Abstract Recent research highlights the critical role of white matter (WM) alterations in psychosis and schizophrenia (SZ), reporting volumetric and structural brain changes in affected individuals. In this study, we explored the role of astroglia in SZ, which is believed to play a role in white matter integrity. We investigated for the first time the associations between advanced diffusion Magnetic Resonance Imaging (dMRI) measures of WM microstructure and Magnetic Resonance Spectroscopy (MRS)-derived glial markers in 30 subjects with early psychosis (EP, mean age 24 ± 6) versus 49 healthy controls (HC, mean age 25 ± 6). We focused on two metabolites involved in glia: myo-Inositol (myo-Ins) and total Choline (tCho), measured in the medial prefrontal cortex (mPFC), relating them to quantitative dMRI metrics derived from Diffusion Kurtosis Imaging (DKI) and WM Tract Integrity-Watson (WMTI-W) biophysical model, including mean diffusivity and kurtosis, axonal water fraction and extra-axonal diffusivities in the whole white matter. Our findings reveal a difference between EP and HC in WM diffusivities, specifically in the extra-axonal parallel direction, but not in MRS metabolites. However, we found that the mPFC myo-Ins concentrations in EP are exclusively and strongly associated with proximal WM microstructure features, in the form of a positive correlation with axonal water fraction, a proxy for axonal density, and a negative correlation with extra-axonal parallel diffusivity, suggesting the white matter alterations could be linked to astrocytic changes in early psychosis.

Studies on schizophrenia feature diffusion magnetic resonance imaging (dMRI) to investigate white matter (WM) anomalies. The heterogeneity in the possible interpretations of typical Diffusion Tensor Imaging (DTI) metrics highlights the importance of increasing their specificity. Here, we characterize WM pathology in early psychosis (EP) and schizophrenia (SZ) with increased specificity using advanced dMRI: Diffusion Kurtosis Imaging and the biophysical model White Matter Tract Integrity - Watson (WMTI-W). This enables us to better characterize WM abnormalities, while preserving good sensitivity to group differences, and relate them to the current literature (ENIGMA-schizophrenia), patient's clinical characteristics and symptomatology. dMRI-derived microstructure features were extracted from all of WM and from individual regions of interest in 275 individuals. 93 subjects diagnosed with EP and 47 with SZ were compared respectively to 135 age-range matched healthy controls (HC). WM DTI diffusivities were higher, while kurtosis was lower in EP vs HC and in SZ vs HC. Differences were more widespread in EP than SZ. The regional alterations found in our cohort matched the DTI patterns found in ENIGMA-schizophrenia. WMTI-W model parameters indicate that the WM alterations in patients come primarily from the extra-axonal compartment, consistent with abnormal myelin integrity in the disease pathology. The direct link between WM alterations and symptomatology is, however, limited.

In groups of patients suffering from schizophrenia (SZ), redox dysregulation was reported in both peripheral fluids and brain. It has been hypothesized that such dysregulation, including alterations of the glutathione (GSH) cycle could participate in the brain white matter (WM) abnormalities in SZ due to the oligodendrocytes' susceptibility to oxidative stress. In this study we aim to assess the differences between 82 schizophrenia patients (PT) and 86 healthy controls (HC) in GSH-redox peripheral blood markers: GSH peroxidase (GPx), reductase (GR) enzymatic activities and their ratio (GPx/GR-ratio), evaluating the hypotheses that alterations in the homeostasis of the systemic GSH cycle may be associated with pathological mechanisms in the brain WM in PT. To do so, we employ the advanced diffusion MRI methods: Diffusion Kurtosis Imaging (DKI) and White Matter Tract Integrity-Watson (WMTI-W), which provide excellent sensitivity to demyelination and neuroinflammation. We show that GPx levels are higher (p = 0.00041) in female control participants and decrease with aging (p = 0.026). We find differences between PT and HC in the association of GR and mean kurtosis (MK, p < 0.0001). Namely, lower MK was associated with higher blood GR activity in HC, but not in PT, suggesting that high GR activity (a hallmark of reductive stress) in HC was linked to changes in myelin integrity. However, GSH-redox peripheral blood markers did not explain the WM anomalies detected in PT, or the design of the present study could not detect subtle phenomenon, if present.

Network science has revolutionized our understanding of brain organization by revealing self-organizing patterns underlying its structural and functional connectivity. However, capturing metabolic contrast remains a challenge, leaving a critical gap in connectomics. Using advanced 3D whole-brain proton MR spectroscopic imaging with high spatial resolution and shortened acquisition times, we constructed the first human brain metabolic connectome in 51 healthy subjects, validated on an independent cohort (N=12) scanned at a different site. Our pipeline generates consistent and reliable metabolic similarity matrices. Upon further analysis, metabolic similarity networks display distinct topological features, notably a smoothly varying gradient delineating functionally and spatially distinct yet integrated brain regions via connector hubs. Although metabolic hubs correlate with structural hubs, overall alignment with structural connectivity is poor. However, metabolic organization aligns more closely with cytoarchitectonic and genetic co-expression patterns, suggesting a neurodevelopmental origin. This work puts forward the metabolic similarity gradient as a hallmark of the brain's overarching biochemical organization, and provides a foundation for incorporating metabolite imaging into the broader domain of connectomics and its potential applications in health and disease. ### Competing Interest Statement A.K. is employed by Siemens Healthcare AG, Switzerland. The other authors have nothing to disclose.

Network science has mapped brain structural and functional organization, yet capturing metabolic contrast remains a major gap in connectomics. Using fast, high-resolution 3D whole-brain proton magnetic resonance spectroscopic imaging (1H-MRSI), we derive a within-subject metabolic connectome in 51 healthy subjects, defined as pairwise correlations among five metabolites (tCr, tNAA, Glx, Ins, Cho) across gray-matter parcels. Results show stability, consistency and replicability, including validation in an independent sample (N = 13) scanned at a different site. A dimensionality reduction analysis shows that the leading metabolic similarity mode forms a continuous caudal-to-rostral gradient across gray-matter regions. We show that this progression is reflective of a balance between local metabolic homogeneity and global metabolic diversity, and can be summarized by a principal path through the metabolic network. While the most metabolically active regions overlap with structural hubs, overall metabolic similarity aligns weakly with tractography-based structural connectivity but more closely with cytoarchitectonic similarity and gene co-expression matrices. These findings introduce the metabolic similarity gradient as a signature of the brain's biochemical organization and position MRSI as a biologically grounded dimension for connectomics in health and disease.

Adverse childhood experiences (ACE) are common risk factors for many psychiatric disorders. Their underlying biological mechanisms may involve oxidative stress (OS), which has deleterious effects on cells through its own actions and through its interactions with inflammation and the stress axes, particularly in the brain. In order to assess the role of OS in the association between ACE and psychopathology, we performed a systematic review of animal and human research (PROSPERO CRD42023378418 and CRD42022378376), funded by the Swiss National Science Foundation (grant number 204033). PubMed, Web of Science, PsycInfo, Scopus and Embase were searched from inception until 31 October 2024. We included 130 studies involving animal models exposed to stressor-paradigms recognized as ACE analogs before they reached adulthood, or human participants with a history of ACE and assessment of psychopathology, and reporting outcomes on OS-related markers. Animal studies overall show increased OS and psychopathology after stress, thus supporting the hypothesis that OS mediates the relationship between ACE and psychopathology. Human studies are heterogeneous and less conclusive. Although the association between ACE exposure and OS, in animals and humans, was likely affected by the nature, the timing, and the intensity of the exposure, these parameters were only evaluated in a small fraction of studies. Similarly, though some studies hinted at sex differences in the OS response to ACE in animals, the majority of studies did not address this issue. Further research, using longitudinal designs and more thorough examination of ACE history in participants, is therefore needed.

Adolescence is marked by significant maturation of brain white matter microstructure, with evidence for sex-specific maturational trajectory. Most studies have examined conventional diffusion tensor imaging (DTI) metrics, which lack specificity to the underlying tissue modifications. In this study, we characterized sex-differences in white matter microstructure cross-sectionally using DTI, advanced diffusion spectrum imaging (DSI) and diffusion kurtosis imaging (DKI), as well as the white matter tract integrity-Watson (WMTI-W) biophysical model. We also aimed to explore the effect of age and biological systems undergoing sex-specific changes during adolescence, namely pubertal hormones, hypothalamic-pituitary-adrenal (HPA)-axis function, and glutathione-redox cycle homeostasis. The results indicate widespread sex-differences in all the white matter derived metrics, suggesting more advanced maturation in females compared to males as well as distinct tissue modifications underlying white matter maturation between males and females during this narrow developmental period. Additionally, the three biological factors explored appeared to be associated with indices of white matter maturation in females specifically, emphasizing this period as critical in female white matter development and sensitivity to environmental factors.

A growing body of evidence indicates that many genetic and environmental factors associated with psychiatric disorders affect redox homeostasis, mitochondria and energy metabolism, and neuroendocrine and immune systems in a complex synergistic manner, leading to oxidative stress and inflammation [...]

OBJECTIVE:Winter birth has consistently been identified as a risk factor for schizophrenia. This study aimed to determine whether individuals born during this season are also at higher risk for early psychosis and whether this is associated with distinct functional and clinical outcomes. METHODS:We conducted a prospective study on 222 patients during their early phase of psychosis in Switzerland, nested in the Treatment and Early Intervention in Psychosis (TIPP) cohort. We compared the birth trimesters of these patients with those of the general Swiss population. Additionally, we evaluated the Global Assessment of Functioning scale (GAF) and the Positive and Negative Syndrome Scale (PANSS) scores among patients born in winter (January to March) versus those born during the rest of the year during a three-year follow-up period. RESULTS:A significantly higher proportion of patients experiencing early psychosis were born in winter compared to the general Swiss population. Patients born in winter had significantly lower GAF scores at 6 months, 24 months, and 36 months of follow-up, compared to patients born during the rest of the year. They also manifested fewer positive symptoms, as indicated by the PANSS positive subscale. CONCLUSION:Birth in winter appears to be associated with a lower functional outcome and potentially distinct symptomatology in the early phase of psychosis.

In groups of patients suffering from psychosis, redox dysregulation was reported in both peripheral fluids and brain. It has been hypothesized that such dysregulation, including alterations of the glutathione (GSH) cycle could participate in the brain white matter (WM) abnormalities in schizophrenia (SZ) due to the oligodendrocytes' susceptibility to oxidative stress (OxS). In this study we aim to assess the differences between 99 psychosis patients (PT) and 86 healthy controls (HC) in GSH-redox peripheral blood markers: GSH peroxidase (GPx), reductase (GR) enzymatic activities and their ratio (GPx/GR-ratio), evaluating the hypotheses that alterations in the homeostasis of the systemic GSH cycle may be associated with pathological mechanisms in the brain WM in PT. We also consider the hypothesis that different homeostatic states of the system (oxidative vs reductive) may reflect differently into the WM microstructure. To do so, we employ the advanced diffusion MRI methods: Diffusion Kurtosis Imaging (DKI) and White Matter Tract Integrity-Watson (WMTI-W), which provide excellent sensitivity to demyelination and neuroinflammation. We show that GPx levels are higher (p=0.00050) in female participants and modulate the effect of aging on the WM. We found differences between PT and HC in the association of GR and mean kurtosis (MK, p=0.028). Namely, lower MK was associated with higher blood GR activity in HC, but not in PT, suggesting that high GR activity (a hallmark of reductive stress) in HC was linked to changes in myelin integrity. Remarkably, GSH-redox peripheral blood markers did not explain the WM anomalies detected in PT. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Swiss National Science Foundation (PCEFP2\_194260, to I.J.; 320030\_197787 to PH and YA), the National Center of Competence in Research (NCCR) "SYNAPSY - The Synaptic Bases of Mental Diseases" from the Swiss National Science Foundation (51NF40_185897 to KQD & PC) and the Foundation Alamaya. Dr. Alameda is supported by Carigest fellowship and by Frutiger Adrian et Simone fellowship. Dr. Dwir and P. Klauser are supported by Frutiger Adrian & Simone fellowship. The authors have nothing to disclose and there are no conflicts of interest. We are grateful to Gloria Reuteler, Adeline Cottier and Morgane Baumgartner for expert technical assistance. Dr Luis Alameda thanks the Foundation Adrian and Simone Frutiger and Carigest SA Foundation for their support ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local Ethics Committee of the Canton of Vaud (Switzerland) under authorization numbers CER-VD 382/11 and 2018-01731. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will not be available, however, the models and scripts used will published online

Adolescence is marked by the maturation of systems involved in emotional regulation and by an increased risk for internalizing disorders (anxiety/depression), especially in females. Hypothalamic-pituitary-adrenal (HPA)-axis function and redox homeostasis (balance between reactive oxygen species and antioxidants) have both been associated with internalizing disorders and may represent critical factors for the development of brain networks of emotional regulation. However, sex-specific interactions between these factors and internalizing symptoms and their link with brain maturation remain unexplored. We investigated in a cohort of adolescents aged 13–15 from the general population (n = 69) whether sex-differences in internalizing symptoms were associated with the glutathione (GSH)-redox cycle homeostasis and HPA-axis function and if these parameters were associated with brain white matter microstructure development. Female adolescents displayed higher levels of internalizing symptoms, GSH-peroxidase (GPx) activity and cortisol/11-deoxycortisol ratio than males. There was a strong correlation between GPx and GSH-reductase (Gred) activities in females only. The cortisol/11-deoxycortisol ratio, related to the HPA-axis activity, was associated with internalizing symptoms in both sexes, whereas GPx activity was associated with internalizing symptoms in females specifically. The cortisol/11-deoxycortisol ratio mediated sex-differences in internalizing symptoms and the association between anxiety and GPx activity in females specifically. In females, GPx activity was positively associated with generalized fractional anisotropy in widespread white matter brain regions. We found that higher levels of internalizing symptoms in female adolescents than in males relate to sex-differences in HPA-axis function. In females, our results suggest an important interplay between HPA-axis function and GSH-homeostasis, a parameter strongly associated with brain white matter microstructure.

Defects in essential metabolic regulation for energy supply, increased oxidative stress promoting excitatory/inhibitory imbalance and phospholipid membrane dysfunction have been implicated in the pathophysiology of schizophrenia (SZ). The knowledge about the developmental trajectory of these key pathophysiological components and their interplay is important to develop new preventive and treatment strategies. However, this assertion is so far limited. To investigate the developmental regulations of these key components in the brain, we assessed, for the first time, in vivo redox state from the oxidized (NAD + ) and reduced (NADH) form of Nicotinamide Adenine Dinucleotide (NAD), energy and membrane metabolites, inhibitory and excitatory neurotransmitters by 31 P and 1 H MRS during the neurodevelopment of an SZ animal model with genetically compromised glutathione synthesis ( gclm -KO mice). When compared to age-matched wild type (WT), an increase in NAD + /NADH redox ratio was found in gclm -KO mice until early adulthood, followed by a decrease in full adults as observed in patients. Especially, in early postnatal life (P20, corresponding to childhood), levels of several metabolites were altered in gclm -KO mice, including NAD + , NAD + /NADH, ATP, and glutamine + glutamate, suggesting an interactive compensation for redox dysregulation between NAD, energy metabolism, and neurotransmission. The identified temporal neurometabolic regulations under deficits in redox regulation provide insights into preventive treatment targets for at-risk individuals, and other neurodevelopmental disorders involving oxidative stress and energetic dysfunction.

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.

Traumatic events during childhood/early adolescence can cause long-lasting physiological and behavioral changes with increasing risk for psychiatric conditions including psychosis. Genetic factors and trauma (and their type, degree of repetition, time of occurrence) are believed to influence how traumatic experiences affect an individual. Here, we compared long-lasting behavioral effects of repeated social defeat stress (SD) applied during either peripuberty or late adolescence in adult male WT and Gclm-KO mice, a model of redox dysregulation relevant to schizophrenia. As SD disrupts redox homeostasis and causes oxidative stress, we hypothesized that KO mice would be particularly vulnerable to such stress. We first found that peripubertal and late adolescent SD led to different behavioral outcomes. Peripubertal SD induced anxiety-like behavior in anxiogenic environments, potentiated startle reflex, and increased sensitivity to the NMDA-receptor antagonist, MK-801. In contrast, late adolescent SD led to increased exploration in novel environments. Second, the long-lasting impact of peripubertal but not late adolescent SD differed in KO and WT mice. Peripubertal SD increased anxiety-like behavior in anxiogenic environments and MK-801-sensitivity mostly in KO mice, while it increased startle reflex in WT mice. These suggest that a redox dysregulation during peripuberty interacts with SD to remodel the trajectory of brain maturation, but does not play a significant role during later SD. As peripubertal SD induced persisting anxiety- and fear-related behaviors in male mice, we then investigated anxiety in a cohort of 89 early psychosis male patients for whom we had information about past abuse and clinical assessment during the first year of psychosis. We found that a first exposure to physical/sexual abuse (analogous to SD) before age 12, but not after, was associated with higher anxiety at 6-12 months after psychosis onset. This supports that childhood/peripuberty is a vulnerable period during which physical/sexual abuse in males has wide and long-lasting consequences.

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.

SEE CORRESPONDING ARTICLE ON PAGE 727 Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell TranscriptomicsBiological PsychiatryVol. 91Issue 8PreviewA number of rare copy number variants (CNVs) have been linked to neurodevelopmental disorders. However, because CNVs encompass many genes, it is often difficult to identify the mechanisms that lead to developmental perturbations. Full-Text PDF Open Access

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.

HCs (N 1⁄4 51) propensity-matched on age, sex, and verbal IQ were also used to confirm initial findings. Results: Individuals with SUDs showed poorer task performance than HCs (p 1⁄4 .03, Cohen’s d 1⁄4 .33). Compared to HCs, model estimates revealed less precise action selection mechanisms (p 1⁄4 .004, d 1⁄4 .43), a lower learning rate after losses (p 1⁄4 .02, d 1⁄4 .36), and a greater learning rate after wins (p 1⁄4 .04, d 1⁄4 .31). Groups did not differ in goal-directed information seeking. Conclusions: Findings suggest a pattern of continued uncertainty after positive outcomes in SUDs combined with a tendency to attribute negative outcomes to chance. This could help explain continual maladaptive choices despite negative consequences in substance users, and associated difficulties in adjusting behavior and maintaining adaptive decision-making during and after treatment. Supported By: William K. Warren Foundation National Institute of Mental Health (K23MH112949 and K23MH108707 ) National Institute of General Medical Sciences (Center Grant, P20GM121312)

Redox imbalance/oxidative stress affect oligodendrocytes precursor cells (OPC) and myelination, leading to dysconnectivity.

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.