A prospective study of associations between early fearfulness and perceptual sensitivity and later restricted and repetitive behaviours in infants with typical and elevated likelihood of autism

Autism is diagnosed based on social and communication difficulties, restricted and repetitive behaviours and sensory anomalies. Existing evidence indicates that anxiety and atypical sensory features are associated with restricted and repetitive behaviours, but cannot clarify the order of emergence of these traits. This study uses data from a prospective longitudinal study of infants with and without a family history of autism ( N = 247; Elevated Likelihood N = 170 and Typical Likelihood N = 77). Longitudinal cross-lag models tested bidirectional pathways between parent-rated infant fear/shyness and perceptual sensitivity at 8, 14 and 24 months, and associations between these domains and parent-rated restricted and repetitive behaviours and social communication scores at 36 months. In addition to within-domain continuity, higher levels of fear/shyness at 14 months were associated with higher levels of perceptual sensitivity at 24 months. Higher levels of both fear/shyness and perceptual sensitivity at 24 months were associated with greater restricted and repetitive behaviours and social communication scores at 36 months. Results demonstrate the directionality of developmental pathways between fear/shyness and perceptual sensitivity in infancy and toddlerhood, but question theories that argue that these domains specifically underlie restricted and repetitive behaviours rather than autism. Identifying how early emerging anxiety and sensory behaviours relate to later autism is important for understanding pathways and developing targeted support for autistic children. Lay abstract Restricted interests and repetitive behaviours are central to the diagnosis of autism and can have profound effects on daily activities and quality of life. These challenges are also linked to other co-occurring conditions such as anxiety and sensory sensitivities. Here, we looked at whether early emerging signs of anxiety and sensory problems appear before symptoms of autism by studying infants with a family history of autism, as these infants are more likely to develop autism themselves. Studying infant siblings provides an opportunity for researchers to focus on early developmental markers of autism as these infants can be followed from birth. This study found that early infant signs of anxiety (e.g. fear/shyness) predicted later perceptual sensitivity, and those infants who scored higher on fear/shyness and sensitivity were more likely to experience more persistent repetitive behaviours, but also social and communication difficulties in toddlerhood. Early signs of anxiety and perceptual sensitivity may thus relate to both later social difficulties and repetitive behaviours. These findings support the importance of further research exploring the causal links between these domains in relation to autism, resulting in increased understanding of children who go onto develop autism in the future and guiding early interventions and supports.

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/− mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/− hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/− mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy.

Repetitive and restricted behaviours and anxiety in autism spectrum disorder: protocol for a systematic review and meta-analysis

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by persistent deficits in social functioning and the presence of restricted and repetitive behaviours (RRBs). RRBs refer to four subtypes of behaviour including repetitive movements, speech, or use of objects; insistence on sameness; restricted interests; and sensory processing abnormalities. Many individuals with ASD also experience anxiety, which compounds ASD-related difficulties and inhibits daily functioning. RRBs have been found to be positively associated with anxiety; however, our understanding of the interplay between RRB subtypes and anxiety remains unclear. Thus, the current review aims to clarify the association between RRBs and anxiety by conducting a systematic review and meta-analysis. Methods To identify relevant studies, we will search five databases: CINAHL Plus, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, PsycINFO, and Scopus. Articles included in the review will have their titles, abstracts, and full texts reviewed by two independent authors and their methodological quality assessed via the modified Newcastle-Ottawa Scale. Random-effects meta-analyses will then be conducted to calculate the pooled association between RRB subtypes and anxiety. Sensitivity analyses will also be conducted to assess the potential impact of bias, missing data, outliers, and methodological differences on this relationship. Additionally, this review will collate the factors which may influence the anxiety-RRB relationship to help identify who is most vulnerable to developing anxiety. Discussion This will be the first review to examine the association between the four subtypes of RRBs and anxiety in individuals with ASD. Understanding this relationship, and the factors associated with this, may help clinicians understand the different underpinnings and presentations of anxiety within this population with potential implications for assessment and treatment. Systematic review registration PROSPERO CRD42020185434

Stimulus-Stimulus-Pairing to Reduce Stereotypes in Three Children with Autism during Movie Watching

Autism spectrum disorders represent a challenge for professionals, who must include in their individualized educational interventions goals for core symptoms (social–communication and stereotypies/restricted interests) and comorbidities. The narrowness of interests and the high frequency of repetitive behaviors in children with autism often constitute an obstacle for learning and the quality of life, and for their caregivers as well. In the scientific literature, behavioral interventions based on both aversive and, less commonly, positive procedures have been implemented to reduce the frequency of stereotypies. The following study was carried out with the intention of replicating a Stimulus-Stimulus Pairing procedure applied by Nuzzolo-Gomez, Leonard, Ortiz, Rivera and Greer (2002) in order to reduce stereotypies in children. This procedure was applied to three children diagnosed with autism aged five, almost six and seven years, in order to reduce stereotypies when children watched movies. An A-B-A experimental design with three subjects was used for this research. The results showed a decrease in stereotypies in favor of appropriate behaviors.

Complete Dental Management of an Autism and Intellectual Disability Patient under General Anaesthesia: A Case Report

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and the presence of restricted interests and repetitive behaviours. Comorbidities following ASD, such as seizure, intellectual disability, and sensory impairment worsen patients’ ability to care for themselves. We present the case of a 22-year-old man with autism, intellectual disability and visual impairment who had recurrent pain in his upper and lower left posterior teeth that had cavities. On the first visit, the patient was observed and had panoramic x-ray. Clinical examination could not be done properly due to lack of patient cooperation. Restoration, pulp capping, tooth extraction, and odontectomy were planned under general anaesthesia.

Toward better characterization of restricted and unusual interests in youth with autism

Despite their high prevalence and clinical importance in autism, unusual and restricted interests remain under-researched and poorly understood. This study aimed to characterize the frequency and type of interests in autism by coding caregivers’ open-ended responses in a sample of 237 autistic children and adolescents ( Mage = 8.27 years, SDage = 4.07; range: 2.08–18.25 years). It further aimed to explore the effects of age, sex, cognitive functioning and social and communication deficits on the number and type of interests. We found that 75% of autistic youth had at least one interest and that 50% of those children showed two or more different interests. The most frequent interests were sensory-based (43%), with a majority of these interests relating to the visual modality. Interest within vehicles/transportation, fictional characters, television/digital versatile disk/movies, computers, and video games, constructive, mechanical objects, animals and plants, and attachment to specific objects were also prevalent. Logistic regression showed that being male, having a co-occurring intellectual disability and having more severe social and communication impairments were associated with a higher probability of having one or more restricted interests. Sex was significantly associated with the type (χ2 = 37.52, Phi = 0.37, p = 0.021) of restricted interests, with females showing a significantly higher percentage of creative interests and males significantly higher percentage of interest in characters, vehicles/transportation, computers/video games, mechanical objects and constructive interests. Theoretical and measurement implications are discussed. Lay abstract Despite being highly prevalent among people with autism, restricted and unusual interests remain under-researched and poorly understood. This article confirms that restricted interests are very frequent and varied among children and adolescents with autism. It also further extends current knowledge in this area by characterizing the relationship between the presence, number, and type of restricted interests with chronological age, sex, cognitive functioning, and social and communication symptoms.

Catatonia: A Common Cause of Late Regression in Autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and restricted interests and behaviors which begin very early in life. In about a quarter of cases, the symptoms emerge about 18–24 months after a period of normal development, a phenomenon commonly described as early regression. However, marked functional decline can also occur in persons with autism after a relatively stable childhood. As opposed to early regression, which occurs in normally developing children, late regression occurs typically in adolescents with an established diagnosis of autism. Apart from their occasional mention in the literature, these individuals have not been examined systematically. This Brief Report describes the presentation, comorbidity and short-term outcome of 20 persons with ASD who developed late regression. The mean age of onset of regression was 13 years. One of the earliest symptoms was an increase in obsessive slowing and compulsive rituals. Other symptoms included motor abnormalities, aggression and mood disturbance. The most common comorbid disorder was catatonia occurring in 17 patients. Despite treatment with several modalities, the outcome was often suboptimal. These findings suggest that catatonia is a common cause of late regression in persons with autism. Clinical and research implications are discussed.

Involvement of the habenula in the pathophysiology of autism spectrum disorder

The habenula is a small epithalamic structure with widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central structure modulating the reward value of social interactions, behavioral adaptation, sensory integration and circadian rhythm. Autism spectrum disorder (ASD) is characterized by social communication deficits, restricted interests, repetitive behaviors, and is frequently associated with altered sensory perception and mood and sleep disorders. The habenula is implicated in all these behaviors and results of preclinical studies suggest a possible involvement of the habenula in the pathophysiology of this disorder. Using anatomical magnetic resonance imaging and automated segmentation we show that the habenula is significantly enlarged in ASD subjects compared to controls across the entire age range studied (6–30 years). No differences were observed between sexes. Furthermore, support-vector machine modeling classified ASD with 85% accuracy (model using habenula volume, age and sex) and 64% accuracy in cross validation. The Social Responsiveness Scale (SRS) significantly differed between groups, however, it was not related to individual habenula volume. The present study is the first to provide evidence in human subjects of an involvement of the habenula in the pathophysiology of ASD.