Developmental Cognitive Neuroscience

Premature birth occurs during a phase of intense brain maturation, making white matter (WM) particularly vulnerable to injury. Beyond major lesions, subtle and widespread microstructural alterations also contribute to later neurodevelopmental impairments. We aimed to characterize the impact of key clinical risk factors on global and tract-specific WM microstructure at term-equivalent age (TEA), using 3T-diffusion-MRI data of 111 infants born before 33 weeks of gestation. We developed a lesion-robust tractography pipeline suitable for heterogeneous neonatal anatomy and extracted diffusion tensor imaging (DTI) metrics in sensorimotor tracts: corticospinal tract (CST), superior thalamic radiation (STR), frontal aslant tract (FAT), forceps minor (FMI) and middle cerebellar peduncle (MCP). Associations with risk factors were assessed accounting for age at MRI or global WM microstructure. Tractography succeeded in most infants despite marked anatomical variability and/or overt lesions. Being a male, small for gestational age (SGA) at birth, encountering sepsis and having severe Kidokoro radiological score for WM were associated with altered global WM metrics. At the tract level, CST and STR showed the strongest susceptibility to SGA, prolonged parenteral nutrition, and Kidokoro score. In contrast, for FAT, associations with extreme prematurity, SGA and invasive ventilation were contrary to the expected direction, after adjustment for global WM microstructure. Findings were partially replicated in infants without macroscopic abnormalities, supporting the presence of WM dysmaturation even in the absence of visible injury. DTI metrics thus provide tract-specific biomarkers of early WM microstructure in preterm infants, which are sensitive to risk factors and could inform targeted prevention and intervention.

ImportancePrenatal cannabis exposure is increasing in prevalence, yet its associations with early brain development--particularly how the timing and frequency of exposure across gestation relate to neonatal brain structure--remain insufficiently understood. Clarifying these associations is essential for informing early risk identification and guiding perinatal care. ObjectiveTo examine associations between patterns of maternal prenatal cannabis exposure, including exposure presence, gestational timing, and frequency of exposure, and neonatal brain structure and microstructure during the first month of life. Design, Setting, and ParticipantsThis cohort study included 1,782 mother-infant dyads (221 with PCE) from the HEALthy Brain and Child Development Study. Mother-reported prenatal cannabis exposure was assessed using the validated Timeline Follow-back method. Infants underwent natural-sleep magnetic resonance imaging, including T2-weighted structural imaging and diffusion imaging, within the first month of life. Main Outcomes and MeasuresAssociations between prenatal cannabis exposure and regional T2-weighted volumes and diffusion white matter microstructure metrics examined (1) exposure presence, (2) gestational timing of exposure, and (3) frequency of exposure within exposed infants. ResultsAny prenatal cannabis exposure was associated with brain volume differences in cerebellar and subcortical limbic regions, including smaller amygdala, thalamic, and cerebellar vermis volumes and larger caudate, hippocampal, and cerebellar cortex volumes. Timing-specific analyses revealed divergent patterns: first trimester exposure was associated with smaller volumes in select regions, whereas exposure that continued into the third trimester was associated with larger volumes in overlapping structures, with additional subcortical volumetric differences observed. White matter microstructure alterations were observed only among infants with exposure that continued into the third trimester. Within the exposed subgroup, higher frequency of cannabis exposure was associated with larger cerebral white matter volumes and white matter microstructural differences in white matter regions. Conclusions and RelevanceIn infants with maternal prenatal cannabis exposure, we observed timing- and frequency-dependent differences in brain development within the first month of life. These findings underscore the importance of considering not only the presence of exposure, but also when and how much cannabis is used during pregnancy to support targeted prenatal counseling and early developmental monitoring for exposed infants. Key PointsO_ST_ABSQuestionC_ST_ABSIs prenatal cannabis exposure associated with brain development in the first month of life? FindingsIn a cohort[ABS] of 1,782 mother-infant dyads, prenatal cannabis exposure was associated with region-specific differences in neonatal brain volumes. Brain volume and diffusion white matter microstructure associations differed between exposure limited to the first trimester versus exposure that continued into the third trimester. Greater frequency of exposure across gestation was also associated with volumetric and microstructural differences. MeaningThe timing and frequency of prenatal cannabis exposure is associated with alterations in neonatal brain development, underscoring the importance of addressing cannabis use in pregnancy.

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

ObjectivesTo assess if maternal stress is higher in pregnancies with congenital heart disease (CHD) compared to low-risk pregnancies and if maternal stress is associated with placental microstructure and function. To explore if CHD alters the relationship between maternal stress and placental measures. MethodsIn this prospective observational study, 27 participants carrying a fetus with CHD and 42 participants with typical low-risk pregnancies underwent 1-2 combined diffusion{square}T2* relaxation placental MRIs from 20 weeks gestation (GA) and completed the Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory [43 male fetuses, median (IQR) GA at assessment 30.86 weeks (27.43-34.00), interval between assessments 6.00 weeks (4.86-7.14)]. 98 complete placental MRI and maternal stress datasets were available. Generalized Estimating Equations were used for analyses. ResultsHigher trait anxiety was associated with higher placental apparent diffusion coefficient (p=0.023) adjusting for CHD, sex, GA at assessment, GA at assessment2, state anxiety, depressive symptoms and previous mental health treatment. Maternal state anxiety (p=0.005) and depressive symptoms (p=0.046) were higher in pregnancies with CHD adjusting for GA at assessment and previous mental health treatment. CHD did not alter these relationships (p>0.119). ConclusionsMaternal proneness to anxiety, measured with the trait anxiety inventory, is associated with increased diffusivity in the placenta, which may reflect altered microstructural maturation. Mothers with fetal CHD show more depressive symptoms and feelings of anxiety and may benefit from screening for elevated maternal stress. The findings contribute to a growing body of research regarding the influence of prenatal stress on placental development. HighlightsO_LIMaternal stress and placental MRI data acquired in pregnancies with and without CHD C_LIO_LIMaternal trait anxiety is associated with increased placental diffusivity C_LIO_LIMaternal state anxiety and depressive symptoms are higher in fetal CHD C_LIO_LIState anxiety and depressive symptoms not associated with placental MRI measures C_LIO_LICHD did not moderate relationships between placental MRI measures and stress C_LI

BackgroundThe present study examines the link between DNA methylation at the nerve growth factor-induced protein A (NGFI-A) binding domain of the NR3C1 1F promoter and later cognitive functions in children from families living in disadvantaged psychosocial conditions. MethodsParticipants were 132 children who took part in a Swiss Parents as Teachers (PAT) randomized controlled trial (72 in the intervention group, 60 in the control group). DNA methylation was quantified from saliva samples collected at age three using sodium bisulfite next-generation sequencing (NGS). Cognitive functions were assessed at age five using the SON-R 2.5-7 Intelligence Test. Results(a) DNA methylation at age three predicted lower IQ at age five through increased concentration problems; (b) participation in the three-year PAT program predicted lower methylation levels at the end of the intervention; and (c) early life stressors predicted lower IQ through increased methylation and concentration problems with descriptively stronger effects in the control group. ConclusionsThese findings demonstrate a link between early DNA methylation at the NGFI-A binding site of the NR3C1 1F promoter and later cognitive functions in children and highlight the role of early life stressors and the PAT intervention in shaping these associations.

BACKGROUNDThe recovery from sport-related concussion (SRC) is highly heterogenous, with many individuals experiencing symptoms that persist beyond typical recovery timeframes. The early identification of individuals at risk of prolonged symptoms is therefore critical to inform timely interventions and set realistic recovery expectations. Although acute symptom burden is one predictor of future symptom burden, reliance on self-reported measures may limit objectivity and reduce clinical utility in settings where symptom evaluation may be unreliable. In this prospective cohort study, we evaluated the discriminatory accuracy of the CogState Brief Battery, alone and in combination with the Sport Concussion Assessment Tool (SCAT), to classify Australian football players with SRC from Australian footballers without SRC at 24-hours post-injury/match. Furthermore, we examined whether CogState performance and symptom severity at 24 hours were associated with symptom outcomes at one-week post-injury. Adult amateur Australian football players (n=181) were recruited following SRC (n=109 SRC, 86% male) or after a non-injured match (n=72, 90% male). Participants completed the CogState Brief Battery, SCAT and Rivermead Post Concussion Questionnaire (RPQ) at 24-hours and one-week post-injury or match. Area under the receiver operating characteristic (AUC) analyses quantified the ability of 24-hour CogState task performance and SCAT symptom severity to distinguish SRC from controls. Linear regression models examined associations between CogState performance and symptom severity (SCAT and RPQ), within and across the 24-hour and one-week time points. Additional models evaluated whether combining 24-hour symptom severity assessments with CogState performance improved prediction of one-week symptom burden and symptomatic status. SCAT symptom severity demonstrated excellent discriminatory classification accuracy for SRC versus controls at 24-hours post-injury (AUC [95% CI]: 0.949 [0.916 - 0.981]). CogState task performance showed lower discriminatory accuracy but demonstrated fair classification and prognostic utility (e.g., Identification task AUC [95% CI]: 0.666 [0.582 - 0.750]). CogState performance at 24-hours was significantly associated with overall symptom severity at both 24-hours and one-week, as well as with symptom severity across individual symptom domains. In combined models, 24-hour symptom severity and CogState performance independently contributed to the prediction of symptomatic from asymptomatic individuals at one-week post-SRC (e.g., Identification task AUC [95% CI]: 0.721 [0.606 - 0.835] for classification based on <4 versus [&ge;]4 symptoms). These findings indicate that CogState performance at 24-hours post-SRC may serve as an objective adjunct to subjective symptom-based reporting, supporting both diagnosis and early prognostication in the clinical evaluation of SRC.

BackgroundOrganization, time management, and planning (OTMP) difficulties are associated with academic underachievement. OTMP skills training programs are effective in reducing OTMP deficits and improving academic performance. A randomized controlled trial of Homework, Organization, and Planning Skills (HOPS) for students ages 11-14 (1) found it to be effective with medium to large effects. In that study, HOPS was provided by counselors employed by the research team. This study is a replication examining HOPS under more authentic conditions when providers are employed by schools serving enrolled students. The primary aim is to evaluate HOPS offered by school providers in relation to treatment-as-usual/waitlist (TAU/WL). To respond to limited school resources post-COVID-19, HOPS is also provided by research team members, creating the opportunity to replicate the findings from the prior trial (1) and explore differential effectiveness when HOPS is implemented by school vs. research providers. MethodsStudents in about 30 schools serving students ages 11-14 will be enrolled. Schools are randomly assigned to HOPS vs. TAU/WL on a 2:1 ratio. Students assigned to HOPS schools are randomly assigned to a school vs. research provider on a 1:1 basis. Providers receive two hours of training and additional assistance on request. Child outcomes related to OTMP skills, homework, and academic performance are assessed at post-treatment, 6-month (from baseline) follow-up, and 12-month follow-up. HOPS sessions are video recorded for fidelity coding. Potential effect modifiers include student ADHD, oppositional defiant, and internalizing symptoms, and family socioeconomic level. Analyses will use mixed effects modeling. The goal of the study is to enroll 135 participants, yielding a minimal detectable effect size of 0.50, within the expected range based on prior research. DiscussionThe study is unique in examining intervention implementation and effectiveness when intervention is provided under authentic practice conditions. Trial RegistrationThis study was registered with clinicaltrials.gov (NCT04465708).

There is a predicted increase in older adults presenting with mild to severe cognitive impairment. Screening tools with high sensitivity are the first frontier in identifying a cognitive pathology; however, to ensure that they are measuring the intended concept or criterion, thorough psychometric procedures should be followed. In this study, convergent criterion validity of Riga Cognitive Screening Task was measured, using cortical thickness of regions of interest as the criterion. 106 older adults (Mage = 70.49, SD =8.08, 35.8% male) with varying levels of cognitive functioning were involved in the study. All participants underwent cognitive assessment with the screening task and a 3T MRI. Cortical thickness of selected temporal and parietal regions was used as a brain measure. Behavioural Partial Least Squares Correlation was conducted and one latent variable was extracted. The results confirmed that Riga Cognitive Screening Task shows good criterion validity, suggesting successful use for screening.

ObjectiveDemographic corrections (e.g., sex, education, race, ethnicity) are often applied when assessing cognition in adults; however, these corrections have significant limitations (e.g., using years of education does not capture the quality of, or access to, education). It is therefore critical to develop novel assessment options that are less susceptible to demographic factors. This study compared demographic effects on a verbal memory test and a performance-based test of cognition and daily functioning in older adults. Based on prior work, we hypothesized the performance-based tests would be less susceptible to demographic factors than paired associates learning. MethodData from 1326 participants (mean{+/-}SD age=61.9{+/-}10.9 yrs; Female = 1066, 80%) were collected through the MindCrowd electronic cohort, with 79 (6%) non-White, 109 (8.2%) identifying as Hispanic/Latino ethnicity, and 327 (25%) reporting education as less than a college degree. Paired associates learning is a well-established measure of medial temporal lobe-dependent learning and memory through recall of word-pairs, scored as the number of correct word pairs entered out of 36 possible. The performance-based test involved functional upper-extremity movement, specifically transporting beans to target cups in a repeating sequence (a task also shown to be dependent on the medial temporal lobe), scored as the intraindividual variability (standard deviation) in trial time across four consecutive trials. ResultsAs hypothesized, linear regression analysis showed that PAL was significantly affected by sex, education, race (particularly Black/African American), and ethnicity, whereas the performance-based test was affected only by sex and with a much smaller effect size than that of PAL. ConclusionsPerformance-based assessments may be an equitable approach to evaluating cognition without requiring score corrections, particularly for diverse populations.

IntroductionResearch has shown that social and physical stressors of early-life adversity (ELA) can negatively affect long-term health trajectories. Despite differences in types of ELA exposure, previous studies have identified common health-related outcomes in adults who had experienced less favourable conditions during developmentally sensitive periods. This meta-analysis investigates the potential role of DNA methylation in mediating these adverse health trajectories by identifying common biological signatures across cohorts with distinct adversity exposures and environmental backgrounds. Materials and MethodsDNA methylation data from previously published studies was used to perform a meta-analysis on 227 individuals across three cohorts. These include the EpiPath cohort consisting of adults who were exposed early institutional care, ImmunoTwin cohort consisting of adversity discordant monozygotic twin pairs and lastly a cohort of young children exposed to early institutional care. ResultsDNA methylation analysis across the three cohorts revealed differential methylation at CpG loci associated with 15 genes common to all cohorts. These genes are involved in neuronal development, chromatin remodeling and metabolism. Pathway enrichment analysis of the combined dataset showed potential associations with oxytocin signalling, regulation of nervous system development, and calcium signalling in relation to the later-life phenotype of the adversity exposed individuals. In addition, a poly-epigenetic score was developed by identifying a subset of 200 differentially methylated CpG sites through PLS-DA analysis with the combined beta matrix of these cohorts. ConclusionThis study highlights the long-term impact of adversity by identifying common DNA methylation signatures of negative life experiences across three cohorts. The development of a poly-epigenetic score represents the first steps towards identifying group differences by combining weighted methylation values for CpG sites of interest. This method illustrates the potential to track changes in individuals across long-term studies that may benefit research in lifelong healthoutcomes.

Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. This cross-sectional study aimed to examine the relationship of RHI exposure proxies (e.g., total years of soccer play, highest level of play, and estimated cumulative heading frequency) with clinical measures (e.g., subjective cognitive complaints, objective cognitive performance, behavioral dysregulations, and depressive symptoms) among 3,174 women, aged 40 years or above, enrolled in the Head Impact and Trauma Surveillance Study (HITSS), all of whom played organized soccer. HITSS participants completed an online battery that elicited self-reported cognitive and behavioral complaints and depressive symptoms, and that assessed cognitive performing via computerized tests. Multivariable linear and logistic regression models estimated associations between soccer-related RHI proxies and outcome measures, adjusting for age and education. Among the former soccer players, longer duration of soccer play, higher level of play, and greater estimated cumulative heading frequency were significantly associated with worse self-reported cognitive functioning, greater behavioral dysregulation, and elevated depressive symptom severity (range of significant unstandardized B coefficients: 0.02 to 0.52). Higher estimated cumulative heading exposure was associated with higher odds of clinically meaningful elevations on subjective measures (OR range: 1.05 to 1.13) There were no associations between any of the RHI proxies and performance on the objective computerized cognitive assessments. Among middle-aged women who played organized soccer, cumulative RHI exposure was associated with small but statistically significant effects for measures of subjective cognitive complaints, behavioral functioning, and depressive symptoms. We found no associations for objective outcomes of cognitive function. Continued monitoring of this large cohort of female former soccer players will improve understanding of long-term consequences of soccer play.

Very preterm infants (<30 weeks gestation) are at elevated risk for neurodevelopmental and social-behavioral challenges. DNA methylation (DNAm) may provide a biological link between preterm birth and later behavioral outcomes. We examined associations between DNAm profiles at neonatal intensive care unit (NICU) discharge and at age 5 with Social Responsiveness Scale (SRS) scores which measure social communication, social interaction, and repetitive behaviors at age 5, including sex-specific effects, in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study. Epigenome-wide buccal DNAm was profiled at NICU discharge (n=218) and at 5 years (n=188). We identified 38 neonatal and 6 age-5 CpG sites associated with SRS scores (all q<0.05) using epigenome-wide association studies (EWAS) at each time point. Several CpGs mapped to genes involved in neurodevelopment including TCF4, KLC4, CAP2, PTDSS1, ADAM12, SENP1, CHN2, SH3D19, and ITGA1, with sex-specific effects observed for CpGs in CAMTA1 and GABBR1. Enriched pathways included neurodevelopment, cytoskeletal regulation, stress-response, and metabolic processes. DNAm patterns during early life, particularly the neonatal period, were associated with social-behavioral development in very preterm children. Findings in key genes such as TCF4 and CAMTA1 highlight potential epigenetic mechanisms linking early-life biology to later behavioral challenges.

Traumatic brain injury (TBI), particularly sports- and recreational activity related mild TBI (mTBI), is common in young adults and can be followed by persistent attentional and executive complaints. This study investigated chronic ([&ge;]6 months post-injury) structural brain alterations in gray matter (GM) and white matter (WM) and their associations with self-reported inattentive and hyperactive/impulsive symptoms, with a focus on sex-differentiated patterns. Structural brain properties in gray matter (GM) and white matter (WM) were acquired from 44 subjects with TBI and 45 matched controls, by utilizing structural MRI and diffusion tensor imaging techniques. Behavioral measures assessing severities of post TBI inattentive and hyperactive/impulsive symptoms were collected from each participant. Between-group and sex-specific differences of these brain and behavioral measures were conducted. Interactions among the TBI-induced significant brain- and behavioral-alterations, and their sex-specific patterns, were assessed as well. Male-dominated pattern of increased cortical thickness in superior parietal lobule (SPL) and female-dominated pattern of higher superior longitudinal fasciculus and superior fronto-occipital fasciculus (sFOF) fractional anisotropy (FA) were observed in the TBI group, when compared to controls. In males with TBI, greater SPL cortical thickness was significantly correlated with increased inattentive behaviors. In females with TBI, higher FA of sFOF was significantly correlated with decreased hyperactive/impulsive behaviors. Findings suggest that TBI-induced superior parietal cortical GM abnormalities may significantly cause attention deficits in patients with TBI, especially in males; while optimal post-TBI WM recovery in sFOF significantly contributes to maintenance of inhibitive control in patients with TBI, especially in females.

BackgroundParental genetics matters for childrens behavioural difficulties, but the extent to which this is due to direct genetic transmission versus environmentally mediated indirect genetic effects remains unclear. MethodsWe studied eight European birth cohorts with over 33,000 family-based trio samples. We analysed polygenic scores (PGSs) for 13 mental health and neurodevelopmental conditions and their composite indices (PC1 and mean) representing general neuropsychiatric liabilities, as well as educational attainment (EA) and alcohol and cigarette use, from children (PGSc), mothers (PGSm), and fathers. Child internalising, externalising, and total difficulties reported by mothers and/or fathers were examined at preschool and school ages. We then conducted multivariate meta-analyses to combine cohort-level results. FindingsWe observed several direct genetic effects on externalising difficulties, while indirect genetic influences were mainly identified for internalising difficulties. Specifically, child PGSs for attention-deficit/hyperactivity disorder (ADHD) and EA predicted higher and lower levels, respectively, of child externalising and total difficulties (all pFDR<0{middle dot}001; for school-aged externalising difficulties, PGSc-ADHD: {beta}=0{middle dot}121 [95% CI 0{middle dot}091 to 0{middle dot}151], pFDR<0{middle dot}0001; PGSc-EA: {beta}=-0{middle dot}095 [95% CI -0{middle dot}127 to -0{middle dot}063], pFDR<0{middle dot}0001), whereas maternal PGSs for major depressive disorder (MDD) and general neuropsychiatric liabilities were associated with internalising and total difficulties across parental raters and child ages (all pFDR<0{middle dot}05; for school-aged internalising difficulties, PGSm-MDD: {beta}=0{middle dot}049 [95% CI 0{middle dot}017 to 0{middle dot}081], pFDR=0{middle dot}016; PGSm-PC1: {beta}=0{middle dot}056 [95% CI 0{middle dot}022 to 0{middle dot}091], pFDR=0{middle dot}011). No statistically significant effects from paternal PGSs were identified. InterpretationIn this multi-cohort study, findings across multiple traits, raters, and ages supported several direct genetic effects of ADHD and EA on child externalising difficulties and indirect genetic effects on internalising difficulties, especially maternal depression and general neuropsychiatric liabilities. These suggest that child internalising difficulties are not solely driven by direct genetic transmission. More comprehensive research is needed to better understand the mechanisms involved, and ultimately how to ameliorate child behavioural difficulties. FundingEU, ERC, RCN, RCF, UKRI, SERI, DFG Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIndirect genetic effects (IGEs) refer to the influence of parental genotypes on offspring outcomes beyond direct genetic effects (DGEs), for example via environmental pathways. While IGEs on offspring cognitive traits are well-established for educational attainment, evidence for IGEs of parental liabilities to mental health and neurodevelopmental conditions remains limited. To assess the current state of evidence, we conducted a systematic search of published studies applying trio-based polygenic score (PGS) designs to child and adolescent mental health outcomes. We identified 141 primary studies in MEDLINE, Embase, PsycInfo, and Web of Science, by 6 March 2025, after removing duplicates; following screening, 12 studies met inclusion criteria (see supplement for a full description including results). Ten out of the 12 studies focused on externalising outcomes, with little or inconsistent support for IGEs. When observed, IGEs were mainly driven by maternal liabilities to autism, educational attainment, and cognitive performance on child outcomes. The current evidence was too limited and heterogeneous to synthesize findings quantitatively, therefore a qualitative synthesis was conducted. Many studies were statistically underpowered, and the observed IGEs were in all cases sample-specific. There were no published multi-cohort studies. Added value of this studyWe integrated information across over 33,000 mother-father-child trios from eight European cohorts, investigating 18 PGSs from parents and children, using maternal and paternal ratings of offsprings internalising, externalising, and total difficulties as outcomes at both preschool and school age. We mainly observed DGEs on externalising difficulties, consistent with previous studies. Some evidence of IGEs was found for internalising and total difficulties. IGEs were often found to be maternally driven, with the most robust evidence across ages and raters emerging for maternal depression and general neuropsychiatric liabilities. Implications of all the available evidenceThe current evidence suggests that childrens behavioural difficulties, especially internalising difficulties, may be partly driven by the environment shaped by maternal neuropsychiatric liabilities. Ours and previous findings highlight a pressing need for more comprehensive studies across different cohorts, raters, outcomes, and time points to understand the true extent of IGEs in the intergenerational transmission of mental health.

BackgroundMental well-being encompasses positive psychological functioning, life satisfaction, and engagement with daily activities. It is influenced by multiple interrelated factors, including symptoms of stress, anxiety, depression, and psychological inflexibility. Network analysis provides a data-driven framework for examining the complex interconnections between these components and for identifying elements that may play a central role in the mental well-being system. The present study aimed to identify key elements related to stress, anxiety, depression, and psychological inflexibility associated with mental well-being in individuals seeking online psychological support. MethodsThis cross-sectional study analyzed data drawn from the Online Well-being intervention. A total of 967 Mexican participants were included. A psychological network comprising seventy-four items was estimated, and centrality indices (strength, closeness, and betweenness) were computed to determine the relative importance of individual elements within the network. Network comparisons by gender were conducted to evaluate global and local differences. ResultsThe network revealed multiple inter-domain associations, particularly negative relationships between mental well-being and symptoms of depression, anxiety, negative stress, and psychological inflexibility. Items reflecting self-evaluation and emotional well-being consistently emerged as the most central elements in the network across centrality metrics. Gender-based comparisons indicated overall structural similarity between networks, although differences were observed in the strength of specific connections. ConclusionsNetwork analysis identified central elements linking mental well-being with psychological distress and inflexibility in a population seeking online psychological support. These findings contribute to a systems-level understanding of mental well-being and highlight potential targets for psychological interventions to enhance well-being and reduce distress.

Alcohol Use Disorder (AUD) is a multifactorial condition with severe individual and societal impacts. Extending our 2024 study, this work examines lifestyle, background, and family history determinants of AUD using an expanded dataset from the All of Us Research Program. The updated analysis includes approximately 2.5 times more participants than the prior study, enabling improved statistical power and evaluation of result stability over time. Using interpretable machine learning models and statistical analyses, we identified annual income, residential stability, recreational drug use, sex/gender, marital status, education, and family history as key contributors to AUD risk. Annual income remained the most influential predictor across both datasets, while other feature rankings showed modest shifts. Family history factors continued to demonstrate non-linear effects, with close relatives AUD status remaining influential despite differences between statistical association and predictive importance. In predicting AUD versus non-AUD status, Random forest models achieved the highest classification accuracy (81%), consistent with 2024 results but with improved precision for identifying AUD cases. Overall, the findings confirm the robustness of previously identified AUD determinants and underscore the need for coordinated, multi-level prevention strategies addressing behavioral, familial, and structural factors contributing to AUD.

In 2024, approximately 30% of U.S. adolescents reported having consumed alcohol at least once in their lifetime, with about 25% of these individuals engaging in binge drinking. Adolescent alcohol use is associated with neurodevelopmental impairments, elevated risk of later alcohol use, and mental health disorders. These findings underscore the importance of identifying the variables driving adolescent alcohol use and leveraging them for early identification and targeted intervention. Previous studies have typically developed machine-learning classification models that use neuroimaging data in combination with limited clinical measurements. Neuroimaging data are expensive and difficult to obtain at scale, whereas clinical measures are more practical for large-scale screening due to their low cost and widespread accessibility. However, clinical-only approaches for alcohol drinking classification remain largely underexplored. Furthermore, prior studies have often focused on adults, limiting generalizability to the broader adolescent population. Additionally, confounding factors such as age and substance use, which are strongly correlated with alcohol consumption, have often been inadequately addressed, potentially inflating classification performance. Finally, class imbalance remains a persistent challenge, with prior attempts yielding only limited improvements. To address these limitations, we propose FocalTab, a framework that integrates TabPFN with focal loss for robust generalization and effective mitigation of class imbalance. The approach also incorporates an initial preprocessing step to remove confounding factors to account for age and substance-use. We compare FocalTab against state-of-the-art methods across different variable selections and dataset settings. FocalTab achieves the highest accuracy (84.3%) and specificity (80.0%) in the most stringent setting, in which both age and substance use variables were excluded, whereas competing models drop to near-chance specificity (12-24%). We further applied SHapley Additive exPlanations (SHAP) analysis to identify key clinical predictors of drinker classification, supporting enhanced screening and early intervention.

Mild Behavioural Impairment (MBI) is defined by later-life onset of persistent behavioural changes and is recognized as a risk marker for cognitive decline and dementia. Apathy, a core MBI domain characterized by diminished interest, initiative, and emotional reactivity, can emerge before dementia and is hypothesized to be associated with structural brain changes. While previous studies have explored Alzheimer disease (AD)-related neuroanatomical substrates of apathy in the dementia clinical stage, few have investigated these associations in cognitively normal (CN) or mild cognitive impairment (MCI) individuals with persistent apathy consistent with MBI. Thus, this study explores structural brain differences between individuals with MBI-apathy and those without neuropsychiatric symptoms (no-NPS). Participants (n = 446; mean age = 69.6 years; 79.8% CN; 62.8% female) were drawn from the National Alzheimers Coordinating Center and categorized into MBI-apathy (n = 59) and no-NPS (n = 387) groups. Linear regressions were used to model associations between NPS group and regional brain measures, with adjustments for age, sex, years of education, apolipoprotein E4 carrier status, intracranial volume, and Mini-Mental State Examination score, with false discovery rate (FDR) correction for multiple comparisons. Primary outcomes included two predefined AD meta-regions-of-interest (ROIs): 1) thickness: a composite measure of mean cortical thickness across the entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, inferior parietal lobule, fusiform gyrus, and precuneus; and 2) volume: a composite measure of mean cortical and subcortical grey matter volume across the hippocampus, entorhinal cortex, amygdala, middle temporal gyrus, inferior parietal lobule, and precuneus. Primary outcomes also included cortical thickness and grey matter volume among individual ROIs including the ventral striatum (VS), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and dorsolateral prefrontal cortex (dlPFC). MBI-apathy status was associated with significantly lower AD-meta-ROI cortical thickness (Z-score difference [95% CI]; FDR-corrected p-value, -0.43 [-0.73 - [-0.12]]; 0.025) and lower AD meta-ROI grey matter volume (-0.50 [-0.71 - [-0.30]]; <0.001). MBI-apathy was also associated with significantly lower dlPFC thickness (-0.40, [-0.70 - [-0.09]]; 0.02) and volume (-0.28 [-0.50- [-0.06]]; 0.026) and lower OFC volume (-0.32, [-0.57 - [-0.07]]; 0.026) compared to the no-NPS group. Within a non-dementia sample, MBI-apathy was more strongly associated with established AD-vulnerable regions than with regions that have been traditionally implicated in apathy in dementia. Results suggests that during CN and MCI stages, MBI-apathy may reflect early AD-related neurodegeneration, with conventional apathy-related structural changes becoming more prominent as disease progresses.

OBJECTIVEUsing two cohorts and synthetic datasets, we estimated effects of prospectively reported alcohol use on memory outcomes across middle age. METHODSData were from National Longitudinal Study of Youth 1979 (NLSY79, n=7540, alcohol reports from ages 18-26), Health and Retirement Study (HRS age 50-56 at enrollment, n=13,090), and a synthetic cohort matching early life exposure information from 3,259 NLSY79 participants to later life memory information from 5,451 HRS participants. Covariate-adjusted linear mixed models regressed memory (word list recall) on alcohol use (none, light/moderate, heavy). RESULTSIn NLSY, we found no evidence that associations between light/moderate drinking in early adulthood and mid-life memory score significantly differed from associations between drinking abstention ({beta} = -0.09 (95% CI: -0.30, 0.11)) or heavy drinking ({beta} = -0.26 (-0.48, -0.04)) with memory score. In HRS, both abstaining from alcohol ({beta} = -0.14 (-0.25, -0.02)) and heavy drinking ({beta} = -0.25 (-0.42, -0.07)) were negatively associated with cognitive level. Results from the synthetic cohort mirrored NLSY, suggesting no significant association between abstention ({beta} = 0.13 (-0.10,0.36)) nor heavy drinking ({beta} = 0.02 (-0.25,0.28)) with mid-to-late life memory score. DISCUSSIONAlcohol consumption may not have an effect on memory until later life, though associations may be affected by residual confounding.

BackgroundThe influence of genetic and environmental factors, especially during early development, is critical in the pathogenesis of autism. Maternal autoantibodies that recognize specific fetal brain proteins can be strong predictors of autism risk. These antibodies cross the placenta and bind to their target antigens, which play critical roles in neurodevelopment, thereby increasing autism risk. This etiologically defined subtype is now referred to as Maternal Autoantibody-Related Autism (MARA). The newly developed MAR-AutismTM test is an indirect multi-ELISA assay designed to detect specific combinations of these maternal antibodies, which strongly predicts increased autism risk. ObjectiveTranslation of the indirect ELISA assays for the eight relevant antibodies (LDH-A, LDH-B, GDA, STIP1, CRMP1, CRMP2, NSE and YBOX) from an academic laboratory to a clinical development laboratory for optimization and determination of the analytical performance of the individual antibody assays. MethodsFeasibility assays were transferred from the academic laboratory and their performance confirmed prior to optimization of all steps from target protein production to preliminary threshold determination. Validation to rigorous standards was conducted. The ELISAs are qualitative assays using an internal continuous response and a cutoff to define positivity and negativity for each analyte. Analytical performance metrics of linearity, sensitivity, specificity, precision, and stability were determined by standard testing methodologies. ResultsThe optimized ELISAs all performed at acceptable standards for analytical performance. All of the assays except one were demonstrated to be linear upon dilution with buffer and with non-reactive plasma, however, recovery was overestimated with buffer diluent. The precision profile results demonstrated that the Lower Limit of Quantification (LOQ) was greater than the Limit of Detection (LOD) and below the preliminary thresholds determined from a general population cohort distribution. Precision studies showed coefficients of variation less than 15% with two minor exceptions. Common interfering substances, apart from whole human IgG, did not affect assay performance. The microtiter assay plates were stable for at least 6 months without significant drift. ConclusionOverall, the individual antibody assays demonstrated high sensitivity, specificity, and robustness sufficient to enable extension to clinical validation. These assays enable evaluation of specific antibody combinations that were previously reported to strongly and specifically correlate with autism risk, particularly in settings of suspected diagnosis or in families with an older sibling with a confirmed autism diagnosis.