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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.
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Síndrome do Cromossomo X Frágil , Peptídeo Intestinal Vasoativo , Humanos , Masculino , Feminino , Animais , Camundongos , Proteína do X Frágil da Deficiência Intelectual/genética , Atividades Cotidianas , Interneurônios , Camundongos Knockout , Modelos Animais de DoençasRESUMO
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).
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Disfunção Cognitiva , Síndrome do Cromossomo X Frágil , Deficiência Intelectual , Humanos , Eletroencefalografia , Encéfalo/fisiologiaRESUMO
Importance: In the US, children with signs of autism often experience more than 1 year of delay before diagnosis and often experience longer delays if they are from racially, ethnically, or economically disadvantaged backgrounds. Most diagnoses are also received without use of standardized diagnostic instruments. To aid in early autism diagnosis, eye-tracking measurement of social visual engagement has shown potential as a performance-based biomarker. Objective: To evaluate the performance of eye-tracking measurement of social visual engagement (index test) relative to expert clinical diagnosis in young children referred to specialty autism clinics. Design, Setting, and Participants: In this study of 16- to 30-month-old children enrolled at 6 US specialty centers from April 2018 through May 2019, staff blind to clinical diagnoses used automated devices to measure eye-tracking-based social visual engagement. Expert clinical diagnoses were made using best practice standardized protocols by specialists blind to index test results. This study was completed in a 1-day protocol for each participant. Main Outcomes and Measures: Primary outcome measures were test sensitivity and specificity relative to expert clinical diagnosis. Secondary outcome measures were test correlations with expert clinical assessments of social disability, verbal ability, and nonverbal cognitive ability. Results: Eye-tracking measurement of social visual engagement was successful in 475 (95.2%) of the 499 enrolled children (mean [SD] age, 24.1 [4.4] months; 38 [8.0%] were Asian; 37 [7.8%], Black; 352 [74.1%], White; 44 [9.3%], other; and 68 [14.3%], Hispanic). By expert clinical diagnosis, 221 children (46.5%) had autism and 254 (53.5%) did not. In all children, measurement of social visual engagement had sensitivity of 71.0% (95% CI, 64.7% to 76.6%) and specificity of 80.7% (95% CI, 75.4% to 85.1%). In the subgroup of 335 children whose autism diagnosis was certain, sensitivity was 78.0% (95% CI, 70.7% to 83.9%) and specificity was 85.4% (95% CI, 79.5% to 89.8%). Eye-tracking test results correlated with expert clinical assessments of individual levels of social disability (r = -0.75 [95% CI, -0.79 to -0.71]), verbal ability (r = 0.65 [95% CI, 0.59 to 0.70]), and nonverbal cognitive ability (r = 0.65 [95% CI, 0.59 to 0.70]). Conclusions and Relevance: In 16- to 30-month-old children referred to specialty clinics, eye-tracking-based measurement of social visual engagement was predictive of autism diagnoses by clinical experts. Further evaluation of this test's role in early diagnosis and assessment of autism in routine specialty clinic practice is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03469986.
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Transtorno Autístico , Tecnologia de Rastreamento Ocular , Comportamento Social , Percepção Visual , Pré-Escolar , Humanos , Lactente , Instituições de Assistência Ambulatorial , Asiático , Transtorno Autístico/diagnóstico , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Movimentos Oculares/fisiologiaRESUMO
The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task.
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Inibição Psicológica , Desempenho Psicomotor , Humanos , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologiaRESUMO
Astrocytic glutamate transporters are crucial for glutamate homeostasis in the brain, and dysregulation of these transporters can contribute to the development of epilepsy. Glutamate transporter-1 (GLT-1) is responsible for the majority of glutamate uptake in the dorsal forebrain and has been shown to be reduced at epileptic foci in patients and preclinical models of temporal lobe epilepsy (TLE). Current antiepileptic drugs (AEDs) work primarily by targeting neurons directly through suppression of excitatory neurotransmission or enhancement of inhibitory neurotransmission, which can lead to both behavioral and psychiatric side effects. This study investigates the therapeutic capacity of astrocyte-specific AAV-mediated GLT-1 expression in the intrahippocampal kainic acid (IHKA) model of TLE. In this study, we used Western blot analysis, immunohistochemistry, and long-term-video EEG monitoring to demonstrate that cell-type-specific upregulation of GLT-1 in astrocytes is neuroprotective at early time points during epileptogenesis, reduces seizure frequency and total time spent in seizures, and eliminates large behavioral seizures in the IHKA model of epilepsy. Our findings suggest that targeting glutamate uptake is a promising therapeutic strategy for the treatment of epilepsy.
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Astrócitos/metabolismo , Epilepsia do Lobo Temporal/genética , Transportador 2 de Aminoácido Excitatório/genética , Hipocampo/metabolismo , Convulsões/genética , Animais , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Técnicas de Introdução de Genes , Ácido Caínico/toxicidade , Camundongos , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/fisiopatologia , Regulação para CimaRESUMO
Social information processing theory hypothesizes that aggressive children pay more attention to cues of hostility and threat in others' behavior, consequently leading to over-interpretation of others' behavior as hostile. While there is abundant evidence of aggressive children demonstrating hostile attribution biases, less well documented is whether such biases stem from over-attendance and hypersensitivity to hostile cues in social situations. Over-attendance to hostile cues would be typified by deviations at any stage of the multi-stage process of social information processing models. While deviations at later stages in social information processing models are associated with aggressive behavior in children, the initial step of encoding has historically been difficult to empirically measure, being a low level automatic process unsuitable for self-report. We employed eye-tracking methodologies to better understand the visual encoding of such social information. Eye movements of ten 13-18 year-old children referred from clinical and non-clinical populations were recorded in real time while the children viewed scenarios varying between hostile, non-hostile and ambiguous social provocation. In addition, the children completed a brief measure of risk of aggression. Aggressive children did attend more to the social scenarios with hostile cues, in particular attending longest to those hostile scenarios where the actor in the scenario had a congruent emotional response. These findings corroborate social information processing theory and the traditional bottom-up processing hypotheses that aggressive behavior relates to increased attention to hostile cues.
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Agressão/psicologia , Fixação Ocular/fisiologia , Comportamento Social , Percepção Social , Adolescente , Feminino , Humanos , Relações Interpessoais , Modelos Lineares , Masculino , Escalas de Graduação Psiquiátrica , Fatores de TempoRESUMO
Angelman Syndrome is a rare neurodevelopmental disorder associated with significant developmental and communication delays, high risk for epilepsy, motor dysfunction, and a characteristic behavioral profile. While Angelman Syndrome is known to be associated with the loss of maternal expression of the ubiquitin-protein ligase E3A gene, the molecular sequelae of this loss remain to be fully understood. Amyloid precursor protein (APP) is involved in neuronal development and APP dysregulation has been implicated in the pathophysiology of other developmental disorders including fragile X syndrome and idiopathic autism. APP dysregulation has been noted in preclinical model of chromosome 15q13 duplication, a disorder whose genetic abnormality results in duplication of the region that is epigenetically silenced in Angelman Syndrome. In this duplication model, APP levels have been shown to be significantly reduced leading to the hypothesis that enhanced ubiquitin-protein ligase E3A expression may be associated with this phenomena. We tested the hypothesis that ubiquitin-protein ligase E3A regulates APP protein levels by comparing peripheral APP and APP derivative levels in humans with Angelman Syndrome to those with neurotypical development. We report that APP total, APP alpha (sAPPα) and A Beta 40 and 42 are elevated in the plasma of humans with Angelman Syndrome compared to neurotypical matched human samples. Additionally, we found that elevations in APP total and sAPPα correlated positively with peripheral brain derived neurotrophic factor levels previously reported in this same patient cohort. Our pilot report on APP protein levels in Angelman Syndrome warrants additional exploration and may provide a molecular target of treatment for the disorder. © 2016 Wiley Periodicals, Inc.
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Precursor de Proteína beta-Amiloide/sangue , Síndrome de Angelman/sangue , Síndrome de Angelman/diagnóstico , Adolescente , Adulto , Síndrome de Angelman/genética , Biomarcadores , Caderinas/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Duplicação Cromossômica , Cromossomos Humanos Par 15 , Feminino , Humanos , Masculino , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Ubiquitina-Proteína Ligases/genética , Adulto JovemRESUMO
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.
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Interneuron loss is a prominent feature of temporal lobe epilepsy in both animals and humans and is hypothesized to be critical for epileptogenesis. As loss occurs concurrently with numerous other potentially proepileptogenic changes, however, the impact of interneuron loss in isolation remains unclear. For the present study, we developed an intersectional genetic approach to induce bilateral diphtheria toxin-mediated deletion of Vgat-expressing interneurons from dorsal and ventral hippocampus. In a separate group of mice, the same population was targeted for transient neuronal silencing with DREADDs. Interneuron ablation produced dramatic seizure clusters and persistent epileptiform activity. Surprisingly, after 1â week seizure activity declined precipitously and persistent epileptiform activity disappeared. Occasional seizures (≈1/day) persisted to the end of the experiment at 4â weeks. In contrast to the dramatic impact of interneuron ablation, transient silencing produced large numbers of interictal spikes, a significant but modest increase in seizure occurrence and changes in EEG frequency band power. Taken together, findings suggest that the hippocampus regains relative homeostasis-with occasional breakthrough seizures-in the face of an extensive and abrupt loss of interneurons.
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PURPOSE: Major depressive disorder (MDD) disproportionately affects those living with autism spectrum disorder (ASD) and is associated with significant impairment and treatment recidivism. METHODS: We studied the use of accelerated theta burst stimulation (ATBS) for the treatment of refractory MDD in ASD (3 treatments daily x 10 days). This prospective open-label 12-week trial included 10 subjects with a mean age of 21.5 years, randomized to receive unilateral or bilateral stimulation of the dorsolateral prefrontal cortex. RESULTS: One participant dropped out of the study due to intolerability. In both treatment arms, depressive symptoms, scored on the Hamilton Depression Rating Scale scores, diminished substantially. At 12 weeks post-treatment, full remission was sustained in 5 subjects and partial remission in 3 subjects. Treatment with ATBS, regardless of the site of stimulation, was associated with a significant, substantial, and sustained improvement in depressive symptomatology via the primary outcome measure, the Hamilton Depression Rating Scale. Additional secondary measures, including self-report depression scales, fluid cognition, and sleep quality, also showed significant improvement. No serious adverse events occurred during the study. Mild transient headaches were infrequently reported, which are expected side effects of ATBS. CONCLUSION: Overall, ATBS treatment was highly effective and well-tolerated in individuals with ASD and co-occurring MDD. The findings support the need for a larger, sham-controlled randomized controlled trial to further evaluate efficacy of ATBS in this population.
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Importance: Mental health (MH) issues in children with cerebral palsy (CP) are poorly understood compared with other pediatric populations. Objective: To examine MH diagnosis code assignment among children and young adults with CP and compare with typically developing (TD) and chronic condition (CC) pediatric populations. Design, Setting, and Participants: This case-control study used International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes to create a CP case set and CC and TD control sets using electronic health record data of children and young adults from a large tertiary care children's hospital in the midwestern United States between 2010 and 2022. Case-control matching was performed to control for demographic factors. Data were analyzed from June to December 2023. Exposures: All MH diagnosis codes were mapped to ICD-10-CM and categorized using Clinical Classifications Software Refined (CCSR). Main Outcomes and Measures: The incidence rates of MH CCSR categories were calculated. Descriptive and comparative statistics were used to evaluate the significance and odds associated with factors. Results: Data from 216â¯794 individuals (mean [SD] baseline age, 4.3 [5.1] years; 118â¯562 [55%] male) were analyzed, including 3544 individuals with CP, 142â¯160 individuals with CC, and 71â¯080 TD individuals. The CP cohort spread across Gross Motor Function Classification System (GMFCS) levels I (981 individuals [28%]), II (645 individuals [18%]), III (346 individuals [10%]), IV (502 individuals [14%]), and V (618 individuals [17%]). Rates varied significantly for anxiety (824 individuals with CP [23%]; 25â¯877 individuals with CC [9%]; 6274 individuals with TD [18%]), attention-deficit/hyperactivity disorder (534 individuals with CP [15%]; 22â¯426 individuals with CC [9%]; 6311 individuals with TD [16%]); conduct or impulse disorder (504 individuals with CP [14%]; 13â¯209 individuals with CC [5%]; 3715 individuals with TD [9%]), trauma or stress disorders (343 individuals with CP [10%]; 18â¯229 individuals with CC [8%]; 5329 individuals with TD [13%]), obsessive-compulsive disorder (251 individuals with CP [7%]; 3795 individuals with CC [1%]; 659 individuals with TD [3%]), depression (108 individuals with CP [3%]; 12â¯224 individuals with CC [5%]; 4007 individuals with TD [9%]), mood disorders (74 individuals with CP [2%]; 4355 individuals with CC [2%]; 1181 individuals with TD [3%]), and suicidal ideation (72 individuals with CP [2%]; 7422 individuals with CC [5%]; 3513 individuals with TD [5%]). There was significant variation in odds of MH diagnoses by GMFCS level (I-II vs III-V: odds ratio [OR], 1.23; 95% CI, 1.09-1.40; P = .001). Among individuals with CP, males were more likely than females to have diagnosis codes for conduct or impulse disorders (OR, 1.41; 95% CI, 1.16-1.73) and attention-deficit/hyperactivity disorder (OR, 1.41 [95% CI, 1.15-1.73]). Black individuals, compared with White individuals, were more likely to have diagnoses for obsessive-compulsive disorder (OR, 1.57 [95% CI, 1.14-2.16]), other mood disorders (OR, 1.85 [95% CI, 1.01-3.38]), and trauma or stress disorders (OR, 1.94 [95% CI, 1.44-2.63]). Odds for trauma or stress disorders were elevated for individuals who identified as other races compared with White individuals (OR, 2.80 [95% CI, 2.03-3.87]). Conclusions and Relevance: In this case-control study of children and young adults with CP and matched comparisons, anxiety and conduct or impulse diagnoses were higher in individuals with CP. The lower diagnosis rates of depression and suicidal ideation may indicate underdiagnosis among individuals with CP. There is likely a need for assessment tools that are more suitable for children with CP.
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Paralisia Cerebral , Transtornos Mentais , Humanos , Paralisia Cerebral/epidemiologia , Masculino , Feminino , Estudos de Casos e Controles , Adolescente , Criança , Doença Crônica/epidemiologia , Adulto Jovem , Transtornos Mentais/epidemiologia , Pré-Escolar , Meio-Oeste dos Estados Unidos/epidemiologiaRESUMO
Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.
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This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1's mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.
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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.
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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.
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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.
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Background: Acquired epilepsies are caused by an initial brain insult that is followed by epileptogenesis and finally the development of spontaneous recurrent seizures. The mechanisms underlying epileptogenesis are not fully understood. MicroRNAs regulate mRNA translation and stability and are frequently implicated in epilepsy. For example, antagonism of a specific microRNA, miR-324-5p, before brain insult and in a model of chronic epilepsy decreases seizure susceptibility and frequency, respectively. Here, we tested whether antagonism of miR-324-5p during epileptogenesis inhibits the development of epilepsy. Methods: We used the intrahippocampal kainic acid (IHpKa) model to initiate epileptogenesis in male wild type C57BL/6 J mice aged 6-8 weeks. Twenty-four hours after IHpKa, we administered a miR-324-5p or scrambled control antagomir intracerebroventricularly and implanted cortical surface electrodes for EEG monitoring. EEG data was collected for 28 days and analyzed for seizure frequency and duration, interictal spike activity, and EEG power. Brains were collected for histological analysis. Results: Histological analysis of brain tissue showed that IHpKa caused characteristic hippocampal damage in most mice regardless of treatment. Antagomir treatment did not affect latency to, frequency, or duration of spontaneous recurrent seizures or interictal spike activity but did alter the temporal development of frequency band-specific EEG power. Conclusion: These results suggest that miR-324-5p inhibition during epileptogenesis induced by status epilepticus does not convey anti-epileptogenic effects despite having subtle effects on EEG frequency bands. Our results highlight the importance of timing of intervention across epilepsy development and suggest that miR-324-5p may act primarily as a proconvulsant rather than a pro-epileptogenic regulator.
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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.
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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.
Assuntos
Transtorno do Espectro Autista , Probióticos , Humanos , Atividades Cotidianas , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/psicologia , Estudos Cross-Over , Método Duplo-Cego , Resultado do TratamentoRESUMO
Objective: Fragile X Syndrome (FXS) is the leading monogenic cause of intellectual disability and autism spectrum disorder. Currently, there are no established biomarkers for predicting and monitoring drug effects in FXS, and no approved therapies are available. Previous studies have shown electrophysiological changes in the brain using electroencephalography (EEG) in individuals with FXS and animal models. These changes may be influenced by drug therapies. In this study, we aimed to assess the reliability of resting-state EEG measures in individuals with FXS, which could potentially serve as a biomarker for drug discovery. Methods: We collected resting-state EEG data from 35 individuals with FXS participating in placebo-controlled clinical trials (23 males, 12 females; visit age mean+/-std 25.6 +/-8.3). The data were analyzed for various spectral features using intraclass correlation analysis to evaluate test-retest reliability. The intervals between EEG recordings ranged from same-day measurements to up to six weeks apart. Results: Our results showed high reliability for most spectral features, with same-day reliability exceeding 0.8. Features of interest demonstrated ICC values of 0.60 or above at longer intervals. Among the features, alpha band relative power exhibited the highest reliability. Conclusion: These findings indicate that resting-state EEG can provide consistent and reproducible measures of brain activity in individuals with FXS. This supports the potential use of EEG as an objective biomarker for evaluating the effects of new drugs in FXS. Significance: The reliable measurements obtained from power spectrum-based resting-state EEG make it a promising tool for assessing the impact of small molecule drugs in FXS.