Qualitative and Quantitative Measures of Joint Attention Development in the First Year of Life: A Scoping Review.

Joint attention (JA) is the purposeful coordination of an individual's focus of attention with that of another and begins to develop within the first year of life. Delayed, or atypically developing, JA is an early behavioral sign of many developmental disabilities and so assessing JA in infancy can improve our understanding of trajectories of typical and atypical development. This scoping review identified the most common methods for assessing JA in the first year of life. Methods of JA were divided into qualitative and quantitative categories. Out of an identified 13,898 articles, 106 were selected after a robust search of four databases. Frequent methods used were eye tracking, electroencephalography (EEG), behavioral coding and the Early Social Communication Scale (ECSC). These methods were used to assess JA in typically and atypically developing infants in the first year of life. This study provides a comprehensive review of the past and current state of measurement of JA in the literature, the strengths and limitations of the measures used, and the next steps to consider for researchers interested in investigating JA to strengthen this field going forwards.

Early concerns in parents of infants at risk for autism.

AIM: To examine parental concerns about children at increased familial risk (i.e. high risk) of developing autism spectrum disorder (ASD) in early infancy. METHOD: ASD-related and general parental concerns were prospectively collected for 76 infants at ages 1.5, 3, 6, 9, 12, and 18 months. Outcome classification was determined at 36 months. Analyses included generalized linear mixed models and qualitative evaluation of parental concerns in relation to risk status (high vs low risk) and outcome classification within the high-risk group (atypically developing vs typically developing) over time. RESULTS: Most parents had no concerns at 1.5 (high risk 71%, low risk 87%) and 3 months (high risk 77%, low risk 86%). Beginning at 6 months, parents of high-risk infants reported more ASD-related (p<0.001) and general concerns (p=0.003) than parents of low-risk infants. Beginning at 12 months, parents of high-risk atypically developing infants reported more ASD-related concerns than parents of high-risk typically developing infants (p=0.013). INTERPRETATION: Clinicians should elicit parental concerns and provide support, as parents are worried about their high-risk infants by age 6 months. Additionally, parents' abilities to identify concerns that are suggestive of ASD by age 12 months may aid in earlier screening and intervention. What this paper adds Most parents did not report concerns during early infancy. By 6 months, parents of high-risk infants reported autism spectrum disorder (ASD)-related and general concerns. By 12 months, parents of high-risk atypically developing infants identified ASD-related concerns.

Using Wearable Sensor Technology to Measure Motion Complexity in Infants at High Familial Risk for Autism Spectrum Disorder.

BACKGROUND: Motor dysfunction has been reported as one of the first signs of atypical development in infants at high familial risk for autism spectrum disorder (ASD) (HR infants). However, studies have shown inconsistent results regarding the nature of motor dysfunction and whether it can be predictive of later ASD diagnosis. This is likely because current standardized motor assessments may not identify subtle and specific motor impairments that precede clinically observable motor dysfunction. Quantitative measures of motor development may address these limitations by providing objective evaluation of subtle motor differences in infancy. METHODS: We used Opal wearable sensors to longitudinally evaluate full day motor activity in HR infants, and develop a measure of motion complexity. We focus on complexity of motion because optimal motion complexity is crucial to normal motor development and less complex behaviors might represent repetitive motor behaviors, a core diagnostic symptom of ASD. As proof of concept, the relationship of the motion complexity measure to developmental outcomes was examined in a small set of HR infants. RESULTS: HR infants with a later diagnosis of ASD show lower motion complexity compared to those that do not. There is a stronger correlation between motion complexity and ASD outcome compared to outcomes of cognitive ability and adaptive skills. CONCLUSIONS: Objective measures of motor development are needed to identify characteristics of atypical infant motor function that are sensitive and specific markers of later ASD risk. Motion complexity could be used to track early infant motor development and to discriminate HR infants that go on to develop ASD.

Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials.

Duplication of 15q11.2-q13.1 (dup15q syndrome) is one of the most common copy number variations associated with autism spectrum disorders (ASD) and intellectual disability (ID). As with many neurogenetic conditions, accurate behavioral assessment is challenging due to the level of impairment and heterogeneity across individuals. Large-scale phenotyping studies are necessary to inform future clinical trials in this and similar ID syndromes. This study assessed developmental and behavioral characteristics in a large cohort of children with dup15q syndrome, and examined differences based on genetic subtype and epilepsy status. Participants included 62 children (2.5-18 years). Across individuals, there was a wide range of abilities. Although adaptive behavior was strongly associated with cognitive ability, adaptive abilities were higher than cognitive scores. Measures of ASD symptoms were associated with cognitive ability, while parent report of challenging behavior was not. Both genetic subtype and epilepsy were related to degree of impairment across cognitive, language, motor, and adaptive domains. Children with isodicentric duplications and epilepsy showed the greatest impairment, while children with interstitial duplications showed the least. On average, participants with epilepsy experienced seizures over 53% of their lives, and half of children with epilepsy had infantile spasms. Parents of children with isodicentric duplications reported more concerns regarding challenging behaviors. Future trials in ID syndromes should employ a flexible set of assessments, allowing each participant to receive assessments that capture their skills. Multiple sources of information should be considered, and the impact of language and cognitive ability should be taken into consideration when interpreting results.

Motor development and delay: advances in assessment of motor skills in autism spectrum disorders.

PURPOSE OF REVIEW: Motor impairments in neurodevelopmental disorders, specifically autism spectrum disorder (ASD), are prevalent and pervasive. Moreover, motor impairments may be the first sign of atypical development in ASD and likely contribute to abnormalities in social communication. However, measurement of motor function in ASD has lagged behind other behavioral phenotyping. Quantitative and neurodiagnostic measures of motor function can help identify specific motor impairments in ASD and the underlying neural mechanisms that might be implicated. These findings can serve as markers of early diagnosis, clinical stratification, and treatment targets. RECENT FINDINGS: Here, we briefly review recent studies on the importance of motor function to other developmental domains in ASD. We then highlight studies that have applied quantitative and neurodiagnostic measures to better measure motor impairments in ASD and the neural mechanisms that may contribute to these abnormalities. SUMMARY: Information from advanced quantitative and neurodiagnostic methods of motor function contribute to a better understanding of the specific and subtle motor impairments in ASD, and the relationship of motor function to language and social development. Greater utilization of these methods can assist with early diagnosis and development of targeted interventions. However, there remains a need to utilize these approaches in children with neurodevelopmental disorders across a developmental trajectory and with varying levels of cognitive function.

Amantadine: A new treatment for refractory electrical status epilepticus in sleep.

PURPOSE: Electrical status epilepticus in sleep (ESES) is an electrographic abnormality linked to language abnormalities and cognitive dysfunction and specifically associated with Landau-Kleffner syndrome (LKS), the syndrome of continuous spike and wave in slow-wave sleep (CSWS), and autistic regression with epileptiform EEG (AREE). As first-line therapies for treatment of ESES display inadequate efficacy and confer substantial risk, we set out to describe our center's experience with amantadine in the treatment of ESES. METHODS: Patients with video-EEG-confirmed ESES who received amantadine were retrospectively identified in a clinical EEG database. Spike-wave index, before and after amantadine exposure, was compared in a pairwise fashion. In an exploratory analysis, we cataloged reported changes in language functioning, cognition, and autistic features, which accompanied treatment. RESULTS: We identified 20 patients with ESES-associated syndromes. Median cumulative weighted average amantadine dosage was 2.1 mg/kg/d (interquartile range (IQR): 1.1, 4.5), and median duration of therapy was 11.5 months (IQR: 7.8, 26.6). In comparison with median baseline spike-wave index (76%), post-amantadine spike-wave index (53%) was reduced, with P = 0.01. Six (30%) patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefit. Amantadine was generally well-tolerated despite substantial dosage and duration of therapy. CONCLUSIONS: This study suggests that amantadine may be effective in the treatment of ESES-associated syndromes but warrants replication in a more rigorous study.

Objective measurement of movement variability using wearable sensors predicts ASD outcomes in infants at high likelihood for ASD and ADHD.

Early motor delays and differences are common among children with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Yet, little work has shown whether there are early atypical motor signs that differentiate these groups. Quantitative measures of movement variability hold promise for improving the identification of subtle and specific differences in motor function among infants and toddlers at high likelihood for ASD and ADHD. To this end, we created a novel quantitative measure of movement variability (movement curvature) and conducted a preliminary investigation as to whether this measure improves outcome predictions. We used a wearable triaxial accelerometer to evaluate continuous motion-based activity in infants at high and low likelihood for ASD and ADHD at 12, 18, 24, and 36 months of age. At 36 months, participants were categorized into three outcome groups: ASD (n = 19), ADHD concerns (n = 17), and a comparison group (n = 82). We examined group differences in movement curvature and whether movement curvature is predictive of a later ASD or ADHD concerns classification. We found that movement curvature was significantly lower in infants with later ASD diagnosis at 18, 24, and 36 months of age compared to infants with either ADHD concerns or those in the comparison group. Movement curvature was also a significant predictor of ASD at 18, 24, and 36 months (AUC 0.66-0.71; p = 0.005-0.039) and when adjusting for high ASD likelihood at 18 and 24 months (AUC 0.90, p = 0.05-0.019). These results indicate that lower movement curvature may be a feature of early motor differences in infants with later ASD diagnosis as early as 18 months of age.

Slower pace in early walking onset is related to communication, motor skills, and adaptive function in autistic toddlers.

The onset of walking is a major developmental milestone in early childhood and is critical to the development of language and social communication. Delays in walking have been described in individuals with ASD. Yet, less is known about the quality of early gait development in toddlers with ASD and the relationship to motor skills, social communication, and language. Quantitative measures of locomotion can improve our ability to evaluate subtle and specific motor differences in toddlers with ASD and their relationship to other developmental domains. We used quantitative gait analysis to evaluate locomotion in toddlers with ASD (n = 51) and compared these data to a reference chronological aged (CA) and mental aged (MA) matched typically developing (TD) cohort (n = 45). We also examined the relationship of quantitative gait metrics to developmental measures among toddlers with ASD. We found that although toddlers with ASD achieved a typical age range of walking onset, they exhibited a pattern of slower pace compared to the TD cohort when matched by CA and MA. We also found that slower measures of pace were associated with lower developmental scores of communication, motor skills, and adaptive function. Our findings improve characterization of locomotion in toddlers with ASD and the relationship of motor skills to other developmental domains.

A novel dance intervention program for children and adolescents with developmental disabilities: a pilot randomized control trial.

BACKGROUND: Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills. METHODS: The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept. RESULTS: We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance. CONCLUSIONS: Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 - Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

Examining the neurodevelopmental and motor phenotypes of Bohring-Opitz syndrome (ASXL1) and Bainbridge-Ropers syndrome (ASXL3).

Background: Chromatin Modifying Disorders (CMD) have emerged as one of the most rapidly expanding genetic disorders associated with autism spectrum disorders (ASD). Motor impairments are also prevalent in CMD and may play a role in the neurodevelopmental phenotype. Evidence indicates that neurodevelopmental outcomes in CMD may be treatable postnatally; thus deep phenotyping of these conditions can improve clinical screening while improving the development of treatment targets for pharmacology and for clinical trials. Here, we present developmental phenotyping data on individuals with Bohring-Optiz Syndrome (BOS - ASXL1) and Bainbridge-Ropers Syndrome (BRS - ASXL3) related disorders, two CMDs highly penetrant for motor and developmental delays. Objectives: To phenotype the motor and neurodevelopmental profile of individuals with ASXL1 and ASXL3 related disorders (BOS and BRS). To provide a preliminary report on the association of motor impairments and ASD. Methods: Neurodevelopmental and motor phenotyping was conducted on eight individuals with pathogenic ASXL1 variants and seven individuals with pathogenic ASXL3 variants, including medical and developmental background intake, movement and development questionnaires, neurological examination, and quantitative gait analysis. Results: Average age of first developmental concerns was 4 months for individuals with BOS and 9 months in BRS. 100% of individuals who underwent the development questionnaire met a diagnosis of developmental coordination disorder. 71% of children with BOS and 0% of children with BRS noted movement difficulty greatly affected classroom learning. Participants with BRS and presumed diagnoses of ASD were reported to have more severe motor impairments in recreational activities compared to those without ASD. This was not the case for the individuals with BOS. Conclusion: Motor impairments are prevalent and pervasive across the ASXL disorders with and without ASD, and these impairments negatively impact engagement in school-based activities. Unique neurodevelopmental and motor findings in our data include a mixed presentation of hypo and hypertonia in individuals with BOS across a lifespan. Individuals with BRS exhibited hypotonia and greater variability in motor skills. This deep phenotyping can aid in appropriate clinical diagnosis, referral to interventions, and serve as meaningful treatment targets in clinical trials.

Updates to the Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda.

INTRODUCTION: Autistic individuals, now representing one in 36 individuals in the U.S., experience disproportionate physical health challenges relative to non-autistic individuals. The Health Resources and Services Administration's (HRSA) Autism Intervention Research Network on Physical Health (AIR-P) is an interdisciplinary, multi-center Research Network that aims to increase the health, well-being, and quality of life of autistic individuals. The current paper builds on the initial AIR-P Research Agenda (proposed in Year 1) and provides an updated vision for the Network. METHODS: Updates to the Research Agenda were made via the administration of a Qualtrics survey, and disseminated widely to all AIR-P entities, including the Research Node Leaders, Steering Committee, Autistic Researcher Review Board, and collaborating academic and non-academic entities. Network members were tasked with evaluating the Year 1 Research Agenda and proposing additional priorities. RESULTS: Within each Research Node, all Year 1 priorities were endorsed as continued priorities for research on autism and physical health. Specific topics, including co-occurring conditions and self-determination, advocacy, and decision-making, were particularly endorsed. Opportunities for exploratory studies and intervention research were identified across Research Nodes. Qualitative responses providing feedback on additional research priorities were collected. CONCLUSION: The updated AIR-P Research Agenda represents an important step toward enacting large-scale health promotion efforts for autistic individuals across the lifespan. This updated agenda builds on efforts to catalyze autism research in historically underrepresented topic areas while adopting a neurodiversity-oriented approach to health promotion.

Can a Community-Based Football Program Benefit Motor Ability in Children with Autism Spectrum Disorder? A Pilot Evaluation Considering the Role of Social Impairments.

This non-randomised pilot study evaluated the impact of a community football program on motor ability in children aged 5-12 years with autism spectrum disorder. Sixteen children were evaluated at baseline-and-post attendance in a football program for a varied number of weeks and compared to 19 children engaging in treatment-as-usual. Primary analyses indicated a statistically significant increase in total MABC-2, aiming and catching, and balance scores for the intervention group, with no changes in scores in the comparison group. There were no changes in manual dexterity across either group. At a between group level, the changes in aiming and catching scores were significantly greater for the intervention group. Further analyses highlighted the potential importance of social impairments regarding aiming and catching.

The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240).

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.

Meta-Analysis Reveals Gait Anomalies in Autism.

Gait abnormalities are frequently reported in autism. The empirical literature, however, is characterized by inconsistent findings concerning which aspects of gait are affected. We conducted a meta-analysis to summarize study findings that examined temporal and spatial (i.e., two-dimensional) gait parameters in pediatric and adult samples comprising individuals with autism and healthy controls. After searching electronic databases, a total of 18 studies were identified and included in this review. Results from the meta-analyses revealed autism is associated with a wider step width, slower walking speed, longer gait cycle, longer stance time and longer step time. Additionally, autism appears to be associated with greater intra-individual variability on measures of stride length, stride time and walking speed. Meta-regression analyses revealed cadence and gait cycle duration differences, between autism and control groups, become more pronounced with age. Overall, this review demonstrates that autism is associated with gait abnormalities. However, assessment of the methodological quality of the studies reveal, additional research is required to understand the extent that gait abnormalities are specifically linked to autism, or whether they may be secondary to other factors commonly found in this group, such as increased weight. LAY SUMMARY: It is often noted by clinicians that individuals with autism have an awkward or unusual walking style, which is also referred to as gait. In this report, we reviewed past studies that compared gait in individuals with and without autism. Our review indicates autism is associated with an abnormal gait. However, it is not yet clear whether gait abnormalities are caused by autism, or arise due to other factors such as heavier weight, which often co-occurs in this group.

Quantitative Gait Analysis in Duplication 15q Syndrome and Nonsyndromic ASD.

Motor impairments occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD) and in individuals with ASD without a genetic diagnosis (nonsyndromic ASD). In particular, abnormalities in gait in ASD have been linked to language delay, ASD severity, and likelihood of having a genetic disorder. Quantitative measures of motor function can improve our ability to evaluate motor differences in individuals with syndromic and nonsyndromic ASD with varying levels of intellectual disability and adaptive skills. To evaluate this methodology, we chose to use quantitative gait analysis to study duplication 15q syndrome (dup15q syndrome), a genetic disorder highly penetrant for motor delays, intellectual disability, and ASD. We evaluated quantitative gait variables in individuals with dup15q syndrome (n = 39) and nonsyndromic ASD (n = 21) and compared these data to a reference typically developing cohort. We found a gait pattern of slow pace, poor postural control, and large gait variability in dup15q syndrome. Our findings improve characterization of motor function in dup15q syndrome and nonsyndromic ASD. Quantitative gait analysis can be used as a translational method and can improve our identification of clinical endpoints to be used in treatment trials for these syndromes. Autism Res 2020, 13: 1102-1110. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Motor impairments, particularly abnormalities in walking, occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD). Here, using quantitative gait analysis, we find that individuals with duplication 15q syndrome have an atypical gait pattern that differentiates them from typically developing and nonsyndromic ASD individuals. Our findings improve motor characterization in dup15q syndrome and nonsyndromic ASD.

Attracting neurology's next generation: A qualitative study of specialty choice and perceptions.

OBJECTIVES: To better understand the reasons medical students select or avoid a career in neurology by using a qualitative methodology to explore these factors, with the long-term objective of attracting more graduates to the field. METHODS: In 2017, 27 medical students and 15 residents participated in 5 focus groups, and 33 fourth-year medical students participated in semistructured individual interviews. Participants were asked predefined open-ended questions about specialty choice, experiences in their basic neuroscience course and neurology clerkship, and perceptions about the field. Interviews were audio recorded and transcribed. We used a flexible coding methodology to generate themes across groups and interviews. RESULTS: Four main analytical themes emerged: (1) early and broad clinical exposure allows students to "try on" neurology and experience the variety of career options; (2) preclerkship experiences and a strong neuroscience curriculum lay the foundation for interest in the field; (3) personal interactions with neurology providers may attract or deter students from considering the specialty; and (4) persistent stereotypes about neurologists, neurology patients, and treatment options harm student perceptions of neurology. CONCLUSION: Efforts to draw more students to neurology may benefit from focusing on clinical correlations during preclerkship neuroscience courses and offering earlier and more diverse clinical experiences, including hands-on responsibilities whenever possible. Finally, optimizing student interactions with faculty and residents and reinforcing the many positive aspects of neurology are likely to favorably affect student perceptions.

Characteristics of graduating US allopathic medical students pursuing a career in neurology.

OBJECTIVES: To identify factors associated with medical students becoming neurologists because, despite the increasing burden of neurologic disorders, there is a growing neurologist shortage. METHODS: Deidentified data from the Association of American Medical Colleges Matriculating Student Questionnaire (MSQ) and Graduation Questionnaire (GQ) were obtained for the graduation years 2013 to 2014 through 2016 to 2017. Logistic regression was used to assess demographic characteristics and responses to training and career-related questions in association with specialty choice (intent to enter neurology). RESULTS: Of the 51,816 students with complete data, 1,456 (2.8%) indicated an intent to enter a neurology residency. Factors associated with an increased likelihood of entering neurology were a student's rating of excellent for their basic neuroscience course and neurology clerkship, participation in an MD/PhD program, majoring in neuroscience or psychology as an undergraduate, a selection response of "content of the specialty was a strong influence on career choice," and indicating interest in neurology on the MSQ. Factors associated with a decreased likelihood of entering neurology were a higher-priority response on the GQ for salary, work/life balance, and personal fit of the specialty. CONCLUSION: Data from surveys at the entry into and graduation from medical school suggest several approaches to increase the number of medical students entering neurology, including a focus on the student-reported quality of the basic neuroscience course and neurology clerkships, targeted engagement with MD/PhD students, and mentoring programs for students interested in neurology. Efforts to improve salaries for neurologists, to reduce medical school debt, and to improve work/life balance may also help to attract more students.