Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.

The role of aperiodic spectral slope in event-related potentials and cognition among children with and without attention deficit hyperactivity disorder.

Aperiodic spectral slope is a measure of spontaneous neural oscillatory activity that is believed to support regulation of brain responses to environmental stimuli. Compared to typically developing (TD) control participants, children with attention deficit hyperactivity disorder (ADHD) have been shown to have flatter aperiodic spectral slope at rest as well as attenuated event-related potential (ERP) amplitudes in response to environmental stimuli. A small body of research suggests that aperiodic slope may also explain differences in behavioral responses. In this study, we examine associations between prestimulus aperiodic slope, stimulus characteristics, environmental demands, and neural as well as behavioral responses to these stimuli. Furthermore, we evaluate whether ADHD diagnostic status moderates these associations. Seventy-nine children with ADHD and 27 TD school-age children completed two visual ERP experiments with predictable alternating presentations of task-relevant and task-irrelevant stimuli. Aperiodic slope was extracted from prestimulus time windows. Prestimulus aperiodic slope was steeper for the TD relative to ADHD group, driven by task-relevant rather than task-irrelevant stimuli. For both groups, the aperiodic slope was steeper during a task with lower cognitive demand and before trials in which they responded correctly. Aperiodic slope did not mediate the association between ADHD diagnosis and attenuated P300 amplitude. The aperiodic spectral slope is dynamic and changes in anticipation of varying stimulus categories to support performance. The aperiodic slope and P300 amplitude reflect distinct cognitive processes. Background neural oscillations, captured via aperiodic slope, support cognitive behavioral control and should be included in etiological models of ADHD.NEW & NOTEWORTHY This study constitutes the first investigation of associations between aperiodic spectral slope and three aspects of neurocognition: event-related potential (ERP) amplitudes, cognitive load, and task performance. We find that background oscillatory activity is dynamic, shifting in anticipation of varying levels of task relevance and in response to increasing cognitive load. Moreover, we report that aperiodic activity and ERPs constitute distinct neurophysiological processes. Children with attention deficit hyperactivity disorder (ADHD) show reduced aperiodic dynamics in addition to attenuated ERP amplitudes.

Absence of dynamic neural oscillatory response to environmental conditions marks childhood attention deficit hyperactivity disorder.

BACKGROUND: Prior research suggests that symptoms of attention deficit hyperactivity disorder (ADHD) and related neurodevelopmental disorders may derive from alterations in the brain's ability to flexibly tune the balance between information integration and segregation and global versus local processing. This balance allows the brain to optimally filter salient stimuli in the environment and can be measured with electroencephalography (EEG) via calculation of the aperiodic spectral slope. A steeper aperiodic slope increases the capacity of global neural networks to process low-salience stimuli, while a flatter aperiodic slope reflects an emphasis on local neural networks that respond preferentially to high-salience input. Although aperiodic slope differences have been reported in ADHD, prior studies have not accounted for differing levels of stimulus input in experimental paradigms. There is evidence to suggest that dynamic shifts in neural oscillation patterns in response to changing environmental conditions could be critical for attention regulation. METHODS: Using high-density resting EEG, we measured aperiodic spectral slope during low contrast (lights off) and high contrast (lights on) environmental conditions in a sample of 88 7-11-year-old children diagnosed with ADHD and 29 controls (30% female). RESULTS: While controls showed a flatter aperiodic slope during the high contrast (lights on) as compared to low contrast (lights off) environmental condition, children with ADHD did not show any change in aperiodic slope across conditions. CONCLUSIONS: This study presents a novel etiological model of biological mechanisms associated with ADHD. Children with ADHD show suboptimal modulation of intrinsic neural activity in response to changing environmental input. The dynamic spectral slope is a promising candidate biomarker for ADHD. The possibility that dynamic spectral slope is associated with cognitive-behavioral regulation more broadly merits further investigation.

Reduced Error Recognition Explains Post-Error Slowing Differences among Children with Attention Deficit Hyperactivity Disorder.

OBJECTIVE: Youth with attention deficit hyperactivity disorder (ADHD) often show reduced post-error slowing (PES) compared to typically developing controls. This finding has been interpreted as evidence that children with ADHD have error recognition and adaptive control impairments. However, several studies report mixed results regarding PES differences in ADHD, and among healthy controls, there is considerable debate about the cognitive-behavioral origin of PES. METHODS: We tested competing hypotheses aimed at clarifying whether reduced PES in children with ADHD is due to impaired error detection, deficits in adaptive control, and/or attention orienting to novelty. Children aged 7-11 years with a diagnosis of ADHD (n = 74) and controls (n = 30) completed four laboratory-based computer tasks with variable cognitive loads and error types. RESULTS: ADHD diagnosis was associated with shorter PES only on a task with high cognitive load and low error-cuing, consistent with impaired error recognition. In contrast, there was no evidence of impaired adaptive control or heightened novelty orienting among children with ADHD. CONCLUSIONS: The cognitive-behavioral origin of PES is multifactorial, but reduced PES among children with an ADHD diagnosis is due to impaired error recognition during cognitively demanding tasks. Behavioral interventions that scaffold error recognition may facilitate improved performance among children with ADHD.

Neural activation, cognitive control, and attention deficit hyperactivity disorder: Evaluating three competing etiological models.

BACKGROUND: Cognitive control impairments are observed across several psychiatric conditions, highlighting their role as a transdiagnostic marker. Individuals with attention deficit hyperactivity disorder (ADHD) have difficulties with inhibition, working memory, processing speed, and attention regulation. These cognitive control impairments may either mediate or moderate the association between neurobiological vulnerabilities and phenotypic presentation in neurodevelopmental disorders. Alternately, neurocognitive vulnerabilities in ADHD may be additive, akin to a multiple deficit model. We tested the mediation, moderation, and additive models using neurocognitive data in youth with ADHD. METHODS: 7-11 year-old children diagnosed with ADHD (n = 75) and control children (n = 29) completed EEG recordings and neuropsychological testing (full scale IQ; cognitive control). Caregivers provided ADHD symptom ratings. Correlations and linear regression analyses were completed to examine the associations among cortical functioning (aperiodic slope), cognitive control, and ADHD symptoms. RESULTS: We found support for an additive model wherein vulnerabilities in aperiodic slope, event-related potentials, and cognitive control each explained unique variance in ADHD symptoms. There was some evidence that cognitive control moderates the effect of atypical cortical development on ADHD symptoms. There was no support for the mediation model. CONCLUSIONS: The etiology of ADHD symptoms is multifaceted and involves multiple "hits" across neurological and cognitive-behavioral factors.

Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk.

BACKGROUND: Symptoms of autism spectrum disorder (ASD) and inattention (IA) are highly comorbid and associated with deficits in executive cognition. Cognitive deficits have been posited as candidate endophenotypes of psychiatric traits, but few studies have conceptualized cognitive deficits as psychiatric comorbidities. The latter model is consistent with a latent factor reflecting broader liability to neuropsychological dysfunction, and explains heterogeneity in the cognitive profile of individuals with ASD and IA. METHODS: We tested competing models of covariance among symptoms of ASD, IA, and cognition in a sample of 73 youth with a known genetic mutation. RESULTS: A common executive factor fit best as a cognitive comorbidity, rather than endophenotype, of the shared variance between measures of IA and ASD symptoms. Known genetic risk explained a third of the shared variance among psychiatric and cognitive measures. CONCLUSIONS: Comorbid symptoms of ASD, IA, and cognitive deficits are likely influenced by common neurogenetic factors. Known genetic risk in ASD may inform future investigation of putative genetic causes of IA.

Literacy acquisition influences children's rapid automatized naming.

Previous research has established that learning to read improves children's performance on reading-related phonological tasks, including phoneme awareness (PA) and nonword repetition. Few studies have investigated whether literacy acquisition also promotes children's rapid automatized naming (RAN). We tested the hypothesis that literacy acquisition should influence RAN in an international, longitudinal population sample of twins. Cross-lagged path models evaluated the relationships among literacy, PA, and RAN across four time points from pre-kindergarten through grade 4. Consistent with previous research, literacy showed bidirectional relationships with reading-related oral language skills. We found novel evidence for an effect of earlier literacy on later RAN, which was most evident in children at early phases of literacy development. In contrast, the influence of earlier RAN on later literacy was predominant among older children. These findings imply that the association between these two related skills is moderated by development. Implications for models of reading development and for dyslexia research are discussed.

Early enhanced processing and delayed habituation to deviance sounds in autism spectrum disorder.

Children with autism spectrum disorder (ASD) exhibit difficulties processing and encoding sensory information in daily life. Cognitive response to environmental change in control individuals is naturally dynamic, meaning it habituates or reduces over time as one becomes accustomed to the deviance. The origin of atypical response to deviance in ASD may relate to differences in this dynamic habituation. The current study of 133 children and young adults with and without ASD examined classic electrophysiological responses (MMN and P3a), as well as temporal patterns of habituation (i.e., N1 and P3a change over time) in response to a passive auditory oddball task. Individuals with ASD showed an overall heightened sensitivity to change as exhibited by greater P3a amplitude to novel sounds. Moreover, youth with ASD showed dynamic ERP differences, including slower attenuation of the N1 response to infrequent tones and the P3a response to novel sounds. Dynamic ERP responses were related to parent ratings of auditory sensory-seeking behaviors, but not general cognition. As the first large-scale study to characterize temporal dynamics of auditory ERPs in ASD, our results provide compelling evidence that heightened response to auditory deviance in ASD is largely driven by early sensitivity and prolonged processing of auditory deviance.

Explaining the sex difference in dyslexia.

BACKGROUND: Males are diagnosed with dyslexia more frequently than females, even in epidemiological samples. This may be explained by greater variance in males' reading performance. METHODS: We expand on previous research by rigorously testing the variance difference theory, and testing for mediation of the sex difference by cognitive correlates. We developed an analytic framework that can be applied to group differences in any psychiatric disorder. RESULTS: Males' overrepresentation in the low performance tail of the reading distribution was accounted for by mean and variance differences across sex. There was no sex difference at the high performance tail. Processing speed (PS) and inhibitory control partially mediated the sex difference. Verbal reasoning emerged as a strength in males. CONCLUSIONS: Our results complement a previous finding that PS partially mediates the sex difference in symptoms of attention deficit/hyperactivity disorder (ADHD), and helps explain the sex difference in both dyslexia and ADHD and their comorbidity.

Links between within-person fluctuations in hyperactivity/attention problems and subsequent conduct problems.

BACKGROUND: The onset of hyperactivity/impulsivity and attention problems (HAP) is typically younger than that of conduct problems (CP), and some research supports a directional relation wherein HAP precedes CP. Studies have tested this theory using between-person and between-group comparisons, with conflicting results. In contrast, prior research has not examined the effects of within-person fluctuations in HAP on CP. METHOD: This study tested the hypothesis that within-person variation in HAP would positively predict subsequent within-person variation in CP, in two population samples of youth (N = 620) who participated in identical methods of assessment over the course of 30 months. Three-level, hierarchical models were used to test for within-person, longitudinal associations between HAP and CP, as well as moderating effects of between-person and between-family demographics. RESULTS: We found a small but significant association in the expected direction for older youth, but the opposite effect in younger and non-Caucasian youth. These results were replicated across both samples. CONCLUSIONS: The process by which early HAP relates to later CP may vary by age and racial identity.

Sex differences in ADHD symptom severity.

BACKGROUND: Males show higher rates of attention deficit hyperactivity disorder (ADHD) than do females. Potential explanations include genuine etiological differences or artifact. METHODS: 2,332 twin and sibling youth participated in behavioral and cognitive testing. Partially competing models of symptom severity distribution differences, the mean difference, and variance difference models, were tested within a randomly selected subsample. The Delta method was used to test for mediation of sex differences in ADHD symptom severity by processing speed, inhibition and working memory. RESULTS: The combined mean difference and variance difference models fully explained the sex difference in ADHD symptom severity. Cognitive endophenotypes mediated 14% of the sex difference effect. CONCLUSIONS: The sex difference in ADHD symptom severity is valid and may be due to differing genetic and cognitive liabilities between the sexes.

Factors influencing attrition in a multisite, randomized, clinical trial following traumatic brain injury in adolescence.

BACKGROUND: Attrition in longitudinal research negatively affects statistical power, disrupts statistical stability, and can produce unwanted bias. OBJECTIVE: To investigate factors associated with shorter length of study participation and lower rates of study completion (ie, attrition) in a large, multisite, longitudinal, randomized, clinical trial examining the efficacy of a Web-based family problem-solving treatment following traumatic brain injury (TBI) in adolescence. SETTING: Five major trauma centers in the central and western regions of the United States. PARTICIPANTS: Children (N = 132) aged 12 to 17 years hospitalized for complicated mild to severe TBI within the previous 6 months. RESULTS: Completers had a higher primary caregiver education and higher family income than noncompleters, whereas ethnicity, latency to baseline assessment, and intervention group were not significantly associated with study completion. CONCLUSION: This is the first study that has specifically examined factors of attrition in a pediatric TBI population. The results suggest that research on pediatric TBI populations may be biased toward higher-income families and highlights the importance of designing studies with increased awareness of the impact of participant demographic factors.

Effortful Control Protects Against Familial Liability for ADHD: Longitudinal Results from the ABCD Study in the United States.

Effortful control, the ability to regulate complex and goal-directed behavior, may protect individuals from developing mental health symptoms. This study tested the potential for child effortful control and executive functioning to buffer the effects of familial liability for attention deficit hyperactivity disorder (ADHD) problems across a one-year timeframe. Data from the prospectively-collected Adolescent Brain Cognitive Development (ABCD)® study were used to examine whether caregiver-rated child effortful control and executive functioning moderated the association between familial ADHD risk and later ADHD symptoms in a sample of children (N = 6,133; ages 9-10 years at baseline). Two independent variables were considered to compare the predictive powers of specific (family ADHD) and broad (family psychopathology) risk factors. Two additional moderating variables (surgency, negative affect) were tested to examine specificity of effortful control and executive functioning as moderators. All variables of interest were measured on a continuum and via caregiver report. At high levels of effortful control and executive functioning, there was no association between familial liability for ADHD or broad psychopathology and later child ADHD problems. The moderator effects were specific to effortful control and executive functioning domains. Etiological models of heritable psychiatric disorders, such as ADHD, should consider the risk and protective contributions of individual traits, such as effortful control and executive functioning. Clinical prevention and intervention efforts may target self-regulation skills in children to buffer against familial liability for ADHD problems.

Longitudinal Stability of Neural Correlates of Pediatric Attention Deficit Hyperactivity Disorder: A Pilot Study of Event Related Potentials and Electroencephalography.

OBJECTIVE: Stability and developmental effects of electroencephalography (EEG) and event related potential (ERP) correlates of ADHD are understudied. This pilot study examined stability and developmental changes in ERP and EEG metrics of interest. METHODS: Thirty-seven 7 to 11-year-old children with ADHD and 15 typically developing (TD) children completed EEG twice, 11 to 36 months apart. A series of mixed effects linear models were run to examine stability and developmental effects of EEG and ERP metrics. RESULTS: Stability and developmental effects of EEG and ERP correlates of ADHD varied considerably across metrics. P3 amplitude was stable over time and showed diverging developmental trajectories across groups. Developmental differences were apparent in error related ERPs and resting aperiodic exponent. Theta-beta ratio was stable over time among all children. CONCLUSIONS: Developmental trajectories of EEG and ERP correlates of ADHD are candidate diagnostic markers. Replication with larger samples is needed.

Resting EEG correlates of neurodevelopment in a socioeconomically and linguistically diverse sample of toddlers: Wave 1 of the Kia Timata Pai best start New Zealand study.

Development of communication and self-regulation skills is fundamental to psychosocial maturation in childhood. The Kia Timata Pai Best Start (KTP) longitudinal study aims to promote these skills through interventions delivered at early childcare centers across New Zealand. In addition to evaluating effects of the interventions on behavioral and cognitive outcomes, the study utilizes electroencephalography (EEG) to characterize cortical development in a subsample of participating children. Here, we present results of the baseline resting EEG assessment with 193 children aged 15 to 33 months. We identified EEG correlates of individual differences in demographics, communication abilities, and temperament. We obtained communication and behavior ratings from multiple informants, and we applied contemporary analytic methods to the EEG data. Periodic spectral power adjusted for aperiodic activity was most closely associated with demographic, language, and behavioral measures. As in previous studies, gamma power was positively associated with verbal language. Alpha power was positively associated with effortful control. Nonverbal and verbal language measures showed distinct associations with EEG indices, as did the three temperament domains. Our results identified a number of candidate EEG measurements for use as longitudinal markers of optimal cortical development and response to interventions in the KTP cohort.

Behavioral and cognitive predictors of educational outcomes in pediatric traumatic brain injury.

Research reveals mixed results regarding the utility of standardized cognitive and academic tests to predict educational outcomes in youth following a traumatic brain injury (TBI). Yet, deficits in everyday school-based outcomes are prevalent after pediatric TBI. The current study used path modeling to test the hypothesis that parent ratings of adolescents' daily behaviors associated with executive functioning (EF) would predict long-term functional educational outcomes following pediatric TBI, even when injury severity and patient demographics were included in the model. Furthermore, we contrasted the predictive strength of the EF behavioral ratings with that of a common measure of verbal memory. A total of 132 adolescents who were hospitalized for moderate to severe TBI were recruited to participate in a randomized clinical intervention trial. EF ratings and verbal memory were measured within 6 months of the injury; functional educational outcomes were measured 12 months later. EF ratings and verbal memory added to injury severity in predicting educational competence post injury but did not predict post-injury initiation of special education. The results demonstrated that measurement of EF behaviors is an important research and clinical tool for prediction of functional outcomes in pediatric TBI.

Auditory-Perceptual and Auditory-Motor Timing Abilities in Children with Developmental Coordination Disorder: A Scoping Review.

Developmental coordination disorder (DCD) remains largely underdiagnosed and masked by other co-occurring conditions. The aim of this study was to (1) provide the first review of research regarding auditory-motor timing and synchronization abilities in children with DCD and (2) examine whether reduced motor performance may be associated with difficulties in auditory perceptual timing. The scoping review was carried out across five major databases (MEDLINE, Embase, PsycINFO, CINAHL, and Scopus) in accordance with the PRISMA-ScR guidelines. Studies were screened by two independent reviewers against the inclusion criteria, without publication date restrictions. From an initial return of 1673 records, 16 articles were included in the final review and synthesized based on the timing modality studied (i.e., auditory-perceptual, motor, or auditory-motor). Results suggest that children with DCD have difficulties with rhythmic movements both with and without external auditory cues and further indicate that variability in and slowness of motor response are key characteristics of DCD, regardless of the experimental task. Importantly, our review highlights a significant gap in the literature regarding auditory perceptual abilities in DCD. In addition to testing auditory perception, future studies should compare the performance of children with DCD on paced and unpaced tasks to determine whether auditory stimuli contribute to a more or less stable performance. This knowledge may inform future therapeutic interventions.

A systematic review of behavioral and neurobiological profiles associated with coexisting attention-deficit/hyperactivity disorder and developmental coordination disorder.

Attention-deficit/hyperactivity disorder (ADHD) and developmental coordination disorder (DCD) co-occur in approximately 50% of cases. This study aimed to characterize the behavioral, cognitive, and neurobiological profiles of co-occurring ADHD and DCD diagnoses by mapping, synthesizing, and providing a critical appraisal of the existing literature. A systematic search was conducted across four databases (MEDLINE, PsycINFO, Embase, and Scopus) to identify studies comparing a coexisting ADHD+DCD diagnosis to ADHD and DCD alone. From 2353 screened articles, 15 behavioral and 10 neuroimaging studies were included. Collectively, these studies suggest that the comorbid ADHD+DCD presentation constitutes a more severe phenotype characterized by neurocognitive differences associated with both conditions. Despite sharing some common neural features, our findings support the separate etiology hypothesis indicating that neural network alterations in individuals with ADHD+DCD represent a unique neural pattern rather than a sum of ADHD and DCD characteristics. Considering the heterogeneity inherent to both ADHD and DCD, future studies should involve rigorous and comprehensive assessment procedures to delineate how different subtypes of each diagnosis relate to distinct performance characteristics.

The role of single trial variability in event related potentials in children with attention deficit hyperactivity disorder.

OBJECTIVE: Children with attention deficit hyperactivity disorder (ADHD) show attenuated mean P3 component amplitudes compared to typically developing (TD) children. This finding may be the result of individual differences in P3 amplitudes, P3 latencies, and/or greater single trial variability (STV) in amplitude or latency, suggesting neural "noise." METHODS: Event related potentials (ERPs) from 75 children with ADHD and 29 TD children were recorded with electroencephalography (EEG). Caregivers provided ratings on child ADHD symptoms. Single-trial ERP amplitudes and latencies were extracted from the P3 component time window during a visual oddball task. Additionally, we computed individual-centered and trial-centered P3 amplitudes to account for inter-individual and inter-trial variability in the timing of the P3 peak. RESULTS: In line with prior research, greater ADHD symptom severity was associated with reduced mean P3 amplitude. This correlation was no longer significant after correcting for inter-trial differences in P3 latency. In contrast, greater ADHD symptom severity was associated with reduced STV in P3 amplitude. CONCLUSIONS: Our results suggest that attenuated average P3 amplitude in ADHD samples is due to a consistent reduction in strength of the neurophysiological signal at the single trial level, as well as increased inter-trial variability in the timing of P3 peak amplitudes. The traditional method of extracting P3 amplitudes based on a single time window for all trials may not adequately capture variability in P3 latencies associated with ADHD. SIGNIFICANCE: Inter- and intra-individual differences in brain signatures should be considered in models of neurobiological differences in neurodevelopmental samples.

Delineating early developmental pathways to ADHD: Setting an international research agenda.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent, impairing, and highly heritable condition typically diagnosed in middle childhood. However, it is now recognized that symptoms emerge much earlier in development. Research focused on understanding-using multiple units of analysis-the cascade of early-life (i.e., prenatal-infant-toddler) developmental changes that will later emerge as ADHD has the potential to transform early identification, prevention, and intervention. To this end, we introduce the recently established Early ADHD Consortium, an international network of investigators engaged in prospective, longitudinal studies of risk for ADHD beginning early in life, conducted within a developmental framework, and which incorporate multimethod approaches. This network seeks to harmonize measures and methodological approaches to increase the potential for data sharing and subsequent impact. Methods: This perspective paper highlights the importance of investigating pre-diagnostic markers of ADHD, and potential models and mechanisms of ADHD risk and development, with the long-term objective of facilitating development of preemptive interventions that will minimize the impact of ADHD symptoms on everyday functioning and maximize health and developmental outcomes. Results: We selectively describe key challenges and questions for this field related to theoretical models and developmental mechanisms in ADHD and recommend next steps for the science, including methodological, measurement, and study design considerations. We then describe potential implications for preemptive intervention development. We conclude by considering other issues including ethical concerns and the critical value of incorporating stakeholder input. Conclusions: It is hoped that this perspective puts forth a research agenda that will enhance collaborative efforts and accelerate progress in understanding developmental mechanisms and the early ADHD phenotype, with implications for early intervention enhancement of healthy development for infants, young children, and their families.