Pupil and Salivary Indicators of Autonomic Dysfunction in Autism Spectrum Disorder

This is the peer reviewed version of the following article: Anderson, C. J., Colombo, J. and Unruh, K. E. (2013), Pupil and salivary indicators of autonomic dysfunction in autism spectrum disorder. Dev. Psychobiol., 55: 465–482. doi:10.1002/dev.21051, which has been published in final form at http://doi.org/10.1002/dev.21051. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Dysregulated tonic pupil size has been reported in Autism Spectrum Disorder (ASD). Among the possible sources of this dysregulation are disruptions in the feedback loop between norepinephrine (NE) and hypothalamic systems. In the current study, we examined afternoon levels of salivary alpha-amylase (sAA, a putative correlate of NE) and cortisol (used to assess stress-based responses) in two independent samples of children with ASD. We found a larger pupil size and lower sAA levels in ASD, compared to typical and clinical age-matched controls. This was substantiated at the individual level, as sAA levels were strongly correlated with tonic pupil size. Relatively little diurnal variation in sAA taken in the home environment in the ASD group was also observed, while typical controls showed a significant linear increase throughout the day. Results are discussed in terms of potential early biomarkers and the elucidation of underlying neural dysfunction in ASD

Cortical and subcortical alterations associated with precision visuomotor behavior in individuals with autism spectrum disorder

In addition to core deficits in social-communication abilities and repetitive behaviors and interests, many 2 patients with autism spectrum disorder (ASD) experience developmental comorbidities, including 3 sensorimotor issues. Sensorimotor issues are common in ASD and associated with more severe clinical 4 symptoms. Importantly, sensorimotor behaviors are precisely quantifiable and highly translational, 5 offering promising targets for neurophysiological studies of ASD. We used functional MRI to identify 6 brain regions associated with sensorimotor behavior using a visually-guided precision gripping task in 7 individuals with ASD (N=20) and age-, IQ-, and handedness-matched controls (N=18). During 8 visuomotor behavior, individuals with ASD showed greater force variability than controls. BOLD signal 9 for multiple cortical and subcortical regions was associated with force variability, including motor and 10 premotor cortex, posterior parietal cortex, extrastriate cortex, putamen, and cerebellum. Activation in 11 right premotor cortex scaled with sensorimotor variability in controls, but not in ASD. Individuals with 12 ASD showed greater activation than controls in left putamen and left cerebellar lobule VIIb and activation 13 in these regions was associated with more severe clinically-rated symptoms of ASD. Together, these 14 results suggest that greater sensorimotor variability in ASD is associated with altered cortical-striatal 15 processes supporting action selection and cortical-cerebellar circuits involved in feedback-guided reactive 16 adjustments of motor output. Our findings also indicate that atypical organization of visuomotor cortical 17 circuits may result in heightened reliance on subcortical circuits typically dedicated to motor skill 18 acquisition. Overall, these results provide new evidence that sensorimotor alterations in ASD involve 19 aberrant cortical and subcortical organization that may contribute to key clinical issues in patients. 20 21 New and noteworthy: This is the first known study to examine functional brain activation during 22 precision visuomotor behavior in autism spectrum disorder (ASD). We replicate previous findings of 23 elevated force variability in ASD and find these deficits are associated with atypical function of ventral 24 premotor cortex, putamen, and posterolateral cerebellum, indicating cortical-striatal processes supporting 25 action selection and cortical-cerebellar circuits involved in feedback-guided reactive adjustments of motor 26 output may be key targets for understanding the neurobiology of ASD.NICHD 055751NIMH R01 12743-01NCATS TL1 TR002368,Kansas Center for Autism Research and Training (K-CART) Research Investment Council Strategic Initiative Gran

Initial action output and feedback-guided motor behaviors in 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 behaviors supported primarily by feedforward mechanisms, and continuous, feedback-guided motor behaviors each have been reported, but the degrees to which they are distinct or co-segregate within individuals and across development are not well understood. Methods We characterized behaviors that varied in their involvement of feedforward control relative to feedback control across skeletomotor (precision grip force) and oculomotor (saccades) control systems in 109 individuals with ASD and 101 age-matched typically developing controls (range: 5–29 years) including 58 individuals with ASD and 57 controls who completed both grip and saccade tests. Grip force was examined across multiple force (15, 45, and 85% MVC) and visual gain levels (low, medium, high). Maximum grip force also was examined. During grip force tests, reaction time, initial force output accuracy, variability, and entropy were examined. For the saccade test, latency, accuracy, and trial-wise variability of latency and accuracy were examined. Results Relative to controls, individuals with ASD showed similar accuracy of initial grip force but reduced accuracy of saccadic eye movements specific to older ages of our sample. Force variability was greater in ASD relative to controls, but saccade gain variability (across trials) was not different between groups. Force entropy was reduced in ASD, especially at older ages. We also find reduced grip strength in ASD that was more severe in dominant compared to non-dominant hands. Limitations Our age-related findings rely on cross-sectional data. Longitudinal studies of sensorimotor behaviors and their associations with ASD symptoms are needed. Conclusions We identify reduced accuracy of initial motor output in ASD that was specific to the oculomotor system implicating deficient feedforward control that may be mitigated during slower occurring behaviors executed in the periphery. Individuals with ASD showed increased continuous force variability but similar levels of trial-to-trial saccade accuracy variability suggesting that feedback-guided refinement of motor commands is deficient specifically when adjustments occur rapidly during continuous behavior. We also document reduced lateralization of grip strength in ASD implicating atypical hemispheric specialization

Cerebellar Volumes and Sensorimotor Behavior in Autism Spectrum Disorder

Background Sensorimotor issues are common in autism spectrum disorder (ASD), though their neural bases are not well understood. The cerebellum is vital to sensorimotor control and reduced cerebellar volumes in ASD have been documented. Our study examined the extent to which cerebellar volumes are associated with multiple sensorimotor behaviors in ASD. Materials and Methods Fifty-eight participants with ASD and 34 typically developing (TD) controls (8–30 years) completed a structural MRI scan and precision grip testing, oculomotor testing, or both. Force variability during precision gripping as well as absolute error and trial-to-trial error variability of visually guided saccades were examined. Volumes of cerebellar lobules, vermis, and white matter were quantified. The relationships between each cerebellar region of interest (ROI) and force variability, saccade error, and saccade error variability were examined. Results Relative to TD controls, individuals with ASD showed increased force variability. Individuals with ASD showed a reduced volume of cerebellar vermis VI-VII relative to TD controls. Relative to TD females, females with ASD showed a reduced volume of bilateral cerebellar Crus II/lobule VIIB. Increased volume of Crus I was associated with increased force variability. Increased volume of vermal lobules VI-VII was associated with reduced saccade error for TD controls but not individuals with ASD. Increased right lobule VIII and cerebellar white matter volumes as well as reduced right lobule VI and right lobule X volumes were associated with greater ASD symptom severity. Reduced volumes of right Crus II/lobule VIIB were associated with greater ASD symptom severity in only males, while reduced volumes of right Crus I were associated with more severe restricted and repetitive behaviors only in females. Conclusion Our finding that increased force variability in ASD is associated with greater cerebellar Crus I volumes indicates that disruption of sensory feedback processing supported by Crus I may contribute to skeletomotor differences in ASD. Results showing that volumes of vermal lobules VI-VII are associated with saccade precision in TD but not ASD implicates atypical organization of the brain systems supporting oculomotor control in ASD. Associations between volumes of cerebellar subregions and ASD symptom severity suggest cerebellar pathological processes may contribute to multiple developmental challenges in ASD

Endophenotype trait domains for advancing gene discovery in autism spectrum disorder

Abstract Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals with ASD, it is likely that the primary causes involve multiple common inherited variants that individually account for only small levels of variation in phenotypic outcomes. This genetic landscape creates a major challenge for detecting small but important pathogenic effects associated with ASD. To address similar challenges, separate fields of medicine have identified endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition and leveraged the study of these traits to map polygenic mechanisms and advance more personalized therapeutic strategies for complex diseases. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to psychiatric and developmental disorders because they are embedded within the causal chain between genotype and clinical phenotype, and they are more proximal to the action of the gene(s) than behavioral traits. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies. In this review, we argue that advancing knowledge of the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs with measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. We also emphasize that clarification of endophenotypic traits necessarily will involve integration of transdiagnostic approaches as candidate traits likely reflect liability for multiple clinical conditions and often are agnostic to diagnostic boundaries. Multiple candidate endophenotypes associated with ASD likelihood are described, and we propose a new focus on the analysis of “endophenotype trait domains” (ETDs), or traits measured across multiple levels (e.g., molecular, cellular, neural system, neuropsychological) along the causal pathway from genes to behavior. To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We also present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical autistic traits, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes associated with ASD as well as overlapping neurodevelopmental disorders

Cerebellar Volumes and Sensorimotor Behavior in Autism Spectrum Disorder

Background: Sensorimotor issues are common in autism spectrum disorder (ASD), though their neural bases are not well understood. The cerebellum is vital to sensorimotor control and reduced cerebellar volumes in ASD have been documented. Our study examined the extent to which cerebellar volumes are associated with multiple sensorimotor behaviors in ASD. Materials and Methods: Fifty-eight participants with ASD and 34 typically developing (TD) controls (8–30 years) completed a structural MRI scan and precision grip testing, oculomotor testing, or both. Force variability during precision gripping as well as absolute error and trial-to-trial error variability of visually guided saccades were examined. Volumes of cerebellar lobules, vermis, and white matter were quantified. The relationships between each cerebellar region of interest (ROI) and force variability, saccade error, and saccade error variability were examined. Results: Relative to TD controls, individuals with ASD showed increased force variability. Individuals with ASD showed a reduced volume of cerebellar vermis VI-VII relative to TD controls. Relative to TD females, females with ASD showed a reduced volume of bilateral cerebellar Crus II/lobule VIIB. Increased volume of Crus I was associated with increased force variability. Increased volume of vermal lobules VI-VII was associated with reduced saccade error for TD controls but not individuals with ASD. Increased right lobule VIII and cerebellar white matter volumes as well as reduced right lobule VI and right lobule X volumes were associated with greater ASD symptom severity. Reduced volumes of right Crus II/lobule VIIB were associated with greater ASD symptom severity in only males, while reduced volumes of right Crus I were associated with more severe restricted and repetitive behaviors only in females. Conclusion: Our finding that increased force variability in ASD is associated with greater cerebellar Crus I volumes indicates that disruption of sensory feedback processing supported by Crus I may contribute to skeletomotor differences in ASD. Results showing that volumes of vermal lobules VI-VII are associated with saccade precision in TD but not ASD implicates atypical organization of the brain systems supporting oculomotor control in ASD. Associations between volumes of cerebellar subregions and ASD symptom severity suggest cerebellar pathological processes may contribute to multiple developmental challenges in ASD