Restoring Shank3 in the rostral brainstem of shank3ab−/− zebrafish autism models rescues sensory deficits

People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly exhibit reduced responses to sensory stimuli; yet the changes in brain-wide activity that link these symptoms to mutations in the shank3 gene remain unknown. Here we quantify movement in response to sudden darkness in larvae of two shank3 zebrafish mutant models and show that both models exhibit dampened responses to this stimulus. Using brain-wide activity mapping, we find that shank3−/− light-sensing brain regions show normal levels of activity while sensorimotor integration and motor regions are less active. Specifically restoring Shank3 function in a sensorimotor nucleus of the rostral brainstem enables the shank3−/− model to respond like wild-type. In sum, we find that reduced sensory responsiveness in shank3−/− models is associated with reduced activity in sensory processing brain regions and can be rescued by restoring Shank3 function in the rostral brainstem. These studies highlight the importance of Shank3 function in the rostral brainstem for integrating sensory inputs to generate behavioral adaptations to changing sensory stimuli.

Caregiver Stress and the Association Between Clinically Observed and Caregiver-Reported Sensory Responsiveness

Date Presented 04/13/21 Sensory processing challenges are measured by caregiver report and clinician observation and affect many people with autism spectrum disorder and their caregivers. It is unclear how caregiver stress influences the correlation between scores on caregiver report and observational measures. The present analysis explores correlations between two formats of tools to assess sensory processing and indicates that caregiver stress moderates the association between sensory-seeking scores on the measures. Primary Author and Speaker: Emily Campi Additional Authors and Speakers: Abdullah S. Alsaeed, Kecia Doyle, Shanda N. Geil, and Kristen A. Pickett Contributing Authors: Noah T. Herzog

Claustral Projections to Anterior Cingulate Cortex Modulate Engagement with the External World

Engagement is a major determinant of performance. Hyper-engagement risks impulsivity and is fatiguing over time, while hypo-engagement could lead to missed opportunities. Even in sleep, when engagement levels are minimal, sensory responsiveness varies. Thus, maintaining an optimal engagement level with the environment is a fundamental cognitive ability. The claustrum, and in particular its reciprocal connectivity with executive regions in the frontal cortex, has been associated with salience, attention and sleep. These apparently disparate roles can be consolidated within the context of engagement. Here we describe the activity of claustro-frontal circuits in a task imposing a tradeoff between response inhibition and sensory acuity (ENGAGE). Recording calcium fiber photometry during >80,000 trials, we characterize claustrum recruitment during salient behavioral events, and find that a moderate level of activity in claustro-cingulate projections defines optimal engagement. Low activity of this pathway is associated with impulsive actions, while high activity is associated with behavioral lapses. Chemogenetic activation of cingulate-projecting claustrum neurons suppressed impulsive behavior and reduced the engagement of mice in the task. This relationship became even clearer upon addressing individual variability in the strategy mice employed during the ENGAGE task. Furthermore, this association of claustrum activity and engagement extends into sleep. Using simultaneous EEG and photometry recordings in the claustrum, we find that cingulate projecting claustrum neurons are most active during deep unresponsive slow-wave sleep, when mice are less prone to awakening by sensory stimuli.

Sensory Responsiveness Is Linked With Communication in Infant Siblings of Children With and Without Autism

Purpose Differences in communication development impact long-term outcomes of children with autism. Previous research has identified factors associated with communication in children with autism, but much of the variance in communication skill remains unexplained. It has been proposed that early differences in sensory responsiveness (i.e., hyporesponsiveness, hyperresponsiveness, and sensory seeking) may produce “cascading effects” on communication. Evidence for this theory is limited, however, as relations between sensory responsiveness and communication in the earliest stages of development have not been well established. The purpose of this study was to evaluate (a) whether infants with a heightened likelihood of autism diagnosis (i.e., infants with an older sibling with autism) differ from infants at general population–level likelihood of autism (i.e., infants with an older, nonautistic sibling) on patterns of sensory responsiveness, (b) whether early sensory responsiveness is correlated with concurrent communication, and (c) whether the aforementioned between-groups differences and associations are moderated by age. Method Participants were 40 infants (20 infants with an older sibling with autism, 20 infants with an older, nonautistic sibling) aged 12–18 months. A series of observational and parent report measures of sensory responsiveness and communication skill were administered. Results Group differences in sensory responsiveness across the 12- to 18-month period were limited (i.e., only observed for one measure of hyporesponsiveness), though selected differences in sensory responsiveness (i.e., parent-reported hyperresponsiveness and sensory seeking) emerged between groups over this developmental window. Parent-reported hyporesponsiveness was unconditionally, negatively associated with communication skills. Associations between expressive communication and (a) parent-reported sensory seeking and (b) an observational measure of hyperresponsiveness were moderated by age. Conclusions This study provides new insights into the nature of sensory responsiveness and theorized links with communication skill in infants at elevated and general population–level likelihood of autism diagnosis. Further work is needed to better characterize the effects of interest in a larger sample spanning a wider age range. Supplemental Material https://doi.org/10.23641/asha.14515542

Restoring Shank3 in a rostral sensorimotor brainstem nucleus rescues reduced light-evoked behaviors in shank3ab-/- zebrafish.

People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly present with symptoms of sensory hyporeactivity. To investigate how shank3 mutations impact brain circuits and contribute to sensory hyporeactivity, we generated two shank3 zebrafish mutant models. These shank3 mutant models both exhibit hyporeactivity to visual stimuli. Using whole-brain activity mapping, we show that light receptive brain nuclei show normal levels of activity while sensorimotor integration and motor regions are less active in shank3-/- mutants. Specifically rescuing Shank3 in a sensorimotor nucleus of the rostral brainstem is sufficient to rescue shank3-/- mutant hyporeactivity. In summary, reduced sensory responsiveness in shank3-/- mutant is associated with reduced activity across the brain and can be rescued by restoring Shank3 function in the rostral brainstem.

Abstract 14053: Problematic Feeding is Common and Related to Gastroesophageal Reflux in the First 6 Months After Neonatal Cardiac Surgery

Introduction: Feeding problems are often reported in infants after cardiac surgery. To date, no studies have followed the development of feeding after cardiac surgery using valid and reliable measures. Purpose: To describe feeding problems and the relationship between feeding and gastrointestinal tract symptoms in infants over the first 6 months (mos) after neonatal cardiac surgery. Methods: Parents of neonates requiring cardiac surgery were invited to complete surveys when their infant was 2, 4, and 6 mos old. The survey included the Neonatal Eating Assessment Tool (NeoEAT), Infant Gastroesophageal Reflux Questionnaire – Revised (I-GERQ-R), and Infant Gastrointestinal Symptoms Questionnaire (IGSQ). Scores on the NeoEAT subscales ( Infant Regulation, Energy & Physiologic Stability, Gastrointestinal Tract Function, Sensory Responsiveness , and Compelling Symptoms of Problematic Feeding) were categorized as problematic (≥ 90 th percentile) or not problematic (< 90 th percentile) based on reference data. Percent of the sample with problematic feeding at each time point was determined. Bivariate correlations were calculated between the NeoEAT, IGSQ, and I-GERQ-R. Results: 27 parents completed the surveys, reporting on 6 infants with single ventricle and 21 with two ventricle conditions. Problematic feeding scores were common at all times and in both cardiac conditions. Problematic scores were reported on Compelling Symptoms of Problematic Feeding for 52% of the sample at 2 mos, 36% at 4 mos, and 22% at 6 mos. Problematic scores occurred in Gastrointestinal Tract Function for 22% at 2 mos, 10% at 4 mos, and 39% at 6 mos. Problems occurred in Sensory Responsiveness in 17% at 2 mos, 24% at 4 mos, and 33% at 6 mos. Energy & Physiologic Stability problems occurred in 13%, 10%, and 22%, respectively. None reported problems in Infant Regulation . Symptoms of gastroesophageal reflux (I-GERQ-R) were significantly correlated with the NeoEAT ( p < .05), but gastrointestinal symptoms (IGSQ) were not. Conclusions: Problematic feeding is common in the first 6 mos after neonatal cardiac surgery and is related to gastroesophageal reflux symptoms. Some areas of feeding improved over time, while others worsened, likely related to developmental and disease-related changes.

Feeding, Eating, and Emotional Disturbances in Children with Avoidant/Restrictive Food Intake Disorder (ARFID)

Avoidant/restrictive food intake disorder (ARFID) is a relatively new diagnostic category. We sought to determine whether the Stanford Feeding Questionnaire (SFQ), an instrument for assessing picky eating, can differentiate children with ARFID from control children, and whether children with ARFID would show more nonfeeding/eating emotional problems than controls. Fifty children with ARFID were compared to 98 controls. Parents completed the SFQ, Screen for Child Anxiety Related Emotional Disorders (SCARED), Strength and Difficulties Questionnaire (SDQ), and Sensory Responsiveness Questionnaire (SRQ). On the SFQ, 12 items represented child ARFID behaviors (SFQ-ARFID Scale), and another 15 items represented parental feeding problems (SFQ-PFP Scale). We found that the SFQ-ARFID and SFQ-PFP Scale scores were significantly higher in children with ARFID vs. controls. Children with ARFID demonstrated higher SDQ-Total-Difficulties, higher SDQ-Internalizing-Difficulties and lower SRQ-Hedonic scores compared with controls. Of all parameters, the SFQ-ARFID Scale best differentiated children with ARFID from control children (area under receiver operating characteristics curve = 0.939, 95% CI, 0.895–0.983, p < 0.001). These findings suggest that parental reports show more eating problems and emotional disturbances in children with ARFID vs. controls, and more parental feeding problems. Further research is required to determine whether the SFQ-ARFID Scale may serve as an effective screening tool for the identification of ARFID.