Modeling intra-individual inter-trial EEG response variability in autism.

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers.

Identifying phenotypic and physiological subgroups of preschoolers with autism spectrum disorder.

BACKGROUND: To understand the emergence of symptoms in autism spectrum disorder (ASD), we need to identify the mechanisms that underpin the development of core social skills. Mounting evidence indicates that young children with later ASD attend less to other people, which could compromise learning opportunities with cascading effects. Passive looking behaviour does not tell us about engagement with visual information, but measures of physiological arousal can provide information on the depth of engagement. In the current study, we use heart rate (HR) and heart rate variability (HRV) to measure engagement with social dynamic stimuli in ASD. METHODS: Sixty-seven preschoolers with ASD and 65 typical developing preschoolers between 2 and 4 years of age participated in a study where HR was measured during viewing of social and non-social videos. Using latent profile analyses, more homogeneous subgroups of children were created based on phenotype and physiology. RESULTS: Preschool-aged children with ASD, regardless of their non-verbal, verbal and social competencies, do not differ in overall HR or HRV compared to TD children. However, the ASD group showed a larger increase in HR (more disengagement) than the TD group to later-presented social stimuli. Phenotypic and physiological profiles showed this was primarily the case for children with below average verbal and non-verbal skills, but not necessarily those with more ASD symptoms. CONCLUSION: Children with ASD, especially a subgroup showing moderate cognitive delays, show an increase in HR to social stimuli over time; this may reflect difficulties re-engaging with social information when attention is waning.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Informed consent in episiotomy: Co-analysis with midwives and distillation of best practice.

BACKGROUND: Performing an episiotomy where clinically indicated is a key intervention in the Obstetric Anal Sphincter Injury Care Bundle (OASI-CB) implemented across England and Wales to reduce the risk and increase the detection of severe perineal trauma after birth. Standards of consent provided to people in maternity care generally and for episiotomy specifically have been reported as suboptimal. Compromising birthing people's personal autonomy or sense of control has been linked to a dissatisfying birth experience, negative psychological sequelae, and litigation. METHODS: This study explored experienced midwives' practice of informed consent for episiotomy during a midwife-led birth. We sampled 43 midwives across eight NHS Trusts in England and Wales using online focus groups and telephone interviews about their experience of consent in episiotomy. Using qualitative content analysis and art-based co-analysis methods with eight midwives from across the research sites, we co-analyzed and co-constructed three themes and four practice recommendations from the data. RESULTS: Three themes were constructed from the data: Assent rather than consent, Change in culture to support best practice, and Standardized information. These themes informed the shaping of four recommendations for best practice in episiotomy informed consent. CONCLUSION: This study has shown how variations in midwifery practice and culture may impact birthing people's experience of informed consent in episiotomy. Midwives may not have the knowledge or skills to conduct a detailed consent conversation, leading to variation in practice and messages for birthing people. The use of antenatal discussion aids can offer women the opportunity to become informed and fully participate in the decision-making process.

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.

Neural mechanisms of language development in infancy.

Understanding the neural processes underpinning individual differences in early language development is of increasing interest, as it is known to vary in typical development and to be quite heterogeneous in neurodevelopmental conditions. However, few studies to date have tested whether early brain measures are indicative of the developmental trajectory of language, as opposed to language outcomes at specific ages. We combined recordings from two longitudinal studies, including typically developing infants without a family history of autism, and infants with increased likelihood of developing autism (infant-siblings) (N = 191). Electroencephalograms (EEG) were recorded at 6 months, and behavioral assessments at 6, 12, 18, 24 and 36 months of age. Using a growth curve model, we tested whether absolute EEG spectral power at 6 months was associated with concurrent language abilities, and developmental change in language between 6 and 36 months. We found evidence of an association between 6-month alpha-band power and concurrent, but not developmental change in, expressive language ability in both infant-siblings and control infants. The observed association between 6-month alpha-band power and 6-month expressive language was not moderated by group status, suggesting some continuity in neural mechanisms.

Multilevel hybrid principal components analysis for region-referenced functional electroencephalography data.

Electroencephalography experiments produce region-referenced functional data representing brain signals in the time or the frequency domain collected across the scalp. The data typically also have a multilevel structure with high-dimensional observations collected across multiple experimental conditions or visits. Common analysis approaches reduce the data complexity by collapsing the functional and regional dimensions, where event-related potential (ERP) features or band power are targeted in a pre-specified scalp region. This practice can fail to portray more comprehensive differences in the entire ERP signal or the power spectral density (PSD) across the scalp. Building on the weak separability of the high-dimensional covariance process, the proposed multilevel hybrid principal components analysis (M-HPCA) utilizes dimension reduction tools from both vector and functional principal components analysis to decompose the total variation into between- and within-subject variance. The resulting model components are estimated in a mixed effects modeling framework via a computationally efficient minorization-maximization algorithm coupled with bootstrap. The diverse array of applications of M-HPCA is showcased with two studies of individuals with autism. While ERP responses to match vs mismatch conditions are compared in an audio odd-ball paradigm in the first study, short-term reliability of the PSD across visits is compared in the second. Finite sample properties of the proposed methodology are studied in extensive simulations.

A neurogenetic analysis of female autism.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

Cross-Omics Analysis of Fenugreek Supplementation Reveals Beneficial Effects Are Caused by Gut Microbiome Changes Not Mammalian Host Physiology.

Herbal remedies are increasing in popularity as treatments for metabolic conditions such as obesity and Type 2 Diabetes. One potential therapeutic option is fenugreek seeds (Trigonella foenum-graecum), which have been used for treating high cholesterol and Type 2 diabetes. A proposed mechanism for these benefits is through alterations in the microbiome, which impact mammalian host metabolic function. This study used untargeted metabolomics to investigate the fenugreek-induced alterations in the intestinal, liver, and serum profiles of mice fed either a 60% high-fat or low-fat control diet each with or without fenugreek supplementation (2% w/w) for 14 weeks. Metagenomic analyses of intestinal contents found significant alterations in the relative composition of the gut microbiome resulting from fenugreek supplementation. Specifically, Verrucomicrobia, a phylum containing beneficial bacteria which are correlated with health benefits, increased in relative abundance with fenugreek. Metabolomics partial least squares discriminant analysis revealed substantial fenugreek-induced changes in the large intestines. However, it was observed that while the magnitude of changes was less, significant modifications were present in the liver tissues resulting from fenugreek supplementation. Further analyses revealed metabolic processes affected by fenugreek and showed broad ranging impacts in multiple pathways, including carnitine biosynthesis, cholesterol and bile acid metabolism, and arginine biosynthesis. These pathways may play important roles in the beneficial effects of fenugreek.

Sex Differences in Functional Connectivity of the Salience, Default Mode, and Central Executive Networks in Youth with ASD.

Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8-17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.

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.

The impact of mode of subsequent birth after obstetric anal sphincter injury on bowel function and related quality of life: a cohort study.

INTRODUCTION AND HYPOTHESIS: The objective was to assess the impact of mode of subsequent birth on bowel function and related quality of life (QoL) in pregnant women with previous obstetric anal sphincter injury (OASI). METHODS: A prospective cohort study, designed, undertaken and reported using the Strengthening the Reporting of Observational Studies in Epidemiology statement and checklist. All pregnant women with previous OASI recruited at a specialist antenatal OASI clinic in a tertiary hospital to discuss mode of subsequent birth, between 1 January 2014 and 31 October 2015. Women are counselled in line with local guidelines based on Royal College of Obstetricians and Gynaecologists Green-top recommendations. In addition to routine endoanal ultrasound scan (EAUS), women recruited to the study were asked to complete the validated Manchester Health Questionnaire (MHQ) at both 34 weeks' gestation and 6 months postnatally. RESULTS: Of the 175 study participants, 125 (71.4%) completed follow-up at 6 months. There was no significant change in frequency of bowel symptoms or QoL domain scores in women who had a subsequent vaginal birth compared with caesarean section. Multivariate analysis showed the odds of having poor "incontinence impact" (OR 2.91, 95% CI 1.03-8.21) and "physical limitations" (OR 4.56, 95% CI 1.02-20.45) were significantly higher for women who had a subsequent caesarean section. CONCLUSIONS: For women with previous OASI, a subsequent vaginal birth is suitable for those with no bowel symptoms and normal EAUS and caesarean section is reasonable for women who do not have normal bowel function and/or normal EAUS findings; however, for some of these women bowel symptoms and QoL may be worsened.

Postpartum perineal pain and dyspareunia related to each superficial perineal muscle injury: a cohort study.

OBJECTIVE: To assess the association between superficial perineal muscle trauma and perineal pain and dyspareunia. MATERIALS AND METHODS: Prospective cohort study of 405 women with a spontaneous vaginal birth comparing an intact perineum and first-degree perineal trauma group (n = 205) with a second-degree perineal trauma and episiotomy group (n = 200). Perineal pain was measured at 2 days, 10 days, 7 weeks, 3 months and 6 months postpartum. Dyspareunia was assessed at 7 weeks, 3 months and 6 months postpartum. RESULTS: All second-degree perineal traumas and episiotomies involved damage to the bulbospongiosus muscle (BSM), but not always to the superficial transverse perineal muscle (STPM). In case of second-degree trauma or episiotomy, the odds of pain at 10 days and dyspareunia at 6 months postpartum were four- and five-fold greater, respectively, than if the perineum had remained intact or suffered a first-degree perineal trauma [OR 4.4 (95% CI: 2.8-6.9) and OR 5.5 (95% CI: 2.8-10.9), respectively]. When comparing injuries where > 50% BSM ± STPM against those with < 50% BSM torn, pain was significantly higher at 10 days postpartum [OR 1.9 (95% CI: 1.1-3.6], with no difference at 7 weeks, while dyspareunia was significantly higher at 6 months postpartum [OR 3.3 (95% CI: 1.4-7.8)]. There was no difference in perineal pain or dyspareunia when comparing first-degree with < 50% BSM traumas. CONCLUSION: When perineal muscle trauma encompasses > 50% BSM ± STPM, perineal pain and dyspareunia persisted until 10 days and 6 months postpartum, respectively.

Incidence of perineal pain and dyspareunia following spontaneous vaginal birth: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Perineal pain and dyspareunia are experienced by women undergoing a vaginal birth that can have short and longer term physical and psychological morbidities. This review aimed to determine the incidence of perineal pain and dyspareunia following spontaneous vaginal birth (SVB) with intact perineum, first and second-degree perineal trauma or episiotomy. METHODS: Searches of MEDLINE, EMBASE, CINAHL, AMED and MIDIRS (inception - December 2017) were undertaken with selection criteria of any study evaluating the effect of intact perineum, first- or second-degree perineal trauma on perineal pain or dyspareunia in women with SVB. RESULTS: Eighteen studies (8 RCTs and 10 NRSs) were included. Fourteen and 12 studies were undertaken to assess perineal pain and dyspareunia after SVB, respectively. Meta-analysis of 16 studies (3133 women) demonstrated that women at 2 days postpartum experienced nearly the same incidence of perineal pain whether perineal trauma existed or not. At 4-10 days postpartum there was a significant reduction in the incidence of perineal pain for both presence and absence of any perineal trauma. Episiotomy was associated with the highest rate of perineal pain. The incidence of dyspareunia was high at resumption of sexual intercourse following SVB with an intact perineum. At 12 months, women still experienced dyspareunia whether perineal trauma existed or not. CONCLUSIONS: Women experience perineal pain and dyspareunia regardless of the presence or absence of perineal trauma after SVB; nonetheless, the reported incidence is higher if perineal trauma occurred.

Linking social motivation with social skill: The role of emotion dysregulation in autism spectrum disorder.

Autism spectrum disorder (ASD) is associated with pervasive social deficits as well as marked emotion dysregulation across the life span. Decreased social motivation accounts in part for social difficulties, but factors moderating its influence are not fully understood. In this paper, we (a) characterize social and emotional functioning among children and adolescents with ASD, (b) explore contributions of social motivation and emotion dysregulation to social skill, and (c) consider biological sex and intellectual functioning as moderators of these associations. In a sample of 2,079 children and adolescents with ASD from the Simons Simplex Collection, we document direct effects of social motivation, internalizing symptoms, aggression, attention problems, irritability, and self-injurious behavior on children's social skills. Furthermore, dysregulation in several domains moderated the association between social motivation and social skill, suggesting a blunting effect on social motivation in the context of emotional difficulties. Moreover, when considering only individuals with intellectual skills in the average range or higher, biological sex further moderated these associations. Findings add to our understanding of social-emotional processes in ASD, suggest emotion dysregulation as a target of intervention in the service of social skill improvements, and build on efforts to understand sources of individual difference that contribute to heterogeneity among individuals with ASD.

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.

Validation of a Measure of Foster Home Integration for Foster Youth.

OBJECTIVES: This article introduces a youth-reported measure (Essential Youth Experiences [EYE]) developed to assess the experiences of foster youth in their home environment and their critical relationships across a number of service systems. Empirically, the article reports on the psychometric properties of a 9-item scale within the EYE that measures the construct of positive home integration (PHI). METHODS: The EYE was administered to 328 preadolescent and adolescent youth (164 sibling dyads) enrolled in a larger randomized clinical trial. RESULTS: Correlational analysis suggests that the PHI Scale shows good psychometric properties and strong current and predictive validity. CONCLUSION: The PHI is a reliable and valid scale that measures youth perspectives of inclusion in the foster home and relationships with their foster care provider. This scale quickly gathers youth perspectives and differentiates between youth who have more versus less significant needs. Implications for research and social work practice are discussed.

Infant social attention: an endophenotype of ASD-related traits?

BACKGROUND: As a neurodevelopmental disorder, symptoms of ASD likely emerge from a complex interaction between preexisting genetic vulnerabilities and the child's environment. One way to understand causal paths to ASD is to identify dimensional ASD-related traits that vary in the general population and that predispose individuals with other risk factors toward ASD. Moving beyond behavioral traits to explore underlying neurocognitive processes may further constrain the underlying genetics. Endophenotypes are quantitative, heritable, trait-related differences that are generally assessed with laboratory-based methods, can be identified in the general population, and may be more closely tied to particular causal chains that have a more restricted set of genetic roots. The most fruitful endophenotypes may be those observed in infancy, prior to the emergence of behavioral symptoms that they are hypothesized to cause. Social motivation is an ASD-related trait that is highly heritable. In this study, we investigate whether infant endophenotypes of social attention relate to familial risk for lower social motivation in the general population. METHODS: We examined whether infant social attention (measured using habituation, EEG power, and event-related potential tasks previously used in infants/toddlers with ASD) varies quantitatively with parental social motivation in 117 six-month-old and 106 twelve-month-old typically developing infants assessed cross-sectionally. To assess heritable aspects of social motivation, primary caregiver biological parents completed two self-report measures of social avoidance and discomfort that have shown high heritability in previous work. RESULTS: Parents with higher social discomfort and avoidance had infants who showed shorter looks to faces but not objects; reduced theta power during naturalistic social attention; and smaller P400 responses to faces versus objects. CONCLUSIONS: Early reductions in social attention are continuously related to lower parental social motivation. Alterations in social attention may be infant endophenotypes of social motivation traits related to ASD.