Deep Phenotyping to Quantify Social Deficits in Autism Spectrum Disorders (ASD)

Autism, a neurodevelopmental disorder characterized by an array of difficulties in social communication and interaction and the presence of repetitive behaviors and interests, is also marked by a striking disturbance in the hard-wired, phylogenetically preserved mechanisms of social orientation. This thesis uses an multimodal approach to explore these disturbances and their implications for early diagnosis and intervention. This thesis begins by presenting introductory notions helpful for understanding key aspects of the field. Chapter 1 opens with the evolution of diagnostic criteria for autism, followed by detailed discussions on the behavioral phenotype, current diagnostic criteria, and developmental trajectories. We argue for early detection to catalyze diagnostic referrals, enabling early and intensive intervention, essential for young children on the spectrum. Chapter 2 reviews basic concepts regarding the typical functioning of the human visual attentional system, with a special emphasis on social attention from a developmental perspective. Additionally, we present eye-tracking evidence highlighting aberrant social visual engagement as a main pathognomonic feature of the disorder and briefly discuss main brain imaging findings relevant to understanding the complexity of autism's manifestations. Chapter 3 discusses the potential of novel technologies to leverage clinical experience and research in autism, aiming to bring clinical practice closer to more fine-grained, objective, and scalable measures to enable earlier intervention. In this thesis, we advance the current understanding of autism through various approaches presented in our four studies. Studies I &amp; II describe a novel method, the Proximity Index (PI), developed to quantify moment-to-moment divergences in gazing patterns in children with autism compared to typically developing children. Our goal was to create a measure that allows flexible conceptualization of normative gaze behavior without imposing priors. Normative gaze behavior is learned from the distribution of gaze in typically developing children and used as a reference point to compare with gazing patterns of children with ASD. We test the clinical relevance of this new method by linking it to the behavioral characteristics of children with ASD. Study II zooms out from micro-structures of gaze deployment to explore the dynamics of gazing patterns over several years during childhood. In Study III, we examine how the content of social scenes influences processing in children with autism. Leveraging a small but growing sample of brain images acquired during night MRI scanning sessions, we explore the cerebral bases of atypical social visual engagement as measured by our Proximity Index method. Finally, Study IV revisits classical imaging methods, using video recordings of interaction sessions, to develop automated recognition of autism signs through machine learning. This work contributes several new insights into understanding the pathognomonic features of ASD by combining various techniques. The complexity of autism manifestations necessitates a plurality of perspectives. Hence, densely sampled, "deep" phenotyping strategies are critical for a more complete understanding of the disorder's manifestations and the mechanisms governing them.</p

La mémoire prospective, le stress et l'âge

La présente étude examine la relation entre la performance de la mémoire prospective, l’âge et le stress. Ce n’est que récemment que ce type de mémoire commencé à attirer l'attention de nombreux chercheurs. La mémoire prospective (MP) est extrêmement importante pour l’autonomie d’une personne (Kliegel & Martin, 2003). Les effets de l'âge sur la mémoire prospective ont été trouvés en particulier dans des paradigmes complexes (Kliegel, McDaniel, & Einstein, 2000; Logie, Maylor, Della Sala, & Smith, 2004). Les effets du stress sur la mémoire prospective ont été moins étudiés. A notre connaissance la présente étude est la seule étude s’intéressant à la fois aux effets d’âge et aux effets de stress sur la mémoire prospective. A ces fins nous avons examiné 66 jeunes adultes (M = 24.55, SD = 3.87) et 57 adultes âgés (M = 69.17, SD = 4.25). Notre manipulation expérimentale comprenait l’utilisation de la procédure standardisée d’induction du stress psychosocial- Trier Social Stress Test (TSST: Kirschbaum, Pirke, & Hellhammer, 1993)..

Measuring the Emergence of Specific Abilities in Young Children with Autism Spectrum Disorders: The Example of Early Hyperlexic Traits

The presence of a restricted interest in written materials, including an early ability to name and recognize letters and numbers, is regularly reported in preschoolers with autism spectrum disorders (ASDs). There is, however, scarce information on this early ability akin to emerging hyperlexic traits in preschoolers with ASD younger than 3 years old. Here, we defined a measure of early naming and recognition of letters and numbers in 155 preschoolers with ASD using a sliding window approach combined with a 90th percentile threshold criterion, and subsequently compared the profiles of children with ASD with and without early hyperlexic traits. Using this measure, we found that 9% of children with ASD showed early hyperlexic traits. The early ability to name and recognize letters and numbers was associated with a higher level of restricted and repetitive behaviors yet more social-oriented behaviors at baseline and with better expressive and written communication at baseline and one year later. This study contributes to a better definition of the profile of children with ASD with an early ability in letters and numbers akin to emerging hyperlexic traits, a skill that is associated with promising social strengths and language abilities in this subgroup of children.</p

Attention to Face as a Predictor of Developmental Change and Treatment Outcome in Young Children with Autism Spectrum Disorder

The beneficial effect of early intervention is well described for children with autism spectrum disorder (ASD). Response to early intervention is, however, highly heterogeneous in affected children, and there is currently only scarce information about predictors of response to intervention. Based on the hypothesis that impaired social orienting hinders the subsequent development of social communication and interactions in children with ASD, we sought to examine whether the level of social orienting modulates treatment outcome in young children with ASD. We used eye-tracking technology to measure social orienting in a group of 111 preschoolers, comprising 95 young children with ASD and 16 children with typical development, as they watched a 29 s video of a woman engaging in child-directed speech. In line with previous studies, we report that attention to face is robustly correlated with autistic symptoms and cognitive and adaptive skills at baseline. We further leverage longitudinal data in a subgroup of 81 children with ASD and show that the level of social orienting at baseline is a significant predictor of developmental gains and treatment outcome. These results pave the way for identifying subgroups of children who show a better response to early and intensive intervention, a first step toward precision medicine for children with autism

Sensory Processing Issues and Their Association with Social Difficulties in Children with Autism Spectrum Disorders

Sensory processing issues have been frequently reported in individuals with Autism Spectrum Disorders (ASD), but their relationship with social and overall adaptive functioning has not been extensively characterized to date. Here, we investigate how sensory processing atypicalities relate with deficits in social skills, impaired social cognition, and general adaptive functioning in a group of preschoolers with ASD. Sixty-four children with ASD aged 3 to 6 were included in this study, along with 36 age-matched typically-developing (TD) peers. Parent-reported measures of sensory processing, social difficulties and overall adaptive functioning were collected for all children. We also obtained precise measures of social attention deployment using a custom-design eye-tracking task depicting naturalistic social scenes. Within the group of children with ASD, higher intensities of sensory issues were associated with more prominent social difficulties and lower adaptive functioning. We also found that children with ASD who had more sensory issues showed visual exploration patterns of social scenes that strongly deviated from the one seen in the TD group. The association of sensory processing atypicalities with &ldquo;higher-order&rdquo; functional domains such as social and adaptive functioning in children with ASD stresses the importance of further research on sensory symptoms in autism

Sensory Processing Issues and Their Association with Social Difficulties in Children with Autism Spectrum Disorders

Sensory processing issues have been frequently reported in individuals with Autism Spectrum Disorders (ASD), but their relationship with social and overall adaptive functioning has not been extensively characterized to date. Here, we investigate how sensory processing atypicalities relate with deficits in social skills, impaired social cognition, and general adaptive functioning in a group of preschoolers with ASD. Sixty-four children with ASD aged 3 to 6 were included in this study, along with 36 age-matched typically-developing (TD) peers. Parent-reported measures of sensory processing, social difficulties and overall adaptive functioning were collected for all children. We also obtained precise measures of social attention deployment using a custom-design eye-tracking task depicting naturalistic social scenes. Within the group of children with ASD, higher intensities of sensory issues were associated with more prominent social difficulties and lower adaptive functioning. We also found that children with ASD who had more sensory issues showed visual exploration patterns of social scenes that strongly deviated from the one seen in the TD group. The association of sensory processing atypicalities with "higher-order" functional domains such as social and adaptive functioning in children with ASD stresses the importance of further research on sensory symptoms in autism

Emotional vs. Neutral Face Exploration and Habituation: An Eye-Tracking Study of Preschoolers With Autism Spectrum Disorders

Diminished orienting to social stimuli, and particularly to faces, is a core feature of autism spectrum disorders (ASDs). Impaired face processing has been linked to atypical attention processes that trigger a cascade of pathological development contributing to impaired social communication. The aim of the present study is to explore the processing of emotional and neutral faces using an eye-tracking paradigm (the emotional faces task) with a group of 24 children with ASD aged 6 and under and a group of 22 age-matched typically developing (TD) children. We also measure habituation to faces in both groups based on the presentation of repeated facial expressions. Specifically, the task consists of 32 pairs of faces, a neutral face and an emotional face from the same identity, shown side by side on the screen. We observe differential exploration of emotional faces in preschoolers with ASD compared with TD. Participants with ASD make fewer fixations to emotional faces than their TD peers, and the duration of their first fixation on emotional faces is equivalent to their first fixation on neutral faces. These results suggest that emotional faces may be less interesting for children with ASD. We also observe a habituation process to neutral faces in both children with ASD and TD, who looked less at neutral faces during the last quarter of the task compared with the first quarter. By contrast, TD children show increased interest in emotional faces throughout the task, looking slightly more at emotional faces during the last quarter of the task than during the first quarter. Children with ASD demonstrate neither habituation nor increased interest in the changing emotional expressions over the course of the task, looking at the stimuli for equivalent time throughout the task. A lack of increased interest in emotional faces may suggest a lack of sensitivity to changes in expression in young children with ASD

Trajectories of imitation skills in preschoolers with autism spectrum disorders

Background: Imitation skills play a crucial role in social cognitive development from early childhood. Many studies have shown a deficit in imitation skills in children with autism spectrum disorders (ASD). Little is known about the development of imitation behaviors in children with ASD. This study aims to measure the trajectories of early imitation skills in preschoolers with ASD and how these skills impact other areas of early development. Methods: For this purpose, we assessed imitation, language, and cognition skills in 177 children with ASD and 43 typically developing children (TD) aged 2 to 5 years old, 126 of which were followed longitudinally, yielding a total of 396 time points. Results: Our results confirmed the presence of an early imitation deficit in toddlers with ASD compared to TD children. The study of the trajectories showed that these difficulties were marked at the age of 2 years and gradually decreased until the age of 5 years old. Imitation skills were strongly linked with cognitive and language skills and level of symptoms in our ASD group at baseline. Moreover, the imitation skills at baseline were predictive of the language gains a year later in our ASD group. Using a data-driven clustering method, we delineated different developmental trajectories of imitation skills within the ASD group. Conclusions: The clinical implications of the findings are discussed, particularly the impact of an early imitation deficit on other areas of competence of the young child.</p

Visual processing of complex social scenes in 22q11.2 deletion syndrome: Relevance for negative symptoms

Current explanatory models of negative symptoms in schizophrenia have suggested the role of social cognition in symptom formation and maintenance. This study examined a core aspect of social cognition, namely social perception, and its association with clinical manifestations in 22q11.2 deletion syndrome (22q11DS), a genetic model of schizophrenia. We used an eye-tracking device to analyze developmental trajectories of complex and dynamic social scenes exploration in 58 participants with 22q11DS compared to 79 typically developing controls. Participants with 22q11DS showed divergent patterns of social scene exploration compared to healthy individuals from childhood to adulthood. We evidenced a more scattered gaze pattern and a lower number of shared gaze foci compared to healthy controls. Associations with negative symptoms, anxiety level, and face recognition were observed. Findings reveal abnormal visual exploration of complex social information from childhood to adulthood in 22q11DS. Atypical gaze patterns appear related to clinical manifestations in this syndrome