Feedforward and Feedback Motor Control Abnormalities Implicate Cerebellar Dysfunctions in Autism Spectrum Disorder

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and among the earliest manifestations of the disorder. They have been studied far less than the social-communication and cognitive deficits that define ASD, but a mechanistic understanding of sensorimotor abnormalities in ASD may provide key insights into the neural underpinnings of the disorder. In this human study, we examined rapid, precision grip force contractions to determine whether feedforward mechanisms supporting initial motor output before sensory feedback can be processed are disrupted in ASD. Sustained force contractions also were examined to determine whether reactive adjustments to ongoing motor behavior based on visual feedback are altered. Sustained force was studied across multiple force levels and visual gains to assess motor and visuomotor mechanisms, respectively. Primary force contractions of individuals with ASD showed greater peak rate of force increases and large transient overshoots. Individuals with ASD also showed increased sustained force variability that scaled with force level and was more severe when visual gain was highly amplified or highly degraded. When sustaining a constant force level, their reactive adjustments were more periodic than controls, and they showed increased reliance on slower feedback mechanisms. Feedforward and feedback mechanism alterations each were associated with more severe social-communication impairments in ASD. These findings implicate anterior cerebellar circuits involved in feedforward motor control and posterior cerebellar circuits involved in transforming visual feedback into precise motor adjustments in ASD

Saccade Adaptation Abnormalities Implicate Dysfunction of Cerebellar-Dependent Learning Mechanisms in Autism Spectrum Disorders (ASD)

The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD

The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders

The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD

Sensorimotor dysfunctions as primary features of autism spectrum disorders

Motor impairments in autism spectrum disorders (ASD) have received far less research attention than core social-communication and cognitive features. Yet, behavioral, neurophysiological, neuroimaging and histopathological studies have documented abnormal motor system development in the majority of individuals with ASD suggesting that these deficits may be primary to the disorder. There are several unique advantages to studying motor development in ASD. First, the neurophysiological substrates of motor skills have been well-characterized via animal and human lesion studies. Second, many of the single- gene disorders associated with ASD also are characterized by motor dysfunctions. Third, recent evidence suggests that the onset of motor dysfunctions may precede the emergence of social and communication deficits during the first year of life in ASD. Motor deficits documented in ASD indicate disruptions throughout the neuroaxis affecting cortex, striatum, the cerebellum and brainstem. Questions remain regarding the timing and development of motor system alterations in ASD, their association with defining clinical features, and their potential for parsing heterogeneity in ASD. Pursuing these questions through neurobiologically informed translational research holds great promise for identifying gene-brain pathways associated with ASD

Social cognitive development during the latency years: an examination of three measures

A host of research has focused on social cognitive development. Still, measurement limitations have hindered progress. Limitations include failures to examine developments in latency aged children and a scarcity of data examining related cognitive skills. We administered three social cognition measures, the Faux Pas Task (FP), the Movie Stills task (MS), and the Animations task, to 64 children between 6-12 years, and assessed children’s verbal ability. Results indicated that chronological age was related to MS and Animations task performance, but not to FP task performance after covarying children’s verbal ability. FP task performance was related to verbal mental age. Individual items of the FP task were separated in difficulty by whether or not they contained a negative word or phrase. Items with a negative word or phrase were answered correctly more often. These results and their implications for future research on social cognitive development are discussed

Resting-State Brain Network Dysfunctions Associated With Visuomotor Impairments in Autism Spectrum Disorder

Background: Individuals with autism spectrum disorder (ASD) show elevated levels of motor variability that are associated with clinical outcomes. Cortical–cerebellar networks involved in visuomotor control have been implicated in postmortem and anatomical imaging studies of ASD. However, the extent to which these networks show intrinsic functional alterations in patients, and the relationship between intrinsic functional properties of cortical–cerebellar networks and visuomotor impairments in ASD have not yet been clarified.Methods: We examined the amplitude of low-frequency fluctuation (ALFF) of cortical and cerebellar brain regions during resting-state functional MRI (rs-fMRI) in 23 individuals with ASD and 16 typically developing (TD) controls. Regions of interest (ROIs) with ALFF values significantly associated with motor variability were identified for for patients and controls respectively, and their functional connectivity (FC) to each other and to the rest of the brain was examined.Results: For TD controls, greater ALFF in bilateral cerebellar crus I, left superior temporal gyrus, left inferior frontal gyrus, right supramarginal gyrus, and left angular gyrus each were associated with greater visuomotor variability. Greater ALFF in cerebellar lobule VIII was associated with less visuomotor variability. For individuals with ASD, greater ALFF in right calcarine cortex, right middle temporal gyrus (including MT/V5), left Heschl's gyrus, left post-central gyrus, right pre-central gyrus, and left precuneus was related to greater visuomotor variability. Greater ALFF in cerebellar vermis VI was associated with less visuomotor variability. Individuals with ASD and TD controls did not show differences in ALFF for any of these ROIs. Individuals with ASD showed greater posterior cerebellar connectivity with occipital and parietal cortices relative to TD controls, and reduced FC within cerebellum and between lateral cerebellum and pre-frontal and other regions of association cortex.Conclusion: Together, these findings suggest that increased resting oscillations within visuomotor networks in ASD are associated with more severe deficits in controlling variability during precision visuomotor behavior. Differences between individuals with ASD and TD controls in the topography of networks showing relationships to visuomotor behavior suggest atypical patterns of cerebellar–cortical specialization and connectivity in ASD that underlies previously documented visuomotor deficits

Postural control processes during standing and step initiation in autism spectrum disorder

This work is licensed under a Creative Commons Attribution 4.0 International License.Background Individuals with autism spectrum disorder (ASD) show a reduced ability to maintain postural stability, though motor control mechanisms contributing to these issues and the extent to which they are associated with other gross motor activities (e.g., stepping) are not yet known. Methods Seventeen individuals with ASD and 20 typically developing (TD) controls (ages 6–19 years) completed three tests of postural control during standing. During the neutral stance, individuals stood with their feet shoulder width apart. During the Romberg one stance, they stood with feet close together. During the circular sway, participants stood with feet shoulder width apart and swayed in a circular motion. The standard deviation (SD) of their center of pressure (COP) in the mediolateral (ML) and anteroposterior (AP) directions and the COP trajectory length were examined for each stance. We also assessed mutual information (MI), or the shared dependencies between COP in the ML and AP directions. Participants also completed a stepping task in which they stepped forward from one force platform to an adjacent platform. The amplitude and duration of anticipatory postural adjustments (APAs) were examined, as were the maximum lateral sway, duration, and velocity of COP adjustments following the initial step. We examined stepping variables using separate one-way ANCOVAs with height as a covariate. The relationships between postural control and stepping measures and ASD symptom severity were assessed using Spearman correlations with scores on the Autism Diagnostic Observation Schedule–Second Edition (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R). Results Individuals with ASD showed increased COP trajectory length across stance conditions (p = 0.05) and reduced MI during circular sway relative to TD controls (p = 0.02). During stepping, groups did not differ on APA amplitude (p = 0.97) or duration (p = 0.41), but during their initial step, individuals with ASD showed reduced ML sway (p = 0.06), reduced body transfer duration (p < 0.01), and increased body transfer velocity (p = 0.02) compared to controls. Greater neutral stance COPML variability (r = 0.55, p = 0.02) and decreased lateral sway (r = − 0.55, p = 0.02) when stepping were associated with more severe restricted and repetitive behaviors in participants with ASD. Conclusions We found that individuals with ASD showed reduced MI during circular sway suggesting a reduced ability to effectively coordinate joint movements during dynamic postural adjustments. Additionally, individuals with ASD showed reduced lateral sway when stepping indicating that motor rigidity may interfere with balance and gait. Postural control and stepping deficits were related to repetitive behaviors in individuals with ASD indicating that motor rigidity and key clinical issues in ASD may represent overlapping pathological processes

Upper and Lower Limb Movement Kinematics in Aging

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation cytosine-guanine-guanine (CGG) trinucleotide repeat expansion of the FMR1 gene. FXTAS is estimated to be the most common single-gene form of ataxia in the aging population. Gait ataxia and intention tremor are the primary behavioral symptoms of FXTAS, though clinical evaluation of these symptoms often is subjective, contributing to difficulties in reliably differentiating individuals with FXTAS and asymptomatic premutation carriers. This study aimed to clarify the extent to which quantitative measures of gait and upper limb kinematics may serve as biobehavioral markers of FXTAS degeneration. Nineteen premutation carriers (aged 46-77 years), including 9 with possible, probable, or definite FXTAS and 16 sex- and IQ-matched healthy controls, completed tests of non-constrained walking and reaching while both standing (static reaching) and walking (dynamic reaching) to quantify gait and upper limb control, respectively. For the non-constrained walking task, participants wore reflective markers and walked at their preferred speed on a walkway. During the static reaching task, participants reached and lifted boxes of different sizes while standing. During the dynamic reaching task, participants walked to reach and lift the boxes. Movement kinematics were examined in relation to clinical ratings of neuromotor impairments and CGG repeat length. During non-constrained walking, individuals with FXTAS showed decreased stride lengths and stride velocities, increased percentages of double support time, and increased variabilities of cadence and center of mass relative to both asymptomatic premutation carriers and controls. While individuals with FXTAS did not show any static reaching differences relative to the other two groups, they showed multiple differences during dynamic reaching trials, including reduced maximum reaching velocity, prolonged acceleration time, and jerkier movement of the shoulder, elbow, and hand. Gait differences during non-constrained walking were associated with more severe clinically rated posture and gait symptoms. Reduced maximum reaching velocity and increased jerkiness during dynamic reaching were each related to more severe clinically rated kinetic dysfunction and overall neuromotor symptoms in FMR1 premutation carriers. Our findings suggest kinematic alterations consistent with gait ataxia and upper limb bradykinesia are each selectively present in individuals with FXTAS, but not asymptomatic aging premutation carriers. Consistent with neuropathological and magnetic resonance imaging (MRI) studies of FXTAS, these findings implicate cerebellar and basal ganglia degeneration associated with neuromotor decline. Our results showing associations between quantitative kinematic differences in FXTAS and clinical ratings suggest that objective assessments of gait and reaching behaviors may serve as critical and reliable targets for detecting FXTAS risk and monitoring progression

Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem

BACKGROUND: Individuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades. METHODS: A total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants’ performance. RESULTS: Saccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups. CONCLUSIONS: Deficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2040-2392-5-47) contains supplementary material, which is available to authorized users