Neurodevelopmental Disorders Including Autism Spectrum Disorder and Intellectual Disability as a Risk Factor for Delayed Diagnosis of Catatonia.

OBJECTIVE: Catatonia is a distinct and severe medical syndrome comprising motor, somatic, and psychiatric symptoms that is reported in upwards of 17% of young patients with autism spectrum disorders. Clinical experience indicates catatonia is often under-recognized in this clinical population. Here we characterize the clinical presentation of catatonia in patients with and without neurodevelopmental disorders (NDDs) including autism, including the time from symptom onset to diagnosis of catatonia. METHOD: Retrospective chart review of electronic medical records at a large, academic pediatric medical center identified 113 pediatric and young adult patients with a charted history of catatonia, as identified by an encounter diagnosis or problem list entry between September 2017 and September 2021. Workup, treatments, and diagnoses (psychiatric, neurodevelopmental, and genetic) were identified. RESULTS: We observed a clear and substantial delay in identification of catatonia in those with NDDs (diagnosis after 330 days for those without psychosis) compared with neurotypical patients (∼16 days). Psychiatry involvement was associated with shorter delays. CONCLUSION: Intellectual disability and autism are risk factors for significantly delayed diagnosis of catatonia. It is unknown whether delayed diagnosis contributes to the difficulty in treating catatonia in this patient population or whether the treatment difficulties relate instead to differential and ongoing biological mechanisms and underlying encephalopathy. Overall, these findings highlight the importance of increased recognition of catatonia symptoms in patients with NDDs and suggest early referral to psychiatric specialists may shorten the delay to diagnosis.

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.

EEG Microstates as Markers for Cognitive Impairments in Fragile X Syndrome.

Fragile X syndrome (FXS) is one of the most common inherited causes of intellectual disabilities. While there is currently no cure for FXS, EEG is considered an important method to investigate the pathophysiology and evaluate behavioral and cognitive treatments. We conducted EEG microstate analysis to investigate resting brain dynamics in FXS participants. Resting-state recordings from 70 FXS participants and 71 chronological age-matched typically developing control (TDC) participants were used to derive microstates via modified k-means clustering. The occurrence, mean global field power (GFP), and global explained variance (GEV) of microstate C were significantly higher in the FXS group compared to the TDC group. The mean GFP was significantly negatively correlated with non-verbal IQ (NVIQ) in the FXS group, where lower NVIQ scores were associated with greater GFP. In addition, the occurrence, mean duration, mean GFP, and GEV of microstate D were significantly greater in the FXS group than the TDC group. The mean GFP and occurrence of microstate D were also correlated with individual alpha frequencies in the FXS group, where lower IAF frequencies accompanied greater microstate GFP and occurrence. Alterations in microstates C and D may be related to the two well-established cognitive characteristics of FXS, intellectual disabilities and attention impairments, suggesting that microstate parameters could serve as markers to study cognitive impairments and evaluate treatment outcomes in this population. Slowing of the alpha peak frequency and its correlation to microstate D parameters may suggest changes in thalamocortical dynamics in FXS, which could be specifically related to attention control. (250 words).

Patterns in Medication Use for Treatment of Depression in Autistic Spectrum Disorder.

INTRODUCTION: Depression impacts many individuals with autism spectrum disorder (ASD), carrying increased risk of functional impairment, hospitalization, and suicide. Prescribing medication to target depression in patients with ASD occurs despite limited available systematic data describing medication management of depression in this population. PURPOSE: The purpose of this study is to discover prescribing patterns for individuals with MDD and ASD during this time period (2004-2012) to inform current and future prescribing practices with historical data. METHOD: Drawing from a large clinical database describing the prescribing practices in patients with ASD, we identified 166 individuals with ASD (mean age 14.5 ± 8.3 years old) who received medication targeting symptoms of depression. We report prescribing rates for specific drugs, drug treatment duration, and reasons for drug discontinuation when applicable. RESULTS: Sertraline, mirtazapine, and fluoxetine were the three most commonly prescribed medications to treat comorbid depression for this patient population. Among 241 drug starts, 123 (49%) drug treatments were continued at the final reviewed follow-up visit (average treatment duration of ± 0.72 years). The most common reason for discontinuation across all medications prescribed was loss of or lack of effectiveness. CONCLUSION: This study raises concern that standard of care pharmacological treatments for depression in individuals with ASD may be less effective than in neurotypical populations. There remains a need to develop effective interventions for depression specifically tailored to the needs of individuals with ASD.

Effects of AFQ056 on language learning in fragile X syndrome.

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

Genetic syndromes are prevalent in patients with comorbid neurodevelopmental disorders and catatonia.

Catatonia occurs at high rates in idiopathic and syndromic neurodevelopmental disorders. At our institution's multidisciplinary catatonia clinic, clinical genetic testing (including microarray, fragile X PCR and methylation, autism/ID expanded panels, and exome sequencing) was commonly completed as part of clinical workup on patients with co-occurring neurodevelopmental disorders and catatonia (performed in 36/48 cases or 75%). This testing identified a pathogenic or likely pathogenic finding in 15/36 patients (42%). Testing identified a VUS (variant of uncertain significance) in 9/36 patients (25%). On review of the VUS findings, 4/9 were felt to be suspicious and potentially diagnostic. Testing was negative for 12/36 patients (33%). Many of the variants identified in this cohort were found in genes involved in gamma aminobutyric acid (GABA) and glutamatergic synaptic signaling; imbalances of these neurotransmitters are hypothesized to be drivers of catatonia. More work is needed to further characterize the molecular underpinnings of catatonia in the setting of neurodevelopmental disorders, including expanding genetic testing to larger cohorts in the future.

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.

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.

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.

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).

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.

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.

Lymphocytic Extracellular Signal-Regulated Kinase Dysregulation in Autism Spectrum Disorder.

OBJECTIVE: Extracellular signal-regulated kinase (ERK1/2) is a conserved central intracellular signaling cascade involved in many aspects of neuronal development and plasticity. Converging evidence support investigation of ERK1/2 activity in autism spectrum disorder (ASD). We previously reported enhanced baseline lymphocytic ERK1/2 activation in autism, and now we extend our work to investigate the early phase kinetics of lymphocytic ERK1/2 activation in idiopathic ASD. METHOD: Study participants included 67 individuals with ASD (3-25 years of age), 65 age- and sex-matched typical developing control (TDC) subjects, and 36 age-, sex-, and IQ-matched developmental disability control (DDC) subjects matched to those with ASD and IQ <90. We completed an additional analysis comparing results from ASD, TDC, and DDC groups with data from 37 individuals with Fragile X syndrome (FXS). All subjects had blood lymphocyte samples analyzed by flow cytometry following stimulation with phorbol ester and sequentially analyzed for ERK1/2 activation (phosphorylation) at several time points. RESULTS: The ASD group (mean = 5.81 minutes; SD = 1.5) had a significantly lower (more rapid) mean ERK1/2 T1/2 activation value than both the DDC group (mean = 6.78 minutes; SD = 1.6; p = .00078) and the TDC group (mean = 6.4 minutes; SD = 1.5; p = .025). More rapid ERK1/2 T1/2 activation times did correlate with increased social impairment across all study groups including the ASD cohort. Differences in ERK1/2 T1/2 activation were more pronounced in younger than in older individuals in the primary analysis. The ASD group additionally had more rapid activation times than the FXS group, and the FXS group activation kinetics did not differ from those of the TDC and DDC groups. CONCLUSION: Our findings indicate that lymphocytic ERK1/2 activation kinetics are dysregulated in persons with ASD, marked by more rapid early phase activation. Group differences in ERK1/2 activation kinetics appear to be driven by findings from the youngest children analyzed. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

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.

Altered frontal connectivity as a mechanism for executive function deficits in fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and autism spectrum disorder. Executive function (EF), necessary for adaptive goal-oriented behavior and dependent on frontal lobe function, is impaired in individuals with FXS. Yet, little is known how alterations in frontal lobe neural activity is related to EF deficits in FXS. METHODS: Sixty-one participants with FXS (54% males) and 71 age- and sex-matched typically-developing controls (TDC; 58% males) completed a five-minute resting state electroencephalography (EEG) protocol and a computerized battery of tests of EF, the Test of Attentional Performance for Children (KiTAP). Following source localization (minimum-norm estimate), we computed debiased weighted phase lag index (dWPLI), a phase connectivity value, for pairings between 18 nodes in frontal regions for gamma (30-55 Hz) and alpha (10.5-12.5 Hz) bands. Linear models were generated with fixed factors of group, sex, frequency, and connection. Relationships between frontal connectivity and EF variables also were examined. RESULTS: Individuals with FXS demonstrated increased gamma band and reduced alpha band connectivity across all frontal regions and across hemispheres compared to TDC. After controlling for nonverbal IQ, increased error rates on EF tasks were associated with increased gamma band and reduced alpha band connectivity. LIMITATIONS: Frontal connectivity findings are limited to intrinsic brain activity during rest and may not generalize to frontal connectivity during EF tasks or everyday function. CONCLUSIONS: We report gamma hyper-connectivity and alpha hypo-connectivity within source-localized frontal brain regions in FXS compared to TDC during resting-state EEG. For the first time in FXS, we report significant associations between EF and altered frontal connectivity, with increased error rate relating to increased gamma band connectivity and reduced alpha band connectivity. These findings suggest increased phase connectivity within gamma band may impair EF performance, whereas greater alpha band connectivity may provide compensatory support for EF. Together, these findings provide important insight into neurophysiological mechanisms of EF deficits in FXS and provide novel targets for treatment development.

Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide expansion on the FMR1 gene and characterized by intellectual disability, sensory hypersensitivity, executive function difficulties, and social anxiety. Recently, efforts to define neural biomarkers for FXS have highlighted disruptions to power in the alpha frequency band; however the dynamic mechanisms supporting these findings are poorly understood. The current study aimed to explore the temporal and hemispheric dynamics supporting alpha phenotypes in FXS and their relationship with neural phenotypes related to auditory processing using electroencephalography during an auditory evoked task. Adolescents and adults (N = 36) with FXS and age/sex matched typically developing controls (N = 40) completed an auditory chirp task. Frontal alpha power in the prestimulus period was decomposed into "bursts" using percentile thresholding, then assessed for number of bursts per second (burst count) and burst length. Data were compared across left and right hemispheres to assess lateralization of neural activity. Individuals with FXS showed more differences in alpha power compared to TDC primarily in the right hemisphere. Notably, alpha hemisphere outcomes in males with FXS were driven by the number of times they entered a dynamically relevant period of alpha (burst count) rather than length of time spent in alpha. Females with FXS showed reduced burst counts but remained in sustained high alpha states for longer periods of time. Length of time spent in alpha may reflect a modulatory or compensatory mechanism capable of recovering sensory processing abilities in females with FXS resulting in a less severe clinical presentation. Right hemisphere abnormalities may impact sensory processing differences between males and females with FXS. The relationship between alpha burst length, count, sex, and hemisphere may shed light on underlying mechanisms for previously observed alpha power abnormalities in FXS and their variation by sex.

Observable Symptoms of Anxiety in Individuals with Fragile X Syndrome: Parent and Caregiver Perspectives.

Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. A comprehensive survey of the presence, frequency, and duration of anxiety-related symptoms and questions to elicit open-ended responses was completed by caregivers of 456 individuals with FXS, ages 2-81 years (87 female, 369 male) and 24 female and 2 male FXS self-advocates ages 15-66 years. Caregivers reported classic behavioral indicators of anxiety, such as avoidance, irritability, motor agitation, and physiological symptoms, as well as behavioral features in FXS such as repetitive behavior, aggression, and self-injury. Self-advocate accounts largely paralleled caregiver data. Factor analyses yielded four factors: (1) increased irritability, aggression, and self-injury; (2) increased physical movement, nervous activity, and restlessness; (3) physical and physiological features of anxiety; and (4) internalizing and gastrointestinal symptoms. Caregivers are capable of observing and reporting behaviors that are valid indicators of anxious states that are usually reported in self-report standardized assessments. These results support the development of an anxiety measure for FXS that minimizes problems with rater inference.

Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. METHODS: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. CONCLUSIONS: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. TRIAL REGISTRATION: The human experiments are registered under NCT02998151.