The impact of social-environmental factors on IQ in syndromic intellectual developmental disabilities.

Despite having the same underlying genetic etiology, individuals with the same syndromic form of intellectual developmental disability (IDD) show a large degree of interindividual differences in cognition and IQ. Research indicates that up to 80% of the variation in IQ scores among individuals with syndromic IDDs is attributable to nongenetic effects, including social-environmental factors. In this narrative review, we summarize evidence of the influence that factors related to economic stability (focused on due to its prevalence in existing literature) have on IQ in individuals with syndromic IDDs. We also highlight the pathways through which economic stability is hypothesized to impact cognitive development and drive individual differences in IQ among individuals with syndromic IDDs. We also identify broader social-environmental factors (e.g., social determinants of health) that warrant consideration in future research, but that have not yet been explored in syndromic IDDs. We conclude by making recommendations to address the urgent need for further research into other salient factors associated with heterogeneity in IQ. These recommendations ultimately may shape individual- and community-level interventions and may inform systems-level public policy efforts to promote the cognitive development of and improve the lived experiences of individuals with syndromic IDDs.

Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership Fragile X Syndrome.

Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined whole-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses best discriminated non-mosaic FXS males via whole-head resting relative power (AUC = .9250), even with data reduced to a 20-channel clinical montage. FXS females were nearly perfectly discriminated by combined theta, alpha, and gamma power during the chirp (AUC = .9522). Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

Brief Report: A Double-Blind, Placebo-Controlled, Crossover, Proof-of-Concept Study of Minocycline in Autism Spectrum Disorder.

Neuroinflammatory mechanisms have been implicated in the pathophysiology of autism spectrum disorder (ASD). Minocycline is a matrix metalloproteinase inhibitor 9 (MMP9) inhibitor tetracycline antibiotic with known anti-inflammatory properties. In preclinical animal models of ASD, minocycline has demonstrated potential positive effects on phenotypes that may have relevance to ASD. We conducted the first placebo-controlled study of minocycline in ASD. This double-blind, placebo-controlled crossover trial employed four week treatment periods with a two week washout period. Twenty-four 12-22 year olds (mean age 17.4 years; range 12.9-22.5 years) with ASD were enrolled. Overall minocycline was well tolerated. No minocycline-associated clinical changes were noted with treatment on any performance or clinician or caregiver completed measures were noted. We hypothesize that either minocycline does not have potential therapeutic effects in ASD or our project was underpowered to define potential subject subgroups who may potentially respond positively to this drug.

Sensorimotor and inhibitory control in aging FMR1 premutation carriers.

Aging FMR1 premutation carriers are at risk of developing neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome (FXTAS), and there is a need to identify biomarkers that can aid in identification and treatment of these disorders. While FXTAS is more common in males than females, females can develop the disease, and some evidence suggests that patterns of impairment may differ across sexes. Few studies include females with symptoms of FXTAS, and as a result, little information is available on key phenotypes for tracking disease risk and progression in female premutation carriers. Our aim was to examine quantitative motor and cognitive traits in aging premutation carriers. We administered oculomotor tests of visually guided/reactive saccades (motor) and antisaccades (cognitive control) in 22 premutation carriers (73% female) and 32 age- and sex-matched healthy controls. Neither reactive saccade latency nor accuracy differed between groups. FMR1 premutation carriers showed increased antisaccade latencies relative to controls, both when considering males and females together and when analyzing females separately. Reduced saccade accuracy and increased antisaccade latency each were associated with more severe clinically rated neuromotor impairments. Findings indicate that together male and female premutation carriers show a reduced ability to rapidly exert volitional control over prepotent responses and that quantitative differences in oculomotor behavior, including control of visually guided and antisaccades, may track with FXTAS - related degeneration in male and female premutation carriers.

Hypersensitivity to Distractors in Fragile X Syndrome from Loss of Modulation of Cortical VIP Interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in humans and mice with FXS but not in typically developing controls. In both species, males and females were examined. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the poststimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1 -/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells could be a potential therapeutic target for attentional difficulties in FXS.SIGNIFICANCE STATEMENT Sensory hypersensitivity, impulsivity, and persistent inattention are among the most consistent clinical features of FXS, all of which impede daily functioning and create barriers to learning. However, the neural mechanisms underlying sensory over-reactivity remain elusive. To overcome a significant challenge in translational FXS research we demonstrate a compelling alignment of sensory over-reactivity in both humans with FXS and Fmr1 -/- mice (the principal animal model of FXS) using a novel analogous distractor task. Two-photon microscopy in mice revealed that lack of modulation by VIP cells contributes to susceptibility to distractors. Implementing research efforts we describe here can help identify dysfunctional neural mechanisms associated not only with sensory issues but broader impairments, including those in learning and cognition.

Health Related Quality of Life in Autistic Youth and Their Families.

PURPOSE: The construct Quality of Life (QoL) involves a range of factors related to one's well-being. Individuals on the autism spectrum have been previously reported to have lower QoL. The purpose of the present study is to examine QoL in autistic individuals and their families and to evaluate associations between QoL and measures of functioning using the PedsQL 4.0. METHOD: Thirty-six autistic youth (ages 9-21 years) and their caregivers completed the PedsQL. Caregivers completed additional measures of their children's adaptive, social, behavioral, and emotional functioning. RESULTS: Parents and youth generally agreed on the PedsQL, with the exception of the Social Functioning domain, which youth rated higher. The parent rated PedsQL did not correlate with most areas of caregiver-rated functioning; however, there were significant negative correlations between irritability and family functioning. CONCLUSION: Limitations of this study included small sample size; broad range of intellectual functioning; lack of sample diversity; and likely recruiting bias for a drug treatment study. Despite limitations, HRQoL is an important feature that should be measured in addition to features of autism or symptoms of co-occurring symptoms.

Behavioral and neuropsychiatric challenges across the lifespan in individuals with Rubinstein-Taybi syndrome.

Introduction: Rubinstein-Taybi syndrome (RSTS) is a rare congenital disorder characterized by developmental and intellectual disability, broadening of thumbs and halluces, and characteristic facial features. Pathogenic variants in CREBBP lead to RSTS type 1 (RSTS1) and in EP300 lead to RSTS type 2 (RSTS2). Individuals with RSTS can demonstrate a variety of behavioral and neuropsychiatric challenges, including anxiety, hyperactivity/inattention, self-injury, repetitive behaviors, and aggression. Behavioral challenges are consistently reported as one of the primary factors impacting quality of life. Despite the high prevalence and morbidity of behavioral and neuropsychiatric features of RSTS, a paucity of data exists regarding its natural history. Methods: To better understand the neurocognitive and behavioral challenges faced by individuals with RSTS, 71 caregivers of individuals with RSTS, ranging in age from one to 61 years, completed four questionnaires measuring obsessive compulsive disorder (OCD)-like symptoms, anxiety, challenging behaviors, and adaptive behavior and living skills. Results: Results revealed a high prevalence of neuropsychiatric and behavioral challenges across ages. We found specific challenging behaviors were worse in school age individuals. Scaled adaptive behavior and living skill scores differed across ages with an increased gap between typically developing peers becoming more apparent at older ages. Between types, individuals with RSTS2 had better adaptive behavior and living skills and less stereotypic behaviors but higher social phobia than individuals with RSTS1. Further, female individuals with RSTS1 appear to have increased hyperactivity. However, both groups had impairments in adaptive functioning compared to typically developing peers. Discussion: Our findings support and expand previous reports of a high prevalence of neuropsychiatric and behavioral challenges in individuals with RSTS. However, we are the first to report differences between types of RSTS. Further, age-related differences were seen with higher challenging behaviors within school-age individuals, which may improve over time, and lower adaptive behavioral skills compared to normative scales. Anticipation of these potential differential challenges across age is vital for proactive management for individuals with RSTS. Our study underscores the importance of enacting neuropsychiatric and behavioral screening earlier in childhood so appropriate management can be implemented. However, further longitudinal studies in larger cohorts are needed to understand better how behavioral and neuropsychiatric characteristics of RSTS evolve over the lifespan and differentially affect subpopulation groups.

Sensorimotor Behavior in Individuals with Autism Spectrum Disorder and Their Unaffected Biological Parents.

Background: Sensorimotor impairments are common in autism spectrum disorder (ASD) and evident in unaffected first-degree relatives, suggesting that they may serve as important endophenotypes associated with inherited risk. We tested the familiality of sensorimotor impairments in ASD across multiple motor behaviors and effector systems and in relation to parental broader autism phenotypic (BAP) characteristics. Methods: Fifty-eight autistic individuals (probands), 109 parents, and 89 control participants completed tests of manual motor and oculomotor control. Sensorimotor tests varied in their involvement of rapid, feedforward control and sustained, sensory feedback control processes. Subgroup analyses compared families with at least one parent showing BAP traits (BAP+) and those in which neither parent showed BAP traits (BAP-). Results: Probands with BAP- parents (BAP- probands) showed rapid manual motor and oculomotor deficits, while BAP+ probands showed sustained motor impairments compared to controls. BAP- parents showed impaired rapid oculomotor and sustained manual motor abilities relative to BAP+ parents and controls. Atypical rapid oculomotor impairments also were familial. Limitations: Larger samples of ASD families including greater samples of probands with BAP+ parents are needed. Genetic studies also are needed to link sensorimotor endophenotype findings directly to genes. Conclusions: Results indicate rapid sensorimotor behaviors are selectively impacted in BAP- probands and their parents and may reflect familial liabilities for ASD that are independent of familial autistic traits. Sustained sensorimotor behaviors were affected in BAP+ probands and BAP- parents re ecting familial traits that may only confer risk when combined with parental autistic trait liabilities. These findings provide new evidence that rapid and sustained sensorimotor alterations represent strong but separate familial pathways of ASD risk that demonstrate unique interactions with mechanisms related to parental autistic traits.

Positive tree diversity effects on arboreal spider abundance are tied to canopy cover in a forest experiment.

Human actions are decreasing the diversity and complexity of forests, and a mechanistic understanding of how these changes affect predators is needed to maintain ecosystem services, including pest regulation. Using a large-scale tree diversity experiment, we investigate how spiders respond to trees growing in plots of single or mixed species combinations (4 or 12) by repeatedly sampling 540 trees spanning 15 species. In 2019 (6 years post-establishment), spider responses to tree diversity varied by tree species. By 2021, diversity had a more consistently positive effect, with trees in 4- or 12-species plots supporting 23% or 50% more spiders, respectively, compared to conspecifics in monocultures. Spiders showed stronger tree species preferences in late summer, and the positive impact of plot diversity doubled. In early summer, the positive diversity effect was tied to higher canopy cover in diverse plots, leading to higher spider densities. This indirect path strengthened in late summer, with an additional direct effect of plot diversity on spiders. Prey availability was higher in diverse plots but was not tied to spider density. Overall, diverse plots supported more predators, partly by increasing available habitat. Adopting planting strategies focused on species mixtures may better maintain higher trophic levels and ecosystem functions.

Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome.

The FMR1 gene is inactive in Fragile X syndrome (FXS), resulting in low levels of FMRP and consequent neurochemical, synaptic, and local circuit neurophysiological alterations in the fmr1 KO mouse. In FXS patients, electrophysiological studies have demonstrated a marked reduction in global alpha activity and regional increases in gamma oscillations associated with intellectual disability and sensory hypersensitivity. Since alpha activity is associated with a thalamocortical function with widely distributed modulatory effects on neocortical excitability, insight into alpha physiology may provide insight into systems-level disease mechanisms. Herein, we took a data-driven approach to clarify the temporal and spatial properties of alpha and theta activity in participants with FXS. High-resolution resting-state EEG data were collected from participants affected by FXS (n = 65) and matched controls (n = 70). We used a multivariate technique to empirically classify neural oscillatory bands based on their coherent spatiotemporal patterns. Participants with FXS demonstrated: 1) redistribution of lower-frequency boundaries indicating a "slower" dominant alpha rhythm, 2) an anteriorization of alpha frequency activity, and 3) a correlation of increased individualized alpha power measurements with auditory neurosensory dysfunction. These findings suggest an important role for alterations in thalamocortical physiology for the well-established neocortical hyper-excitability in FXS and, thus, a role for neural systems level disruption to cortical hyperexcitability that has been studied primarily at the local circuit level in animal models.

Functional connectivity of cortical-cerebellar networks in relation to sensorimotor behavior and clinical features in autism spectrum disorder.

Sensorimotor issues are present in the majority of individuals with autism spectrum disorder (ASD) and are associated with core symptoms. The neural systems associated with these impairments remain unclear. Using a visually guided precision gripping task during functional magnetic resonance imaging, we characterized task-based connectivity and activation of cortical, subcortical, and cerebellar visuomotor networks. Participants with ASD (n = 19; ages 10-33) and age- and sex-matched neurotypical controls (n = 18) completed a visuomotor task at low and high force levels. Relative to controls, individuals with ASD showed reduced functional connectivity of right primary motor-anterior cingulate cortex and left anterior intraparietal lobule (aIPL)-right Crus I at high force only. At low force, increased caudate, and cerebellar activation each were associated with sensorimotor behavior in controls, but not in ASD. Reduced left aIPL-right Crus I connectivity was associated with more severe clinically rated ASD symptoms. These findings suggest that sensorimotor problems in ASD, particularly at high force levels, involve deficits in the integration of multimodal sensory feedback and reduced reliance on error-monitoring processes. Adding to literature positing that cerebellar dysfunction contributes to multiple developmental issues in ASD, our data implicate parietal-cerebellar connectivity as a key neural marker underlying both core and comorbid features of ASD.

A Paradigm Shifting View of Intellectual Disability: A Near Normal Distribution of IQ in Fragile X Syndrome.

Fragile X Syndrome (FXS) is an X-linked disorder leading to the loss of expression of FMR1-protein product, FMRP. The absence or deficiency of FMRP is thought to result in the characteristic FXS phenotypes, including intellectual disability. Identifying the relationship between FMRP levels and IQ may be critical to better understand underlying mechanisms and advance treatment development and planning. A sample of 80 individuals with FXS (67% male), aged 8-45 years, completed IQ testing and blood draw via venipuncture to determine the relationship between IQ scores and FMRP levels as well as the normalcy of IQ distributions. In females with FXS only, higher FMRP levels were associated with higher IQ. In contrast, males with FXS showed a downward shifted but otherwise normal distribution of IQ scores. Our findings offer a paradigm-shifting views of FXS-males with FXS have normally distributed IQ that is downshifted 5 standard deviations. Our novel work provides evidence of a "FXS standard curve", and is a critical step towards establishing molecular markers of disease severity in FXS. There is much future work to better understand the mechanism by which FMRP loss leads to intellectual disability and what biological/genetic and socio-environmental factors contribute to variation in IQ.

Developing improved outcome measures in FXS: Key stakeholder feedback.

BACKGROUND: There is a critical need for the development of improved outcome measures in Fragile X Syndrome (FXS). Because the majority of respondents of behavior outcome measures are caregivers or individuals with FXS, it is important to consider stakeholders' firsthand experiences when designing a caregiver- or self-report measure. AIMS: The current research study aimed to understand experiences of completing commonly used caregiver-/self-report measures of behavior in FXS via focus groups. METHODS AND PROCEDURES: This study employed a focus group methodology. Semi-structured focus groups were conducted with 22 caregivers and 3 self-advocates. All interviews occurred via secured videoconferencing. A thematic analysis was used to identify major themes and subthemes. OUTCOMES AND RESULTS: We identified four themes: (1) content of measure, (2) structure of the measure, (3) potential accommodations to complete measure, and (4) impact of measure on family. Importantly, focus groups revealed that certain aspects of content, structure, and implementation of the available measures were related to distress and negative emotions of caregivers of FXS and individuals with FXS themselves. CONCLUSIONS AND IMPLICATIONS: The focus group data yielded a wide range of feedback and has significant implications, highlighting the critical need to take key stakeholder perspectives into account when using and/or developing caregiver- or self-report measures for FXS.

A sensitive and reproducible qRT-PCR assay detects physiological relevant trace levels of FMR1 mRNA in individuals with Fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS is caused by a trinucleotide repeat expansion in the 5' untranslated region of the FMR1 gene, which leads to gene methylation, transcriptional silencing, and lack of expression of Fragile X Messenger Riboprotein (FMRP). Currently available FXS therapies are inefficient, and the disease severity is highly variable, making it difficult to predict disease trajectory and treatment response. We and others have recently shown that a subset of full-mutation, fully-methylated (FM-FM) males with FXS express low amounts of FMRP which could contribute to phenotypic variability. To better understand the underlying mechanisms, we developed a sensitive qRT-PCR assay to detect FMR1 mRNA in blood. This assay reproducibly detects trace amounts of FMR1 mRNA in a subset of FM-FM males, suggesting that current Southern Blot and PCR determination of FM-FM status is not always associated with complete transcriptional silencing. The functional relevance of trace-level FMR1 mRNA is confirmed by showing a positive correlation with cognitive function; however, phenotypic variability is not fully explained by FMR1 expression. These results corroborate the need for better molecular assays for FXS diagnosis and encourage studies to elucidate the factors contributing to the phenotypic variability of FXS.

Behavioral inflexibility in fragile X syndrome: Accounts from caregivers and self-advocates.

Introduction: Behavioral difficulties in individuals with fragile X Syndrome (FXS) are one of the primary reasons families seek medical and psychological support. Among these, behavioral inflexibility is very common, and when left untreated, can negatively impact quality of life for the individuals with FXS and their families. Behavioral inflexibility refers to the difficulty in changing one's behaviors based on environmental demands or social contexts, thus impeding daily functioning, opportunities for learning, and social interactions. In addition to the individual and family impact, behavioral inflexibility is often recognized as a defining phenotype of FXS and appears to be specific to FXS when compared to other genetic forms of intellectual disability. Despite the pervasiveness and severity of behavioral inflexibility in FXS, there are limited measures that adequately assess behavioral inflexibility in FXS. Methods: We conducted semi-structured virtual focus groups with 22 caregivers, 3 self-advocates, and 1 professional to gather key stakeholders' perspectives on and experiences of inflexible behavior observed in FXS. Audio-recordings from focus groups were transcribed using NVivo, then verified and coded. Two trained professionals reviewed codes to extract primary themes. Results: Six themes were extracted: (1) Intolerance of change, (2) Intolerance to uncertainty, (3) Repetitive interests and behaviors, (4) Family impact, (5) Change in behavior across the lifespan, and (6) Impact of the COVID pandemic. Our findings show common examples of these themes included intolerance to disruption to routine, perseverative questioning, watching the same things over and over, and caregivers having to extensively pre-plan for events. Discussion: The purpose of the current study was to gain key stakeholders' perspectives via focus groups to elicit information and understand patterns of inflexible behaviors in FXS, with the goal of developing a disorder-specific measure to accurately assess behavioral inflexibility across the lifespan and in response to treatment. We were able to capture several phenotypic examples of behavioral inflexibility in FXS as well as their impact on individuals with FXS and their families. The wealth of information gained through our study will aid in our next steps of item generation for measure development of Ratings of Inflexibility in Genetic Disorders associated with Intellectual Disability - Fragile X Syndrome (RIGID-FX).

Results of a phase Ib study of SB-121, an investigational probiotic formulation, a randomized controlled trial in participants with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by core impairments in social communication as well as restricted, repetitive patterns of behavior and/or interests. Individuals with ASD, which includes about 2% of the US population, have challenges with activities of daily living and suffer from comorbid medical and mental health concerns. There are no drugs indicated for the core impairments of ASD. As such, there is a significant need for the development of new medication strategies for individuals with ASD. This first-in-human placebo-controlled, double-blind, crossover study investigated the safety (primary objective) and efficacy of oral SB-121, a combination of L. reuteri, Sephadex® (dextran microparticles), and maltose administered once daily for 28 days in 15 autistic participants. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted. These results provide support for further clinical evaluation of SB-121 as a treatment in autistic patients. To evaluate the safety and tolerability of multiple doses of SB-121 in subjects with autism spectrum disorder. Single-center, randomized, placebo-controlled, double-blind, crossover trial. 15 patients with autism spectrum disorder were randomized and analyzed. Daily dosing of SB-121 or placebo for 28 days, followed by approximately a 14 day washout, then 28 days of dosing with other treatment. Incidence and severity of adverse events, presence of Limosilactobacillus reuteri and Sephadex® in stool, and incidence of bacteremia with positive L. reuteri identification. Additional outcomes include changes from baseline on cognitive and behavior tests as well as biomarker levels. Adverse event rates were similar between SB-121 and placebo, with most reported as mild. There were no severe or serious adverse events. No participants had features of suspected bacteremia or notable changes in vital signs, safety laboratory, or ECG parameters from baseline. There was a statistically significant increase from baseline in the Vineland-3 Adaptive Behavior Composite score (p = 0.03) during SB-121 treatment. There was a trend for increased social/geometric viewing ratio following SB-121 treatment compared to placebo. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted.Trial registration: clinicaltrials.gov Identifier: NCT04944901.

Neuropsychiatric feature-based subgrouping reveals neural sensory processing spectrum in female FMR1 premutation carriers: A pilot study.

Introduction: Fragile X Syndrome (FXS) is rare genetic condition characterized by a repeat expansion (CGG) in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene where individuals with greater than 200 repeats are defined as full mutation. FXS clinical presentation often includes intellectual disability, and autism-like symptoms, including anxiety and sensory hypersensitivities. Individuals with 55 to <200 CGG repeats are said to have the FMR1 premutation, which is not associated with primary characteristics of the full mutation, but with an increased risk for anxiety, depression, and other affective conditions, as well as and impaired cognitive processing differences that vary in severity. Defining subgroups of premutation carriers based on distinct biological features may identify subgroups with varying levels of psychiatric, cognitive, and behavioral alterations. Methods: The current pilot study utilized 3 cluster subgroupings defined by previous k means cluster analysis on neuropsychiatric, cognitive, and resting EEG variables in order to examine basic sensory auditory chirp task-based EEG parameters from 33 females with the FMR1 premutation (ages 17-78). Results: Based on the predefined, neuropsychiatric three-cluster solution, premutation carriers with increased neuropsychiatric features and higher CGG repeat counts (cluster 1) showed decreased stimulus onset response, similar to previous ERP findings across a number of psychiatric disorders but opposite to findings in individuals with full mutation FXS. Premutation carriers with increased executive dysfunction and resting gamma power (cluster 2) exhibited decreased gamma phase locking to a chirp stimulus, similar to individuals with full mutation FXS. Cluster 3 members, who were relatively unaffected by psychiatric or cognitive symptoms, showed the most normative task-based EEG metrics. Discussion: Our findings suggest a spectrum of sensory processing characteristics present in subgroups of premutation carriers that have been previously understudied due to lack of overall group differences. Our findings also further validate the pre-defined clinical subgroups by supporting links between disturbances in well-defined neural pathways and behavioral alterations that may be informative for identifying the mechanisms supporting specific risk factors and divergent therapeutic needs in individuals with the FMR1 premutation.

Hypersensitivity to distractors in Fragile X syndrome from loss of modulation of cortical VIP interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in both humans and mice with FXS, but not their typically developing controls. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as 'error' signals. Strikingly, however, VIP cells from Fmr1-/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties in FXS.

Regulating Together: Emotion Dysregulation Group Treatment for ASD Youth and Their Caregivers.

Individuals with autism spectrum disorder (ASD) experience behavioral and emotional symptoms hypothesized to arise from emotion dysregulation (ED), difficulty modulating emotional experience, expression, and intensity in an acceptable and contextually appropriate manner. We developed Regulating Together (RT)-an intensive-outpatient, caregiver-assisted group program to meet the ASD + ED intervention critical need. A within-subjects trial was conducted (5-week-control lead-in period, 5-week-treatment, and 5-and 10-weeks-post-treatment follow-ups). Forty-four youth with ASD + ED (25 8-12, 19 13-18 yr-olds, 88% male, mean FSIQ of 96) participated. Improvements were found in reactivity, emotion regulation knowledge, and flexibility post-treatment and 10-weeks post-treatment. A reduction in inpatient hospitalization rates by 16% from the 12 months pre-RT to 12 months post-RT was observed. RT shows promise to reduce ED in ASD.