Activity In Schizophrenia Research Articles

Illness-related variables and abnormalities of resting-state brain activity in schizophrenia.

The development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain resting-state (rs)-activity with disease-related features. Sixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables. Attention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity. Neurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes.

Generalized Slowing of Resting-State Neural Oscillations in People With Schizophrenia

BackgroundRecent interest in how neural oscillations reflect the flow of information through the brain has led to partitioning electroencephalography (EEG) recordings into periodic (i.e., oscillatory) and aperiodic (i.e., nonoscillatory) components. While both contribute to conventional measures of power within the frequencies that compose EEG recordings, the periodic aspect characterizes true oscillations, the speed of which is thought to be critical to efficient functioning of neural systems. Given evidence of EEG power abnormalities in schizophrenia (SCZ), we sought to determine whether the periodic aspect of EEG was aberrant in people with SCZ and could serve as a general measure of brain efficiency. MethodsResting-state EEGs were gathered from 104 participants with SCZ and 105 healthy control participants. We used the FOOOF toolbox to remove aperiodic neural activity. We computed the cross-correlation between power spectra for individual participants and the mean power spectrum for all participants to quantify the relative speed of neural oscillations. ResultsPeriodic activity in SCZ was shifted toward lower frequencies than control participants during eyes-closed rest. On average, participants with SCZ had a 0.55-Hz shift toward oscillatory slowing across the frequency spectrum that predicted worse perceptual reasoning. Slower neural oscillations were associated with weaker perceptual reasoning in SCZ. ConclusionsSlowed periodic activity at rest is evident in SCZ and may represent inefficient functioning of neural circuits as reflected in worse perceptual reasoning. A slower pace of neural oscillations may be a general limitation on the transmission of information within the brain.

Effects of N-Methyl-d-Aspartate Receptor Antagonists on Gamma-Band Activity During Auditory Stimulation Compared With Electro/Magneto-encephalographic Data in Schizophrenia and Early-Stage Psychosis: A Systematic Review and Perspective.

N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity. This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis. The following gamma-band parameters were examined: (1) evoked spectral power, (2) intertrial phase coherence (ITPC), (3) induced spectral power, and (4) baseline power. Animal and human pharmacological data reported a reduction, especially for evoked gamma-band power and ITPC, as well as an increase and biphasic effects of gamma-band activity following NMDA-R antagonist administration. In addition, NMDA-R antagonists increased baseline gamma-band activity in preclinical studies. Reductions in ITPC and evoked gamma-band power were broadly compatible with findings observed in ScZ and early-stage psychosis patients where the majority of studies observed decreased gamma-band spectral power and ITPC. In regard to baseline gamma-band power, there were inconsistent findings. Finally, a publication bias was observed in studies investigating auditory gamma-band activity in ScZ patients. Our systematic review indicates that NMDA-R antagonists may partially recreate reductions in gamma-band spectral power and ITPC during auditory stimulation in ScZ. These findings are discussed in the context of current theories involving alteration in E/I balance and the role of NMDA hypofunction in the pathophysiology of ScZ.

Aberrant patterns of spontaneous brain activity in schizophrenia: A resting-state fMRI study and classification analysis

BackgroundSchizophrenia is a prevalent mental disorder, leading to severe disability. Currently, the absence of objective biomarkers hinders effective diagnosis. This study was conducted to explore the aberrant spontaneous brain activity and investigate the potential of abnormal brain indices as diagnostic biomarkers employing machine learning methods. MethodsA total of sixty-one schizophrenia patients and seventy demographically matched healthy controls were enrolled in this study. The static indices of resting-state functional magnetic resonance imaging (rs-fMRI) including amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated to evaluate spontaneous brain activity. Subsequently, a sliding-window method was then used to conduct temporal dynamic analysis. The comparison of static and dynamic rs-fMRI indices between the patient and control groups was conducted using a two-sample t-test. Finally, the machine learning analysis was applied to estimate the diagnostic value of abnormal indices of brain activity. ResultsSchizophrenia patients exhibited a significant increase ALFF value in inferior frontal gyrus, alongside significant decreases in fALFF values observed in left postcentral gyrus and right cerebellum posterior lobe. Pervasive aberrations in ReHo indices were observed among schizophrenia patients, particularly in frontal lobe and cerebellum. A noteworthy reduction in voxel-wise concordance of dynamic indices was observed across gray matter regions encompassing the bilateral frontal, parietal, occipital, temporal, and insular cortices. The classification analysis achieved the highest values for area under curve at 0.87 and accuracy at 81.28% when applying linear support vector machine and leveraging a combination of abnormal static and dynamic indices in the specified brain regions as features. ConclusionsThe static and dynamic indices of brain activity exhibited as potential neuroimaging biomarkers for the diagnosis of schizophrenia.

Lymphocyte level and selected cognitive functions in patients with schizophrenia – preliminary results

IntroductionSchizophrenia is a mental disorder characterized by negative symptoms, such as cognitive impairment. Recent reports indicate the importance of the immune system in the pathophysiology of schizophrenia. The development of inflammation affects cognitive functioning.ObjectivesThe aim of the study was to analyze the association between the level of lymphocytes in venous blood and selected cognitive functions in patients with schizophrenia.MethodsLymphocyte levels were determined in the venous blood of patients suffering from schizophrenia and the control group. Additionally, a verbal fluency test (VFT) and a Stroop test were conducted on the same day. The VFT evaluates the ability to express words, and the Stroop test assesses verbal working memory. The inclusion criteria were age up to fifty years, and for the study group – diagnosis of schizophrenia and treatment with neuroleptics. Exclusion criteria included organic brain diseases, electroconvulsive therapy, and use of benzodiazepines within 48 hours before the study. Currently, six patients and six healthy people have been studied.Results Patients diagnosed with schizophrenia have an increased lymphocyte concentration in the blood compared to healthy individuals constituting the control group. There are discrepancies in the results of the phonemic fluency test, no significant differences were found between schizophrenics and the control group. Healthy men and women achieved higher results in the semantic fluency test compared to men and women with schizophrenia. Women constituting the control group achieved higher results in the Stroop test compared to women suffering from schizophrenia. Table 1 illustrates the concentration of lymphocytes in venous blood and the number of points in the phonemic fluency test, semantic fluency test, and in the Stroop test of the study and the control groups.Image:Conclusions Patients with schizophrenia are characterized by higher levels of immune system parameters and worse results in terms of semantic fluency. Men with schizophrenia showed no verbal working memory deficits. In turn, women with schizophrenia obtained worse results in the verbal working memory test. In conclusion, there is evidence of immune system activation in schizophrenia, which affects the cognitive functioning of patients.Disclosure of InterestNone Declared

Multicausal disruption of complement system activity in schizophrenia: abnormal transcription of C4, complement control proteins and microglia specific genes in brain and blood

IntroductionThe synaptic pruning process is based on the joint action of the complement system and microglia. In schizophrenia, accumulating evidence support that abnormal synaptic pruning during adolescence may be due to an altered Complement system activity. While this hypothesis is supported by C4 overexpression in various brain regions of individuals with schizophrenia, such alterations should be replicated and extended to other brain regions. Moreover, transcriptional studies of genes encoding regulators of the complement system activity (complement control proteins, CCP) and microglia-specific genes are lacking. Furthermore, it remains unknown whether brain and peripheral expression of such genes are related.ObjectivesTo explore expression of C4 as well as 4 CCP encoding genes and 10 microglia-specific genes at the brain and peripheral levels in individuals with schizophrenia as compared to healthy controls.MethodsWe analyzed candidate gene expression from 9 Gene Expression Omnibus datasets obtained from 333 individuals with schizophrenia and 306 healthy controls (HC). We first compared expression of the candidate genes between individuals with schizophrenia and HC in postmortem brain samples from 7 different brain regions. Then, the same comparison was made in 4 different peripheral tissues.ResultsRegarding the complement system, we observed C4 overexpression in the DLPFC, parietal, temporal cortex and associative striatum of individuals with schizophrenia. We report distinct altered expression patterns of CCP genes in the DLPFC, hippocampus and cerebellum of individuals with schizophrenia. Only CD46 expression was altered in the blood of individuals with schizophrenia. Regarding microglia, we report an underexpression of several microglia-specific genes in the cerebellum, associative striatum, hippocampus and parietal cortex of individuals with schizophrenia vs. HC. At the peripheral level, we observed a mixed altered expression pattern in the whole blood of individuals with schizophrenia.ConclusionsFirstly, our results suggest that the CCP-mediated regulatory mechanisms of the Complement system are impaired in the brain of individuals with schizophrenia, potentially contributing to an excessive Complement system activity (CSA). Secondly, our results support the hypothesis of a widespread underexpression of microglia-specific genes in brain tissues of individuals with schizophrenia. Functionally, the observed transcriptional alterations may be related to the synaptic pruning impairment. Alternatively, they may translate a compensatory mechanism for neuroinflammation. In the whole blood, the altered transcriptional pattern may represent a potential peripheral signature of SZ.Disclosure of InterestNone Declared

Genetic contribution to microglial activation in schizophrenia

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia.

Previous electroencephalography (EEG) studies have indicated altered brain oscillatory α-band activity in schizophrenia, and treatment with repetitive transcranial magnetic stimulation (rTMS) using individualized α-frequency has shown therapeutic effects. Magnetic resonance imaging-based neuronavigation methods allow stimulation of a specific cortical region and improve targeting of rTMS; therefore, we sought to study the efficacy of navigated, individual α-peak-frequency-guided rTMS (αTMS) on treatment-refractory schizophrenia. We recruited medication-refractory male patients with schizophrenia or schizoaffective disorder in this doubleblind, sham-controlled study. We randomized patients to a 3-week course of either active αTMS or sham stimulation applied to the left dorsolateral prefrontal cortex (DLPFC). We assessed participants with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) at baseline and after treatment. We conducted a follow-up assessment with the PANSS 3 months after intervention. We included 44 patients. After treatment, we observed a significantly higher PANSS total score (p = 0.029), PANSS general psychopathology score (p = 0.027) and PANSS 5-factor model cognitive-disorganized factor score (p = 0.011) in the αTMS group than the sham group. In addition, the CGI-Improvement score was significantly higher among those who received αTMS compared with sham stimulation (p = 0.048). The limited number of study participants included only male patients. Depression was not formally evaluated. Navigated αTMS to the left DLPFC reduced total, general psychopathological, and cognitive-disorganized symptoms of schizophrenia. These results provide evidence for the therapeutic efficacy of individual α-peak-frequency-guided rTMS in treatment-refractory schizophrenia. NCT01941251; ClinicalTrials.gov.

Plasma exosomes carrying mmu-miR-146a-5p and Notch signalling pathway-mediated synaptic activity in schizophrenia.

Schizophrenia is characterized by a complex interplay of genetic and environmental factors, leading to alterations in various molecular pathways that may contribute to its pathogenesis. Recent studies have shown that exosomal microRNAs could play essential roles in various brain disorders; thus, we sought to explore the potential molecular mechanisms through which microRNAs in plasma exosomes are involved in schizophrenia. We obtained sequencing data sets (SUB12404730, SUB12422862, and SUB12421357) and transcriptome sequencing data sets (GSE111708, GSE108925, and GSE18981) from mouse models of schizophrenia using the Sequence Read Archive and the Gene Expression Omnibus databases, respectively. We performed differential expression analysis on mRNA to identify differentially expressed genes. We conducted Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to determine differentially expressed genes. Subsequently, we determined the intersection of differentially expressed microRNAs in plasma exosomes and in prefrontal cortex tissue. We retrieved downstream target genes of mmu-miR-146a-5p from TargetScan and used Cytoscape to visualize and map the microRNA-target gene regulatory network. We conducted in vivo experiments using MK-801-induced mouse schizophrenia models and in vitro experiments using cultured mouse neurons. The role of plasma exosomal miR-146a-5p in schizophrenia was validated using a cell counting kit, detection of lactate dehydrogenase, dual-luciferase assay, quantitative reverse transcription polymerase chain reaction, and Western blot analysis. Differential genes were mainly enriched in synaptic regulation-related functions and pathways and were associated with neuronal degeneration. We found that mmu-miR-146a-5p was highly expressed in both prefrontal cortical tissue and plasma exosomes, which may be transferred to lobe cortical vertebral neurons, leading to the synergistic dysregulation of gene network functions and, therefore, promoting schizophrenia development. We found that mmu-miR-146a-5p may inhibit the Notch signalling pathway-mediated synaptic activity of mouse pyramidal neurons in the lobe cortex by targeting NOTCH1, which in turn could promote the onset and development of schizophrenia in mice. The study's findings are based on animal models and in vitro experiments, which may not fully replicate the complexity of human schizophrenia. Our findings suggest that mmu-miR-146a-5p in plasma-derived exosomes may play an important role in the pathogenesis of schizophrenia. Our results provide new insights into the underlying molecular mechanisms of the disease.

Spectral decomposition of resting state electroencephalogram reveals unique theta/alpha activity in schizophrenia.

Resting state electroencephalographic (EEG) activity in schizophrenia (SZ) is frequently characterised by increased power at slow frequencies and/or a reduction of peak alpha frequency. Here we investigated the nature of these effects. As most studies to date have been limited by reliance on a priori frequency bands which impose an assumed structure on the data, we performed a data-driven analysis of resting EEG recorded in SZ patients and healthy controls (HC). The sample consisted of 39 chronic SZ and 36 matched HC. The EEG was recorded with a dense electrode array. Power spectral densities were decomposed via Varimax-rotated principal component analysis (PCA) over all participants and for each group separately. Spectral PCA was repeated at the cortical level on cortical current source density computed from standardised low resolution brain electromagnetic tomography. There was a trend for power in the theta/alpha range to be increased in SZ compared to HC, and peak alpha frequency was significantly reduced in SZ. PCA revealed that this frequency shift was because of the presence of a spectral component in the theta/alpha range (6-9 Hz) that was unique to SZ. The source distribution of the SZ > HC theta/alpha effect involved mainly prefrontal and parahippocampal areas. Abnormal low frequency resting EEG activity in SZ was accounted for by a unique theta/alpha oscillation. Other reports have described a similar phenomenon suggesting that the neural circuits oscillating in this range are relevant to SZ pathophysiology.

Temporal Dynamic Synchronous Functional Brain Network for Schizophrenia Classification and Lateralization Analysis.

Available evidence suggests that dynamic functional connectivity can capture time-varying abnormalities in brain activity in resting-state cerebral functional magnetic resonance imaging (rs-fMRI) data and has a natural advantage in uncovering mechanisms of abnormal brain activity in schizophrenia (SZ) patients. Hence, an advanced dynamic brain network analysis model called the temporal brain category graph convolutional network (Temporal-BCGCN) was employed. Firstly, a unique dynamic brain network analysis module, DSF-BrainNet, was designed to construct dynamic synchronization features. Subsequently, a revolutionary graph convolution method, TemporalConv, was proposed based on the synchronous temporal properties of features. Finally, the first modular test tool for abnormal hemispherical lateralization in deep learning based on rs-fMRI data, named CategoryPool, was proposed. This study was validated on COBRE and UCLA datasets and achieved 83.62% and 89.71% average accuracies, respectively, outperforming the baseline model and other state-of-the-art methods. The ablation results also demonstrate the advantages of TemporalConv over the traditional edge feature graph convolution approach and the improvement of CategoryPool over the classical graph pooling approach. Interestingly, this study showed that the lower-order perceptual system and higher-order network regions in the left hemisphere are more severely dysfunctional than in the right hemisphere in SZ, reaffirmings the importance of the left medial superior frontal gyrus in SZ. Our code was available at: https://github.com/swfen/Temporal-BCGCN.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

53 Working Memory Network Load Engagement in Schizophrenia

Objective:Cognitive deficits in patients diagnosed with schizophrenia are a core feature of the disorder. There are currently no treatments for these cognitive deficits. Our aim was to examine and compare patterns of increased versus decreased activity in the central executive network (CEN), salience network (SN), and default mode network (DMN) between healthy controls (HCs) and patients diagnosed with schizophrenia (SZs) as well as to explore the influence of task load on these networks between HCs and SZs.Participants and Methods:Analyses focused on a secondary dataset comprising Blood Oxygen-Level Dependent (BOLD) data collected from 25 HCs and 27 SZs who completed a working memory (WM) task (N-back) with 5 load conditions while undergoing functional magnetic resonance imaging (fMRI). Region of interest (ROI) data were analyzed using linear mixed-effects models.Results:Group activation differences were found in the posterior salience network (pSN), default mode network (DMN), dorsal default mode network (dDMN), and ventral default mode network (vDMN) showing greater activity for SZs. Specifically, pSN, DMN, dDMN, and vDMN all showed increased activity in SZs compared to HCs. The curve of brain activity was consistent between HCs and SZs with the exception of the vDMN, where HCs show greater activation at modest mental workload (quadratic curve) and SZs showed greater brain activation at lower mental workload (linear). In the CEN, there were no group differences, and the response curve was the same for both groups.Conclusions:These group differences demonstrate network difference between HCs and SZs and could show value in treatments targeting cognitive deficits in SZs from a large-scale brain network connectivity perspective. Future studies are needed to confirm these results with larger sample size in order to examine potential subtleties of interactions between these networks.

Terminal type-specific cannabinoid CB1 receptor alterations in patients with schizophrenia: A pilot study

BackgroundIndividuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types – a factor previously unaccounted for when examining CB1R changes in schizophrenia – may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia. MethodsUsing co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals (nine male pairs and one female pair) diagnosed with schizophrenia and non-psychiatric comparisons. ResultsSignificantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples. ConclusionGiven CB1R's role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.

Temporal imprecision and phase instability in schizophrenia resting state EEG

Schizophrenia is characterized by temporal imprecision and irregularities on neuronal, psychological cognitive, and behavioral levels which are usually tested during task-related activity. This leaves open whether analogous temporal imprecision and irregularities can already be observed in the brain's spontaneous activity as measured during the resting state; this is the goal of our study. Building on recent task-related data, we, using EEG, aimed to investigate the temporal precision and regularity of phase coherence over time in healthy, schizophrenia, and bipolar disorder participants. To this end, we developed a novel methodology, nominal frequency phase stability (NFPS), that allows to measure stability over phase angles in selected frequencies. By applying sample entropy quantification to the time-series of the nominal frequency phase angle time series, we found increased irregularities in theta activity over a frontocentral electrode in schizophrenia but not in bipolar disorder. We therefore assume that temporal imprecision and irregularity already occur in the brain's spontaneous activity in schizophrenia.

Paraoxonase/Arylesterase Activity of Serum Paraoxonase-1 and Schizophrenia: A Systematic Review and Meta-Analysis.

The presence of a pro-oxidant state in patients with schizophrenia may account for the increased risk of atherosclerosis and cardiovascular disease in this group and supports the potential utility of circulating biomarkers of oxidative stress for risk stratification and management. We investigated this issue by conducting a systematic review and meta-analysis of the association between the circulating concentrations of paraoxonase-1, an antioxidant calcium-dependent high-density lipoprotein (HDL)-associated esterase, with paraoxonase and arylesterase activity in schizophrenia. We searched electronic databases from inception to 31 May 2023 for studies investigating paraoxonase-1 in patients with schizophrenia and healthy controls and assessed the risk of bias and the certainty of evidence (PROSPERO registration number: CRD42023435442). Thirteen studies were identified for analysis. There were no significant between-group differences in paraoxonase (standard mean difference, SMD = 0.12, 95% CI -0.23 to 0.48, p = 0.50; extremely low certainty of evidence) or arylesterase activity (SMD = -0.08, 95% CI -0.39 to 0.23, p = 0.61; very low certainty of evidence). However, in meta-regression and subgroup analysis we observed significant associations between the SMD of paraoxonase and age (p = 0.003), HDL-cholesterol (p = 0.029), and study country (p = 0.04), and the SMD of arylesterase and age (p = 0.007), body mass index (p = 0.012), HDL-cholesterol (p = 0.002), and pharmacological treatment for schizophrenia (p < 0.001). In the absence of overall between-group differences, our systematic review and meta-analysis suggests that alterations in paraoxonase-1 may reflect a pro-oxidant state in specific subgroups of patients with schizophrenia that require further assessment in appropriately designed studies.

An fNIRS investigation of novel expressed emotion stimulations in schizophrenia

Living in high expressed emotion (EE) environments tends to increase the relapse rate in schizophrenia (SZ). At present, the neural substrates responsible for high EE in SZ remain poorly understood. Functional near-infrared spectroscopy (fNIRS) may be of great use to quantitatively assess cortical hemodynamics and elucidate the pathophysiology of psychiatric disorders. In this study, we designed novel low- (positivity and warmth) and high-EE (criticism, negative emotion, and hostility) stimulations, in the form of audio, to investigate cortical hemodynamics. We used fNIRS to measure hemodynamic signals while participants listened to the recorded audio. Healthy controls (HCs, n=42) showed increased hemodynamic activation in the major language centers across EE stimulations, with stronger activation in Wernicke’s area during the processing of negative emotional language. Compared to HCs, people with SZ (n=41) exhibited smaller hemodynamic activation in the major language centers across EE stimulations. In addition, people with SZ showed weaker or insignificant hemodynamic deactivation in the medial prefrontal cortex. Notably, hemodynamic activation in SZ was found to be negatively correlated with the negative syndrome scale score at high EE. Our findings suggest that the neural mechanisms in SZ are altered and disrupted, especially during negative emotional language processing. This supports the feasibility of using the designed EE stimulations to assess people who are vulnerable to high-EE environments, such as SZ. Furthermore, our findings provide preliminary evidence for future research on functional neuroimaging biomarkers for people with psychiatric disorders.

The altered network complexity of resting-state functional brain activity in schizophrenia and bipolar disorder patients

Schizophrenia (SZ) and bipolar disorder (BD) are two of the most frequent mental disorders. These disorders exhibit similar psychotic symptoms, making diagnosis challenging and leading to misdiagnosis. Yet, the network complexity changes driving spontaneous brain activity in SZ and BD patients are still unknown. Functional entropy (FE) is a novel way of measuring the dispersion (or spread) of functional connectivities inside the brain. The FE was utilized in this study to examine the network complexity of the resting-state fMRI data of SZ and BD patients at three levels, including global, modules, and nodes. At three levels, the FE of SZ and BD patients was considerably lower than that of normal control (NC). At the intra-module level, the FE of SZ was substantially higher than that of BD in the cingulo-opercular network. Moreover, a strong negative association between FE and clinical measures was discovered in patient groups. Finally, we classified using the FE features and attained an accuracy of 66.7% (BD vs. SZ vs. NC) and an accuracy of 75.0% (SZ vs. BD). These findings proposed that network connectivity’s complexity analyses using FE can provide important insights for the diagnosis of mental illness.

Multiple genes encoding mitochondrial ribosomes are downregulated in brain and blood samples of individuals with schizophrenia

Objectives Schizophrenia is a chronic, debilitating mental disorder whose pathophysiology is complex and not fully understood. Numerous studies suggest mitochondrial dysfunction may contribute to the development of schizophrenia. While mitochondrial ribosomes (mitoribosomes) are essential for proper mitochondrial functioning, their gene expression levels have not been studied yet in schizophrenia. Methods We performed a systematic meta-analysis of the expression of 81 mitoribosomes subunits encoding genes, integrating ten brain samples datasets of patients with schizophrenia compared to healthy controls (overall 422 samples, 211 schizophrenia, and 211 controls). We also performed a meta-analysis of their expression in blood, integrating two blood sample datasets (overall 90 samples, 53 schizophrenia, and 37 controls). Results Multiple mitoribosomes subunits were significantly downregulated in brain samples (18 genes) and in blood samples (11 genes) of individuals with schizophrenia, where two showed significant downregulation in both brain and blood, MRPL4 and MRPS7. Conclusions Our results support the accumulating evidence of impaired mitochondrial activity in schizophrenia. While further research is needed to validate mitoribosomes’ role as biomarkers, this direction has the potential to promote patients’ stratification and personalised treatment for schizophrenia.

Systematic Review of the Apomorphine Challenge Test in the Assessment of Dopaminergic Activity in Schizophrenia.

So far, neuroendocrine studies conducted in schizophrenic patients have yielded conflicting results. Many of these discrepancies may be explained by the diversity of factors that influence the hormonal levels (at baseline and in response to pharmacological stimuli), the heterogeneity of the populations studied, the absence of standardization of test challenges and the confounding and long-lasting effects of previous treatments. Numerous studies have used apomorphine (APO) in the evaluation of dopaminergic (DA) function in schizophrenic patients. APO, a direct acting DA receptor agonist, decreases prolactin (PRL) and stimulates growth hormone (GH), adrenocorticotropic hormone (ACTH) and cortisol secretion. Therefore, the magnitude of hormonal responses to APO is an indirect assessment of the functionality of DA receptors at the hypothalamic-pituitary level. This review provides an update on the applications of the APO test in schizophrenia in clinical, pathophysiological and therapeutic fields.