Distinct Sensorimotor Feedforward and Feedback Deficits Vary with Age in Individuals with Autism Spectrum disorder


 Background: Sensorimotor issues are common in autism spectrum disorder (ASD), related to core symptoms, and predictive of worse functional outcomes. Deficits in rapid, feedforward processes executed prior to availability of sensory feedback, and continuous, feedback-guided motor behaviors each have been reported, but the degree to which these deficits are distinct or co-segregate in individuals is not well understood. Methods: To characterize feedforward and feedback control of motor behavior in ASD, we examined saccadic eye movements (feedforward) and sustained precision gripping (feedback) in 109 individuals with ASD and 101 age-matched typically developing (TD) controls (range: 5-28 years). We measured latency and gain of saccades and error, variability, and regularity of precision grip. Linear mixed effects models were conducted to examine whether sensorimotor behavior varied according to diagnostic group, age, handedness, and sex. Results: Individuals with ASD showed reduced accuracy of saccadic eye movements relative to controls, and their dysmetria was more severe at older ages. Individuals with ASD showed increased precision grip force variability relative to controls, especially at younger ages, while increased motor regularity was more pronounced in older individuals with ASD. Feedforward and feedback motor behaviors were strongly inter-related among controls, but not among individuals with ASD. Saccade dysmetria and increased force variability were associated with ASD symptom severity. Limitations: Our age-related findings rely on cross-sectional data. Longitudinal studies of component motor skills and their associations with clinical outcomes are needed to clarify neurodevelopmental mechanisms of core and associated symptoms of ASD. Feedforward behavior was characterized in the oculomotor system using ballistic movements completed too rapidly to be guided by online feedback; however, future studies are needed to examine feedforward and feedback processes across both manual and oculomotor systems. Conclusions: These findings suggest that separate neurodevelopmental mechanisms contribute to feedforward and feedback motor deficits in ASD, and that they are more manifest at different stages in life span development. Our results highlight the needs for more fine-grained approaches to parse separate motor impairments that often are considered as a unitary deficit in ASD, and to characterize variation in motor behaviors across development.

diagnosed according to updated criteria. Participants with ASD were excluded for known genetic or metabolic disorders 5 associated with ASD (e.g., fragile X syndrome, Tuberous sclerosis). Handedness was determined using self-report.

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General exclusion criteria included self-or caregiver report of any history of substance dependence or abuse within the 8 previous six months, history of non-febrile seizures or head trauma with loss of consciousness, complications during 9 pregnancy, delivery, or perinatal period, or current use of medications known to interfere with sensorimotor behavior 10 including stimulants, antipsychotics, anticonvulsants or benzodiazepines (Reilly et al., 2008). TD controls were excluded 11 if they had a known lifetime history of psychiatric or significant medical disorder, had a family history of a major 12 psychiatric disorder in their first-degree relatives, or a history of ASD in first or second-degree relatives. Participants 13 refrained from caffeine, nicotine, and alcohol on the day of testing and over-the-counter drugs with sedating properties 14 (e.g., cold medicine) within 12 hours of testing. Written informed consent was obtained from all participants, with assent 15 and parental consent obtained for minors. Study procedures were approved by the local Institutional Review Boards. 1 Before testing, each participant's maximum voluntary contraction (MVC) was calculated separately for each hand using 2 the average of the maximum force output during three consecutive three second trials. During testing, participants viewed 3 a horizontal white bar (FORCE) on a black screen that moved upward when force was applied to the load cells ( Figure   4 1b). A static TARGET bar turned from red to green to indicate the beginning of each trial and participants were instructed 5 to 1) press the load cells as quickly as possible when the TARGET bar turned green and 2) hold the FORCE bar steady at System; Astro-Med, Inc., West Warwick, RI). EOG electrodes were placed above and below the left eye and were linked

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to an AC-coupled bioamplifier. At UTSW, eye movements were recorded using an infrared, binocular camera-based eye 20 tracking system (500 Hz; EyeLink II, SR Research Ltd., Canada). Across both sites, participants performed a nine-point 21 calibration before each block of trials.

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During the visually guided saccade test (Figure 1d), visual stimuli subtending 0.5° of visual angle were presented in the 24 horizonal plane at eye level. Following the presentation of a central fixation appearing for 1.5-2.5 s (varied randomly), a 25 peripheral target was presented for 1.5 s at +12°. Fifteen trials were administered for each location (30 total trials); 26 location order varied pseudo randomly. Participants were instructed to look to the target as quickly as possible.
Force data were analyzed with a custom algorithm and scoring program developed previously by our group using 3 MATLAB (MathWorks; Wang et al., 2015). The first two seconds and the last second of each force trace were excluded 4 from analyses due to variability in the rate at which individuals reached the target force and terminated the trial 5 (Robichaud et al., 2005). Trials for which participants produced fewer than 6 seconds of continuous force data were 6 excluded from analyses. Trials also were excluded if the mean force exceeded twice the target force or was less than half 7 of the target force. Force data were linearly detrended to account for systematic changes in the mean force over the 8 duration of the trial. Data from each trial were visually inspected offline and scored blind to participant characteristics.

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Digital finite impulse response filters with non-linear transition bands were applied with a gradual transition band (from pass to no pass) between 20 and 65 Hz for velocity and position data, and between 30 and 65 Hz for acceleration data.

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Data from each trial were visually inspected offline and scored blind to participant characteristics. Trials were calibrated 24 independently using fixation data from central and peripheral target locations. Each trial was manually calibrated by 25 marking the stable center fixation prior to trial onset, and at the target location after the participant acquired the peripheral 26 target. Trials were evaluated for signal drift and head movement and re-calibrated using within-trial data from fixation of exceeded or fell back below 30 deg per s, respectively. Trials with latencies < 70 ms were considered anticipatory and 1 were not included in analyses. Trials were excluded if a blink occurred 100 ms prior to stimulus presentation or prior to 2 the end of the primary saccade.

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Saccade latency and gain were examined. Saccade latency was defined as the difference between peripheral target onset

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Level two (between-subjects) predictors were the same for grip and eye movement tests and included age, sex, and 26 diagnostic group. Location of data collection (UIC or UTSW) was included as a level two covariate of no interest. To 1 hypotheses and their nested two-way interactions. To identify the best-fitting models, predictors were iteratively removed 2 and model fit was compared between the previous and subsequent models using log likelihood ratio tests (Hox et al.,

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Dynamic adaptation of behavior is the product of integrated inputs across multiple modalities that operate on varying 8 timescales, including rapid feedforward processes and slower visual, proprioceptive, and haptic feedback information. The 9 integration of these multiple control processes is reflected in the time-dependent structure of the motor output, with 10 greater irregularity reflecting greater integration of independent systems (e.g., Pincus & Goldberger, 1994). Consistent 11 with our previous studies, we found reduced ApEn in ASD relative to controls suggesting a diminished ability to integrate control processes that may reflect multiple neurodevelopmental alterations contributing to impairment of continuous 24 motor behaviors in ASD. Finally, we found that females with ASD showed relatively preserved sensorimotor abilities at 25 low force suggesting sex-specific impacts on motor development. Though it is important to note that our study included 22 connectivity in males compared to hyper-connectivity in females with ASD within cerebellar sensory-motor networks 1 (Smith et al., 2019). While ASD disproportionately affects males, our findings highlight the need for future research on We demonstrate reduced saccade accuracy in individuals with ASD, implicating deficits in internal models that support

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Longitudinal studies of saccade accuracy across a range of severity of core and associated symptoms will help clarify 20 patterns of maturation of feedforward motor control processes.  We failed to identify significant relationships between deficits in feedback and feedforward motor control processes in 2 ASD. Along with our data showing feedback deficits in ASD were more severe during early childhood while impairments 3 in feedforward processes were more severe at older ages, these findings suggest that separate sensorimotor deficits 4 involve distinct neurodevelopmental mechanisms. Feedforward and feedback-guided processes are governed by separate, 5 but integrated brain systems that are thought to operate along a continuum (Seidler et al., 2004). Rapid, feedforward 6 behaviors primarily are controlled by highly precise internal models which are thought to be refined and stored in the