Neuroscience & Biobehavioral Reviews

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.

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.

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.

Pain captures attention and interferes with executive and motor processes but task performance may be preserved at the cost of more effort. In a preregistered fMRI study, 40 participants performed a visuomotor force-matching task at two force levels under individually calibrated painful or non-painful thermal stimulation, while reporting the intensity of perceived effort. Maintaining task performance under pain was associated with increased perceived effort and recruited brain regions involved in pain modulation and cognitive control. Region-of-interest analysis showed perceived effort was consistently linked to decreased anterior midcingulate cortex activity, whereas supplementary motor area contributions varied depending on its role in motor execution or pain processing. Across experimental condition, motor, pain-modulatory and cognitive-control regions were associated with effort perception. Independently of condition, effort perception was modulated by ventromedial prefrontal cortex and ventral striatum. These findings indicate that effort perception reflects brain activity within areas involved in motor, executive and valuation processes.

Objective: Childhood poverty is a high-risk context that involves diverse adversities, making it difficult to understand how poverty confers later psychopathology risk and why some children remain resilient despite growing up in poverty. To address this heterogeneity, we quantified adversity-linked vulnerability as adversity-psychopathology coupling and tested whether childhood poverty amplifies this coupling and whether multilevel inhibitory-control profiles stratify vulnerability and resilience within poverty-exposed youth. Methods: We analyzed 10,112 youth (48.4% female; mean age = 9.92 years) from the Adolescent Brain Cognitive Development Study, linking baseline cumulative early-life adversity (ELA) to later behavioral problems across 4 waves. In the stop-signal task fMRI subsample of 7,401 youth, semi-supervised clustering of inhibitory-control activation identified neurofunctional subtypes within poverty-exposed youth. We also tested temperamental inhibitory control as an additional moderator. Results: Childhood poverty amplified the association between cumulative ELA and behavioral problems at baseline ({Delta}{beta} = 0.088; P < .001) and across follow-up waves. Two neurofunctional subtypes were identified within poverty-exposed youth: subtype-1 showed greater vulnerability than higher-income peers ({Delta}{beta} = 0.149; P < .001), whereas subtype-2 showed attenuated vulnerability and did not differ from higher-income peers ({Delta}{beta} = 0.049; P = .135); this pattern persisted longitudinally. Among poverty-exposed youth in subtype-2 with high temperamental inhibitory control, the association between cumulative ELA and later behavioral problems was no longer significant. Conclusions: Childhood poverty strengthened the translation of adversity burden into later behavioral problems, but inhibitory-control profiles differentiated higher- and lower-risk pathways within poverty, highlighting inhibitory control as a candidate target for prevention.

BackgroundSpinal cord injury (SCI) triggers remote pathological changes in supraspinal regions, including neuroendocrine dysfunction that manifests clinically as hyponatremia and central diabetes insipidus. Clinical observations of lesion-level dependency and sequential transformation between these disorders suggest a temporally ordered hypothalamic cascade in which a compensatory arginine vasopressin (AVP)-driven neuroendocrine surge may precede a later neuroinflammation and endoplasmic reticulum (ER) stress-mediated neuronal exhaustion. Direct transcriptomic evidence for the temporal ordering of these events, however, has been lacking. MethodsWe performed a dual-cohort transcriptomic analysis. A discovery cohort (NCBI Sequence Read Archive PRJNA953752) comprised hypothalamic tissue from adult male Sprague-Dawley rats subjected to high-thoracic (T3) SCI, low-thoracic (T10) SCI, or sham surgery, sampled at post-injury day 7 and analyzed with edgeR/DESeq2 (|log2FC| > 1, Padj < 0.05). An independent chronic-phase validation cohort (Gene Expression Omnibus GSE297887) of hippocampal tissue from SCI and sham mice was interrogated as a sensitive supraspinal proxy for remote neuroinflammatory and ER-stress signatures. Pre-defined gene panels covered neuroendocrine, neuroinflammation, and ER-stress/unfolded-protein-response categories. ResultsIn the discovery cohort, high-thoracic SCI produced a lesion-level-dependent neuroendocrine surge in the hypothalamus: Avp (fold change 7.23; Padj = 0.002), Oxt (fold change 14.25; Padj = 2.3 x 10-7), and Ucn3 (fold change 9.22; Padj = 0.002) were among the most significantly upregulated genes genome-wide, whereas low-thoracic SCI failed to reach significance for any of these targets. Classical neuroinflammation markers and canonical ER-stress effectors remained transcriptionally silent (all Padj > 0.69). The PERK-pathway sentinel genes Trib3 and Ppp1r15a/GADD34 exhibited coordinated sub-threshold trends indicative of early activation, and Avp expression was tightly correlated with Mmp9 (r = 0.833; P = 0.0004). In the chronic-phase validation cohort, microglial P2ry12 and ferroptosis signatures were significantly upregulated (P2ry12 fold change 1.33; P = 0.008) suggesting a primed microglial state, while ER-stress effectors remained silent. ConclusionsThese data support a temporally ordered hypothalamic cascade after SCI in which an early compensatory neuroendocrine surge precedes -- and may precipitate, through biosynthetic overload and blood-brain-barrier disruption -- a subsequent neuroinflammation and ER-stress crisis. The defined molecular window between neuroendocrine activation and inflammatory/ER-stress engagement identifies a candidate therapeutic window for early neuroprotective intervention in acute SCI.

Alzheimer's disease (AD) is increasingly recognized to have systemic physiological correlates alongside central neurodegeneration. Here, we explored brain-organ network (BON) connectivity in AD (n=28) and healthy controls (n=23) using time-resolved quasi-dynamic analysis of plateau-phase total-body 18F-tau-PET. We found that AD-related pathophysiology was linked not only to cerebral tau aggregation, but also to altered signal synchronization across the brain-organ network, despite comparable body tracer distribution. Network topology analyses revealed the occipitotemporal cortex and the spinal cord as key nodes in this altered systemic network. Furthermore, exploratory mediation analyses demonstrated that BON dysregulation is cross-sectionally linked to cognitive deficits, with statistical associations observed for both cortical tau burden and imaging markers of impaired glymphatic clearance. This total-body PET study provides first-ever direct evidence repositioning AD as a multi-organ disorganization disease. These findings provide a novel framework for investigating brain-body interactions and systemic vulnerabilities in neurodegenerative disorders.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.

BackgroundTheory of Mind (ToM) deficits are well-documented in right-hemisphere stroke but remain understudied in post-stroke aphasia. Prior work suggests that performance on tasks assessing ToM may be relatively preserved in aphasia and dissociable from language impairment, but these findings are based largely on small studies. This study examined performance on nonverbal false-belief tasks in post-stroke aphasia, its relationship with aphasia severity, and whether vascular brain health, operationalized using cerebral small vessel disease (CSVD) markers, contributed to variability in performance. MethodsForty-four individuals with aphasia completed two nonverbal belief-reasoning tasks assessing spontaneous perspective-taking and self-perspective inhibition. Task accuracy served as the primary outcome. Linear regression models examined associations between task performance, aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient), and CSVD markers, including white matter hyperintensities, cerebral microbleeds, lacunes and enlarged perivascular spaces in the basal ganglia and centrum semiovale. ResultsPerformance was heterogeneous across tasks, with reduced performance observed in 23% of participants on the Reality-Unknown task and 36% on the Reality-Known task. Aphasia severity was not associated with task accuracy. Greater cerebral microbleed count was associated with lower accuracy on both tasks, while greater basal ganglia enlarged perivascular spaces burden showed a more selective association with lower performance. ConclusionsPerformance on nonverbal false-belief tasks in aphasia is variable and not explained by aphasia severity alone. These findings suggest that apparent ToM-related difficulties in aphasia may be shaped by broader vascular brain health, supporting a more multidimensional framework for interpreting social-cognitive task performance after stroke.

ObjectiveTo examine whether menopausal women who initiate systemic menopausal hormone therapy (MHT) around menopause (45-60 years old) have a different risk of developing dementia than those not taking MHT. DesignSystematic review and meta-analysis of randomised controlled trials and longitudinal observational studies. Risk of bias was assessed using ROB-2 and ROBINS I-V2. Data sourcesMEDLINE, Web of Science, EMBASE, and Cochrane Library to 27 March 2026. Eligibility criteria for selecting studiesStudies which measured dementia or cognitive decline in women who initiated systemic MHT between ages 45-60 or within 5 years of menopause, compared with placebo or no MHT. Authors contacted for additional details if needed. Main outcome measuresDementia, Alzheimers disease (AD), cognitive decline. Results10 studies totalling 213,678 participants (189,525 in studies with the primary population). There was no significant increased risk in women with a uterus for all cause dementia (pooled hazard ratio (HR): 1.12; 95% CI 0.91-1.31, N=78,613, I2 = 96.9%), but increased AD risk (HR: 1.14; 95% CI 1.02, 1.29, N=134,865, I2 = 35.6%). Results were similar in sensitivity analyses including women with or without a uterus. Results for cognitive decline were variable. ConclusionsMHT initiated around the age of menopause should not be prescribed for cognition or dementia prevention. It is not protective against dementia and may increase risk slightly. The magnitude of risk was similar in AD and dementia, but the latter with larger confidence intervals. Studies which followed up individuals rather than on health records lost people to follow up. This may account for difference in cognitive decline outcomes between studies, as people with cognitive impairment and dementia are more likely not to attend. MHT prescribing should balance benefits against risks, including evidence of a small increased dementia risk. There are few high-quality studies, so further research would inform recommendations. Systematic review registration Prospero CRD420251010663 What is already known on this topic?O_LIMenopausal hormone therapy (MHT) is effective for alleviating vasomotor symptoms. Contemporary guidelines recommend treatment should be initiated for such symptoms under age 60 and or within 10 years of menopause onset. C_LIO_LIA large randomised trial on the topic found increased risk of dementia in women initiating MHT after the age of 65. C_LIO_LIIt is unknown whether initiating MHT around the age of menopause impacts the risk of dementia or cognitive decline. C_LI What this study addsO_LIThere was no evidence that taking MHT around the time of menopause decreases the risk of dementia or cognitive impairment. C_LIO_LIThey should not be prescribed for these indications. C_LIO_LIWe were able to find more studies which examine this question by contacting authors for additional data. C_LIO_LIInitiating MHT in women with a uterus around the age of menopause increased the risk of Alzheimers disease slightly, by over 10%, and there is a similar but not significant effect in the fewer studies of all cause dementia. Women with or without a uterus show similar results. C_LIO_LIWe found no significant difference shown in cognitive decline, possibly due to loss to follow up. This may be because most studies of cognitive decline follow up C_LI

Background: Alzheimer's disease (AD) exhibits marked sex differences. While sex hormone levels across the lifespan likely contribute to this, little remains known about their causal impact and their relation to sex-biased genetic risk for AD. We therefore sought to identify potential shared genetic architectures, as well as causal genes and relationships, between sex hormone-related traits and AD risk. Methods: Large-scale AD sex-stratified genome-wide association study (GWAS) results were available from case-control, proxy-based, and population-based cohorts, including the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, UK Biobank, and FinnGen. Sex hormone-related trait GWAS were available for age at menarche, menopause, and voice breaking, as well as testosterone, sex hormone-binding globulin (SHBG), progesterone, follicle stimulating hormone, luteinizing hormone, and estradiol levels. Cross-trait conjunctional analyses were conducted to identify pleiotropic overlap between sex-hormone traits and AD, followed by prioritization of candidate causal sex-biased AD genes through quantitative trait locus genetic colocalization analyses. The potential regulatory impact of sex hormones on these genes was assessed through transcription factor motif analyses. Finally, sex-stratified mendelian randomization analyses were used to infer causal effects of sex hormones on AD risk. Results: Genome-wide pleiotropy analyses demonstrated enrichment of AD with testosterone, SHBG, and age-at-menarche traits in women. We identified 12 high-confidence pleiotropic loci, 9 of which showed stronger AD effect sizes in women (3 in men) and 8 that were novel. Genes at these loci were often causally implicated in brain tissues and enriched for promoter-associated androgen receptor transcription factor binding motifs. Mendelian randomization indicated higher bioavailable testosterone in women (OR:0.88; 95%-CI:0.82-0.96) and higher SHBG levels in men (OR:0.86; 95%-CI:0.77-0.96) were associated with lower AD risk. Conclusions: Our findings reveal sex-specific shared genetic architectures between AD and sex hormone-related traits and nominate related genes that may drive sex-biases in AD risk. Several of the implicated female-biased genes are relevant to phosphatidylinositol and lipid metabolism, including Fatty Acid Desaturase 2 (FADS2). While we observed no causal effect of estradiol-related traits on AD risk, the protective effects of bioavailable testosterone in women and SHBG in men provide targets for sex-informed AD risk stratification and prevention strategies.

Progress in pharmacological treatment development for neurodevelopmental disorders is hindered by a misalignment between targeted mechanisms, outcome measures, and trial designs. This study was initiated as a post-trial access pathway for bumetanide and later expanded with treatment-naive participants. Within this framework, we implemented a parent-cocreated sensory outcome measure set (PROMset) in an unmasked, multiple-baseline single-case experimental design with randomized baseline periods of 2-12 weeks, followed by 6 months of bumetanide treatment (up to 1.5 mg twice daily). Participants (7-19 years) had atypical sensory reactivity and a diagnosis of ASD, ADHD, epilepsy, or TSC. The primary outcome was a PROMset comprising seven PROMIS item banks assessing anxiety, depressive symptoms, sleep disturbance, fatigue, sleep-related impairment, cognitive function, and peer relationships. Secondary outcomes included SSP, SRS-2, RBS-R, and ABC. Of 113 enrolled participants (mean age 13.2 [SD 2.7], 64% male), 102 completed the trial and 95 had analyzable PROMsets. At baseline, PROMset scores showed substantial impairment across domains (mean deviation =9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r=-0.40, p<.001). Individual-level analyses showed improvement in 24-41% of participants per PROM domain, most frequently in anxiety and depressive symptoms (41% and 38%; mean across-case Cohen's d=-1). Overall, 83% improved on at least one domain. Group-level analyses showed improvement across all secondary outcomes (p<.001), with superiority over historic placebo for RBS-R and SSP. Integrating PROMsets with individualized trial designs can reveal clinically meaningful changes, supporting a more sensitive and patient-centered framework for treatment evaluation in heterogeneous populations.

Post-stroke depressive symptoms (PSDS) are a frequent and disabling consequence of stroke. While lesion-network studies implicate disruption of large-scale affective circuits in PSDS, the neurobiological factors determining why certain network disruptions confer vulnerability to PSDS remain insufficiently understood. We analyzed data from two independent stroke cohorts (total n = 435). Acute lesion masks were embedded within normative structural connectomes, weighted by positron-emission tomography-derived maps of 19 neurotransmitter receptors and transporters, to quantify neurotransmitter (NT)-informed network damage. Partial least squares regression with variable importance measures was used to identify NT-specific damage scores that were informative for PSDS, as quantified by the Hospital Anxiety and Depression Scale at follow-up. Informative NT-systems were subsequently evaluated in multivariable logistic regression models adjusted for age, sex, lesion volume, and neurological deficit. Across cohorts, multivariate analyses converged on a neurochemical signature involving serotonergic, cholinergic, dopaminergic, and GABAergic networks. Damage to networks related to the serotonin transporter (5-HTT) and the vesicular acetylcholine transporter (VAChT) was independently associated with increased odds of PSDS in covariateadjusted models and improved model fit beyond clinical and lesion-based predictors. In contrast, associations with other NT systems, including dopaminergic networks, were not consistently implicated across cohorts. These findings identify the serotonergic and cholinergic network architecture as a key neurochemical substrate that modulates vulnerability to PSDS. By integrating structural disconnection mapping with NT-informed connectomics, this study provides a mechanistic framework that links stroke-induced network disruption to PSDS and highlights serotonergic and cholinergic systems as central pathways for hypothesis-driven risk stratification and future multimodal investigations.

ImportanceEmerging data show that B-cell depleting chemotherapies, which are increasingly used to treat autoimmune disorders and multiple sclerosis, can be associated with mucosal side effects such as inflammatory vaginitis. ObjectiveEvaluate the impact of rituximab treatment on vaginal mucosal immune markers, endocervical immune cell populations and vaginal microbiome. DesignCross-sectional observational study conducted between 2022 - 2024. SettingAcademic medical center, Boston Massachusetts. ParticipantsWe enrolled women aged >18 years who were either 1) receiving rituximab for autoimmune renal disease or were 2) healthy controls ExposureTreatment with rituximab, an anti CD20 monoclonal antibody. Main outcome and measureWe compared endocervical immune cell populations, vaginal fluid immune markers, vaginal fluid immunoglobulins and vaginal microbiome composition between individuals being treated with rituximab and healthy controls. ResultsWe enrolled 26 women treated with rituximab for autoimmune renal disease and 26 healthy controls. Median circulating and endocervical B-cell and plasma cell proportions were significantly lower in treated participants compared to controls. Median vaginal fluid IgA concentrations were significantly lower in participants treated with rituximab, while ILE, IgM, IgG1, IgG2, IgG3 and IgG4 were not different between groups. Total T cell frequencies were similar between groups, but the proportion of activated T cells (CD4+CD38+HLADR+) was significantly lower in people treated with rituximab. Concentrations of IL10, IL13, IL17, IL21, IL23, IL4, ITAC and TNFa were elevated in vaginal fluid from the rituximab group, while IL-8 was lower. A CST-IV-C, low-Lactobacillus pattern of vaginal microbiota was more common in the rituximab group. Conclusions and RelevanceSystemic B-cell depletion is associated with reduced vaginal fluid IgA, a more diverse microbiome composition, and increases in many vaginal fluid immune markers compared to healthy controls. The reduction in vaginal fluid IgA may provide opportunities for vaginal bacteria to induce inflammation. Key pointsO_ST_ABSQuestionC_ST_ABSHow does circulating B-cell depletion impact the vaginal microenvironment? FindingsIn this cross-sectional study of 52 women, B cell and plasma cell proportions were significantly lower in both blood and vaginal mucosa among rituximab-treated participants compared to healthy controls. Vaginal IgA concentrations, but not other immunoglobulins, were significantly lower in rituximab treated participants. In treated participants, vaginal cytokine concentrations were elevated, and microbiome composition shifted toward non-Lactobacillus-dominant communities. In six people with inflammatory vaginitis, both circulating and endocervical B cells were lowest in people with the most severe symptoms. MeaningSystemic B cell depletion is associated with alterations in vaginal mucosal immune markers and microbiome composition which increase local inflammation.

Regular cannabis use has been associated with alterations in reward-related neural processes, yet findings remain inconsistent and the relationship between neural activity and behavioural performance is not fully understood. The present study aimed to characterise neural and behavioural correlates of reward processing in regular cannabis users (CU) compared with matched non-users (NU) using the Monetary Incentive Delay Task (MIDT). Firstly, we assessed behavioural performance through reaction times, accuracy and monetary earnings to determine whether potential neural alterations were reflected in task performance. Secondly, focusing on reward-related brain regions, we examined group differences in BOLD functional MRI activity during anticipation and outcome phases separately for monetary win and loss conditions. Finally, we explored the association between behavioural performance and neural activation. Our findings indicate that regular cannabis use is associated with altered engagement of key nodes within the mesocorticolimbic circuit during both anticipatory and outcome phases of reward processing, accompanied by impaired behavioural performance. Particularly, compared with NU, CU showed (I) lower striatal activity during anticipation of monetary win and higher ventral striatum and frontal pole activity during anticipation of monetary loss; (II) greater VTA activation during outcome of successful monetary win and loss avoidance and lower frontal pole activity during outcome of unsuccessful loss avoidance; (III) impaired behavioural performance, reflected in lower monetary rewards and a trend towards slower reaction times and reduced accuracy; (IV) disrupted brain-behaviour coupling. Results from this study may help inform future research on the neurobiological mechanisms underlying changes in reward function and the resultant behavioural consequences of cannabis use.

INTRODUCTIONAlzheimers disease (AD) manifests a specific spatial progression pattern, but its propagation mechanisms remain unclear. METHODSWe employed nine brain connectomes spanning multiple biological levels to investigate the mechanisms underlying cortical atrophy propagation in AD. Individual gray matter atrophy maps were quantified using normative modeling and were then mapped onto the connectomes by assessing the relationship between regional atrophy and the atrophy of neighboring regions defined by each connectome. RESULTSCross-sectionally, node-neighbor relationship was weak in the preclinical stage, suggesting limited influence of connectome architecture. Longitudinally, atrophy became progressively more aligned with the neurotransmitter receptor similarity connectome in individuals with MCI converting to AD dementia and dementia patients. DISCUSSIONOur findings described a stage-dependent shift in cortical atrophy propagation, with neurotransmitter receptor similarity playing an increasing role as AD progresses.

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

The early somatosensory nuclei of the brainstem and thalamus are traditionally considered relays of bottom-up peripheral input, yet animal studies indicate that they also receive top-down cortical projections. Whether such top-down processing exists in humans remains unknown. Here, we used cervical spinal cord injury (SCI), in which peripheral somatosensory input is reduced or absent while cortical representations are preserved, to test whether top-down processing can elicit activation across the somatosensory nuclei. We combined 3 Tesla functional and quantitative MRI data to assess activity and structural integrity along the somatosensory hand pathway in 16 individuals with chronic cervical SCI (mean age {+/-} s.e.m.=52.4 {+/-} 3.5 years) and 20 age-, sex-, and handedness-matched able-bodied control subjects (mean age=50.8 {+/-} 3.5 years). Participants were visually cued to make overt or, in case of hand paralysis, attempted right- and left-hand movements. We quantified activation across the cuneate nucleus, ventroposterior lateral thalamus, and primary somatosensory hand cortex, and assessed macro- and microstructural indices sensitive to myelin and tissue integrity (MTsat, R2*). Despite reduced or absent peripheral input, SCI participants exhibited robust and lateralised activation across all levels of the somatosensory pathway. This pattern persisted even in a participant with complete hand paralysis who lacked bottom-up afferent input during the fMRI task, indicating that top-down processing alone is sufficient to drive activity in early somatosensory relays. We simultaneously observed structural degeneration in the cuneate nucleus of SCI participants, marked by reductions in volume and myelin-sensitive metrics, suggestive of secondary degeneration. The extent of atrophy was related to time since injury and reduced sensorimotor hand function, but showed no significant relationship with functional activation, suggesting that preserved corticocuneate signalling is not dependent on the degree of structural degeneration. Together, these findings provide the first evidence in humans that the cuneate nuclei are subject to both bottom-up and top-down somatosensory processing. Although these nuclei are vulnerable to structural atrophy following dorsal column injury, our results suggest that top-down processing remains intact decades after spinal cord injury. This may have implications for the development of rehabilitation treatments targeting preserved somatosensory processing after injury.

WAC is an autism-associated gene involved in neurodevelopment. However, the effects of reduced WAC function on behavior and synaptic regulation in vivo remain unclear. Taking cues from the previous studies on the wac gene and the C. elegans model of ASD, we elucidated the effects of wac gene deletion on food-leaving behavior, a known parameter linked to ASD associated genes along with the cholinergic pathway. wac-deficient worms exhibited curtailed food-leaving behavior. Notably, observed phenotype was similar to that exhibited by nematodes with mutation in ASD related gene, neuroligin. In addition, wac-deficient worms showed impaired growth, reduced pharyngeal pumping, and lifespan. To examine potential synaptic mechanisms, we analyzed expression of genes related to cholinergic signaling across all developmental stages (L1-L4) through young adult (YA). Stage-specific transcriptional changes were observed, with increased expression of ace-1 and acr-3 at L1, acr-3 at L3, and acr-3, cha-1, lev-1, and lev-10 at L4. The transcriptomic alteration was most prominent at YA stage, exhibiting upregulation of ace-1, cha-1, cho-1, lev-1, lev-10, unc-17, unc-29, unc-38, and unc-50. To identify specific suppressor of upmodulated Ach signaling, RNAi of the upregulated genes was performed. cho-1 was identified as a specific suppressor of elevated Ach signaling. cho-1 encodes a high-affinity choline transporter responsible for choline uptake in the pre-synapse. These studies identify the molecular mechanisms pertaining to up-modulation of cholinergic signaling in wac mutant worms. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/719318v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1bdf8a9org.highwire.dtl.DTLVardef@1104825org.highwire.dtl.DTLVardef@1f09682org.highwire.dtl.DTLVardef@293b08_HPS_FORMAT_FIGEXP M_FIG C_FIG

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation ({Delta}) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation?rather than baseline adiposity?drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.