Autism spectrum disorder: neuropathology and animal models.

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

Von Economo Neuron Pathology in Familial Dysautonomia: Quantitative Assessment and Possible Implications.

Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general.

Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats.

BACKGROUND: Deletion or mutations of SHANK3 lead to Phelan-McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC). METHODS: We assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses. RESULTS: Basal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan-McDermid syndrome. LIMITATIONS: The Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats. CONCLUSIONS: We observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan-McDermid syndrome.

Digital Attention-Related Augmented-Reality Game: Significant Correlation between Student Game Performance and Validated Clinical Measures of Attention-Deficit/Hyperactivity Disorder (ADHD).

As many as half of school children with autism spectrum disorder (ASD) exhibit symptoms of attention-deficit/hyperactivity disorder (ADHD), resulting in marked negative academic, social, and behavioral outcomes. The focus of the US Food and Drug Administration (FDA) on real-world data from novel digital sources, and the emergence of Current Procedural Terminology (CPT) codes to reimburse for digital monitoring and neurobehavioral testing suggest an increasing acceptance of the role of technology in augmenting clinical care and research. Empowered Brain is an augmented reality and artificial intelligence-based social-emotional communication aid for students with ASD. In this study, student performance on Empowered Brain is correlated to validated clinical measures of ADHD. Seven high school students with a diagnosis of ASD were recruited from a public high school. All students were assessed for severity of ADHD-related symptoms via three clinical gold-standard assessments, namely the Aberrant Behavioral Checklist (ABC), Social Responsiveness Scale 2 (SRS-2), and Teacher Report Form (TRF). Students used Empowered Brain over a one-week period. We measured the correlation of student in-game performance (as measured by point- and star-based rewards) relative to the hyperactivity subscale of the ABC (ABC-H), and the ADHD-subscale of the TRF. All seven students completed the study and managed to successfully use Empowered Brain. Students received a culminative total of 32 sessions, an average of 4.6 sessions per student (range 2-8). Student in-game performance demonstrated highly significant correlation relative to ABC-H (points: p = 0.0013; stars: p = 0.0013)., and significant correlation to TRF ADHD scores (points: p = 0.012; stars: p = 0.012). No adverse effects were noted among students who used Empowered Brain. New technologies may herald novel ways of identifying and characterizing symptoms of ADHD in student populations. This study provides evidence that Empowered Brain in-game performance correlates with ADHD symptom severity in students with ASD. Larger samples are required to validate these findings, with more diverse participants that can also widen the generalizability of these findings to a broader range of brain conditions that manifest with inattention, impulsivity, and hyperactivity. Through further research, we may find that such technologies can help us to identify and longitudinally monitor such symptoms, and potentially aid in severity stratification and digital phenotyping.

Improvement of Attention-Deficit/Hyperactivity Disorder Symptoms in School-Aged Children, Adolescents, and Young Adults With Autism via a Digital Smartglasses-Based Socioemotional Coaching Aid: Short-Term, Uncontrolled Pilot Study.

BACKGROUND: People with autism spectrum disorder (ASD) commonly experience symptoms related to attention-deficit/hyperactivity disorder (ADHD), including hyperactivity, inattention, and impulsivity. One-third of ASD cases may be complicated by the presence of ADHD. Individuals with dual diagnoses face greater barriers to accessing treatment for ADHD and respond less positively to primary pharmacologic interventions. Nonpharmacologic technology-aided tools for hyperactivity and inattention in people with ASD are being developed, although research into their efficacy and safety remains limited. OBJECTIVE: The objective of this preliminary study was to describe the changes in ADHD-related symptoms in children, adolescents, and young adults with ASD immediately after use of the Empowered Brain system, a behavioral and social communication aid for ASD running on augmented reality smartglasses. METHODS: We recruited 8 children, adolescents, and young adults with ASD (male to female ratio of 7:1, mean age 15 years, range 11.7-20.5 years) through a Web-based research signup form. The baseline score on the hyperactivity subscale of the Aberrant Behavioral Checklist (ABC-H), a measure of hyperactivity, inattention, and impulsivity, determined their classification into a high ADHD-related symptom group (n=4, ABC-H≥13) and a low ADHD-related symptom group (n=4, ABC-H<13). All participants received an intervention with Empowered Brain, where they used smartglasses-based social communication and behavioral modules while interacting with their caregiver. We then calculated caregiver-reported ABC-H scores at 24 and 48 hours after the session. RESULTS: All 8 participants were able to complete the intervention session. Postintervention ABC-H scores were lower for most participants at 24 hours (n=6, 75%) and for all participants at 48 hours (n=8, 100%). At 24 hours after the session, average participant ABC-H scores decreased by 54.9% in the high ADHD symptom group and by 20% in the low ADHD symptom group. At 48 hours after the session, ABC-H scores compared with baseline decreased by 56.4% in the high ADHD symptom group and by 66.3% in the low ADHD symptom group. CONCLUSIONS: This study provides initial evidence for the possible potential of the Empowered Brain system to reduce ADHD-related symptoms, such as hyperactivity, inattention, and impulsivity, in school-aged children, adolescents, and young adults with ASD. This digital smartglasses intervention can potentially be targeted at a broader array of mental health conditions that exhibit transdiagnostic attentional and social communication deficits, including schizophrenia and bipolar disorder. Further research is required to understand the clinical importance of these observed changes and to conduct longitudinal studies on this intervention with control groups and larger sample sizes.

Safety and Lack of Negative Effects of Wearable Augmented-Reality Social Communication Aid for Children and Adults with Autism.

There is a growing interest in the use of augmented reality (AR) to assist children and adults with autism spectrum disorders (ASD); however, little investigation has been conducted into the safety of AR devices, such as smartglasses. The objective of this report was to assess the safety and potential negative effects of the Empowered Brain system, a novel AR smartglasses-based social communication aid for people with ASD. The version of the Empowered Brain in this report utilized Google Glass (Google, Mountain View, CA, USA) as its hardware platform. A sequential series of 18 children and adults, aged 4.4 to 21.5 years (mean 12.2 years), with clinically diagnosed ASD of varying severity used the system. Users and caregivers were interviewed about the perceived negative effects and design concerns. Most users were able to wear and use the Empowered Brain (n = 16/18, 89%), with most of them reporting no negative effects (n = 14/16, 87.5%). Caregivers observed no negative effects in users (n = 16/16, 100%). Most users (77.8%) and caregivers (88.9%) had no design concerns. This report found no major negative effects in using an AR smartglasses-based social communication aid across a wide age and severity range of people with ASD. Further research is needed to explore longer-term effects of using AR smartglasses in this population.

Concussion Assessment With Smartglasses: Validation Study of Balance Measurement Toward a Lightweight, Multimodal, Field-Ready Platform.

BACKGROUND: Lightweight and portable devices that objectively measure concussion-related impairments could improve injury detection and critical decision-making in contact sports and the military, where brain injuries commonly occur but remain underreported. Current standard assessments often rely heavily on subjective methods such as symptom self-reporting. Head-mounted wearables, such as smartglasses, provide an emerging platform for consideration that could deliver the range of assessments necessary to develop a rapid and objective screen for brain injury. Standing balance assessment, one parameter that may inform a concussion diagnosis, could theoretically be performed quantitatively using current off-the-shelf smartglasses with an internal accelerometer. However, the validity of balance measurement using smartglasses has not been investigated. OBJECTIVE: This study aimed to perform preliminary validation of a smartglasses-based balance accelerometer measure (BAM) compared with the well-described and characterized waist-based BAM. METHODS: Forty-two healthy individuals (26 male, 16 female; mean age 23.8 [SD 5.2] years) participated in the study. Following the BAM protocol, each subject performed 2 trials of 6 balance stances while accelerometer and gyroscope data were recorded from smartglasses (Glass Explorer Edition). Test-retest reliability and correlation were determined relative to waist-based BAM as used in the National Institutes of Health's Standing Balance Toolbox. RESULTS: Balance measurements obtained using a head-mounted wearable were highly correlated with those obtained through a waist-mounted accelerometer (Spearman rho, ρ=.85). Test-retest reliability was high (intraclass correlation coefficient, ICC2,1=0.85, 95% CI 0.81-0.88) and in good agreement with waist balance measurements (ICC2,1=0.84, 95% CI 0.80-0.88). Considering the normalized path length magnitude across all 3 axes improved interdevice correlation (ρ=.90) while maintaining test-retest reliability (ICC2,1=0.87, 95% CI 0.83-0.90). All subjects successfully completed the study, demonstrating the feasibility of using a head-mounted wearable to assess balance in a healthy population. CONCLUSIONS: Balance measurements derived from the smartglasses-based accelerometer were consistent with those obtained using a waist-mounted accelerometer. Additional research is necessary to determine to what extent smartglasses-based accelerometry measures can detect balance dysfunction associated with concussion. However, given the potential for smartglasses to perform additional concussion-related assessments in an integrated, wearable platform, continued development and validation of a smartglasses-based balance assessment is warranted. This approach could lead to a wearable platform for real-time assessment of concussion-related impairments that could be further augmented with telemedicine capabilities to integrate professional clinical guidance. Smartglasses may be superior to fully immersive virtual reality headsets for this application, given their lighter weight and reduced likelihood of potential safety concerns.

Second Version of Google Glass as a Wearable Socio-Affective Aid: Positive School Desirability, High Usability, and Theoretical Framework in a Sample of Children with Autism.

BACKGROUND: Computerized smartglasses are being developed as an assistive technology for daily activities in children and adults with autism spectrum disorder (ASD). While smartglasses may be able to help with educational and behavioral needs, their usability and acceptability in children with ASD is largely unknown. There have been reports of negative social perceptions surrounding smartglasses use in mainstream populations, a concern given that assistive technologies may already carry their own stigma. Children with ASD may also have a range of additional behavioral, developmental, and social challenges when asked to use this emerging technology in school and home settings. OBJECTIVE: The usability and acceptability of Glass Enterprise Edition (Glass), the successor to Google Glass smartglasses, were explored in children with ASD and their caregivers. METHODS: Eight children with ASD and their caregivers were recruited to attend a demonstration session with Glass smartglasses the week they were publicly released. The children had a wide range of ability, including limited speech to speaking, and represented a full range of school ages (6 to 17 years). Children and caregivers were interviewed about their experience of using the smartglasses and whether they would use them at school and home. RESULTS: All 8 children succeeded in using Glass and did not feel stressed (8/8, 100%) or experience any overwhelming sensory or emotional issues during the session (8/8, 100%). All 8 children (8/8, 100%) endorsed that they would be willing to wear and use the device in both home and school settings. Caregivers felt the experience was fun for the children (8/8, 100%), and most caregivers felt the experience was better than they had expected (6/8, 75%). CONCLUSIONS: A wide age and ability range of children with ASD used Glass immediately after it was released and found it to be usable and acceptable. Despite concerns about potential stigma or social acceptability, all of the children were prepared to use the technology in both home and school settings. Encouragingly, most caregivers noted a very positive response. There were no behavioral, developmental, or social- or stigma-related concerns during or after the session. Smartglasses may be a useful future technology for children with ASD and are readily accepted for use by children with ASD and their caregivers.

Improved Socio-Emotional and Behavioral Functioning in Students with Autism Following School-Based Smartglasses Intervention: Multi-Stage Feasibility and Controlled Efficacy Study.

Background: Students with Autism Spectrum Disorder (ASD) commonly demonstrate prominent social communication deficits, symptoms of attention-deficit/hyperactivity disorder, and chronic irritability. These challenges hinder academic progress and frequently persist despite educational, behavioral, and medical interventions. An assistive smartglasses technology may aid these individuals, especially if the technology is efficacious in ecologically-valid school settings. This study explored the feasibility and efficacy of Empowered Brain, a computerized smartglasses intervention designed as a socio-emotional behavioral aid for students with ASD. Methods: This two-part six-week study involved four school children with ASD from a public elementary school. The study incorporated an initial three-week feasibility stage followed by a three-week controlled longitudinal efficacy stage. Both stages involved the use of a twice-daily socio-emotional intervention with the smartglasses. Educators completed pre-intervention and post-intervention Aberrant Behavioral Checklist (ABC) ratings at the start of the feasibility stage, and weekly during the efficacy stage. Primary outcome measures were improvements in the ABC subscales of irritability, hyperactivity, and social withdrawal. Results: Students in both feasibility and efficacy stages demonstrated improvements (decreases) in irritability, hyperactivity, and social withdrawal compared to a baseline period and control periods, respectively. Participants in the controlled efficacy stage demonstrated decreased ABC subscale scores of 90% for irritability, 41.6% for hyperactivity, and 45.6% for social withdrawal. An intervention exposure-response improvement in irritability and hyperactivity was found during the efficacy stage. Educators rated the technology as superior or vastly superior compared to other assistive technologies. Conclusion: A substantial number of school children with ASD demonstrate chronic and impairing cognitive and behavioral challenges. This study provides evidence that Empowered Brain, a smartglasses-based socio-emotional aid for autism, is both feasible and efficacious in improving symptoms of social withdrawal, irritability, and hyperactivity in students with autism. The improvement is demonstrated as part of a longitudinal school-based intervention. Further studies involving larger samples and incorporation of randomized controlled trial methodology are underway to further elucidate the impact of this technology.

Social Communication Coaching Smartglasses: Well Tolerated in a Diverse Sample of Children and Adults With Autism.

BACKGROUND: Augmented reality (AR) smartglasses are an emerging technology that is under investigation as a social communication aid for children and adults with autism spectrum disorder (ASD) and as a research tool to aid with digital phenotyping. Tolerability of this wearable technology in people with ASD is an important area for research, especially as these individuals may experience sensory, cognitive, and attentional challenges. OBJECTIVE: The aim of this study was to assess the tolerability and usability of a novel smartglasses system that has been designed as a social communication aid for children and adults with autism (the Brain Power Autism System [BPAS]). BPAS runs on Google Glass Explorer Edition and other smartglasses, uses both AR and affective artificial intelligence, and helps users learn key social and emotional skills. METHODS: A total of 21 children and adults with ASD across a spectrum of severity used BPAS for a coaching session. The user's tolerability to the smartglasses, user being able to wear the smartglasses for 1 minute (initial tolerability threshold), and user being able to wear the smartglasses for the entire duration of the coaching session (whole session tolerability threshold) were determined through caregiver report. RESULTS: Of 21 users, 19 (91%) demonstrated tolerability on all 3 measures. Caregivers reported 21 out of 21 users (100%) as tolerating the experience, while study staff found only 19 out of 21 users managed to demonstrate initial tolerability (91%). Of the 19 users who demonstrated initial tolerability, all 19 (100%) were able to use the smartglasses for the entire session (whole session tolerability threshold). Caregivers reported that 19 out of 21 users (91%) successfully used BPAS, and users surpassed caregiver expectations in 15 of 21 cases (71%). Users who could communicate reported BPAS as being comfortable (94%). CONCLUSIONS: This preliminary report suggests that BPAS is well tolerated and usable to a diverse age- and severity-range of people with ASD. This is encouraging as these devices are being developed as assistive technologies for people with ASD. Further research should focus on improving smartglasses design and exploring their efficacy in helping with social communication in children and adults with ASD.