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BACKGROUND: Neurochemical dysregulations resulting from N-methyl-D-aspartate hypofunction (NMDA), are exacerbated by neuroimmune and oxidative stress and are known risk factors for neuropsychiatric disorders like schizophrenia-like diseases. Here, we investigate the protective and curative effects, and mechanisms of silymarin, a polyphenolic flavonoid with neuroprotective functions in preventive-reversal model of ketamine, an NMDA antagonist in mice. METHODS: Mice were grouped into 6 cohorts (n = 9). In the pre-treatment, groups 1 and 2 received saline (10 mL/kg/p.o.), groups 3 and 4 (silymarin, 50 and 100 mg/kg/p.o.), and group 5 (risperidone, 0.5 mg/kg/p.o.) consecutively for 14 days, then combined with ketamine (20 mg/kg/i.p.) injection in groups 2-5 from days 8-14. However, mice in reversal study received intraperitoneal injection of ketamine for 14 days before silymarin (50 and 100 mg/kg, p.o) and risperidone (0.5 mg/kg, p.o.) treatment between days 8-14. The consequences on schizophrenia-like behavior, neurochemistry, inflammation, and oxidative/nitrergic stress markers were evaluated in critical brain regions of the disease. RESULTS: Silymarin prevented and reversed ketamine-induced increase in dopamine, 5-hydroxyltryptamine, acetylcholinesterase, malondialdehyde and nitrite levels in the striatum, prefrontal-cortex and hippocampus. These were accompanied by improvement in hyperlocomotion, stereotypy, memory, and social impairments, notably devoid of cataleptogenic potential. Complementarily, silymarin reduced myeloperoxidase, tumor-necrosis factor-α, and interleukin-6 concentrations relative to the ketamine group. Moreover, ketamine-induced decreased brain-derived neurotrophic factor, glutathione, catalase, superoxide-dismutase levels were normalized by silymarin in the brain regions relative to ketamine. CONCLUSIONS: Overall, these findings suggest that silymarin's antipsychotic effect might be primarily associated, among other mechanisms, with the normalization of neurochemical and neurotrophic changes in the mice brains.

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Introduction: Schizophrenia is a mental health condition that severely impacts well-being. Cognitive impairment is among its core features, often presenting well before the onset of overt psychosis, underscoring a critical need to study it in the psychosis proneness (clinical high risk; CHR) stage, to maximize the benefits of interventions and to improve clinical outcomes. However, given the heterogeneity of cognitive impairment in this population, a one-size-fits-all approach to therapeutic interventions would likely be insufficient. Thus, identifying cognitive subtypes in this population is crucial for tailored and successful therapeutic interventions. Here we identify, validate, and characterize cognitive subtypes in large CHR samples and delineate their baseline and longitudinal cognitive and functional trajectories. Methods: Using machine learning, we performed cluster analysis on cognitive measures in a large sample of CHR youth (n = 764), and demographically comparable controls (HC; n = 280) from the North American Prodrome Longitudinal Study (NAPLS) 2, and independently validated our findings with an equally large sample (NAPLS 3; n = 628 CHR, 84 HC). By utilizing several statistical approaches, we compared the clusters on cognition and functioning at baseline, and over 24 months of followup. We further delineate the conversion status within those clusters. Results: Two main cognitive clusters were identified, "impaired" and "intact" across all cognitive domains in CHR compared to HC. Baseline differences between the cognitively intact cluster and HC were found in the verbal abilities and attention and working memory domains. Longitudinally, those in the cognitively impaired cluster group demonstrated an overall floor effect and did not deteriorate further over time. However, a "catch up" trajectory was observed in the attention and working memory domain. This group had higher instances of conversion overall, with these converters having significantly more non-affective psychotic disorder diagnosis versus bipolar disorder, than those with intact cognition. In the cognitively intact group, we observed differences in trajectory based on conversion status, where those who start with intact cognition and later convert demonstrate a sharp decline in attention and functioning. Functioning was significantly better in the cognitively intact than in the impaired group at baseline. Most of the cognitive trajectories demonstrate a positive relationship with functional ones. Conclusion: Our findings provide evidence for intact and impaired cognitive subtypes in youth at CHR, independent of conversion status. They further indicate that attention and working memory are important to distinguish between the CHR with intact cognition and controls. The cognitively intact CHR group becomes less attentive after conversion, while the cognitively impaired one demonstrates a catch up trajectory on both attention and working memory. Overall, early evaluation, covering several cognitive domains, is crucial for identifying trajectories of improvement and deterioration for the purpose of tailoring intervention for improving outcomes in individuals at CHR for psychosis.

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BACKGROUND: The profiles of cortical gyrification across schizophrenia, bipolar I disorder, and schizoaffective disorder have been studied to a limited extent, report discordant findings, and are rarely compared in the same study. Here we assess gyrification in a large dataset of psychotic disorder probands, categorized according to the DSM-IV. Furthermore, we explore gyrification changes with age across healthy controls and probands. METHODS: Participants were recruited within the Bipolar-Schizophrenia Network of Intermediate Phenotypes study and received T1-MPRAGE and clinical assessment. Gyrification was measured using FreeSurfer 7.1.0. Pairwise t-tests were conducted in R, and age-related gyrification changes were analyzed in MATLAB. P values <0.05 after false discovery rate correction were considered significant. RESULTS: Significant hypogyria in schizophrenia, bipolar disorder, and schizoaffective disorder probands compared to controls was found, with a significant difference bilaterally in the frontal lobe between schizophrenia and bipolar disorder probands. Verbal memory was associated with gyrification in the right frontal and right cingulate cortex in schizophrenia. Age-fitted gyrification curves differed significantly among psychotic disorders and controls. CONCLUSIONS: Findings indicate hypogyria in DSM-IV psychotic disorders compared to controls and suggest differential patterns of gyrification across the different diagnoses. The study extends age related models of gyrification to psychotic disorder probands and supports that age-related differences in gyrification may differ across diagnoses. Fitted gyrification curves among probands categorized by DSM-IV significantly deviate from controls, with the model capturing early hypergyria and later hypogyria in schizophrenia compared to controls; this suggests unique disease and age-related changes in gyrification across psychotic disorders.

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Brain aging, which involves a progressive loss of neuronal functions, has been reported to be premature in probands affected by schizophrenia (SCZ). Evidence shows that SCZ and accelerated aging are linked to changes in epigenetic clocks. Recent cross-sectional magnetic resonance imaging analyses have uncovered reduced brain reserves and connectivity in patients with SCZ compared to typically aging individuals. These data may indicate early abnormalities of neuronal function following cyto-architectural alterations in SCZ. The current mechanistic knowledge on brain aging, epigenetic changes, and their neuropsychiatric disease association remains incomplete. With this review, we explore and summarize evidence that the dynamics of gut-resident bacteria can modulate molecular brain function and contribute to age-related neurodegenerative disorders. It is known that environmental factors such as mode of birth, dietary habits, stress, pollution, and infections can modulate the microbiota system to regulate intrinsic neuronal activity and brain reserves through the vagus nerve and enteric nervous system. Microbiota-derived molecules can trigger continuous activation of the microglial sensome, groups of receptors and proteins that permit microglia to remodel the brain neurochemistry based on complex environmental activities. This remodeling causes aberrant brain plasticity as early as fetal developmental stages, and after the onset of first-episode psychosis. In the central nervous system, microglia, the resident immune surveillance cells, are involved in neurogenesis, phagocytosis of synapses and neurological dysfunction. Here, we review recent emerging experimental and clinical evidence regarding the gut-brain microglia axis involvement in SCZ pathology and etiology, the hypothesis of brain reserve and accelerated aging induced by dietary habits, stress, pollution, infections, and other factors. We also include in our review the possibilities and consequences of gut dysbiosis activities on microglial function and dysfunction, together with the effects of antipsychotics on the gut microbiome: therapeutic and adverse effects, role of fecal microbiota transplant and psychobiotics on microglial sensomes, brain reserves and SCZ-derived accelerated aging. We end the review with suggestions that may be applicable to the clinical setting. For example, we propose that psychobiotics might contribute to antipsychotic-induced therapeutic benefits or adverse effects, as well as reduce the aging process through the gut-brain microglia axis. Overall, we hope that this review will help increase the understanding of SCZ pathogenesis as related to chronobiology and the gut microbiome, as well as reveal new concepts that will serve as novel treatment targets for SCZ.

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BACKGROUND: Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier psychosis onset; but their interaction in relation to psychosis risk and association with endocannabinoid-receptor rich brain regions, i.e. the hippocampus (HP), remains unclear. The objective was to determine whether lower age of psychosis onset (AgePsyOnset) is associated with CA and CT through mediation by the HP volumes, and genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS). METHODS: Cross-sectional, case-control, multicenter sample from 5 metropolitan US regions. Participants (n = 1185) included 397 controls not affected by psychosis (HC); 209 participants with bipolar disorder type-1; 279 with schizoaffective disorder; and 300 with schizophrenia (DSM IV-TR). CT was assessed using the Childhood Trauma Questionnaire (CTQ); CA was assessed by self-reports and trained clinical interviewers. Assessment included neuroimaging, symptomatology, cognition and calculation of the SZ polygenic risk score (SZ-PGRS). RESULTS: In survival analysis, CT and CA exposure interact to be associated with lower AgePsyOnset. At high CT or CA, CT or CA are individually sufficient to affect AgePsyOnset. CT relation with AgePsyOnset is mediated in part by the HP in CA users before AgePsyOnset. CA before AgePsyOnset is associated with higher SZ-PGRS and correlated with younger age at CA usage. DISCUSSION: CA and CT interact to increase risk when moderate; while severe CT and/or CA abuse/dependence are each sufficient to affect AgePsyOnset, indicating a ceiling effect. Probands with/out CA before AgePsyOnset differ on biological variables, suggesting divergent pathways to psychosis. FUNDING: MH077945; MH096942; MH096913; MH077862; MH103368; MH096900; MH122759.

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The study presented here aims at bringing a global perspective to the phenomenon of unequal representation of females in science by offering empirical data of female representation in neuroscience/schizophrenia academic or clinical departments in several institutions around the world. We took advantage of a budding network of scientists and colleagues from different countries to bring the data together. The data presented are related to sex, that is the biological distinction between males and females, based on genetics and reproductive anatomy, while gender, considered a cultural concept was harder to determine. We report data from two clinical/academic departments in Nigeria, Africa; 2 clinical/academic departments from Sudan, Africa; 1 clinical/academic department from South Africa, Africa; 3 academic institutions from Ireland, Europe; 1 clinical/academic institution from Spain, Europe; 2 academic institutions from Buenos Aires University, Argentina; and the Psychiatry Departments at Harvard Medical School, Boston, USA.

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The 22q11.2 deletion syndrome (22q11DS) is a developmental genetic syndrome associated with a 30% risk for developing schizophrenia. Lateral ventricles and subcortical structures are abnormal in this syndrome as well as in schizophrenia. Here, we investigated whether these structures are related in young adults with 22q11DS with and without prodromal symptoms (PS) for schizophrenia and whether abnormalities in volumes are associated with global functioning. MR images were acquired on a 3T scanner from 51 individuals with 22q11DS and 30 healthy controls (mean age: 21±2 years). Correlations were performed to evaluate the relationship between ventricular and subcortical volumes, with Global Assessment of Functioning (GAF) and Premorbid Adjustment Scale (PAS) in each group. Lateral ventricular volumes correlated negatively with subcortical volumes in individuals with 22q11DS. In individuals with 22q11DS with PS only, GAF correlated positively with volumes of the lateral ventricles and negatively with subcortical volumes. PAS correlated negatively with lateral ventricle volumes, and positively with volumes of subcortical structures. The results suggest a common neurodevelopmental mechanism related to the growth of these brain structures. Further, the ratio between the volumes and clinical measures could potentially be used to characterize individuals with 22q11DS and those from the general population for the risk of the development of schizophrenia.

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OBJECTIVE: To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC). METHODS: Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained. RESULTS: CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters. CONCLUSIONS: These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions.

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AIM: We previously reported abnormal P300 and N200 in a visual oddball task, and progressive P300 amplitude reduction at 1-year follow-up in patients with first-episode schizophrenia. P300 reduction as well as intact P1/N1 were also observed in clinical high-risk subjects (CHR), but whether or not these components change over time is unknown. This study evaluates, longitudinally, the visual P300, as well as P1, N1, and N200, in CHR. METHODS: Visual event-related potentials (ERP) were recorded twice, once at baseline and once at 1-year follow-up in CHR (n = 19) and healthy comparison subjects (HC; n = 28). Participants silently counted infrequent target stimuli ('x') among standard stimuli ('y') presented on the screen while the 64-channel electroencephalogram was recorded. RESULTS: No CHR converted to psychosis from baseline to 1-year follow-up in this study. Visual P300 amplitude was reduced and the latency was delayed significantly in CHR at both time points compared with HC. Furthermore, CHR subjects who had more positive symptoms showed more amplitude reduction at both time points. P1, N1, and N200 did not differ between groups. CONCLUSION: Visual P300 amplitude was found to be reduced in CHR individuals compared with HC. We note that this finding is in subjects who did not convert to psychosis at 1-year follow-up. The association between visual P300 amplitude and symptoms suggests that for CHR who often experience clinical symptoms and seek medical care, visual P300 may be an important index that reflects the pathophysiological impairment underlying such clinical states.

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Auditory hallucinations (AH) are one of the core symptoms of schizophrenia (SZ) and constitute a significant source of suffering and disability. One third of SZ patients experience pharmacology-resistant AH, so an alternative/complementary treatment strategy is needed to alleviate this debilitating condition. In this study, real-time functional Magnetic Resonance Imaging neurofeedback (rt-fMRI NFB), a non-invasive technique, was used to teach 10 SZ patients with pharmacology-resistant AH to modulate their brain activity in the superior temporal gyrus (STG), a key area in the neurophysiology of AH. A functional task was designed in order to provide patients with a specific strategy to help them modify their brain activity in the desired direction. Specifically, they received neurofeedback from their own STG and were trained to upregulate it while listening to their own voice recording and downregulate it while ignoring a stranger's voice recording. This guided performance neurofeedback training resulted in a) a significant reduction in STG activation while ignoring a stranger's voice, and b) reductions in AH scores after the neurofeedback session. A single, 21-minute session of rt-fMRI NFB was enough to produce these effects, suggesting that this approach may be an efficient and clinically viable alternative for the treatment of pharmacology-resistant AH.

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Auditory hallucinations (AHs) are one of the most distressing symptoms of schizophrenia (SZ) and are often resistant to medication. Imaging studies of individuals with SZ show hyperactivation of the default mode network (DMN) and the superior temporal gyrus (STG). Studies in SZ show DMN hyperconnectivity and reduced anticorrelation between DMN and the central executive network (CEN). DMN hyperconnectivity has been associated with positive symptoms such as AHs while reduced DMN anticorrelations with cognitive impairment. Using real-time fMRI neurofeedback (rt-fMRI-NFB) we trained SZ patients to modulate DMN and CEN networks. Meditation is effective in reducing AHs in SZ and to modulate brain network integration and increase DMN anticorrelations. Consequently, patients were provided with meditation strategies to enhance their abilities to modulate DMN/CEN. Results show a reduction of DMN hyperconnectivity and increase in DMNCEN anticorrelation. Furthermore, the change in individual DMN connectivity significantly correlated with reductions in AHs. This is the first time that meditation enhanced through rt-fMRI-NFB is used to reduce AHs in SZ. Moreover, it provides the first empirical evidence for a direct causal relation between meditation enhanced rt-fMRI-NFB modulation of DMNCEN activity and post-intervention modulation of resting state networks ensuing in reductions in frequency and severity of AHs.

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Background. Abnormalities of mismatch negativity (MMN), an event-related potential, indexing preattentive mechanisms, are consistently reported in schizophrenia (SZ). MMN abnormalities elicited to different deviant types have been recently shown to distinguish among patients according to length of their illness as well as inpatient versus outpatient status, and to be modulated by premorbid IQ. The objective of this study was to evaluate the MMN elicited by both frequency and duration deviant stimuli in patients with early schizophrenia (EP) recruited from an outpatient clinic in Boston, Massachusetts. Methods. Twenty-two healthy controls (HC) and 22 age-, handedness-, and gender-matched EP were tested using a frequency and duration MMN paradigm. Clinical data were also collected. Results. Frequency MMN amplitude but not duration MMN was significantly reduced in EP relative to HC subjects (P = .015). Conclusions. These results indicate that in this sample of early psychosis outpatient group, reductions in frequency MMN but not in duration MMN index clinical status. The relationship between age at first hospitalization and MMN frequency and duration amplitude and latency indicates that neurodevelopmental stage, auditory function, and clinical status are tightly linked.

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The early auditory-evoked gamma band response (EAGBR) may serve as an index of the integrity of fast recurrent inhibition or synaptic connectivity in the auditory cortex, where abnormalities in individuals with schizophrenia have been consistently found. The EAGBR has been rarely investigated in first episode schizophrenia patients (FESZ) and individuals at clinical high risk (CHR) for schizophrenia, and never been compared directly between these populations nor evaluated longitudinally. Here we examined the EAGBR in FESZ, CHR, and matched healthy controls (HC) at baseline and 1-year follow-up assessments to determine whether the EAGBR was affected in these clinical groups, and whether any EAGBR abnormalities changed over time. The electroencephalogram was recorded with a dense electrode array while subjects (18 FESZ, 18 CHR, and 40 HC) performed an auditory oddball task. Event-related spectral measures (phase locking factor [PLF] and evoked power) were computed on Morlet-wavelet-transformed single epochs from the standard trials. At baseline, EAGBR PLF and evoked power did not differ between groups. FESZ showed progressive reductions of PLF and evoked power from baseline to follow-up, and deficits in PLF at follow-up compared to HC. EAGBR peak frequency also increased at temporal sites in FESZ from baseline to follow-up. Longitudinal effects on the EAGBR were not found in CHR or HC, nor did these groups differ at follow-up. In conclusion, we detected neurophysiological changes of auditory cortex function in FESZ during a one-year period, which were not observed in CHR. These findings are discussed within the context of neurodevelopmental models of schizophrenia.

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