Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Exploring Subfactors of Adult Cognitive Disengagement Syndrome and Impact on Neuropsychological Performance.

OBJECTIVE: This study investigated subfactors of cognitive disengagement syndrome (CDS; previously referred as sluggish cognitive tempo) among adults referred for neuropsychological evaluation of attentiondeficit/hyperactivity disorder (ADHD). METHOD: Retrospective analyses of data from 164 outpatient neuropsychological evaluations examined associations between CDS subfactors and self-reported psychological symptoms and cognitive performance. RESULTS: Factor analysis produced two distinct but positively correlated constructs: "Cognitive Complaints'' and "Lethargy." Both correlated positively with symptom reports (rs = 0.26-0.57). Cognitive Complaints correlated negatively with working memory, processing speed, and executive functioning performance (rs = -0.21 to -0.37), whereas Lethargy correlated negatively only with processing speed and executive functioning performance (rs = -0.26 to -0.42). Both predicted depression symptoms, but only Cognitive Complaints predicted inattention symptoms. Both subfactors demonstrated modest to nonsignificant associations with cognitive performance after accounting for estimated premorbid intelligence and inattention. CONCLUSION: Findings indicate a bidimensional conceptualization of CDS, with differential associations between its constituent subfactors, reported symptoms, and cognitive performance.

Differentiating Performance on the Connors Continuous Performance Test (CPT-3) as a Function of Comorbid Internalizing Psychopathology.

OBJECTIVE: Internalizing psychopathology commonly co-occurs with attention-deficit/hyperactivity disorder (ADHD). Attention concerns are present in both ADHD and internalizing disorders, yet the neuropsychological functioning of those with comorbid ADHD and internalizing psychopathology is underexamined. METHOD: This study compared Conners' Continuous Performance Test-Third Edition (CPT-3) profiles across ADHD (n = 141), internalizing psychopathology (n = 78), and comorbid (ADHD/internalizing psychopathology; n = 240) groups. RESULTS: Compared to the internalizing psychopathology group, the comorbid group had higher mean T-scores on CPT-3 indices indicative of inattentiveness and impulsivity and more clinically elevated T-scores (T>60) on indices measuring inattentiveness and impaired sustained attention. Patients in the comorbid group were also more likely to have abnormal overall CPT-3 profiles (>2 elevated T-scores) than the ADHD and psychopathology only groups. CONCLUSION: Patients with comorbid ADHD/internalizing psychopathology may evidence a more impaired attentional performance on the CPT-3, which could aid in more tailored treatment planning.

Developmental Trajectories of Irritability across the Transition to Toddlerhood: Associations with Effortful Control and Psychopathology.

Preschool-age irritability is a transdiagnostic marker of internalizing and externalizing problems. However, researchers have generally been reluctant to examine irritability within a clinically salient framework at younger ages due to some instability during the "terrible twos" period. Developmentally sensitive and dense measurements to capture intra- and inter-individual variability, as well as exploration of developmental processes that predict change, are needed. This study aimed to examine (1) the trajectories of irritability at the transition to toddlerhood (12-24 months of age) using repeated measures, (2) whether effortful control was associated with individual differences in level and growth rate of irritability, and (3) whether individual differences in the irritability trajectories were associated with later psychopathology. Families were recruited when the child was 12-18 months old (N = 333, 45.65% female). Mothers reported on their toddler's irritability at baseline and every two months until a follow-up laboratory assessment approximately one year later. Effortful control was measured at baseline. Clinical internalizing/externalizing symptoms were measured at the follow-up assessment. Hierarchical linear models revealed an increase in irritability over time, yet there was relatively little within-person variability. Effortful control was only associated with the level of irritability and not growth rate. Level of irritability was associated with internalizing, externalizing, and combined symptoms, but growth rate was not. Findings suggest intraindividual stability in irritability at the transition to toddlerhood and the possibility that screening for elevated irritability at toddler age is meaningful.

What is typical: Atypical in young children's attention regulation?: Characterizing the developmental spectrum with the Multidimensional Assessment Profiles-Attention Regulation Infant-Toddler (MAPS-AR-IT) Scale.

While attention dysregulation is a promising early indicator of neurodevelopmental risk, in particular attention-deficit/hyperactivity disorder (ADHD), it is difficult to characterize clinical concern due to its developmental expectability at the transition to toddlerhood. Thus, explicating the typical:atypical continuum of risk indicators is among the key future directions for research to promote early identification and intervention, and prevent decrements in the attainment of developmental milestones into early childhood. In this paper, we present the Multidimensional Assessment Profiles-Attention Regulation Infant-Toddler (MAPS-AR-IT) Scale, a novel parent-report survey of dimensional, developmentally specified indicators of attention (dys)regulation. Item Response Theory was employed to characterize the typical:atypical spectrum of both normative and more concerning dysregulation (including the contexts in which behavior occurs). We provide evidence of the validity of this measure in capturing the full typical:atypical spectrum via a longitudinal sample of typically developing children at 12-18 months of age (baseline) via concurrent scores on well-validated temperament and clinical measures. We also examine longitudinal stability and predictive validity if the MAPS-AR-IT via a clinical interview of ADHD symptoms at 24-30 months (follow-up). While not diagnostic, we present evidence of the utility of the MAPS-AR-IT in explicating individual neurodevelopmental risk and elucidating the broader typicality of behaviors related to attention (dys)regulation.

Aunque la desregulación de la atención es un prometedor indicador temprano del riesgo neural de desarrollo, en particular el trastorno de déficit en la atención/hiperactividad (ADHD), es difícil caracterizar las preocupaciones clínicas debido al factor de expectativa de desarrollo al momento de la transición a la temprana niñez. De manera que explicar la progresión típica:atípica de indicadores de riesgo está entre las futuras directrices claves para la investigación con el fin de promover la temprana identificación e intervención, y prevenir disminuciones en el alcance de hitos críticos hacia la temprana niñez. En este ensayo, presentamos la Escala de Perfiles de Evaluación Multidimensional - Regulación de la Atención del Infante-Niño Pequeñito (MAPS-AR-IT) una novedosa encuesta de reporte del progenitor, acerca de la (des)regulación de la atención, dimensional y específica para el desarrollo. Aportamos evidencia de la validez de esta medida para captar la completa gama típica:atípica por medio de una muestra longitudinal de niños típicamente en desarrollo, a los 12-18 meses de edad (edad base) por medio de puntajes concurrentes sobre el temperamento bien validado y las medidas clínicas, así como también la estabilidad longitudinal y la validez de predicción por medio de una entrevista clínica de síntomas de ADHD a los 24-30 meses (seguimiento). Se empleó la Teoría de Respuesta al Asunto para caracterizar la gama típica:atípica tanto de la desregulación normativa como de la más preocupante (incluyendo los contextos en los cuales ocurre el comportamiento). Aunque no se trata de diagnóstico, presentamos evidencia de la utilidad de MAPS-AR-IT para explicar el riesgo individual de desarrollo neural y elucidar el más amplio aspecto típico de comportamientos relacionados con la (des)regulación de la atención.

Bien que la dysrégulation de l'attention soit un indicateur précoce prometteur du risque neurodéveloppemental, en particulier le trouble déficitaire de l'attention/hyperactivité (TDHA) il est difficile de caractériser la préoccupation clinique du fait de sa prévisibilité développementale à la transition à la petite enfance. Par conséquent, expliquer le continuum typique:atypique des indicateurs de risque s'avère être une des directions futures de recherches clé pour promouvoir l'identification et l'intervention précoce, et prévenir les baisses dans la réalisation d'étapes développementales importantes jusque dans la petite enfance. Dans cet article nous présentons l'Echelle Multidimensional Assessment Profiles - Attention Regulation Infant-Toddler (MAPS-AR-IT) (échelle de profils d'évaluation multidimensionnelle - régulation de l'attention bébé-petit enfant, abrégée selon l'anglais MAP-AR-IT), une étude nouvelle basée sur les rapports faits par les parents de la (dys)régulation de l'attention dimensionnelle et spécifiée selon le développement. Nous démontrons la validité de cette mesure en capturant l'éventail total typique:atypique au moyen d'un échantillon longitudinal d'enfants se développement typiquement, à 12-18 mois (ligne de case) au moyen de scores concurrents de mesures cliniques et de tempérament bien validées, ainsi qu''une stabilité longitudinale et d'une validité prédictive au moyen d'un entretien Clinique des symptômes THHA à 24-30 mois (suivi). La Item Response Theory (IRT) a été employée pour caractériser l'éventail typique:atypique de la dysrégulation à la fois normative et celle plus inquiétante (y compris les contextes dans lesquels le comportement prend place). Bien que cela ne soit pas diagnostique, nous présentons la preuve de l'utilité de la MAPS-AR-IT en expliquant le risqué neurodéveloppemental individuel et en élucidant la typicalité plus large de comportements liés à la (dys)régulation de l'attention.

Multivariate examination of embedded indicators of performance validity for ADHD evaluations: A targeted approach.

This study investigated the individual and combined utility of 10 embedded validity indicators (EVIs) within executive functioning, attention/working memory, and processing speed measures in 585 adults referred for an attention-deficit/hyperactivity disorder (ADHD) evaluation. Participants were categorized into invalid and valid performance groups as determined by scores from empirical performance validity indicators. Analyses revealed that all of the EVIs could meaningfully discriminate invalid from valid performers (AUCs = .69-.78), with high specificity (≥90%) but low sensitivity (19%-51%). However, none of them explained more than 20% of the variance in validity status. Combining any of these 10 EVIs into a multivariate model significantly improved classification accuracy, explaining up to 36% of the variance in validity status. Integrating six EVIs from the Stroop Color and Word Test, Trail Making Test, Verbal Fluency Test, and Wechsler Adult Intelligence Scale-Fourth Edition was as efficacious (AUC = .86) as using all 10 EVIs together. Failing any two of these six EVIs or any three of the 10 EVIs yielded clinically acceptable specificity (≥90%) with moderate sensitivity (60%). Findings support the use of multivariate models to improve the identification of performance invalidity in ADHD evaluations, but chaining multiple EVIs may only be helpful to an extent.

Joint Consideration of Inhibitory Control and Irritability in Young Children: Contributions to Emergent Psychopathology.

Deficits in self-regulation capacity have been linked to subsequent impairment and clinical symptomology across the lifespan. Prior work has identified difficulty regulating angry emotions (i.e., irritability) as a powerful transdiagnostic indicator of current and future clinical concerns. Less is known regarding how irritability intersects with cognitive features of self-regulation, in particular inhibitory control, despite its mental health relevance. A promising avenue for improving specificity of clinical predictions in early childhood is multi-method, joint consideration of irritability and inhibitory control capacities. To advance early identification of impairment and psychopathology risk, we contrast group- and variable-based models of neurodevelopmental vulnerability at the interface of irritability and inhibitory control in contexts of varied motivational and emotional salience. This work was conducted in a longitudinal study of children recruited at well-child visits in Midwestern pediatric clinics at preschool age (N = 223, age range = 3-7 years). Group-based models (clustering and regression of clusters on clinical outcomes) indicated significant heterogeneity of self-regulation capacity in this sample. Meanwhile, variable-based models (continuous multiple regression) evidenced associations with concurrent clinical presentation, future symptoms, and impairment across the broad spectrum of psychopathology. Irritability transdiagnostically indicated internalizing and externalizing problems, concurrently and longitudinally. In contrast, inhibitory control was uniquely associated with attention-deficit/hyperactivity symptoms. We present these findings to advance a joint consideration approach to two promising indicators of neurodevelopmental vulnerability and mental health risk. Models suggest that both emotional and cognitive self-regulation capacities can address challenges in characterizing the developmental unfolding of psychopathology from preschool to early childhood age.

A high-resolution probabilistic in vivo atlas of human subcortical brain nuclei.

Recent advances in magnetic resonance imaging methods, including data acquisition, pre-processing and analysis, have benefited research on the contributions of subcortical brain nuclei to human cognition and behavior. At the same time, these developments have led to an increasing need for a high-resolution probabilistic in vivo anatomical atlas of subcortical nuclei. In order to address this need, we constructed high spatial resolution, three-dimensional templates, using high-accuracy diffeomorphic registration of T1- and T2- weighted structural images from 168 typical adults between 22 and 35 years old. In these templates, many tissue boundaries are clearly visible, which would otherwise be impossible to delineate in data from individual studies. The resulting delineations of subcortical nuclei complement current histology-based atlases. We further created a companion library of software tools for atlas development, to offer an open and evolving resource for the creation of a crowd-sourced in vivo probabilistic anatomical atlas of the human brain.