Atypical Pupillary Light Reflex and Heart Rate Variability in Children with Autism Spectrum Disorder

We investigated pupillary light reflex (PLR) in 152 children with ASD, 116 typically developing (TD) children, and 36 children with non-ASD neurodevelopmental disorders (NDDs). Heart rate variability (HRV) was measured simultaneously to study potential impairments in the autonomic nervous system (ANS) associated with ASD. The results showed that the ASD group had significantly longer PLR latency, reduced relative constriction amplitude, and shorter constriction/redilation time than those of the TD group. Similar atypical PLR parameters were observed in the NDD group. A significant age effect on PLR latency was observed in children younger than 9 years in the TD group, but not in the ASD and NDD groups. Atypical HRV parameters were observed in the ASD and NDD groups. A significant negative correlation existed between the PLR constriction amplitude and average heart rate in children with an ASD, but not in children with typical development.     

Abnormal Transient Pupillary Light Reflex in Individuals with Autism Spectrum Disorders

Computerized binocular infrared pupillography was used to measure the transient pupillary light reflex (PLR) in both children with autism spectrum disorders (ASDs) and children with typical development. We found that participants with ASDs showed significantly longer PLR latency, smaller constriction amplitude and lower constriction velocity than children with typical development. The PLR latency alone can be used to discriminate the ASD group from the control group with a cross-validated success rate of 89.6%. By adding the constriction amplitude, the percentage of correct classification can be further improved to 92.5%. In addition, the right-lateralization of contraction anisocoria that was observed in participants with typical development was not observed in those with ASDs. Further studies are necessary to understand the origin and implications of these observations. It is anticipated that as potential biomarkers, these pupillary light reflex measurements will advance our understanding of neurodevelopmental differences in the autism brain.     

Atypical autonomic nervous system complexity accompanies social cognition task performance in ASD

BackgroundEmerging evidence suggests that autonomic nervous system (ANS) function is affected in ASD. Existing literature has focused on quantifying the activity of ANS components (i.e. sympathetic/parasympathetic systems) individually. To this end, measures such as respiratory sinus arrhythmia (RSA) and high- and low-frequency spectral components of heart rate variability have been employed. Recent findings indicate that these methods employ assumptions that do not fully consider the complexity of the ANS system and the interaction of its components. To this end, we propose a new method for examining ANS function in ASD.MethodsA sample of typically developing (TD) children (n = 34) and children with ASD (n = 45) performed the Reading the Mind in the Eyes Task (RMET), preceded and followed by periods of baseline movie-watching. Multiscale Entropy (MSE) was employed as a new tool to examine the complexity of the cardiac signal.ResultsSignificant group differences in MSE emerged to suggest atypicality in the regularity of the autonomic signal at short and long time scales in the ASD group during the RMET task.ConclusionsFor the RMET task, our results may suggest atypical activation of parasympathetic influences on the heart, which contributes to short-term patterns in the heartbeat signal, as well as atypicalities in the slower acting processes. Results also suggest that the coupling between the fast-acting and slow-acting influences may be atypical in ASD during the examined social cognition task.     

Computerized dynamic pupillometry as a screening tool for evaluation of autonomic activity

ObjectivesDynamic pupillometry is a simple screening tool for quantifying pupillary light reflex (PLR), to indicate autonomic nervous system (ANS) activity. Heart rate variability (HRV) is the gold standard method for assessing ANS effects on the heart. The present study aimed to compare ANS activity as measured using dynamic pupillometry (DP) with short term HRV in healthy volunteers.MethodsThe study includes 200 participants aged between 20–60 years. PLR was measured using infrared videography and categorized into different quantitative parameters that reflect ANS activity. Simultaneously, Lead II ECG was recorded for 5 min to evaluate the short term HRV of time and frequency domain parameters. The data obtained from the two methods were compared with each other to provide the relationship between PLR and HRV.ResultsStudy participants’ mean age was 36.95 ± 9.45 years. The different pupillary indices of PLR and all the HRV parameters were within the range of normative data. Several PLR indicators of the parasympathetic function include mean constriction velocity (MCV; r = 0.60, P < 0.001), absolute constriction amplitude (ACA; r = 0.57, P < 0.001) baseline pupil diameter (BPD; r = 0.44, p < 0.001), and minimum pupil diameter (MPD; r = −0.35, p < 0.001) were significantly correlated with high-frequency power (HF in normalized units) of HRV signal.ConclusionPLR variables showed a significant relationship to HRV indices. Dynamic pupillometry can be a complementary tool to HRV for evaluating ANS activity.     

Emotional prosodic change detection in autism Spectrum disorder: an electrophysiological investigation in children and adults

Background

Autism spectrum disorder (ASD) is characterized by atypical behaviors in social environments and in reaction to changing events. While this dyad of symptoms is at the core of the pathology along with atypical sensory behaviors, most studies have investigated only one dimension. A focus on the sameness dimension has shown that intolerance to change is related to an atypical pre-attentional detection of irregularity. In the present study, we addressed the same process in response to emotional change in order to evaluate the interplay between alterations of change detection and socio-emotional processing in children and adults with autism.

Methods

Brain responses to neutral and emotional prosodic deviancies (mismatch negativity (MMN) and P3a, reflecting change detection and orientation of attention toward change, respectively) were recorded in children and adults with autism and in controls. Comparison of neutral and emotional conditions allowed distinguishing between general deviancy and emotional deviancy effects. Moreover, brain responses to the same neutral and emotional stimuli were recorded when they were not deviants to evaluate the sensory processing of these vocal stimuli.

Results

In controls, change detection was modulated by prosody: in children, this was characterized by a lateralization of emotional MMN to the right hemisphere, and in adults, by an earlier MMN for emotional deviancy than for neutral deviancy. In ASD, an overall atypical change detection was observed with an earlier MMN and a larger P3a compared to controls suggesting an unusual pre-attentional orientation toward any changes in the auditory environment. Moreover, in children with autism, deviancy detection depicted reduced MMN amplitude. In addition in children with autism, contrary to adults with autism, no modulation of the MMN by prosody was present and sensory processing of both neutral and emotional vocal stimuli appeared atypical.

Conclusions

Overall, change detection remains altered in people with autism. However, differences between children and adults with ASD evidence a trend toward normalization of vocal processing and of the automatic detection of emotion deviancy with age.

     

Is there a relationship between restricted, repetitive, stereotyped behaviors and interests and abnormal sensory response in children with autism spectrum disorders?

This study examined the relation between restricted, repetitive, and stereotyped behaviors and interests (RBs) and sensory responses in a group of 70 children and adolescents diagnosed with an autism spectrum disorder (ASD). Caregivers completed the Repetitive Behavior Scale-Revised (RBS-R) and the Sensory Profile. Controlling for IQ and age, total RBS-R and Sensory Profile scores revealed significant correlations both prior to and after removing overlapping items. Examination of the co-occurrence of RBs and atypical sensory responses in this population suggests a subgroup has consistently high rates of problems in both RBs and sensory processing. In addition, this subgroup has high rates of prescribed psychoactive medications and co-morbid psychiatric diagnoses. The IQ and age of this subgroup did not differ significantly from the rest of the participants. Results are consistent with previous research describing the co-occurrence of RBs and sensory response abnormalities in the ASD population. Further investigation of the subset of individuals with ASD who have high rates of RBs and abnormal sensory responses may lead to a more comprehensive understanding of their clinical picture and improve interventions. Additionally, research with this subgroup may have significance for identifying a specific phenotype in ASD.     

Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders

A role for immune dysfunction has been suggested in autism spectrum disorders (ASD). Elevated levels of chemokines have been detected in the brain and CSF of individuals with ASD but, to date, no study has examined chemokine levels in the plasma of children with this disorder. In the current study, we determined whether there were differential profiles of chemokines in the plasma of children with ASD compared to age-matched typically developing controls and children with developmental disabilities other than ASD. Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p<0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance. Chemokines and their receptors might provide unique targets for future therapies in ASD.     

Respiratory Sinus Arrhythmia Predicts Restricted Repetitive Behavior Severity

In addition to social communication deficits, restricted repetitive behaviors (RRBs) are a key diagnostic feature of autism spectrum disorder (ASD). Dysfunction of the autonomic nervous system (ANS) in ASD has been posited as a mechanism of RRBs; however, most studies investigating ANS activity in ASD have focused on its relation to social functioning. This study used respiratory sinus arrhythmia (RSA) patterns to measure ANS functioning and analyze its relation to RRBs in children with and without an ASD diagnosis. Baseline RSA and RSA reactivity predicted RRB severity and exploratory analyses revealed these measures may be associated with RRB subgroups. These results are discussed in regards to the behavioral literature on RRBs and the benefits of finding biomarkers for these behaviors.     

Genetic variation in serotonin transporter modulates tactile hyperresponsiveness in ASD

Several lines of evidence implicate dysfunction of the serotonin (5-HT) system in autism spectrum disorder (ASD). Specifically, the serotonin transporter (5-HTT, SERT) has been scrutinized as an ASD candidate risk gene. SERT plays key roles in the development of circuits that underlie sensory function, particularly in the somatosensory system. One previous study in ASD found association of a rare, hyperfunctional SERT variant with sensory aversion, but studies of common SERT variants have never examined sensory symptoms in ASD. Using standardized caregiver assessments of sensory function in children, we evaluated patterns of sensory responsiveness in 47 children with ASD and 38 typically developing (TD) children. Study participants were genotyped for the functional SERT promoter polymorphisms, 5-HTTLPR and rs25531, to test the hypothesis that the higher expressing genotypes would be associated with hyperresponsiveness to touch, a common sensory aversion in ASD. All measures of sensory hypo- and hyperresponsiveness were increased in children with ASD, with hyporesponsive sensory patterns negatively correlated to age and hyperresponsive sensory patterns positively correlated to repetitive behavior. Strikingly, high-expressing SERT genotypes were associated with increased tactile hyperresponsiveness in the ASD group. Our findings indicate genetic variation that increases SERT function may specifically impact somatosensory processing in ASD.     

Risk Factors Associated with Self-Injurious Behaviors in Children and Adolescents with Autism Spectrum Disorders

While self-injurious behaviors (SIB) can cause significant morbidity for children with autism spectrum disorders (ASD), little is known about its associated risk factors. We assessed 7 factors that may influence self-injury in a large cohort of children with ASD: (a) atypical sensory processing; (b) impaired cognitive ability; (c) abnormal functional communication; (d) abnormal social functioning; (e) age; (f) the need for sameness; (g) rituals and compulsions. Half (52.3%, n?=?126) of the children (n?=?241, aged 2–19?years) demonstrated SIB. Abnormal sensory processing was the strongest single predictor of self-injury followed by sameness, impaired cognitive ability and social functioning. Since atypical sensory processing and sameness have a greater relative impact on SIB, treatment approaches that focus on these factors may be beneficial in reducing self-harm in children with ASD.     

Atypical Sensory behaviours in children with Tourette’s Syndrome and in children with Autism Spectrum Disorders

Certain visual disturbances make it difficult to read text and have been attributed to visual stress, also called “pattern-related visual stress”. 12 Children with ASD, 12 children with Tourette's syndrome and without ASD and 12 controls, all matched on age and non verbal ability, participated in an experiment exploring sensory behaviours and visual stress. Reading rate and accuracy were assessed with the Wilkins Rate of Reading test with and without the Intuitive Overlays. Both the children with Tourette's and the children with ASD showed a higher prevalence of atypical sensory behaviours and symptoms of visual stress than the typically developing control children. Six out of twelve children with Tourette's syndrome (50%) read more accurately and over 15% more quickly with a coloured overlay. Four of the 12 children with ASD and none of the control children read over 15% more quickly with an overlay. The findings are discussed in relation to problems in sensory modulation.     

The role of immune dysfunction in the pathophysiology of autism

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD.     

Relationships Between Feeding Problems,Behavioral Characteristics and Nutritional Quality in Children with ASD

Many children with autism spectrum disorders (ASD) have co-occurring feeding problems. However, there is limited knowledge about how these feeding habits are related to other behavioral characteristics ubiqitious in ASD. In a relatively large sample of 256 children with ASD, ages 2–11, we examined the relationships between feeding and mealtime behaviors and social, communication, and cognitive levels as well repetitive and ritualistic behaviors, sensory behaviors, and externalizing and internalizing behaviors. Finally, we examined whether feeding habits were predictive of nutritional adequacy. In this sample, we found strong associations between parent reported feeding habits and (1) repetitive and ritualistic behaviors, (2) sensory features, and (3) externalizing and internalizing behavior. There was a lack of association between feeding behaviors and the social and communication deficits of ASD and cognitive levels. Increases in the degree of problematic feeding behaviors predicted decrements in nutritional adequacy.     

Relations among restricted and repetitive behaviors,anxiety and sensory features in children with autism spectrum disorders

The purpose of this study was to explore how atypical reactions to sensory stimuli contribute to the relation between restricted and repetitive behaviors and anxiety in children with autism spectrum disorders (ASD). In Study 1, factor analysis of restricted and repetitive behaviors was carried out using the Repetitive Behavior Questionnaire-2 (RBQ-2), completed by 120 parents of 2- to 17-year-olds with ASD. Two subtypes resulted: repetitive sensory and motor behaviors, and insistence on sameness, accounting for 40% of the variance. This two-factor solution was retained even when the sensory items of the RBQ-2 were removed. In Study 2, 49 of the same parents also completed the Spence Anxiety Scales and the Sensory Profile. The insistence on sameness factor was significantly associated with anxiety while the repetitive motor behaviors factor was not. The relation between anxiety and insistence on sameness was mediated by sensory avoiding and to a lesser extent by sensory sensitivity. Implications for arousal explanations of ASD and for clinical practice are discussed.     

Uniqueness of action monitoring in children with autism spectrum disorder: Response types and temporal aspects

Background: Action monitoring, the process for evaluating the appropriateness of one’s own actions, is reported to be atypical in individuals with autism spectrum disorder (ASD). Method: We examined the characteristics of action monitoring in 11 children with ASD and 12 children with typical development (TD), analyzing stimulus-locked and response-locked event-related potential components (i.e., N2; error-related negativity, ERN; and error positivity, Pe) related to execution of a flanker task. Results: We found a smaller N2 amplitude in children with ASD than in those with TD. Children with ASD also had a larger amplitude of ERN for partial error responses (electromyographic activity corresponding to the inappropriate hand side before response execution) than did children with TD. Additionally, the ERN amplitude for the partial error response was correlated with the Autistic Mannerisms of the Social Responsiveness Scale. There were no significant differences in Pe amplitudes between children with ASD and those with TD. Conclusion: The results suggest that action monitoring in children with ASD is significantly different both before and after response execution. We hypothesized that the detail-focused processing style of ASD reduces the demands of action monitoring before response execution; however, autistic mannerisms evoke excessive concern regarding trivial mistakes after response execution.     

Pupillometry and 123I-DaTSCAN imaging in Parkinson's disease: a comparison study

The purpose of this study was the evaluation of pupil light reflex (PLR) in patients with Parkinson's disease (PD) by using a modern pupillometry system and the investigation of its potential relationship with dopamine transporter imaging (DaTSCAN), which is an objective method for the evaluation of presynaptic dopaminergic system. PLR was evaluated using pupillometry in 35 patients with PD without clinical evidence of autonomic dysfunction and 44 healthy matched controls. PLR was elicited using a fully automated pupillometry system and six parameters were measured. Dopamine transporter imaging was performed using radioactive ioflupane (123)I-FP-CIT [(123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane]. A significant increase in latency and a significant decrease in amplitude, maximum constriction velocity, as well as maximum acceleration were observed in PD patients. There was no significant difference in initial radius and minimum radius values. Investigating the relationship between pupillometry parameters and (123)I-FP-CIT binding values, we correlated values from the semiquantitative analysis of radioligand uptake with pupillometry parameters, but we found no significant correlation. This study demonstrates PLR impairment in patients with PD without overt autonomic dysfunction. This impairment does not seem to correspond to the reduction of radioligand binding in the striatum as the result of presynaptic dopaminergic dysfunction, suggesting a different deterioration rate of these systems.     

Altered T cell responses in children with autism

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential etiologic role for immune dysfunction in ASD has been suggested. Dynamic adaptive cellular immune function was investigated in 66 children with a confirmed diagnosis of ASD and 73 confirmed typically developing (TD) controls 2-5 years-of-age. In vitro stimulation of peripheral blood mononuclear cells with PHA and tetanus was used to compare group-associated cellular responses. The production of GM-CSF, TNFα, and IL-13 were significantly increased whereas IL-12p40 was decreased following PHA stimulation in ASD relative to TD controls. Induced cytokine production was associated with altered behaviors in ASD children such that increased pro-inflammatory or T_H1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors. In contrast, production of GM-CSF and T_H2 cytokines were associated with better cognitive and adaptive function. Following stimulation, the frequency of CD3⁺, CD4⁺ and CD8⁺ T cells expressing activation markers CD134 and CD25 but not CD69, HLA-DR or CD137 were significantly reduced in ASD, and suggests an altered activation profile for T cells in ASD. Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder.     

The Relationship of Challenging Behaviors to Severity and Symptoms of Autism Spectrum Disorders

Challenging behaviors were assessed in 313 children, and it was demonstrated that children with autism spectrum disorders (ASD) exhibited greater levels of challenging behavior than both normally developing controls and children with psychopathology or atypical development. Next, we examined the relation between challenging behaviors and symptoms of autism in children with ASD. Severity of ASD was positively related to the number and intensity of challenging behaviors, and those with severe ASD exhibited significantly higher levels of problem behaviors than children with mild or moderate ASD. In addition, clusters of ASD symptoms were able to accurately predict endorsements of 8 of the 18 challenging behaviors assessed. Implications for the assessment and intervention of ASD and challenging behaviors are discussed.     

The Relationship Between Autistic Traits and Atypical Sensory Functioning in Neurotypical and ASD Adults: A Spectrum Approach

Sensory processing atypicalities are a common feature in Autism Spectrum Disorders (ASD) and have previously been linked to a range of behaviours in individuals with ASD and atypical neurological development. More recently research has demonstrated a relationship between autistic traits in the neurotypical (NT) population and increased levels of atypical sensory behaviours. The aim of the present study is to extend previous research by examining specific patterns across aspects of autistic traits and sensory behaviours within both ASD and NT populations. The present study recruited 580 NT adults and 42 high-functioning ASD adults with a confirmed diagnosis to investigate the relationship between specific aspects of autistic traits and sensory processing using the subscales of the autism spectrum quotient (AQ) and adult/adolescent sensory profile (AASP). Results showed a significant relationship between all subscales except for attention to detail and imagination on the AQ and provided the first evidence that the strength and pattern of this relationship is identical between NT and ASD adults. These data also provided support for the broader autism phenotype, uncovering a clear progression of sensory atypicalities in line with an increase in autistic traits, regardless of diagnostic status, which has potential implications for the spectrum approach to ASD and how sensory behaviours across the whole of the neurotypical population are conceptualised.     

Sensory Symptoms and Processing of Nonverbal Auditory and Visual Stimuli in Children with Autism Spectrum Disorder

Atypical sensory responses are common in autism spectrum disorder (ASD). While evidence suggests impaired auditory–visual integration for verbal information, findings for nonverbal stimuli are inconsistent. We tested for sensory symptoms in children with ASD (using the Adolescent/Adult Sensory Profile) and examined unisensory and bisensory processing with a nonverbal auditory–visual paradigm, for which neurotypical adults show bisensory facilitation. ASD participants reported more atypical sensory symptoms overall, most prominently in the auditory modality. On the experimental task, reduced response times for bisensory compared to unisensory trials were seen in both ASD and control groups, but neither group showed significant race model violation (evidence of intermodal integration). Findings do not support impaired bisensory processing for simple nonverbal stimuli in high-functioning children with ASD.