Neuroscience & Biobehavioral Reviews

Youth alcohol use is a significant global health concern. Despite the widespread nature of alcohol use-related problems, the longitudinal effects of alcohol on brain structure in youth remain unclear. This review aimed to systematically synthesise the findings from the longitudinal structural magnetic resonance imaging (sMRI) literature on how alcohol use is associated with changes in brain structure in youth. Following PRISMA guidelines, five databases were searched, and studies of youth alcohol use that measured brain structure using sMRI at more than one time-point were included. A label-based meta-analysis (i.e., ratio of number of significant effects for a specific brain region to total number of analyses for that brain region) approach was employed to synthesise the findings. Sixteen studies were included. There was preliminary evidence that youth alcohol use is associated with reduced cortical volume (particularly in temporal regions) and attenuated increases in white matter volume over time. The role of pre-existing structural differences, and other moderating factors remains unclear due to limited research. Future longitudinal studies are needed to clarify the clinical significance of neurodevelopmental changes associated with youth alcohol use. Significance statementThis systematic review synthesises evidence from 16 longitudinal neuroimaging studies on youth alcohol use and brain structure. Preliminary findings suggest adolescent drinking may be associated with reduced grey and white matter volume over time, with heavier consumption amplifying these effects. While methodological limitations prevent definitive conclusions, these potential neurodevelopmental disruptions during a critical brain maturation window could influence cognitive and behavioural outcomes. The review highlights the need for rigorous future research to further clarify the impact of alcohol on developmental brain trajectories, which could support targeted prevention approaches for adolescent brain health.

Background and HypothesisSchizophrenia is a disease characterized by various symptoms and has severe lifelong impacts on patients and their families. Despite various hypotheses and associated studies, the key mechanism in schizophrenia is not fully elucidated. In the present study, we focused on adropin, a peptide regulating energy metabolism, antioxidation, and neuroprotection. Study DesignIn both the group of healthy volunteers (HV) and the group of patients with some schizophrenia spectrum and other psychotic disorders (SZ), we evaluated adropin along with other variables such as anthropological factors, psychological well-being indicators, and laboratory test results. Study ResultsThe adropin levels in SZ were not significantly different from those in HV. Correlation analysis indicated five significant correlations beyond various natural correlations arising from fundamental proportional relationships and multifaceted psychological well-being indicators: (1) adropin versus right handgrip strength in the SZ group ({tau} = -0.82, P = 0.066); (2) adropin versus selenium in the total group ({tau} = 0.44, P = 0.053); (3) ferritin versus perceived stress in the total group ({tau} = -0.44, P = 0.053); (4) right versus left handgrip strength in the total group ({tau} = 0.70, P = 0.001) and in the SZ group ({tau} = 0.82, P = 0.075); and (5) selenium versus state anxiety in the total group ({tau} = 0.44, P = 0.053) and the SZ group ({tau} = 0.84, P = 0.066). ConclusionsThe present study provides a foundation for future studies and sheds light on the role of adropin in schizophrenia.

ObjectiveAlthough mental health and healthy lifestyle interventions are associated with functional outcomes in adolescence, the extent to which particular lifestyle factors explain relationships between mental health and outcome are unclear. Here we examined mediating effects of lifestyle factors on relationships between mental health and two functional outcomes measured 2-3 years later as well as the moderating effect of environmental risk factors on mediation strength in early adolescence. MethodsThis study analyzed data from 3 waves of the Adolescent Brain Cognitive Development Study (ages 10-11, 11-12, and 12-13). Mediating effects of sleep quality, screen time, physical activity and Mediterranean diet on the relationships between depression, anxiety, psychotic-like experience (PLE) distress, and total problems with two subsequent functional outcomes (academic functioning and social problems) were examined. Secondary analyses included environmental factors as moderators. ResultsSleep quality mediated 18.5%, 36.3%, 8.3%, and 3.4% of the relationships between depression, anxiety, PLE distress and total problems with academic functioning, respectively. Screen time was the second strongest mediating factor. For social problems, only sleep quality showed > 3% mediation (19.6% - 23.3%). Mediating effects of sleep and screen time on academic functioning decreased as financial adversity increased. Conversely, mediating effects of sleep quality on social problems increased with worsening family conflict, financial adversity, and school environment. ConclusionsThese results suggest that healthy lifestyle factors (in particular sleep quality) may partially explain the associations between mental health and functioning in adolescents and suggest that these effects are modulated by environmental factors. These results may have important implications for future intervention studies.

Major depressive disorder (MDD) involves dysregulated neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways. Recently, it was shown that NIMETOX pathways should be evaluated in MDD patients stratified for metabolic syndrome (MetS). The current study aims to characterize the metabolic hormone and adipokine profiles of Chinese MDD patients stratified for MetS and to delineate their associations with overall severity of depression (OSOD), suicidal ideation (SI), recurrence of illness (ROI), and physiosomatic symptoms. We enrolled 125 MDD inpatients and 40 healthy controls and measured fasting serum insulin, glucose, glucagon, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-Like Peptide-1 (GLP-1), leptin, secretin, Plasminogen Activator Inhibitor-1 (PAI-1), resistin, ghrelin, and adiponectin, as well as the acute-phase inflammatory (API) response using albumin, transferrin (Tf), and monomeric CRP (mCRP). The results revealed a distinct metabolic hormone and adipokine signature in MDD with significantly lower insulin, glucagon, and PAI-1 levels, alongside an elevated API index (after adjusting for age, MetS, and body mass index). A composite GAP index (ghrelin, adiponectin, PAI-1) correlated negatively with OSOD, SI, ROI, physiosomatic symptoms, and adverse childhood experiences (ACEs). Integrative modeling combining the GAP index, API index, and ACEs achieved an area under the receiver operating characteristic (ROC) curve of 0.864 with an accuracy of 80% for discriminating MDD from controls. In conclusion, the findings delineated that many inpatients with severe MDD suffer from suppressed anabolic hormones and lower adipokine levels coupled with a mild, chronic inflammatory response. The deviations in this "hormonal-immune-metabolic" axis are components of the NIMETOX pathways in MDD and are not associated with MetS.

The brain age gap (BAG) -- the difference between chronological and neuroimaging-based predicted brain age -- has emerged as a sensitive biomarker of brain health. A higher BAG, reflecting an older-appearing brain, has been linked to cognitive decline, neurodegenerative disease, and mental disorders. Whether such apparent aging can be mitigated by targeted interventions remains unclear. Oestradiol (E2), a sex hormone fluctuating across the menstrual cycle and known for its neuromodulatory and cognitive effects, may represent one such target intervention. To test this, we conducted a double-blind, randomized, placebo-controlled crossover study in 28 premenopausal females. Each participant was assessed twice during the follicular phase, with at least two cycles between sessions, and received either 12 mg E2-valerate or a placebo before undergoing a T1-weighted MRI scan. BAG was estimated using a pre-trained Simple Fully Convolutional Network model. Predicted brain age was significantly younger following E2 administration compared to placebo. Exploratory analyses indicated that this effect may be moderated by resilience factors for mental health: Higher self-esteem and use of greater social support seeking was nominally associated with lower BAG, whereas females applying more expressive suppression showed more apparent brain aging. These findings suggest that even short-term increases in E2, together with resilience factors, can influence brain age estimates. Thus, E2 interventions may provide a targeted approach to support both brain and mental health. These findings underscore the urgent need for further research into the impact of E2 on mental health across the female lifespan.

Numerous studies have shown that adults with depression have distinct oculomotor alterations during saccade tasks, but whether similar alterations occur in adolescents is largely unknown. The purpose of this study was to test if eye-tracking during a structured saccade task could distinguish a group of adolescents with depression from healthy controls. We hypothesized that, due to overlapping circuitry between depression pathology and the oculomotor system, adolescents with depression would show alterations in fixation, saccade, and pupil behaviour. 51 adolescents with depression and 66 age-matched healthy controls completed the Interleaved Pro- and Anti-Saccade Task (IPAST) and several self-reported questionnaires for psychiatric symptoms. Oculomotor outcomes included fixation acquisition, fixation breaks, correct rate, saccadic reaction time, rate of correct express-latency pro-saccades, rate of express- and regular-latency anti-saccade errors, baseline pupil size, as well as pupil constriction and dilation sizes following task instruction. In comparison to healthy controls, adolescents with depression displayed impairments acquiring fixation (p<.001), made more fixation breaks in pro- (p=.023) and anti-saccade trials (p=.005), more anti-saccade errors (p=.013), more express-latency saccades overall (ps=.016), had a smaller pupil constriction in pro-saccade trials (p=.047) and had a smaller pupil dilation in pro- (p=.011) and anti-saccade trials (p=.041). No differences were found for saccadic reaction time, rate of correct pro-saccades, rate of regular-latency anti-saccade errors, pupil constriction size during anti-saccade trials, or baseline pupil size. Patients had psychiatric comorbidities and were using psychotropic medication. While this reflected clinical reality, these factors may have influenced oculomotor behaviour. Adolescents with depression had altered fixation, saccade, and pupil behaviour during IPAST. Given that many cases of adolescent depression remain undetected, accessible and objective screening approaches are highly needed. This oculomotor phenotype may be used in the development of such a screening tool to detect those at risk.

Chronic pain is increasingly conceptualized within a stress-related framework. However, it remains unclear whether chronic pain and prototypical stress-related conditions--such as post-traumatic stress disorder (PTSD)--share common neurobiological substrates. To this end, we conducted a pre-registered transdiagnostic meta-analytic study of gray matter volume alterations in chronic pain (60 studies) and PTSD (20 studies). Disorder-specific meta-analyses revealed that chronic pain was associated with distributed volume reductions across ventromedial prefrontal, middle cingulate, and insular cortices, whereas PTSD exhibited a single cluster of reduced volume in the anterior cingulate/dorsomedial prefrontal cortices. A conjunction analysis revealed that both conditions converged onto an overlapping cluster of reduced volume in the bilateral medial orbitofrontal/anterior cingulate area. Using normative resting-state fMRI data (HCP 7T dataset), we found that chronic pain neuroanatomical abnormalities were embedded within a distributed architecture of large-scale circuits encompassing mesocorticolimbic/reward, default mode, salience, frontoparietal, dorsal attention, and somatosensory networks. On the other hand, the PTSD focal neuroanatomical alteration was embedded in a single large-scale circuit mapping onto the mesocorticolimbic/reward, default mode, salience, and visual networks. In both conditions, the mesocorticolimbic/reward circuit emerged as the most robustly involved large-scale network. Notably, the shared cluster of reduced volume showed functional integration within the mesocorticolimbic/reward and default mode networks, with neurochemical fingerprinting revealing robust spatial correspondence with dopaminergic, serotonergic, opioid, and endocannabinoid receptor/transporter maps. Overall, these findings suggest that chronic pain and PTSD, beyond disorder-specific alterations, converge on a shared large-scale network organization. The overlap between chronic pain and a prototypical stress-related disorder at the network level provides neurobiological support for conceptualizing chronic pain within a stress-related framework.

BackgroundAttention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by attentional deficits, hyperactivity and impulsivity that often persists into adulthood. While dysfunction of dopaminergic neurotransmitter systems has been observed, underlying mechanisms remain incompletely understood. Current treatments with methylphenidate and amphetamines show limited long-term effectiveness and do not address broader clinical needs. The endocannabinoid system represents a promising therapeutic target. Cannabinoid type 1 (CB1) receptors are highly concentrated in the prefrontal cortex and striatum, brain regions central to ADHD pathophysiology. The "dual pathway model of ADHD" describes deficits in inhibition-related executive functions and reward-related functions, both mediated by fronto-striatal networks. Striatal CB1 receptor availability correlates negatively with impulsivity. Given the interaction between dopaminergic and endocannabinoid systems, CB1 receptors may play a key role in ADHD pathogenesis. MethodsThis controlled study will investigate CB1 receptor availability in ADHD using positron emission tomography (PET) with the CB1-selective radiotracer [18F]MK-9470. The primary outcome is the CB1 receptor distribution volume (VT) in the striatum. Secondary outcomes include CB1 receptor availability in prefrontal cortex and other ADHD-relevant brain regions, plasma concentrations of endocannabinoids (anandamide, 2-arachidonoylglycerol), and validated neuropsychological assessments of attention and impulsivity. We will compare three groups (n=34 each): medication-naive participants with ADHD, methylphenidate-treated participants with ADHD, and healthy controls. Statistical analysis will employ ANOVA with post-hoc comparisons and correlation analyses between neuroimaging and behavioral measures. DiscussionThis first investigation of the endocannabinoid system in ADHD will provide crucial insights into disease mechanisms and identify potential therapeutic targets. Results may inform development of novel cannabinoid-based treatments and improve evidence-based therapeutic strategies for ADHD management. Trial registration: German Clinical Trials Register (DRKS-ID: DRKS00037526, Registration date: 25 September 2025)

The present study focuses on the role of amygdala reactivity to negative facial expressions in major depressive disorder (MDD). A number of studies have found amygdala hyperreactivity in depressed patients compared with control subjects. This has been interpreted in terms of a negative depressive bias in attention and memory, given the amygdalas role in attending to and remembering negatively valenced stimuli. However, failure to find amygdala hyperreactivity in depression is not uncommon, and a recent failure to replicate the effect with an extremely well-powered analysis of UK Biobank data led many to conclude that amygdala reactivity plays no role in depression. In the present study, the same UK Biobank sample is used to evaluate an alternative hypothesis about the relation between MDD and amygdala reactivity, namely that people who are vulnerable to MDD, whether or not they are currently depressed, will show elevated amygdala activity. Depression history was used as a proxy for vulnerability and regression analyses assessed the strength of the relation between three MDD history measures and amygdala reactivity. Two of three assessments of depression history showed highly significant relations with amygdala reactivity, the third showing a combination of significant and nonsignificant trends depending on the analysis.

Schizophrenia is a severe neuropsychiatric disorder characterized by positive and negative symptoms and cognitive impairments. The present study aimed to investigate the potential interference of ambient noise on the performance of executive function (EF) tasks in individuals with schizophrenia. The sample consisted of 40 participants, divided equally into two groups: a group of individuals with schizophrenia (SchG) and a healthy control group without neuropsychiatric disorders (HC). All participants did three EF assessment instruments: Trail Making Test, Corsi Block Test, and Maze Test. The experimental design included a test-retest procedure with order counterbalancing: half of the sample began the assessment in the noise condition and the other half in the no-noise condition, to control for order and learning effects. The results indicate that ambient noise has a negative impact on the cognitive performance of individuals with schizophrenia. Specifically, the SchG group performed significantly worse on the Maze Test in the noise condition compared to the no-noise condition. These findings contribute to the understanding of the interactions between sensory and cognitive processes underlying the symptoms of schizophrenia. In addition to their theoretical potential, the results have practical implications, as they support the development of intervention strategies and ambiental adaptations that can improve the functionality and quality of life of people with the disorder.

BackgroundWorldwide, common mental disorders such as anxiety and depression are major contributors to disability. However, the role of diet as a risk factor for anxiety and depression remains underexplored. Therefore, we investigated the associations between food groups and major depressive disorder (MDD) and anxiety disorders, following a harmonized protocol to enable integration of studies. MethodsWe analysed data from 1,634 participants in the Netherlands Study of Depression and Anxiety to examine cross-sectional associations between 14 dietary exposures--derived from a 238-item Food Frequency Questionnaire (fruit, vegetables, legumes, whole grains, nuts and seeds, milk, red meat, processed meat, sweet drinks, fibre, calcium, omega-3 fatty acids, polyunsaturated fatty acids, and trans fats)--and anxiety and depressive disorders in the past month (assessed with the Composite International Diagnostic Interview). Secondary outcomes were depressive symptoms (Quick Inventory of Depressive Symptomatology score [&ge;]13 vs. <13) and anxiety symptoms (Beck Anxiety Index score [&ge;]16 vs. <16). Logistic regression analyses were conducted for each dietary exposure, with depression and anxiety measures as outcomes. Results8.7% had MDD and 14.4% had an anxiety disorder in the past month. Higher vegetable intake was associated with lower odds of depression and anxiety disorders. Additionally, higher intakes of omega-3 fatty acids, red meat, whole grains, and fibre were associated with lower odds of depression and anxiety, whereas higher intake of trans fats was associated with increased odds of these disorders. Other dietary exposures were not significantly related to depression or anxiety. DiscussionCertain dietary exposures, particularly vegetables, as well as omega-3 fatty acids, red meat, whole grains, and fibre, were associated with depression and anxiety outcomes. These findings may contribute to integration of results in Global Burden of Diseases initiatives on exploring dietary risk factors of depression and anxiety.

BackgroundTourette syndrome is a childhood-onset neuropsychiatric disorder characterised by recurrent motor and vocal tics. It shows a marked male predominance and is frequently associated with comorbid conditions such as attention-deficit/hyperactivity disorder (ADHD) and obsessive- compulsive disorder (OCD). Histaminergic dysregulation in the brain has been proposed as one of the mechanisms underlying Tourette syndrome. Vitamin B6, a key cofactor in histamine metabolism, may therefore play a contributory role in its pathophysiology. MethodThe clinical features of 25 children diagnosed with Tourette syndrome were assessed using the Yale Global Tic Severity Scale. Plasma vitamin B6 levels were measured using enzyme-linked immunosorbent assay (ELISA) and compared with those of a control group. ResultMost participants were males, and 16% had comorbid ADHD or OCD. The most common motor tics were eye blinking, shoulder shrugging, head jerking, and orofacial movements. Frequent vocal tics included throat clearing, sniffing, uttering syllables, and breathing-related tics. Coprolalia was observed in four children. The median plasma vitamin B6 level in the Tourette syndrome group was 25.01ng/ml, which was significantly lower than the 36.33ng/ml in the control group (Mann-Whitney U = 225, p = 0.03). The rank-biserial correlation indicated a moderate effect size (r = 0.35). ConclusionTourette syndrome in children predominantly affects males and is commonly associated with ADHD and OCD. Coprolalia-a clinically distressing symptom - was present only in a small subgroup. The lower plasma vitamin B6 levels observed in children with Tourette syndrome suggest a possible role for vitamin B6 in disease pathogenesis, potentially through its involvement in histaminergic and GABAergic neurotransmission, as well as in the modulation of neuroinflammatory processes.

BackgroundMajor depressive disorder (MDD) severely impairs individual health and creates heavy societal burdens. Diagnostic and therapeutic research remains hindered by MDDs marked heterogeneity and the absence of valid biomarkers. As a neuro-immune, metabolic, and oxidative stress (NIMETOX) disorder, MDD exhibits metabolomic signatures as a final common pathway in the Chinese population. ObjectivesTo identify lipidomic profile differences between MDD patients and healthy controls and examine associations between lipidomic alterations and clinical phenotypes. MethodsWe recruited 125 MDD patients and 40 healthy controls, and measured serum lipidomic profiles using liquid chromatography-mass spectrometry. A rigorously controlled multistage machine learning pipeline with leakage-prevention measures was utilized to examine disparities between MDD and control groups and to predict phenome features. ResultsWe identified 43 differentially abundant lipids between the MDD and control groups. Subsequent factor analysis clustered the 43 lipids into 3 functional modules, namely the increased ceramide/GM3/LNAPE (CERLNAPE) module, the decreased mitochondrial fatty acid oxidation/acetyl-flux (CARSM) module, and the reduced lysophospholipid/ether-lysolipid (LYSOPE) module. The three lipidomic modules correlated with six previously reported metabolomic functional domains, establishing an integrated metabolomics-lipidomics architecture in MDD. A substantial portion of the variance in the overall severity of depression (74.0%), physiosomatic symptoms (58.5%), suicidal ideation (11.1%), and recurrence of illness (36.6%) was associated with the integrated metabolomics-lipidomics architecture. ConclusionThe MDD lipotype indicates a unified metabolic network linked to the NIMETOX pathophysiology of MDD. Lipidomics provides a robust foundation for subtyping and precision psychiatry. Ceramide, acetyl carnitine, lipotoxicity, and plasmalogens are potential drug targets to treat MDD.

BackgroundEarly low-level alcohol use predicts subsequent alcohol use and problems. Impulsivity and poor inhibitory control also predict later problematic alcohol use. However, few studies prospectively examine early sipping in combination with modeling impulsivity and inhibitory control change over time as predictors of adolescent alcohol use. MethodsData Release 6.0 from the Adolescent Brain Cognitive Development (ABCD) Study was used (n=11,866; 48% Female). A series of linear mixed-effect models examined trajectories of non-religious sipping at baseline (ages 9-10) and self-reported impulsivity (UPPS-P) and task-based inhibitory control (Flanker task) over time as predictors of past year drinks and problematic alcohol use by ages 15-16. Predictors were run as separate models and a full model with all predictors together. Models were nested within the participant and study site. Interactions with age (to measure change over time from Baseline to Year 6) were included. Corrections for multiple comparisons were employed. ResultsIn individual models, four impulsivity interactions were significant: (1) negative urgency*age ({beta}=.04, FDR-p<.001), (2) positive urgency*age ({beta}=.04, FDR-p<.001), (3) lack of planning*age ({beta}=.04, FDR-p<.001), and (4) sensation seeking*age ({beta}=.04, FDR-p<.001), suggesting that as age increases, the relationship between impulsivity and alcohol use strengthens. Sipping*age ({beta}=.02, FDR-p<.001) interactions also predicted standard drinks. Regarding problematic use, there was a significant interaction in the full model: negative urgency*age ({beta}=-.07, p=.05), indicating that this relationship is more pronounced at earlier ages. ConclusionsTrait impulsivity and sipping in late childhood relate to future alcohol use, and the relationship strengthens with age. Our results found a negative interaction between negative urgency and age on problematic use, potentially indicating negative urgency as a phenotype of vulnerability to experiencing alcohol related problems at younger ages. Findings indicate the importance of understanding facets of impulsivity in the context of adolescent alcohol use for prevention and intervention efforts.

BackgroundImpairments in cognitive functioning (CF) contribute to the onset, severity, and persistence of psychiatric symptoms. While specific CF domains may relate differentially to psychopathology, evidence also supports a general factor of cognitive impairment (the C-factor). We aimed to examine how general and domain-specific CF impairments relate to psychopathology using both diagnosis-specific and transdiagnostic symptom frameworks. MethodsData were drawn from five cognitive tasks administered in the deep-phenotyped, naturalistic MIND-Set cohort. A bifactor model of CF was estimated in a discovery sample (n = 206) and internally validated in a separate subsample (n = 312). Factor scores were then explored in relation to broad diagnostic clusters (stress-related disorders, neurodevelopmental disorders, comorbid disorders, and healthy controls), presence of specific diagnoses, number of diagnoses, and transdiagnostic symptom domains. ResultsThe bifactor model comprised a general CF factor (C-factor) and five specific subfactors--Reaction Time, Incompatibility, Working Memory, Inhibition, and Flexibility--and successfully replicated, although the general factor was relatively weak. Diagnosis-specific analyses showed that only individuals with stress-related disorders differed significantly from healthy controls on the C-factor and the Incompatibility factor. Higher impairment on the Incompatibility factor was associated with mood disorder diagnoses, while both the C-factor and Incompatibility factor were correlated with greater diagnostic burden. At the symptom level, the Incompatibility factor was associated with Negative Valence and Arousal domains, the C-factor with Negative Valence, and the Flexibility factor with Arousal. ConclusionThese findings indicate that broader cognitive impairment and deficits on tasks requiring inhibition under cognitive load are primarily related to mood disorders, ADHD, and transdiagnostic symptoms of negative valence and arousal. More generally, cognitive impairment appears to reflect symptom burden and transdiagnostic expression rather than diagnostic category alone, suggesting that dimensional symptom measures may provide a more informative framework for understanding cognitive impairment in clinical populations.

BackgroundMajor depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. ObjectivesTo identify metabolic abnormalities that differentiate inpatients with severe MDD from healthy controls through high-resolution, untargeted metabolomics. MethodsSerum samples from 125 MDD inpatients and 40 healthy controls were analyzed utilizing liquid chromatography and mass spectrometry. A meticulously regulated multistage machine learning pipeline with leakage-prevention protocols was employed to analyze differences between MDD and controls and to predict phenome scores. ResultsFeature selection showed that 16 metabolites and 6 functional modules reliably distinguished MDD. The functional profile of the metabolites indicates a convergence of lipotoxicity, phospholipid remodeling, disruptions in fatty acid metabolism, mitochondrial redox imbalance, ether-lipid metabolism, and antioxidant depletion. This MDD metabotype was not affected by metabolic syndrome. A substantial portion of the variance in overall depression severity (72.5%), physiosomatic symptoms (55.8%) and suicidal ideation (23.6%) was accounted for by increased lipitoxicity, phospholipid remodeling, and fatty acid storage/signaling. The recurrence of illness (27.7%) was associated with a self-reinforcing-lipid-redox-inflammatory module that maintains cellular stress. DiscussionThe MDD metabotype represents a cohesive metabolic network that is associated with the NIMETOX pathogenesis of MDD. Metabolomics provides a comprehensive foundation for subtyping and precision psychiatry. Lipoxygenase-15, lipotoxicity, phospholipase A2, and lipid-redox intersections are important drug targets to treat MDD.

BackgroundExercise therapy reduces depressive and anxiety symptoms, but its neural mechanisms are not fully understood. We examined whether and how running therapy reorganizes dynamic brain functional connectivity in affective disorders. MethodsAt baseline, resting-state fMRI was collected from 66 healthy controls and 50 individuals with affective disorders. Co-activation patterns analyses (CAPs) identified recurring whole-brain network states characterized by spatial patterns of regional co-activation/codeactivation patterns and their temporal occurrence rates. We compared CAPs between groups at baseline. Participants with affective disorders then received 16 weeks of running therapy or antidepressant treatment. We examined: (1) treatment-induced changes in brain CAPs and clinical symptoms, (2) brain-symptom associations at baseline versus post-treatment, and (3) associations between network reorganization and symptom improvement. ResultsAt baseline, individuals with affective disorders showed fewer occurrences of the visual-somatomotor-subcortical network state (VS-SCCAP) than controls (F=5.4, P=0.02, {superscript 2}=0.04). Running therapy significantly altered the temporal dynamics of two brain systems: the default mode (DMCAP: {beta} = -0.88, P = 0.006, d =- 0.88) and VS-SCCAP ({beta} = 0.87, P = 0.006, d = 0.85). These reorganizations were accompanied by significant improvements in depressive and anxiety symptoms (IDS: {beta} = -1.23, P < 0.001, d = -1.15; BAI: {beta} = - 0.98, P = 0.008, d = -0.93). DMCAP-symptom coupling changed significantly from baseline to post-treatment ({Delta}RHO=-0.48, Z{approx}-2.0, P<0.05). ConclusionsRunning therapy altered dynamic brain networks in association with clinical symptom improvement. These findings provide neurobiological evidence for exercise-induced therapeutic effects through transient brain-state reorganization, demonstrating the utility of dynamic connectivity approaches for characterizing neural mechanisms in affective disorders.

Evidence-based psychotherapies are first-line treatments for psychiatric disorders, yet response rates remain suboptimal. Noninvasive brain stimulation (NIBS) may augment psychotherapy by modulating treatment-engaged circuits. We conducted a systematic review and meta-analysis of randomized controlled trials comparing active NIBS plus evidence-based psychotherapy versus sham NIBS plus psychotherapy. Following Cochrane methods, we searched six databases through February 2025, screening 1,017 records. Twenty-eight trials (31 treatment arms; 1,506 participants) met inclusion criteria. Active NIBS combined with psychotherapy produced significantly greater symptom improvement than sham NIBS with psychotherapy (standardized mean difference = -0.38, 95% confidence interval [-0.68, -0.08]), with substantial heterogeneity. Moderator analyses revealed critical implementation parameters: repetitive transcranial magnetic stimulation (rTMS) showed significant benefit while transcranial direct current stimulation did not. Non-concurrent delivery--stimulation before or after psychotherapy sessions--was significantly effective, whereas concurrent administration was not. Among psychotherapy modalities, cognitive behavioral therapy combined with NIBS produced significant benefit. Human-delivered psychotherapy, but not computerized formats, significantly enhanced outcomes. By diagnosis, significant effects were observed only for anxiety disorders. Secondary analyses revealed significant anxiety symptom reduction specific to rTMS. Treatment integrity was under-reported: only 39.3% of studies used fully manualized protocols and 10.7% documented therapist adherence. Non-concurrent rTMS paired with human-delivered, manualized cognitive behavioral therapy emerges as the most effective strategy, particularly for anxiety disorders. These findings provide an evidence-based framework for optimizing combined treatment protocols and highlight the need for standardized psychotherapy fidelity monitoring in future trials.

BackgroundNeuropathic pain (NP) is a debilitating chronic pain condition caused by injury or disease of the somatosensory nervous system. Accumulating evidence indicates that astrocytes play a central role in neuroinflammatory regulation and synaptic remodeling, thereby critically influencing the initiation and persistence of neuropathic pain. However, a comprehensive overview of research trends and knowledge structures in this field is still lacking. MethodsThe analysis was conducted based on publications retrieved from the Web of Science Core Collection and Scopus, covering the period from 2000 to 2025. Studies focusing on astrocytes and neuropathic pain were systematically identified. Visualization and network analyses were performed using CiteSpace, VOSviewer, and the R package bibliometrix. Collaboration networks, co-citation patterns, keyword co-occurrence, and thematic evolution were analyzed to delineate research hotspots, developmental trajectories, and scholarly contributions across countries, institutions, authors, and journals. Results1,828 publications were included, showing a 15% average annual growth in output, which accelerated post-2010. The USA and China led in research and international collaboration, with studies concentrated in North American and East Asian institutions. Author productivity was uneven, with key researchers (Ji RR, Zhang Y, Watkins LR) contributing heavily to publications and citations. Pain and Molecular Pain were the core journals. Key themes included spinal astrocytic mechanisms, glial activation, and therapeutic modulation, with the focus evolving from injury models/markers to astrocytic activation and targeted pathways. ConclusionOur analysis shows a substantial growth in astrocyte-related NP research the past 25 years, underscoring astrocytes key role in chronic pain pathophysiology. Current trends underscore the integration of mechanistic insights with translational relevance, thereby informing future therapeutic and mechanistic advancements in NP.

BackgroundNeuropsychological deficits are common in obsessive-compulsive disorder (OCD) and may influence functional and treatment outcomes. Only a few studies have effectively targeted these deficits, with most failing to show broad transfer of training. This study aimed to evaluate the efficacy of an integrated cognitive control training (ICCT) program on neuropsychological functioning in OCD patients and assess related changes in clinical and socio-occupational functions. MethodA single-group open-label design with pre-, mid-, post-treatment, and follow-up assessments was employed with 38 participants diagnosed with OCD, who were on stable doses of serotonin reuptake inhibitors (SRIs). The ICCT program, integrating task- and game-based cognitive stimulation with metacognitive strategy training and generalization exercises, included 24 hours of training over eight weeks across therapist-guided and homework sessions. The intervention was systematically adapted and validated, and its efficacy was examined across neuropsychological, clinical, and socio-occupational domains. ResultsThe intervention demonstrated moderate to large improvements in neuropsychological functioning (R{superscript 2}M range = .15 to .27) and self-reported cognitive difficulties (R{superscript 2}M = .58) and further demonstrated transfer to untrained domains such as OCD symptom reduction (R{superscript 2}M = .54), anxiety (R{superscript 2}M = .61), depression (R{superscript 2}M = .60), metacognitive regulation (R{superscript 2}M = .30), and socio-occupational functioning (R{superscript 2}M = .26). However, response inhibition saw only small improvements (R{superscript 2}M = .11). ConclusionThe ICCT program achieved both near and far transfer of cognitive training, improving neuropsychological, clinical, and socio-occupational outcomes. This contrasts with prior interventions with limited transfer of training. The small effect on response inhibition may reflect the trait nature of the deficit, assessment limitations, or gaps in the intervention. Future studies should use randomized control designs to validate and compare ICCT with other interventions.