Sensorimotor Behavior in Individuals with Autism Spectrum Disorder and Their Unaffected Biological Parents.

Background: Sensorimotor impairments are common in autism spectrum disorder (ASD) and evident in unaffected first-degree relatives, suggesting that they may serve as important endophenotypes associated with inherited risk. We tested the familiality of sensorimotor impairments in ASD across multiple motor behaviors and effector systems and in relation to parental broader autism phenotypic (BAP) characteristics. Methods: Fifty-eight autistic individuals (probands), 109 parents, and 89 control participants completed tests of manual motor and oculomotor control. Sensorimotor tests varied in their involvement of rapid, feedforward control and sustained, sensory feedback control processes. Subgroup analyses compared families with at least one parent showing BAP traits (BAP+) and those in which neither parent showed BAP traits (BAP-). Results: Probands with BAP- parents (BAP- probands) showed rapid manual motor and oculomotor deficits, while BAP+ probands showed sustained motor impairments compared to controls. BAP- parents showed impaired rapid oculomotor and sustained manual motor abilities relative to BAP+ parents and controls. Atypical rapid oculomotor impairments also were familial. Limitations: Larger samples of ASD families including greater samples of probands with BAP+ parents are needed. Genetic studies also are needed to link sensorimotor endophenotype findings directly to genes. Conclusions: Results indicate rapid sensorimotor behaviors are selectively impacted in BAP- probands and their parents and may reflect familial liabilities for ASD that are independent of familial autistic traits. Sustained sensorimotor behaviors were affected in BAP+ probands and BAP- parents re ecting familial traits that may only confer risk when combined with parental autistic trait liabilities. These findings provide new evidence that rapid and sustained sensorimotor alterations represent strong but separate familial pathways of ASD risk that demonstrate unique interactions with mechanisms related to parental autistic traits.

Autism spectrum disorders in extremely preterm infants and placental pathology findings: a matched case-control study.

BACKGROUND: The prevalence of autism spectrum disorders (ASD) is 5-fold higher in preterm (PT) infants born ≤28 weeks gestational age (GA) as compared to the general population. The relationship between placental pathologic lesions and ASD in PT infants has not been studied. OBJECTIVES: The objective of this study was to determine the association of placental pathology with the occurrence of ASD in PT infants born ≤28 weeks GA. STUDY DESIGN: A matched case-control study to identify confirmed ASD cases (n = 16) and matched controls (n = 48) born at Parkland Hospital between January 2012 and December 2015. Patients were matched using known variables associated with increased risk of ASD in PT infants. Placental histology from all births was reviewed. RESULTS: Children with ASD had 2-fold greater incidence of multiple placental pathologic lesions vs. matched controls [11/16 (69%) vs.16/48 (33%), respectively; P = 0.01]. In contrast, single placental pathologic lesions were not associated with ASD [5/16 (31%) vs. 21/48 (43%), respectively; P = 0.1]. CONCLUSIONS: In this study, we have demonstrated an association between the increasing complexity of histologic placental lesions and the later risk for ASD in infants born ≤28 weeks GA. Thus, placental pathology findings may be valuable in further understanding the prenatal pathologic processes underlying ASD in PT infants. IMPACT: PT infants with ASD have a 2-fold greater incidence of multiple placental pathologies. This is the first study to report an association between the complexity of histologic placental lesions and later risk of ASD in infant born extremely PT (i.e., ≤28 weeks GA). This study reiterates the importance of examining placental pathologic lesions, since placental evidence of antenatal insults correlates with postnatal morbidities and mortality in PT infants.

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

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.

Familiality of behavioral flexibility and response inhibition deficits in autism spectrum disorder (ASD).

Background: Diminished cognitive control, including reduced behavioral flexibility and behavioral response inhibition, has been repeatedly documented in autism spectrum disorder (ASD). We evaluated behavioral flexibility and response inhibition in probands and their parents using a family trio design to determine the extent to which these cognitive control impairments represent familial traits associated with ASD. Methods: We examined 66 individuals with ASD (probands), 135 unaffected biological parents, and 76 typically developing controls. Participants completed a probabilistic reversal learning task (PRL) and a stop-signal task (SST) to assess behavioral flexibility and response inhibition respectively. Rates of PRL and SST errors were examined across groups, within families, and in relation to clinical and subclinical traits of ASD. Based on prior findings that subclinical broader autism phenotypic (BAP) traits may co-segregate within families and reflect heritable risk factors, we also examined whether cognitive control deficits were more prominent in families in which parents showed BAP features (BAP+). Results: Probands and parents each showed increased rates of PRL and SST errors relative to controls. Error rates across tasks were not related. SST error rates inter-correlated among probands and their parents. PRL errors were more severe in BAP+ parents and their children relative to BAP- parents and their children. For probands of BAP+ parents, PRL and SST error rates were associated with more severe social-communication abnormalities and repetitive behaviors, respectively. Conclusion: Reduced behavioral flexibility and response inhibition are present among probands and their unaffected parents, but represent unique familial deficits associated with ASD that track with separate clinical issues. Specifically, behavioral response inhibition impairments are familial in ASD and manifest independently from parental subclinical features. In contrast, behavioral flexibility deficits are selectively present in families with BAP characteristics, suggesting they co-segregate in families with parental subclinical social, communication, and rigid personality traits. Together, these findings provide evidence that behavioral flexibility and response inhibition impairments track differentially with ASD risk mechanisms and related behavioral traits.

Precision Sensorimotor Control in Aging FMR1 Gene Premutation Carriers.

BACKGROUND: Individuals with premutation alleles of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition affecting sensorimotor function. Information on quantitative symptom traits associated with aging in premutation carriers is needed to clarify neurodegenerative processes contributing to FXTAS. MATERIALS AND METHODS: 26 FMR1 premutation carriers ages 44-77 years and 31 age-matched healthy controls completed rapid (2 s) and sustained (8 s) visually guided precision gripping tasks. Individuals pressed at multiple force levels to determine the impact of increasing the difficulty of sensorimotor actions on precision behavior. During initial pressing, reaction time, the rate at which individuals increased their force, the duration of pressing, and force accuracy were measured. During sustained gripping, the complexity of the force time series, force variability, and mean force were examined. During relaxation, the rate at which individuals decreased their force was measured. We also examined the relationships between visuomotor behavior and cytosine-guanine-guanine (CGG) repeat length and clinically rated FXTAS symptoms. RESULTS: Relative to controls, premutation carriers showed reduced rates of initial force generation during rapid motor actions and longer durations of their initial pressing with their dominant hand. During sustained force, premutation carriers demonstrated reduced force complexity, though this effect was specific to younger premutation carries during dominant hand pressing and was more severe for younger relative to older premutation carriers at low and medium force levels. Increased reaction time and lower sustained force complexity each were associated with greater CGG repeat length for premutation carriers. Increased reaction time and increased sustained force variability were associated with more severe clinically rated FXTAS symptoms. CONCLUSION: Overall our findings suggest multiple sensorimotor processes are disrupted in aging premutation carriers, including initial force control guided by feedforward mechanisms and sustained sensorimotor behaviors guided by sensory feedback control processes. Results indicating that sensorimotor issues in aging premutation carriers relate to both greater CGG repeat length and clinically rated FXTAS symptoms suggest that quantitative tests of precision sensorimotor ability may serve as key targets for monitoring FXTAS risk and progression.

Developmental Effects on Auditory Neural Oscillatory Synchronization Abnormalities in Autism Spectrum Disorder.

Previous studies have found alterations in 40 Hz oscillatory activity in response to auditory stimuli in adults with Autism Spectrum Disorder (ASD). The current study sought to examine the specificity and developmental trajectory of these findings by driving the cortex to oscillate at a range of frequencies in both children and adults with and without ASD. Fifteen participants with ASD (3 female, aged 6-23 years) and 15 age-matched controls (4 female, aged 6-25 years) underwent dense-array EEG as they listened to a carrier tone amplitude-modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. EEG data were analyzed for inter-trial phase coherence (ITPC) and single-trial power (STP). Older participants with ASD displayed significantly decreased ability to phase-lock to the stimulus in the low gamma frequency range relative to their typically developing (TD) counterparts, while younger ASD and TD did not significantly differ from each other. An interaction between age and diagnosis suggested that TD and ASD also show different developmental trajectories for low gamma power; TD showed a significant decrease in low gamma power with age, while ASD did not. Regardless of age, increased low gamma STP was significantly correlated with increased clinical scores for repetitive behaviors in the ASD group, particularly insistence on sameness. This study contributes to a growing body of evidence supporting alterations in auditory processing in ASD. Older ASD participants showed more pronounced low gamma deficits than younger participants, suggesting an altered developmental trajectory for neural activity contributing to auditory processing deficits that may also be more broadly clinically relevant. Future studies are needed employing a longitudinal approach to confirm findings of this cross-sectional study.

Cognitive mechanisms of inhibitory control deficits in autism spectrum disorder.

BACKGROUND: Inhibitory control deficits are common in autism spectrum disorder (ASD) and associated with more severe repetitive behaviors. Inhibitory control deficits may reflect slower execution of stopping processes, or a reduced ability to delay the onset of behavioral responses in contexts of uncertainty. Previous studies have documented relatively spared stopping processes in ASD, but whether inhibitory control deficits in ASD reflect failures to delay response onset has not been systematically assessed. Further, while improvements in stopping abilities and response slowing are seen through adolescence/early adulthood in health, their development in ASD is less clear. METHODS: A stop-signal test (SST) was administered to 121 individuals with ASD and 76 age and IQ-matched healthy controls (ages 5-28). This test included 'GO trials' in which participants pressed a button when a peripheral target appeared and interleaved 'STOP trials' in which they were cued to inhibit button-presses when a stop-signal appeared at variable times following the GO cue. STOP trial accuracy, RT of the stopping process (SSRT), and reaction time (RT) slowing during GO trials were examined. RESULTS: Relative to controls, individuals with ASD had reduced accuracy on STOP trials. SSRTs were similar across control and ASD participants, but RT slowing was reduced in patients compared to controls. Age-related increases in stopping ability and RT slowing were attenuated in ASD. Reduced stopping accuracy and RT slowing were associated with more severe repetitive behaviors in ASD. DISCUSSION: Our findings show that inhibitory control deficits in ASD involve failures to strategically delay behavioral response onset. These results suggest that reduced preparatory behavioral control may underpin inhibitory control deficits as well as repetitive behaviors in ASD. Typical age-related improvements in inhibitory control during late childhood/early adolescence are reduced in ASD, highlighting an important developmental window during which treatments may mitigate cognitive alterations contributing to repetitive behaviors.

Erratum to: Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome.

[This corrects the article DOI: 10.1186/s13229-017-0140-1.].

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome.

BACKGROUND: Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. METHODS: EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. RESULTS: Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. CONCLUSIONS: This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.

A resting EEG study of neocortical hyperexcitability and altered functional connectivity in fragile X syndrome.

BACKGROUND: Cortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr1 KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability. METHODS: We collected resting state dense-array electroencephalography data from 21 fragile X syndrome (FXS) patients and 21 age-matched healthy participants. RESULTS: FXS patients exhibited greater gamma frequency band power, which was correlated with social and sensory processing difficulties. Second, FXS patients showed increased spatial spreading of phase-synchronized high frequency neural activity in the gamma band. Third, we observed increased negative theta-to-gamma but decreased alpha-to-gamma band amplitude coupling, and the level of increased theta power was inversely related to the level of resting gamma power in FXS. CONCLUSIONS: Increased theta band power and coupling from frontal sources may represent a mechanism providing compensatory inhibition of high-frequency gamma band activity, potentially contributing to the widely varying level of neurophysiological and behavioral abnormalities and treatment response seen in full-mutation FXS patients. These findings extend preclinical observations and provide new mechanistic insights into brain alterations and their variability across FXS patients. Electrophysiological measures may provide useful translational biomarkers for advancing drug development and individualizing treatments for neurodevelopmental disorders with associated neuronal hyperexcitability.

Increased Force Variability Is Associated with Altered Modulation of the Motorneuron Pool Activity in Autism Spectrum Disorder (ASD).

Force control deficits have been repeatedly documented in autism spectrum disorder (ASD). They are associated with worse social and daily living skill impairments in patients suggesting that developing a more mechanistic understanding of the central and peripheral processes that cause them may help guide the development of treatments that improve multiple outcomes in ASD. The neuromuscular mechanisms underlying force control deficits are not yet understood. Seventeen individuals with ASD and 14 matched healthy controls completed an isometric index finger abduction test at 60% of their maximum voluntary contraction (MVC) during recording of the first dorsal interosseous (FDI) muscle to determine the neuromuscular processes associated with sustained force variability. Central modulation of the motorneuron pool activation of the FDI muscle was evaluated at delta (0-4 Hz), alpha (4-10 Hz), beta (10-35 Hz) and gamma (35-60 Hz) frequency bands. ASD patients showed greater force variability than controls when attempting to maintain a constant force. Relative to controls, patients also showed increased central modulation of the motorneuron pool at beta and gamma bands. For controls, reduced force variability was associated with reduced delta frequency modulation of the motorneuron pool activity of the FDI muscle and increased modulation at beta and gamma bands. In contrast, delta, beta, and gamma frequency oscillations were not associated with force variability in ASD. These findings suggest that alterations of central mechanisms that control motorneuron pool firing may underlie the common and often impairing symptoms of ASD.

Postural orientation and equilibrium processes associated with increased postural sway in autism spectrum disorder (ASD).

BACKGROUND: Increased postural sway has been repeatedly documented in children with autism spectrum disorder (ASD). Characterizing the control processes underlying this deficit, including postural orientation and equilibrium, may provide key insights into neurophysiological mechanisms associated with ASD. Postural orientation refers to children's ability to actively align their trunk and head with respect to their base of support, while postural equilibrium is an active process whereby children coordinate ankle dorsi-/plantar-flexion and hip abduction/adduction movements to stabilize their upper body. Dynamic engagement of each of these control processes is important for maintaining postural stability, though neither postural orientation nor equilibrium has been studied in ASD. METHODS: Twenty-two children with ASD and 21 age and performance IQ-matched typically developing (TD) controls completed three standing tests. During static stance, participants were instructed to stand as still as possible. During dynamic stances, participants swayed at a comfortable speed and magnitude in either anterior-posterior (AP) or mediolateral (ML) directions. The center of pressure (COP) standard deviation and trajectory length were examined to determine if children with ASD showed increased postural sway. Postural orientation was assessed using a novel virtual time-to-contact (VTC) approach that characterized spatiotemporal dimensions of children's postural sway (i.e., body alignment) relative to their postural limitation boundary, defined as the maximum extent to which each child could sway in each direction. Postural equilibrium was quantified by evaluating the amount of shared or mutual information of COP time series measured along the AP and ML directions. RESULTS: Consistent with prior studies, children with ASD showed increased postural sway during both static and dynamic stances relative to TD children. In regard to postural orientation processes, children with ASD demonstrated reduced spatial perception of their postural limitation boundary towards target directions and reduced time to correct this error during dynamic postural sways but not during static stance. Regarding postural equilibrium, they showed a compromised ability to decouple ankle dorsi-/plantar-flexion and hip abduction/adduction processes during dynamic stances. CONCLUSIONS: These results suggest that deficits in both postural orientation and equilibrium processes contribute to reduced postural stability in ASD. Specifically, increased postural sway in ASD appears to reflect patients' impaired perception of their body movement relative to their own postural limitation boundary as well as a reduced ability to decouple distinct ankle and hip movements to align their body during standing. Our findings that deficits in postural orientation and equilibrium are more pronounced during dynamic compared to static stances suggests that the increased demands of everyday activities in which children must dynamically shift their COP involve more severe postural control deficits in ASD relative to static stance conditions that often are studied. Systematic assessment of dynamic postural control processes in ASD may provide important insights into new treatment targets and neurodevelopmental mechanisms.

Neurophysiological hyperresponsivity to sensory input in autism spectrum disorders.

BACKGROUND: Atypical sensory processing is a common clinical observation in autism spectrum disorder (ASD). Neural hyperexcitability has been suggested as the cause for sensory hypersensitivity, a frequently reported clinical observation in ASD. We examined visual evoked responses to parametric increases in stimulus contrast in order to model neural responsivity of sensory systems in ASD. METHODS: Thirteen high-functioning individuals with ASD and 12 typically developing (TD) individuals completed a steady-state visual evoked potential study. Stimuli were vertical circular gratings oscillating at 3.76 Hz at varying contrasts (5, 10, 20,…, 90 % contrast, 10 levels). The average spectral power at the stimulus oscillation frequency was calculated for each contrast level. RESULTS: The magnitude of evoked sensory responses increased at a significantly greater rate and resulted in disproportionately elevated activation with higher contrasts in the ASD group. Approximately 45 % of ASD participants had rates of response increases greater than any TD participant. This alteration was highly associated with parental reports of these participants' sensory difficulties. CONCLUSIONS: Greater increases in visual responses over contrast manipulation suggest heightened excitability in the sensory cortex in ASD participants. Heightened neural excitability was observed in a substantial portion but not all of the ASD participants. This pattern suggests that individuals with higher excitability may constitute a neurobiologically distinct subgroup requiring individualized treatment interventions.

Individuals with autism spectrum disorder show abnormalities during initial and subsequent phases of precision gripping.

Sensorimotor impairments are common in autism spectrum disorder (ASD), but they are not well understood. Here we examined force control during initial pulses and the subsequent rise, sustained, and relaxation phases of precision gripping in 34 individuals with ASD and 25 healthy control subjects. Participants pressed on opposing load cells with their thumb and index finger while receiving visual feedback regarding their performance. They completed 2- and 8-s trials during which they pressed at 15%, 45%, or 85% of their maximum force. Initial pulses guided by feedforward control mechanisms, sustained force output controlled by visual feedback processes, and force relaxation rates all were examined. Control subjects favored an initial pulse strategy characterized by a rapid increase in and then relaxation of force when the target force was low (Type 1). When the target force level or duration of trials was increased, control subjects transitioned to a strategy in which they more gradually increased their force, paused, and then increased their force again. Individuals with ASD showed a more persistent bias toward the Type 1 strategy at higher force levels and during longer trials, and their initial force output was less accurate than that of control subjects. Patients showed increased force variability compared with control subjects when attempting to sustain a constant force level. During the relaxation phase, they showed reduced rates of force decrease. These findings suggest that both feedforward and feedback motor control mechanisms are compromised in ASD and these deficits may contribute to the dyspraxia and sensorimotor abnormalities often seen in this disorder.