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.

A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

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.

Complex syntax in autism spectrum disorders: a study of relative clauses.

BACKGROUND: The few studies that have evaluated syntax in autism spectrum disorder (ASD) have yielded conflicting findings: some suggest that once matched on mental age, ASD and typically developing controls do not differ for grammar, while others report that morphosyntactic deficits are independent of cognitive skills in ASD. There is a need for a better understanding of syntax in ASD and its relation to, or dissociation from, nonverbal abilities. AIMS: Syntax in ASD was assessed by evaluating subject and object relative clause comprehension in adolescents and adults diagnosed with ASD with a performance IQ within the normal range, and with or without a history of language delay. METHODS & PROCEDURES: Twenty-eight participants with ASD (mean age 21.8) and 28 age-matched controls (mean age 22.07) were required to point to a character designated by relative clauses that varied in syntactic complexity. OUTCOMES & RESULTS: Scores indicate that participants with ASD regardless of the language development history perform significantly worse than age-matched controls with object relative clauses. In addition, participants with ASD with a history of language delay (diagnosed with high-functioning autism in the DSM-IV-TR) perform worse on subject relatives than ASD participants without language delay (diagnosed with Asperger syndrome in the DSM-IV-TR), suggesting that these two groups do not have equivalent linguistic abilities. Performance IQ has a positive impact on the success of the task for the population with ASD. CONCLUSIONS & IMPLICATIONS: This study reveals subtle grammatical difficulties remaining in adult individuals with ASD within normal IQ range as compared with age-matched peers. Even in the absence of a history of language delay in childhood, the results suggest that a slight deficit may nevertheless be present and go undetected by standardized language assessments. Both groups with and without language delay have a similar global performance on relative clause comprehension; however, the study also indicates that the participants with reported language delay show more difficulty with subject relatives than the participants without language delay, suggesting the presence of differences in linguistic abilities between these subgroups of ASD.

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

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.

Face processing and facial emotion recognition in adults with Down syndrome.

Face processing and facial expression recognition was investigated in 17 adults with Down syndrome, and results were compared with those of a child control group matched for receptive vocabulary. On the tasks involving faces without emotional content, the adults with Down syndrome performed significantly worse than did the controls. However, their performance was good on the tests with complete faces. On the facial expression tasks, participants with Down syndrome exhibited particular difficulties with the neutral and surprised expressions. Analysis of their error pattern suggest they had a tendency to judge faces more positively than did the controls. Finally, there were significant relationships among emotional processing, receptive vocabulary, and inhibition measures; nonverbal reasoning ability was not related to any of the tasks.

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.

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.

The effect of constraining eye-contact during dynamic emotional face perception-an fMRI study.

Eye-contact modifies how we perceive emotions and modulates activity in the social brain network. Here, using fMRI, we demonstrate that adding a fixation cross in the eye region of dynamic facial emotional stimuli significantly increases activation in the social brain of healthy, neurotypical participants when compared with activation for the exact same stimuli observed in a free-viewing mode. In addition, using PPI analysis, we show that the degree of amygdala connectivity with the rest of the brain is enhanced for the constrained view for all emotions tested except for fear, and that anxiety and alexithymia modulate the strength of amygdala connectivity for each emotion differently. Finally, we show that autistic traits have opposite effects on amygdala connectivity for fearful and angry emotional expressions, suggesting that these emotions should be treated separately in studies investigating facial emotion processing.

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.

The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition.

BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Improving emotional face perception in autism with diuretic bumetanide: a proof-of-concept behavioral and functional brain imaging pilot study.

Clinical observations have shown that GABA-acting benzodiazepines exert paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl-)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer antagonist bumetanide, that decreases (Cl-)i and reinforces GABAergic inhibition, reduces the severity of autism symptoms. Here, we report results from an open-label trial pilot study in which we used functional magnetic resonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism. We show that bumetanide treatment improves emotion recognition and enhances the activation of brain regions involved in social and emotional perception during the perception of emotional faces. The improvement of emotion processing by bumetanide reinforces the usefulness of bumetanide as a promising treatment to improve social interactions in autism.

Investigation of memory, executive functions, and anatomic correlates in asymptomatic FMR1 premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset movement disorder associated with FMR1 premutation alleles. Asymptomatic premutation (aPM) carriers have preserved cognitive functions, but they present subtle executive deficits. Current efforts are focusing on the identification of specific cognitive markers that can detect aPM carriers at higher risk of developing FXTAS. This study aims at evaluating verbal memory and executive functions as early markers of disease progression while exploring associated brain structure changes using diffusion tensor imaging. We assessed 30 aPM men and 38 intrafamilial controls. The groups perform similarly in the executive domain except for decreased performance in motor planning in aPM carriers. In the memory domain, aPM carriers present a significant decrease in verbal encoding and retrieval. Retrieval is associated with microstructural changes of the white matter (WM) of the left hippocampal fimbria. Encoding is associated with changes in the WM under the right dorsolateral prefrontal cortex, a region implicated in relational memory encoding. These associations were found in the aPM group only and did not show age-related decline. This may be interpreted as a neurodevelopmental effect of the premutation, and longitudinal studies are required to better understand these mechanisms.

Perception of social cues of danger in autism spectrum disorders.

Intuitive grasping of the meaning of subtle social cues is particularly affected in autism spectrum disorders (ASD). Despite their relevance in social communication, the effect of averted gaze in fearful faces in conveying a signal of environmental threat has not been investigated using real face stimuli in adults with ASD. Here, using functional MRI, we show that briefly presented fearful faces with averted gaze, previously shown to be a strong communicative signal of environmental danger, produce different patterns of brain activation than fearful faces with direct gaze in a group of 26 normally intelligent adults with ASD compared with 26 matched controls. While implicit cue of threat produces brain activation in attention, emotion processing and mental state attribution networks in controls, this effect is absent in individuals with ASD. Instead, individuals with ASD show activation in the subcortical face-processing system in response to direct eye contact. An effect of differences in looking behavior was excluded in a separate eye tracking experiment. Our data suggest that individuals with ASD are more sensitive to direct eye contact than to social signals of danger conveyed by averted fearful gaze.

It's all in the eyes: subcortical and cortical activation during grotesqueness perception in autism.

Atypical face processing plays a key role in social interaction difficulties encountered by individuals with autism. In the current fMRI study, the Thatcher illusion was used to investigate several aspects of face processing in 20 young adults with high-functioning autism spectrum disorder (ASD) and 20 matched neurotypical controls. "Thatcherized" stimuli were modified at either the eyes or the mouth and participants discriminated between pairs of faces while cued to attend to either of these features in upright and inverted orientation. Behavioral data confirmed sensitivity to the illusion and intact configural processing in ASD. Directing attention towards the eyes vs. the mouth in upright faces in ASD led to (1) improved discrimination accuracy; (2) increased activation in areas involved in social and emotional processing; (3) increased activation in subcortical face-processing areas. Our findings show that when explicitly cued to attend to the eyes, activation of cortical areas involved in face processing, including its social and emotional aspects, can be enhanced in autism. This suggests that impairments in face processing in autism may be caused by a deficit in social attention, and that giving specific cues to attend to the eye-region when performing behavioral therapies aimed at improving social skills may result in a better outcome.

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.

Differences in white matter reflect atypical developmental trajectory in autism: A Tract-based Spatial Statistics study.

Autism is a neurodevelopmental disorder in which white matter (WM) maturation is affected. We assessed WM integrity in 16 adolescents and 14 adults with high-functioning autism spectrum disorder (ASD) and in matched neurotypical controls (NT) using diffusion weighted imaging and Tract-based Spatial Statistics. Decreased fractional anisotropy (FA) was observed in adolescents with ASD in tracts involved in emotional face processing, language, and executive functioning, including the inferior fronto-occipital fasciculus and the inferior and superior longitudinal fasciculi. Remarkably, no differences in FA were observed between ASD and NT adults. We evaluated the effect of age on WM development across the entire age range. Positive correlations between FA values and age were observed in the right inferior fronto-occipital fasciculus, the left superior longitudinal fasciculus, the corpus callosum, and the cortical spinal tract of ASD participants, but not in NT participants. Our data underscore the dynamic nature of brain development in ASD, showing the presence of an atypical process of WM maturation, that appears to normalize over time and could be at the basis of behavioral improvements often observed in high-functioning autism.