Pubertal maturation and timing effects on resting state electroencephalography in autistic and comparison youth.

Autistic and comparison individuals differ in resting-state electroencephalography (EEG), such that sex and age explain variability within and between groups. Pubertal maturation and timing may further explain variation, as previous work has suggested alterations in pubertal timing in autistic youth. In a sample from two studies of 181 autistic and 94 comparison youth (8 years to 17 years and 11 months), mixed-effects linear regressions were conducted to assess differences in EEG (midline power for theta, alpha, and beta frequency bands). Alpha power was analyzed as a mediator in the relation between pubertal maturation and timing with autistic traits in the autistic groups to understand the role of puberty in brain-based changes that contribute to functional outcomes. Individuals advanced in puberty exhibited decreased power in all bands. Those who experienced puberty relatively early showed decreased power in theta and beta bands, controlling for age, sex, and diagnosis. Autistic individuals further along in pubertal development exhibited lower social skills. Alpha mediated the relation between puberty and repetitive behaviors. Pubertal maturation and timing appear to play unique roles in the development of cognitive processes for autistic and comparison youth and should be considered in research on developmental variation in resting-state EEG.

EEG-IP: an international infant EEG data integration platform for the study of risk and resilience in autism and related conditions.

BACKGROUND: Establishing reliable predictive and diganostic biomarkers of autism would enhance early identification and facilitate targeted intervention during periods of greatest plasticity in early brain development. High impact research on biomarkers is currently limited by relatively small sample sizes and the complexity of the autism phenotype. METHODS: EEG-IP is an International Infant EEG Data Integration Platform developed to advance biomarker discovery by enhancing the large scale integration of multi-site data. Currently, this is the largest multi-site standardized dataset of infant EEG data. RESULTS: First, multi-site data from longitudinal cohort studies of infants at risk for autism was pooled in a common repository with 1382 EEG longitudinal recordings, linked behavioral data, from 432 infants between 3- to 36-months of age. Second, to address challenges of limited comparability across independent recordings, EEG-IP applied the Brain Imaging Data Structure (BIDS)-EEG standard, resulting in a harmonized, extendable, and integrated data state. Finally, the pooled and harmonized raw data was preprocessed using a common signal processing pipeline that maximizes signal isolation and minimizes data reduction. With EEG-IP, we produced a fully standardized data set, of the pooled, harmonized, and pre-processed EEG data from multiple sites. CONCLUSIONS: Implementing these integrated solutions for the first time with infant data has demonstrated success and challenges in generating a standardized multi-site data state. The challenges relate to annotation of signal sources, time, and ICA analysis during pre-processing. A number of future opportunities also emerge, including validation of analytic pipelines that can replicate existing findings and/or test novel hypotheses.

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.

Wanting it Too Much: An Inverse Relation Between Social Motivation and Facial Emotion Recognition in Autism Spectrum Disorder.

This study examined social motivation and early-stage face perception as frameworks for understanding impairments in facial emotion recognition (FER) in a well-characterized sample of youth with autism spectrum disorders (ASD). Early-stage face perception (N170 event-related potential latency) was recorded while participants completed a standardized FER task, while social motivation was obtained via parent report. Participants with greater social motivation exhibited poorer FER, while those with shorter N170 latencies exhibited better FER for child angry faces stimuli. Social motivation partially mediated the relationship between a faster N170 and better FER. These effects were all robust to variations in IQ, age, and ASD severity. These findings augur against theories implicating social motivation as uniformly valuable for individuals with ASD, and augment models suggesting a close link between early-stage face perception, social motivation, and FER in this population. Broader implications for models and development of FER in ASD are discussed.

Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to >1000. We considered 7 extended families (size 12-47 individuals), each with ≥3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p = 0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation- and association-based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.

Consensus paper: radiological biomarkers of cerebellar diseases.

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine.

Developmental changes in infant brain activity during naturalistic social experiences.

Between 6 and 12 months, typically developing infants undergo a socio-cognitive "revolution." The Interactive Specialization (IS) theory of brain development predicts that these behavioral changes will be underpinned by developmental increases in the power and topographic extent of socially selective cortical responses. To test this hypothesis, we used EEG to examine developmental changes in cortical selectivity for ecologically valid dynamic social versus non-social stimuli in a large cohort of 6- and 12-month-old infants. Consistent with the Interactive Specialization model, results showed that differences in EEG Θ activity between social and non-social stimuli became more pronounced and widespread with age. Differences in EEG activity were most clearly elicited by a live naturalistic interaction, suggesting that measuring brain activity in ecologically valid contexts is central to mapping social brain development in infancy.

Social motivation by self- and caregiver-report: Reporter concordance and social correlates among autistic and neurotypical youth.

Differences in social motivation underlie the core social-communication features of autism according to several theoretical models, with decreased social motivation among autistic youth relative to neurotypical peers. However, research on social motivation often relies on caregiver reports and rarely includes firsthand perspectives of children and adolescents with autism. Furthermore, social motivation is typically assumed to be constant across social settings when it may actually vary by social context. Among a sample of 58 verbally fluent youth (8-13 years old; 22 with autism, 36 neurotypical), we examined correspondence between youth and caregiver reports of social motivation with peers and with adults, as well as diagnostic group differences and associations with social outcomes. Results suggest youth and caregivers provide overlapping but distinct information. Autistic youth had lower levels of social motivation relative to neurotypical youth, and reported relatively consistent motivation toward peers and adults. Youth self- and caregiver-report were correlated for motivation toward adults, but not toward peers. Despite low correspondence between self- and caregiver-reported motivation toward peers, autistic youths' self-report corresponded to caregiver-reported social skills and difficulties whereas caregiver-report of peer motivation did not. For neurotypical youth, self- and caregiver-reported motivation toward adults was correlated, but motivation by both reporters was largely independent of broader social outcomes. Findings highlight the unique value of self-report among autistic children and adolescents, and warrant additional work exploring the development, structure, and correlates of social motivation among autistic and neurotypical youth.

Linking cortical surface area to computational properties in human visual perception.

Cortical structure and function are closely linked, shaping the neural basis of human behavior. This study explores how cortical surface area (SA), a structural feature, influences computational properties in human visual perception. Using a combination of psychophysical, neuroimaging, and computational modeling approaches, we find that variations in SA across the parietal and frontal cortices are linked to distinct behavioral patterns in a motion perception task. These differences in behavior correspond to specific parameters within a divisive normalization model, indicating a unique contribution of SA to the spatial organization of cortical circuitry. This work highlights the importance of cortical architecture in modifying computational processes that underlie perception, enhancing our understanding of how structural differences can influence neural function and behavior.

Autistic Individuals Do Not Alter Visual Processing Strategy During Encoding Versus Recognition of Faces: A Hidden Markov Modeling Approach.

PURPOSE: Visual face recognition-the ability to encode, discriminate, and recognize the faces of others-is fundamentally supported by eye movements and is a common source of difficulty for autistic individuals. We aimed to evaluate how visual processing strategies (i.e., eye movement patterns) directly support encoding and recognition of faces in autistic and neurotypical (NT) individuals. METHODS: We used a hidden Markov modeling approach to evaluate the spatiotemporal dynamics of eye movements in autistic (n = 15) and neurotypical (NT) adolescents (n = 17) during a face identity recognition task. RESULTS: We discovered distinct eye movement patterns among all participants, which included a focused and exploratory strategy. When evaluating change in visual processing strategy across encoding and recognition phases, autistic individuals did not shift their eye movement patterns like their NT peers, who shifted to a more exploratory visual processing strategy during recognition. CONCLUSION: These findings suggest that autistic individuals do not modulate their visual processing strategy across encoding and recognition of faces, which may be an indicator of less efficient face processing.

Mobile Media Content Exposure and Toddlers' Responses to Attention Prompts and Behavioral Requests.

Importance: With personalized touch-screen tablets, young children can choose content and engage in play-like activities. However, tablets may also reduce shared engagement as the action of viewing or touching the screen is often not visible to nearby adults. This may impact communicative gazing and pointing, which is critical to the formation of shared awareness and in turn supports language development. Objective: To assess the association of tablet media content with toddlers' responses to joint attention prompts and behavioral requests. Design, Setting, and Participants: This cohort study took place at a behavioral research laboratory and included toddlers who were aged 18 to 32 months with neurotypical development who were recruited from a volunteer and community sample. Toddlers engaged with a real toy or 3 different types of tablet content (ie, viewing video of toy play, playing with a digital toy, or playing a commercial game) while an experimenter delivered joint attention prompts. Data were acquired from June 2021 November XX 2022, and data analysis occurred from January 2023 to May 2024. Main Outcomes and Measures: Main outcomes included child response to joint attention (number of prompts with joint attention response per number of prompts delivered) and child response to behavioral request (ie, the prompt on which the child responded to the behavioral request). Measures included crossed random effects, Wald tests, and likelihood ratio tests. Results: In this study, 63 toddlers were enrolled, and data from 62 were included (31 female [49%]; mean [SD] age, 26.1 [3.4] months; median [IQR] age, 25.0 [18.6-32.6] months). When toddlers were playing a commercial game on a tablet, they responded to fewer joint attention prompts (crossed random effects model, -0.15; 95% CI, -0.24 to -0.06 prompts) and male toddlers took longer to acknowledge a behavioral request (interaction of content and sex, -0.75; 95% CI, -1.36 to -0.17). The negative impact of the tablet game was larger as child age increased (τ = -2.30; 95% CI, -0.05 to 0; P = .03). Greater media use at home was associated with decreased responding to joint attention prompts during the tablet game (ρ = -0.47; P < .001), while better language skills were associated with more joint attention during play with a real toy (ρ = 0.31; P = .02). Conclusions and Relevance: In this cohort study, a touch-screen tablet game was associated with decreased joint attention among toddlers and they were less likely to respond to a behavioral request. In a laboratory setting, it was difficult for toddlers to engage in social-communicative interactions with adults when using a tablet media device.

Spatiotemporal Eye Movement Dynamics Reveal Altered Face Prioritization in Early Visual Processing Among Autistic Children.

BACKGROUND: Reduced social attention - looking at faces - is one of the most common manifestations of social difficulty in autism central to social development. Although reduced social attention is well-characterized in autism, qualitative differences in how social attention unfolds across time remains unknown. METHODS: We used a computational modeling (i.e., hidden Markov modeling) approach to assess and compare the spatiotemporal dynamics of social attention in a large, well-characterized sample of autistic (n = 280) and neurotypical (n = 120) children (ages 6-11) that completed three social eye-tracking assays across three longitudinal time points (Baseline, 6 weeks, 24 weeks). RESULTS: Our analysis supported the existence of two common eye movement patterns that emerged across three ET assays. A focused pattern was characterized by small face regions of interest, which had high probability of capturing fixations early in visual processing. In contrast, an exploratory pattern was characterized by larger face regions of interest, with lower initial probability of fixation, and more non-social regions of interest. In the context of social perception, autistic children showed significantly more exploratory eye movement patterns than neurotypical children across all social perception assays and all three longitudinal time points. Eye movement patterns were associated with clinical features of autism, including adaptive function, face recognition, and autism symptom severity. CONCLUSIONS: Decreased likelihood of precisely looking to faces early in social visual processing may be an important feature of autism that was associated with autism-related symptomology and may reflect less visual sensitivity to face information.

Parsing evoked and induced gamma response differences in Autism: A visual evoked potential study.

OBJECTIVE: Electroencephalography (EEG) measures of visual evoked potentials (VEPs) provide a targeted approach for investigating neural circuit dynamics. This study separately analyses phase-locked (evoked) and non-phase-locked (induced) gamma responses within the VEP to comprehensively investigate circuit differences in autism. METHODS: We analyzed VEP data from 237 autistic and 114 typically developing (TD) children aged 6-11, collected through the Autism Biomarkers Consortium for Clinical Trials (ABC-CT). Evoked and induced gamma (30-90 Hz) responses were separately quantified using a wavelet-based time-frequency analysis, and group differences were evaluated using a permutation-based clustering procedure. RESULTS: Autistic children exhibited reduced evoked gamma power but increased induced gamma power compared to TD peers. Group differences in induced responses showed the most prominent effect size and remained statistically significant after excluding outliers. CONCLUSIONS: Our study corroborates recent research indicating diminished evoked gamma responses in children with autism. Additionally, we observed a pronounced increase in induced power. Building upon existing ABC-CT findings, these results highlight the potential to detect variations in gamma-related neural activity, despite the absence of significant group differences in time-domain VEP components. SIGNIFICANCE: The contrasting patterns of decreased evoked and increased induced gamma activity in autistic children suggest that a combination of different EEG metrics may provide a clearer characterization of autism-related circuitry than individual markers alone.

Visual and auditory attention in individuals with DYRK1A and SCN2A disruptive variants.

This preliminary study sought to assess biomarkers of attention using electroencephalography (EEG) and eye tracking in two ultra-rare monogenic populations associated with autism spectrum disorder (ASD). Relative to idiopathic ASD (n = 12) and neurotypical comparison (n = 49) groups, divergent attention profiles were observed for the monogenic groups, such that individuals with DYRK1A (n = 9) exhibited diminished auditory attention condition differences during an oddball EEG paradigm whereas individuals with SCN2A (n = 5) exhibited diminished visual attention condition differences noted by eye gaze tracking when viewing social interactions. Findings provide initial support for alignment of auditory and visual attention markers in idiopathic ASD and neurotypical development but not monogenic groups. These results support ongoing efforts to develop translational ASD biomarkers within the attention domain.

A common genetic variant in the Neurexin family member CNTNAP2 is related to language but not communication skills in youth with Autism Spectrum Disorder.

One of the candidate genes related to language variability in individuals with Autism Spectrum Disorder (ASD) is the contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin family. However, due to the different assessment tools used, it is unknown whether the polymorphisms of the CNTNAP2 gene are linked to structural language skills or more general communication abilities. A total of 302 youth aged 7 to 18 years participated in the present study: 131 verbal youth with ASD (62 female), 130 typically developing (TD) youth (64 female), and 41 unaffected siblings (US) of youth with ASD (25 female). Blood samples were collected to obtain genomic DNA and processed by the Rutgers University Cell and Data Repository or using standard protocols (Gentra Puregene Blood DNA extraction kit; Qiagen). Language and verbal communication skills were screened with the Clinical Evaluation of Language Fundamental-4 (CELF-4) and Vineland-II Communication domain, subsequently. The results showed that the polymorphism of CNTNAP2 (SNP rs2710102) was related to structural language abilities, such that participants carrying the A-allele had lower language skills in comparison to the G-allele homozygotes. No relationship was found between the polymorphism of CNTNAP2 and more general communication abilities. Although the study revealed genetic mechanisms that are associated with CELF-4 measures but not Vineland-II in youth with ASD, follow-up studies are needed that will include measures of language and communication that are less correlated to each other as well as will include a group of minimally and/or non-verbal individuals with ASD.

Multi-site EEG studies in early infancy: Methods to enhance data quality.

Brain differences linked to autism spectrum disorder (ASD) can manifest before observable symptoms. Studying these early neural precursors in larger and more diverse cohorts is crucial for advancing our understanding of developmental pathways and potentially facilitating earlier identification. EEG is an ideal tool for investigating early neural differences in ASD, given its scalability and high tolerability in infant populations. In this context, we integrated EEG into an existing multi-site MRI study of infants with a higher familial likelihood of developing ASD. This paper describes the comprehensive protocol established to collect longitudinal, high-density EEG data from infants across five sites as part of the Infant Brain Imaging Study (IBIS) Network and reports interim feasibility and data quality results. We evaluated feasibility by measuring the percentage of infants from whom we successfully collected each EEG paradigm. The quality of task-free data was assessed based on the duration of EEG recordings remaining after artifact removal. Preliminary analyses revealed low data loss, with average in-session loss rates at 4.16 % and quality control loss rates at 11.66 %. Overall, the task-free data retention rate, accounting for both in-session issues and quality control, was 84.16 %, with high consistency across sites. The insights gained from this preliminary analysis highlight key sources of data attrition and provide practical considerations to guide similar research endeavors.

The relationship between gamma-band neural oscillations and language skills in youth with Autism Spectrum Disorder and their first-degree relatives.

BACKGROUND: Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance. METHODS: We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals. RESULTS: First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills. LIMITATIONS: We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis. CONCLUSIONS: Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles.

Cortical Surface Area Relates to Distinct Computational Properties in Human Visual Perception.

Understanding the relationship between cortical structure and function is essential for elucidating the neural basis of human behavior. However, the impact of cortical structural features on the computational properties of neural circuits remains poorly understood. In this study, we demonstrate that a simple structural feature - cortical surface area (SA) - relates to specific computational properties underlying human visual perception. By combining psychophysical, neuroimaging, and computational modeling approaches, we show that differences in SA in the parietal and frontal cortices are associated with distinct patterns of behavior in a motion perception task. These behavioral differences can be accounted for by specific parameters of a divisive normalization model, suggesting that SA in these regions contributes uniquely to the spatial organization of cortical circuitry. Our findings provide novel evidence linking cortical structure to distinct computational properties and offer a framework for understanding how cortical architecture can impact human behavior.

Sex Differences on the ADOS-2.

The sex difference in the prevalence of autism spectrum disorder (ASD) may be magnified by sex differences on diagnostic measures. The current study compared autistic males and females on items on the gold-standard diagnostic measure, the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In a sample of 8-to-17-year old autistic individuals from research (n = 229) and clinical settings (n = 238), females were less likely to show atypicalities on most items related to social-communication behaviors and on total and subscale scores. When controlling for overall intensity of symptomatology, no sex differences survived statistical corrections. Diagnostic criteria and/or gold-standard assessments may be less sensitive to female presentations of ASD and/or autistic females may exhibit fewer or less intense behaviors characteristic of ASD.

EEG functional connectivity in infants at elevated familial likelihood for autism spectrum disorder.

BACKGROUND: Many studies have reported that autism spectrum disorder (ASD) is associated with atypical structural and functional connectivity. However, we know relatively little about the development of these differences in infancy. METHODS: We used a high-density electroencephalogram (EEG) dataset pooled from two independent infant sibling cohorts, to characterize such neurodevelopmental deviations during the first years of life. EEG was recorded at 6 and 12 months of age in infants at typical (N = 92) or elevated likelihood for ASD (N = 90), determined by the presence of an older sibling with ASD. We computed the functional connectivity between cortical sources of EEG during video watching using the corrected imaginary part of phase-locking values. RESULTS: Our main analysis found no significant association between functional connectivity and ASD, showing only significant effects for age, sex, age-sex interaction, and site. Given these null results, we performed an exploratory analysis and observed, at 12 months, a negative correlation between functional connectivity and ADOS calibrated severity scores for restrictive and repetitive behaviors (RRB). LIMITATIONS: The small sample of ASD participants inherent to sibling studies limits diagnostic group comparisons. Also, results from our secondary exploratory analysis should be considered only as potential relationships to further explore, given their increased vulnerability to false positives. CONCLUSIONS: These results are inconclusive concerning an association between EEG functional connectivity and ASD in infancy. Exploratory analyses provided preliminary support for a relationship between RRB and functional connectivity specifically, but these preliminary observations need corroboration on larger samples.