Mapping Comorbidities Related to Autism Spectrum Disorder from Infancy to Adolescence: A Scoping Review

Background Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental disorder in children (Polanczyk, Willcutt, Salum, Kieling, & Rohde, 2014) and is highly comorbid with Autism Spectrum Disorder (ASD) (Green et al., 2015; Kotte et al., 2013). Although it is well established that children with ADHD or ASD and their families experience poorer functioning including child and parent mental health problems, child peer problems, poorer family quality of life (FQoL) and parenting difficulties, it is unknown how comorbid ASD symptoms contribute to child and family functioning in children with ADHD. It is important to understand which comorbidities contribute to poorer child and family functioning to guide treatment planning. Aims This study aimed to examine the prevalence of ASD symptoms in children with ADHD and the association between ASD symptoms and child and family functioning across three connected studies. The specific aims of each study are outlined below. Study 1. To examine the prevalence and type of ASD symptoms (social interaction, communication and stereotyped behaviour) in children with ADHD and non-ADHD controls. Within the ADHD group only, we also examined the relationship between ADHD subtype, hyperactive/impulsive and inattentive symptoms, ADHD symptom severity and child gender and ASD symptom severity. Study 2. To examine the association between ASD symptoms and (a) social functioning; (b) mental health; (c) quality of life and (d) sleep, in children with and without ADHD. Study 3. To examine the association between ASD symptoms (measured dimensionally) in children with and without ADHD and a broad range of family functioning variables and to examine differences between ADHD+ASD, ADHD and control groups on family functioning variables. Methods Participants were 6-10 year old children (164 ADHD; 198 non-ADHD control) attending 43 schools in Melbourne, Australia, who were participating in the Children’s Attention Project. ADHD was assessed in two stages using the parent and teacher Conners’ 3 ADHD index and the Diagnostic Interview Schedule for Children IV (DISC-IV). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Child functioning measures were social functioning (Strengths and Difficulties Questionnaire (SDQ), mental health (DISC-IV, SDQ), quality of life (QoL: Pediatric Quality of Life Inventory 4.0) and sleep problem severity. Family functioning outcome variables were parent mental health, family quality of life (FQoL), and scales assessing couple conflict, couple support and parenting behaviours. Unadjusted and adjusted linear and logistic regression examined continuous and categorical outcomes, respectively. Results Study 1. Children with ADHD had more ASD symptoms than non-ADHD controls (adjusted mean difference = 4.0, 95% confidence interval (CI) 2.8; 5.3, p < 0.001, effect size = 0.7). Boys with ADHD had greater ASD symptom severity than girls with ADHD (adjusted mean difference = 2.9, 95% CI 0.8; 5.2, p = 0.01, effect size = 0.4). Greater ADHD symptom severity was associated with greater ASD symptom severity (regression co-efficient = 1.6, 95% CI 1.2; 2.0, p < 0.001). No differences were observed by ADHD subtype. Greater hyperactive/impulsive symptoms were associated with greater ASD symptoms (regression coefficient = 1.0; 95% CI 0.0; 2.0, p = 0.04) however, this finding attenuated in adjusted analyses, which accounted for parent educational attainment, socioeconomic status, child internalising and externalising comorbidities (p = 0.45). Study 2. Each standard deviation (SD) increase in SCQ scores was associated with a 6.7 unit reduction in QoL (p < 0.001) and greater parent and teacher-reported peer problems, emotional and conduct problems. For every SD increase in SCQ scores, internalising (OR = 1.8, 95% CI 1.3, 2.6, p = 0.001) and externalising disorders (OR = 1.5, 95% CI 1.1, 2.1, p = 0.02) increased, as did moderate/severe sleep problems (OR = 1.5, 95% CI 1.0, 2.2, p = 0.04). Most findings held in analyses adjusting for socio-demographic factors, ADHD symptom severity, and comorbidities (when not the outcome), with the exception of externalising disorders and sleep problems. Study 3. In unadjusted dimensional analyses, higher ASD symptoms were associated with more couple conflict (p = 0.04) and poorer FQoL for all subscales (p ≤ 0.001), with non-significant trends for less couple support (R2 = 0.10, p = 0.06), more hostile parenting (R2 = 0.02, p = 0.06) and poorer parent mental health (R2 = 0.02, p = 0.07). In adjusted dimensional analyses, higher ASD symptoms were only associated with poorer FQoL, across all subscales only (p ≤ 0.01). The trend association between ASD symptoms and parent mental health attenuated due to meaningful associations with comorbid internalising disorder (p = 0.003) and ADHD symptom severity (p = 0.05). The trend association between ASD symptoms and hostile parenting attenuated due to significant associations with comorbid externalising disorders (p = 0.002), lower parent education attainment (p = 0.03) and greater ADHD symptom severity (p = 0.04). Less couple support attenuated due to a significant association with socioeconomic status (p = 0.004). In unadjusted categorical analyses, parents of children with ADHD+ASD reported more couple conflict (p = 0.04), less couple support (p = 0.001), poorer FQoL (p <0.001) and a non-significant trend for greater mental health difficulties (p = 0.07), compared to the ADHD group. In adjusted categorical analyses, parents of children with ADHD+ASD had poorer parent self-efficacy (p = 0.02), poorer FQoL (p < 0.05) (p < 0.05) and a non-significant trend for less couple support (p = 0.06), compared to parents of children with ADHD. In unadjusted categorical analyses, family functioning was significantly poorer for the ADHD and ADHD+ASD groups, compared to controls for most outcomes (p <0.001). In adjusted categorical analyses, all findings attenuated except FQoL was significantly poorer for the ADHD and ADHD+ASD groups, compared to controls. Conclusion ASD symptoms are common, and associated with poorer functioning in children with ADHD. It is important for clinicians working with children with ADHD to identify and manage ASD symptoms, given that they exacerbate functional impairments in this already vulnerable group. The relationship between ASD symptoms and broader family functioning appears to be largely driven by internalising and externalising disorders, ADHD severity, and socioeconomic status. Poorer FQoL appears to be independently associated with ASD symptoms in children with ADHD.

Background:Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions.Methods:In a cross-sectional design, we recorded high-density sleep EEG in young people (6–20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep.Results:22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures.Conclusions:This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders.Funding:This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award ‘Defining Endophenotypes From Integrated Neurosciences’ Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG. The views and opinions expressed are those of the author(s), and not necessarily those of the NHS, the NIHR or the Department of Health funders.

Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder

Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have been related to an increased risk for behavioral addictions including online gaming. However, the relationship between these two conditions and Internet gaming disorder (IGD) is still debated. The aim of this study is to address this topic by exploring the prevalence of IGD in a consecutive sample of ASD youth and ADHD youth, compared with a normal control group, and by assessing selected psychopathological and neuropsychological features in ASD and ADHD patients with and without IGD. This study included 77 ASD patients (67 males, mean age 13.58 ± 2.75 years), 94 ADHD patients (79 males, mean age 11.46 ± 2.47 years), and 147 normal controls (NC) (mean age 13.9 ± 3.0 years, 114 males) that received structured measures for IGD (IAT, IGDS9-SF, and UADI). In the ADHD group, 72.34% of the sample were above the IGD cut-off, compared with 45.45% in the ASD group and 9.5% in the NC group. ASD patients with IGD presented with greater severity and more severe attention problems, with no difference in the ASD core symptoms between patients with and without IGD. In the comparison between the ASD and ADHD groups according to the presence of IGD, ASD patients with IGD were the most severe group according to the CGI (Clinical Global Impression) scale. The follow-up, conducted on 45 patients affected by ASD, showed an improvement in CGI and CGAS (Children's Global Assessment Scale) scores, but not in the IGD symptoms. These findings could place the diagnosis of ASD as a negative prognostic factor in the follow-up of aspects of video game addiction compared with ADHD.

Children and adolescents with autism spectrum disorder (ASD) experience various sleep problems. Sleep problems co-occur in a bidirectional relationship with ASD core symptoms and behavioral problems. However, studies on how these three factors are intricately linked to each other are limited. This meta-analysis examined the differential relationship between specific sleep problems, core symptoms, and behavioral problems in this population. This study was registered in PROSPERO (CRD42022339695). We systematically searched the PubMed/MEDLINE, Web of Science, and Scopus databases from inception to April 27, 2022. Observational studies that reported correlations between measures of sleep problems, ASD core symptoms, or ASD behavioral problems were included, and participants aged 18years or below were enrolled. The correlation coefficient (r) was assessed as the primary effect metric. Total 22 cross-sectional studies were included, which comprised 2655 participants (mean age = 6.60years old; mean percentage of boys = 80.64%). We found correlations between total sleep problems and total core symptoms (r 0.293 [95% confidence interval - 0.095 to 0.604]), total sleep problems and total behavioral problems (r 0.429 [0.299-0.544]), and total core symptoms and total behavioral problems (r - 0.050 [- 0.177 to 0.079]) and identified statistically significant correlations between specific components of sleep problems, ASD core symptoms, and ASD behavioral problems. Each specific sleep problem showed a unique association with core symptoms and behavioral problems. Sleep problems in ASD should be explored in detail, and the closely linked core symptoms and behavioral problems should be common therapeutic targets.

Sleep disorder emerges as a common comorbidity in children with autism spectrum disorder (ASD), and the interaction between the core symptoms of ASD and its sleep disorder remains unclear. Repetitive transcranial magnetic stimulation (rTMS) was used on the bilateral dorsolateral prefrontal cortex (DLPFC) to investigate the efficacy of rTMS on the core symptoms of ASD and comorbid sleep problems as well as the mediation role of the ASD symptoms between rTMS intervention and sleep improvement. A total of 41 Chinese children with ASD and who met the criteria in the fifth edition of the American Diagnostic and Statistical Manual of Mental Disorders were recruited, and 39 of them (mean age: 9.0 ± 4.4 years old; the male–female ratio was 3.9: 1) completed the study with the stimulating protocol of high frequency on the left DLPFC and low frequency on the right DLPFC. They were all assessed three times (before, at 4 weeks after, and at 8 weeks after the stimulation) by the Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), Childhood Autism Rating Scale, Repetitive Behavior Questionnaire-2, and Short Sensory Profile (SSP). The repeated-measures ANOVA showed that the main effect of “intervention time” of CSHQ (F = 25.103, P < 0.001), SSP (F = 6.345, P = 0.003), and SDQ (F = 9.975, P < 0.001) was statistically significant. By Bayesian mediation analysis, we only found that the total score of SSP mediated the treating efficacy of rTMS on CSHQ (αβ = 5.11 ± 1.51, 95% CI: 2.50–8.41). The percentage of mediation effect in total effect was 37.94%. Our results indicated the treating efficacy of rTMS modulation on bilateral DLPFC for both autistic symptoms and sleep disturbances. The sensory abnormality of ASD mediated the improvement of rTMS on sleep problems of ASD.

Background: The increase in prevalence of Autism Spectrum Disorder (ASD) has led to a corresponding surge in demand for novel, effective, and safe clinical interventions. Evidence-based treatment options for ASD are limited, resulting in a high utilization rate of complementary and alternative medicine (CAM) treatments in the ASD population. Yoga is a CAM practiced by over 20 million people in the United States, and multiple studies have investigated yoga as a possible effective treatment intervention for patients with ASD. Patients with ASD could potentially benefit from yoga either directly, through the targeting of core ASD symptoms, or indirectly through the improvement of commonly occurring co-morbid psychiatric conditions. Objective: To review the evidence for yoga as an effective treatment option for patients with ASD. Method: Using a variety of online databases, including PubMed, PsychINFO, Scopus, CINAHL, and Google Scholar, published studies meeting the authors' selection criteria were reviewed for evidence of improvement in core ASD and related symptoms in patients with ASD. Results: There is a paucity of studies published in peer-reviewed journals that met the search criteria. While each of the studies investigated the use of yoga with ASD subjects, they targeted a broad range of symptom clusters, and varied greatly in overall quality, methods, outcome measures, and results. Conclusion: Based on published studies, there is little current evidence that yoga improves core autism symptoms and co-morbid psychiatric symptoms in patients with ASD. However, there is a clear need for additional, larger randomized trials targeting both core ASD symptoms and co-morbid psychiatric conditions. Future clinical trials should utilize more uniform intervention methods, a standardized set of outcome measures, and blinded raters in order to determine whether yoga is indeed an evidence-based treatment option for patients with ASD.

Reconciling Dimensional and Categorical Models of Autism Heterogeneity: A Brain Connectomics and Behavioral Study

To review recent literature on the overlap of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), now both conditions can be dually diagnosed in the Diagnostic and Statistical Manual of Mental disorders 5th edition. There is a high comorbidity with rates of comorbid ASD and ADHD ranging from 40 to 83%. Multidisciplinary assessment and management of the combined presentation is thus required. Language difficulties are a common comorbidity in both ASD and ADHD with around 60% of children with ASD and 40% of those with ADHD having language problems. Twin studies show up to 72% of the co-variance of ADHD, and ASD symptoms can be explained by shared additive genetic factors providing a genetic basis for the observed clinical overlap. There are still many gaps in our knowledge with limited research exploring well-defined groups of children with ASD only, ADHD only and ASD with ADHD. Clinicians should thoroughly assess ADHD symptomatology in children with ASD and vice versa to understand the challenges for these children and inform treatment planning.

Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction.

BackgroundThe continuous performance task (CPT) may help identify coexistent attention deficit hyperactivity disorder (ADHD) in autism spectrum disorder (ASD). The Quantified behavior Test (QbTest) combines a CPT and motion-tracking data to assess ADHD symptoms. This study aimed to evaluate the QbTest performance of children and adolescents with ASD plus ADHD, including estimating the effects of single-dose methylphenidate (MPH). To achieve these aims, (1) the QbTest performances were evaluated in ASD alone, ASD plus ADHD, and ADHD alone, and (2) the effects on the QbTest performance of single-dose MPH before and after intake were estimated across the groups. It was assumed that the ASD plus ADHD performance, including the MPH response, would preferably resemble the performance in ADHD alone, rather than ASD alone.MethodsRetrospective data were analyzed for 482 children and adolescents: 69 with ASD alone, 142 with ASD plus ADHD (ASD/ADHD), and 271 with ADHD alone. For 343 subjects, the QbTest was performed before and up to four hours after a single-dose MPH intake. A summary index of the CPT and motion-capture data was provided for QbTest cardinal parameters.ResultsOf 12 QbTest parameters assessed before given MPH, the ASD/ADHD group had scores in line with the ASD group regarding four parameters and the ADHD group regarding nine parameters. Significant differences between groups were seen with respect to QbInattention (p > 0.05); the lowest scores in ASD and the highest in ADHD. Those with ASD/ADHD and ADHD had similar QbActivity and QbImpulsivity scores, but significantly higher than those with ASD. After MPH intake, scores for QbActivity decreased similarly in ASD/ADHD and ADHD, as well as scores for QbImpulsivity. QbImpulsivity increased in ASD. QbInattention scores decreased similarly in all groups after MPH intake.ConclusionsChildren and adolescents with ASD plus ADHD exhibited more atypical QbTest performances than those with ASD alone, while most of their performances were similar to those observed in ADHD alone. In addition, a single dose of MPH mitigated attention deficits and decreased hyperactivity while improved impulsivity in these children. Prospective studies should further clarify the role of the QbTest in the diagnostic and therapeutic interventions in ASD with ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common comorbidity in Autism Spectrum Disorder (ASD). ADHD is a risk factor for alcohol misuse whereas ASD is often regarded as protective; however, research on ASD and alcohol use has yielded conflicting findings, sometimes implicating the role of comorbid ADHD. The possibility that certain transdiagnostic features (i.e., characteristics associated with multiple disorders) may underlie relationships of both disorders to alcohol use in adults was examined in the present study. A nonclinical young adult sample of 248 alcohol users (117 men, 131 women) completed validated self-report measures of ASD and ADHD symptoms as well as the transdiagnostic features alexithymia, impulsivity, and negative moods. ASD and ADHD symptoms were normally distributed, suggesting that the respective disorders represent extreme, dysfunctional ends of population distributions of symptoms. Path analysis indicated that the significant positive association between ASD and ADHD symptom measures was fully mediated by alexithymia, impulsivity, and negative moods. Hierarchical regression and path analysis indicated that the positive relationship between ADHD symptoms and alcohol use severity was fully mediated by transdiagnostic features, particularly alexithymia and impulsivity, whereas the relationship between ASD and alcohol use severity was positively mediated by these features (especially alexithymia), with a highly significant and negative direct effect. Present findings may help reconcile previous conflicting evidence on the relationship of ASD to alcohol use, and the role of comorbid ADHD, by emphasizing the roles of alexithymia and impulsivity in both ASD and ADHD as transdiagnostic traits promoting excessive drinking.

Background: Many phenotypic studies have estimated the degree of comorbidity between Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), but few have examined the latent, or unobserved, structure of combined ASD and ADHD symptoms. This is an important perquisite toward better understanding the overlap between ASD and ADHD.Methods: We conducted a scoping review of studies that examined the factor or latent class structure of ASD and ADHD symptoms within the same clinical or general population sample.Results: Eight studies met final inclusion criteria. Four factor analysis studies found that ASD and ADHD domains loaded separately and one found that some ASD and ADHD domains loaded together. In the three latent class studies, there were evidence of profiles with high levels of co-occurring ASD and ADHD symptoms.Conclusions: Our scoping review provides some evidence of phenotypic overlap between ASD and ADHD at the latent, or unobserved, level, particularly when using a “person-centered” (latent class analysis) vs. a “variable-centered” (factor analysis) approach.

It is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5–2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5–6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core symptoms. Here, we quantified Longitudinal changes in core autism spectrum disorder symptoms of 131 children diagnosed at 1.2–5 years of age using the Autism Diagnostic Observation Schedule–Second Edition Calibrated Severity Scores over a 1-2 year period. We examined the prevalence and magnitude of Calibrated Severity Scores changes across children who were diagnosed at different ages. The results revealed that age of diagnosis was significantly correlated with poorer outcome (r(129) = 0.41, p < 0.001). Approximately 65% of the children diagnosed before 2.5 years of age exhibited improvements in Autism Diagnostic Observation Schedule–Second Edition Calibrated Severity Scores (⩾2 points) in contrast to only 23% of the children diagnosed after this age. Changes in younger children were driven by improvements in social symptoms despite deterioration in restricted and repetitive behaviors. These findings reveal that autism spectrum disorder diagnosis before the age of 2.5 is associated with considerable improvement in social symptoms. We suggest that greater brain plasticity and behavioral flexibility enable younger children to benefit more from autism spectrum disorder interventions even in community settings with heterogeneous services. This motivates further prioritization of early autism spectrum disorder screening as recommended by American Academy of Pediatrics guidelines.Lay abstractIt is widely believed that early diagnosis and treatment of autism spectrum disorder is essential for better outcome. This is demonstrated by the American Academy of Pediatrics recommendation to screen all 1.5–2.5-year-old toddlers for autism spectrum disorder. However, multiple longitudinal studies of children diagnosed with autism spectrum disorder at 1.5–6 years of age and treated in community settings have not reported any associations between earlier diagnosis and improved outcome in core autism spectrum disorder symptoms. In this study, we measured changes in core autism spectrum disorder symptoms over a 1–2-year period in 131 children diagnosed with autism spectrum disorder at 1.2–5 years of age, and treated in the community. The results revealed that children who were diagnosed before 2.5 years of age were three times more likely to exhibit considerable improvements in social autism spectrum disorder symptoms in comparison to children diagnosed at later ages. These results highlight the importance of early diagnosis and treatment of autism spectrum disorder even in community settings with heterogeneous services. In addition, these results motivate further prioritization of universal screening for autism spectrum disorder before 2.5 years of age.