Autism Symptom Presentation and Hierarchical Models of Intelligence.

BACKGROUND: There is a substantial history studying the relationship between general intelligence and the core symptoms of autism. However, a gap in knowledge is how dimensional autism symptomatology associates with different components of clinically-relevant hierarchical models of intelligence. METHOD: We examined correlations between autism diagnostic symptom magnitude (Autism Diagnostic Observational Schedule; ADOS) and a hierarchical statistical model of intelligence. One autistic cohort was tested on the fourth edition of Wechsler Intelligence Scale for Children (WISC-IV; N = 131), and another on the fifth edition (WISC-V; N = 83). We anticipated a convergent pattern of results between cohorts. RESULTS: On WISC-IV, ADOS scores were correlated significantly with g and three out of four intermediate factor scores, which was a broader pattern of correlations than anticipated from the literature. In the WISC-V cohort, only one intermediate factor correlated significantly with the ADOS; correlations with g and the other intermediate factors were less statistically certain. ADOS-factor correlations were larger in the WISC-IV than WISC-V cohort; this difference was significant at the 90% level. CONCLUSIONS: WISC-IV shows dimensional relationships with ADOS at multiple points in the hierarchical model of intelligence. Moreover, the current results provide evidence that relationship between core autism symptomatology and the construct of general intelligence may depend on how intelligence is measured. Known cohort effects in the relationship between categorical autism diagnosis and general intelligence have previously been attributed to changes in autism diagnostic practices. To our knowledge, this is the first evidence that differing versions of IQ tests may be implicated.

A Multi-Trait Multi-Method Examination of Psychometric Instrument Performance in Autism Spectrum Disorder.

Anecdotal evidence has suggested that rater-based measures (e.g., parent report) may have strong across-trait/within-individual covariance that detracts from trait-specific measurement precision; rater measurement-related bias may help explain poor correlation within Autism Spectrum Disorder (ASD) samples between rater-based and performance-based measures of the same trait. We used a multi-trait, multi-method approach to examine method-associated bias within an ASD sample (n = 83). We examined performance/rater-instrument pairs for attention, inhibition, working memory, motor coordination, and core ASD features. Rater-based scores showed an overall greater methodology bias (57% of variance in score explained by method), while performance-based scores showed a weaker methodology bias (22%). The degree of inter-individual variance explained by method alone substantiates an anecdotal concern associated with the use of rater measures in ASD.

Autism and Hierarchical Models of Intelligence.

BACKGROUND: The Wechsler Intelligence Scale for Children (WISC) employs a hierarchical model of general intelligence in which index scores separate out different clinically-relevant aspects of intelligence; the test is designed such that index scores are statistically independent from one another within the normative sample. Whether or not the existing index scores meet the desired psychometric property of being statistically independent within autistic samples is unknown. METHOD: We conducted a factor analysis on WISC fifth edition (WISC-V) (N = 83) and WISC fourth edition (WISC-IV) (N = 131) subtest data in children with autism. We compared the data-driven exploratory factor analysis with the manual-derived index scores, including in a typically developing (TD) WISC-IV cohort (N = 209). RESULTS: The WISC-IV TD cohort showed the expected 1:1 relationship between empirically derived factors and manual-derived index scores. We observed less unique correlations between our data-driven factors and manualized IQ index scores in both ASD samples (WISC-IV and WISC-V). In particular, in both WISC-IV and -V, working memory (WM) influenced index scores in autistic individuals that do not load on WM in the normative sample. CONCLUSIONS: WISC index scores do not show the desired statistical independence within autistic samples, as judged against an empirically-derived exploratory factor analysis. In particular, within the currently used WISC-V version, WM influences multiple index scores.

Evaluating causal psychological models: A study of language theories of autism using a large sample.

We used a large convenience sample (n = 22,223) from the Simons Powering Autism Research (SPARK) dataset to evaluate causal, explanatory theories of core autism symptoms. In particular, the data-items collected supported the testing of theories that posited altered language abilities as cause of social withdrawal, as well as alternative theories that competed with these language theories. Our results using this large dataset converge with the evolution of the field in the decades since these theories were first proposed, namely supporting primary social withdrawal (in some cases of autism) as a cause of altered language development, rather than vice versa. To accomplish the above empiric goals, we used a highly theory-constrained approach, one which differs from current data-driven modeling trends but is coherent with a very recent resurgence in theory-driven psychology. In addition to careful explication and formalization of theoretical accounts, we propose three principles for future work of this type: specification, quantification, and integration. Specification refers to constraining models with pre-existing data, from both outside and within autism research, with more elaborate models and more veridical measures, and with longitudinal data collection. Quantification refers to using continuous measures of both psychological causes and effects, as well as weighted graphs. This approach avoids "universality and uniqueness" tests that hold that a single cognitive difference could be responsible for a heterogeneous and complex behavioral phenotype. Integration of multiple explanatory paths within a single model helps the field examine for multiple contributors to a single behavioral feature or to multiple behavioral features. It also allows integration of explanatory theories across multiple current-day diagnoses and as well as typical development.

Dissociation in Neural Correlates of Hyperactive/Impulsive vs. Inattentive Symptoms in Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders characterized in current diagnostic criteria by two dominant symptoms, inattention and hyperactivity/impulsivity. Here, we show that task-related alpha (8-12 Hz) interhemispheric connectivity changes, as assessed during a unimanual finger-tapping task, is correlated with inattentive symptom severity (r = 0.55, p = 0.01) but not with severity of hyperactive/impulsive symptoms. Prior published analyses of the same dataset have already show that alpha event-related desynchronization (ERD) in the hemisphere contralateral to unimanual tapping is related to hyperactive/impulsive symptom severity (r = 0.43, p = 0.04) but not to inattentive symptom severity. Our findings demonstrate a neurobiological dissociation in ADHD symptom severity, with implications for understanding the structure of endophenotypes in the disorder as well as for biomarker development.

B-value and empirical equivalence bound: A new procedure of hypothesis testing.

In this study, we propose a two-stage procedure for hypothesis testing, where the first stage is conventional hypothesis testing and the second is an equivalence testing procedure using an introduced empirical equivalence bound (EEB). In 2016, the American Statistical Association released a policy statement on P-values to clarify the proper use and interpretation in response to the criticism of reproducibility and replicability in scientific findings. A recent solution to improve reproducibility and transparency in statistical hypothesis testing is to integrate P-values (or confidence intervals) with practical or scientific significance. Similar ideas have been proposed via the equivalence test, where the goal is to infer equality under a presumption (null) of inequality of parameters. However, the definition of scientific significance/equivalence can sometimes be ill-justified and subjective. To circumvent this drawback, we introduce the B-value and the EEB, which are both estimated from the data. Performing a second-stage equivalence test, our procedure offers an opportunity to improve the reproducibility of findings across studies.

Neurobehavioral Biomarkers: An EEG Family Reunion.

SUMMARY: The field of clinical EEG has had an uneasy relationship with the use of this technology for clinical cognitive applications and often for good reason. However, apart from its clinical use, EEG has had a tradition as a major tool in cognitive psychology and cognitive neuroscience dating back at least to the 1960s. Based on accumulated knowledge from its research application, EEG-based biomarkers are beginning to see applications in clinical trials and may eventually enter clinical care. We address concerns surrounding quality control, the treatment of artifact, and normal variants and how developments in engineering, biomarker validation, and implementation science rigorously applied to these tools can lead to well-justified approaches.

Altered cortical activation associated with mirror overflow driven by non-dominant hand movement in attention-deficit/hyperactivity disorder.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8-12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.

BIOMARKERS AND NEUROBEHAVIORAL DIAGNOSIS.

Our current diagnostic methods for treatment planning in Psychiatry and Neurodevelopmental Disabilities leave room for improvement, and null results in clinical trials in these fields may be a result of insufficient tools for patient stratification. Great hope has been placed in novel technologies to improve clinical and trial outcomes, but we have yet to see a substantial change in clinical practice. As we examine attempts at biomarker validation within these fields, we find that it may be the diagnoses themselves that fall short. We now need to improve neuropsychiatric nosologies with a focus on validity based not solely on behavioral features, but on a synthesis that includes genetic and biological data as well. The eventual goal is diagnostic biomarkers and diagnoses themselves based on distinct mechanisms, but such an understanding of the causal relationship across levels of analysis is likely to be elusive for some time. Rather, we propose an approach in the near-term that deconstructs diagnosis into a series of independent, empiric and clinically relevant associations among a single, defined patient group, a single biomarker, a single intervention and a single clinical outcome. Incremental study across patient groups, interventions, outcomes and modalities will lead to a more interdigitated network of knowledge, and correlations in metrics across levels of analysis will eventually give way to the causal understanding that will allow for mechanistically based diagnoses.

Quantitative EEG improves prediction of Sturge-Weber syndrome in infants with port-wine birthmark.

OBJECTIVE: Port-wine birthmark (PWB) is a common occurrence in the newborn, and general pediatricians, dermatologists, and ophthalmologists are often called on to make an assessment of risk for Sturge-Weber syndrome (SWS) due to workforce shortages in pediatric neurologists and MRI's low sensitivity for SWS brain involvement in infants. We therefore aimed to develop a quantitative EEG (qEEG) approach to safely screen young infants with PWB for SWS risk and optimal timing of diagnostic MRI. METHODS: Forty-eight infants (prior to first birthday) underwent EEG recording. Signal processing methods compared voltage between left and right sides using a previously defined pipeline and diagnostic threshold. In this test sample, we compared sensitivity/specificity of the qEEG metric against MRI performed after the first birthday. We also used likelihood ratio testing to determine whether qEEG adds incremental information beyond topographical extent of PWB, another risk marker of brain involvement. RESULTS: qEEG helped predict SWS risk in the first year of life (p = 0.031), with a sensitivity of 50% and a specificity of 81%. It added about 40% incremental information beyond PWB extent alone (p = 0.042). CONCLUSION: qEEG adds information to risk prediction in infants with facial PWB. SIGNIFICANCE: qEEG can be used to help determine whether to obtain an MRI in the first year of life. The data collected can assist in developing a predictive model risk calculator that incorporates both PWB extent and qEEG results, which can be validated and then employed in the community.

Associations between Task-Related Modulation of Motor-Evoked Potentials and EEG Event-Related Desynchronization in Children with ADHD.

Children with attention-deficit/hyperactivity disorder (ADHD) have previously shown a decreased magnitude of event-related desynchronization (ERD) during a finger-tapping task, with a large between-group effect. Because the neurobiology underlying several transcranial magnetic stimulation (TMS) measures have been studied in multiple contexts, we compared ERD and 3 TMS measures (resting motor threshold [RMT], short-interval cortical inhibition [SICI], and task-related up-modulation [TRUM]) within 14 participants with ADHD (ages 8-12 years) and 17 control children. The typically developing (TD) group showed a correlation between greater RMT and greater magnitude of alpha (10-13 Hz, here) ERD, and there was no diagnostic interaction effect, consistent with a rudimentary model of greater needed energy input to stimulate movement. Similarly, inhibition measured by SICI was also greater in the TD group when the magnitude of movement-related ERD was higher; there was a miniscule diagnostic interaction effect. Finally, TRUM during a response-inhibition task showed an unanticipated pattern: in TD children, the greater TMS task modulation (TRUM) was associated with a smaller magnitude of ERD during finger-tapping. The ADHD group showed the opposite direction of association: Greater TRUM was associated with larger magnitude of ERD. Prior EEG results have demonstrated specific alterations of task-related modulation of cortical physiology, and the current results provide a fulcrum for multimodal study.

Altered Inferior Parietal Functional Connectivity is Correlated with Praxis and Social Skill Performance in Children with Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) have difficulties perceiving and producing skilled gestures, or praxis. The inferior parietal lobule (IPL) is crucial to praxis acquisition and expression, yet how IPL connectivity contributes to autism-associated impairments in praxis as well as social-communicative skill remains unclear. Using resting-state functional magnetic resonance imaging, we applied independent component analysis to test how IPL connectivity relates to praxis and social-communicative skills in children with and without ASD. Across all children (with/without ASD), praxis positively correlated with connectivity of left posterior-IPL with the left dorsal premotor cortex and with the bilateral posterior/medial parietal cortex. Praxis also correlated with connectivity of right central-IPL connectivity with the left intraparietal sulcus and medial parietal lobe. Further, in children with ASD, poorer praxis and social-communicative skills both correlated with weaker right central-IPL connectivity with the left cerebellum, posterior cingulate, and right dorsal premotor cortex. Our findings suggest that IPL connectivity is linked to praxis development, that contributions arise bilaterally, and that right IPL connectivity is associated with impaired praxis and social-communicative skills in autism. The findings underscore the potential impact of IPL connectivity and impaired skill acquisition on the development of a range of social-communicative and motor functions during childhood, including autism-associated impairments.

A novel sleep stage scoring system: Combining expert-based features with the generalized linear model.

In this study, we aim to automate the sleep stage scoring process of overnight polysomnography (PSG) data while adhering to expert-based rules. We developed a sleep stage scoring algorithm utilizing the generalized linear modelling (GLM) framework and extracted features from electroencephalogram (EEG), electromyography (EMG) and electrooculogram (EOG) signals based on predefined rules of the American Academy of Sleep Medicine (AASM) Manual for Scoring Sleep. Specifically, features were computed in 30-s epochs in the time and frequency domains of the signals and were then used to model the probability of an epoch being in each of five sleep stages: N3, N2, N1, REM or Wake. Finally, each epoch was assigned to a sleep stage based on model predictions. The algorithm was trained and tested on PSG data from 38 healthy individuals with no reported sleep disturbances. The overall scoring accuracy reached on the test set was 81.50 ± 1.14% (Cohen's kappa, κ=0.73±0.02 ). The test set results were highly comparable to the training set, indicating robustness of the algorithm. Furthermore, our algorithm was compared to three well-known commercialized sleep-staging tools and achieved higher accuracies than all of them. Our results suggest that automatic classification is highly consistent with visual scoring. We conclude that our algorithm can reproduce the judgement of a scoring expert and is also highly interpretable. This tool can assist visual scorers to speed up their process (from hours to minutes) and provides a method for a more robust, quantitative, reproducible and cost-effective PSG evaluation, supporting assessment of sleep and sleep disorders.

Increased mirror overflow movements in ADHD are associated with altered EEG alpha/beta band desynchronization.

Children with ADHD show developmentally abnormal levels of mirror overflow-unintentional movements occurring symmetrically opposite of intentional movements. Because mirror overflow correlates with ADHD behavioral symptoms, the study of disinhibition in motor control may shed light on physiologic mechanisms underlying impaired behavioral/cognitive control. This is a case-controlled study of EEG recording from 25 children with ADHD and 25 typically developing (TD) controls performing unilateral sequential finger tapping, with overflow movements measured using electronic goniometers. Consistent with previously published findings, children with ADHD showed increased mirror overflow as compared with TD peers. EEG findings revealed less lateralized alpha modulation (event-related desynchronization; ERD) and decreased magnitude of beta ERD in ADHD; both alpha and beta ERD reflect cortical activation. Moderation analysis revealed a significant association between beta ERD and overflow, independent of diagnosis; and an equivocal (p = .08) effect of diagnosis on the relationship between alpha ERD and overflow, with a significant effect in children with ADHD but not TD children. These results suggest two mechanisms involved with mirror overflow: one reflected in beta ipsilateral to the intentional movement and relevant to both children with ADHD and controls, and the other seemingly more specific to ADHD (alpha, contralateral to movement).

Learning of skilled movements via imitation in ASD.

Autism spectrum disorder (ASD) consists of altered performance of a range of skills, including social/communicative and motor skills. It is unclear whether this altered performance results from atypical acquisition or learning of the skills or from atypical "online" performance of the skills. Atypicalities of skilled actions that require both motor and cognitive resources, such as abnormal gesturing, are highly prevalent in ASD and are easier to study in a laboratory context than are social/communicative skills. Imitation has long been known to be impaired in ASD; because learning via imitation is a prime method by which humans acquire skills, we tested the hypothesis that children with ASD show alterations in learning novel gestures via imitation. Eighteen participants with ASD and IQ > 80, ages 8-12.9 years, and 19 typically developing peers performed a task in which they watched a video of a model performing a novel, meaningless arm/hand gesture and copied the gesture. Each gesture video/copy sequence was repeated 4-6 times. Eight gestures were analyzed. Examination of learning trajectories revealed that while children with ASD made nearly as much progress in learning from repetition 1 to repetition 4, the shape of the learning curves differed. Causal modeling demonstrated the shape of the learning curve influenced both the performance of overlearned gestures and autism severity, suggesting that it is in the index of learning mechanisms relevant both to motor skills and to autism core features. Autism Res 2020, 13: 777-784.. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Imitation is a route by which humans learn a wide range of skills, naturally and in therapies. Imitation is known to be altered in autism spectrum disorder (ASD), but learning via imitation has not been rigorously examined. We found that the shape of the learning curve is altered in ASD, in a way that has a significant impact both on measures of autism severity and of other motor skills.

Conceptual, Regulatory and Strategic Imperatives in the Early Days of EEG-Based Biomarker Validation for Neurodevelopmental Disabilities.

Biological treatment development for syndromal neuropsychiatric conditions such as autism has seen slow progress for decades. Speeding drug discovery may result from the judicious development and application of biomarker measures of brain function to select patients for clinical trials, to confirm target engagement and to optimize drug dose. For neurodevelopmental disorders, electrophysiology (EEG) offers considerable promise because of its ability to monitor brain activity with high temporal resolution and its more ready application for pediatric populations relative to MRI. Here, we discuss conceptual/definitional issues related to biomarker development, discuss practical implementation issues, and suggest preliminary guidelines for validating EEG approaches as biomarkers with a context of use in neurodevelopmental disorder drug development.

Epilepsy and Autism Severity: A Study of 6,975 Children.

Epilepsy is known to occur in a higher-than-expected proportion of individuals with autism spectrum disorders (ASDs). Prior studies of this heterogeneous disorder have suggested that intelligence quotient (IQ) may drive this relationship. Because intellectual disability (ID) is, independently of ASD, a risk factor for epilepsy, current literature calls into question the long-understood unique relationship between ASD and epilepsy. Second, data have been unclear about whether developmental regression in ASD is associated with epilepsy. Using two cohorts from an online research registry, totaling 6,975 children with ASD, we examined the independent role of four ASD severity measures in driving the relationship with epilepsy: ID, language impairment, core ASD symptom severity, and motor dysfunction, controlling for two known relevant factors: age and sex. We also examined whether developmental regression and epilepsy have an independent statistical link. All four ASD severity factors showed independent statistical associations with epilepsy in one cohort, and three in the other. ID showed the largest relative risk (RR) in both cohorts. Effect sizes were modest. Regression similarly showed an independent statistical association with epilepsy, but with small effect size. Similar to previous work, ID showed the greatest contribution to RR for epilepsy among children with ASD. However, other ASD severity markers showed statistical associations, demonstrating that the ASD-epilepsy association is not reducible to the effect of ID. Inconsistencies in the literature may be due to underpowered studies, yet moving forward with larger-n studies, clinical significance and scientific relevance may be dictated by effect size and not merely statistical significance. Autism Res 2019, 12: 1251-1259. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Epilepsy is known to occur more often in individuals with autism spectrum disorders (ASDs) than is the case in the general population. The association between ASD and epilepsy is of interest because studying the two disorders in combination may help advance our understanding of genetic, molecular, and cellular mechanisms-as well as therapies-for both. Recent studies have suggested that intelligence quotient (IQ) alone in individuals with ASD may account for the increased prevalence of epilepsy. However, our approach was to look at a range of severity factors relevant to ASD and to look for correlations between each severity factor and epilepsy, within two large samples of children with ASD. In summary, we found that each severity factor-presence of intellectual disability, presence of language atypicalities, ASD-specific symptoms severity, and presence of motor issues-independently predicted a small increased risk for epilepsy, countering the argument that IQ alone is a risk factor. We also examined whether epilepsy is associated with developmental regression. Although severe epilepsy syndromes such as Landau-Kleffner syndrome are known to cause autistic-like symptoms following developmental regression, there is controversy about whether other forms of epilepsy are associated with the more common developmental regression seen in many young children with epilepsy. Indeed, we found a small association between epilepsy and developmental regression.

Cortical Functional Connectivity during Praxis in Autism Spectrum Disorder.

Abnormal functional connectivity was reported as one of the underlying characteristics of autism spectrum disorder (ASD). Considering the motor deficits in ASD, we utilized praxis to investigate the neural mechanisms of ASD during motor task. Since the previous functional connectivity studies reported divergent results, we explored the properties of the functional connectivity using graph metrics to address brain organization alterations of ASD. We proposed the use of eLORETA to investigate the cortical connectivity during praxis based on a cohort of 45 high-functioning ASD (HFA) children and 45 typically developing (TD) children. The between-group comparison revealed higher clustering coefficient and lower global efficiency for HFA relative to TD while the between-phase comparison suggested decreasing global efficiency, increasing characteristic path length for TD. Nodal metrics exhibited significant differences between groups in frontal and occipital regions. These regions also showed significant changes of nodal metrics and connection strengths between baseline and praxis execution for TD. However, there were no significant changes in global, nodal metrics and connection strengths between phases for HFA. Our study suggested that cortical connectivity in ASD exhibited lower overall efficiency and a deficit in reorganization, which deepens the understanding of abnormal brain organization in ASD.