Slowness Therapy for Children with Autism Spectrum Disorder: A Blind Longitudinal Randomized Controlled Study.

The world often goes too fast for children with autism spectrum disorder (ASD) to process. We tested the therapeutic effectiveness of input slowing in children with ASD. Over 12 months, 12 children with ASD had weekly speech therapy sessions where stimuli were slowly played on a PC, while 11 age- and level-matched children with ASD had speech therapy using real-time stimuli. At the beginning and end of the study, all participants were assessed on communication, imitation, facial emotion recognition, behavior, and face exploration. Whereas communication and facial emotion recognition improved in both groups, imitation increased, inappropriate behaviors decreased, and time spent fixating mouth and eyes increased solely in the group using slowness. Slowness therapy seems very promising for ASD children.

Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells.

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.

Reducing facial dynamics' speed during speech enhances attention to mouth in children with autism spectrum disorder: An eye-tracking study.

Facial movements of others during verbal and social interaction are often too rapid to be faced and/or processed in time by numerous children and adults with autism spectrum disorder (ASD), which could contribute to their face-to-face interaction peculiarities. We wish here to measure the effect of reducing the speed of one's facial dynamics on the visual exploration of the face by children with ASD. Twenty-three children with ASD and 29 typically-developing control children matched for chronological age passively viewed a video of a speaker telling a story at various velocities, i.e., a real-time speed and two slowed-down speeds. The visual scene was divided into four areas of interest (AOI): face, mouth, eyes, and outside the face. With an eye-tracking system, we measured the percentage of total fixation duration per AOI and the number and mean duration of the visual fixations made on each AOI. In children with ASD, the mean duration of visual fixations on the mouth region, which correlated with their verbal level, increased at slowed-down velocity compared with the real-time one, a finding which parallels a result also found in the control children. These findings strengthen the therapeutic potential of slowness for enhancing verbal and language abilities in children with ASD.

Evidence of Authorship on Messages in Facilitated Communication: A Case Report Using Accelerometry.

Facilitated communication (FC) belongs to augmentative and alternative methods of communication. Currently, FC is very rarely and unofficially used with people suffering from verbal/communicative disorders or neurodevelopmental disorders such as intellectual deficiency or autism spectrum disorder (ASD). FC consists of physical support exerted by a facilitator at the hand/wrist/forearm/elbow of a patient/participant, aimed at helping him/her to point at pictures/words, and sometimes to type letters/words on a keyboard. Given most of (but not all) validation studies using control procedures failed to confirm that ASD participants themselves were authoring the messages via FC, this method has been massively disputed and rejected. However, firm and definitive conclusions for/against the validity of FC requires more robust demonstrations, particularly when considering the motor participation of both protagonists. We present here a case report investigating the motor contribution of both protagonists during a typing process using the non-invasive technique of accelerometry. A 17-year-old boy diagnosed with congenital deafness, ASD, and developmental delay, and his facilitator, were equipped with small accelerometers fixed on their index finger, aimed at transforming index acceleration along the three spatial axes into electric signals. Typing on a PC keyboard was performed under three support conditions: hand support, forearm support, elbow support, plus a solo-typing condition. Accelerometric signals and video data were recorded during four FC sessions. We measured and compared the typing speed, the number/percentage of acceleration peaks produced by the participant or by the facilitator first, and those of "signal under detection threshold" in the facilitator, the time offset between acceleration peaks of both protagonists, and the difference of the amount of acceleration between them, across the different support conditions. Results indicate that in the hand support, most of the time, acceleration motions of the participant's index finger preceded those of the facilitator's index finger. Then, the more distal the physical support (i.e., farer from the participant's hand), the slower the speed of typing, the higher the percentage of "signal under detection threshold" in the facilitator, the bigger the motor contribution from the participant. Altogether, in all the support conditions, the participant's authorship or, at least, co-authorship on the messages seems warranted. Finally, accelerometry seems relevant to objectivize authorship or co-authorship in FC and delineate various forms of FC.

Reducing Information's Speed Improves Verbal Cognition and Behavior in Autism: A 2-Cases Report.

According to the temporal theory of autism spectrum disorders (ASDs), audiovisual changes in environment, particularly those linked to facial and verbal language, are often too fast to be faced, perceived, and/or interpreted online by many children with ASD, which could help explain their facial, verbal, and/or socioemotional interaction impairments. Our goal here was to test for the first time the impact of slowed-down audiovisual information on verbal cognition and behavior in 2 boys with ASD and verbal delay. Using 15 experimental sessions during 4 months, both boys were presented with various stimuli (eg, pictures, words, sentences, cartoons) and were then asked questions or given instructions regarding stimuli. The audiovisual stimuli and instructions/questions were presented on a computer's screen and were always displayed twice: at real-time speed (RTS) and at slowed-down speed (SDS) using the software Logiral. We scored the boys' verbal cognition performance (ie, ability to understand questions/instructions and answer them verbally/nonverbally) and their behavioral reactions (ie, attention, verbal/nonverbal communication, social reciprocity), and analyzed the effects of speed and order of the stimuli presentation on these factors. According to the results, both participants exhibited significant improvements in verbal cognition performance with SDS presentation compared with RTS presentation, and they scored better with RTS presentation when having SDS presentation before rather than after RTS presentation. Behavioral reactions were also improved in SDS conditions compared with RTS conditions. This initial evidence of a positive impact of slowed-down audiovisual information on verbal cognition should be tested in a large cohort of children with ASD and associated speech/language impairments.

Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology.

BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic.

Isolating nasal olfactory stem cells from rodents or humans.

The olfactory mucosa, located in the nasal cavity, is in charge of detecting odours. It is also the only nervous tissue that is exposed to the external environment and easily accessible in every living individual. As a result, this tissue is unique for anyone aiming to identify molecular anomalies in the pathological brain or isolate adult stem cells for cell therapy. Molecular abnormalities in brain diseases are often studied using nervous tissue samples collected post-mortem. However, this material has numerous limitations. In contrast, the olfactory mucosa is readily accessible and can be biopsied safely without any loss of sense of smell(1). Accordingly, the olfactory mucosa provides an "open window" in the adult human through which one can study developmental (e.g. autism, schizophrenia)(2-4) or neurodegenerative (e.g. Parkinson, Alzheimer) diseases(4,5). Olfactory mucosa can be used for either comparative molecular studies(4,6) or in vitro experiments on neurogenesis(3,7). The olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria(8-10). We recently developed a method to purify the adult stem cells located in the lamina propria and, after having demonstrated that they are closely related to bone marrow mesenchymal stem cells (BM-MSC), we named them olfactory ecto-mesenchymal stem cells (OE-MSC)(11). Interestingly, when compared to BM-MSCs, OE-MSCs display a high proliferation rate, an elevated clonogenicity and an inclination to differentiate into neural cells. We took advantage of these characteristics to perform studies dedicated to unveil new candidate genes in schizophrenia and Parkinson's disease(4). We and others have also shown that OE-MSCs are promising candidates for cell therapy, after a spinal cord trauma(12,13), a cochlear damage(14) or in an animal models of Parkinson's disease(15) or amnesia(16). In this study, we present methods to biopsy olfactory mucosa in rats and humans. After collection, the lamina propria is enzymatically separated from the epithelium and stem cells are purified using an enzymatic or a non-enzymatic method. Purified olfactory stem cells can then be either grown in large numbers and banked in liquid nitrogen or induced to form spheres or differentiated into neural cells. These stem cells can also be used for comparative omics (genomic, transcriptomic, epigenomic, proteomic) studies.

Slowing down the presentation of facial and body movements enhances imitation performance in children with severe autism.

Imitation deficits observed among individuals with autism could be partly explained by the excessive speed of biological movements to be perceived and then reproduced. Along with this assumption, slowing down the speed of presentation of these movements might improve their imitative performances. To test this hypothesis, 19 children with autism, 37 typically-developing children and 17 children with Down syndrome were asked to reproduce facial and body movements presented on a computer at a normal/ecological and two slowed down speeds. Our main result showed that a subgroup of individuals with severe autism better reproduced the movements when presented slowly than at the ecological speed. This finding opens a new window for comprehension and rehabilitation of perceptual and imitative deficits in autism.

Autism: a world changing too fast for a mis-wired brain?

Disorders in verbal and emotional communication and imitation, social reciprocity and higher order cognition observed in individuals with autism spectrum disorders (ASD) are presented here as phenotypic expressions of temporo-spatial processing disorders (TSPDs). TSPDs include various degrees of disability in (i) processing multi-sensory dynamic stimuli online, (ii) associating them into meaningful and coherent patterns and (iii) producing real-time sensory-motor adjustments and motor outputs. In line with this theory, we found that slowing down the speed of facial and vocal events enhanced imitative, verbal and cognitive abilities in some ASD children, particularly those with low functioning autism. We then argue that TSPDs may result from Multi-system Brain Disconnectivity-Dissynchrony (MBD), defined as an increase or decrease in functional connectivity and neuronal synchronization within/between multiple neurofunctional territories and pathways. Recent functional magnetic resonance imaging (fMRI) and electrophysiological studies supporting MBD are outlined. Finally, we review the suspected underlying neurobiological mechanisms of MBD as evidenced in neuroimaging, genetic, environmental and epigenetic studies. Overall, our TSPD/MBD approach to ASD may open new promising avenues for a better understanding of neuro-physio-psychopathology of ASD and clinical rehabilitation of people affected by these syndromes.

Abnormal cerebral effective connectivity during explicit emotional processing in adults with autism spectrum disorder.

Several recent studies suggest that autism may result from abnormal communication between brain regions. We directly assessed this hypothesis by testing the presence of abnormalities in a model of the functional cerebral network engaged during explicit emotion processing in adults with high functioning autism or Asperger syndrome. Comparison of structural equation models revealed abnormal patterns of effective connectivity, with the prefrontal cortex as a key site of dysfunction. These findings provide evidence that abnormal long-range connectivity between structures of the 'social brain' could explain the socio-emotional troubles that characterize the autistic pathology.

Slowing down presentation of facial movements and vocal sounds enhances facial expression recognition and induces facial-vocal imitation in children with autism.

This study examined the effects of slowing down presentation of facial expressions and their corresponding vocal sounds on facial expression recognition and facial and/or vocal imitation in children with autism. Twelve autistic children and twenty-four normal control children were presented with emotional and non-emotional facial expressions on CD-Rom, under audio or silent conditions, and under dynamic visual conditions (slowly, very slowly, at normal speed) plus a static control. Overall, children with autism showed lower performance in expression recognition and more induced facial-vocal imitation than controls. In the autistic group, facial expression recognition and induced facial-vocal imitation were significantly enhanced in slow conditions. Findings may give new perspectives for understanding and intervention for verbal and emotional perceptive and communicative impairments in autistic populations.

Spatial frequency and face processing in children with autism and Asperger syndrome.

Two experiments were designed to investigate possible abnormal face processing strategies in children with autistic spectrum disorders. A group of 11 children with autism was compared to two groups of normally developing children matched on verbal mental age and on chronological age. In the first experiment, participants had to recognize faces on the basis of identity, emotion, gaze direction, gender, and lip reading. All aspects of face processing, except for identity matching, were deficient in the autistic population compared with controls. In the second study, children had to match faces on either high-(i.e., local facial features) or low-spatial frequency information (i.e., global configuration of faces). Contrary to the control subjects, children with autism showed better performance when using high rather than low spatial frequency, confirming face-processing peculiarities in this population.

Inner and outer face perception in children with autism.

Possible peculiarities in face perception in the autistic population were explored through two experiments. Fourteen autistic children (mean age=10 years 1 month) were individually matched to verbal mental age (VMA) and chronological age (CA) subjects. In a first experiment, subjects were to match faces on the basis of either their outer (hair, chin, ears) or their inner (eyes, nose, mouth) aspects. Autistic children performed equally well in both conditions, while VMA-matched children performed better in the outer than the inner part condition. In a second experiment, chimeric faces consisting of the outer part of an individual's face and the inner part of another individual's face were presented to the subjects. None of the groups showed a preference for neither the outer nor the inner part of the face in this condition. Results were discussed in terms of the existence of a local visual processing strategy in this population.

Brief report: postural reactivity to fast visual motion differentiates autistic from children with Asperger syndrome.

The aim of the present study was to search for a sensorimotor marker (i.e., visuopostural tuning) that could be correlated with the severity of motor impairments in children with autistic spectrum disorders. Given that autistic children were previously reported to be posturally hyporeactive to visually perceived environmental motion in comparison with normal control children (Gepner et al., 1995), we sought to determine whether children with Asperger syndrome (AS) would share the same postural hyporeactivity to visual motion. Three autistic children with mild to severe motor impairments, three AS children with soft motor signs, and nine normal control children were tested for overall postural instability and postural reactivity to environmental motion. Results indicate, first, that overall postural instability is significantly reduced in autistic children compared with both AS and normal children. Second, although postural oscillations in the fore-aft axis become more attuned to the oscillation frequency of an immersive dynamic visual display as visual speed is increased, in both control and AS subjects, this is not the case in autistic children. Despite the small number of subjects tested in this study, our data confirm the existence of a visuopostural detuning in autistic children. Third, they argue for a correlation between visuopostural tuning and severity of motor signs in children with autistic spectrum disorders. Finally, they suggest a differentiation between children with autism and children with AS with regard to postural reactivity to fast visual motion. Neurophysiological implications of these results are discussed. In particular, a visuocerebellar pathway deficit hypothesis in autism is proposed.