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Mathematical algorithms known as "epigenetic clocks" use methylation values at a set of CpG sites to estimate the biological age of an individual in a tissue-specific manner. These clocks have demonstrated both acceleration and delays in epigenetic aging in multiple neuropsychiatric conditions, including schizophrenia and neurodevelopmental disorders such as autism spectrum disorder. However, no study to date has examined epigenetic aging in ADHD despite its status as one of the most prevalent neurodevelopmental conditions, with 1 in 9 children having ever received an ADHD diagnosis in the US. Only a handful of studies have examined epigenetic age in brain tissue from neurodevelopmental conditions, with none focused on ADHD, despite the obvious relevance to pathogenesis. Thus, here we asked if post-mortem brain tissue in those with lifetime histories of ADHD would show accelerated or delayed epigenetic age, as has been found for other neurodevelopmental conditions. We applied four different epigenetic clocks to estimate epigenetic age in individuals with ADHD and unaffected controls from cortical (anterior cingulate cortex, N = 55) and striatal (caudate, N = 56) post-mortem brain tissue, as well as peripheral blood (N = 84) and saliva (N = 112). After determining which epigenetic clock performed best in each tissue, we asked if ADHD was associated with altered biological aging in corticostriatal brain and peripheral tissues. We found that a range of epigenetic clocks accurately predicted chronological age in all tissues. We also found that a diagnosis of ADHD was not significantly associated with differential epigenetic aging, neither for the postmortem ACC or caudate, nor for peripheral tissues. These findings held when accounting for comorbid psychiatric diagnoses, substance use, and stimulant medication. Thus, in this study of epigenetic clocks in ADHD, we find no evidence of altered epigenetic aging in corticostriatal brain regions nor in peripheral tissue. We consider reasons for this unexpected finding, including the limited sampling of brain regions, the age range of individuals studied, and the possibility that processes that accelerate epigenetic age may be counteracted by the developmental delay posited in some models of ADHD.
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Objective: This systematic review aims to comprehensively analyze the efficacy and underlying mechanisms of vagus nerve stimulation (VNS) in enhancing cognitive functions and its therapeutic potential for various cognitive impairments. The review focuses on the impact of VNS on emotional processing, executive functions, learning, memory, and its clinical applications in conditions such as epilepsy, depression, Alzheimer's disease, and other neurological disorders. Methods: A systematic search of electronic databases (PubMed, Scopus, Web of Science) was conducted using the keywords "vagus nerve stimulation," "cognitive enhancement," "emotional processing," "executive function," "learning and memory," "epilepsy," "depression," "Alzheimer's disease," "neurological disorders," "attention-deficit/hyperactivity disorder," "sleep disorders," and "long COVID." The inclusion criteria encompassed controlled trials, longitudinal studies, and meta-analyses published in English between 2000 and July 2024. Results: A comprehensive review of 100 articles highlighted the cognitive effects of Vagus Nerve Stimulation (VNS). Studies show that VNS, especially through transcutaneous auricular VNS (taVNS), enhances emotional recognition, particularly for facial expressions, and improves selective attention under high cognitive demands. Additionally, VNS enhances learning and memory, including associative memory and spatial working memory tasks. In clinical applications, VNS exhibits promising benefits for improving cognitive functions in treatment-resistant epilepsy, depression, and Alzheimer's disease. Conclusion: VNS represents a promising therapeutic approach for enhancing cognitive function across diverse patient populations. The reviewed evidence highlights its efficacy in modulating cognitive domains in healthy individuals and improving cognition in neurological conditions. However, the comparative effectiveness of different VNS modalities and the differential effects of online versus offline VNS on cognitive psychology require further investigation. Future research should focus on optimizing VNS protocols and elucidating specific cognitive domains that benefit most from VNS interventions. This ongoing exploration is essential for maximizing the therapeutic potential of VNS in clinical practice.
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Background: Attention deficit hyperactivity disorder (ADHD) is a neurobiological disorder characterized by inattention, hyperactivity, and impulsivity. We hypothesized that chiropractic adjustments could improve these symptoms by enhancing prefrontal cortex function. This pilot study aimed to explore the feasibility and efficacy of 4 weeks of chiropractic adjustment on inattention, hyperactivity, and impulsivity in children with ADHD. Methods: 67 children with ADHD were randomly allocated to receive either chiropractic adjustments plus usual care (Chiro+UC) or sham chiropractic plus usual care (Sham+UC). The Vanderbilt ADHD Diagnostic Teacher Rating Scale (VADTRS), Swanson, Nolan and Pelham Teacher and Parents Rating Scale (SNAP-IV), and ADHD Rating Scale-IV were used to assess outcomes at baseline, 4 weeks, and 8 weeks. Feasibility measures such as recruitment, retention, blinding, safety, and adherence were recorded. Linear mixed regression models were used for data analysis. Results: 56 participants (mean age ± SD: 10.70 ± 3.93 years) were included in the analysis. Both the Chiro+UC and Sham+UC groups showed significant improvements in total and subscale ADHD scores at 4 weeks and 8 weeks. However, there were no significant differences between the two groups. Conclusion: This pilot study demonstrated that it was feasible to examine the effects of chiropractic adjustment when added to usual care on ADHD outcomes in children. While both groups showed improvements, the lack of significant between-group differences requires caution in interpretation due to the small sample size. Further research with larger samples and longer follow-up periods is needed to conclusively evaluate the effects of chiropractic adjustments on ADHD in children.
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Background: ADHD is a condition with extensively researched increased risks of psychiatric disorders, traumatic injury, impulsivity, and delayed response times. Objectives: To analyze the incidences of fractures in patients with ADHD on various medication regimens. Methods: Using the TriNetX database, we created seven patient cohorts, all of age under 25, based on medication types commonly used for ADHD. The cohorts we created were: no medication use, exclusive use of a -phenidate class stimulant, exclusive use of an amphetamine class stimulant, nonexclusive use of formations of either stimulant, exclusive use of non-stimulant medications approved for ADHD, nonexclusive use, and no medications. We then examined rates while controlling for age, sex, race, and ethnicity. Results: The comparison of ADHD to neurotypical individuals revealed an increased risk for all fracture types. For the controlled analysis, all but one cohort had significant differences in each fracture type compared to the baseline cohort of ADHD patients without any medication use. Patients in the "phenidate" cohort had an insignificant difference in risk of lower limb fractures. Patients in the "any medication," "-etamine," "stimulant," and "not ADHD" groups all had significant decreased risks for all fracture types, with confidence intervals often overlapping between treatment modalities. Conclusions: As patients experiment with different medication regimens, providers should be aware of the difference in risk of fracture by medication type. Our results highlight the need for continued research to better discern appropriate medication regimens with the goal of improving overall risk reduction and producing better outcomes for individuals with ADHD.
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Cognitive function is essential for daily activities. Acceptance and commitment therapy (ACT) may improve cognitive function by enhancing psychological flexibility, but the underlying mechanism is unknown. This systematic review evaluated the effectiveness of ACT on cognitive function. Seven research databases (PubMed, ProQuest Dissertations and Theses, Web of Science, EBSCOhost, CNKI, Scopus, Wanfang) were searched to collect articles with trials published in English and Chinese. After applying inclusion and exclusion criteria, we identified 12 studies published between 1994 and 2022 that included a combined total of 904 participants. Among the included studies were within-group (N = 3) and randomized controlled trial (RCT, N = 9) study designs. Outcome measures included cognitive scales and behavioral measurements. Of the 12 articles, 10 studies showed improvements in certain domains of cognitive function due indirectly to ACT intervention. We found that the ability of ACT intervention to promote psychological flexibility is due to its transdiagnostic nature. Also, the effects of the ACT intervention were observed in multiple cognitive domains: attention, subjective cognitive function, executive function, and memory. In conclusion, cognitive trainers could consider practicing ACT as part of their strategy to enhance an individual's psychological flexibility and cognitive function.
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Pharmacoepigenetic studies are important to understand the mechanisms through which medications influence the developing fetus. For instance, we and others have reported associations between prenatal paracetamol exposure and offspring DNA methylation (DNAm). Additionally, folic acid (FA) intake during pregnancy has been associated with DNAm in genes linked to developmental abnormalities. In this study, we aimed to: (i) expand on our previous findings showing differential DNAm associated with long-term prenatal paracetamol exposure in offspring with attention-deficit/hyperactivity disorder (ADHD), and (ii) examine if there is an interaction effect of FA and paracetamol on DNAm in children with ADHD. We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). We did not identify any impact of paracetamol or any interaction effect of paracetamol and FA on cord blood DNAm in children with ADHD. Our results contribute to the growing literature on prenatal pharmacoepigenetics, but should be replicated in other cohorts. Replication of pharmacoepigenetic studies is essential to ensure robust findings and to increase the clinical relevance of such studies.
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Objective: Distractions inordinately impair attention in children with Attention-Deficit Hyperactivity Disorder (ADHD) but examining this behavior under real-life conditions poses a challenge for researchers and clinicians. Virtual reality (VR) technologies may mitigate the limitations of traditional laboratory methods by providing a more ecologically relevant experience. The use of eye-tracking measures to assess attentional functioning in a VR context in ADHD is novel. In this proof of principle project, we evaluate the temporal dynamics of distraction via eye-tracking measures in a VR classroom setting with 20 children diagnosed with ADHD between 8 and 12 years of age. Method: We recorded continuous eye movements while participants performed math, Stroop, and continuous performance test (CPT) tasks with a series of "real-world" classroom distractors presented. We analyzed the impact of the distractors on rates of on-task performance and on-task, eye-gaze (i.e., looking at a classroom whiteboard) versus off-task eye-gaze (i.e., looking away from the whiteboard). Results: We found that while children did not always look at distractors themselves for long periods of time, the presence of a distractor disrupted on-task gaze at task-relevant whiteboard stimuli and lowered rates of task performance. This suggests that children with attention deficits may have a hard time returning to tasks once those tasks are interrupted, even if the distractor itself does not hold attention. Eye-tracking measures within the VR context can reveal rich information about attentional disruption. Conclusions: Leveraging virtual reality technology in combination with eye-tracking measures is well-suited to advance the understanding of mechanisms underlying attentional impairment in naturalistic settings. Assessment within these immersive and well-controlled simulated environments provides new options for increasing our understanding of distractibility and its potential impact on the development of interventions for children with ADHD.
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BACKGROUND: The diagnosis of Attention deficit hyperactivity disorder (ADHD) is primarily dependent on parents' and teachers' reports, while children's own perspectives on their difficulties and strengths are often overlooked. GOAL: To further increase our insight into children's ability to reliably report about their ADHD-related symptoms, the current study examined the associations between children's self-reports, parents' and teachers' reports, and standardized continuous performance test (CPT) data. We also examined whether the addition of children's perceptions of ADHD-symptoms to parents' and teachers' reports would be reflected by objective and standardized data. METHODS: The study included 190 children with ADHD, aged 7-10 years, who were referred to a pediatric neurologic clinic. A retrospective analysis was conducted using records of a clinical database. Obtained data included children's self-reports of their attention level and ADHD-related symptoms, parent, and teacher forms of the Conners ADHD rating scales, Child Behavior Checklist (CBCL), Teacher's Report Form (TRF), and CPT scores. RESULTS: Children's self-evaluations of their functioning were globally associated with their teachers' and parents' evaluations, but not uniquely. Children's self-reports of ADHD symptoms were not uniquely linked to a specific CPT impairment index, but to a general likelihood of having an impaired CPT. The CPT performance successfully distinguished between the group of children who defined themselves as inattentive and those who did not. CONCLUSION: Primary school children with ADHD are able to identify their limitations and needs difficulties and that their perspectives should inform clinical practice and research. The clinical and ethical imperative of taking children's perspectives into account during ADHD diagnosis and treatment is highlighted.
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Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset usually in childhood characterized by inattention, impulsivity, and hyperactivity causing a functional impairment. Untreated ADHD, or treatment delay is associated with adverse outcomes and poor quality of life. Although conservative management strategies such as behavioral and psychological interventions are important, pharmacological treatment has a strong evidence base with improved outcomes. ADHD medications are broadly divided into stimulant and non-stimulant medications. Stimulant medications are generally more effective than non-stimulants. Cardiovascular safety of ADHD medication has been a matter of debate for decades. Treatment guidelines advise the careful consideration of risks and benefits in people with cardiovascular diseases such as congenital heart disease or cardiomyopathy. Although stimulants can increase systemic blood pressure and heart rate, no significant associations were found between their use and serious cardiovascular events. Concerns regarding QT effects and attendant sudden cardiac death risks deter clinicians from initiating much-needed ADHD medications in patients with heart disease. This overly cautious approach is potentially depriving low-risk individuals from significant benefits associated with timely ADHD drug treatment. This review discusses the cardiovascular risks reportedly associated with ADHD medications, the evidence base for their safe usage in persons with established cardiovascular disease, and highlights future research directions.
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Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental disorder diagnosed in children. Questions regarding its increased diagnostic rates and pharmacological treatments in developing children have led to a more holistic review of the multi-system pathophysiology observed in ADHD. The dopaminergic neurotransmitter system, known for its influence on reward-motivated behaviors and motor control, and the frontostriatal systems, that mediate motor, cognition, and behavior, are associated with ADHD's development. However, studies have shown that these neural systems do not wholly account for ADHD's multilayered and heterogeneous symptom presentation. For instance, the literature suggests that emotional dysregulation, the inability to regulate one's emotional responses to provoking stimuli, is associated with increased risk for social impairment in ADHD. A broader examination of physiological systems in children with ADHD has found potential markers in the heart-brain and gut-brain axes that correspond with certain behaviors associated with emotional dysregulation in recent studies. Hence, the purpose of this meta-analysis is to aggregate ten applicable published case studies and analyze task-related heart rate reactivity (HRR; n = 5 studies) and gut microbiota (n = 5 studies) data in children with and without ADHD. Data from a total of 531 youth with ADHD and 603 youth without ADHD revealed significant small and medium effect sizes for higher Chao1 levels and Actinobacteria levels in the ADHD group, respectively, but no evidence of altered task-related HRR. Thus, further research into multi-system psychophysiological measures of emotional dysregulation and ADHD is warranted. The clinical, empirical, and educational implications of these findings are discussed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021236819).
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Transtorno do Deficit de Atenção com Hiperatividade , Microbioma Gastrointestinal , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Encéfalo , Criança , Emoções , Humanos , RecompensaRESUMO
Background: Excessive daytime sleepiness (EDS) is central in Attention deficit hyperactivity disorder (ADHD) but its causes remain unclear. The aim of this study was to explore objective EDS and homeostatic sleep pressure buildup, evaluated by power theta-alpha frequency (PTAF), in drug-free sleepy adults with ADHD and controls. Methods: Participants were placed during a 36-h period of extended wakefulness under constant routine protocol to strictly control sleep time, sleep duration, and circadian zeitgebers. Results: Eight drug-free sleepy patients with ADHD and 7 matched controls were included. The ADHD group had significantly shorter sleep latency on the Maintenance of Wakefulness Test (MWT) throughout extended wakefulness than the control group. There was no significant difference between the groups in PTAF evolution during extended wakefulness and in kinetic sleep pressure buildup, evaluated by the time constant of saturating exponential function. Limitations: The sample was small, so the findings cannot be generalized. Moreover, psychiatric comorbidities and circadian regulation should be taken into account in future studies. Conclusion: In very controlled conditions, mean sleep latency on the MWT during the whole extended wakefulness was significantly shorter in sleepy patients with ADHD than in control subjects. However, the difficulty to remain awake during soporific circumstances observed in these patients with ADHD cannot be explained by changes in the kinetic of sleep pressure buildup. Clinical Trials Registration: www.clinicaltrials.gov/, Identifier: NCT02217371.
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Objective: Cognitive and motor disintegration and other functional disturbances in various neuropsychiatric disorders may be related to inhibitory deficits that may manifest as a persistence or re-expression of primitive reflexes and few recent data suggest that these deficits may occur in Attention Deficit and Hyperactivity Disorder (ADHD). Methods: We have tested a hypothesis to which extent ADHD symptoms and balance deficits are related to persisting primitive reflexes, such as Asymmetric Tonic Neck Reflex (ATNR) and Symmetric Tonic Neck Reflex (STNR) in 80 medication-naïve children with ADHD (40 boys and 40 girls) in the school age (8-11 years) and compared these data with a control group of 60 children (30 boys and 30 girls). Results: These data show new finding that ADHD symptoms and balance deficits are strongly and specifically associated with persistent ATNR in girls and STNR in boys. Conclusions: These results provide first evidence in medical literature that ADHD in girls and boys is specifically related to distinguished neurological developmental mechanisms related to disinhibition of primitive reflexes.
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Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders. Several studies have confirmed the co-existence of other neuropsychiatric disorders with ADHD. Out of 106 individuals suspected to have ADHD, eight Saudi Arabian pediatric patients were diagnosed with ADHD using a dual assessment procedure based on highly significant scores from the international criteria for diagnosis; (full form DMS) DSM-5. Then, these patients were examined for the co-existence of autism and ADHD using different international diagnostic protocols. Four patients with combined ADHD and autism and four ADHD patients without autism were examined for the presence of genetic variants. Six variants (chr1:98165091, chr6:32029183, chr6:32035603, chr6:32064098, chr8:2909992, chr16:84213434) were identified in 75% of the patients with ADHD and autism, indicating that these genes may have a possible role in causing autism. Five variants (The chr2:116525960, chr15:68624396, chr15:91452595, chr15:92647645, and chr16:82673047) may increase to the severity of ADHD. This study recommends screening these eleven variants in ADHD cases and their relevant controls to confirm the prevalence in the Saudi population. It is recommended that future studies examine the 11 variants in detail.
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Individuals with Attention Deficit Hyperactivity Disorder (ADHD) tend to perform cognitive tasks with greater Response Time Variability (RTV). Greater RTV in ADHD may be due to inefficient functional connectivity of the brain during information processing. This study aimed to investigate the relationship between brain connectivity, RTV, and levels of ADHD symptoms. Twenty-eight children aged 9-12 years and 49 adolescents aged 15-18 years performed the Sustained Attention to Response Task (SART) while EEG was recorded. The participants' levels of ADHD symptoms were measured using self- and parent-rated questionnaires. The ex-Gaussian analysis and The Fast Fourier Transform were used to measure multiple aspects of RTV. Functional connectivity between 64 electrodes was computed during task performance, and global efficiency and modularity were calculated, reflecting integration and segregation of the brain, respectively. There was a positive association between multiple RTV measures and the level of ADHD symptoms, where participants with higher levels of ADHD symptoms showed greater RTV, except for sigma from the ex-Gaussian analysis. More efficient brain network activity, measured by global efficiency, was associated with reduced RTV. Children showed greater RTV and less efficient brain network activity compared with the adolescents. These findings support the view that stable responses are achieved with more integrated (and efficient) brain connectivity.
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Attention deficit hyperactivity disorder (ADHD) is a disorder most frequently diagnosed in children and adolescents. Although ADHD can be effectively treated with psychostimulants, a significant proportion of patients discontinue treatment because of adverse events or insufficient improvement of symptoms. In addition, cognitive abilities that are frequently impaired in ADHD are not directly targeted by medication. Therefore, additional treatment options, especially to improve cognitive abilities, are needed. Because of its relatively easy application, well-established safety, and low cost, transcranial direct current stimulation (tDCS) is a promising additional treatment option. Further research is needed to establish efficacy and to integrate this treatment into the clinical routine. In particular, limited evidence regarding the use of tDCS in children, lack of clear translational guidelines, and general challenges in conducting research with vulnerable populations pose a number of practical and ethical challenges to tDCS intervention studies. In this paper, we identify and discuss ethical issues related to research on tDCS and its potential therapeutic use for ADHD in children and adolescents. Relevant ethical issues in the tDCS research for pediatric ADHD center on safety, risk/benefit ratio, information and consent, labeling problems, and nonmedical use. Following an analysis of these issues, we developed a list of recommendations that can guide clinicians and researchers in conducting ethically sound research on tDCS in pediatric ADHD.
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OBJECTIVE: This study investigated the auditory sensory-perceptual level of specific learning disorder (SLD) and explored relationships among neuropsychological assessments for SLD, auditory processing, and short and long latencies of auditory event-related potentials (ERPs). METHODS: Fifteen children (7-14â¯years old) comprised the control group; 34 children comprised the SLD group. Audiologic assessments included tone audiometry, acoustic immittance measurements, acoustic reflex, central auditory processing, brainstem evoked response audiometry, and long latency potentials (P3 and N2). Children's intelligence levels were assessed with 2 intelligence batteries, 1 verbal and 1 non-verbal, as well as with visuomotor skills. RESULTS: Multiple regression showed a significant interaction effect of APE tests and P3/N2 over Wechsler Scale performance in freedom of distractibility indexes and multiple subtests. Errors in the Bender Visual Motor Gestalt Test were predicted by lower parental education, lower performance in APE tests: dichotic digits and pediatric/synthetic sentence identification-ipsilateral, and longer P3/N2 latencies, particularly regarding integration and rotation distortions. CONCLUSIONS: Children with altered auditory processing exhibit a specific cognitive profile, including lower verbal and spatial reasoning performance, that is sensitive to parental education level. SIGNIFICANCE: Children with SLD should undergo a complete multimodal examination to identify their specific difficulties and needs.
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High rates of attention deficit/hyperactivity disorder (ADHD) and anxiety symptoms have been documented in autism spectrum disorder (ASD), and have been associated with social and adaptive impairments. The study examined the frequency of clinically elevated ADHD and anxiety symptoms in an ASD group in comparison to a non-clinical group, compared the clinical presentation in the ASD group with and without ADHD and anxiety, assessed which child and familial variables add to the severity of Inattention, Hyperactivity/Impulsivity (HI), and anxiety symptoms, and evaluated whether having clinically elevated ADHD and/or anxiety symptoms adds to the prediction of adaptive functioning in ASD. The study included 260 participants diagnosed with ASD (mean age: 7.5 ± 1.1), using standardized tests. The rate of clinically elevated ADHD and anxiety symptoms in ASD was 62.7 and 44.6%, respectively, and symptom severity was significantly greater than the non-clinical sample. The entire population was divided into four subgroups: ASD alone, ASD+ADHD, ASD+anxiety, ASD+ADHD+anxiety, based on the parental behavioral questionnaire. The ASD alone group showed less severe autism symptoms in comparison to the other groups. Having ASD+ADHD symptoms was associated with greater impairments in socialization adaptive skills. Only the group with ASD+ADHD+anxiety was associated with poorer daily living adaptive skills. Regression analyses for prediction of ADHD and anxiety symptoms revealed that being a female and having lower adaptive skills scores predicted higher Inattention severity; being older, having better cognition, and more severe Restrictive Repetitive Behavior symptoms predicted more severe HI symptoms; being older and having more severe social impairments predicted higher anxiety scores. A regression analysis for the prediction of adaptive skills revealed that in addition to cognition and autism severity, the severity of Inattention symptoms added to the prediction of overall adaptive skills. In light of these findings, clinicians should diagnose these comorbidities in ASD early on, and provide effective interventions to reduce their negative impact on functioning, thereby improving outcome.