A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability.

BACKGROUND: In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. METHODS: Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. RESULTS: Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). CONCLUSION: Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

Tracking the acquisition of anticipatory postural adjustments during a bimanual load-lifting task: A MEG study.

During bimanual coordination, that is, manipulating with the dominant hand an object held by the postural hand, anticipatory postural adjustments are required to cancel the perturbations and ensure postural stabilization. Using magnetoencephalography (MEG), we investigated changes mediating the acquisition of anticipatory postural adjustments during a bimanual load-lifting task. Participants lifted a load with their right hand, hence triggering the fall of a second load fixed to their left (postural) forearm. During Acquisition, the onset of load-lifting and the fall of the second load were experimentally delayed after few trials. During Control, load-lifting triggered the fall of the second load without delay. Upward elbow rotation decreased with trial repetition during Acquisition, hence attesting the ongoing acquisition of anticipatory postural adjustments. Bilateral event-related desynchronisation (ERD) of the alpha rhythm (8-12 Hz) was recorded. Generators of the mu rhythm were found within central and associative motor regions. Their spatial distribution within the hemisphere contralateral to the load-lifting arm was less refined and circumscribed during Acquisition compared to Control. Regression analyses emphasized the specific involvement of the precuneus in the right hemisphere contralateral to the postural forearm, and a medial prefrontal region in the left hemisphere. Analyses of the time course power showed that an increase in preunloading activation within the precuneus and a decrease in postunloading inhibition within the medial prefrontal region were associated with the acquisition of anticipatory postural adjustments. The study provides original insights into cortical activations mediating the progressive tuning of anticipatory postural adjustments during the acquisition stage of motor learning.

Mu-oscillation changes related to the development of anticipatory postural control in children and adolescents.

Anticipatory postural adjustments (APAs) cancel the destabilizing effects of movement on posture. Across development, the maturation of APAs is characterized by an accurate adjustment of the timing parameters of electromyographic (EMG) response. The study aimed at investigating the maturation of cortical oscillations involved in the improvement of APAs efficiency. Thirty-six healthy participants (8-16 yr) performed the bimanual load-lifting task in which subjects are instructed to lift a load, placed on the left forearm, with the right hand. EMG data were acquired over the biceps brachii on the postural arm to the determine EMG response onset. Electroencephalographic signals were analyzed in the time-frequency domain by convolution with complex Gaussian Morlet wavelets. Electrophysiological signature of APAs in children and adolescents consisted of a mu-rhythm desynchronization over the sensorimotor cortex contralateral to the postural arm. Across development, the mu-rhythm desynchronization was characterized by a progressive shift forward of the onset of the desynchronization, lower amplitude, and velocity. These changes occurred along with an alteration of the timing of the EMG response, as shown by an earlier onset of the flexor inhibition with increasing age. The maturational changes in the Mu-oscillations might sustain the development of APAs. A possible role of the Mu-oscillation in the generation of postural command is discussed. NEW & NOTEWORTHY Across development, our study showed a progressive shift forward of the parameters of the mu-rhythm desynchronization. These changes occurred along with an alteration of the timing parameters of the electromyographic response, as shown by an earlier onset of the flexor inhibition with increasing age. The progressive development of APAs during childhood and adolescence might therefore be sustained by maturational electrophysiological changes that include mu-rhythm oscillation modifications in the postural sensorimotor cortex.

Motor deficits in autism differ from that of developmental coordination disorder.

LAY ABSTRACT: A vast majority of individuals with autism spectrum disorder experience impairments in motor skills. Those are often labelled as additional developmental coordination disorder despite the lack of studies comparing both disorders. Consequently, motor skills rehabilitation programmes in autism are often not specific but rather consist in standard programmes for developmental coordination disorder. Here, we compared motor performance in three groups of children: a control group, an autism spectrum disorder group and a developmental coordination disorder group. Despite similar level of motor skills evaluated by the standard movement assessment battery for children, in a Reach-to-Displace Task, children with autism spectrum disorder and developmental coordination disorder showed specific motor control deficits. Children with autism spectrum disorder failed to anticipate the object properties, but could correct their movement as well as typically developing children. In contrast, children with developmental coordination disorder were atypically slow, but showed a spared anticipation. Our study has important clinical implications as motor skills rehabilitations are crucial to both populations. Specifically, our findings suggest that individuals with autism spectrum disorder would benefit from therapies aiming at improving their anticipation, maybe through the support of their preserved representations and use of sensory information. Conversely, individuals with developmental coordination disorder would benefit from a focus on the use of sensory information in a timely fashion.

Disentangling sensory precision and prior expectation of change in autism during tactile discrimination.

Predictive coding theories suggest that core symptoms in autism spectrum disorders (ASD) may stem from atypical mechanisms of perceptual inference (i.e., inferring the hidden causes of sensations). Specifically, there would be an imbalance in the precision or weight ascribed to sensory inputs relative to prior expectations. Using three tactile behavioral tasks and computational modeling, we specifically targeted the implicit dynamics of sensory adaptation and perceptual learning in ASD. Participants were neurotypical and autistic adults without intellectual disability. In Experiment I, tactile detection thresholds and adaptation effects were measured to assess sensory precision. Experiments II and III relied on two-alternative forced choice tasks designed to elicit a time-order effect, where prior knowledge biases perceptual decisions. Our results suggest a subtler explanation than a simple imbalance in the prior/sensory weights, having to do with the dynamic nature of perception, that is the adjustment of precision weights to context. Compared to neurotypicals, autistic adults showed no difference in average performance and sensory sensitivity. Both groups managed to implicitly learn and adjust a prior that biased their perception. However, depending on the context, autistic participants showed no, normal or slower adaptation, a phenomenon that computational modeling of trial-to-trial responses helped us to associate with a higher expectation for sameness in ASD, and to dissociate from another observed robust difference in terms of response bias. These results point to atypical perceptual learning rather than altered perceptual inference per se, calling for further empirical and computational studies to refine the current predictive coding theories of ASD.

Imaging of Podocytic Proteins Nephrin, Actin, and Podocin with Expansion Microscopy.

Disruption of the glomerular filter composed of the glomerular endothelium, glomerular basement membrane and podocytes, results in albuminuria. Podocyte foot processes contain actin bundles that bind to cytoskeletal adaptor proteins such as podocin. Those adaptor proteins, such as podocin, link the backbone of the glomerular slit diaphragm, such as nephrin, to the actin cytoskeleton. Studying the localization and function of these and other podocytic proteins is essential for the understanding of the glomerular filter's role in health and disease. The presented protocol enables the user to visualize actin, podocin, and nephrin in cells with super resolution imaging on a conventional microscope. First, cells are stained with a conventional immunofluorescence technique. All proteins within the sample are then covalently anchored to a swellable hydrogel. Through digestion with proteinase K, structural proteins are cleaved allowing isotropical swelling of the gel in the last step. Dialysis of the sample in water results in a 4-4.5-fold expansion of the sample and the sample can be imaged via a conventional fluorescence microscope, rendering a potential resolution of 70 nm.

Blunted emotion judgments of body movements in Parkinson's disease.

Some of the behavioral disorders observed in Parkinson's disease (PD) may be related to an altered processing of social messages, including emotional expressions. Emotions conveyed by whole body movements may be difficult to generate and be detected by PD patients. The aim of the present study was to compare valence judgments of emotional whole body expressions in individuals with PD and in healthy controls matched for age, gender and education. Twenty-eight participants (13 PD patients and 15 healthy matched control participants) were asked to rate the emotional valence of short movies depicting emotional interactions between two human characters presented with the "Point Light Displays" technique. To ensure understanding of the perceived scene, participants were asked to briefly describe each of the evaluated movies. Patients' emotional valence evaluations were less intense than those of controls for both positive (p < 0.001) and negative (p < 0.001) emotional expressions, even though patients were able to correctly describe the depicted scene. Our results extend the previously observed impaired processing of emotional facial expressions to impaired processing of emotions expressed by body language. This study may support the hypothesis that PD affects the embodied simulation of emotional expression and the potentially involved mirror neuron system.

Anticipatory postural adjustments in a bimanual load-lifting task in children with developmental coordination disorder.

AIM: Postural control is a fundamental component of action in which deficits have been shown to contribute to motor difficulties in children with developmental coordination disorder (DCD). The purpose of this study was to examine anticipatory postural adjustments (APAs) in children with DCD in a bimanual load-lifting task. METHOD: Sixteen children with reported motor problems (two females, 14 males; mean age 9 y; SD 2 y) and 16 typically developing, age-matched children (six females, 10 males; mean age 9 y; SD 2 y) took part in the study. The task required the children to maintain a stable elbow angle, despite imposed or voluntary unloading of the forearm. APAs were assessed using electromyography and kinematics analysis. RESULTS: Although children with DCD could compensate for the consequences of unloading, the results demonstrated that APAs were less efficient in children with DCD than in typically developing children. A positive and significant coefficient of regression between the flexor inhibition latency and the postural stabilization was only found in typically developing children. INTERPRETATION: The impaired fine-tuning of the muscle contribution and the poor stabilization performances demonstrate poor predictive modelling in DCD.

Highs and Lows in Motor Control Development.

Motor control is classically described as relying on two components: anticipatory control (feedforward processing) and online control (feedback processing). Here we aimed to unveil the developmental steps of both feedback and feedforward control in 5-10 years old children, using a simple and ecological task. We manipulated object's weight in a reach-to-displace paradigm. When the weight was known before lifting it, anticipatory processes were quantifiable during the reaching phase. Conversely, an unknown weight triggered online corrections during the displacing phase. Movement kinematics revealed that children anticipate this objet property as young as 5 y-o. This anticipation becomes adequate around 7 y-o and is paralleled by poor online corrections. This simple yet relevant paradigm should allow quantifying deviations from neurotypical patterns in disorders of motor control.

Tactile hypersensitivity and GABA concentration in the sensorimotor cortex of adults with autism.

Sensory hypersensitivity is frequently encountered in autism spectrum disorder (ASD). Gamma-aminobutyric acid (GABA) has been hypothesized to play a role in tactile hypersensitivity. The aim of the present study was twofold. First, as a study showed that children with ASD have decreased GABA concentrations in the sensorimotor cortex, we aimed at determining whether the GABA reduction remained in adults with ASD. For this purpose, we used magnetic resonance spectroscopy to measure GABA concentration in the sensorimotor cortex of neurotypical adults (n = 19) and ASD adults (n = 18). Second, we aimed at characterizing correlations between GABA concentration and tactile hypersensitivity in ASD. GABA concentration in the sensorimotor cortex of adults with ASD was lower than in neurotypical adults (decrease by 17%). Interestingly, GABA concentrations were positively correlated with self-reported tactile hypersensitivity in adults with ASD (r = 0.50, P = 0.01), but not in neurotypical adults. In addition, GABA concentrations were negatively correlated with the intra-individual variation during threshold measurement, both in neurotypical adults (r = -0.47, P = 0.04) and in adults with ASD (r = -0.59, P = 0.01). In other words, in both groups, the higher the GABA level, the more precise the tactile sensation. These results highlight the key role of GABA in tactile sensitivity, and suggest that atypical GABA modulation contributes to tactile hypersensitivity in ASD. We discuss the hypothesis that hypersensitivity in ASD could be due to suboptimal predictions about sensations. Autism Research 2019, 12: 562-575. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often experience tactile hypersensitivity. Here, our goal was to highlight a link between tactile hypersensitivity and the concentration of gamma-aminobutyric acid (GABA) (an inhibitory neurotransmitter) in the brain of adults with ASD. Indeed, self-reported hypersensitivity correlated with reduced GABA levels in brain areas processing touch. Our study suggests that this neurotransmitter may play a key role in tactile hypersensitivity in autism.

The Glasgow Sensory Questionnaire: Validation of a French Language Version and Refinement of Sensory Profiles of People with High Autism-Spectrum Quotient.

Sensory sensitivity peculiarities represent an important characteristic of Autism Spectrum Disorders (ASD). We first validated a French language version of the Glasgow Sensory Questionnaire (GSQ) (Robertson and Simmons in J Autism Dev Disord 43(4):775-784, 2013). The GSQ score was strongly positively correlated with the Autism-Spectrum Quotient (AQ) (r = 0.81, p < 10-6, n = 245). We further examined sensory profiles of groups with high versus low AQ. The high AQ group scored higher at the GSQ than the low AQ group for every sensory modality. Moreover, the high AQ group showed greater consistency in their patterns of hypersensitivity and hyposensitivity between sensory modalities, and stronger correlations between hyper and hyposensitivity. Results are discussed in the context of theories accounting for atypical sensory perception in ASD.

Adults with Autism Tend to Underestimate the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task.

The learning-style theory of Autism Spectrum Disorders (ASD) (Qian, Lipkin, Frontiers in Human Neuroscience 5:77, 2011) states that ASD individuals differ from neurotypics in the way they learn and store information about the environment and its structure. ASD would rather adopt a lookup-table strategy (LUT: memorizing each experience), while neurotypics would favor an interpolation style (INT: extracting regularities to generalize). In a series of visual behavioral tasks, we tested this hypothesis in 20 neurotypical and 20 ASD adults. ASD participants had difficulties using the INT style when instructions were hidden but not when instructions were revealed. Rather than an inability to use rules, ASD would be characterized by a disinclination to generalize and infer such rules.

Correction to: Adults with Autism Tend to Underestimate the Hidden Environmental Structure: Evidence from a Visual Associative Learning Task.

The original version of this article unfortunately contained a mistake in the article title.

Lighter or heavier than predicted: neural correlates of corrective mechanisms during erroneously programmed lifts.

A central concept in neuroscience is that the CNS signals the sensory discrepancy between the predicted and actual sensory consequences of action. It has been proposed that the cerebellum and parietal cortex are involved in this process. A discrepancy will trigger preprogrammed corrective responses and update the engaged sensorimotor memories. Here we use functional magnetic resonance imaging with an event-related design to investigate the neuronal correlates of such discrepancies. Healthy adults repeatedly lifted an object between their right index fingers and thumbs, and on some lifting trials, the weight of the object was unpredictably changed between light (230 g) and heavy (830 g). Regardless of whether the weight was heavier or lighter than predicted, activity was found in the right inferior parietal cortex (supramarginal gyrus). This suggests that this region is involved in the comparison of the predicted and actual sensory input and the updating of the sensorimotor memories. When the object was lighter or heavier than predicted, two different types of preprogrammed force corrections occurred. There was a slow force increase when the weight of the object was heavier than predicted. This corrective response was associated with activity in the left primary motor and somatosensory cortices. The fast termination of the excessive force when the object was lighter than predicted activated the right cerebellum. These findings show how the parietal cortex, cerebellum, and motor cortex are involved in the signaling of the discrepancy between predicated and actual sensory feedback and the associated corrective mechanisms.

Use-dependent up- and down-regulation of sensorimotor brain circuits in stroke patients.

OBJECTIVE: To examine whether cerebral activity during passive movements decreases with time after stroke, and if reduced activity in the representation for the upper extremity can be reversed with training. METHODS: Brain activity was measured by functional magnetic resonance imaging (fMRI) during passive wrist flexion-extension in 7 patients at varying time points after stroke, in a cross-sectional design. Upper limb function was also measured in all patients. Five of the patients took part in a training program and were measured again, behaviorally and with fMRI posttraining. Healthy control individuals of comparable age were also studied. RESULTS: In patients, reduced activity over time after stroke was found for the group in the supplementary motor area (SMA), contralateral primary motor cortex, and prefrontal and parietal association areas along with ipsilateral cerebellum. Activity in most of these areas was also reduced in the patient group as compared to the control group. After a half-hour of daily training for 4 weeks with repetitive passive and active arm movements, cerebral activation increased in the pre-SMA and SMA, ipsilateral primary sensory cortex and intraparietal sulcus, and contralateral cerebellum in parallel with functional improvements of the upper limb. Areas common to both analyses included the SMA, pre-SMA, primary sensory cortex, intraparietal sulcus, and cerebellum. CONCLUSIONS: Our findings suggest that a down-regulation of sensorimotor activity occurs progressively over time as a result of inactivity and that training may reverse the reduced brain activity.

Wallerian degeneration of the corticofugal tracts in chronic stroke: a pilot study relating diffusion tensor imaging, transcranial magnetic stimulation, and hand function.

OBJECTIVE: This study tested the hypothesis that degeneration of the corticofugal tracts (CFTs) is related to poor functional outcome in the upper limb after stroke. METHODS: . The authors used diffusion tensor imaging to determine the degree of white matter integrity of the CFT (FA(AH/UH)) in chronic stroke patients and controls. The functional integrity of the corticospinal pathway was examined using transcranial magnetic stimulation. Recruitment curves and silent period duration were measured. The relationship between FA(AH/UH) and functional outcome of the upper limb was also assessed using a battery of upper limb function tests. RESULTS: In patients, FA( AH/UH) correlated positively with the slope of recruitment curves (RC(AH/UH)) and grip strength. FA(AH/UH) also correlated negatively with the silent period duration (SP(AH/UH)). According to the FA(AH/UH), patients were also classified into groups with minimal or extensive Wallerian degeneration (WD). Patients with more extensive WD had poorer grip strength, dexterity, and range of movement. CONCLUSIONS: The authors' results suggest that structural and functional integrity of the CFT is essential to maintain function of the upper limb after stroke.

Gravity Cues Embedded in the Kinematics of Human Motion Are Detected in Form-from-Motion Areas of the Visual System and in Motor-Related Areas.

The present study investigated the cortical areas engaged in the perception of graviceptive information embedded in biological motion (BM). To this end, functional magnetic resonance imaging was used to assess the cortical areas active during the observation of human movements performed under normogravity and microgravity (parabolic flight). Movements were defined by motion cues alone using point-light displays. We found that gravity modulated the activation of a restricted set of regions of the network subtending BM perception, including form-from-motion areas of the visual system (kinetic occipital region, lingual gyrus, cuneus) and motor-related areas (primary motor and somatosensory cortices). These findings suggest that compliance of observed movements with normal gravity was carried out by mapping them onto the observer's motor system and by extracting their overall form from local motion of the moving light points. We propose that judgment on graviceptive information embedded in BM can be established based on motor resonance and visual familiarity mechanisms and not necessarily by accessing the internal model of gravitational motion stored in the vestibular cortex.

Deciphering human motion to discriminate social interactions: a developmental neuroimaging study.

Non-verbal communication plays a major role in social interaction understanding. Using functional magnetic resonance imaging, we explored the development of the neural networks involved in social interaction recognition based on human motion in children (8-11), adolescents (13-17), and adults (20-41). Participants watched point-light videos depicting two actors interacting or moving independently and were asked whether these agents were interacting or not. All groups successfully performed the discrimination task, but children had a lower performance and longer response times than the older groups. In all three groups, the posterior parts of the superior temporal sulci and middle temporal gyri, the inferior frontal gyri and the anterior temporal lobes showed greater activation when observing social interactions. In addition, adolescents and adults recruited the caudate nucleus and some frontal regions that are part of the mirror system. Adults showed greater activations in parietal and frontal regions (part of them belonging to the social brain) than adolescents.An increased number of regions that are part of the mirror system network or the social brain, as well as the caudate nucleus, were recruited with age. In conclusion, a shared set of brain regions enabling the discrimination of social interactions from neutral movements through human motion is already present in 8-year-old children. Developmental processes such as refinements in the social brain and mirror system would help grasping subtle cues in non-verbal aspects of social interactions.

Anticipatory postural adjustments in a bimanual load-lifting task in children with Duchenne muscular dystrophy.

We investigated the consequences of a progressive damage to the muscular system on the organization of anticipatory postural adjustments (APA) in children with Duchenne muscular dystrophy (DMD). We used a bimanual load-lifting task requiring the stabilization of the forearm position despite its voluntary or imposed unloading. Eight children with DMD from 4 to 11 years of age were compared to eight typically developing (TD) children. Elbow angle and multiple surface EMGs were recorded and assessed the use of APA. The muscle weakness did not impair (1) the proprioceptive afference and the motor efference constituting the unloading reflex; and (2) the use of an anticipatory function in children with DMD. However, APA used for the forearm stabilization were less efficient in the group of children with DMD. We conclude that in DMD the muscular weakness could be a restraint to the efficiency of APA with respect to TD children.

Shift of the Muscular Inhibition Latency during On-Line Acquisition of Anticipatory Postural Adjustments.

During action, Anticipatory Postural Adjustments (APAs) cancel the consequences of a movement on postural stabilization. Their muscular expression is characterized by early changes in the activity of the postural muscles, before the movement begins. To explore the mechanisms enabling the acquisition of APAs, a learning paradigm was designed in which the voluntary lifting of a load with one hand triggered the unloading of another load suspended below the contralateral forearm. The aim of this study was to investigate changes in the muscular expression that uncovers the progressive learning of new APAs. A trial-by-trial analysis of kinematic and electromyographic signals recorded on the right arm was conducted in twelve adults through six sessions of learning. Kinematic results reported an enhancement of the postural stabilization across learning. The main EMG pattern found during learning consisted of a flexor inhibition, where latency was shifted towards an earlier occurrence in parallel with the improvement of the postural performance. A linear regression analysis conducted between the inhibition latency and the maximal amplitude of elbow rotation showed that the earlier the inhibition onset, the better the postural stabilization. This study revealed that the progressive shift of the postural flexor inhibition latency could be considered as a reliable neurophysiological marker of the progressive learning of new APAs. Importantly, this marker could be used to track motor learning abnormalities in pathology. We relate our findings to the update of a forward predictive model of action, defined as a system that predicts beforehand the consequences of the action on posture.