Remotely supervised at-home delivery of taVNS for autism spectrum disorder: feasibility and initial efficacy.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has potential clinical application for autism spectrum disorder (ASD). At-home sessions are necessary to allow delivery of repeated sessions, and remove burden on patients for daily visits, and reduce costs of clinic delivery. Our objective was to validate a protocol for remote supervised administration for home delivery of taVNS using specially designed equipment and platform. Methods: An open-label design was followed involving administration by caretakers to 12 patients with ASD (ages:7-16). Daily 1-h sessions over 2 weeks were administered under remote supervision. The primary outcome was feasibility, which was assessed by completion rate, stimulation tolerability, and confirmation of programmed stimulation delivery. The secondary measures were initial efficacy assessed by Childhood Anxiety Sensitivity Index-Revised (CASI-R), Parent Rated Anxiety Scale for Youth with ASD (PRAS-ASD), and Clinician Global Impression (CGI) scales. Sleep measures were also tracked using Cleveland Adolescent Sleep Questionnaire (CASQ). Results: Across 132 sessions, we obtained an 88.5% completion rate. A total of 22 expected adverse events were reported with headache being the most common followed by transient pain, itchiness, and stinging at the electrode site. One subject dropped out of the study unrelated to the stimulation or the study. Average scores of anxiety (CASI-R, PRAS-ASD, and CGI) and sleepiness (CASQ) were all improved at the 2 week time point. While not powered to determine efficacy, benefits were suggested in this open label pilot. Conclusion: Remotely supervised, proxy-administered, at-home delivery of taVNS is feasible in patients with ASD. Initial efficacy supports pursuing larger scale trials.

Potential Neuroprotective Effects of Dietary Omega-3 Fatty Acids on Stress in Alzheimer's Disease.

BACKGROUND: A large number of individual potentially modifiable factors are associated with risk for Alzheimer's disease (AD). However, less is known about the interactions between the individual factors. METHODS: In order to begin to examine the relationship between a pair of factors, we performed a pilot study, surveying patients with AD and controls for stress exposure and dietary omega-3 fatty acid intake to explore their relationship for risk of AD. RESULTS: For individuals with the greatest stress exposure, omega-3 fatty acid intake was significantly greater in healthy controls than in AD patients. There was no difference among those with low stress exposure. CONCLUSIONS: These initial results begin to suggest that omega-3 fatty acids may mitigate AD risk in the setting of greater stress exposure. This will need to be examined with larger populations and other pairs of risk factors to better understand these important relationships. Examining how individual risk factors interact will ultimately be important for learning how to optimally decrease the risk of AD.

The Relationship between Maternal Antibodies to Fetal Brain and Prenatal Stress Exposure in Autism Spectrum Disorder.

Environmental and genetic factors contribute to the etiology of autism spectrum disorder (ASD), but their interaction is less well understood. Mothers that are genetically more stress-susceptible have been found to be at increased risk of having a child with ASD after exposure to stress during pregnancy. Additionally, the presence of maternal antibodies for the fetal brain is associated with a diagnosis of ASD in children. However, the relationship between prenatal stress exposure and maternal antibodies in the mothers of children diagnosed with ASD has not yet been addressed. This exploratory study examined the association of maternal antibody response with prenatal stress and a diagnosis of ASD in children. Blood samples from 53 mothers with at least one child diagnosed with ASD were examined by ELISA. Maternal antibody presence, perceived stress levels during pregnancy (high or low), and maternal 5-HTTLPR polymorphisms were examined for their interrelationship in ASD. While high incidences of prenatal stress and maternal antibodies were found in the sample, they were not associated with each other (p = 0.709, Cramér's V = 0.051). Furthermore, the results revealed no significant association between maternal antibody presence and the interaction between 5-HTTLPR genotype and stress (p = 0.729, Cramér's V = 0.157). Prenatal stress was not found to be associated with the presence of maternal antibodies in the context of ASD, at least in this initial exploratory sample. Despite the known relationship between stress and changes in immune function, these results suggest that prenatal stress and immune dysregulation are independently associated with a diagnosis of ASD in this study population, rather than acting through a convergent mechanism. However, this would need to be confirmed in a larger sample.

Altered Allocation of Vertical Attention in Individuals With Autism Spectrum Disorder.

BACKGROUND: Typical adults most frequently orient their attention to other people's eyes, whereas individuals with autism spectrum disorder (ASD) orient their attention to other people's mouths. Typical adults also reveal visuospatial biases on tasks such as vertical and horizontal line bisections. Therefore, the difference in face viewing might be related to a more general group difference in the allocation of vertical attention. OBJECTIVE: To use vertical line bisection and quadrisection tasks to evaluate whether individuals with ASD have a more downward-oriented vertical attentional bias than do typical individuals. METHOD: We recruited 20 individuals with ASD and 20 control participants matched for age (6-23 years), IQ, and sex. We asked the individuals to bisect and quadrisect lines on the top and bottom when the vertical lines were placed at the intersection of their right, left, and center egocentric sagittal planes and their coronal plane. The distances from the true midpoint and quadripoint were measured, and between-group performances were compared. RESULTS: No significant difference was found between the ASD and control groups for vertical line bisections or lower line quadrisections. However, when the ASD group was compared with the control group for higher line quadrisections, the ASD group exhibited a greater upward deviation. CONCLUSION: There is no downward vertical attentional spatial bias associated with ASD that could help to explain these individuals' attentional bias toward the mouth. However, additional studies are required to learn if this atypical upward vertical attentional bias might account for some of the symptoms and signs associated with ASD.

Pilot Study of the Effects of Paced Breathing on Measures of Convergent and Divergent Thinking.

BACKGROUND: The ability of the autonomic nervous system's stress response to impair aspects of cognitive flexibility is known. However, the ability to modulate the sympathetic response and improve these cognitive impairments via nonpharmacological intervention, such as paced breathing (PB), requires further investigation. OBJECTIVE: To better elucidate the effects of PB on cognition. METHOD: We employed a PB protocol in a total of 52 healthy men and women and measured performance on convergent and divergent cognitive tasks, perceived stress, and physiological measures (eg, blood pressure, heart rate). Participants attended two experimental sessions consisting of either PB or normal breathing followed by cognitive assessments including convergent (compound remote associate, anagram) and divergent (alternate use, fluency) tasks. Experiment 2 consisted of more difficult versions of cognitive tasks compared with Experiment 1. RESULTS: In Experiment 1, PB significantly reduced the female participants' systolic and diastolic blood pressure immediately after the breathing protocol without affecting their cognition. In Experiment 2, PB significantly reduced perceived stress immediately after the breathing protocol, regardless of sex. There was no effect on cognition in Experiment 2, but a correlation was observed between perceived stress change and anagram number solved change. CONCLUSION: While PB modulates sympathetic activity in females, there was a lack of improvement in cognitive flexibility performance. At least for a single trial of PB, cognitive flexibility did not improve.

Bidirectional relationship between internalizing symptoms and gastrointestinal problems in youth with Autism Spectrum Disorder.

Many youth with autism spectrum disorder (ASD) experience co-occurring conditions, such as gastrointestinal (GI) problems and internalizing symptoms. However, the relationship among these co-occurring problems is not well-understood. We analyzed parent reports of GI problems and internalizing symptoms of 621 youth with ASD using path models in a structural equation modeling framework. The best-fitting model was a bidirectional model wherein internalizing symptoms, including withdrawn and anxious behavior, were correlated with GI problems, including constipation, diarrhea, nausea, and stomach pain. This study provides a better understanding of the relationship among co-occurring conditions in youth with ASD and should encourage clinicians to consider treatment of underlying internalizing symptoms or GI problems when providing services for individuals with ASD.

Pilot Study of Real-World Monitoring of the Heart Rate Variability in Amyotrophic Lateral Sclerosis.

Aims: Cardiovascular dysautonomia may impact the quality of life and survival in amyotrophic lateral sclerosis (ALS). Such dysfunction is not systematically assessed in these patients. Wearable devices could help. The feasibility of a wearable biosensor to detect heart rate variability (HRV), a physiological marker of sympathovagal balance, was studied for the first time in real-world settings in ALS. Methods: Five ALS patients (two early/three late; one bulbar-onset; mildly-to-moderately disabled) and five age/sex/BMI/comorbidities-matched controls underwent assessment of 3-day HRV via VitalConnect biosensor (worn on the left thorax). De-identified data captured by the biosensor were transferred to a secure cloud server via a relay Bluetooth device. Baseline ALS severity/anxiety and physical activity during testing were documented/quantified. Time-domain HRV measures (i.e., pNN50) were analyzed. Results: An overall 3-day abnormal HRV (pNN50 < 3%), was found in three out of five patients (mean ± SD for the group, 2.49 ± 1.51). Similar changes were reported in controls (12.32 ± 21.14%). There were no statistically significant relationships between pNN50 values and baseline anxiety or physical activity during the tested days (p > 0.05 for both groups). A negative correlation was found between pNN50 values and age in patients (p = 0.01) and controls (p = 0.09), which is similar with what is found in the general population. In line with prior studies, pNN50 values were independent of disease stage (p = 0.6) and disability (p = 0.4). Conclusions: These preliminary results suggest that remote HRV measures using the VitalConnect is feasible and may constitute an improved strategy to provide insights into sympathovagal balance in ALS. Further work with larger sample sizes is warranted.

Examination of five- and four-subtest short form IQ estimations for the Wechsler Intelligence Scale for Children-Fifth edition (WISC-V) in a mixed clinical sample.

Evaluating general cognitive ability (i.e., intelligence) is common in neuropsychological practice, and identifying abbreviated assessments of intelligence is often advantageous. Despite the Wechsler Intelligence Scale for Children, Fifth Edition's (WISC-V) widespread contemporary use, limited research has identified clinically useful short form (SF) full scale IQ (FSIQ) estimations in clinical samples. This study sought to address this gap in the literature. Two hundred sixty-eight pediatric participants (M age = 9.79; 69% male; 88% Caucasian/White) who underwent psychological/neuropsychological evaluation were included. Mean scores for WISC-V scores fell in the low average-to-average ranges, consistent with the clinical nature of this sample (e.g., M FSIQ = 85.3). Ten unique SF combinations with five (pentad) and four (tetrad) subtests, each intentionally selected to represent a breadth of domains subsumed by WISC-V FSIQ, were described by summing subtest age-corrected scaled scores. Regression-based and prorated FSIQ estimates were calculated, and mean differences suggested some prorated estimates should be arithmetically adjusted. Both regression-based and prorated/adjusted methods provided FSIQ estimates that were accurate within five Standard Score points of true FSIQ for approximately 81-92% (pentad) and 65-76% (tetrads) of participants. Prorated/adjusted estimates appeared to provide somewhat better accuracy than regression-based estimates. Relationships between SFs and true FSIQ did not appear to be moderated by participant age, gender, nor how many WISC-V subtests were administered to participants within this archival sample (i.e., 7 vs. 10). Implications of these findings, including benefits, detriments, and other considerations of each SF combination, in addition to limitations of this study, are discussed in detail.

The dimensionality of the Behavior Rating Inventory of Executive Function, Second Edition in a clinical sample.

The parent-report Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) is a widely used pediatric neuropsychological measure. Unfortunately, despite meaningful changes from its predecessor, few studies have examined its internal factor structure (now with Behavioral Regulation [BRI], Emotion Regulation [ERI], and Cognitive Regulation [CRI]), and no available literature has investigated higher order models for the BRIEF-2. This study sought to address this shortcoming in the literature by investigating and reporting on the dimensionality of the parent-report BRIEF-2 in a clinical sample. Two hundred and two (202) pediatric neuropsychology examinees (M age = 9.90; 68% males) with complete data for the parent-report BRIEF-2 were included. Descriptive results revealed generally elevated scores across BRIEF-2 scales (Global Executive Composite M T = 70.16). Exploratory factor analyses suggested two factors (CRI and BRI/ERI) should be extracted, and that higher order models should be considered. Confirmatory factor analyses suggested that a direct hierarchical/bifactor two-factor structure (which was more parsimonious than the theoretical three-factor model) provided the best fit, with a bulk of the variance explained by the general GEC factor. The BRIEF-2 may be best interpreted at the overall level, with relatively less weight given to the index variables, particularly within clinical samples with high levels of reported executive functioning difficulties. Implications of these findings, limitations of the present study, and appropriate directions for future inquiry were discussed.

microRNAs and Gene-Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression.

Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting. Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low). Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies. Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.

Beta-adrenergic antagonism alters functional connectivity during associative processing in a preliminary study of individuals with and without autism.

Beta-adrenergic antagonism (e.g. propranolol) has been associated with cognitive/behavioral benefits following stress-induced impairments and for some cognitive/behavioral domains in individuals with autism spectrum disorder. In this preliminary investigation, we examined whether the benefits of propranolol are associated with functional properties in the brain. Adolescents/adults (mean age = 22.54 years) with (n = 13) and without autism spectrum disorder (n = 13) attended three sessions in which propranolol, nadolol (beta-adrenergic antagonist that does not cross the blood-brain barrier), or placebo was administered before a semantic fluency task during functional magnetic resonance imaging. Autonomic nervous system measures and functional connectivity between language/associative processing regions and within the fronto-parietal control, dorsal attention, and default mode networks were examined. Propranolol was associated with improved semantic fluency performance, which was correlated with the baseline resting heart rate. Propranolol also altered network efficiency of regions associated with semantic processing and in an exploratory analysis reduced functional differences in the fronto-parietal control network in individuals with autism spectrum disorder. Thus, the cognitive benefits from beta-adrenergic antagonism may be generally associated with improved information processing in the brain in domain-specific networks, but individuals with autism spectrum disorder may also benefit from additional improvements in domain-general networks. The benefits from propranolol may also be able to be predicted from baseline autonomic nervous system measures, which warrants further investigation.

Effects of stress on functional connectivity during verbal processing.

Effects of stress on functional connectivity (FC) in specific language processing regions of the brain during verbal fluency tasks were explored. Roles of gender and serotonin transporter gene polymorphisms (5-HTTLPR), associated with stress susceptibility, were also examined to understand their effect. Forty-five healthy volunteers (Mean age: 19.6 ± 1.6 years; 28 females) participated. Functional magnetic resonance imaging was carried out while participants performed letter and category fluency tasks. These tasks were interposed with the Montreal Imaging Stress Test to induce stress or a no-stress control task. Buccal swabs collected were used to genotype for the presence of polymorphisms on the SLC6A4 gene known to contribute to atypical stress responses. Significant variations in strength of FC were noted between several ROIs, including left inferior frontal gyrus and left middle temporal gyrus. Overall, males showed regional increases in FC strength over long and short distances during task under stress. Additionally, variability in effects of stress on task performance was associated with effects of stress on FC. Results suggest that long distance FC may be strengthened to compensate for additional cognitive load of the stressor but that specific short distance functional connections may be strengthened in a gender specific manner. Additionally, FC may serve as a marker for effects of stress on performance. This is the first study exploring stress effects on language tasks with imaging markers. Future studies will need to explore stress susceptible populations and establish the role of FC as a marker, with implications for targeted therapeutic interventions.

Effects of stress on functional connectivity during problem solving.

AIM: Our purpose was to examine how stress affects functional connectivity (FC) in language processing regions of the brain during a verbal problem solving task associated with creativity. We additionally explored how gender and the presence of the stress-susceptible short allele of the serotonin transporter gene polymorphism influenced this effect. METHODS: Forty-five healthy participants (Mean age: 19.6 â€‹± â€‹1.6 years; 28 females) were recruited to be a part of this study and genotyped to determine the presence or absence of at least one copy of the short (S) allele of the serotonin transporter gene, which is associated with greater susceptibility to stress. The participants underwent functional magnetic resonance imaging in two separate sessions (stress and no stress control). One session utilized a modified version of the Montreal Imaging Stress Test (MIST) to induce stress while the other session consisted of a no stress control task. The MIST and control tasks were interleaved with task blocks during which the participants performed the compound remote associates task, a convergent task that engages divergent thinking, which is a critical component of creativity. We examined the relationship between stress effects on performance and effects on connectivity of language processing regions activated during this task. RESULTS: There was no main effect of stress on functional connectivity for individual ROI pairs. However, in the examination of whether stress effects on performance related to effects on connectivity, changes in middle temporal gyrus connectivity with stress correlated positively with changes in solution latency for individuals with the S allele, but anti-correlated for those with only the L allele. A trend towards a gene â€‹× â€‹stress interaction on solution latency was also observed. DISCUSSION: Results from the study suggest that genetic susceptibility to stress, such as the presence of the S allele, affects neural correlates of performance on tasks related to verbal problem solving, as indicated by connectivity of the middle temporal gyrus. Future work will need to determine whether connectivity of the middle temporal gyrus serves as a marker for the effect of stress susceptibility on cognition, extending into stress susceptible patient populations.

Examining the Association Between Electrodermal Activity and Problem Behavior in Severe Autism Spectrum Disorder: A Feasibility Study.

Background: Many individuals with autism spectrum disorder (ASD) engage in problem behavior, presenting significant challenges for those providing care and services for this population. Psychophysiological measures of arousal, such as electrodermal activity (EDA), may provide an early indication of subsequent problem behavior. However, variability in EDA patterns associated with behaviors may limit this predictive ability. Methods: EDA data was sampled from eight individuals with severe ASD in a naturalistic setting, while participating in educational programming in a school setting at a residential facility for severely affected individuals with developmental disabilities, to examine variability in EDA patterns. Results: An anticipatory rise in EDA only occurred 60% of the time prior to the problem behavior. Additionally, EDA after a problem behavior returned to median baseline levels only 45% of the time. Conclusions: Heterogeneity of EDA responses in those with the most severe forms of ASD will be an important consideration in future studies utilizing psychophysiological tools such as EDA to anticipate problem behavior, including the need for monitoring of return to baseline after problem behaviors. Incorporation of this consideration may lead to greater reliability of these approaches to help anticipate and manage problem behaviors.

Lack of Associations Between Dietary Intake and Gastrointestinal Symptoms in Autism Spectrum Disorder.

Background: Many individuals with autism spectrum disorder (ASD) have significant gastrointestinal (GI) symptoms, but their etiology is currently unknown. Dietary interventions are common in children and adolescents with ASD, including diets with increased omega-3 fatty acids or diets free of gluten and/or casein, which may also impact GI symptoms and nutrition. However, little is known about the relationship between nutritional intake and GI symptomatology in ASD. The objective of this study was to assess the relationships between GI symptoms, omega-3 intake, micronutrients, and macronutrients in children with ASD. Methods: A total of 120 children diagnosed with ASD participated in this multisite study. A food frequency questionnaire was completed by the patient's caretaker. The USDA Food Composition Database was utilized to provide nutritional data for the food items consumed by each participant. GI symptomatology was assessed using a validated questionnaire on pediatric gastrointestinal symptoms. Results: There were no significant associations between GI symptoms and the amount of omega-3 fatty acids and/or other micro- and macronutrients contained in the diet. Conclusions: This study suggests that dietary variations do not appear to drive GI symptoms, nor do GI symptoms drive dietary variations in those with ASD, although causation cannot be determined with this observational assessment. Furthermore, there may be other factors associated with lower GI tract symptoms in ASD, such as increased stress response.

The Relationship Among Gastrointestinal Symptoms, Problem Behaviors, and Internalizing Symptoms in Children and Adolescents With Autism Spectrum Disorder.

Background: Many individuals with autism spectrum disorder (ASD) have co-occurring gastrointestinal (GI) symptoms, but the etiology is poorly understood. These GI symptoms often coincide with problem behaviors and internalizing symptoms, which reduces the quality of life for these individuals. Methods: This study examined the relationships among GI problems, problem behaviors, and internalizing symptoms in a sample of 340 children and adolescents with ASD who are patients at the University of Missouri Thompson Center for Autism & Neurodevelopmental Disorders. Results: The majority of patients experienced constipation (65%), about half experienced stomachaches or stomach pain (47.9%), and others experienced nausea (23.2%) or diarrhea (29.7%). Young children with aggressive problem behaviors were 11.2% more likely to have co-occurring nausea; whereas, older children showed more complex relationships between internalizing symptoms and GI symptoms. Older children with greater anxiety symptoms were 11% more likely to experience constipation, but 9% less likely to experience stomachaches. Older children with greater withdrawn behavior were 10.9% more likely to experience stomachaches, but 8.7% less likely to experience constipation. Older children with greater somatic complaints were 11.4% more likely to experience nausea and 11.5% more likely to experience stomachaches. Conclusions: Results suggest that the presentation of externalizing problem behavior and internalizing symptoms associated with GI problems differs between young children and older children with ASD. Therefore, behavior may have different relationships with GI symptoms at different ages, which may have implications for the treatment of and clinical approach to GI disturbances in ASD.

Association of Rigid-Compulsive Behavior with Functional Constipation in Autism Spectrum Disorder.

Based upon checklist data from the Autism Speaks Autism Treatment Network, we hypothesized that functional constipation (FC) would be associated with rigid-compulsive behavior in children with autism spectrum disorder (ASD). We used the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III to assess FC symptoms in 108 children with ASD. As hypothesized, FC was associated with parent ratings on the Repetitive Behavior Scales-Revised (RBS-R) Compulsive, Ritualistic, and Sameness subscales in the overall population. Of note, FC was less common in children who were not taking medications that target behavior or treat FC. In the medication-free children, rigid-compulsive behavior was not significantly associated with FC. More research is needed to understand the mechanisms underlying these associations.

Psychophysiological Associations with Gastrointestinal Symptomatology in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is often accompanied by gastrointestinal disturbances, which also may impact behavior. Alterations in autonomic nervous system functioning are also frequently observed in ASD. The relationship between these findings in ASD is not known. We examined the relationship between gastrointestinal symptomatology, examining upper and lower gastrointestinal tract symptomatology separately, and autonomic nervous system functioning, as assessed by heart rate variability and skin conductance level, in a sample of 120 individuals with ASD. Relationships with co-occurring medical and psychiatric symptoms were also examined. While the number of participants with significant upper gastrointestinal tract problems was small in this sample, 42.5% of participants met criteria for functional constipation, a disorder of the lower gastrointestinal tract. Heart rate variability, a measure of parasympathetic modulation of cardiac activity, was found to be positively associated with lower gastrointestinal tract symptomatology at baseline. This relationship was particularly strong for participants with co-occurring diagnoses of anxiety disorder and for those with a history of regressive ASD or loss of previously acquired skills. These findings suggest that autonomic function and gastrointestinal problems are intertwined in children with ASD; although it is not possible to assess causality in this data set. Future work should examine the impact of treatment of gastrointestinal problems on autonomic function and anxiety, as well as the impact of anxiety treatment on gastrointestinal problems. Clinicians should be aware that gastrointestinal problems, anxiety, and autonomic dysfunction may cluster in children with ASD and should be addressed in a multidisciplinary treatment plan. Autism Res 2017, 10: 276-288. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Beta-adrenergic antagonism modulates functional connectivity in the default mode network of individuals with and without autism spectrum disorder.

The beta-adrenergic antagonist propranolol benefits some social and communication domains affected in autism spectrum disorder (ASD), and these benefits appear to be associated with increased functional connectivity (FC) in the brain during task performance. FC is implicated in ASD, with the majority of studies suggesting long distance hypo-connectivity combined with regionally specific local hyper-connectivity. The objective in the current investigation was to examine the effect of propranolol on FC at rest and determine whether ASD-specific effects exist. Participants with and without ASD attended three sessions in which propranolol, nadolol (a beta-adrenergic antagonist that does not cross the blood-brain barrier), or placebo were administered. Resting-state fMRI data were acquired, and graph theory techniques were utilized to assess additional aspects of FC. Compared to placebo, propranolol administration was associated with decreased FC in the dorsal medial prefrontal cortex subnetwork of the default mode network and increased FC in the medial temporal lobe subnetwork, regardless of diagnosis. These effects were not seen with nadolol suggesting that the alterations in FC following propranolol administration were not exclusively due to peripheral cardiovascular effects. Thus, beta-adrenergic antagonism can up- or down- regulate FC, depending on the network, and alter coordinated functional activation in the brain. These changes in information processing, as demonstrated by FC, may mediate some of the clinical and behavioral effects of beta-adrenergic antagonism previously reported in patients with ASD.

Effects of acute beta-adrenergic antagonism on verbal problem solving in autism spectrum disorder and exploration of treatment response markers.

Autism spectrum disorder (ASD) is characterized by impairments in social communication as well as restricted, repetitive behaviors. Evidence suggests that some individuals with ASD have cognitive impairments related to weak central coherence and hyperrestricted processing. Reducing noradrenergic activity may improve aspects of network processing and thus improve cognitive abilities, such as verbal problem solving, in individuals with ASD. The present pilot study explores the effects of acute administration of the beta-adrenergic antagonist propranolol on verbal problem solving in adults and adolescents with ASD. In a within-subject crossover-design, 20 participants with ASD received a single dose of propranolol or placebo on one of two sessions in a double-blinded, counterbalanced manner. Verbal problem solving was assessed via an anagram task. Baseline measurements of autonomic nervous system functioning were obtained, and anxiety was assessed at baseline and following drug administration. Participants solved the anagrams more quickly in the propranolol condition, as compared to the placebo condition, suggesting a potential cognitive benefit of this agent. Additionally, we observed a negative linear relationship between response to propranolol on the anagram task and two measures of baseline autonomic activity, as well as a positive linear relationship between drug response and baseline anxiety. These relationships propose potential markers for treatment response, as propranolol influences both autonomic functioning and anxiety. Further investigation is needed to expand on the present single-dose psychopharmacological challenge and explore the observed effects of propranolol in a serial-dose setting.