Utility of the Language Use Inventory in Young Children at Elevated Likelihood of Autism.

PURPOSE: The aims of this study were (a) to evaluate the convergent validity of the Language Use Inventory (LUI) with measures of autism spectrum disorder (ASD) symptoms, language, and social skills and (b) to assess discriminant validity of the LUI with measures of nonlanguage skills, including daily living skills and motor development. METHOD: This study sample included participants from a longitudinal study (n = 239) of infant siblings with elevated familial likelihood of ASD and lower familial likelihood. Assessment measures completed at 36 months included the LUI, the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), the Mullen Scales of Early Learning, and the Vineland Adaptive Behavior Scales-Second Edition. Bivariate Pearson correlations were estimated between ADOS-2 comparison scores and four language and social skills measures. Additional correlations were estimated between LUI total scores and standard scores from nonlanguage measures. A series of Fisher's Z transformations were applied to evaluate whether bivariate correlations were significantly different. RESULTS: All four language and social skill measures were moderately to strongly associated with each other and ASD symptom severity scores. The correlation between ADOS-2 comparison scores and LUI total scores was significantly stronger than ADOS-2 correlations with all other measures. CONCLUSIONS: Our findings provide support for the LUI as a feasible, pragmatic language-targeted instrument for inclusion in early developmental evaluations prompted by language concerns. Administration of the LUI may accelerate earlier referral for a comprehensive assessment of ASD symptoms. Given the high correlation with ADOS-2 scores, an LUI total score in a clinical range of concern may encourage a clinician to refer families for a full diagnostic evaluation of ASD.

Central Executive and Default Mode Networks: An Appraisal of Executive Function and Social Skill Brain-Behavior Correlates in Youth with Autism Spectrum Disorder.

Atypical connectivity patterns have been observed for individuals with autism spectrum disorders (ASD), particularly across the triple-network model. The current study investigated brain-behavior relationships in the context of social skills and executive function profiles for ASD youth. We calculated connectivity measures from diffusion tensor imaging using Bayesian estimation and probabilistic tractography. We replicated prior structural equation modeling of behavioral measures with total default mode network (DMN) connectivity to include comparisons with central executive network (CEN) connectivity and CEN-DMN connectivity. Increased within-CEN connectivity was related to metacognitive strengths. Our findings indicate behavior regulation difficulties in youth with ASD may be attributable to impaired connectivity between the CEN and DMN and social skill difficulties may be exacerbated by impaired within-DMN connectivity.

Intrinsic Structural Connectivity of the Default Mode Network and Behavioral Correlates of Executive Function and Social Skills in Youth with Autism Spectrum Disorders.

Brain connectivity of individuals with autism spectrum disorders (ASD) is heterogenous, as are the behavioral manifestations. The current study investigated brain-behavior relationships in the context of social skills and executive function profiles with data from the Autism Brain Imaging Database Exchange II. We calculated connectivity measures from diffusion tensor imaging using Bayesian estimation and probabilistic tractography. Subsequently, we performed structural equation modeling by regressing three latent factors, yielded from an exploratory factor analysis, onto total default mode network (DMN) connectivity. Both social regulation processing and self-directed cognitive processing factors moderately, negatively correlated with total DMN connectivity. Our findings indicate social regulation processing difficulties in youth with ASD may be attributable to impaired connectivity between the anterior and posterior DMN.

Predicting Language in Children with ASD Using Spontaneous Language Samples and Standardized Measures.

This longitudinal study examined the degree to which standardized measures of language and natural language samples predicted later language usage in a heterogeneous sample of children with autism spectrum disorder (ASD), and how this relationship is impacted by ASD severity and interventions. Participants with a diagnosis of ASD (N = 54, 41 males) completed standardized assessments of language and social functioning; natural language samples were transcribed from play-based interactions. Findings indicated that standardized language measures, natural language measures, and ADOS severity were each unique predictors of later lexical use. Intervention types also appeared to impact later language; in particular, participation in mainstream inclusion accounted for significant amounts of variance in children's mean length of utterance at T3.

Say that again: Quantifying patterns of production for children with autism using recurrence analysis.

The current research study characterized syntactic productivity across a range of 5-year-old children with autism and explored the degree to which this productivity was associated with standardized measures of language and autism symptomatology. Natural language samples were transcribed from play-based interactions between a clinician and participants with an autism diagnosis. Speech samples were parsed for grammatical morphemes and were used to generate measures of MLU and total number of utterances. We applied categorical recurrence quantification analysis, a technique used to quantify patterns of repetition in behaviors, to the children's noun-related and verb-related speech. Recurrence metrics captured the degree to which children repeated specific lexical/grammatical units (i.e., recurrence rate) and the degree to which children repeated combinations of lexical/grammatical units (i.e., percent determinism). Findings indicated that beyond capturing patterns shown in traditional linguistic analysis, recurrence can reveal differences in the speech productions of children with autism spectrum disorder at the lexical and grammatical levels. We also found that the degree of repeating noun-related units and grammatical units was related to MLU and ADOS Severity Score, while the degree of repeating unit combinations (e.g., saying "the big fluffy dog" or the determiner-adjective-adjective-noun construction multiple times), in general, was only related to MLU.

Explicating Child-Driven Patterns of Parent-Child Responsivity in Fragile Families: A Longitudinal Approach.

It has been well-established that development occurs in the context of a transactional framework, with bidirectional parent-child interactions influencing both proximal and distal outcomes. In particular, child vocabulary development is sensitive to parenting qualities including warmth, sensitivity, and control as well as parental stimulation including language input and access to learning enrichment activities. Similarly, these parenting qualities are influenced by and influence children's development of pro-social behaviors. Given the foundational role of both language and pro-social skills for academic achievement and the establishment of healthy relationships across the lifespan, a comprehensive understanding of the magnitude, stability, and reciprocity of such interactions across childhood has the potential to better inform early intervention and prevention practices and highlight risk and resilience factors. This study investigated the concurrent and successive transactional relationships between child pro-social behavior, child emergent language, and parenting qualities within a large, longitudinal sample. This study utilized Waves 3, 4, and 5 of the Fragile Families and Child Well Being Study (FFCWBS), corresponding to focal child age 3, 5, and 9 years, respectively. A series of Structural Equation Modeling (SEM) with full-information likelihood (FIML) estimation (n = 3,422) including child prosocial behavior, receptive vocabulary, and supportive parenting behaviors was tested and compared. Our findings indicate significant, positive associations over time between child pro-social behavior and receptive vocabulary, and parenting quality across all three stages of early child development. The steady decline in magnitude of these associations over time highlights the importance of synergistic parent-child interactions in toddlerhood as an early opportunity to propel these developmental outcomes and supportive parenting behaviors. Patterns of change in child pro-social behavior skills and parenting qualities remained positive and relatively stable, while observed growth in child receptive vocabulary skills increased in magnitude over time. Additional investigation of indirect effects specified the role of receptive vocabulary, as well as the bolstering role of prosocial behavior, in eliciting responsive parenting qualities over time.

Eye-Tracking in Infants and Young Children at Risk for Autism Spectrum Disorder: A Systematic Review of Visual Stimuli in Experimental Paradigms.

Eye-tracking represents a sensitive, direct measure of gaze allocation and goal-directed looking behaviors that correspond to visual information processing. Clear definitions and standardization of research protocols to document the utility and feasibility of these methods are warranted. This systematic review provides an account of stimuli dimensions and experimental paradigms used in eye-tracking research for young children at risk for ASD published from 2005 through 2019. This review identifies variability in eye-tracking protocols and heterogeneity of stimuli used for eye-tracking as factors that undermine the value of eye-tracking as an objective, reliable screening tool. We underscore the importance of sharing eye-tracking stimuli to enhance replicability of findings and more importantly the need to develop a bank of publicly available, validated stimuli.

Language Growth in Young Children with Autism: Interactions Between Language Production and Social Communication.

Young children with autism spectrum disorder (ASD) present with a broad range of spoken language abilities, as well as delays in precursor skills such as gesture production and joint attention skills. While standardized assessments describe language strengths, the Communication and Symbolic Behavior Scales (CSBS-DP) is a particularly robust measure as it additionally characterizes precise aspects of social communication. This study provides a unique contribution by assessing the interactional effects of CSBS-DP Social Composite performance with early language samples on later language outcomes. Our results indicate that multiple social communication elements significantly interact with early spoken language to predict later language. Our findings also highlight the transactional relationship between early spoken vocabulary and social communication skills that bolster language development growth.

Effects of L-theanine-caffeine combination on sustained attention and inhibitory control among children with ADHD: a proof-of-concept neuroimaging RCT.

We examined the acute effects of L-theanine, caffeine and their combination on sustained attention, inhibitory control and overall cognition in boys with attention deficit hyperactivity disorder (ADHD). L-Theanine (2.5 mg/kg), caffeine (2.0 mg/kg), their combination and a placebo were administered in a randomized four-way repeated-measures crossover with washout, to five boys (8-15 years) with ADHD. Functional magnetic resonance imaging (fMRI) was performed during a Go/NoGo task and a Stop-signal task ~ 1 h post-dose. NIH Cognition Toolbox was administered ~ 2 h post-dose. Treatment vs. placebo effects were examined in multi-level mixed-effects models. L-Theanine improved total cognition composite in NIH Cognition Toolbox (p = 0.040) vs. placebo. Caffeine worsened and L-theanine had a trend of worsening inhibitory control (i.e. increased Stop-signal reaction time; p = 0.031 and p = 0.053 respectively). L-Theanine-caffeine combination improved total cognition composite (p = 0.041), d-prime in the Go/NoGo task (p = 0.033) and showed a trend of improvement of inhibitory control (p = 0.080). L-Theanine-caffeine combination was associated with decreased task-related reactivity of a brain network associated with mind wandering (i.e. default mode network). L-Theanine-caffeine combination may be a potential therapeutic option for ADHD-associated impairments in sustained attention, inhibitory control and overall cognitive performance.

The risk of overweight and obesity in children with autism spectrum disorders: A systematic review and meta-analysis.

Multiple studies have suggested that autism spectrum disorders seem to increase the risk of overweight and obesity. We examined the pooled prevalence and relative risk of developing overweight or obesity among children with autism spectrum disorders in a systematic review and meta-analysis. We searched PubMed, Scopus, ProQuest, and Web of Science databases and subsequently screened the records to identify studies that reported prevalence of overweight and/or obesity in children with ASD and matched groups of neurotypical children. DerSimonian-Laird random-effects meta-analyses were performed to examine pooled prevalence and relative risk of obesity in children with autism spectrum disorders using the "meta" package in R software. Among children with autism spectrum disorders, the prevalence of obesity was 22.2%. Children with ASD had a 41.1% greater risk (P = .018) of development of obesity. Non-Caucasian race, increasing age, female sex, and living in the United States emerged as positive moderators of the association between autism spectrum disorders and prevalence of overweight or obesity. Autism spectrum disorders seem to increase the risk of childhood obesity. Increased awareness of this association may allow the implementation of early interventions to reduce obesity and prevent potential deterioration of quality-of-life in this population.

In vitro investigations of a novel wound dressing concept based on biodegradable polyurethane.

Non-healing and partially healing wounds are an important problem not only for the patient but also for the public health care system. Current treatment solutions are far from optimal regarding the chosen material properties as well as price and source. Biodegradable polyurethane (PUR) scaffolds have shown great promise for in vivo tissue engineering approaches, but accomplishment of the goal of scaffold degradation and new tissue formation developing in parallel has not been observed so far in skin wound repair. In this study, the mechanical properties and degradation behavior as well as the biocompatibility of a low-cost synthetic, pathogen-free, biocompatible and biodegradable extracellular matrix mimicking a PUR scaffold was evaluated in vitro. The novel PUR scaffolds were found to meet all the requirements for optimal scaffolds and wound dressings. These three-dimensional scaffolds are soft, highly porous, and form-stable and can be easily cut into any shape desired. All the material formulations investigated were found to be nontoxic. One formulation was able to be defined that supported both good fibroblast cell attachment and cell proliferation to colonize the scaffold. Tunable biodegradation velocity of the materials could be observed, and the results additionally indicated that calcium plays a crucial role in PUR degradation. Our results suggest that the PUR materials evaluated in this study are promising candidates for next-generation wound treatment systems and support the concept of using foam scaffolds for improved in vivo tissue engineering and regeneration.

Calsyntenins mediate TGN exit of APP in a kinesin-1-dependent manner.

Kinesin motors are required for the export of membranous cargo from the trans-Golgi network (TGN), yet information about how kinesins are recruited to forming transport intermediates is sparse. Here we show that the Kinesin-1 docking protein calsyntenin-1 localizes to the TGN in vivo and directly and specifically recruits Kinesin-1 to Golgi/TGN membranes as well as to dynamic post-Golgi carriers. Overexpression of various calsyntenin chimeras and kinesin light chain 1 (KLC1) at high levels caused the formation of aberrant membrane stacks at the endoplasmic reticulum (ER) or the Golgi, disrupted overall Golgi structure and blocked exit of calsyntenin from the TGN. Intriguingly, this blockade of calsyntenin exit strongly and selectively impeded TGN exit of amyloid precursor protein (APP). Using live cell microscopy we found that calsyntenins exit the TGN in Kinesin-1-decorated tubular structures which may serve as carriers for calsyntenin-1-mediated post-TGN transport of APP. Abrogation of this pathway via virus-mediated knockdown of calsyntenin-1 expression in primary cultured neurons caused a marked elevation of APP C-terminal fragments. Together, these results indicate a role for calsyntenin-1 in Kinesin-1-dependent TGN exit and post-Golgi transport of APP-containing organelles and further suggest that distinct intracellular routes may exhibit different capacities for proteolytic processing of APP.

Tissue inhibitor of metalloproteinase-1 modulates allergic lung inflammation in murine asthma.

Matrix metalloproteinases (MMPs) modulate development, inflammation, and repair in lungs. Tissue inhibitors of MMPs (TIMPs) interact with MMPs, controlling the intensity and nature of the response to injury. Absence of MMP-9, -2, and -8 activities is associated with altered lung inflammation during allergic sensitization. To test the hypothesis that the absence of TIMP-1 enhances allergic lung inflammation, airway hyperreactivity (AHR), and lung remodeling in asthma, we studied TIMP-1 null (TIMP-1 KO) mice and their WT controls using an ovalbumin (OVA) asthma model. TIMP-1 KO mice, compared to WT controls, developed an asthma phenotype characterized by AHR, pronounced cellular lung infiltrates, greater reduction in lung compliance, enhanced Th2 cytokine mRNA and protein expression, and altered collagen lung content associated with enhanced MMP-9 activity. Our findings support the hypothesis that TIMP-1 plays a protective role by preventing AHR and modulating inflammation, remodeling, and cytokine expression in an animal model of asthma.

EHD proteins are associated with tubular and vesicular compartments and interact with specific phospholipids.

The four Eps15 homology (EH) domain-containing proteins, EHD1-EHD4, have recently been ascribed roles in the regulation of the recycling of distinct receptor molecules and are often found associated with tubular structures. Here, we report the analysis of all four EHD proteins with regard to tissue distribution, intracellular localization and lipid binding properties. Specific antibodies reveal distinct expression profiles for the individual proteins in tissues and at intracellular locations, where they potentially interact with specific phospholipids. Moreover, EHD proteins colocalize with vesicular and tubular structures, implying roles in transport processes and cytoskeletal dynamics. Protein variants carrying mutations in the N-terminal nucleotide-binding P-loop region are no longer associated with phospholipids or membrane compartments, while deletion of the C-terminal EH domain affects targeting to tubular structures. All EHD proteins are able to bind to phospholipids, but localizations differ for each protein.