Pupillary Contagion in Autism.

Pupillary contagion is an involuntary change in the observer's pupil size in response to the pupil size of another person. This effect, presumed to be an important adaption for individuals living in groups, has been documented in both typical infants and adults. Here, for the first time, we report pupillary contagion in individuals with autism, a disorder of social communication. We found that, compared with a typical group ( n = 63), individuals with autism ( n = 54) exhibited comparable pupillary contagion when observing pictures of emotional faces, despite less spontaneous attention toward the eye region. Furthermore, the magnitude of the pupillary response in the autism group was negatively correlated with time spent fixating the eye region. The results suggest that even with less looking toward the eyes, individuals with autism respond to the affective and arousal levels transmitted from other individuals. These results are discussed in the context of an overarousal account of socioaffective-processing differences in autism.

Effect of visual stimuli of pain on empathy brain network in people with and without Autism Spectrum Disorder.

The extent to which affective empathy is impaired in Autism Spectrum Disorder (ASD) remains unclear, as some-but not all-previous neuroimaging studies investigating empathy for pain in ASD have shown similar activation levels to those of neurotypicals individuals. These inconsistent results could be due to the use of different empathy-eliciting stimuli. While some studies used pictures of faces exhibiting a painful expression, others used pictures of limbs in painful situations. In this study, we used fMRI to compare activation in areas associated with empathy processing (empathy network) for these two types of stimuli in 31 participants (16 with ASD, 15 controls). We found a group difference in the inferior frontal gyrus (IFG) and the thalamus when participants viewed stimuli of limbs in painful situations, but not when they viewed face stimuli with a painful expression. Both groups of participants activated their empathy network more when viewing pictures of limbs in painful situations than when viewing pictures of faces with a painful expression; this increased activation for limbs versus faces was significantly enhanced in controls relative to ASD participants, especially in the secondary somatosensory cortex (SII). Our findings suggest that empathy defect of people with ASD is contingent upon the type of stimuli used, and may be related to the level of Mirror Neuron System involvement, as brain regions showing group differences (IFG, SII) underlie embodiment. We discuss the potential clinical implications of our findings in terms of developing interventions boosting the empathetic abilities of people with ASD.

Hypersensitivity to low intensity fearful faces in autism when fixation is constrained to the eyes.

Previous studies that showed decreased brain activation in people with autism spectrum disorder (ASD) viewing expressive faces did not control that participants looked in the eyes. This is problematic because ASD is characterized by abnormal attention to the eyes. Here, we collected fMRI data from 48 participants (27 ASD) viewing pictures of neutral faces and faces expressing anger, happiness, and fear at low and high intensity, with a fixation cross between the eyes. Group differences in whole brain activity were examined for expressive faces at high and low intensity versus neutral faces. Group differences in neural activity were also investigated in regions of interest within the social brain, including the amygdala and the ventromedial prefrontal cortex (vmPFC). In response to low intensity fearful faces, ASD participants showed increased activation in the social brain regions, and decreased functional coupling between the amygdala and the vmPFC. This oversensitivity to low intensity fear coupled with a lack of emotional regulation capacity could indicate an excitatory/inhibitory imbalance in their socio-affective processing system. This may result in social disengagement and avoidance of eye-contact to handle feelings of strong emotional reaction. Our results also demonstrate the importance of careful control of gaze when investigating emotional processing in ASD. Hum Brain Mapp 38:5943-5957, 2017. © 2017 Wiley Periodicals, Inc.

Interest towards human, animal and object in children with autism spectrum disorders: an ethological approach at home.

Autistic spectrum disorders (ASD) are characterised by attention deficits in communication and social interactions and a lack of interest in people. Data are mostly based on clinical situations. However, recent studies have shown a more mixed situation where children with ASD (ASD children) displayed interest towards humans, in both experimental and natural settings. The aim of this study was to assess the interest of ASD children in a natural standardised home setting. Here, we hypothesised that ASD children would display more interest towards animate stimuli-human and pet-when in the child's home than in the lab experimental setting. We used an ethological approach involving observations, a methodological alternative to lab static techniques, to investigate the behaviour of ninety 6- to 12-year-old ASD and typical development (TD) children. Our results were consistent with those of the literature revealing that the ASD children displayed interest towards animate stimuli as did children with TD children. Interestingly, while the ASD children showed higher interest towards humans, e.g. their parent, than the TD children did, they showed less interest towards pet compared to the TD children. Our results suggested that animals are not inherently easy to decode for ASD children, in contrast with previous experiences where a pet was regarded as a more attractive partner, easier to be understood. At last, the ASD children changed more frequently their focus point than the TD children did. These differences may be explained by the reduced attention skills in ASD or the study's context. To conclude, larger exploratory studies in natural settings conducted beyond ordinary human to human interactions are crucial for better understanding of the underlying mechanisms involved in social interactions in ASD.

Autism spectrum disorders: head circumference and body length at birth are both relative.

AIM: Although the body length and weight of an infant are related to head circumference, little research on ASDs has examined these factors. Our study compared the head circumferences of neonates who were later diagnosed with ASD with a control group. Additional comparisons on morphological disproportions at birth included the head circumference-to-height and head circumference-to-weight ratios. METHODS: We recruited 422 children with ASD and 153 typically developing children. Head circumference, body length and weight at birth were collected and standardized as percentile scores according to gestational age and gender. RESULTS: Our results revealed that genuine macrocephaly was significantly higher in children with other pervasive developmental disorders compared with the control group. This difference was not observed with regard to genuine microcephaly. Relative macrocephaly and relative microcephaly were significantly more frequent in children with autism disorder compared with the control group with regard to body length. CONCLUSIONS: The differences in relative macrocephaly and microcephaly, as well as in other parameters, between diagnostic subgroups suggest that the presence of several neurological mechanisms plays a role in the later expression of different phenotypes. An increased head circumference-to-body length ratio in newborns may be a factor to follow that could be related to ASD.

Treating Fragile X syndrome with the diuretic bumetanide: a case report.

UNLABELLED: We report that daily administration of the diuretic NKCC1 chloride co-transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX. CONCLUSION: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double-blind clinical trials are warranted to test the efficacy of bumetanide in FRX.

Balance rehabilitation for postural control in children with Autism Spectrum Disorder: A two-case report study.

OBJECTIVE: This study aimed to investigate the effect of balance rehabilitation on postural control in both low and increased cognitive load conditions in two children with Autism Spectrum Disorders (ASD). METHODS: Two children diagnosed with ASD participated in a 4-week personalized balance rehabilitation program with two sessions per week. We assessed postural control in two single task (ST) conditions with low cognitive load: Eyes Closed (EC), Eyes Open (EO); and in five increased cognitive load conditions. Those dual task (DT) conditions consisted of presenting images representing a neutral condition, sadness, anger, happiness, and fear. Postural control parameters (surface, velocity, medio-lateral and antero-posterior sway amplitudes of the center of pressure (CoP)) were collected by a posturographic platform before and after the balance rehabilitation. RESULTS: The rehabilitation program resulted in a 30-96% improvement of postural control parameters in the ST condition for both participants. In DT, participant 1 progressed on all conditions while participant 2 progressed on 3 of the 5 conditions (sadness, anger and fear). CONCLUSION: This suggests that these two children with ASD improved their balance control in both low and increased cognitive load conditions. These encouraging results need to be replicated before recommending balance rehabilitation as standard health rehabilitation in children with ASD.

[Early prognostic of ASD: A challenge]. / Pronostiquer tôt les troubles du spectre autistique : Un défi ?

Autism Spectrum Disorders (ASD) are born in the womb generated by intrauterine genetic or environmental insult. ASD diagnostic is made at the age of 3-5 years in Europe and in the US. Relying on this, we have tested the hypothesis of identifying already at birth babies who might be diagnosed later with ASD, thereby facilitating an early use of psychoeducative techniques to attenuate the severity of the symptoms. Here, we discuss the various approaches that have been used to enable an early diagnosis. We have ourselves used an approach based on a "without a priori" machine learning analysis of all maternity biological and ultrasound data available in French maternities (around 116) in utero and after birth. This program made it possible to identify at birth almost all (96%) of babies who will be later neurotypical and around half of those who will be diagnosed with ASD. Some of the parameters allowing this identification were largely unexpected with no known links with ASD. This approach will enable an early identification of babies at risk, but also might be used to diagnose ASD later on, and perhaps could help to get a better understanding of the heterogeneity of ASD.

Title: Pronostiquer tôt les troubles du spectre autistique : Un défi ? Abstract: Les troubles du spectre de l'autisme (TSA) « naissent ¼ in utero à la suite d'évènements pathologiques génétiques ou environnementaux. Le diagnostic des TSA n'est cependant effectué que vers l'âge de 3-5 ans en Europe et aux États-Unis. Un pronostic précoce permettrait pourtant d'atténuer la sévérité des atteintes cognitives, grâce à des approches psycho-éducatives. Une large panoplie d'approches a été suggérée pour établir un pronostic précoce des TSA, se fondant sur l'imagerie cérébrale, sur des enregistrements EEG, sur des biomarqueurs sanguins ou sur l'analyse des contacts visuels. Nous avons développé une approche fondée sur l'analyse par machine learning des données biologiques et échographiques recueillies en routine, du début de la grossesse au lendemain de la naissance, dans les maternités françaises. Ce programme qui permet d'identifier la presque totalité des bébés neurotypiques et la moitié des bébés qui auront un diagnostic de TSA quelques années plus tard, permet aussi d'identifier les paramètres ayant un impact sur le pronostic. Si quelques-uns d'entre eux étaient attendus, d'autres n'ont aucun lien avec les TSA. L'étude sans a priori des données de maternité devrait ainsi permettre un pronostic des TSA dès la naissance, ainsi que de mieux comprendre la pathogenèse de ces syndromes et de les traiter plus tôt.

Dyadic coping and coparenting among couples after their child's recent autism diagnosis.

LAY ABSTRACT: We investigated how couples support each other after their child's autism diagnosis and whether this affects the way they work together to raise their child. We recruited 70 couples raising a child on the autism spectrum. Both partners were asked to complete the same questionnaires measuring how they perceived the experience of having a child on the autism spectrum, how they used their relationship to support each other during stressful situations, how competent they felt completing their parenting tasks, and the coparenting relationship to explore how they worked together as a team when parenting their child. Parents participated in the study 1-36 months after their child's autism diagnosis. We used statistical techniques that allowed us to see the impact mothers and fathers had on each other. Overall, parents who felt more competent and supported by their partner worked better as a team to raise their child on the spectrum. Fathers invested in the coparenting relationship more when mothers felt more supported by fathers. Mothers invested in the coparenting relationship more when fathers felt more competent parenting their child. Further research is needed to better understand how we can support couples as their child gets older.

[Aripiprazole use in children and adolescent psychiatric patients]. / Prescription de l'aripiprazole chez l'enfant et l'adolescent.

Aripiprazole inaugurates a new generation of antipsychotics called dopamine-serotonin system stabilizers. Its mechanism of action is different as aripiprazole is a partial dopamine D(2) and serotonin 5-HT(1A) receptor agonist and 5-HT(2A) receptor antagonist. Therefore, aripiprazole is thought to have an antagonistic action in the mesolimbic pathway but an agonistic action in the mesocortical pathway, tending to normalize the dopaminergic transmission regardless of the type of imbalance. Clinical trials involving children and adolescents have demonstrated the efficacy of aripiprazole in bipolar disorders, schizophrenia, mood disorders associated with pervasive developmental disorders, in tics and Tourette's. The most frequent side effects are extrapyramidal symptoms and sleepiness and are dose-dependent. Nevertheless, contrary to other second-generation antipsychotics available in France, it induces little weight gain, does not modify lipid and glucidic profiles, does not increase prolactin levels, or induce QTc lengthening. The main advantage of aripiprazole is its good safety profile, with different toxicity targets to other second-generation antipsychotics available in France. Aripiprazole appears to be an alternative for children and adolescents who are vulnerable to these side effects and are having trouble coping with them.

[Not Available]. / Prescription de l'aripiprazole chez l'enfant et l'adolescent.

Aripiprazole inaugurates a new generation of antipsychotics called dopamine-serotonin system stabilizers. Its mechanism of action is different as aripiprazole is a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist. Therefore, aripiprazole is thought to have an antagonistic action in the mesolimbic pathway but an agonistic action in the mesocortical pathway, tending to normalize the dopaminergic transmission regardless of the type of imbalance. Clinical trials involving children and adolescents have demonstrated the efficacy of aripiprazole in bipolar disorders, schizophrenia, mood disorders associated with pervasive developmental disorders, in tics and Tourette's. The most frequent side effects are extrapyramidal symptoms and sleepiness and are dose-dependant. Nevertheless, contrary to other second-generation antipsychotics available in France, it induces little weight gain, does not modify lipid and glucidic profiles, does not increase prolactin levels, or induce QTc lengthening. The main advantage of aripiprazole is its good safety profile, with different toxicity targets to other secondgeneration antipsychotics available in France. Aripiprazole appears to be an alternative for children and adolescents who are vulnerable to these side effects and are having trouble coping with them.

Treating Autism With Bumetanide: Are Large Multicentric and Monocentric Trials on Selected Populations Complementary?

In their article in the Journal, Sprengers et al.1 conclude that bumetanide does not attenuate autism spectrum disorder (ASD) despite a nominally significant treatment effect in repetitive behaviors, which is a core symptom of ASD but was defined as a secondary measure in this trial. Four earlier studies performed by 3 independent institutes, including 2 studies2,3 not mentioned by Sprengers et al., testing a total of 169 children (versus 122 placebo) showed a significant amelioration of ASD symptoms. Bumetanide also significantly attenuated behavioral features of patients with tuberous sclerosis according to another study by Sprengers' same group.4.

Machine learning analysis of pregnancy data enables early identification of a subpopulation of newborns with ASD.

To identify newborns at risk of developing ASD and to detect ASD biomarkers early after birth, we compared retrospectively ultrasound and biological measurements of babies diagnosed later with ASD or neurotypical (NT) that are collected routinely during pregnancy and birth. We used a supervised machine learning algorithm with a cross-validation technique to classify NT and ASD babies and performed various statistical tests. With a minimization of the false positive rate, 96% of NT and 41% of ASD babies were identified with a positive predictive value of 77%. We identified the following biomarkers related to ASD: sex, maternal familial history of auto-immune diseases, maternal immunization to CMV, IgG CMV level, timing of fetal rotation on head, femur length in the 3rd trimester, white blood cell count in the 3rd trimester, fetal heart rate during labor, newborn feeding and temperature difference between birth and one day after. Furthermore, statistical models revealed that a subpopulation of 38% of babies at risk of ASD had significantly larger fetal head circumference than age-matched NT ones, suggesting an in utero origin of the reported bigger brains of toddlers with ASD. Our results suggest that pregnancy follow-up measurements might provide an early prognosis of ASD enabling pre-symptomatic behavioral interventions to attenuate efficiently ASD developmental sequels.

The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects.

UNLABELLED: The inhibitory transmitter GABA has been suggested to play an important role in infantile autistic syndrome (IAS), and extensive investigations suggest that excitatory actions of GABA in neurological disorders are because of a persistent increase of [Cl(-) ](I) . AIMS: To test the effects of the chloride co-transporter NKCC1 diuretic compound Bumetanide that reduces [Cl(-) ](I) on IAS. METHODS: Bumetanide was administered daily (1mg daily) during a 3-month period and clinical and biological tests made. We used 5 standard IAS severity tests - Childhood Autism Rating Scale, Aberrant Behaviour Checklist, Clinical Global Impressions; Repetitive and Restrictive Behaviour and the Regulation Disorder Evaluation Grid. RESULTS: We report a significant improvement in IAS with no side effects. CONCLUSION: Bumetanide decreases autistic behaviour with no side effects suggesting that diuretic agents may exert beneficial effects on IAS and that alterations of the actions of GABA may be efficient in IAS treatment calling for large scale randomized trials.

Influence of anxiety and alexithymia on brain activations associated with the perception of others' pain in autism.

The circumstances under which empathy is altered in ASD remain unclear, as previous studies did not systematically find differences in brain activation between ASD and controls in empathy-eliciting paradigms, and did not always monitor whether differences were primarily due to ASD "per se", or to conditions overlapping with ASD, such as alexithymia and anxiety. Here, we collected fMRI data from 47 participants (22 ASD) viewing pictures depicting hands and feet of unknown others in painful, disgusting, or neutral situations. We computed brain activity for painful and disgusting stimuli (vs. neutral) in whole brain and in regions of interest among the brain areas typically activated during the perception of nociceptive stimuli. Group differences in brain activation disappeared when either alexithymia or anxiety - both elevated in the ASD group - were controlled for. Regression analyses indicated that the influence of symptoms was mainly shared between autistic symptomatology, alexithymia and anxiety or driven by unique contributions from alexithymia or anxiety. Our results suggest that affective empathy may be affected in ASD, but that this association is complex. The respective contribution of alexithymia and anxiety to decreased affective empathy of people with ASD may be due to the association of those psychiatric conditions with reduced motor resonance/Theory of Mind.

Bumetanide for autism: more eye contact, less amygdala activation.

We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.

Perception of odors and tastes in autism spectrum disorders: A systematic review of assessments.

Olfaction and gustation are major sensory functions implied in processing environmental stimuli. Some evidences suggest that loss of olfactory function is an early biomarker for neurodegenerative disorders and atypical processing of odor and taste stimuli is present in several neurodevelopmental disorders, notably in Autism Spectrum Disorders (ASD). In this paper, we conducted a systematic review investigating the assessments of olfaction and gustation with psychophysics methods in individuals with ASD. Pubmed, PMC and Sciencedirect were scrutinized for relevant literature published from 1970 to 2015. In this review, fourteen papers met our inclusion criteria. They were analyzed critically in order to evaluate the occurrence of olfactory and gustatory dysfunction in ASD, as well as to report the methods used to assess olfaction and gustation in such conditions. Regarding to these two senses, the overall number of studies is low. Most of studies show significant difference regarding to odor or taste identification but not for detection threshold. Overall, odor rating through pleasantness, intensity and familiarity do not differ significantly between control and individuals with ASD. The current evidences can suggest the presence of olfactory and gustatory dysfunction in ASD. Therefore, our analysis show a heterogeneity of findings. This is due to several methodological limitations such as the tools used or population studied. Understanding these disorders could help to shed light on other atypical behavior in this population such as feeding or social behavior. Autism Res 2017, 0: 000-000. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1045-1057. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Autism and emotional face-viewing.

Atypical patterns of face-scanning in individuals with autism spectrum disorder (ASD) may contribute to difficulties in social interactions, but there is little agreement regarding what exactly characterizes face-viewing in ASD. In addition, little research has examined how face-viewing is modulated by the emotional expression of the stimuli, in individuals with or without ASD. We used eye-tracking to explore viewing patterns during perception of dynamic emotional facial expressions in relatively large groups of individuals with (n = 57) and without ASD (n = 58) and examined diagnostic- and age-related effects, after subgrouping children and adolescents (≤18 years), on the one hand, and adults (>18 years), on the other. Results showed that children/adolescents with ASD fixated the mouth of happy and angry faces less than their typically developing (TD) peers, and conversely looked more to the eyes of happy faces. Moreover, while all groups fixated the mouth in happy faces more than in other expressions, children/adolescents with ASD did relatively less so. Correlation analysis showed a similar lack of relative orientation towards the mouth of smiling faces in TD children/adolescents with high autistic traits, as measured by the Autism-Spectrum Quotient (AQ). Among adults, participants with ASD only attended less to the eyes for neutral faces. Our study shows that the emotional content of a face influences gaze behaviour, and that this effect is not fully developed in children/adolescents with ASD. Interestingly, this lack of differentiation observed in the younger ASD group was also seen in younger TD individuals with higher AQ scores. Autism Res 2017, 10: 901-910. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Look me in the eyes: constraining gaze in the eye-region provokes abnormally high subcortical activation in autism.

Individuals with Autism Spectrum Disorder (ASD) seem to have difficulties looking others in the eyes, but the substrate for this behavior is not well understood. The subcortical pathway, which consists of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic face processing. A specific component of this pathway - i.e., the amygdala - has been shown to be abnormally activated in paradigms where individuals had to specifically attend to the eye-region; however, a direct examination of the effect of manipulating the gaze to the eye-regions on all the components of the subcortical system altogether has never been performed. The subcortical system is particularly important as it shapes the functional specialization of the face-processing cortex during development. Using functional MRI, we investigated the effect of constraining gaze in the eye-region during dynamic emotional face perception in groups of participants with ASD and typical controls. We computed differences in activation in the subcortical face processing system (superior colliculus, pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals with ASD show abnormally high activation in the subcortical system, which may be at the basis of their eye avoidance in daily life.