Autism Spectrum Disorder in Anorexia Nervosa: An Updated Literature Review

Purpose of Review

There is growing interest in the relationship between anorexia nervosa (AN) and autism spectrum disorder (ASD). This review aimed to synthesise the most recent research on this topic to identify gaps in current knowledge, directions for future research and reflect on implications for treatment.

Recent Findings

Eight studies assessing the presence of ASD in AN were identified in the literature along with three studies examining the impact of symptoms of ASD on treatment outcome. Research with young people and using parental-report measures suggest lower rates of co-morbidity than previous adult studies.

Conclusions

The wide range of diagnostic tools, methodologies and populations studied make it difficult to determine the prevalence of ASD in AN. Despite this, studies consistently report over-representation of symptoms of ASD in AN. Co-morbid AN and ASD may require more intensive treatment or specifically tailored interventions. Future longitudinal research and female-specific diagnostic tools would help elucidate the relationship between these two disorders.

     

Intense/obsessional interests in children with gender dysphoria: a cross-validation study using the Teacher’s Report Form

Objective

This study assessed whether children clinically referred for gender dysphoria (GD) show symptoms that overlap with Autism Spectrum Disorder (ASD). Circumscribed preoccupations/intense interests and repetitive behaviors were considered as overlapping symptoms expressed in both GD and ASD.

Methods

To assess these constructs, we examined Items 9 and 66 on the Teacher’s Report Form (TRF), which measure obsessions and compulsions, respectively.

Results

For Item 9, gender-referred children (n = 386) were significantly elevated compared to the referred (n = 965) and non-referred children (n = 965) from the TRF standardization sample. For Item 66, gender-referred children were elevated in comparison to the non-referred children, but not the referred children.

Conclusions

These findings provided cross-validation of a previous study in which the same patterns were found using the Child Behavior Checklist (Vanderlaan et al. in J Sex Res 52:213–19, 2015). We discuss possible developmental pathways between GD and ASD, including a consideration of the principle of equifinality.

     

Victimisation in a French population of children and youths with autism spectrum disorder: a case control study

Background

Children and youths with autism spectrum disorder (ASD) have behavioural characteristics and severe social disabilities that make them vulnerable to victimisation. The current study explores the prevalence of peer victimisation in this population in France.

Methods

We used the Juvenile Victimization Questionnaire—Screener Sum Version in a French sample of 39 children and youths with ASD and 53 typically developing (TD) children and youths and tested the association of the victimisation with socio-demographic factors and clinical factors of anxiety and post-traumatic stress.

Results

The results indicate that 72% of the subjects with ASD had been victimised during the previous year and 94.9% during their entire lifetime. Of all students victimised at least once over the course of their lives, 75% had been victimised at school. Their peer victimisation score was significantly higher than in the TD group and was correlated to clinical factors such as a deficit in social skills and the severity of post-traumatic symptoms. Symptoms of anxiety were reported by parents of children and youths with ASD in 80% of cases.

Conclusions

Children and youths with ASD are particularly vulnerable to victimisation at school. Discussion focuses on the importance of considering the impacts and needs of school integration of this population in France in order to prevent these phenomena and their consequences.

     

Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism

Background

Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous disorder. Promising initiatives utilizing interdisciplinary characterization of ASD suggest phenotypic subtypes related to specific likely gene-disrupting mutations (LGDMs). However, the role of functionally associated LGDMs in the neural social phenotype is unknown.

Methods

In this study of 26 children with ASD (n?=?13 with an LGDM) and 13 control children, we characterized patterns of mu attenuation and habituation as children watched videos containing social and nonsocial motions during electroencephalography acquisition.

Results

Diagnostic comparisons were consistent with prior work suggesting aberrant mu attenuation in ASD within the upper mu band (10–12 Hz), but typical patterns within the lower mu band (8–10 Hz). Preliminary exploration indicated distinct social sensitization patterns (i.e., increasing mu attenuation for social motion) for children with an LGDM that is primarily expressed during embryonic development. In contrast, children with an LGDM primarily expressed post-embryonic development exhibited stable typical patterns of lower mu attenuation. Neural social indices were associated with social responsiveness, but not cognition.

Conclusions

These findings suggest unique neurophysiological profiles for certain genetic etiologies of ASD, further clarifying possible genetic functional subtypes of ASD and providing insight into mechanisms for targeted treatment approaches.

     

Neurophysiological correlates of holistic face processing in adolescents with and without autism spectrum disorder

Background

Face processing has been found to be impaired in autism spectrum disorders (ASD). One hypothesis is that individuals with ASD engage in piecemeal compared to holistic face processing strategies. To investigate the role of possible impairments in holistic face processing in individuals with autism, the current study investigated behavioral and electroencephalography (EEG) correlates of face processing (P1/N170 and gamma-band activity) in adolescents with ASD and sex-, age-, and IQ-matched neurotypical controls.

Methods

Participants were presented with upright and inverted Mooney stimuli; black and white low information faces that are only perceived as faces when processed holistically. Participants indicated behaviorally the detection of a face. EEG was collected time-locked to the presentation of the stimuli.

Results

Adolescents with ASD perceived Mooney stimuli as faces suggesting ability to use holistic processing but displayed a lower face detection rate and slower response times. ERP components suggest slowed temporal processing of Mooney stimuli in the ASD compared to control group for P1 latency but no differences between groups for P1 amplitude and at the N170. Increases in gamma-band activity was similar during the perception of the Mooney images by group, but the ASD group showed prolonged temporal elevation in activity.

Conclusion

Overall, our results suggest that adolescents with ASD were able to utilize holistic processing to perceive a face within the Mooney stimuli. Delays in early processing, marked by the P1, and elongated elevation in gamma activity indicate that the neural systems supporting holistic processing are slightly altered suggesting a less automatic and less efficient facial processing system.

Trial registration

Non-applicable.

     

Neurodevelopmental Disorders Affecting Sociability: Recent Research Advances and Future Directions in Autism Spectrum Disorder and Williams Syndrome

Purpose of Review

In this review, we summarize current knowledge and hypotheses on the nature of social abnormalities in autism spectrum disorder (ASD) and Williams syndrome (WS).

Recent Findings

Social phenotypes in ASD and WS appear to reflect analogous disruptions in social cognition, and distinct patterns of social motivation, which appears to be reduced in ASD and enhanced in WS. These abnormalities likely originate from heterogeneous vulnerabilities that disrupt the interplay between domain-general and social domain-specific cognitive and motivational processes during early development. Causal pathways remain unclear.

Summary

Advances and research gaps in our understanding of the social phenotypes in ASD and WS highlight the importance of (1) parsing the construct of sociability, (2) adopting a developmental perspective, (3) including samples that are representative of the spectrum of severity within ASD and WS in neuroscientific research, and (4) adopting transdiagnostic treatment approaches to target shared areas of impairment across diagnostic boundaries.

     

Heart rate variability during sleep in children with autism spectrum disorder

Purpose

Autonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD).

Methods

We studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD).

Results

In both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD.

Conclusion

Our findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence.

     

Verbal labels increase the salience of novel objects for preschoolers with typical development and Williams syndrome,but not in autism

Background

Early research has documented that young children show an increased interest toward objects that are verbally labeled by an adult, compared to objects that are presented without a label. It is unclear whether the same phenomenon occurs in neurodevelopmental disorders affecting social development, such as autism spectrum disorder (ASD) and Williams syndrome (WS).

Methods

The present study used a novel eye-tracking paradigm to determine whether hearing a verbal label increases the salience of novel objects in 35 preschoolers with ASD, 18 preschoolers with WS, and 20 typically developing peers.

Results

We found that typically developing children and those with WS, but not those with ASD, spent significantly more time looking at objects that are verbally labeled by an adult, compared to objects that are presented without a label.

Conclusions

In children without ASD, information accompanied by the speaker’s verbal label is accorded a “special status,” and it is more likely to be attended to. In contrast, children with ASD do not appear to attribute a special salience to labeled objects compared to non-labeled objects. This result is consistent with the notion that reduced responsivity to pedagogical cues hinders social learning in young children with ASD.

     

Anxiety Disorders and Obsessive-Compulsive Disorder in Individuals with Autism Spectrum Disorder

Purpose of Review

This review aims to synthesize the most recent research on anxiety disorders and obsessive-compulsive disorder (OCD) in individuals with autism spectrum disorder (ASD) and discuss the relationship between these conditions and challenges for assessment. Furthermore, implications for treatment and future directions are discussed.

Recent Findings

Research suggests that anxiety disorders and OCD are highly prevalent in individuals with ASD. However, the significant overlap of ASD features with anxiety and OCD symptomology makes differential diagnosis of these disorders particularly challenging. Though several treatments for anxiety have been adapted for youth with ASD (e.g., cognitive behavior therapy), pharmacological treatments and treatments for adults are still marked undeveloped.

Summary

Despite the high prevalence of anxiety disorders and OCD in ASD and some recent advances in assessment and treatment, research is needed to clarify the multifaceted relationship of these conditions and develop tailored assessment and treatment approaches appropriate for a full range of individuals with ASD.

     

Onset of bladder and motor symptoms in multiple system atrophy: differences according to phenotype

Purpose

To compare the order of presentation of bladder and motor symptoms between multiple system atrophy phenotypes.

Methods

Medical records were retrospectively reviewed in 144 patients.

Results

Bladder symptoms occurred either before or within 12 months after onset of motor symptoms in significantly more patients with the cerebellar phenotype than the parkinsonian phenotype (80 vs. 53%, p = 0.003); similar results were observed for urinary incontinence (79 vs. 45%, p = 0.001).

Conclusions

Urinary dysfunction is more likely to appear either before or shortly after motor symptoms in the cerebellar phenotype than in the parkinsonian phenotype.

     

Mindfulness Meditation for Chronic Pain: Systematic Review and Meta-analysis

Background

Chronic pain patients increasingly seek treatment through mindfulness meditation.

Purpose

This study aims to synthesize evidence on efficacy and safety of mindfulness meditation interventions for the treatment of chronic pain in adults.

Method

We conducted a systematic review on randomized controlled trials (RCTs) with meta-analyses using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Quality of evidence was assessed using the GRADE approach. Outcomes included pain, depression, quality of life, and analgesic use.

Results

Thirty-eight RCTs met inclusion criteria; seven reported on safety. We found low-quality evidence that mindfulness meditation is associated with a small decrease in pain compared with all types of controls in 30 RCTs. Statistically significant effects were also found for depression symptoms and quality of life.

Conclusions

While mindfulness meditation improves pain and depression symptoms and quality of life, additional well-designed, rigorous, and large-scale RCTs are needed to decisively provide estimates of the efficacy of mindfulness meditation for chronic pain.

     

A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees

Background

Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees.

Methods

ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale.

Results

The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent.

Conclusions

Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.

     

Neurophysiological hyperresponsivity to sensory input in autism spectrum disorders

Background

Atypical sensory processing is a common clinical observation in autism spectrum disorder (ASD). Neural hyperexcitability has been suggested as the cause for sensory hypersensitivity, a frequently reported clinical observation in ASD. We examined visual evoked responses to parametric increases in stimulus contrast in order to model neural responsivity of sensory systems in ASD.

Methods

Thirteen high-functioning individuals with ASD and 12 typically developing (TD) individuals completed a steady-state visual evoked potential study. Stimuli were vertical circular gratings oscillating at 3.76 Hz at varying contrasts (5, 10, 20,…, 90 % contrast, 10 levels). The average spectral power at the stimulus oscillation frequency was calculated for each contrast level.

Results

The magnitude of evoked sensory responses increased at a significantly greater rate and resulted in disproportionately elevated activation with higher contrasts in the ASD group. Approximately 45 % of ASD participants had rates of response increases greater than any TD participant. This alteration was highly associated with parental reports of these participants’ sensory difficulties.

Conclusions

Greater increases in visual responses over contrast manipulation suggest heightened excitability in the sensory cortex in ASD participants. Heightened neural excitability was observed in a substantial portion but not all of the ASD participants. This pattern suggests that individuals with higher excitability may constitute a neurobiologically distinct subgroup requiring individualized treatment interventions.

     

A developmental,longitudinal investigation of autism phenotypic profiles in fragile X syndrome

Background

Targeting overlapping behavioral phenotypes in neurogenetic disorders can help elucidate gene-behavior relationships. Fragile X syndrome (FXS) and autism spectrum disorder (ASD) have been studied as a model for this approach, and important areas of phenotypic overlap and divergence have been documented. However, few studies have examined how the manifestation of ASD-related phenotypes in FXS may change over development, a question which has important implications for conceptualizing shared etiologies of these disorders and their constituent phenotypes. The goal of this study was to characterize ASD phenotypes in boys and girls with FXS across development, as well as to compare individual component phenotypes among boys with FXS and boys with idiopathic ASD (ASD-O) over time.

Methods

Sixty-five boys and girls with FXS and 19 boys with ASD-O completed a battery of diagnostic, cognitive, and language assessments at two time points (mean 2.5 years apart). Nonparametric tests assessed changes in diagnostic classification in FXS over time, and hierarchical linear modeling and repeated measures assessed changes in individual ASD symptoms in FXS over time. Additionally, ANCOVAs compared ASD symptom severity and component phenotypes in boys with FXS-O, FXS-ASD, and ASD-O at both time points.

Results

Overall, ASD symptom manifestation for children with FXS significantly increased over time, and developmental predictors varied based on the domain of symptoms assessed. The greatest degree of overlap was observed between boys with FXS-ASD and ASD-O in the domain of reciprocal social communication across time points, whereas boys with ASD-O demonstrated greater impairment in restricted and repetitive behaviors at the later time point.

Conclusions

ASD symptoms increased in FXS with age, and social language impairment emerged as a potential core shared feature of FXS and ASD that may help elucidate underlying molecular genetic variation related to phenotypic variance, and aid intervention planning for subgroups of children showing distinct phenotypes. Results highlight the value of a developmental perspective, and longitudinal data in particular, in evaluating shared behavioral phenotypes across genetic conditions, lending insight into underlying cognitive, neural, and genetic mechanisms associated with key developmental phenotypes in ASD and FXS.

     

Beyond Self-Report: Performance Measures of Emotional Competencies Predict Symptoms of Depression and Anxiety,Physical Symptoms,Self-Rated Health,and Immunoregulatory Molecules

Background

Most work testing links between emotional competencies and health has focused on self-reported and/or trait assessments. However, more objective assessments of skills and knowledge may also predict health relevant outcomes.

Purpose

The current study investigated whether performance-based tests of emotional knowledge and expressive skill predicted symptoms of depression and anxiety, self-reported physical symptoms, perceived health, and a range of immunoregulatory molecules.

Methods

Eighty females aged 18–35 completed self-report assessments before attending a testing session in which they provided blood samples and completed performance-based assessments of expressive skill and emotional knowledge.

Results

Greater expressive skill predicted better self-reported outcomes, but links to immunoregulatory molecules were mixed. Expressive skill for contempt and anger predicted higher, whereas skill for happiness predicted lower, concentrations of immunoregulatory molecules.

Conclusions

These data highlight the need to extend research beyond self-reported emotional competencies and suggest that performance-based skill and knowledge metrics may be associated with health relevant outcomes.

     

The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders

Purpose of Review

There is a growing body of evidence indicating the gut microbiota influence neurodevelopment and behavior. The purposes of this review are to provide an overview of studies analyzing the microbiota and their metabolites in autism spectrum disorders (ASD) and to discuss the possible mechanisms of action involved in microbial influence on the brain and behavior.

Recent Findings

The microbiota-gut-brain (MGB) axis has been extensively studied in animal models, and it is clear that alterations in the composition of microbiota alter neurological and behavioral outcomes. However, findings in human studies are less abundant. Although there are several studies so far showing altered microbiota (dysbiosis) in ASD, the results are heterogeneous and often contradictory. Intervention studies such as fecal microbiota transplant therapies show promise and lend credence to the involvement of the microbiota in ASD.

Summary

A role for the microbiota in ASD is likely; however, further studies elucidating microbial or metabolomic signatures and mechanisms of action are needed. Future research should focus on intervention studies that can identify specific metabolites and immune mediators that improve with treatment to help identify etiologies and pathological mechanisms of ASD.

     

Development of fine motor skills is associated with expressive language outcomes in infants at high and low risk for autism spectrum disorder

Background

A growing body of research suggests that fine motor abilities are associated with skills in a variety of domains in both typical and atypical development. In this study, we investigated developmental trajectories of fine motor skills between 6 and 24 months in relation to expressive language outcomes at 36 months in infants at high and low familial risk for autism spectrum disorder (ASD).

Methods

Participants included 71 high-risk infants without ASD diagnoses, 30 high-risk infants later diagnosed with ASD, and 69 low-risk infants without ASD diagnoses. As part of a prospective, longitudinal study, fine motor skills were assessed at 6, 12, 18, and 24 months of age and expressive language outcomes at 36 months using the Mullen Scales of Early Learning. Diagnosis of ASD was determined at the infant’s last visit to the lab (18, 24, or 36 months) using the Autism Diagnostic Observation Schedule.

Results

Hierarchical linear modeling revealed that high-risk infants who later developed ASD showed significantly slower growth in fine motor skills between 6 and 24 months, compared to their typically developing peers. In contrast to group differences in growth from age 6 months, cross-sectional group differences emerged only in the second year of life. Also, fine motor skills at 6 months predicted expressive language outcomes at 3 years of age.

Conclusions

These results highlight the importance of utilizing longitudinal approaches in measuring early fine motor skills to reveal subtle group differences in infancy between ASD high-risk and low-risk infant populations and to predict their subsequent language outcomes.

     

Language delay aggregates in toddler siblings of children with autism spectrum disorder

Background

Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype.

Methods

We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample.

Results

Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n?=?235) versus LR-noASD group (n?=?115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition.

Conclusions

Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms.

     

Attention and motor deficits index non-specific background liabilities that predict autism recurrence in siblings

Background

Recent research has demonstrated that subclinical autistic traits of parents amplify the effects of deleterious mutations in the causation of autism spectrum disorder (ASD) in their offspring. Here, we examined the extent to which two neurodevelopmental traits that are non-specific to ASD—inattention/hyperactivity and motor coordination—might contribute to ASD recurrence in siblings of ASD probands.

Methods

Data from a quantitative trait study of 114 ASD probands and their brothers, 26% of whom also had ASD, were analyzed. Autistic trait severity was ascertained using the Social Responsiveness Scale-2, attention/hyperactivity problems using the Achenbach System of Empirically Based Assessment, and motor coordination (in a subset of participants) using the Developmental Coordination Disorder Questionnaire.

Results

Among siblings (affected and unaffected), both categorical recurrence of ASD (Nagelkerke R ² = 0.53) and quantitative ASD trait burden (R ² = 0.55) were predicted by sibling ADHD and motor coordination impairment scores, even though these traits, on average, were not elevated among the unaffected siblings.

Conclusions

These findings in a clinical family cohort confirm observations from general population studies that inattention/hyperactivity and motor impairment—axes of behavioral development that are non-specific to ASD, and often appreciable before ASD is typically diagnosed—jointly account for over 50% of the variation in autistic impairment of siblings, whether ascertained quantitatively or categorically. This finding within a sibling design suggests that background ASD susceptibilities that are inherited but non-specific (“BASINS”) may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as parental subclinical ASD traits and deleterious mutations) engender ASD risk.