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BACKGROUND: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score". METHODS: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. RESULTS: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex. CONCLUSIONS: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:326 pages:249-261 ispartof: location:Netherlands status: published

Background and Hypothesis Although the thalamus has a central role in schizophrenia pathophysiology, contributing to sensory, cognitive, and sleep alterations, the nature and dynamics of the alterations occurring within this structure remain largely elusive. Using a multimodal magnetic resonance imaging (MRI) approach, we examined whether anomalies: (1) differ across thalamic subregions/nuclei, (2) are already present in the early phase of psychosis (EP), and (3) worsen in chronic schizophrenia (SCHZ). Study Design T1-weighted and diffusion-weighted images were analyzed to estimate gray matter concentration (GMC) and microstructural parameters obtained from the spherical mean technique (intra-neurite volume fraction [VFINTRA)], intra-neurite diffusivity [DIFFINTRA], extra-neurite mean diffusivity [MDEXTRA], extra-neurite transversal diffusivity [TDEXTRA]) within 7 thalamic subregions. Results Compared to age-matched controls, the thalamus of EP patients displays previously unreported widespread microstructural alterations (VFINTRA decrease, TDEXTRA increase) that are associated with similar alterations in the whole brain white matter, suggesting altered integrity of white matter fiber tracts in the thalamus. In both patient groups, we also observed more localized and heterogenous changes (either GMC decrease, MDEXTRA increase, or DIFFINTRA decrease) in mediodorsal, posterior, and ventral anterior parts of the thalamus in both patient groups, suggesting that the nature of the alterations varies across subregions. GMC and DIFFINTRA in the whole thalamus correlate with global functioning, while DIFFINTRA in the subregion encompassing the medial pulvinar is significantly associated with negative symptoms in SCHZ. Conclusion Our data reveals both widespread and more localized thalamic anomalies that are already present in the early phase of psychosis.

Impairment of parvalbumin interneurons induced by oxidative stress (OxS) is a “hub” on which converge several genetic and environmental risk factors associated with schizophrenia. In patients, this could be a mechanism leading to anomalies of the thalamic reticular nucleus (TRN) whose major neuronal population expresses parvalbumin. The TRN shapes the information flow within thalamo-cortical circuits. The low-threshold voltage-gated T-type Ca2+ (T-Ca2+) channels (CaV3.2, CaV3.3) contribute to the excitability and rhythmic bursting of TRN neurons which mediates cortical sleep spindles, known to be affected in schizophrenia. Here, we investigated the impact of OxS during postnatal development and adulthood on firing properties and T-Ca2+ channels of TRN neurons. In Gclm knock-out (KO) mice, which display GSH deficit and OxS in TRN, we found a reduction of T-Ca2+ current density in adulthood, but not at peripuberty. In KO adults, the decreased T-Ca2+ currents were accompanied with a decrease of CaV3.3 expression, and a shift towards more hyperpolarized membrane potentials for burst firing leading to less prominent bursting profile. In young KO mice, an early-life oxidative challenge precipitated the hypofunction of T-Ca2+ channels. This was prevented by a treatment with N-acetylcysteine. The concomitant presence of OxS and hypofunction of T-Ca2+ channels were also observed in TRN of a neurodevelopmental model relevant to psychosis (MAM mice). Collectively, these data indicate that OxS-mediated T-Ca2+ hypofunction in TRN begins early in life. This also points to T-Ca2+ channels as one target of antioxidant-based treatments aiming to mitigate abnormal thalamo-cortical communication and pathogenesis of schizophrenia.

In view of its heterogeneity, schizophrenia needs new diagnostic tools based on mechanistic biomarkers that would allow early detection. Complex interaction between genetic and environmental risk factors may lead to NMDAR hypofunction, inflammation and redox dysregulation, all converging on oxidative stress. Using computational analysis, the expression of 76 genes linked to these systems, known to be abnormally regulated in schizophrenia, was studied in skin-fibroblasts from early psychosis patients and age-matched controls (N = 30), under additional pro-oxidant challenge to mimic environmental stress. To evaluate the contribution of a genetic risk related to redox dysregulation, we investigated the GAG trinucleotide polymorphism in the key glutathione (GSH) synthesizing enzyme, glutamate-cysteine-ligase-catalytic-subunit (gclc) gene, known to be associated with the disease. Patients and controls showed different gene expression profiles that were modulated by GAG-gclc genotypes in combination with oxidative challenge. In GAG-gclc low-risk genotype patients, a global gene expression dysregulation was observed, especially in the antioxidant system, potentially induced by other risks. Both controls and patients with GAG-gclc high-risk genotype (gclcGAG-HR) showed similar gene expression profiles. However, under oxidative challenge, a boosting of other antioxidant defense, including the master regulator Nrf2 and TRX systems was observed only in gclcGAG-HR controls, suggesting a protective compensation against the genetic GSH dysregulation. Moreover, RAGE (redox/inflammation interaction) and AGMAT (arginine pathway) were increased in the gclcGAG-HR patients, suggesting some additional risk factors interacting with this genotype. Finally, the use of a machine-learning approach allowed discriminating patients and controls with an accuracy up to 100%, paving the way towards early detection of schizophrenia.

Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia.

Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores., National Center of Competence in Research (NCCR) “SYNAPSY-The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (n°51AU40_125759 to KQD & PC), and Alamaya Foundation. SP was supported by European Union’s Horizon 2020 Research and Innovation Program (Psych-STRATA). The PAFIP cohort was funded by the following grants (to BC-F): Instituto de Salud Carlos III (FIS00/3095, PI020499, PI050427, PI060507), Plan Nacional de Drogas Research (2005-Orden sco/3246/2004), SENY Fundatio Research (2005-0308007), Fundacion Marques de Valdecilla (A/02/07, API07/011) and MINECO/FEDER (SAF2016-76046-R, SAF2013-46292-R). JV-B was supported by Instituto de Investigación Sanitaria Valdecilla (INT/A21/10, INT/A20/04). Open access funding provided by University of Lausanne.

Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.

IntroductionRecent efforts have been made to apply machine learning and deep learning approaches to the automated classification of schizophrenia using structural magnetic resonance imaging (sMRI) at the individual level. However, these approaches are less accurate on early psychosis (EP) since there are mild structural brain changes at early stage. As cognitive impairments is one main feature in psychosis, in this study we apply a multi-task deep learning framework using sMRI with inclusion of cognitive assessment to facilitate the classification of patients with EP from healthy individuals. MethodUnlike previous studies, we used sMRI as the direct input to perform EP classifications and cognitive estimations. The proposed deep learning model does not require time-consuming volumetric or surface based analysis and can provide additionally cognition predictions. Experiments were conducted on an in-house data set with 77 subjects and a public ABCD HCP-EP data set with 164 subjects. ResultsWe achieved 74.9 +/- 4.3% five-fold cross-validated accuracy and an area under the curve of 71.1 +/- 4.1% on EP classification with the inclusion of cognitive estimations. DiscussionWe reveal the feasibility of automated cognitive estimation using sMRI by deep learning models, and also demonstrate the implicit adoption of cognitive measures as additional information to facilitate EP classifications from healthy controls.

Converging evidence implicates redox dysregulation as a pathological mechanism driving the emergence of psychosis. Increased oxidative damage and decreased capacity of intracellular redox modulatory systems are consistent findings in persons with schizophrenia as well as in persons at clinical high risk who subsequently developed frank psychosis. Levels of glutathione, a key regulator of cellular redox status, are reduced in the medial prefrontal cortex, striatum, and thalamus in schizophrenia. In humans with schizophrenia and in rodent models recapitulating various features of schizophrenia, redox dysregulation is linked to reductions of parvalbumin containing gamma-aminobutyric acid (GABA) interneurons and volumes of their perineuronal nets, white matter abnormalities, and microglia activation. Importantly, the activity of transcription factors, kinases, and phosphatases regulating diverse aspects of neurodevelopment and synaptic plasticity varies according to cellular redox state. Molecules regulating interneuron function under redox control include NMDA receptor subunits GluN1 and GluN2A as well as KEAP1 (regulator of transcription factor NRF2). In a rodent schizophrenia model characterized by impaired glutathione synthesis, the Gclm knockout mouse, oxidative stress activated MMP9 (matrix metalloprotease 9) via its redox-responsive regulatory sites, causing a cascade of molecular events leading to microglia activation, perineural net degradation, and impaired NMDA receptor function. Molecular pathways under redox control are implicated in the etiopathology of schizophrenia and are attractive drug targets for individualized drug therapy trials in the contexts of prevention and treatment of psychosis.

The structural complexity of the thalamus, due to its mixed composition of gray and white matter, make it challenging to disjoint and quantify each tissue contribution to the thalamic anatomy. This work promotes the use of partial‐volume‐based over probabilistic‐based tissue segmentation approaches to better capture thalamic gray matter differences between patients at different stages of psychosis (early and chronic) and healthy controls. The study was performed on a cohort of 23 patients with schizophrenia, 41 with early psychosis and 69 age and sex‐matched healthy subjects. Six tissue segmentation approaches were employed to obtain the gray matter concentration/probability images. The statistical tests were applied at three different anatomical scales: whole thalamus, thalamic subregions and voxel‐wise. The results suggest that the partial volume model estimation of gray matter is more sensitive to detect atrophies within the thalamus of patients with psychosis. However all the methods detected gray matter deficit in the pulvinar, particularly in early stages of psychosis. This study demonstrates also that the gray matter decrease varies nonlinearly with age and between nuclei. While a gray matter loss was found in the pulvinar of patients in both stages of psychosis, reduced gray matter in the mediodorsal was only observed in early psychosis subjects. Finally, our analyses point to alterations in a sub‐region comprising the lateral posterior and ventral posterior nuclei. The obtained results reinforce the hypothesis that thalamic gray matter assessment is more reliable when the tissues segmentation method takes into account the partial volume effect., Three partial‐volume‐based and three probabilistic‐based tissue segmentation approaches were employed to assess thalamic gray matter integrity in patients at different stages of psychosis (early and chronic). This study demonstrates also that the gray matter decrease varies nonlinearly with age and between nuclei. The obtained results reinforce the hypothesis that thalamic gray matter assessment is more reliable when the tissues segmentation method takes into account the partial volume effect.

Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients’ blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients’ group with mitochondrial dysfunction “Psy-D”, having high miR-137 and low COX6A2 levels in exosomes, and (b) a “Psy-ND” subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

Recent evidence showed thalamic abnormalities in schizophrenia involving disruptions to the parvalbumin neurons in the thalamic reticular nucleus (TRN). However, their functional consequences, as well as a potential linkage to oxidative stress, are unclear. The TRN is posited to gate prefrontal control of dopamine neuron activity in the ventral tegmental area (VTA). Thus, we hypothesized that schizophrenia-related TRN abnormalities might contribute to dopamine dysregulation, a well-known feature of the disorder. To test this, in adult rats exposed prenatally to methylazoxymethanol acetate (MAM rats), oxidative impairments to the parvalbumin neurons in the anterior TRN were assessed by immunohistochemistry. Using in vivo electrophysiology, we investigated whether inactivation of the prefrontal cortex would produce differential effects on VTA dopamine neurons in MAM rats. We show that MAM rats displayed reduced markers of parvalbumin and wisteria floribunda agglutinin-labeled perineuronal nets, correlating with increased markers of oxidative stress (8-oxo-7, 8-dihydro-20-deoxyguanosine, and 3-nitrotyrosine). Moreover, MAM rats displayed heightened baseline and abnormal prefrontal control of VTA dopamine neuron activity, as tetrodotoxin-induced inactivation of the infralimbic prefrontal cortex decreased the dopamine population activity, contrary to the normal increase in controls. Such dopamine neuron dysregulation was recapitulated by enzymatic perineuronal net digestion in the TRN of normal rats. Furthermore, juvenile (postnatal day 11-25) antioxidant treatment (N-acetyl-cysteine, 900 mg/L drinking water) prevented all these impairments in MAM rats. Our findings suggest that early accumulation of oxidative stress in the TRN may shape the later onset of schizophrenia pathophysiology, highlighting redox regulation as a potential target for early intervention.

Background: Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. Methods: Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. Results: Significantly lower [GSH mPFC ] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSH mPFC ] and blood GPx activities correlate positively in controls ( P = .021), but negatively in patients ( P = .039). In GCLC low-risk genotypes, [Glu mPFC ] are lower in patients, while it is not the case for high-risk genotypes. Conclusions: GCLC high-risk genotypes are associated with low [GSH mPFC ], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.

Impairment of parvalbumin interneurons induced by oxidative stress (OxS) is a "hub" on which converge several genetic and environmental risk factors associated with schizophrenia. In patients, this could be a mechanism leading to anomalies of the thalamic reticular nucleus (TRN) whose major neuronal population expresses parvalbumin. The TRN shapes the information flow within thalamo-cortical circuits. The low-threshold voltage-gated T-type Ca

A growing body of evidence has emerged demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or “central hub” for schizophrenia genetic and environmental risk factors. Here we review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology. We focus on evidence supporting the crucial role of either redox dysregulation, N-methyl-D-aspartate receptor hypofunction, neuroinflammation or mitochondria bioenergetics dysfunction, initiating “vicious circles” centered on oxidative stress during neurodevelopment. These processes would amplify one another in positive feed-forward loops, leading to persistent impairments of the maturation and function of local parvalbumin-GABAergic neurons microcircuits and myelinated fibers of long-range macrocircuitry. This is at the basis of neural circuit synchronization impairments and cognitive, emotional, social and sensory deficits characteristic of schizophrenia. Potential therapeutic approaches that aim at breaking these different vicious circles represent promising strategies for timely and safe interventions. In order to improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidant, anti-inflammatory and NMDAR modulator drugs, a reverse translation of validated circuitry approach is needed. The above presented processes allow to identify mechanism based biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry.

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress “hub” affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258–70); (Nat Rev Neurosci. 2016;17:125–34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm−/−), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721–8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets., SCOPUS: ar.j, info:eu-repo/semantics/published

Key Points Question Are clinical and demographic factors associated with brain glutamate or glutamate plus glutamine (Glx) levels in schizophrenia? Findings In this mega-analysis of 1251 patients with schizophrenia and 1197 healthy volunteers, medial frontal cortex glutamatergic metabolite levels were lower in patients and negatively associated with the dose of antipsychotic medication, although a reduction in glutamate levels with age was not accelerated in patients with schizophrenia compared with healthy individuals. Higher medial frontal cortex and medial temporal lobe glutamate levels were associated with more severe symptoms in patients with schizophrenia. Meaning Lower brain glutamate levels may be associated with antipsychotic exposure rather than with greater age-related decline, whereas higher glutamate levels may serve as a biomarker of illness severity in patients with schizophrenia., Importance Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P, This mega-analysis assesses whether age, symptom severity, level of functioning, and antipsychotic treatment are associated with glutamate or glutamatergic metabolite levels measured with proton magnetic resonance spectroscopy in the medial frontal cortex or medial temporal lobe of patients with schizophrenia.

Psychosis, characterized by hallucinations and delusions, is a common feature of psychiatric disease, especially schizophrenia. One prominent theory posits that psychosis is driven by abnormal sensorimotor predictions leading to the misattribution of self-related events. This misattribution has been linked to passivity experiences (PE), such as loss of agency and, more recently, to presence hallucinations (PH), defined as the conscious experience of the presence of an alien agent while no person is actually present. PH has been observed in schizophrenia, Parkinson’s disease, and neurological patients with brain lesions and, recently, the brain mechanisms of PH (PH-network) have been determined comprising bilateral posterior middle temporal gyrus (pMTG), inferior frontal gyrus (IFG), and ventral premotor cortex (vPMC). Given that the experience of an alien agent is a common feature of PE, we here analyzed the functional connectivity within the PH-network in psychotic patients with (N = 39) vs without PE (N = 26). We observed reduced fronto-temporal functional connectivity in patients with PE compared to patients without PE between the right pMTG and the right and left IFG of the PH-network. Moreover, when seeding from these altered regions, we observed specific alterations with brain regions commonly linked to auditory-verbal hallucinations (such as Heschl’s gyrus). The present connectivity findings within the PH-network extend the disconnection hypothesis for hallucinations to the specific case of PH and associates the PH-network with key brain regions for frequent psychotic symptoms such as auditory-verbal hallucinations, showing that PH are relevant to the study of the brain mechanisms of psychosis and PE.

International audience; Alzheimer's disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of individuals with AD. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in hilar astrocytes of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.

Nicotinamide adenine dinucleotide (NAD) is an important cofactor of energy-producing pathways. The redox ratio (NAD + /NADH) reflects the cellular oxidoreductive state. Oxidative stress and redox dysregulation have been suggested to contribute to various neurological diseases. The assessment of NAD content has been recently demonstrated in large animals and human brains by 31 P magnetic resonance spectroscopy. However, its measurement in small rodents has never been attempted. The purpose of this study was to investigate, in vivo, the NAD content during mouse brain neurodevelopment. 31 P-MR-spectra were acquired in the mouse brain at postnatal days P20, P40, P90 and P250 at 14.1 T using a 3D-localization sequence. High spectral quality was achieved at 14.1 T. NAD + and NADH were quantified with mean Cramér-Rao lower bound of 10% and 14%, respectively. An increase in NAD + /NADH was observed from P20 to P250 due to a decrease in [NADH]. The intracellular pH was significantly reduced with age, while the free [Mg 2+ ] in the brain was significantly increased. This study demonstrates for the first time the feasibility of the measurement of NAD content in vivo in mouse brains during development, which opens the prospect of longitudinally studying energy metabolism and redox dysfunction in mouse models of brain pathology.

Nicotinamide adenine dinucleotide (NAD) is an important cofactor of energy-producing pathways. The redox ratio (NAD+/NADH) reflects the cellular oxidoreductive state. Oxidative stress and redox dysregulation have been suggested to contribute to various neurological diseases. The assessment of NAD content has been recently demonstrated in large animals and human brains by 31P magnetic resonance spectroscopy. However, its measurement in small rodents has never been attempted. The purpose of this study was to investigate, in vivo, the NAD content during mouse brain neurodevelopment. 31P-MR-spectra were acquired in the mouse brain at postnatal days P20, P40, P90 and P250 at 14.1 T using a 3D-localization sequence. High spectral quality was achieved at 14.1 T. NAD+ and NADH were quantified with mean Cramér-Rao lower bound of 10% and 14%, respectively. An increase in NAD+/NADH was observed from P20 to P250 due to a decrease in [NADH]. The intracellular pH was significantly reduced with age, while the free [Mg2+] in the brain was significantly increased. This study demonstrates for the first time the feasibility of the measurement of NAD content in vivo in mouse brains during development, which opens the prospect of longitudinally studying energy metabolism and redox dysfunction in mouse models of brain pathology.

In the original version of this article ‘Abdelwahed Chtarto’ was omitted from the author list. This author has now been added to the author list in 10th position. Additionally, the following acknowledgement was accidentally omitted from the original article: ‘We are grateful to Catherine Melas, from the ULB, and Laetitia Thieren, from the CHUV, for their valuable help on producing the viruses used in this study’. This has been corrected in both the PDF and HTML versions of this article., SCOPUS: er.j, info:eu-repo/semantics/published

[Background] Although evidence from psychosis patients demonstrates the adverse effects of cannabis use (CU) at a young age and that the rate of CU is high in subgroups of young violent patients with psychotic disorders, little is known about the possible effect of the age of onset of CU on later violent behaviors (VB). So, we aimed to explore the impact of age at onset of CU on the risk of displaying VB in a cohort of early psychosis patients., [Method] Data were collected prospectively over a 36-month period in the context of an early psychosis cohort study. A total of 265 patients, aged 18–35 years, were included in the study. Logistic regression was performed to assess the link between age of onset of substance use and VB., [Results] Among the 265 patients, 72 had displayed VB and 193 had not. While violent patients began using cannabis on average at age 15.29 (0.45), nonviolent patients had started on average at age 16.97 (0.35) (p = 0.004). Early-onset CU (up to age 15) was a risk factor for VB (odds ratio = 4.47, confidence interval [CI]: 1.13–20.06) when the model was adjusted for age group, other types of substance use, being a user or a nonuser and various violence risk factors and covariates. History of violence and early CU (until 15) were the two main risk factors for VB., [Conclusions] Our results suggest that early-onset CU may play a role in the emergence of VB in early psychosis., This work was supported by National Center of Competence in Research (NCCR) “SYNAPSY—The Synaptic Bases of Mental Diseases” (JG and VM, project number 33).

The GluN2A subunit of NMDA receptors (NMDARs) plays a critical role during postnatal brain development as its expression increases while Glun2B expression decreases. Mutations and polymorphisms in GRIN2A gene, coding for GluN2A, are linked to developmental brain disorders such as mental retardation, epilepsy, schizophrenia. Published data suggest that GluN2A is involved in maturation and phenotypic maintenance of parvalbumin interneurons (PVIs), and these interneurons suffer from a deficient glutamatergic neurotransmission via GluN2A-containing NMDARs in schizophrenia. In the present study, we find that although PVIs and their associated perineuronal nets (PNNs) appear normal in anterior cingulate cortex of late adolescent/young adult GRIN2A KO mice, a lack of GluN2A delays PNN maturation. GRIN2A KO mice display a susceptibility to redox dysregulation as sub-threshold oxidative stress and subtle alterations in antioxidant systems are observed in their prefrontal cortex. Consequently, an oxidative insult applied during early postnatal development increases oxidative stress, decreases the number of parvalbumin-immunoreactive cells, and weakens the PNNs in KO but not WT mice. These effects are long-lasting, but preventable by the antioxidant, N-acetylcysteine. The persisting oxidative stress, deficit in PVIs and PNNs, and reduced local high-frequency neuronal synchrony in anterior cingulate of late adolescent/young adult KO mice, which have been challenged by an early-life oxidative insult, is accompanied with microglia activation. Altogether, these indicate that a lack of GluN2A-containing NMDARs alters the fine control of redox status, leading to a delayed maturation of PNNs, and conferring vulnerability for long-term oxidative stress, microglial activation, and PVI network dysfunction.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.

Growing evidence points to a disruption of cortico-thalamo-cortical circuits in schizophrenia (SZ) and bipolar disorder (BD). Clues for a specific involvement of the thalamic reticular nucleus (TRN) come from its unique neuronal characteristics and neural connectivity, allowing it to shape the thalamo-cortical information flow. A direct involvement of the TRN in SZ and BD has not been tested thus far. We used a combination of human postmortem and rodent studies to test the hypothesis that neurons expressing parvalbumin (PV neurons), a main TRN neuronal population, and associated Wisteria floribunda agglutinin-labeled perineuronal nets (WFA/PNNs) are altered in SZ and BD, and that these changes may occur early in the course of the disease as a consequence of oxidative stress. In both disease groups, marked decreases of PV neurons (immunoreactive for PV) and WFA/PNNs were observed in the TRN, with no effects of duration of illness or age at onset. Similarly, in transgenic mice with redox dysregulation, numbers of PV neurons and WFA/PNN+PV neurons were decreased in transgenic compared with wild-type mice; these changes were present at postnatal day (P) 20 for PV neurons and P40 for WFA/PNN+PV neurons, accompanied by alterations of their firing properties. These results show profound abnormalities of PV neurons in the TRN of subjects with SZ and BD, and offer support for the hypothesis that oxidative stress may play a key role in impacting TRN PV neurons at early stages of these disorders. We put forth that these TRN abnormalities may contribute to disruptions of sleep spindles, focused attention and emotion processing in these disorders.

Environmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (-/-) of the glutamate-cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post-natal day 65. Using magnetic resonance methods at high-field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N-acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine-to-glutamate (Gln/Glu), and by a reduction in levels of myo-inositol and choline-containing compounds in the frontal cortex of -/- animals with respect to wild-type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo-inositol concentration (-8.4%, p

Exposure to environmental toxicants during vulnerable windows of brain development is suspected to raise the prevalence for neurological dysfunctions at later stages in life. Differentiation processes and changes in morphology, as well as a lack of physiological barriers, might be reasons that render a developing brain more susceptible to neurotoxicants than an adult. However, also the intrinsic capacity of cells to combat toxicant induced cellular stress might differ between the immature- and mature brain. In order to study whether this intrinsic protection capacity differs between immature and maturated brain cells we chose to study the maturation-dependent adverse effects of the known neurotoxicant Paraquat Dichloride (PQ) in 3D rat brain cell cultures. This in vitro system consists of the major brain cell types - neurons, astrocytes, oligodendrocytes and microglia - and over the time in vitro cultured cells undergo differentiation and maturation into a tissue-like organization. PQ was applied repeatedly over ten days in the sub-micromolar range, and effects were evaluated on neurons and glial cells. We observed that despite a higher PQ-uptake in mature cultures, PQ-induced adverse effects on glutamatergic-, GABAergic- and dopaminergic neurons, as assessed by gene expression and enzymatic activity, were more pronounced in immature cultures. This was associated with a stronger astrogliosis in immature- as compared to mature cultures, as well as perturbations of the glutathione-mediated defense against oxidative stress. Furthermore we observed evidence of microglial activation only in mature cultures, whereas immature cultures appeared to down-regulate markers for neuroprotective M2-microglial phenotype upon PQ-exposure. Taken together our results indicate that immature brain cell cultures have less intrinsic capacity to cope with cellular stress elicited by PQ as compared to mature cells. This may render immature brain cells more susceptible to the adverse effects of PQ.

Background The ability to recognize whether sensory consequences have been self-generated or externally produced is an important element of motor control and self-monitoring. Deficits in self-monitoring have been proposed to cause abnormal bodily experiences and psychotic symptoms such as hallucinations. A recent study designed a robotic system that applies sensorimotor stimulation in healthy subjects and safely induces mild presence hallucinations (PH) and passivity experiences (Blanke et al., 2014). PH are defined as the sensation that someone is close by when actually no one is present and passivity experiences are characterized by perceptions or beliefs that an external agent is controlling one’s actions, perceptions, and/or thoughts. Although, both symptoms occur in schizophrenia and Parkinson’s disease, their neural mechanisms are unknown. Methods Here, we first investigated the neural mechanisms of PH and passivity experiences in 25 healthy subjects. We developed a new MR-compatible robotic system able to generate the aforementioned sensorimotor conflicts, while recording subjects’ brain activity using fMRI. In addition, we applied lesion network mapping to 11 neurological patients with symptomatic PH and compared both populations to find a common PH network. In a final step, we investigated the relevance of the PH network by analyzing the connectivity of the PH network in resting state fMRI data from 58 psychotic patients. Results We first evaluated the regions associated with the general sensorimotor conflict, which revealed the left sensorimotor area, the left putamen, the right inferior parietal lobule and the right cerebellum. Then, we analyzed the regions that were more activated during the condition eliciting PH and passivity experiences and found the inferior frontal gyrus (IFG), the insula, the superior medial gyrus and the middle temporal gyrus (MTG). Comparison of these two networks with the symptomatic PH network in neurological patients highlighted the IFG, the MTG and the vPMc. The resting state analysis within those regions in psychotic patients revealed no global differences between the groups but a functional connectivity decrease between MTG and IFG (bilaterally) specific for psychotic patients experiencing passivity experiences. Discussion Collectively, we showed that through the use of a robotic system generating sensorimotor conflicts, the neural correlates of induced-PH and passivity experiences can be studied in healthy subjects in a controlled manner. In addition, we found two networks associated with induced-PH and passivity experience. Of these regions, three were also recruited in patients with PH of neurological origin, forming the PH network. MTG-IFG connectivity in the PH network was altered selectively in psychotic patients with passivity experiences, revealing the relevance of the neural mechanisms of PH and passivity experiences in psychosis.

Background Proton Magnetic Resonance Spectroscopy (1H-MRS) studies indicate that altered brain glutamate signalling contributes to the pathophysiology of schizophrenia and treatment response. However it is unclear whether clinical and demographic factors affect glutamate levels in the brain. Here we aim to determine the effects of age, antipsychotic medication, symptom severity and duration of illness on levels of glutamatergic metabolites and creatine, in a large multicentre dataset of patients with schizophrenia and healthy volunteers. Methods Authors of 1H-MRS studies in schizophrenia were contacted between January 2014 and August 2017 and asked to provide individual glutamate, Glx, glutamine and creatine values alongside demographic and clinical data. Forty-five 1H-MRS studies contributed data to the multicentre dataset, and data was available from 1194 healthy volunteers and 1526 patients with schizophrenia and those at high risk of developing psychosis. Results Age was associated with reduced glutamate levels in the medial frontal cortex, but the effect of aging was not accelerated in patients compared to healthy volunteers. Higher glutamate and Glx in the medial frontal and temporal lobes were associated with more severe symptoms, whereas Glx in subcortical regions, specifically the thalamus and striatum, did not relate to symptom severity. In the medial frontal cortex and striatum, exposure to antipsychotic medication was associated with lower levels of glutamatergic metabolites. Duration of illness was not associated with glutamatergic metabolites. Lastly, creatine in the medial frontal cortex and thalamus increased with age. Discussion These data suggest that future 1H-MRS studies should control for the effects of age, symptom severity, and antipsychotic medication exposure. Caution is needed when using creatine as a reference to scale metabolites.