anxiety disorder in the normal-weight group. In contrast, in the overweight and obese groups the patients with mood disorders showed higher HRV than those with the other disorders. The HRV variables were significantly associated with BMI, and higher BMI was associated with higher heart rates and lower HRV. These results indicate that weight gain in psychiatric disorders is associated with an imbalance in autonomic nerve activity. However, the relationship between autonomic activity, weight gain, and psychiatric disorders warrants further investigation.

Association between serum cytokines and timeframe for conversion from clinical high-risk to psychosis.

AIM: Although many studies have explored the link between inflammatory markers and psychosis, there is a paucity of research investigating the temporal progression in individuals at clinical high-risk (CHR) who eventually develop full psychosis. To address this gap, we investigated the correlation between serum cytokine levels and Timeframe for Conversion to Psychosis (TCP) in individuals with CHR. METHODS: We enrolled 53 individuals with CHR who completed a 5-year follow-up with a confirmed conversion to psychosis. Granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-1ß, 2, 6, 8, 10, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) levels were measured at baseline and 1-year. Correlation and quantile regression analyses were performed. RESULTS: The median TCP duration was 14 months. A significantly shorter TCP was associated with higher levels of TNF-α (P = 0.022) and VEGF (P = 0.016). A negative correlation was observed between TCP and TNF-α level (P = 0.006) and VEGF level (P = 0.04). Quantile regression indicated negative associations between TCP and GM-CSF levels below the 0.5 quantile, IL-10 levels below the 0.3 quantile, IL-2 levels below the 0.25 quantile, IL-6 levels between the 0.65 and 0.75 quantiles, TNF-α levels below the 0.8 quantile, and VEGF levels below the 0.7 quantile. A mixed linear effects model identified significant time effects for IL-10 and IL-2, and significant group effects for changes in IL-2 and TNF-α. CONCLUSIONS: Our findings underscore that a more pronounced baseline inflammatory state is associated with faster progression of psychosis in individuals with CHR. This highlights the importance of considering individual inflammatory profiles during early intervention and of tailoring preventive measures for risk profiles.

Does Electroencephalography Seizure Duration Account for an Adequate Treatment of Magnetic Seizure Therapy for Schizophrenia?

OBJECTIVES: A seizure lasting >15 s has been considered to indicate treatment for magnetic seizure therapy (MST), a modification of electroconvulsive therapy (ECT), without much validation. This study aimed to investigate whether this seizure duration was suitable for the treatment of schizophrenia. METHODS: Altogether, 34 and 33 in-patients with schizophrenia received 10 sessions of MST and ECT, respectively. Clinical symptoms were assessed using the Positive and Negative Symptom Scale at baseline and at the 4-week follow-up. Electroencephalogram (EEG) was monitored during each MST or ECT treatment using bifrontal electrodes. RESULTS: The proportion of participants who achieved the 15-second threshold was only 28.6% in the MST group, with a significant difference between responders and nonresponders. For patients receiving MST, the average EEG seizure duration correlated with the percentage of Positive and Negative Symptom Scale reduction (t(32) = 2.51, P = 0.017, uncorrected; t(32) = 2.00, P = 0.055, corrected with clinical characteristics). The average EEG seizure duration predicted the clinical response at a trend level (Z = 1.76, P = 0.078) with an optimal cutoff of 11.3 seconds. All patients in the ECT group achieved the 15-second threshold. However, their average EEG seizure duration was uncorrelated with clinical improvement. CONCLUSIONS: The duration of EEG seizures may be associated with the antipsychotic effects of MST. This association may have been influenced by various clinical and technical factors. More research is needed to define the specific criteria for adequate MST in schizophrenia in order to achieve personalized dosing.

Effects of polygenic risk of schizophrenia on interhemispheric callosal white matter integrity and frontotemporal functional connectivity in first-episode schizophrenia.

BACKGROUND: Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported. METHODS: Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts. RESULTS: Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)-left inferior temporal gyrus (ITG), right IFG-left ITG, right IFG-left middle frontal gyrus (MFG), and right IFG-right MFG in the FES group. CONCLUSION: Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.

Serum angioneurin levels following electroconvulsive therapy for mood disorders.

OBJECTIVES: The efficacy of electroconvulsive therapy (ECT) in treating mood disorders (MDs) is hypothesized to be mediated by the induction of neurotrophic factors (denoted "angioneurins") that trigger neuronal plasticity. This study aimed to assess the effects of ECT on serum angioneurin levels in patients with MD. METHODS: A total of 110 patients with MDs including 30 with unipolar depression, 25 with bipolar depression (BD), 55 with bipolar mania (BM), and 50 healthy controls were included in the study. Patients were subdivided into two groups: those who received ECT + medication (12 ECT sessions) and those who received only medication (no-ECT). Depressive and manic symptom assessments and measurements of vascular endothelial growth factor (VEGF), fibroblast growth factor-2, nerve growth factor (NGF), and insulin-like growth factor-1 levels in blood samples were performed at baseline and week 8. RESULTS: Patients in the ECT group, specifically those with BD and BM, had significantly increased levels of VEGF compared to their baseline VEGF levels (p = 0.002). No significant changes in angioneurin levels were observed in the no-ECT group. Serum NGF levels were significantly associated with a reduction in depressive symptoms. Angioneurin levels were not associated with manic symptom reduction. CONCLUSIONS: This study hints that ECT may increase VEGF levels with angiogenic mechanisms that amplify NGF signaling to promote neurogenesis. It may also contribute to changes in brain function and emotional regulation. However, further animal experiments and clinical validation are needed.

Changes in Inflammatory Markers in Clinical High Risk of Developing Psychosis.

INTRODUCTION: Immune alterations are associated with the progression of psychosis. However, there are few studies designed to longitudinally measure inflammatory biomarkers during psychotic episodes. We aimed to assess changes in biomarkers from the prodromal phase to psychotic episodes in individuals with clinical high risk (CHR) of psychosis and compare converters and non-converters to psychosis as well as healthy controls (HCs). METHODS: We enrolled 394 individuals with CHR and 100 HCs. A total of 263 individuals with CHR completed the 1-year follow-up, and 47 had converted to psychosis. Interleukin (IL)-1ß, 2, 6, 8, 10, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor levels were measured at baseline and 1 year after completion of the clinical assessment. RESULTS: The baseline serum levels of IL-10, IL-2, and IL-6 were significantly lower in the conversion group than in the non-conversion group (IL-10, p = 0.010; IL-2, p = 0.023; IL-6, p = 0.012) and HC (IL-6: p = 0.034). Self-controlled comparisons showed that IL-2 changed significantly (p = 0.028), and IL-6 levels tended toward significance (p = 0.088) in the conversion group. In the non-conversion group, serum levels of TNF-α (p = 0.017) and VEGF (p = 0.037) changed significantly. Repeated measures analysis of variance revealed a significant time effect related to TNF-α (F = 4.502, p = 0.037, effect size (η2) = 0.051), a group effect related to IL-1ß (F = 4.590, p = 0.036, η2 = 0.062), and IL-2 (F = 7.521, p = 0.011, η2 = 0.212), but no time × group effect. DISCUSSION: Alterations in the serum levels of inflammatory cytokines were found to precede the first episode of psychosis in the CHR population, particularly for those who later converted to psychosis. Longitudinal analysis supports the varied roles of cytokines in individuals with CHR with later psychotic conversion or non-conversion outcomes.

Attenuated niacin response is associated with a subtype of first-episode drug-naïve psychosis characterized as serious negative symptoms.

Although the phenomenon of attenuated niacin response (ANR) has been widely replicated in some patients with first-episode psychosis (FEP), its relevance to the negative symptoms (NS) of psychosis remains unclear. Total of 240 patients with drug-naïve FEP and 101 healthy controls (HCs) were recruited, and 209 were followed up for 1 year. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and niacin-induced responses were measured using laser Doppler flowmetry. We calculated the log-transform EC50 [concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response] and MBF values. Core-NS was generated by factor analysis of the PANSS-NS subscale and cluster analysis to produce subtypes. Significant differences were found in the log10 (EC50) values between the FEP and HC groups (p < 0.001), supporting the ANR in patients with FEP. A higher NS severity was found in the ANR subgroup than that in other patients. Factor analysis determined that a two-dimensional model included core NS and rigidity of thinking. The log10 (EC50) value was significantly associated with only the core NS. Cluster analysis revealed three subtypes-36.7% (cluster-1, n = 88), 16.7% (cluster-2, n = 40), and 46.7% (cluster-3, n = 112). Cluster-2 characterized by extensive NS appeared to have a more remarkable ANR and less symptomatic improvement than those with other clusters during follow-up. No significant changes were found in the niacin response trajectories between the baseline and follow-up. Our findings indicate a significant correlation between ANR and core NS in patients with FEP. ANR may be a potential biomarker for certain subtypes with NS-dominated characteristics and poor symptomatic remission.

Eye movement indices as predictors of conversion to psychosis in individuals at clinical high risk.

Eye movement abnormalities have been established as an "endophenotype" of schizophrenia. However, less is known about the possibility of these abnormalities as biomarkers for psychosis conversion among clinical high risk (CHR) populations. In the present study, 108 CHR individuals and 70 healthy controls (HC) underwent clinical assessments and eye-tracking tests, comprising fixation stability and free-viewing tasks. According to three-year follow-up outcomes, CHR participants were further stratified into CHR-converter (CHR-C; n = 21) and CHR-nonconverter (CHR-NC; n = 87) subgroups. Prediction models were constructed using Cox regression and logistic regression. The CHR-C group showed more saccades of the fixation stability test (no distractor) and a reduced saccade amplitude of the free-viewing test than HC. Moreover, the CHR-NC group exhibited excessive saccades and an increased saccade amplitude of the fixation stability test (no distractor; with distractor) compared with HC. Furthermore, two indices could effectively discriminate CHR-C from CHR-NC with an area under the receiver-operating characteristic (ROC) curve of 0.80, including the saccade number of the fixation stability test (no distractor) and the saccade amplitude of the free-viewing test. Combined with negative symptom scores of the Scale of Prodromal Symptoms, the area was 0.81. These findings support that eye movement alterations might emerge before the onset of clinically overt psychosis and could assist in predicting psychosis transition among CHR populations.

Magnetic seizure therapy for people with schizophrenia.

BACKGROUND: Schizophrenia is one of the most common and disabling mental disorders. About 20% of people with schizophrenia do not respond to antipsychotics, which are the mainstay of the treatment for schizophrenia today, and need to seek other treatment options. Magnetic seizure therapy (MST) is one of the novel non-invasive brain stimulation techniques that are being investigated in recent years.  OBJECTIVES: To evaluate the efficacy and tolerability of MST for people with schizophrenia. SEARCH METHODS: On 6 March 2022, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on CENTRAL, CINAHL, ClinicalTrials.Gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed, and WHO ICTRP. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing MST alone or plus standard care with ECT or any other interventions for people with schizophrenia.  DATA COLLECTION AND ANALYSIS: We performed reference screening, study selection, data extraction and risk of bias and quality assessment in duplicate. We calculated the risk ratios (RRs) and their 95% confidence intervals (CIs) for binary outcomes and the mean difference (MD) and their 95% CIs for continuous outcomes. We used the original risk of bias tool for risk of bias assessment and created a Summary of findings table using GRADE. MAIN RESULTS: We included one four-week study with 79 adults in acute schizophrenia, comparing MST plus standard care to ECT plus standard care in this review. We rated the overall risk of bias as high due to high risk of bias in the domains of selective reporting and other biases (early termination and baseline imbalance) and unclear risk of bias in the domain of blinding of participants and personnel. We found that MST and ECT may not differ in improving the global state (n = 79, risk ratio (RR) 1.12, 95% confidence interval (CI) 0.73 to 1.70), overall (n = 79, mean difference (MD) -0.20, 95% CI -8.08 to 7.68), the positive symptoms (n = 79, MD 1.40, 95% CI -1.97 to 4.77) and the negative symptoms (n = 79, MD -1.00, 95% CI -3.85 to 1.85) in people with schizophrenia.  We found  that MST compared to ECT may cause less delayed memory deficit and less cognitive deterioration (n = 79, number of people with a delayed memory deficit, RR 0.63, 95% CI 0.41 to 0.96; n = 79, mean change in global cognitive function, MD 5.80, 95% CI 0.80 to 10.80), but also may improve more cognitive function (n = 47, number of people with any cognitive improvement, RR 3.30, 95% CI 1.29 to 8.47).  We found that there may be no difference between the two groups in terms of leaving the study early due to any reason (n = 79, RR 2.51, 95% CI 0.73 to 8.59), due to adverse effects (n = 79, RR 3.35, 95% CI 0.39 to 28.64) or due to inefficacy (n = 79, RR 2.52, 95% CI 0.11 to 60.10).  Since all findings were based on one study with high risk of bias and the confidence in the evidence was very low, we were not sure these comparable or favourable effects of MST over ECT were its true effects.  AUTHORS' CONCLUSIONS: Due to the paucity of data, we cannot draw any conclusion on the efficacy and tolerability of MST for people with schizophrenia. Well-designed RCTs are warranted to answer the question.

Random Matrix Transformation and Its Application in Image Hiding.

Image coding technology has become an indispensable technology in the field of modern information. With the vigorous development of the big data era, information security has received more attention. Image steganography is an important method of image encoding and hiding, and how to protect information security with this technology is worth studying. Using a basis of mathematical modeling, this paper makes innovations not only in improving the theoretical system of kernel function but also in constructing a random matrix to establish an information-hiding scheme. By using the random matrix as the reference matrix for secret-information steganography, due to the characteristics of the random matrix, the secret information set to be retrieved is very small, reducing the modification range of the steganography image and improving the steganography image quality and efficiency. This scheme can maintain the steganography image quality with a PSNR of 49.95 dB and steganography of 1.5 bits per pixel and can ensure that the steganography efficiency is improved by reducing the steganography set. In order to adapt to different steganography requirements and improve the steganography ability of the steganography schemes, this paper also proposes an adaptive large-capacity information-hiding scheme based on the random matrix. In this scheme, a method of expanding the random matrix is proposed, which can generate a corresponding random matrix according to different steganography capacity requirements to achieve the corresponding secret-information steganography. Two schemes are demonstrated through simulation experiments as well as an analysis of the steganography efficiency, steganography image quality, and steganography capacity and security. The experimental results show that the latter two schemes are better than the first two in terms of steganography capacity and steganography image quality.

From Receptive to Perceptive Fields: Size-Dependent Asymmetries in Both Negative Afterimages and Subcortical On and Off Post-Stimulus Responses.

Negative afterimages are perceptual phenomena that occur after physical stimuli disappear from sight. Their origin is linked to transient post-stimulus responses of visual neurons. The receptive fields (RFs) of these subcortical ON- and OFF-center neurons exhibit antagonistic interactions between central and surrounding visual space, resulting in selectivity for stimulus polarity and size. These two features are closely intertwined, yet their relationship to negative afterimage perception remains unknown. Here we tested whether size differentially affects the perception of bright and dark negative afterimages in humans of both sexes, and how this correlates with neural mechanisms in subcortical ON and OFF cells. Psychophysically, we found a size-dependent asymmetry whereby dark disks produce stronger and longer-lasting negative afterimages than bright disks of equal contrast at sizes >0.8°. Neurophysiological recordings from retinal and relay cells in female cat dorsal lateral geniculate nucleus showed that subcortical ON cells exhibited stronger sustained post-stimulus responses to dark disks, than OFF cells to bright disks, at sizes >1°. These sizes agree with the emergence of center-surround antagonism, revealing stronger suppression to opposite-polarity stimuli for OFF versus ON cells, particularly in dorsal lateral geniculate nucleus. Using a network-based retino-geniculate model, we confirmed stronger antagonism and temporal transience for OFF-cell post-stimulus rebound responses. A V1 population model demonstrated that both strength and duration asymmetries can be propagated to downstream cortical areas. Our results demonstrate how size-dependent antagonism impacts both the neuronal post-stimulus response and the resulting afterimage percepts, thereby supporting the idea of perceptual RFs reflecting the underlying neuronal RF organization of single cells.SIGNIFICANCE STATEMENT Visual illusions occur when sensory inputs and perceptual outcomes do not match, and provide a valuable tool to understand transformations from neural to perceptual responses. A classic example are negative afterimages that remain visible after a stimulus is removed from view. Such perceptions are linked to responses in early visual neurons, yet the details remain poorly understood. Combining human psychophysics, neurophysiological recordings in cats and retino-thalamo-cortical computational modeling, our study reveals how stimulus size and the receptive-field structure of subcortical ON and OFF cells contributes to the parallel asymmetries between neural and perceptual responses to bright versus dark afterimages. Thus, this work provides a deeper link from the underlying neural mechanisms to the resultant perceptual outcomes.

Automatic auditory processing features in distinct subtypes of patients at clinical high risk for psychosis: Forecasting remission with mismatch negativity.

Individuals at clinical high risk (CHR) for psychosis exhibit a compromised mismatch negativity (MMN) response, which indicates dysfunction of pre-attentive deviance processing. Event-related potential and time-frequency (TF) information, in combination with clinical and cognitive profiles, may provide insight into the pathophysiology and psychopathology of the CHR stage and predict the prognosis of CHR individuals. A total of 92 individuals with CHR were recruited and followed up regularly for up to 3 years. Individuals with CHR were classified into three clinical subtypes demonstrated previously, specifically 28 from Cluster 1 (characterized by extensive negative symptoms and cognitive deficits), 31 from Cluster 2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 33 from Cluster 3 (characterized by the mildest symptoms and cognitive deficits). Auditory MMN to frequency and duration deviants was assessed. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired using TF analysis. Predictive indices for remission were identified using logistic regression analyses. As expected, reduced frequency MMN (fMMN) and duration MMN (dMMN) responses were noted in Cluster 1 relative to the other two clusters. In the TF analysis, Cluster 1 showed decreased theta and alpha ITC in response to deviant stimuli. The regression analyses revealed that dMMN latency and alpha ERSP to duration deviants, theta ITC to frequency deviants and alpha ERSP to frequency deviants, and fMMN latency were significant MMN predictors of remission for the three clusters. MMN variables outperformed behavioral variables in predicting remission of Clusters 1 and 2. Our findings indicate relatively disrupted automatic auditory processing in a certain CHR subtype and a close affinity between these electrophysiological indexes and clinical profiles within different clusters. Furthermore, MMN indexes may serve as predictors of subsequent remission from the CHR state. These findings suggest that the auditory MMN response is a potential neurophysiological marker for distinct clinical subtypes of CHR.

Resolving heterogeneity in schizophrenia through a novel systems approach to brain structure: individualized structural covariance network analysis.

Reliable mapping of system-level individual differences is a critical first step toward precision medicine for complex disorders such as schizophrenia. Disrupted structural covariance indicates a system-level brain maturational disruption in schizophrenia. However, most studies examine structural covariance at the group level. This prevents subject-level inferences. Here, we introduce a Network Template Perturbation approach to construct individual differential structural covariance network (IDSCN) using regional gray-matter volume. IDSCN quantifies how structural covariance between two nodes in a patient deviates from the normative covariance in healthy subjects. We analyzed T1 images from 1287 subjects, including 107 first-episode (drug-naive) patients and 71 controls in the discovery datasets and established robustness in 213 first-episode (drug-naive), 294 chronic, 99 clinical high-risk patients, and 494 controls from the replication datasets. Patients with schizophrenia were highly variable in their altered structural covariance edges; the number of altered edges was related to severity of hallucinations. Despite this variability, a subset of covariance edges, including the left hippocampus-bilateral putamen/globus pallidus edges, clustered patients into two distinct subgroups with opposing changes in covariance compared to controls, and significant differences in their anxiety and depression scores. These subgroup differences were stable across all seven datasets with meaningful genetic associations and functional annotation for the affected edges. We conclude that the underlying physiology of affective symptoms in schizophrenia involves the hippocampus and putamen/pallidum, predates disease onset, and is sufficiently consistent to resolve morphological heterogeneity throughout the illness course. The two schizophrenia subgroups identified thus have implications for the nosology and clinical treatment.

The D2R-DISC1 protein complex and associated proteins are altered in schizophrenia and normalized with antipsychotic treatment.

BACKGROUND: For decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 (DISC1) is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia. METHODS: We used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples. RESULTS: Levels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment. LIMITATIONS: Sample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands. CONCLUSION: Levels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia.

Further evidence that antipsychotic medication does not prevent long-term psychosis in higher-risk individuals.

OBJECTIVE: Although existing guidelines have discouraged use of antipsychotics for general clinical high-risk (CHR) individuals, it is unclear if antipsychotics can prevent psychosis in higher-risk population. We aimed to study the comparative real-world effectiveness of antipsychotic treatments for preventing psychosis in higher-risk CHR individuals. METHODS: A total of 300 CHR individuals were identified using the structured interview for prodromal syndromes (SIPS) and followed the participants for 3 years. In total, 228(76.0%) individuals completed baseline assessments using the NAPLS-2 risk calculator (NAPLS-2-RC), and 210(92.1%) completed the follow-up. The sample was further stratified according to risk level. "Higher-risk" was defined based on the NAPLS-2-RC risk score (≥ 20%) and SIPS positive symptom total scores (≥ 10). The main outcome was conversion to psychosis and poor functional outcomes, defined as a global assessment of function (GAF) score lower than 60 at follow-up. RESULTS: In higher-risk CHR individuals, we found no significant difference in the rate of conversion to psychosis or poor functional outcomes between the antipsychotic and no-antipsychotic groups. Low-risk individuals treated with antipsychotic drugs were more likely exhibit poor functional outcomes compared with the no-antipsychotics group(NAPLS-2-RC estimated risk: χ2 = 8.330, p = 0.004; Positive symptom severity: χ2 = 12.997, p < 0.001). No significant effective factors were identified for prevention of the conversion to psychosis; conversely, CHR individuals who were treated with high dose antipsychotics (olanzapine, aripiprazole) showed a significantly increased risk of poor functional outcomes. CONCLUSIONS: In CHR individuals, antipsychotic treatment should be provided with caution because of the risk of poor functional outcomes. Further, antipsychotic treatment does not appear to prevent onset of psychosis in real-world settings.

Temporal and time-frequency features of auditory oddball response in distinct subtypes of patients at clinical high risk for psychosis.

Individuals at clinical high risk (CHR) for psychosis exhibit a reduced P300 oddball response, which indicates deficits in attention and working memory processes. Previous studies have mainly researched these responses in the temporal domain; hence, non-phase-locked or induced neural activities may have been ignored. Event-related potential (ERP) and time-frequency (TF) information, combined with clinical and cognitive profiles, may provide an insight into the pathophysiology and psychopathology of the CHR stage. The 104 CHR individuals who completed cognitive assessments and ERP tests were recruited and followed up between 2016 and 2018. Individuals with CHR were classified by three clinical subtypes demonstrated before, specifically 32 from Cluster-1 (characterized by extensive negative symptoms and cognitive deficits, at the highest risk for conversion to psychosis), 34 from Cluster-2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 38 from Cluster-3 (characterized by the mildest symptoms and cognitive deficits). Electroencephalograms were recorded during the auditory oddball paradigm. The P300 ERPs were analyzed in the temporal domain. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired by TF analysis. A reduced P300 response to target tones was noted in Cluster-1 relative to the other two clusters. Moreover, the P300 amplitude of Cluster-1 was associated with speed of processing (SoP) scores. Furthermore, the P300 amplitude of Cluster-3 was significantly correlated with verbal and visual learning scores. In the TF analysis, decreased delta ERSP and ITC were observed in Cluster-1; delta ITC was associated with SoP scores in Cluster-3. The results indicate relatively disrupted oddball responses in a certain CHR subtype and a close affinity between these electrophysiological indexes and attention, working memory, and declarative memory within different CHR clusters. These findings suggest that the auditory oddball response is a potential neurophysiological marker for distinct clinical subtypes of CHR.