JCPP Advances

ABSTRACT IMPORTANCE Childhood obesity is a growing global health concern associated with adverse physical, psychiatric, and neurodevelopmental outcomes. Although previous neuroimaging studies have linked obesity to widespread alterations in brain structure and function, it remains unclear how well multimodal neuroimaging measures and genetic markers can predict future weight gain and inform early intervention strategies. OBJECTIVE To evaluate the predictive utility of multimodal MRI measures and polygenic risk scores for obesity in estimating proportional body weight at baseline and predicting weight gain over one year in preadolescent children. DESIGN, SETTING, AND PARTICIPANTS This study used data from the Adolescent Brain Cognitive Development (ABCD) Study, a large-scale, multisite longitudinal cohort of children aged 9 to 10 years (N = 11,880). Analyses included baseline data collected between 2016 and 2018, and one-year follow-up data collected between 2018 and 2020 across multiple imaging sites. MAIN OUTCOMES AND MEASURES Elastic net regression models were applied to structural MRI (including diffusion tensor imaging) and resting-state functional MRI data to predict baseline triponderal mass index (TMI), a weight-for-height measure that more accurately reflects adiposity in children than body-mass index (BMI). Longitudinal classification models were developed to predict excess weight gain relative to normative developmental trajectories at one-year follow-up. Models were evaluated with and without the inclusion of polygenic risk scores and other non-imaging covariates. Generalizability was assessed using leave-one-site-out cross-validation. RESULTS Structural MRI measures predicted baseline TMI with an R^2 of 0.21, whereas resting-state functional MRI measures predicted TMI with an R^2 of 0.08. Classification models predicted one-year weight gain with area under the receiver operating characteristic curve (AUC) values of 0.73 for structural MRI and 0.60 for resting-state functional MRI. Including polygenic risk scores and other covariates improved model performance (structural MRI: R^2 = 0.25, AUC = 0.75; resting-state functional MRI: R^2 = 0.15, AUC = 0.69). Leave-one-site-out cross-validation revealed reduced generalizability across imaging sites (structural MRI R^2 = 0.13-0.17; resting-state functional MRI R^2 = 0.02-0.09; structural MRI AUC = 0.73-0.74; resting-state functional MRI AUC = 0.60-0.67). CONCLUSIONS AND RELEVANCE Multimodal MRI measures were associated with proportional body weight and demonstrated modest predictive utility for future weight gain in preadolescent children, explaining up to one fifth of the variance in weight-related outcomes. The addition of genetic and non-imaging variables improved prediction accuracy, underscoring the multifactorial nature of childhood obesity. However, the observed decline in performance under site-wise cross-validation highlights the need to address site-related variability to enhance reproducibility and generalizability in neuroimaging-based predictive models of pediatric obesity.

Neurobiological mechanisms underlying child maltreatment perpetration remain poorly understood, and the role of immune dysregulation has rarely been examined. Here, we tested whether peripheral inflammatory signatures are linked to brain structural alterations in mothers who have perpetrated maltreatment, and whether such alterations mediate this link to perpetration. In this cross-sectional study integrating structural MRI and inflammatory proteomics, 16 mothers with histories of maltreatment perpetration and 145 age-matched control mothers underwent brain imaging; a subgroup (n = 52; 11 maltreatment, 41 control) also completed plasma proteomic profiling using the Olink Target 96 Inflammation panel. Whole-brain voxel-based morphometry revealed significantly reduced gray matter volume (GMV) in the right middle/inferior temporal gyri, a region implicated in social cognition and contextual interpretation, in the maltreatment group. Proteomic analysis identified 16 inflammation-related proteins differentially expressed between groups; among these, nine were significantly associated with GMV in this temporal region. Lower GMV was associated with higher levels of pro-inflammatory proteins (CCL20, IL-17C) and with lower levels of immune-regulatory and metabolic proteins (CXCL1, CXCL6, SIRT2, STAMBP, MCP-2, MCP-4, 4E-BP1). Mediation analyses revealed that both protein sets were indirectly associated with perpetration through this regional GMV, with opposing patterns of direct association. These findings suggest that peripheral immune imbalance, characterized by elevated inflammatory signaling and diminished immune-regulatory capacity, is linked to structural vulnerability in a temporal cortical region involved in social cognition, specifically in perpetrating mothers. This neuroimmune pathway may contribute to maladaptive interpretation of child signals during caregiving and represents a potential target for biomarker-informed preventive intervention.

Autism development involves multiple genetic and early-life environmental factors. Studying the placenta's gene expression profile may reveal key mechanistic pathways in autism development. Here, using a nested case-cohort design within an Australian population-derived prebirth cohort study (n=1074), we identified 1,644 differentially expressed genes (DEGs; FDR<0.05) in the placenta of children with autism diagnosis (n=43), compared to those without (n=120). The top enriched pathways related to mitochondrial translation, oxidative stress, RNA processing and transcription regulation. CYP1A1, the most important xenobiotic-metabolising enzyme of the placenta, was the top downregulated DEG in the placenta of children with autism, while immuno-regulatory human leukocyte antigen (HLA)-related genes were among the top upregulated DEGs. A machine learning-based approach predicted autism from the transcriptomic data with a median sensitivity of 0.57 (2.5th-97.5th centiles: 0.29, 0.76) and median specificity of 0.92 (2.5th-97.5th centiles: 0.78, 0.98). Weighted Gene Correlation Network Analysis identified eight affected placental gene modules, with the largest five modules being enriched primarily for mitochondrial bioenergetics, oxidative phosphorylation and RNA processing pathways. This placental transcriptomic signature of impaired mitochondrial function and gene transcription regulation among infants subsequently diagnosed with autism has profound implications for understanding both risk factors and prediction, suggesting the possibility of identifying modifiable prenatal pathways to improve autism outcomes.

Background: Long COVID is a syndrome characterized by symptoms and conditions across all biological systems. This breadth of Long COVID phenotypes impedes efforts to identify the mechanistic pathways of Long COVID. Low serotonin may play a role in long-term sequelae of COVID-19, and selective serotonin reuptake inhibitors (SSRIs) may prevent these sequelae. Evaluation of the relationship between SSRIs and distinct categories of symptoms and conditions associated with Long COVID can highlight the mechanistic pathways that drive these relationships. Methods: We evaluated electronic health record data from a retrospective cohort of patients in the National Clinical Cohort Collaborative with comorbid depression and COVID-19 between October 2021 and February 2024. We estimated the relationship between SSRI prescription (versus no SSRI prescription) during acute COVID-19 and the one-year cumulative incidence of Long COVID-related conditions and symptoms across 14 human phenotype ontology categories. We applied Super Learner and targeted maximum likelihood estimation to estimate risk ratios while adjusting for confounders of interest and correcting for false discoveries from repeated testing. Results: We evaluated EHR data from 542,938 patients. We found that patients who were prescribed SSRIs during COVID-19 had a significantly lower risk of symptoms and conditions related to gastrointestinal factors (adjusted risk ratio (aRR) 0.95, 95% CI 0.92, 0.97), general health (aRR 0.91, 95% CI 0.88, 0.95), headaches (aRR 0.96, 95% CI 0.92, 0.99) and skin (aRR 0.92, 95% CI 0.87, 0.98). Discussion: We found that the prescription of SSRIs during acute COVID-19 was associated with a significantly lower risk of post-COVID sequelae related to gastrointestinal, headache-related, skin-related, and general symptoms and conditions, compared with no SSRI prescription. These findings highlight the role of serotonin in Long COVID and specific sequelae that may be reduced by SSRIs.

Globally, 60% of the population has experienced at least one type of adversity (e.g., emotional abuse, bullying) across infancy, childhood, and adolescence. Such experiences have been linked to an increased risk for mental health disorders. Changes in brain structure following experiences of childhood adversity have been hypothesised to be a mechanistic pathway explaining later mental health issues. However, to understand how changes in brain structure might mediate the effects of adversity, it is essential to identify which underlying neuronal processes may be affected by different types of adverse experiences. A key open question is whether grey or white matter is more vulnerable to adversity, as these two structures reflect distinct neurobiological mechanisms. This study investigated whether differences in trajectories of grey and white matter development during adolescence can be explained by exposure to different types of adversity. We applied the Adverse Adolescent Experiences Framework (Pollmann et al., 2025) categorising adversity into four levels: Intrapersonal (e.g., accidents), Caregiver (e.g., emotional neglect), Peer (e.g., bullying), and Community (e.g., neighbourhood safety). Exposure to each of the four factors was estimated through principal components analyses. We analysed two large longitudinal datasets: the Adolescent Brain Cognitive Development study (~12,000 adolescents measured at ages 10, 12, and 14) and the IMAGEN study (~1,400 adolescents measured at ages 14, 19, and 22). Using latent growth curve models, we captured individual differences in brain development by estimating baseline levels (intercepts) and rates of change (slopes) for total grey matter volume and mean white matter fractional anisotropy. In both cohorts, we found significant interindividual variability in baseline levels and rates of change for both grey matter volume and fractional anisotropy. Caregiver, Peer, and Community adversities were negatively associated only with the intercepts of grey matter volume and white matter fractional anisotropy. Importantly, associations differed between grey and white matter. In ABCD, Peer and Community adversities were more strongly associated with grey matter volume intercepts. In contrast, in IMAGEN, Caregiver, Peer and Community adversities were more strongly linked to white matter fractional anisotropy intercepts. This suggests that adversity has unique associations with grey and white matter, rather than exerting a uniform influence on brain structure. By demonstrating that different environments generate distinct biological associations with brain maturation, this work underscores the need to consider both grey and white matter when assessing the neurodevelopmental pathways to outcomes across the lifespan.

Neuropsychiatric polygenic indices (NPGIs) are used as genetic predictors of poor mental health. However, NPGIs are also associated with environmental factors which could affect mental health in adulthood, including the rearing environment. Hence, their "genetic" effects are both direct and environmentally mediated. There is a need to identify alternative genetic predictors without environmental signal. Endophenotype-based polygenic indices (EPGIs) trained on brain structure and function are under-studied alternatives which, due to their relative biological proximity, may exhibit associations with mental health outcomes which are less environmentally mediated than those of NPGIs. Using four representative UK samples (Understanding Society; UKHLS, NCDS, BCS70 and MCS) we employ sex-stratified path models to estimate the direct and environmentally mediated effects of eleven NPGIs and 30 EPGIs on adult mental health, focussing on the rearing environment. The depression NPGI is consistently associated with mental health symptoms across most sex-stratified sub-samples (best meta-analysis beta = 0.091, p 0.001) but demonstrates 1.6 - 24.5% environmental mediation. Seven other NPGIs and three EPGIs show sample- and sex-specific associations with mental health symptoms. NPGIs for attention deficit hyperactivity disorder, depression and substance use disorder are robustly associated with measures of the rearing environment, which in turn are frequently associated with mental health symptoms. Sensitivity analyses find that NPGI associations vary substantially depending on who is included in the sample. In conclusion, the rearing environment likely mediates a substantial portion of NPGIs' so-called "genetic" effects on mental health symptoms, but EPGIs are not currently powerful enough to replace them.

Observational studies in behavioural health often produce conflicting evidence because exposures are entangled with familial, clinical and social determinants. Rather than treating non-convergence as an obstacle to synthesis, we propose bias-domain triangulation, a causal-structure-aware framework that treats it as a diagnostic target. The framework distinguishes actual covariate adjustments from candidate background causal structures, adjudicates the causal roles of adjustment variables and maps core back-door pathways into distinct bias domains before quantitative synthesis, thereby reframing the question from whether estimates are heterogeneous to which bias structure changes the estimate. We apply this framework to a systematically derived literature on prenatal paracetamol exposure and offspring autism spectrum disorder or attention-deficit/hyperactivity disorder, comprising 22 studies and 33 adjusted estimates. Stronger overall control was associated with attenuation of the pooled association from 2.08 under weak control to 0.98 under strong control. Domain-specific analyses showed that pooled estimates approached the null only under strong familial/genetic control, whereas strong control of clinical-indication or social-behavioural domains left residual associations. This pattern suggests that shared familial liability is the bias structure most consistently associated with attenuation in the current evidence. Beyond this case, bias-domain triangulation offers a reusable strategy for diagnosing why observational evidence may persistently diverge, moving evidence synthesis beyond heterogeneity toward structural explanation. This study was registered on PROSPERO (CRD420261365276).

Child maltreatment is a leading cause of preventable harm, yet how diverse risk factors accumulate to precipitate caregiving failure remains unclear. In non-human mammals, fatal abandonment or aggression toward offspring occurs under specific ecological conditions, suggesting evolutionarily conserved pathways for caregiving breakdown. To test whether similar structures apply to humans, we conducted a case-control study enrolling 39 caregivers imprisoned for (near-) lethal child maltreatment and 351 control caregivers in Japan. Across 70 examined factors spanning caregivers' childhood, socioeconomic, neurobiological, and proximate environmental profiles, severe maltreatment was associated with 4.6- and 5.9-fold higher exposure to cross-species factors in men and women, respectively. Developmental pathway modeling identified significant standardized total effects of low educational attainment, non-kin caregiving, isolated parenting, behavioral addiction, and maternal absence before age 15. This proof-of-concept study presents an integrated framework bridging evolutionary biology with contemporary human caregiving and suggests targets for actionable intervention.

Identifying generalizable brain-based biotypes across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust subtypes spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness data from 1,531 MDD individuals in UK Biobank (UKB), with external validation in 144 inpatients from IRCCS Ospedale San Raffaele (HSR). Two distinguishable clusters emerged (accuracy=87.5%), with one showing widespread cortical thinning, anergy-related symptoms, childhood trauma, and diabetes comorbidity. This profile generalized with 96.5% accuracy in a hold-out UKB sample and 80.6% in HSR. Mapping clusters cortical profiles onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified dopamine transporter as the dominant contributor in UKB, and histamine receptor H3 in HSR. These findings provide a reproducible framework linking MDD subtypes to multiscale biological complexity.

Background Depressive disorders are among the most common mental disorders, often emerging in adolescence. Despite advances in biological psychiatry, research on early psychopathology remains scarce. Given the heterogeneity and comorbidity of depressive disorders, identifying biologically informed phenotypes could enhance diagnostic accuracy and personalized treatment approaches. Methods This study utilized baseline and 6-month follow-up plasma samples (n=47) and clinical data (n=103) of adolescent outpatients with depression (DD, aged 14-19) from the Finnish SMART study and healthy control samples (HC, n=53, aged 15-16) from the Finnish PANIC study. Fasting plasma samples were analyzed using untargeted liquid chromatography-tandem mass spectrometry for proteomics. Data analyses included dimensionality reduction, regression models, correlation analysis, functional enrichment, and factor analysis of mixed data with k-means clustering, including 72 symptom-related items, lifestyle, and socioeconomic scales. Results Among 756 proteins detected in DD and HC, 308 proteins showed notable, significant (adjusted p<0.01 and Log2FC [&ge;]|1|) alterations in depression. These proteins were enriched in stress-response pathways, including complement and coagulation cascades, energy metabolism, the proteasome complex, and growth factor signaling. Additionally, extracellular matrix proteins were altered. Clinical phenotypes were mostly distinguished by symptom severity, bullying victimization and other trauma-related experiences, social relationships, and medication. Improvement in mood over the 6-month follow-up was associated with shifts in proteins involved in extracellular matrix, cytoplasmic vesicles, and complement and coagulation cascades. Conclusions Together, adolescent depression displays shared plasma proteomic signatures across its clinical phenotypes, and systemic immune dysfunction, oxidative stress, and extracellular matrix are potential targets for biologically informed interventions in depression.

Reported perceptual differences in autism may arise from reduced use of prior context to shape incoming sensory input. Speech perception provides a critical test of this account because stable perception requires listeners to integrate variable acoustic signals with contextual expectations. This study examined context-dependent modulation of speech encoding in autistic and non-autistic adults using the frequency-following response (FFR), a neurophysiological measure of phase-locked auditory encoding. Participants heard English intonational pitch contours presented in repetitive and variable contexts while EEG was recorded. Principal component analysis of FFR metrics yielded components indexing neural encoding fidelity and timing. Non-autistic participants showed enhanced encoding fidelity in more predictable contexts, whereas autistic participants showed reduced context-dependent modulation. Neural encoding timing also showed divergent context effects across groups, suggesting altered balance between feedback-based predictive mechanisms and locally driven adaptation processes. Within the autistic group, greater context-related modulation of encoding fidelity was associated with lower ADOS-2 Social Affect severity but poorer speech-in-noise perception, suggesting that the functional impact of contextual modulation depends on input reliability and task demands. These findings indicate that context-dependent modulation of speech encoding is altered in autism and may contribute to individual differences in auditory and social-communicative function.

Importance: In adolescence, attempts to lose weight are common, but their long-term impacts on mental and physical health are not known. Objective: To investigate the association between adolescent dieting and exercising to lose weight and adult trajectories of depressive symptoms and body mass index (BMI). Design: A longitudinal cohort study of children born between April 5 and 11, 1970, and followed up to age 51 years. Setting: Adolescents in the 1970 British Cohort Study in England, Wales and Scotland. Participants: A total of 4,650 adolescents with available exposure data. Exposures: Self-reported lifetime dieting or exercising for weight loss measured at age 16 years. Main Outcomes and Measures: Depressive symptoms measured with the nine-item Malaise Inventory, and BMI derived from self-reported height and weight, at ages 26, 30, 34, 42, 46, and 51 years. Results: Among 4,650 adolescents (56.7% girls, 97.7% White), 1,938 (41.7%) had dieted and 343 (7.4%) had exercised for weight loss by age 16 years. In fully adjusted analyses controlling for a wide range of child- and family-based confounders including prior BMI and emotional difficulties, there was evidence that adolescents who had dieted had higher adult depressive symptom trajectories (adjusted mean difference [aMD] 0.13, 95% CI 0.03-0.24, p=0.015) and higher and increasing adult BMI trajectories than those who had not dieted. There was also evidence that adolescents who exercised for weight loss had higher adult depressive symptom (aMD 0.18, 95% CI 0.02-0.34, p=0.031), and BMI trajectories (aMD 0.37, 95% CI -0.03, 0.78, p=0.071), though evidence of the latter was weak. Conclusions and Relevance: Behaviours aimed at weight loss occurring in adolescence might be a shared risk factor for depressive symptoms and high BMI in adulthood. If causal, these findings could suggest that reducing pressures to lose weight in adolescence may help prevent poor mental and physical health across the lifecourse.

Background: Behavioral crises are common and distressing in children with neurodevelopmental or behavioral conditions, and many escalate to emergency service use. Access to behavioral therapy is often constrained. Smartphone applications, in-home systems, and wearable sensors that could support caregivers during crises at home are in active development, but few studies have asked caregivers what they would accept or want from such tools. Methods: We conducted a single-center cross-sectional online survey (REDCap) of caregivers of children aged 5-17 years with neurodevelopmental or behavioral conditions, recruited as a convenience sample through flyers, email invitations, and in-person invitations during clinic visits from the neurobehavioral continuum of care at Cincinnati Children's Hospital Medical Center. The response rate is undetermined due to the open-ended recruitment process. Prior behavioral-crisis experience was not an eligibility requirement. The 24-item instrument covered crisis burden, service utilization, caregiver confidence and training, therapy access and barriers, and technology preferences. Analyses were estimation-first (proportions with Wilson 95% confidence intervals [CIs]; medians with interquartile ranges [IQRs]); three pre-specified bivariate analyses used ordinal methods (Kendall's tau-b and Jonckheere-Terpstra for ordinal pairs; Friedman for repeated ratings of five support functions). Recruitment is ongoing toward a target of 75; this interim analysis includes the first 55 respondents, and all findings are hypothesis-generating. Results: All 55 respondents reported that their child had experienced a behavioral crisis; 44% (95% CI 31-57%) reported crises at least weekly, and 35% (95% CI 23-48%) had ever used 911 or an emergency department for a crisis. Half of caregivers (51%) felt not at all or only a little confident managing crises, and only 46% (95% CI 33-59%) had received informal or formal crisis-management training. The most frequent barrier to behavioral therapy was long waitlists (51%; 95% CI 38-64%). Stated openness to hypothetical technology-based crisis support was high, with 64% (95% CI 50-75%) very interested in a smartphone app or in-home support system, 80% (95% CI 68-88%) willing to have their child use a wearable sensor (1 of 55 declined), and 49% (95% CI 36-62%) willing to share video or audio with a future support tool (a further 42% answered "maybe"; 9% declined). The most-valued features were a personalized crisis plan (58%) and safe de-escalation scripts (49%); the most-cited concern was privacy and data security (36%). Conclusions: In this small, self-selected, single-center sample, caregivers of children with neurodevelopmental or behavioral conditions reported substantial crisis burden, limited training, and constrained access to therapy, alongside high stated openness to technology-based crisis support; personalization and privacy were their leading priorities. These preliminary, hypothesis-generating findings can inform the design of caregiver-facing crisis-support technologies and larger representative studies.

Bayesian accounts of autism propose that perception is less influenced by prior expectations and more strongly driven by incoming sensory information in autistic than non-autistic individuals, with this altered balance cascading through the cognitive hierarchy to also influence higher cognitive functions. However, empirical support for these accounts remains mixed. Previous work has mostly tested these ideas in the context of objective environmental statistics, but recent work suggests that it may be subjective experience of structure, rather than structure itself, that shapes perceptual processing. Characterising these subjective experiences in autistic individuals is therefore crucial for understanding predictive processing in autism. In the present study, we thus examined subjective experience of statistical structure in autistic and non-autistic adults and tested how this experience relates to perceptual decisions. Participants were exposed to statistical regularities between action cues and visual stimuli (shapes), and we measured their speed and accuracy in reporting which shape they had seen. At the end of the study, participants were asked to estimate the probability and rate their surprise for each action-shape combination. Autistic and non-autistic participants showed similar subjective probability and surprise ratings and a comparable relationship between these ratings and perceptual decisions. Across participants, subjective ratings explained perceptual decisions better than objective structure. Together, these findings show that autistic and non-autistic adults experience statistical structure similarly, with these experiences exerting a similar influence on perceptual decisions - therefore suggesting that subjective experience plays a comparable role in predictive processing in autistic and non-autistic adults.

Importance Childhood sexual abuse (CSA) is linked to adverse psychiatric outcomes in adulthood, but evidence on its association with cardiovascular disease and mortality from large, diagnostically ascertained cohorts remains limited. Objective To assess the 10-year risk of all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease among patients with a diagnosed history of CSA compared with a matched unexposed cohort. Methods In this retrospective cohort study, we used deidentified electronic health record data from 68 health care organizations in the TriNetX US Collaborative Network. Patients diagnosed with confirmed or suspected childhood sexual abuse (CSA) before age 18 between January 1, 2003, and December 31, 2015, who had a subsequent adult encounter, were propensity score matched 1:1 with unexposed patients on age, sex, race and ethnicity, and baseline psychiatric and medical comorbidities (n = 9,083 per cohort). Outcomes--all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease--were assessed over 10 years from the index adult encounter using risk and time-to-event analyses to estimate risks, risk ratios, and hazard ratios. Results Among 18,166 matched patients (mean [SD] age, 19.0 [2.0] years; 14,813 [81.6%] female), CSA was associated with significantly elevated risk of suicide or self-harm (5.1% vs 2.8%; risk ratio [RR], 1.84; 95% CI, 1.57-2.16), drug overdose or poisoning (5.5% vs 3.7%; RR, 1.47; 95% CI, 1.28-1.69), and cardiovascular disease (12.3% vs 9.3%; RR, 1.31; 95% CI, 1.20-1.44), with concordant hazard ratios (all P < .001). All-cause mortality was numerically higher but not statistically significant (0.5% vs 0.4%; RR, 1.16; 95% CI, 0.75-1.79; P = .51). Conclusions and Relevance A diagnostically confirmed history of CSA was associated with substantially elevated 10-year risk of self-harm, overdose, and cardiovascular disease, independent of baseline demographic and psychiatric comorbidity. These findings support integrated psychiatric and cardiovascular screening for adult survivors of CSA and trauma-informed care extending beyond mental health services alone.

Background: Rett syndrome (RTT), a rare neurodevelopmental disorder caused primarily by pathogenic variants in the MECP2 gene, is characterized by severe cognitive, motor, and autonomic impairments. Atypical sensory processing, including co-occurring hypo- and hyper-responsivity, is a core yet poorly understood feature. While evoked potentials (EPs) show delayed and attenuated sensory responses in RTT, the underlying mechanisms of these impairments remain unclear. Inter-trial phase coherence (ITPC), which quantifies trial-by-trial neural response consistency, offers a promising functional biomarker of variability in sensory processing. Methods: We characterized caregiver-reported sensory responsivity in 32 individuals with RTT (all female) and 28 typically developing controls (26 female, 2 male). EPs were then recorded during passive visual and auditory stimulation and ITPC was computed to assess whether variability in the timing of neural responses could account for reduced EP amplitudes and atypical sensory responsivity. Results: Hypo- and hyper-responsivity to sensory stimuli were both significantly elevated in RTT and were positively correlated, co-occurring within individuals. ITPC was significantly reduced in RTT across visual and auditory modalities and was associated with reduced EP amplitudes. Notably, reduced ITPC in visual-evoked potentials was further associated with elevated visual responsivity and greater behavioral symptom severity. Conclusions: Increased variability in neural response timing may contribute to both reduced EPs and atypical sensory responsivity in RTT, supporting ITPC as a functional biomarker. Decreased temporal precision of neural activity may explain the co-occurrence of hypo- and hyper-responsivity and provide a unifying framework for sensory dysfunction across neurodevelopmental disorders.

Autism is a heterogeneous neurodevelopmental condition, often accompanied by challenges in language and cognitive development. Although atypical functional connectivity (FC) has been reported in autism, the timing of when it first emerges and its relevance for later behavior remain poorly understood. In this study, we examined developmental trajectories of alpha-band FC and network organization across the first three years of life. We computed global alpha-band measures, including peak alpha connectivity frequency (PACF), mean FC, clustering coefficient, and modularity, to characterize nonlinear developmental trajectories from longitudinal EEGs collected from 238 children (3-to-36-month-olds) with (Autism; n=58) and without (LL-noAutism; n=180) autism. Network-based statistics (NBS-Predict) identified subnetworks contributing to group differences at each age. Exploratory graph analyses (EGA) examined associations among FC, network measures, and language outcomes. We observed that PACF increased linearly with age in both groups. Global alpha-band connectivity measures showed a similar developmental pattern, with mean global FC, clustering coefficient, and modularity all increasing rapidly during the first year in both groups. Thereafter, these measures declined in the Autism group but continued to gradually increase in the LL-noAutism group. Compared to LL-noAutism, NBS-Predict identified both hyper- and hypo-connectivity subnetworks in Autism at 3 months, followed by a hypo-connectivity subnetwork at 24 and 36 months. EGA indicated that early hyperconnectivity predicted later hypoconnectivity and was associated with subsequent network organization and language outcomes. These findings indicate that altered alpha-band connectivity trajectories are detectable in infancy in children later diagnosed with autism and may contribute to later differences in developmental outcomes.

Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromosomes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.

Objective: Pediatric epilepsy patients undergoing stereo-electroencephalography (sEEG) for ictal onset evaluation provide a rare window to study the developing brain. While methodological frameworks for task-based sEEG research are well-established in adults, pediatric-specific guidance remains underdeveloped. Furthermore, many pediatric epilepsy patients have comorbidities that might typically exclude them from participating in research. We examine factors that influence research participation and discuss considerations for conducting sEEG research in children. Methods: Here, we present a retrospective analysis of task-based research participation patterns from an NIH-funded study of speech and language representations (1R01DC018579) in 66 patients (ages 4-24) undergoing sEEG monitoring at Texas Children's Hospital to determine whether specific comorbidities influenced research participation. Results: Eighty-nine percent (n=66) of patients approached for consent agreed to participate in the study. Despite high rates of comorbidities including neurocognitive disorder (66.67%), language delay (31.75%), global developmental delay (23.81%), mood disorders (33.33%), ADHD (46.03%), autism spectrum disorder (14.29%) or other cognitive/intellectual disabilities (36.51%), all participants engaged in at least one task. While the majority of these diagnoses did not appear to influence subject participation, global developmental delay was associated with a significant reduction in time spent on active tasks. Discussion: Despite high prevalence of neuropsychological comorbidities among participants, our evidence suggests that these participants contribute meaningfully to studies investigating important developmental questions. We suggest strategies for tailoring task-based research to accommodate the unique needs of individuals in this population. Such practices are important for ensuring that research studies reflect the true diversity of the population.

Smooth pursuit eye movement abnormalities are well established in psychosis, but the specific components of pursuit performance that vary across clinical states and symptom profiles remain insufficiently characterized. Here, we used a rapid smooth pursuit paradigm combining standard linear tracking (repeated short trials moving in different directions) with structured target occlusion to examine oculomotor performance in individuals with acute psychosis, chronic psychosis, and healthy controls. The occlusion condition allowed assessment of tracking when the target was temporarily hidden and gaze had to be maintained along the expected trajectory. Basic oculomotor measures, including full pursuit gain and initial catch-up saccade properties, were largely preserved in patients. In contrast, more specific trajectory-based measures revealed distinct abnormalities. Saccade-free smooth tracking gain was selectively reduced in acute psychosis, whereas tracking deviation during non-occluded pursuit was altered in both patient groups, reflecting reduced forward tracking relative to controls. During structured occlusion, patients showed reduced forward gaze progression along the expected trajectory, with a graded pattern across groups: controls showed the strongest predictive lead, chronic patients an intermediate response, and acute patients the weakest predictive lead. Tracking deviation and occlusion-related deviation were both associated with positive symptom severity, whereas smooth tracking gain was not. These findings suggest that smooth pursuit abnormalities in psychosis are measure-specific rather than uniform, involving both broader psychosis-related alterations in gaze-target alignment and state-sensitive disruptions in occlusion-related tracking. Structured occlusion may therefore offer a useful extension of conventional smooth pursuit paradigms for probing prediction-related sensorimotor control in psychosis and distinguishing acute from chronic clinical states.