Research on sex-related differences in child and adolescent neurocognitive development has often been framed around whether boys and girls differ and which group performs better. This framing is increasingly inadequate because it treats developmental timing, observable phenotypes, and clinical recognition as interchangeable forms of evidence. Drawing on developmental neuroscience, cognitive development, research on gendered experience, and clinical studies of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), this integrative narrative review proposes a developmental-visibility framework. The framework interprets sex-related differences across three analytically distinct layers: developmental timing, phenotypic expression, and clinical recognition. Developmental timing refers to age-related trajectories, pubertal coupling, maturation tempo, and variability. Phenotypic expression refers to how developmental differences may appear in language, executive function, emotion, and social cognition under specific task and measurement conditions. Clinical recognition refers to how informants, referral thresholds, compensatory or camouflaging behavior, and diagnostic tools influence which difficulties are identified. ASD and ADHD illustrate the clinical-recognition layer because less externally disruptive or more compensated presentations may remain underrecognized despite meaningful developmental burden. The framework helps explain why modest average effects, inconsistent behavioral findings, and unequal clinical recognition can coexist. It shifts the field from asking whether sex-related differences exist to asking when, how, and under what social and clinical conditions they become visible.
Background: Early childhood nutrition is strongly associated with neurodevelopmental outcomes, particularly in socially vulnerable settings. Limited evidence is available describing the relationship between nutritional status, food security, and neurodevelopment among preschool children in low-income urban areas of Colombia. This study aimed to evaluate nutritional status, household food insecurity, and neurodevelopmental outcomes in children attending early childhood centers in El Codito, Bogotá, and to explore the association between anthropometric indicators and neurodevelopmental performance. Methods: A cross-sectional study was conducted in children enrolled in community childcare centers. Nutritional status was assessed using anthropometric indicators according to World Health Organization growth standards, including weight for age, height for age, and body mass index for age. Neurodevelopment was evaluated using the Escala Abreviada de Desarrollo (EAD). Household food insecurity was measured through a validated questionnaire. Descriptive statistics were performed, and associations between variables were analyzed using correlation tests and group comparisons according to data distribution. Results: Most participants presented adequate nutritional status; however, a proportion of children showed risk of stunting or excess weight. Neurodevelopmental scores were generally within expected ranges, although variability was observed across developmental domains. Significant associations were identified between certain anthropometric indicators and neurodevelopmental outcomes. Moderate to severe household food insecurity was identified in 21.4% of participating households. Conclusions: Nutritional status and household food insecurity represent important contextual factors for child health in vulnerable urban populations. These findings highlight the importance of integrated nutritional and developmental monitoring strategies within early childhood programs. Further longitudinal studies are required to clarify causal pathways and to guide targeted public health interventions in similar contexts.
Vitamin D is a nutrient-related secosteroid system with endocrine, paracrine, immunological, and neurodevelopmental actions relevant to nutritional psychiatry. Psychiatric research has often treated vitamin D either as a cross-sectional correlate of depression or as a non-specific supplement expected to act across heterogeneous diagnostic categories. This narrative review aimed to develop a more discriminating framework in which vitamin D is considered a lifespan neuroimmune and immunometabolic signal whose psychiatric relevance depends on developmental timing, biological context, and phenotype. Evidence was integrated from developmental epidemiology, neonatal dried-blood-spot studies, randomized trials, meta-analyses, Mendelian randomization studies, clinical guidelines, and mechanistic neuroscience. The review focuses on prenatal and neonatal 25-hydroxyvitamin D, vitamin D-binding protein, free and bioavailable vitamin D, vitamin D receptor signaling, immune and microglial pathways, neurotransmitter systems, neurotrophic signaling, mitochondrial function, oxidative stress, hypothalamic-pituitary-adrenal-axis regulation, and the gut-microbiota-immune-brain axis. The available evidence does not support vitamin D as a universal treatment for psychiatric disorders. Instead, vitamin D deficiency and altered vitamin D biology appear most relevant in biologically and clinically defined risk states, including neurodevelopmental vulnerability, inflammatory depression, psychosis liability, severe mental illness with nutritional deprivation, metabolic comorbidity, and cognitive frailty. Mechanistic data support plausible links with cytokine biology, the tryptophan-kynurenine pathway, dopaminergic and serotonergic systems, stress regulation, and neuroimmune homeostasis. Vitamin D should be conceptualized in psychiatry as a context-dependent neuroimmune and immunometabolic signal rather than a generic psychotropic intervention. Future studies should prioritize biomarker-enriched, developmentally timed, nutrition-centered models of precision prevention and adjunctive care.
Copy number variants (CNVs) are genomic rearrangements that carry a substantial risk for neurodevelopmental and neuropsychiatric disorders. Among these, recurrent deletions and duplications at the 16p11.2 locus are robustly associated with autism spectrum disorders, schizophrenia, epilepsy, and related conditions, yet also display marked variability in penetrance and phenotypic expression. Accumulating evidence indicates that 16p11.2 gene dosage influences multiple stages of brain development, from early progenitor dynamics and neuronal migration to synaptic formation, refinement, and plasticity. However, how disruptions across these processes are integrated over time, and how they relate to the observed variability and incomplete penetrance, remains poorly understood. In this review, we summarize the current evidence on the impact of 16p11.2 CNVs on brain development, focusing on cellular and circuit-level processes that shape neural connectivity. We discuss how gene dosage imbalance influences early developmental trajectories, synaptic formation and pruning, interneuron maturation, and activity-dependent plasticity, and consider how these processes interact across developmental stages. We suggest a conceptual framework wherein 16p11.2 CNVs do not impose fixed pathogenic outcomes, but rather they contribute towards developmental constraints that shape the timing and stability of neural circuit development. Consequently, these constraints increase vulnerability to neurodevelopmental and psychiatric outcomes in a context-dependent manner.
Despite its increasing use in pediatric neurorehabilitation, Cuevas Medek Exercise (CME) remains rooted in clinical tradition, with limited theoretical articulation in relation to contemporary models of motor development, control, and learning. While clinical observations and reports from practice suggest possible functional benefits in children with motor delays, the absence of a conceptual framework limits its integration into evidence-informed physical therapy practice and education. This perspective proposes a conceptual model for CME that aligns its core principles with current theoretical constructs in motor behavior and developmental neuroscience. By examining key elements of CME-such as distal initiation, postural challenge, and task variability-through the lens of affordances, self-organization, and experience-dependent plasticity, the article presents CME not merely as a technique, but as a conceptual developmental approach informed by embodied action. We argue that such reframing may support more rigorous clinical reasoning, contribute to interdisciplinary dialogue, and inform a theoretical basis for future research exploring the proposed mechanisms and potential effects of CME. More broadly, this perspective contributes to ongoing discussions on how clinically derived interventions can be conceptually integrated within contemporary rehabilitation science. While the present article does not provide empirical validation, it offers a theoretical framework intended to inform future investigation and critical reflection in pediatric physical therapy.
Over the past two decades, virtual reality (VR) has emerged as a technique for studying neurodevelopmental conditions (NDCs) such as attention deficit hyperactivity disorder, autism spectrum disorder, and developmental coordination disorder. Until now, the predominant focus of VR applications in this field has been on developing new assessment and diagnostic tools, aiming to identify NDC symptoms in engaging and ecologically valid digital environments. However, despite these advancements, VR remains underutilized as a tool for basic NDC research. This paper urges researchers to harness the potential of VR in testing embodied cognitive mechanisms underlying NDCs. That is, leveraging VR's functionality to systematically manipulate sensory and social experiences in real-world simulations and test participants in active, whole-body, daily tasks. Specifically, we argue that VR's distinctive value is that it allows researchers to manipulate distractor load, sensory congruence, social contingency, and action demands within everyday-like tasks while concurrently recording gaze, movement, and physiology. Such capabilities enable richer experimental phenotyping of NDCs and support mechanistic questions that are difficult to test cleanly with either de-contextualized laboratory tasks or uncontrolled real-world observation. We conclude by pointing to future directions for VR-based research of neurodiversity.
The sensory/neural Temporal Sampling (TS) theory of developmental language disorder (DLD) is based on the sensory and linguistic impairments in rhythm processing that are found in children with both developmental dyslexia (DD) and DLD. These sensory/linguistic impairments include decreased sensitivity to amplitude rise times (ARTs, the sensory triggers related to automatic cortical speech tracking), syllable stress patterns and speech rhythm. At the neural level TS theory predicts impairments in the cortical tracking of different rates of amplitude modulation (AM) in the speech signal <10 Hz. To date, the accuracy of low-frequency cortical tracking in natural continuous speech has not been measured in children with DLD. Here, EEG was recorded during story listening from children with and without DLD aged around 9 years, and decoding analyses in the delta, theta and alpha (control) bands were carried out. EEG power was computed in the delta, theta and gamma bands, and phase-amplitude coupling and phase-phase coupling (PAC, PPC) were also computed between bands. Whole-brain analyses showed that the accuracy of low-frequency decoding (delta, theta) did not differ between groups. However, region-specific analyses revealed significantly reduced delta-band speech tracking in the right temporal cortex in the children with DLD. PAC and PPC dynamics did not differ between groups. The data suggest that low-frequency cortical tracking impairments in DLD may be spatially constrained to the right hemisphere rather than globally present as in DD. The data are discussed using TS theory.
In the last 25 years, research on dehumanization-the tendency to perceive others as less than fully human-has spiked and evolved in many ways. In the current review, we will provide an overview of the various methodological and conceptual trends in this research area and introduce a new way of conceptualizing dehumanizing perceptions. Focusing on developments in neuroscience that have shown how human and object stimuli are typically processed in different ways using specific brain areas, dehumanization can be understood as the fading of this human-object divide. We will demonstrate what this process account of dehumanization implies for the understanding of the concept, how it can respond to some of the recent controversies and critiques, and how a research agenda integrating the study of developmental mechanisms can bolster our understanding of dehumanization processes.
RLIM encodes an E3 ubiquitin ligase associated with Tonne-Kalscheuer syndrome (TOKAS) with occasional seizures, but its roles in epilepsy are unelucidated. This study aimed to explore the association of RLIM with epilepsy. Trio-based whole-exome sequencing was performed in patients with unknown causes. We systematically reviewed reported RLIM variants for genotype-phenotype correlations. Spatiotemporal expression profiles and protein-protein interaction network enrichment were investigated to explore the underlying mechanisms of phenotypic features. Four hemizygous RLIM missense variants were identified in four unrelated male patients, which are absent in gnomAD controls. All variants altered amino acid hydrophobicity/protein stability and localized to mutation-intolerant regions. All patients had early-onset epilepsy (13-36 months). Case 3 with a variant in the basic domain (BD) had developmental and epileptic encephalopathy, while other patients with variants in other regions presented milder epilepsy with motor/speech delay. Analysis of 13 additional variants indicated possible molecular subregional effects: BD/RING variants caused severe/fatal developmental disorders, while N-terminal variants had milder phenotypes. RLIM was highly expressed in the developing brain and showed high expression in neurons, suggesting its vital role in neurodevelopment. RLIM exhibited an increased expression after late childhood, indicating an increased functional dependence in the late stage, which is consistent with the phenotype of seizure relapse. Its protein-protein interaction(PPI) network contained 72 nodes, interacting with epilepsy/neurodevelopmental disorders (NDDs) causative genes. RLIM variants are associated with X-linked epilepsy with NDDs. Molecular subregional effects, genotype-phenotype association, and expression-phenotype correlations provide critical insights into the clinical diagnosis, management and mechanistic investigation of RLIM-related disorders.
How progenitor lineage relationships shape the cellular diversity and organization of the human cortex remains a central question in developmental neuroscience. Lineage tracing provides a framework for understanding how developmental trajectories generate this diversity by capturing cellular history rather than static molecular identity, revealing progenitor fate potential, temporal regulation of developmental competence, and spatial patterns of clonal organization. In this review, we examine advances in prospective viral barcoding, clustered regularly interspaced short palindromic repeats (CRISPR)-based evolvable lineage recording, and retrospective inference from endogenous somatic mutations, highlighting how these complementary approaches are reshaping our understanding of human cortical development. We discuss evidence that human cortical progenitors exhibit expanded fate potential, prolonged temporal control of lineage output, and regionally patterned lineage dispersion, distinct from canonical rodent models. We further consider how integrating lineage information with molecular profiling and genetic perturbation enables causal dissection of developmental programs. Finally, we explore how disrupted lineage dynamics contribute to neurodevelopmental disorders, suggesting disease mechanisms as deviations in developmental trajectories. Recognizing lineage dynamics as an organizing principle will be essential for linking developmental ancestry to cortical organization and disease vulnerability.
Neuroticism, a Big Five trait characterized by emotional instability and susceptibility to negative affect, is a robust transdiagnostic predictor for the onset, severity, and persistence of anxiety disorders, major depressive disorder (MDD), and other affective conditions. Recent advances in functional magnetic resonance imaging (fMRI) techniques-including resting-state fMRI, multimodal neuroimaging, and their integration with machine learning-have enabled multi-perspective investigations into the neural substrates of neuroticism. Current research in this field primarily follows three complementary approaches: cross-sectional studies identifying key brain regions for emotional processing and cognitive control (e.g., amygdala (AMG), prefrontal cortex); longitudinal studies capturing neural mechanisms evolution across adolescence, middle age, and old age to elucidate relationships between neuroticism and brain plasticity; and intervention studies exploring plastic pathways for reshaping the neural representations of neuroticism, challenging the classic "trait stability" paradigm. This review synthesizes recent progress in the cognitive neuroscience of neuroticism across these three approaches, proposes a unified emotion-cognition neural model centered on the AMG-prefrontal-default mode network circuit, and outlines a hypothesized lifespan trajectory of Limbic Sensitivity → Regulatory Strain → Prefrontal Decline. While accumulated evidence broadly supports the cross-sectional and interventional pillars of this framework, the lifespan trajectory remains a theoretically informed working model requiring further longitudinal validation. The field still faces critical limitations, including small effect sizes, methodological heterogeneity, and unresolved questions regarding causality and circuit specificity. This review aims to provide a conceptual integration of existing findings, identify key uncertainties, and propose evidence-based future directions. We further link the proposed neural model to clinical phenotypic characteristics of high neuroticism and discuss its implications for targeted neural interventions, thereby advancing our understanding of the biological basis of neuroticism and providing a theoretical framework for prevention and intervention in neuroticism-related affective disorders.
Ethanol exposure during brain development has been associated with hippocampal oxidative stress, neuroinflammation, and apoptosis, resulting in lasting cognitive and emotional deficits characteristic of fetal alcohol spectrum disorders (FASD). This study evaluated the neuroprotective potential of Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory actions, against developmental ethanol neurotoxicity. Neonatal Wistar rats received ethanol (5.25 g/kg/day; 11.9% v/v) from postnatal days 2-10 and were subsequently treated intraperitoneally with Hesperidin (25, 50, or 100 mg/kg). Behavioral testing on days 39-45 using the Elevated Plus Maze (EPM) and Morris Water Maze (MWM) showed that ethanol markedly decreased open arm time (Oat%) and entries (OAE%) (P < 0.001, P < 0.01 vs Control), increased escape latency (P < 0.001), and reduced probe target time (P < 0.001 vs Control). Hesperidin at 50 and 100 mg/kg improved all indices (P < 0.05-0.01 vs Ethanol). Ethanol elevated hippocampal MDA and TNF-α (P < 0.001) while decreasing SOD (P < 0.01) and GSH-Px (P < 0.001), Hesperidin normalized these values (P < 0.01-0.001 vs Ethanol). GFAP and cleaved caspase-3 immunoreactivity were also reduced by hesperidin (P < 0.001 vs Ethanol). Overall, Hesperidin afforded dose-dependent neuroprotection by mitigating oxidative stress, inflammation, and apoptosis, thereby improving ethanol-induced behavioral impairments.
Extensive explorations in neuroscience, psychology, and psychotherapy increasingly recognized the embodied and relational foundations of selfhood, underscoring the need for an integrated framework spanning development, psychopathology, and therapeutic change. This narrative review synthesizes empirical and theoretical literature across neuroscience, embodiment research, predictive processing, developmental science, phenomenology, and psychodynamic theory, proposing a multidimensional neuropsychodynamic framework of embodied selfhood and its clinical implications. A central contribution is the positioning of Peripersonal Space (PPS) as an embodied action-oriented interface that functions as a primary developmental scaffold for bodily self-consciousness, self-other relations, affect regulation and temporal continuity. PPS is proposed as a dynamic matrix linking embodied predictive self-processes with relational experience, thereby shaping subjective temporality and autobiographical processes. Within this framework, subjective time emerges through bodily rhythms, interpersonal synchronization, and predictive engagement with environmental affordances. These embodied temporal processes gradually extend toward autobiographical continuity and mentalizing capacities, supported by coordinated interactions among large-scale brain networks. Psychodynamic concepts including holding, containment, dimensionality, and symbolic transformation are revisited in dialogue with contemporary embodied and relational neuroscience. Clinically, disturbances of selfhood across psychopathological conditions are discussed in relation to altered PPS organization, disturbances in self-evidencing, and embodied temporal continuity. Psychotherapeutic change is conceptualized as involving gradual reorganization across embodied, affective, and reflective dimensions through co-regulation, interpersonal attunement, and temporally extended relational engagement. Overall, this perspective advances a process-oriented and interdisciplinary framework linking embodiment, temporality, autobiographical integration, and psychotherapy, while highlighting directions for future interdisciplinary research at the interface of neuroscience, embodiment and psychodynamics.
Autism spectrum disorder (ASD) comprises diverse neurodevelopmental trajectories in which altered circuit dynamics converge on a disturbance of excitation-inhibition balance. Genetic, postmortem, neuroimaging, and model-system evidence implicates γ-aminobutyric acid type A (GABAA) receptors as a major molecular node within this imbalance. ASD has been associated with changes in GABAA receptor subunit expression and assembly, notably within 15q11-q13 clusters, impaired receptor trafficking and synaptic anchoring, and a shift in the relative contribution of phasic (synaptic, containing the γ2 subunit) versus tonic (extra-synaptic with δ or ρ) inhibition. Postmortem studies reported reduced expression of GABAA subunits, which correlates with decreased expression of glutamic acid decarboxylase 65/67, interneuron loss, particularly in parvalbumin networks that support gamma oscillations, and disrupted chloride homeostasis, which can delay the developmental "GABA switch" from depolarizing to hyperpolarizing signalling. Here, we review mechanistic advances across environmental and monogenic ASD models [e.g., prenatal valproate exposure, maternal immune activation, shank3 (SH3 and multiple ankyrin repeat domains 3), fmr1 (fragile X messenger ribonucleoprotein 1), and mecp2 (methyl-CpG binding protein 2) alongside human biomarker studies using proton magnetic resonance spectroscopy and positron emission tomography, highlighting how GABA receptor subtype- and circuit-specific inhibitory deficits map onto sensory, social, cognitive, and comorbid seizure phenotypes. We evaluate emerging therapeutic strategies that move beyond nonselective sedation, including α2/α3-and α5-preferring positive allosteric modulators, neurosteroid-based enhancers of tonic inhibition, and interventions targeting sodium-potassium chloride cotransporter 1/potassium chloride cotransporter 2-regulated chloride gradients, as well as activity-dependent approaches such as environmental enrichment. Finally, we outline priorities for precision translation: multimodal biomarker-guided stratification, developmentally timed intervention windows, and trials aligned to receptor subtype pharmacology and circuit endpoints. This review integrates molecular and translational research on GABAA receptor dysfunction in ASD, emphasizing key mechanistic insights and potential therapeutic approaches. To develop precise GABAergic treatments, a comprehensive strategy that includes molecular profiling, biomarker-guided clinical trials, and insights from developmental neuroscience is necessary.
Since 2017, the European Journal of Neuroscience has featured interviews with 27 female neuroscientists to showcase and celebrate their excellent scientific contributions and to hear their personal stories and advice for younger neuroscientists. Although these women represent different fields in neuroscience, countries, and levels of seniority, their stories share some remarkable commonalities, which we briefly discuss in this editorial. Highlighted topics include: the circuitous route of some of the careers; the importance of having good mentors and belonging to networks; the role of "good fortune" versus abilities and skills; the upsides and downsides of an academic career; some of the aspects in which women's academic careers may differ from those of men; and the advice the interviewees would like to pass on to the next generations. Although it is clear from these personal accounts that some aspects of women's careers in neuroscience have improved over the past decade, other elements seem stagnant. The European Journal of Neuroscience remains committed to equity and will continue to feature the stories of women in neuroscience to inspire future generations.
This case report addresses a clinical gap in the management of severe challenging behaviors (CBs) in Xia-Gibbs Syndrome (XGS), a rare genetic disorder caused by variants in the AHDC1 gene, highlighting the importance of integrative, multidisciplinary assessment to disentangle overlapping medical, developmental, and psychiatric contributors. A 17-year-old French adolescent girl of Chinese descent with XGS and intellectual development disorder was referred to inpatient care for severe CBs and suspected schizophrenia. A comprehensive assessment of pain-related factors led to the identification and treatment of several co-occurring medical conditions (gastritis, local care for atopic dermatitis, progestin for dysmenorrhea). Prolonged clinical observations showed that most psychotic-like symptoms resulted instead from developmentally appropriate stress-coping strategies and depressive symptoms. Other identified risk factors for CBs were medication side effects, unmet sensory integration needs, and environmental stressors. Providing interventions on all these factors associated with environmental adaptations and optimized developmental care led to marked clinical improvement. This case illustrates that in patients with complex neurodevelopmental disorders, comprehensive medical assessment should be prioritized over psychiatric assessment when possible, considering symptoms overlap and communication difficulties. As most risk factors for CBs can mutually reinforce and self-sustain, integrative care for these patients should consider concomitant interventions targeting both risk factors and CBs themselves.
Text-only large language models (LLMs) used as general-purpose reasoners achieve remarkable performance on linguistic and reasoning tasks yet remain limited on intervention-sensitive and individual-level counterfactual reasoning. This article offers a cross-level synthesis linking formal causal competence, cognitive simulation, neural implementation, and artificial intelligence (AI) design criteria. Drawing on formal causal inference theory, developmental cognitive science, and cognitive neuroscience, we first characterize the three levels of causal cognition-association, intervention, and counterfactual reasoning-and show why each is formally irreducible to the one below it. We then discuss concrete, domain-specific categories of LLM failure that are consistent with the absence of a structured causal model capable of supporting individual-level counterfactual invariance. We review neuroscientific evidence for component processes relevant to counterfactual cognition-including episodic construction, fictive evaluation, and internally generated scenario simulation-with the Default Mode Network and hippocampal systems playing important but not exclusive roles. Finally, we propose that the most productive path forward is not to implement Pearl's formal rules in AI systems, but to study how the brain approximates counterfactual reasoning without ever following those rules explicitly-just as neuroscience has historically provided useful constraints, architectural motifs, and evaluation criteria for AI research.
The CCDC22 gene is a key regulator of endosomal trafficking and NF-κB signaling, and its dysfunction is implicated in a spectrum of X-linked neurodevelopmental disorders, including Ritscher-Schinzel syndrome 2, intellectual disability, and epilepsy. Despite the identification of CCDC22 variants having increased, a comprehensive biological characterization, including its spatiotemporal expression and functional molecular networks, remains to be systematically delineated. Furthermore, the rarity of CCDC22 variants created a significant challenge in distinguishing their pathogenicity. This study aimed to explore the integration of biological context-informed and clinical genetic analysis workflows and to perform an exploratory evaluation of prediction algorithms to better optimize the genetic diagnosis process for CCDC22. Multilevel biological analysis was performed to evaluate the spatiotemporal expression patterns of CCDC22 across developmental stages. A protein-protein interaction network was constructed to identify key functional modules and pathway enrichments. Additionally, an expert-classified dataset of CCDC22 missense variants was utilized to conduct an exploratory performance evaluation of twenty prediction algorithms, specifically assessing the effect of filtering out variants observed as population hemizygotes. CCDC22 exhibits distinct spatiotemporal expression dynamics and chromatin accessibility patterns closely associated with neurodevelopmental processes. PPI and functional enrichment analyses highlighted its core involvement in endocytic recycling and vesicle transport. In the exploratory missense variant evaluation, meta-predictors, notably ClinPred and MetaRNN, demonstrated the highest predictive potential within this limited cohort. After filtering out variants observed as hemizygotes in the gnomAD database, most of the algorithms' performance improved in distinguishing the pathogenicity of variants and genetic diagnosis. ClinPred, M-CAP, MetaRNN, and SIFT achieved the highest balanced accuracy (84.6%, 80.8%, 78.7%, and 76.1%, respectively). ClinPred, M-CAP, and MetaRNN achieved the highest AUC value (> 0.9). This study delineates the spatiotemporal and functional molecular network of CCDC22 in neurodevelopment. A combination of population-based strategy and prediction enhanced the performance of most algorithms. ClinPred and MetaRNN showed higher predictive potential. This study may provide insights into the evaluation of variants in CCDC22-related diseases.
Hormonal contraceptives (HCs) contain synthetic gonadal hormones that act on receptors widely distributed throughout the brain, thereby altering the body's endogenous hormonal milieu in ways that may influence brain and behavior. Although HCs are among the most commonly prescribed medications for female adolescents, their effects on the developing brain and mental health remain poorly understood. This gap is concerning given that adolescence is marked by substantial hormonal change, neurodevelopment, and a sharp rise in depression risk among female youth. In this review, we synthesize current evidence on associations between adolescent HC use, depression risk, and brain structure and function. Epidemiological studies have consistently reported associations between HC use during adolescence and increased depression risk, but causal interpretation is limited by residual confounding. Neuroimaging research remains scarce, particularly in adolescents, and rarely accounts for heterogeneity in HC formulations and characteristics of use or for endogenous hormonal variation related to puberty or the menstrual cycle. We outline 3 considerations to guide future research: accounting for HC heterogeneity, incorporating developmental features of adolescent menstrual cycles, and situating HC use within its broader developmental and sociocultural context. We conclude by emphasizing the need for rigorous developmentally sensitive research to counter misinformation and better support adolescents' reproductive and mental health care needs. Hormonal contraceptives (HCs) are widely used by adolescent girls, but their potential effects on the developing brain and mental health are not well understood. This matters because puberty brings major hormonal and brain changes, and depression risk rises for girls during adolescence. Many population studies link adolescent HC use to higher depression risk, but these findings may reflect other differences between users and nonusers. In this review, we evaluate evidence linking adolescent HC use with depression risk and with brain structure and function. We highlight key research gaps and priorities to reduce misinformation about HCs and better support adolescents’ reproductive and mental health.
Variants in KCNC1 encoding the voltage-gated potassium (K+) channel subunit KV3.1 are an emerging cause of a spectrum of neurological disease including developmental delay/intellectual disability, ataxia, myoclonus, and epilepsy, including progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Here, we report novel biophysical properties of a recurrent de novo missense variant in KCNC1 c.1196C>T (p.Thr399Met) associated with epilepsy, mild developmental delay, and nonprogressive ataxia. The variant is localized to the highly conserved pore region of the channel, and voltage-clamp electrophysiological recording demonstrated a complete loss of function, as seen in more severe forms of KCNC1-related disorders. When expressed with wild-type (WT) to mimic the heterozygous state of the variant as would occur in a disease context, current density was not markedly reduced; however, resulting currents displayed a ∼20 mV hyperpolarizing shift of the voltage dependence of activation along with slowed deactivation kinetics, consistent with gain of function. In order to better understand this "dominant-positive effect" exerted on the WT channel, we co-expressed the KV3.1 p.Thr399Met variant with the recurrent p.Ala421Val variant known to act via loss of function with near-complete absence of current and associated with severe KCNC1-related disease. Co-expression of the two nonfunctioning variants led to a mild rescue of K+ current compared with the KCNC1-p.Ala421Val variant alone, further supporting a dominant-positive effect. Both KCNC1-p.Thr399Met and p.Ala421Val displayed trafficking deficiency. These results suggest that inclusion of the p.Thr399Met variant in heterotetrameric KV3 channels alters the gating kinetics of WT channel subunits, and highlight the unique features of this variant. The apparent complete loss of function of the p.Thr399Met variant when expressed alone is inconsistent with the relatively mild clinical presentation of the patient, subsequently explained via the "dominant-positive" action when combined with WT subunits.