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.

Background: Cognitive impairment poses a significant challenge to healthcare systems worldwide, impacting patient autonomy, social participation, and quality of life, while placing a considerable burden on caregivers. Non pharmacological interventions, particularly cognitive training and non invasive brain stimulation, have emerged as promising therapeutic strategies. Objective: This study aims to quantify the synergistic effects of transcranial direct current stimulation (tDCS) with cognitive training on cognitive function across a spectrum of pathologies that induce cognitive impairment. Methods: We conducted a systematic review and metaanalysis following PRISMA guidelines. We searched PubMed for randomized controlled trials that investigated the effect of combined tDCS and cognitive training compared with cognitive training alone. The analysis was based on the GRADE framework for systematic reviews and metaanalyses. Results: Across 27 studies including 1,012 participants, tDCS combined with cognitive training showed a small effect compared with cognitive training alone (SMD = 0.36, 95% CI: 0.15 0.56). The effect was found only immediately after the intervention and declined during follow-up. Conclusion: tDCS combined with cognitive training may provide a small, short term benefit for cognitive function, but high heterogeneity across studies and loss of effect at follow up underscore the need for larger, better standardized trials to clarify its clinical value.

BackgroundMindfulness-based interventions (MBIs) have been increasingly adopted in educational settings to support cognitive development in youth. Executive function (EF)--encompassing inhibitory control, working memory, and cognitive flexibility--is a plausible target of MBI given its reliance on attention regulation. However, prior reviews have yielded mixed conclusions, partly due to inconsistent construct definitions and the pooling of heterogeneous outcome measures. ObjectivesTo (1) estimate the pooled effect of MBI on EF in youth aged 3-18 years using only construct-validated, direct EF measures, (2) examine potential moderators including age group, EF domain, and risk of bias, and (3) test dose-response relationships via meta-regression on intervention duration. MethodsWe searched PubMed, PsycINFO, CINAHL, Scopus, and Web of Science from inception to March 2026, supplemented by reference-list searches from two existing systematic reviews and a scoping review. Only English-language publications were eligible. Eligible studies were randomised controlled trials (RCTs) or quasi-RCTs of MBI (excluding yoga-only interventions) in typically developing youth, with at least one direct behavioural or computerised EF outcome. Risk of bias was assessed using Cochrane RoB 2. Hedges g was computed for each study, and pooled using a DerSimonian-Laird random-effects model. Subgroup analyses by age group, EF domain, and risk of bias were conducted, alongside leave-one-out sensitivity analyses, Eggers regression test, trim-and-fill, and Knapp-Hartung-adjusted meta-regression on intervention duration. Evidence certainty was rated using GRADE. ResultsThirteen RCTs (nine school-age, four preschool; total N = 1,560) met inclusion criteria. The pooled effect was g = 0.365 (95% CI 0.264 to 0.465; p < .00001), with negligible heterogeneity (I2 = 0.0%; Q = 6.76, p = .87). Effects were consistent across age groups (school-age g = 0.389; preschool g = 0.318) and EF domains (inhibitory control, working memory, cognitive flexibility; pbetween = .60). Meta-regression on intervention duration (4-20 weeks) was non-significant (p = .79). The effect was robust in leave-one-out analyses, in the low risk-of-bias subgroup (g = 0.361; k = 8), and after trim-and-fill adjustment (g = 0.354). The 95% prediction interval (0.252 to 0.477) was entirely positive. GRADE certainty was rated MODERATE, downgraded once for risk of bias. ConclusionsMBIs appear to produce a small, statistically significant improvement in EF in youth aged 3-18 years, with moderate certainty of evidence per the GRADE framework. The effect is consistent across preschool and school-age samples and across EF domains, with no significant dose-response relationship within the 4-20 week range studied. Emerging mediation evidence suggests that EF improvement may serve as an important pathway through which MBI supports emotion regulation, though this requires replication. Further large-scale, pre-registered RCTs with active control conditions and longitudinal follow-up are warranted.

3,4-methylenedioxymethamphetamine (MDMA) has emerged as a potential treatment for post-traumatic stress disorder (PTSD), generating considerable enthusiasm in the field. However, rapidly changing evidence in a fast-moving field can be challenging to integrate. Here, we present a living systematic review and open-data meta-analytic resource on MDMA treatment for PTSD. In this initial release, six randomized controlled trials comprising 286 participants are included in the database. Our primary model uses inverse-variance random-effects meta-analysis of standardized mean differences on primary outcomes of PTSD. Compared to control conditions, MDMA showed a greater reduction in PTSD symptoms (Hedges' g = -0.71). Meta-regression on both the number of dosing sessions and cumulative dose showed that a higher number of dosing sessions and a higher cumulative dose was related to larger effects of MDMA. Treatment with MDMA as compared to placebo also resulted in higher response (risk ratio (RR) = 1.35) and remission (RR = 2.25) rates. Most studies included in the database had a low risk of bias according to Cochrane guidelines, though these fail to capture pertinent challenges in the field such as expectancy, functional unblinding, potential issues with study conduct, and safety. The current findings were assigned an overall low certainty rating using the GRADE approach. Together, this systematic review and meta-analysis suggests that MDMA-assisted therapy results in short-term decreases in PTSD symptoms across studies to date, though more trials are needed. This living systematic review, meta-analysis, database, and online dashboard (sypres.io) will continue to be updated as evidence emerges, providing a valuable, open, and transparent resource for researchers in a rapidly evolving field.

Patients with brain tumors involving language-critical regions face surgical limitations when balancing resection with preservation of function. Non-invasive neuromodulation-induced prehabilitation (NIP) aims to guide preoperative neuroplastic reorganization, potentially facilitating larger resections while preserving function. We investigated whether NIP selectively modulates the targeted language network compared with control networks, and whether such modulation is behaviorally safe. We enrolled 26 patients (mean age = 55.9) from the Prehabilita project (Clinical Trial: NCT05844605) with operable brain tumors affecting language or motor regions. Eleven received language-targeted NIP, combining transcranial magnetic stimulation and/or transcranial direct current stimulation with intensive language training. Fourteen patients with NIP targeting non-language networks, primarily motor networks, served controls. Assessments included task-based functional magnetic resonance imaging (tb-fMRI) and a neuropsychological battery assessing language and cognitive domains before and after prehabilitation. Results indicated a group-specific NIP effect on the language network. In the language-targeted group, tb-fMRI revealed reduced overlap between a region of interest centered on the stimulation target and fMRI-derived language activation maps, whereas no comparable changes were observed in controls. No significant modulation effects were detected in the motor network in either group. These findings indicate that NIP can selectively reorganize the language network, with modulation patterns differing in sensorimotor networks. Importantly, language network modulation occurred while preserving language and cognitive performance. These results support NIP targeting higher-order functions such as language as a safe preoperative strategy that may reduce functional constraints on surgery and enable larger and safer resections in patients with tumors involving language-critical regions.

BackgroundEarly-life adversity (ELA) is a risk factor for enduring pain in youth and is associated with alterations in brain morphology and function. However, it remains unclear whether ELA-related neurobiological changes contribute to the development of enduring pain in early adolescence. MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study, we examined multimodal magnetic resonance imaging (MRI) markers in children assessed at baseline (ages 9-11 years) and at 2-year follow-up (ages 11-13 years). ELA exposure was defined at baseline to maximise temporal separation between early adversity and later enduring pain. Participants with enduring pain at follow-up (n = 322) were compared to matched pain-free controls (n = 644). Structural MRI, diffusion MRI (fractional anisotropy, mean diffusivity), and resting-state functional connectivity data were analysed. Linear models tested main effects of enduring pain, ELA, and their interaction on brain metrics, controlling for relevant covariates. ResultsELA exposure was associated with smaller caudate and nucleus accumbens volumes, and reduced surface area of the left rostral middle frontal gyrus. No significant effects of enduring pain or ELA-by-enduring pain interaction were observed across grey matter, white matter, or functional connectivity measures. ConclusionsELA was associated with alterations in fronto-striatal regions in late childhood, but these changes were not linked to enduring pain in early adolescence. These findings suggest that ELA-related neurobiological alterations may represent early markers of vulnerability rather than concurrent correlates of enduring pain. Longitudinal follow-up is needed to determine whether these alterations contribute to later chronic pain risk.

Background: Spinal cord injury (SCI) is associated with widespread reorganisation of cortical sensorimotor circuits. Persistent complications such as spasticity and neuropathic pain suggest that homeostatic plasticity, which normally helps stabilise and constrain activity-dependent changes in sensorimotor circuits, may be disrupted after SCI. Homeostatic plasticity can be probed using repeated blocks of transcranial direct current stimulation (tDCS); in healthy individuals, two closely spaced excitatory blocks typically leads to an inhibitory response, reflected as a reduction in corticomotor excitability. Objective: To determine whether individuals with SCI show reduced homeostatic suppression of corticospinal excitability in response to repeated anodal tDCS, compared with healthy controls. Methods: Twenty adults with thoracic or below SCI and 20 healthy controls completed three counterbalanced sessions. Each session comprised two 10-minute blocks of 2 mA tDCS separated by 5 minutes, with the second block always being anodal tDCS over left primary motor cortex. The first block was either anodal, cathodal, or sham tDCS, yielding 3 condition types: anodal-anodal, cathodal-anodal, and sham-anodal. To assess corticomotor excitability, transcranial magnetic stimulation-evoked motor evoked potentials (MEPs) were elicited at baseline, after priming, and every 5 minutes for 60 minutes after the second block. The primary outcome was percent change in MEP amplitude from baseline. Results: In the anodal-anodal condition, the SCI group showed greater facilitation than controls over 0-30 minutes (estimate = 83.09, 95% CI 49.75 to 116.43, p < 0.001), suggestive of a weaker homeostatic response. The cathodal-anodal condition led to a significant overall facilitatory effect with no between-group difference, while the sham-anodal condition showed no change in MEP amplitude relative to baseline. Within the SCI group, exploratory subgroup analysis suggests that those with neuropathic pain and a traumatic injury showed greater facilitation in the anodal-anodal condition than those without these features, indicative of a weaker homeostatic response. Conclusions: SCI is associated with impairment in the homeostatic regulation of corticomotor excitability following repeated excitatory brain stimulation. Disrupted plasticity stabilisation may be relevant to persistent symptoms such as neuropathic pain.

Here, we test the hypothesis that early sustained exposure to complex bilingual environments can positively affect reading development by altering structural interhemispheric connectivity via the corpus callosum (CC). Interhemispheric connectivity has been shown to be inefficient in dyslexia, but also to support compensatory pathways when genetic risk for reading difficulties is present, by enabling the preserved right hemisphere to support a dysfunctional left hemisphere. Mediation models were conducted on children aged 9-10 years (with a 2-year follow-up assessment) from the Adolescent Brain Cognitive Development database (N>10,000). Polygenic scores (PGS) for dyslexia and cognitive performance and continuous bilingualism indices were used as predictors, with reading aloud as the outcome. Bilingualism showed a positive effect on reading partially mediated by the anterior CC, independently of overall brain size. In contrast, genetic predispositions to reading difficulties influenced reading primarily through overall brain size rather than CC connectivity specifically. These two pathways were independent, suggesting that bilingual experience and genetic risk operate through distinct neuroanatomical mechanisms. These findings suggest that recurrent early exposure to complex bilingual environments may shape the brains structural connectivity toward a more balanced and integrated bilateral frontal organisation. The results highlight potential brain compensatory pathways induced by environmental experiences that may support more efficient reading development and mitigate risks for developmental dyslexia.

Individuals with autism spectrum disorder (ASD) often exhibit atypical auditory processing, yet it remains unclear whether and how the integration of simple acoustic features and contextual information is impacted in ASD. One real-world example of this integration is the auditory looming bias, the prioritized processing and perception of approaching auditory stimuli. We designed a paradigm that presents intensity-rising (looming) and intensity-falling (receding) auditory stimuli to 3-4-year-old children with ASD (n = 21), children with sensory processing concerns who do not have ASD (SPC; n = 16) and children with typical development (TD; n = 30). We recorded neural responses using electroencephalography (EEG) and found evidence of looming bias in the SPC and TD groups, as indexed by greater P1 peak amplitude during the looming than receding stimuli (TD: t(64) = 6.87, p < .001; SPC: t(64) = 4.07, p < .001). But this finding was not present in the ASD group (p = .194). Additionally, the ASD group showed reduced differentiation between looming and receding stimuli, as indicated by significantly lower Rise-Fall Difference Score (RFDS) in comparison to the TD group (Z = -3.00, padj = .008). These findings suggested altered context-dependent modulation of sensory input in ASD.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to propose a composite meta-analytic risk index for interventional pain medicine requiring prospective validation. Methods: We searched PubMed/MEDLINE, Scopus, and the Cochrane Library through March 2026 for studies reporting adjusted odds ratios linking (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, and (4) preoperative opioid use/polypharmacy to chronic pain chronification or treatment failure. DerSimonian-Laird random-effects meta-analyses were performed per loop. Publication bias was assessed via Egger's test (k>=8). Effect sizes were integrated into a logistic regression model--the Pain Amplifier Loop Framework (PALF). Neurobiological convergence on TLR4/NF-kB microglial signaling was examined. Results: Forty-four studies (>500,000 participants) were included. Pooled odds ratios: sleep disturbance 1.80 (95% CI 1.65-1.96; k=16; I2=51%), pain catastrophizing 2.11 (1.71-2.61; k=8; I2=0%), metabolic/fat mass 2.02 (1.32-3.09; k=7), preoperative opioid use 4.48 (2.87-6.97; k=6; I2=84%), and opioid-benzodiazepine co-prescription 2.62 (1.76-3.89; k=7; I2=79%). Egger's test showed no significant asymmetry for sleep (p=0.21) or catastrophizing (p=0.84). All loops converge on TLR4/NF-kB microglial signaling. The PALF yields a Systemic Load Score and failure probability P=1/(1+e^-theta), enabling low (<0.30), moderate (0.30-0.60), and high (>=0.60) risk stratification. Conclusions: Four biopsychosocial amplifier loops independently and substantially increase chronic pain risk. The PALF proposes a transparent, hypothesis-driven composite risk index anchored in meta-analytic evidence from >500,000 participants. As a meta-analytic synthesis rather than a fitted prediction model, the PALF requires prospective multicenter validation with individual patient data before clinical application.

Substance use disorders (SUD) are chronic conditions with devastating effects on brain health, functioning, and survival. In this study, we compared brain morphometry of 2,782 individuals with SUD to 1,951 controls and assessed the topographic overlap of these differences with brain connectivity and receptor architecture. Across SUD, we identified a morphometric signature involving frontal, parietal, temporal and limbic systems that overlapped with cortical hub regions and harbored cortical and subcortical disease epicenters. Findings were highly consistent across six substances and numerous robustness and generalizability analyses. Transdiagnostic comparisons showed high spatial overlap of SUD epicenters with those of schizophrenia and bipolar disorder, suggesting shared network-constrained cortical differences. Finally, multivariate mapping revealed that SUD brain differences aligned with two neurotransmitter axes contrasting cannabinoid-opioid and dopaminergic systems. These findings indicate that addiction-related brain differences are shaped by connectome and neurotransmitter architecture, positioning brain network and neurochemical organization as key principles of SUD-related brain alterations.

Background Chronic pain and depression are prevalent and burdensome conditions that frequently co-occur. Separate neuroimaging studies of each disorder suggest overlapping brain-structure alterations, however, relatively few studies have examined their comorbidity directly, and the neuroanatomical profile of co-occurring chronic pain and depression remains unclear. Methods Using UK Biobank data (n = 71,214), we conducted cross-sectional pairwise association analyses of brain structure (cortical measures, subcortical volumes, and white matter microstructure) comparing participants with current comorbid chronic pain and depression, current chronic pain only, current depression only, and controls. Results Compared with controls, the comorbidity group showed regional differences in cortical surface area and thickness ({beta} range = -0.096 to 0.098, pFDR < 0.05), widespread lower cortical volume ({beta} range = -0.096 to -0.050, pFDR < 0.05), lower thalamic (left: {beta} = -0.048, pFDR = 0.038; right: {beta} = -0.060, pFDR = 0.007), hippocampal (left: {beta} = -0.062, pFDR = 0.035; right: {beta} = -0.088, pFDR = 0.002) and left accumbens volume ({beta} = -0.073, pFDR = 0.011), and evidence of widespread white matter microstructure alterations (fractional anisotropy: {beta} range = -0.116 to -0.080, pFDR < 0.05; mean diffusivity: {beta} range = 0.063 to 0.137, pFDR < 0.05). Pairwise comparisons with the disorder-specific groups also identified several alterations unique to the comorbidity group. Compared to controls, those with chronic pain only had widespread lower cortical surface area and volume ({beta} range = -0.043 to -0.015, pFDR < 0.05), whereas non-comorbid depression showed more regionally specific lower cortical thickness and volume ({beta} range = -0.140 to -0.062, pFDR < 0.05) and lower thalamic volume (left: {beta} = -0.067, pFDR = 0.016; right: {beta} = -0.066, pFDR = 0.015), alongside widespread white matter microstructure deficits (fractional anisotropy: {beta} range = -0.104 to -0.083, pFDR < 0.05; mean diffusivity: {beta} range = 0.079 to 0.149, pFDR < 0.05). Conclusion These results provide a robust characterisation of brain structure alterations in comorbid chronic pain and depression, highlighting a distinct neuroanatomical profile and advancing understanding of its underlying neurobiology.

Sustained attention is an important neurobiological process. Difficulties with attention play a key role in neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) and autism. Here, we identified functional connections consistently associated with sustained attention across datasets, participant populations, and fMRI scan types. We interrogated five transdiagnostic, previously published connectome-based models predicting attention and autistic phenotypes. All models were related to sustained attention, including in samples comprising participants with autism. We found that model similarity was associated with participant characteristics, including age and clinical diagnosis, and predicted behavioral measure. As expected, models predicting attention phenotypes shared more similar features with each other than models predicting autism symptoms. Furthermore, predictive features overlapped more between datasets that included participants of similar ages (i.e., youth vs. adult) and diagnostic status (autism diagnosis vs. no diagnosis). This suggests that functional connectivity patterns predicting individual differences in behavior are phenotype-specific and may vary as a function of age and clinical diagnosis.

Opioid and methamphetamine use disorders (OUD and MUD) are characterized by enduring neural adaptations within brain reward circuitry, yet the cell-type-specific post-transcriptional mechanisms underlying these changes remain poorly understood. While microglia are essential for maintaining central nervous system homeostasis and modulating neuroinflammatory responses to drugs of abuse, their alternative splicing (AS) programs have not been defined in the context of addiction. This study characterized the microglial AS landscape in the mouse dorsal striatum during morphine and methamphetamine intravenous self-administration (IVSA), as well as following a 21-day period of abstinence. Analysis of RNA-sequencing data using rMATS and DEXSeq revealed that both drugs significantly dysregulate core splicing machinery, with skipped exons (SE) emerging as the most prevalent splicing event. Notably, morphine exposure induced a robust persistent splicing signature, comprising 736 exonic regions in 221 genes that remained altered through abstinence, whereas methamphetamine-induced changes were primarily reversible. Functional annotation predicted that approximately 27.5% of these events induce frameshifts, potentially impacting critical microglial pathways such as autophagy (Wdr81), chromatin remodeling (Chd4, Kmt2c), and RNA processing (Hnrnpl, Mbnl2, Tia1). These findings identify previously unrecognized post-transcriptional neuroimmune mechanisms and suggest that persistent splicing dysregulation in microglia may contribute to the long-term pathophysiology of OUD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/716002v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1c30f01org.highwire.dtl.DTLVardef@10e16d7org.highwire.dtl.DTLVardef@1fd80dforg.highwire.dtl.DTLVardef@17c80f_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundPersistent automatic approach tendencies toward alcohol cues that resist goal-directed control are a key feature of harmful alcohol use, yet the causal neural mechanisms underlying this imbalance remain poorly understood. Converging evidence implicates the frontoparietal network (FPN) in actively regulating alcohol approach-avoidance behavior, but whether its constituent nodes make dissociable causal contributions has not been established. MethodsIn a within-subject, active-sham counterbalanced design, inhibitory continuous theta burst stimulation (cTBS) was applied to right dorsolateral prefrontal cortex (rDLPFC) and right posterior parietal cortex (rPPC) in separate groups of non-clinical alcohol users (rDLPFC: n = 29; rPPC: n = 28), followed by an Alcohol Approach-Avoidance Task. ResultsActive rDLPFC cTBS selectively slowed down alcohol push responses, whereas rPPC suppression produced a bidirectional action-specific shift in response to alcohol cues, where pull responses accelerated, and push slowed simultaneously. Suppression of either node shifted automatic tendencies toward greater alcohol approach through mechanistically distinct routes. ConclusionThese dissociable profiles indicate that rDLPFC is causally necessary for effortful top-down avoidance control, while rPPC supports the priority-based selection of alcohol cue-driven actions. These findings provide the first node-specific causal evidence for functional specialization within the FPN in the context of automatic tendencies towards alcohol. Alcohol avoidance emerges as an active, prefrontal-dependent process, whereas priority-based regulation emerges as a parietal-dependent process, together indicating rDLPFC and rPPC as mechanistically independent targets for intervention in maladaptive alcohol approach behavior.

Children with developmental language disorder (DLD) have persistent language learning difficulties and often perform poorly on pseudoword repetition, a task that probes phonological, memory, and speech-motor processes that support vocabulary acquisition. Research on the neural basis of pseudoword repetition in DLD is limited. We used whole-brain functional MRI (fMRI) to examine pseudoword repetition and repetition-based learning in 46 children with DLD (ages 10-15 years) and 71 age-matched children with typical language development. During scanning, children heard and repeated pseudowords paired with visual referents, allowing us to track learning-related changes in neural activity across repetitions. Repeated pseudoword production yielded comparable behavioural learning across groups, with faster productions by later repetitions. Post-scan, form-referent recognition was comparable across groups, whereas pseudoword repetition accuracy was lower in DLD. Pseudoword repetition engaged a distributed neural network, including inferior frontal cortex bilaterally (greater on the left), premotor and sensorimotor cortex, and posterior temporal and occipital regions. Group differences emerged primarily in regions where activity was task negative (i.e., below baseline or deactivated): lateral occipito-parietal cortex (posterior angular gyrus), medial parieto-occipital cortex (retrosplenial), and right posterior cingulate cortex. Learning-related decreases in activity were similar across groups, but region-of-interest analyses showed reduced leftward lateralisation of activity in inferior frontal gyrus in DLD. These findings suggest weaker disengagement of the default mode network during a linguistically demanding task in DLD. Although repetition-based pseudoword learning recruited similar neural mechanisms in both groups, these mechanisms may operate less efficiently in DLD, alongside reduced hemispheric specialisation in inferior frontal cortex. HighlightsO_LISimilar repetition-related neural attenuation across groups during pseudoword learning. C_LIO_LIReduced default-mode network suppression during pseudoword repetition in DLD. C_LIO_LIReduced left-hemisphere specialisation of inferior frontal cortex in DLD. C_LIO_LIRepetition-based learning in DLD supported by less efficient neural networks. C_LI

Background: Gamma oscillation dysfunction has been implicated in neuropsychiatric disorders. Restoring gamma oscillations via brain stimulation represents an emerging therapeutic approach. However, the strength of its clinical effects and treatment moderators remain unclear. Method: We conducted a systematic review and meta-analysis to examine the clinical effects of gamma neuromodulation in neuropsychiatric disorders. A literature search for controlled trials using gamma stimulation was performed across five databases up until April 2025. Effect sizes were calculated using Hedge's g. Separate analyses using the random-effects model examined the clinical effects in schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism spectrum disorder. For SZ and MDD, subgroup analyses evaluated the effects of stimulation modality, stimulation frequency, treatment duration, and pulses per session. Result: Fifty-six studies met the inclusion criteria (NSZ = 943, NMDD = 916, NBD = 175, NASD = 232). In SZ, gamma stimulation was associated with improvements in positive (k = 10, g = -0.60, p < 0.001), negative (k = 12, g = -0.37, p = 0.03), depressive (k = 8, g = -0.39, p < 0.001), anxious symptoms (k = 5, g = -0.59, p < 0.001), and overall cognitive function (k = 7, g = 0.55, p < 0.001). Stimulation frequency and treatment duration moderated therapeutic effects. In MDD, reductions in depressive symptoms were observed (k = 23, g = -0.34, p = 0.007). Conclusion: Gamma neuromodulation showed moderate therapeutic benefits in SZ and MDD. Substantial heterogeneity likely reflects protocol differences, highlighting the need for well-powered future trials.

BackgroundDepression is a mood disorder frequently associated with episodic memory impairment. However, it remains unclear whether functional brain activity differs between depressed and non-depressed individuals during encoding or retrieval of autobiographical or non-autobiographical memories. Clarifying these differences is important for refining theoretical models of memory impairment in depression and, potentially, for developing targeted interventions. MethodsWe conducted three coordinate-based meta-analyses examining encoding and retrieval of autobiographical and non-autobiographical memory in control participants and individuals with current, remitted, or subthreshold depression, or those at risk for depression. Studies were identified via database searches and analysed using Seed-based d Mapping. ResultsWe included coordinates from 21 fMRI studies. During encoding, depression was associated with reduced activity in the thalamus, the caudate, the salience network, the frontoparietal executive control network, and motor-related areas (ten studies, N = 506). During non-autobiographical retrieval, depression was associated with higher activity in the right inferior frontal gyrus (six studies, N = 332). During autobiographical retrieval, depression was associated with reduced activity in the right insula and fusiform gyrus, alongside increased activity in the left anterior cingulate cortex and the left middle frontal gyrus (ten studies, N = 423). Between-study heterogeneity was low and no evidence for publication bias was found. DiscussionOur results indicate that depression may be associated with impaired salience integration during encoding and autobiographical retrieval. In contrast, during non-autobiographical retrieval, increased frontal activity suggests a more vigilant or self-monitoring retrieval mode. Functional brain activity changes in depression therefore appear stage- and content-specific.

BackgroundNicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are NAD+ precursor supplements widely marketed for metabolic health benefits. Despite billions of dollars in annual sales, no head-to-head randomized controlled trial (RCT) has compared their effects on metabolic endpoints, and no systematic characterization of why reliable comparison is currently impossible has been published. ObjectiveTo characterize the structural heterogeneity of the NMN and NR trial evidence bases across population, dose, duration, and biomarker dimensions; to formally assess transitivity; and to estimate indirect NMN versus NR effects where methodologically feasible using the Bucher indirect comparison method. MethodsFive databases (PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL) were searched from January 2018 to May 2025. Eligible studies were RCTs of oral NMN or NR versus placebo in adults reporting metabolic outcomes. A formal transitivity assessment was conducted comparing effect modifier distributions across NMN and NR trial arms. Random-effects pairwise meta-analyses were conducted for each precursor versus placebo, and Bucher indirect comparisons estimated NMN versus NR effects through the common placebo node. Risk of bias was assessed using RoB 2 and certainty of evidence using the GRADE/CINeMA framework. ResultsFifteen studies (5 NMN, 10 NR; 740 participants) were included. The NMN and NR trial evidence bases were systematically asymmetric across every major effect modifier: NR was dosed 1.9 to 9.2 times higher than NMN on a molar basis; NMN trials were conducted predominantly in East Asian populations while NR trials were predominantly Western; and available NAD+ pharmacodynamic measures used incompatible assay matrices precluding indirect comparison. Across 14 metabolically comparable outcomes, no indirect comparison reached statistical significance and all were rated Very Low certainty by GRADE/CINeMA, consistent with the structural limitations of the evidence base. Leave-one-out sensitivity analyses showed zero pairwise significance changes and one indirect significance change (triglycerides upon exclusion of Conze 2019). ConclusionCurrent evidence is structurally insufficient to support reliable indirect comparison of NMN and NR for metabolic outcomes. The barriers are quantifiable and modifiable: future head-to-head trials should use equimolar dosing (approximately 1,150 mg NMN is molar-equivalent to 1,000 mg NR), harmonized whole-blood NAD+ assays reported in mol/L, minimum 24 weeks duration, and enrollment of metabolically at-risk populations to generate interpretable comparative evidence. RegistrationPROSPERO 2026 CRD420261330487; registered prior to data screening.

Objective: While ADHD symptoms often decline from childhood into adulthood, the underlying neurobiological mechanisms, such as altered brain maturation or neural reorganization, remain incompletely understood. This study investigated how grey matter development relates to ADHD symptom trajectories into adulthood. Method: We analyzed data of individuals with ADHD and controls from the longitudinal Dutch NeuroIMAGE cohort, utilizing dimensional ADHD symptom scores (Conners Parent Rating Scale) from three waves and T1-weighted structural MRI scans from the final two waves. Using General Linear Models with permutation-based inference, we examined: 1) cross-sectional associations between ADHD symptoms and vertex-wise cortical thickness and surface area, and subcortical volumes at Wave 1 (n = 765, mean age = 16.95 years); and 2) longitudinal associations between symptom progression and brain morphometric changes (Wave 0 to 1: n = 644, mean age = 11.55-17.24 years; Wave 1 to 2: n = 149, mean age = 16.45-20.11 years). Results: Cross-sectionally, at Wave 1, more ADHD symptoms were related to widespread reductions in surface area, most prominently in the frontal cortex, and smaller volumes of the cerebellum, amygdala, and hippocampus. Longitudinally, symptom improvement from Wave 1 to Wave 2 was associated with stronger reductions in surface area, particularly in prefrontal and occipital regions, and with more pronounced cortical thinning across multiple brain regions. Conclusion: These findings suggest an association between symptom trajectories and structural brain changes, indicating that clinical improvement in ADHD behaviors might coincide with ongoing neural refinement during the transition to adulthood.