Neuroscience & Biobehavioral Reviews

Importance: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A2ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A2ND glucose dysregulation spatial signature remains undescribed. Objective: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A2ND. Data Sources: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET). Study Selection: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included. Data Extraction and Synthesis: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria. Main Outcomes and Measures: Cluster peak and subpeak coordinates, cluster-wise t- or Z- values, and annotations indicating the disease of interest, whether the outcome was for hyper- (disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE. Results: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5412 individuals with A2ND and 3549 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A2ND which included both hypo- and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A2ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities. Conclusions and Relevance: These data demonstrate dysregulated glucose metabolism as a common A2ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A2ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.

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.

Meta-analyses are a valuable tool in evidence-based research and have contributed to our understanding of structural brain changes in chronic pain. Meta-analyses are also limited by published summary statistics and quality/completeness of underlying studies. To address these limitations, we conducted the first individual participant data (IPD) meta-analysis of brain structure alterations in chronic pain. Using traditional morphometric measures (i.e., volume, cortical thickness, and surface area) and differential-geometric shape metrics (i.e., intrinsic and extrinsic curvature), we aimed to reveal alterations in brain structure convergent across chronic pain conditions. Eight publicly available datasets spanning five conditions and 401 individuals with chronic pain were analyzed: 1) knee osteoarthritis, 2) chronic low back pain, 3) fibromyalgia, 4) migraine, and 5) primary trigeminal neuralgia. FreeSurfer was used to parcellate T1-weighted anatomical images, and metrics for cortical and subcortical structures were extracted. Meta-analysis of study-level comparisons revealed a range of structural changes in the brain associated with chronic pain. Cortical thinning and volume loss were small and localized to the temporo-occipital regions, including bilateral volumetric reductions in the entorhinal cortex. Increases in intrinsic curvature were widespread, involving 49 out of 68 cortical regions. No significant alterations were detected in subcortical volumes. Intrinsic curvature and subcortical volumetric estimates had higher levels of inter-study heterogeneity compared to other metrics, reflecting potential condition and sample specific variability. Leveraging harmonized processing across a large sample size, our novel IPD meta-analysis highlights both widespread and region-specific structural remodeling of chronic pain-related neuroanatomy.

Sex differences exist in many neurological and psychiatric diseases. Mandates have been initiated across funding agencies for research to include males and females. What has been lacking in the literature is a detailed assessment of how sex is incorporated into the design (e.g. balanced design) and into the analyses (e.g. covariate). We surveyed papers in 2009 and 2019 across six journals in Neuroscience and Psychiatry. There was a 30% increase in the percentage of papers that included both sexes to 68% in 2019. Despite this increase, in 2019 only 19% of studies used an optimal design for discovery of possible sex differences and only 5% analyzed sex as a discovery variable. Here we show that little progress has been made in harnessing the power that sex differences can afford in research for discovery and therapeutic potential for neurological and psychiatric disease to improve the health of men, women and gender diverse individuals. Highlights68% of Neuroscience and Psychiatry papers reported the use of both sexes in 2019 Only 19% of studies in 2019 used sex consistently throughout the study analyses Of the studies that used males and females, 59% did not include sex in the analyses Only 5% of studies in 2019 used sex as a discovery variable in their analyses Male only papers were 8.4 times more prevalent than female-only papers

Dysregulated brain reward systems have been observed in chronic pain. Using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in patients with fibromyalgia. The current study aimed to replicate these results in a separate cohort of patients with fibromyalgia recruited at a new location using a similar study design. Twenty patients with fibromyalgia and 20 healthy controls were included in the replication study. Group fMRI analyses revealed a solid and consistent trend of main findings similar to the previous results. Specifically, in the replication cohort of patients with fibromyalgia, medial prefrontal cortex (MPFC) activity was reduced during gain anticipation and increased during no-loss (non-punishment) outcomes, as compared to controls. Similar to the Martucci et al. results, again in the replication cohort, nucleus accumbens activity during gain anticipation did not differ in patients compared to controls. The same behavioral, correlational, and exploratory analyses that were conducted in the Martucci et al. study were conducted in the present replication study, with prior results largely replicated here. Thus, the present replication study results solidify observations of altered cortico-striatal processing to monetary rewards in chronic pain, which underscore relevance of altered brain reward circuits, particularly as related to the MPFC in patients with fibromyalgia.

The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.

Detecting a sex difference in response to a treatment or intervention, often reported as a "sex-specific effect," requires statistical comparison of the response across sex. Here, we investigated analytical approaches used to test for such effects in the behavioral and brain sciences. Of 200 recent articles containing terms such as sex-specific or gender-dependent in their titles, only 24% presented appropriate evidence supporting the claim: the effect was compared statistically across sex and results consistent with the claim were reported. In most articles (58%), no test was conducted that could have supported the title claim. Only 15% of studies on non-human animals supported the claim with appropriate evidence, which was significantly less frequently than studies on human participants (34%; p = 0.002). The use of appropriate analytical approaches was unrelated to journal rank or the citation impact of the article. We conclude that claims of sex/gender-dependent effects in the behavioral and brain sciences are only infrequently supported by appropriate evidence.

ImportanceThe pathophysiology of ADHD is complicated by high rates of psychiatric comorbidities, thus delineating unique versus shared functional brain perturbations is critical in elucidating illness pathophysiology. ObjectiveTo investigate resting-state fMRI (rsfMRI)-complexity alterations among children with ADHD, oppositional defiant disorder (ODD), and obsessive-compulsive disorder (OCD), respectively, and comorbid ADHD, ODD, and OCD, within the cool and hot executive function (EF) networks. DesignWe leveraged baseline data (wave 0) from the Adolescent Brain and Cognitive Development (ABCD) Study. SettingThe data was collected between September 2016 and September 2019 from 21 sites in the USA. ParticipantsChildren who singularly met all DSM-5 behavioral criteria for ADHD (N = 61), ODD (N = 38), and OCD (N = 48), respectively, were extracted, alongside children with comorbid ADHD, ODD, OCD, and/or other psychiatric diagnoses (N = 833). A control sample of age-, sex-, and developmentally-matched children was also extracted (N = 269). Main Outcomes and MeasuresVoxel-wise sample entropy (SampEn) was computed using the LOFT Complexity Toolbox. Mean SampEn within all regions of the EF networks was calculated for each participant and hierarchical models with Generalized Estimating Equations compared SampEn of comorbid-free and comorbid ADHD, ODD, and OCD within the EF networks. ResultsSampEn was reduced in comorbid-free ADHD and ODD in overlapping regions of both EF networks, including the bilateral superior frontal gyrus, anterior/posterior cingulate gyrus, and bilateral caudate (Wald statistic = 5.682 to 10.798, p < 0.05 & BH corrected), with ADHD additionally affected in the right inferior/middle frontal gyrus and bilateral frontal orbital cortex (Wald statistic = 7.231 to 9.420, p < 0.05 & BH corrected). Among comorbid presentations, the additional presence of ADHD symptomatology was associated with significantly lower SampEn in every region of interest (z = -3.973 to -2.235, p < 0.05 & BH corrected). Conclusions and RelevanceADHD and ODD shared common impairments underlying the EF networks in the comorbid-free presentations, with ADHD showing more widespread complexity reduction. When ADHD co-occurred with other psychiatric disorders, the reduction in SampEn extended beyond the regions affected in comorbid-free ADHD, indicating that comorbidities amplify neural complexity deficits.

BackgroundAutism spectrum disorder (ASD) represents a panel of conditions that begin during the developmental period and result in impairments of personal, social, academic, or occupational functioning. Early diagnosis is directly related to a better prognosis. Unfortunately, the diagnosis of ASD requires a long and exhausting subjective process. ObjectiveTo review the state of the art for the automated autism diagnosis. MethodsIn February 2022, we searched multiple databases and several sources of grey literature for eligible studies. We used an adapted version of the QUADAS-2 tool to assess the risk of bias in the studies. A brief report of the methods and results of each study is presented. Data were synthesized for each modality separately using the Split Component Synthesis (SCS) method. We assessed heterogeneity using the I2 statistics and evaluated publication bias using trim and fill tests combined with ln DOR. Confidence in cumulative evidence was evaluated using the GRADE approach for diagnostic studies. ResultsWe included 344 studies from 186020 participants (51129 are estimated to be unique) for nine different modalities in this review, from which 232 reported sufficient data for meta-analysis. The area under the curve was in the range of 0.71-0.90 for all the modalities. The studies on EEG data provided the best accuracy, with the area under the curve ranging between 0.85 to 0.93. ConclusionsThe literature is rife with bias and methodological/reporting flaws. Recommendations are provided for future research to provide better studies and fill in the current knowledge gaps.

IntroductionWe previously described preclinical literature, which supports umbilical cord blood-derived cell (UCBC) therapy use for perinatal brain injury. However, efficacy of UCBCs may be influenced by different patient populations and intervention characteristics. ObjectivesTo systematically review effects of UCBCs on brain outcomes in animal models of perinatal brain injury across subgroups to better understand contribution of model type (preterm versus term), brain injury type, UCB cell type, route of administration, timing of intervention, cell dosage and number of doses. MethodsA systematic search of MEDLINE and Embase databases was performed to identify studies using UCBC therapy in animal models of perinatal brain injury. Subgroup differences were measured by chi2 test where possible. ResultsDifferential benefits of UCBCs were seen in a number of subgroup analyses including intraventricular haemorrhage (IVH) vs. hypoxia ischaemia (HI) model (apoptosis white matter (WM): chi2=4.07; P=0.04, neuroinflammation-TNF-: chi2=5.99; P=0.01), UCB-derived mesenchymal stromal cells (MSCs) vs. UCB-derived mononuclear cells (MNCs) (oligodendrocyte WM: chi2=5.01; P=0.03, neuroinflammation-TNF-: chi2=3.93; P=0.05, apoptosis grey matter (GM), astrogliosis WM) and intraventricular/intrathecal vs. systemic routes of administration (microglial activation GM: chi2=7.51; P=0.02, astrogliosis WM: chi2=12.44; P=0.002). We identified a serious risk of bias and overall low certainty of evidence. ConclusionsPreclinical evidence suggests greater efficacy for UCBCs in IVH compared to HI injury model, use of UCB-MSCs compared to UCB-MNCs, and use of local administrative routes compared to systemic routes in animal models of perinatal brain injury. Further research is needed to improve certainty of evidence found and address knowledge gaps. SIGNIFICANCE STATEMENTIn neonatal medicine there is a clear need for the development of new therapies that can provide neuroregenerative benefits for infants with brain injuries. This review offers a unique and comprehensive resource to inform the development of future preclinical and clinical studies. In part A of this review, we systematically reviewed the preclinical literature surrounding UCBCs as a therapy for perinatal brain injury. In part B of this review, we investigated the effect variables, such as UCB cell type, timing of administration and dosage, have on the efficacy of UCB-derived cell therapy in animal models of perinatal brain injury. We identified UCBCs to show greater efficacy in the brain injury model of IVH compared to HI, the use of UCB-derived MSCs compared to MNCs and the use of local administrative routes compared to systemic routes. In addition to this, we identified knowledge gaps such as the limited preclinical literature surrounding the effect of dose number and sex.

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.

IntroductionThis is a follow-up study on our recent systematic review by Storebo and colleagues on methylphenidate for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) published in The Cochrane Library. We aim to investigate the risks of research waste and publication bias in randomised clinical trials investigating methylphenidate versus placebo or no intervention for children and adolescents with ADHD. MethodThe method used includes our initial cohort of randomised clinical trials selected from searching Clinicaltrials.gov and the EUCTR with the following criteria: methylphenidate versus placebo or no intervention with or without co-interventions for children or adolescents with ADHD, randomised clinical trials, any dosage, any delivery method, and at least 75% children and adolescents with ages less than 18 years as well as a time period of 1999-2022. Our primary objective is to assess how many randomised clinical trials of methylphenidate on children and adolescents with ADHD are registered in protocol databases, but never published in academic literature or as tabular summary results. The number of participants included in these trials is a secondary objective. Our third objective is to examine the relationship between trial results and the chance of being published. Our fourth objective is to assess the time from registry to publication of randomised clinical trials of methylphenidate on children and adolescents with ADHD in either a journal or as summary results, and the number of participants in these trials. The cutoff time for a publication to be considered timely published will be 6 months, as per European Medicines Agency guidelines for clinical trials involving children. ResultsThis is our protocol for the study and no results are presently available.

A persistent effort in neuroscience has been to pinpoint the neurobiological substrates that support mental processes. The Research Domain Criteria (RDoC) aims to develop a new framework based on fundamental neurobiological dimensions. However, results from several meta-analysis of task-based fMRI showed substantial spatial overlap between several mental processes including emotion and anticipatory processes, irrespectively of the valence. Consequently, there is a crucial need to better characterize the core neurobiological processes using a data-driven techniques, given that these analytic approaches can capture the core neurobiological processes across neuroimaging literature that may not be identifiable through expert-driven categories. Therefore, we sought to examine the main data-driven co-activation networks across the past 20 years of published meta-analyses on task-based fMRI studies. We manually extracted 19,822 coordinates from 1,347 identified meta-analytic experiments. A Correlation-Matrix-Based Hierarchical Clustering was conducted on spatial similarity between these meta-analytic experiments, to identify the main co-activation networks. Activation likelihood estimation was then used to identify spatially convergent brain regions across experiments in each network. Across 1,347 meta-analyses, we found 13 co-activation networks which were further characterized by various psychological terms and distinct association with receptor density maps and intrinsic functional connectivity networks. At a fMRI activation resolution, neurobiological processes seem more similar than different across various mental functions. We discussed the potential limitation of linking brain activation to psychological labels and investigated potential avenues to tackle this long-lasting research question.

Electroencephalography (EEG) has emerged as a key method for investigating the neural mechanisms through which oxytocin influences cognition and behaviour. EEG is cost-effective, has excellent temporal precision, and may elucidate neural correlates of emotional and cognitive processes. EEG studies evaluating oxytocins electrophysiological effects have, however, yielded mixed results, which is likely driven by heterogeneity in EEG measures, study designs, dosages, and samples. To investigate the effect of oxytocin administration on EEG measures, we performed two multilevel random effects meta-analyses: The first meta-analysis synthesized studies investigating the effects of oxytocin administration on different neural correlates of social and cognitive processing; the second meta-analysis synthesized studies evaluating effects of oxytocin administration on exploratory, less task-specific neural activity measures, such as the modulation of microstates. Across both meta-analyses, we synthesized 161 effect sizes from 28 randomised controlled trials with a total of 1361 participants from different population groups. These multilevel meta-analyses yielded small effect sizes of oxytocin administration across different EEG measures reflecting social and cognitive processes (Hedges g = 0.14), and exploratory neural activity (Hedges g = 0.28) with significant heterogeneity estimates (p < 0.01 and p < 0.001, respectively). Moderator analyses revealed that the different EEG measurements of interest (e.g., event-related potentials) and the proportion of female participants were found to significantly moderate the effect of oxytocin on neural EEG activity. Altogether, these meta-analyses present tentative evidence for oxytocin administration modulating a wide range of neural activity. We observed substantial heterogeneity across studies - in terms of study designs, experimental paradigms and EEG measurements, and participant characteristics. More research is warranted to map out the context-specific effects of oxytocin administration on different neural markers, to better understand the neurobiological mechanisms of oxytocin.

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)--the rhythmic heart rate modulation accompanying respiration--has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortical substrates that coordinate rhythmic cardiovascular-respiratory coupling are not well understood. Our current findings highlight the involvement of the left orbitofrontal cortex (OFC) in oscillatory cardiorespiratory dynamics. In adults aged 50-70 (N = 55; mean age = 60.1 {+/-} 6.0 years; 29 female), across both a slow-paced breathing condition and a random-paced breathing condition, greater heart rate oscillatory power during 9-week breathing training sessions predicted OFC volume increases. OFC changes were most strongly linked with upper low-frequency range power during practice (0.09-0.13 Hz; p < 0.005, cluster-corrected) but were not tightly constrained by precise breathing frequency. These effects covaried with improved attentional and executive performance, including reduced pupil responses to distractors and enhanced working-memory and associative-memory scores. Our findings identify the orbitofrontal cortex as a key site of cortical plasticity linked to rhythmic cardiovascular-respiratory engagement. By delineating how oscillatory body-brain coupling supports cognitive control-related processes, including attentional filtering and memory updating, this work bridges mechanistic neuroscience and translational intervention science, suggesting a frequency-general pathway through which simple breathing practices may enhance neurovisceral integration and cognitive resilience in aging. SummaryO_LIGreater oscillatory heart rate power during breathing training, particularly within the upper low-frequency range (0.09-0.13 Hz), predicted increases in left orbitofrontal cortex (OFC) volume. C_LIO_LIOFC volume increases were associated with improved attentional and executive performance, including reduced pupil reactivity to distractors and enhanced working-memory and associative-memory scores. C_LIO_LIThese findings suggest that rhythmic cardiovascular-respiratory coupling supports cortical plasticity and cognitive resilience, providing a frequency-general mechanism through which breathing practices enhance neurovisceral integration in aging. C_LI

Identifying early biomarkers of restricted and repetitive behaviours among children with neurodevelopmental disorders may support the development of targeted therapeutic interventions in both clinical and educational settings, ultimately improving their learning experiences and long-term developmental trajectories. The objectives of the study were to examine midbrain dopamine and norepinephrine integrity in children with and without neurodevelopmental disorders using neuromelanin-sensitive magnetic resonance imaging, and the association with restricted and repetitive behaviours. Participants were enrolled in the Child and Adolescent Brain Imaging Network (CABIN) or the Fetal Imaging and Neurodevelopment (FIND) studies. All participants completed MRI and behavioural assessments, including parent-reported RRBs measured with the Repetitive Behavior Scale-Revised. A total of 88 infants, children and adolescents (mean [SD] age, 9.47 [5.41] years; 46 males) were included. Age positively predicted neuromelanin-MRI signal intensity in the substantia nigra ({beta}=.75, p<.001) and locus coeruleus ({beta}=.38, p=0.007). Further, locus-coeruleus neuromelanin-MRI signal intensity was significantly higher in children with ASD and ADHD compared to TD peers (both, p<.007). Among children with autism, lower signal predicted more severe self-injurious behaviours ({beta}=-.420, p=.006) and restricted interests ({beta}=-.629, p<.001). Findings indicate a role for neuromelanin concentration in the locus coeruleus as a candidate biomarker for restricted and repetitive behaviours, particularly in children with autism. These behaviours may reflect reduced noradrenergic signalling and impaired capacity for arousal regulation and behavioural control in children with lower LC neuromelanin signal. Findings highlight the importance of targeting the noradrenergic system when developing therapeutic strategies. Pharmacological interventions aimed at modulating the noradrenergic system and school-based strategies supporting arousal regulation, behavioural flexibility, and cognitive control may help reduce symptom severity and improve functioning.

BackgroundGlioblastoma (GBM) is characterized by aggressive clinical behavior and profound resistance to conventional therapies. As a result, non-pharmacologic strategies that exploit tumor metabolic vulnerabilities, particularly dietary interventions, are gaining attention. Ketogenic diets (KD) and methionine restriction (MR) aim to disrupt tumor bioenergetics and epigenetic regulation by modifying systemic nutrient availability. ObjectiveTo systematically evaluate preclinical and clinical evidence on the efficacy, safety, and mechanistic rationale of KD and MR in glioma treatment. MethodsWe conducted a systematic review of PubMed and Embase (through June 10, 2025), including preclinical and clinical studies involving KD or MR in gliomas. Eligible studies included in vivo preclinical models and clinical trials involving high grade gliomas. Data on study design, intervention characteristics, outcomes (survival, metabolic biomarkers, feasibility), and proposed mechanisms were extracted and synthesized narratively. ResultsA total of 31 studies were included: 10 preclinical and 13 clinical for KD; 6 preclinical and 2 clinical for MR. Preclinical studies demonstrated consistent anti-tumor effects, including survival prolongation and metabolic disruption, particularly when combined with radiotherapy or chemotherapy. Clinical outcomes were variable. KDs were feasible and well-tolerated, though adherence varied and survival benefits were inconsistent. MR showed promising metabolic effects and some clinical responses, but trials were limited by small sample sizes and high toxicity when combined with chemotherapy. ConclusionDietary interventions such as KD and MR target critical metabolic vulnerabilities in gliomas and show strong preclinical rationale. However, clinical translation is challenged by tumor heterogeneity, metabolic adaptability, and dietary adherence. Future trials should incorporate metabolic imaging, flux analysis, and cross-disciplinary strategies to optimize and personalize dietary therapies as adjuncts in glioma care.

Early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in children. Increasingly, the importance of microglia in these disorders has been recognised. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-expoure of human iPS-microglia to GCs during primitive haematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia. The iPS-microglia predominately expressed glucocorticoid receptors over mineralocorticoid receptors, and the GR- splice variant. Chronic GCs exposure during primitive haematopoiesis was able to recapitulate in vivo ELS effects. Thus pre-exposure to prolonged GCs resulted in increased type I interferon signalling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, and cellular senescence in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC-mediated ELS- associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder. HighlightsO_LIHuman iPS-derived-microglia predominantly express glucocorticoid receptor NR3C1 compared with mineralocorticoid receptor NR3C2, and a predominant splice variant of the NR3C1 of GR-. C_LIO_LIGC expression shows a differentiation-linked increment from iPSC to iPS-microglia. C_LIO_LIAn early-life stress model was established by exposing iPSC to glucocorticoids during primitive haematopoiesis. C_LIO_LIRNA-seq analysis revealed that this early glucocorticoid exposure led to enhanced type I interferon inducible gene expression in the subsequent iPS-microglia. C_LIO_LIFurthermore, micronuclei formation and cellular senescence markers were upregulated in the iPSC-microglia, indicating genomic instability due to early chronic GC exposure. C_LIO_LIThese findings have ramifications for the microglial responses in ELS linked neurodevelopmental disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/493044v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@27854aorg.highwire.dtl.DTLVardef@9fc488org.highwire.dtl.DTLVardef@11fdfeaorg.highwire.dtl.DTLVardef@1a5a74f_HPS_FORMAT_FIGEXP M_FIG C_FIG

Adverse childhood experiences (ACEs) are common, altering behaviour and stress reactivity, with persistent structural and functional brain changes. ACEs are associated with a greater risk of physical and mental health morbidities, including depression and chronic pain (CP), which often co-exist. While changes in the reward system have been implicated in each condition, it remains unclear whether there are common neural mechanisms. Using brain scans from a large community sample, we examined how ACEs, depression, and CP affected the reward system. Individuals reporting both ACEs and CP exhibited reduced volume in the nucleus accumbens, a brain region associated with motivation and pleasure, particularly among women. Blunted reward-related activity in the basal ganglia was linked to higher depression scores, CP severity, and experiences of childhood sexual abuse. Importantly, these functional changes remained significant even after accounting for structural brain differences. Interestingly, brain structural-functional associations were weak, suggesting distinct underlying mechanisms. Structural brain alterations likely represent cumulative, enduring consequences of ACEs and CP, whereas altered reward activity appears more closely tied to current symptom severity. These findings reveal separable but converging neurobiological signatures of early adversity, pain, and depression within the brains reward system.

Identifying brain biomarkers of disease risk is a growing priority in neuroscience. The ability to identify meaningful biomarkers is limited by measurement reliability; unreliable measures are unsuitable for predicting clinical outcomes. Measuring brain activity using task-fMRI is a major focus of biomarker development; however, the reliability of task-fMRI has not been systematically evaluated. We present converging evidence demonstrating poor reliability of task-fMRI measures. First, a meta-analysis of 90 experiments (N=1,008) revealed poor overall reliability (mean ICC=.397). Second, the test-retest reliabilities of activity in a priori regions of interest across 11 common fMRI tasks collected in the context of the Human Connectome Project (N=45) and the Dunedin Study (N=20) were poor (ICCs=.067-.485). Collectively, these findings demonstrate that common task-fMRI measures are not currently suitable for brain biomarker discovery or individual differences research. We review how this state of affairs came to be and highlight avenues for improving task-fMRI reliability.