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

Visuomotor brain network activation and functional connectivity among individuals with autism spectrum disorder

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and predictive of functional outcomes, though their neural underpinnings remain poorly understood. Using functional magnetic resonance imaging, we examined both brain activation and functional connectivity during visuomotor behavior in 27 individuals with ASD and 30 typically developing (TD) controls (ages 9–35 years). Participants maintained a constant grip force while receiving visual feedback at three different visual gain levels. Relative to controls, ASD participants showed increased force variability, especially at high gain, and reduced entropy. Brain activation was greater in individuals with ASD than controls in supplementary motor area, bilateral superior parietal lobules, and contralateral middle frontal gyrus at high gain. During motor action, functional connectivity was reduced between parietal-premotor and parietal-putamen in individuals with ASD compared to controls. Individuals with ASD also showed greater age-associated increases in functional connectivity between cerebellum and visual, motor, and prefrontal cortical areas relative to controls. These results indicate that visuomotor deficits in ASD are associated with atypical activation and functional connectivity of posterior parietal, premotor, and striatal circuits involved in translating sensory feedback information into precision motor behaviors, and that functional connectivity of cerebellar–cortical sensorimotor and nonsensorimotor networks show delayed maturation

Involvement of 5-HT(1B/1D) and 5-HT(2A) receptors in 5-HT-induced contraction of endothelium-denuded rabbit epicardial coronary arteries

1. The receptors responsible for 5-hydroxytryptamine (5-HT)-mediated contraction of rabbit isolated epicardial coronary artery denuded of endothelium was examined by bioassay. 2. A variety of 5-HT mimetics caused concentration-dependent contractions. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT)>5-HT>(±)-α-methyl-5-hydroxytryptamine ((±)-α-me-5-HT)=sumatriptan. This was not consistent with relative potencies at any single recognized 5-HT receptor, suggesting the presence of a mixed receptor population. In one subset of preparations precontracted with U46619 (10–30 nM) with the endothelium intact, none of the agonists caused a relaxation. 3. Contractions to 5-HT were antagonized by ketanserin, a 5-HT(2A)-selective antagonist, but the displacement of concentration-response curves was inconsistent with an interaction between 5-HT and a single receptor population; the slope of regression between antagonist log M concentration and agonist log (concentration-ratio −1) was shallow (0.57). Responses to 5-HT were also antagonized by the 5-HT(1B/1D)-receptor antagonist GR127935 and, again, the slope of regression was shallow (0.68). These data suggest a possible involvement of 5-HT(2A) and 5-HT(1B) or 5-HT(1D) receptors in the response to 5-HT. 4. Contractions to (±)-α-me-5-HT, which is selective for 5-HT(2A) over 5-HT(1B) and 5-HT(1D) receptors, were competitively antagonized by low concentrations of ketanserin. The regression between antagonist log M concentration and agonist log (concentration-ratio −1) fitted the Schild equation with a slope that was not significantly different from unity (0.95), giving a pA(2) value of 9.0. GR127935 (3–30 nM), had no effect on the contractile response to (±)-α-me-5-HT. These data establish, unequivocally, the presence of 5-HT(2A) receptors in the tissue. 5. Sumatriptan, a relatively selective 5-HT(1B/1D)-receptor agonist, induced contractions that were antagonized competitively by GR127935 (3–30 nM), although there was a reduction in the maximum response when concentrations of GR127935 exceeded 3 nM. The apparent pA(2) (estimated by imposing a unit slope on the log agonist (concentration-ratio −1) value in the presence of 3 nM GR127935) was 8.92. Contractions to sumatriptan were not affected by low (5-HT(2A) receptor-selective) concentrations of ketanserin, but were antagonized in a competitive manner at higher concentrations (pA(2) 6.5). These data appear to confirm the presence of 5-HT(1B) and/or 5-HT(1D) receptors in the tissue. 6. Antagonism of 5-HT responses by GR127935 was reassessed after blockade of 5-HT(2A) receptors with 1 μM ketanserin. Under these conditions, GR127935 was able to antagonize 5-HT-induced contractions fully. The slope of regression between log M antagonist concentration and log agonist (concentration-ratio −1) fitted the Schild equation with a slope not significantly different from unity (1.1) (albeit there was still a reduction in maximum response when GR127935 concentration exceeded 3 nM). The apparent pA(2) value was 8.8. This reinforces the evidence that 5-HT(1B) and/or 5-HT(1D) receptors contribute to the effects of 5-HT in the tissue. 7. In conclusion, in endothelium denuded rabbit epicardial coronary arteries, 5-HT activates 5-HT(2A) and 5-HT(1D) and/or 5-HT(1B) receptors to cause contraction. This appears to be similar to the situation in man