Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

Background Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. Methods EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0–100 Hz over 2 s. Results Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. Conclusions This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics

A resting EEG study of neocortical hyperexcitability and altered functional connectivity in fragile X syndrome

(A) Scalp topographies of “local coupling”, showing correlations in each electrode between relative power of activity in the theta, and lower and upper alpha power bands and gamma power for male FXS and male healthy control participants, with significant group differences presented in the bottom row (p < 0.05, corrected), with dark blue reflecting no group difference. (B) Mean and standard error of correlations for all electrodes showing group differences as are plotted in A. * denotes correlations of spectral power in theta and upper alpha bands with gamma band power that are significantly different from zero based on the results of permutation analyses at p < 0.05. (TIF 4297 kb

Auditory EEG Biomarkers in Fragile X Syndrome: Clinical Relevance

Sensory hypersensitivities are common and distressing features of Fragile X Syndrome (FXS). While there are many drug interventions that reduce behavioral deficits in Fmr1 mice and efforts to translate these preclinical breakthroughs into clinical trials for FXS, evidence-based clinical interventions are almost non-existent potentially due to lack of valid neural biomarkers. Local circuit function in sensory networks is dependent on the dynamic balance of activity in inhibitory/excitatory synapses. Studies are needed to examine the association of electrophysiological alterations in neural systems with sensory and other clinical features of FXS to establish their clinical relevance. Adolescents and adults with FXS (n = 38, Mean age = 25.5, std = 10.1; 13 females) and age matched typically developing controls (n = 40, Mean age = 27.7, std = 12.1; 17 females) completed auditory chirp and auditory habituation tasks while undergoing dense array electroencephalography (EEG). Amplitude, latency, and percent change (habituation) in N1 and P2 event-related potential (ERP) components were characterized for the habituation task; time-frequency calculations using Morlet wavelets characterized phase-locking and single trial power for the habituation and chirp tasks. FXS patients showed increased amplitude but some evidence for reduced habituation of the N1 ERP, and reduced phase-locking in the low and high gamma frequency range and increased low gamma power to the chirp stimulus. FXS showed increased theta power in both tasks. While the habituation finding was weaker than previously found, the remaining findings replicate our previous work in a new sample of patients with FXS. Females showed less deficit in the chirp task but not the habituation task. Abnormal increases in gamma power were related to more severe behavioral and psychiatric features as well as reductions in neurocognitive abilities. Replicating electrophysiological deficits in a new group of patients using different EEG equipment at a new data collection site with differing levels of environmental noise that were robust to data processing techniques utilizing multiple researchers, indicates a potential for scalability to multi-site clinical trials. Given the robust replicability, relevance to clinical measures, and preclinical evidence for sensitivity of these EEG measures to pharmacological intervention, the observed abnormalities may provide novel translational markers of target engagement and potentially outcome measures in large-scale studies evaluating new treatments targeting neural hyperexcitability in FXS.This study was supported by NIMH/NICHD grant U54 HD082008-01 (Huber and JS). Open Access fees paid for in whole or in part by the University of Oklahoma Libraries.Ye

Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible.

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1-/-) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1-/- mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome

SignalFlowEEG Example Data

The SignalFlowEEG Example Data dataset contains sample EEG recordings that demonstrate the capabilities and usage of the SignalFlowEEG Python package. This package provides a comprehensive set of tools for processing, analyzing, and visualizing electroencephalography (EEG) data, with a focus on neuroscience research applications.The example dataset includes EEG recordings from various paradigms:Resting-state EEG: A 5-minute recording where the subject relaxed with eyes closed.Auditory chirp stimulation: EEG recorded while the subject listened to chirp sounds with varying frequencies.Visual evoked potentials: EEG recorded as the subject viewed checkerboard pattern stimuli to elicit visual responses.These recordings were collected at the Cincinnati Children's Hospital Medical Center and are made available for educational and testing purposes.SignalFlowEEG builds upon MNE-Python, a popular open-source library for EEG analysis, and offers additional functionality tailored for clinical research workflows. This example dataset allows users to explore SignalFlowEEG's features and gain hands-on experience analyzing EEG data with this powerful Python package.The dataset consists of .set files, a format used by the EEGLAB toolbox. Each file contains raw EEG data, channel info, and event markers for a specific experimental paradigm. Files can be loaded using mne.io.read_raw_eeglab() from MNE-Python, a SignalFlowEEG dependency. The dataset has no missing data or special abbreviations. Channel names and event markers follow standard EEGLAB conventions.</p

Toddlers requiring pediatric intensive care unit admission following at-home exposure to buprenorphine/naloxone

BACKGROUND: Sublingual buprenorphine is an alternative to methadone for office-based treatment of opioid dependence. Recent reports have examined a growing number of unintentional buprenorphine exposures in children resulting in significant toxicity, even after a single lick or taste of a sublingual tablet. Here, we report a series of unintentional buprenorphine exposures in toddlers over a 2.5-yr period that led to admission to the pediatric intensive care unit. OBJECTIVES: The goals of this study were to determine: 1) the prevalence of symptomatic buprenorphine exposure in children \u3c3 yrs of\u3eage; 2) the severity of toxicity associated with such exposures; and 3) effective clinical interventions. METHODS AND MAIN RESULTS: A retrospective case review was performed on records from the pediatric intensive care unit at an academic medical center located in the northeastern United States. Unintentional buprenorphine/naloxone exposure (n = 9) accounted for the largest single fraction of toxic ingestions among patients younger than 3 yrs within the study period (9/33, 27%). All exposures occurred at the child\u27s place of residence (n = 9, 100%). Clinical signs of opioid toxicity were evident in all nine cases, with the most common symptom being drowsiness or lethargy (n = 9, 100%), followed by miosis (n = 6, 67%) and respiratory depression (n = 5, 56%). Six patients were effectively treated with naloxone (n = 6, 67%). CONCLUSIONS: The increased use and similarity to candy of the current formulation of buprenorphine pose a special risk to children, especially toddlers. Buprenorphine exposure in children \u3c3 yrs old can cause significant opioid toxidrome. Naloxone is an effective agent for reversal of\u3esymptoms; however, given buprenorphine\u27s high affinity and long action, higher doses or continuous infusion may be required. Adults on buprenorphine should be educated on the risks posed to young children in their household and the appropriate storage of medication

Prolonged delirium after quetiapine overdose

Quetiapine is an atypical antipsychotic agent increasingly used to treat schizophrenia and bipolar disorder in pediatric patients. Few published data exist concerning quetiapine\u27s effects in therapeutic settings or short-term overdose in pediatric and adolescent populations. In this report, we describe a 15-year-old adolescent girl who experienced continued delirium 5 days after an overdose of quetiapine, trazodone, and clonidine. The patient initially presented with sedation and stable vital signs. After 3 days of gradual improvement, she experienced episodes of delirium coinciding with an increase in resting heart rate. On the basis of suspicion for quetiapine-associated antimuscarinic effects, the patient was administered intravenously with physostigmine on the fifth day after ingestion. Treatment resulted in a brief resolution of symptoms. Serum quetiapine levels measured 1 day and 5 days after ingestion were 3400 and 4800 ng/mL, respectively. The use of physostigmine and interpretation of serum levels are discussed further

Safety and Tolerability of Theta Burst Stimulation versus Single and Paired Pulse Transcranial Magnetic Stimulation: A Comparative Study of 165 Pediatric Subjects

Background: Although single- and paired-pulse (sp/pp) transcranial magnetic stimulation (TMS) studies are considered minimal risk in adults and children, the safety profile for theta-burst TMS (TBS) is unknown.Objective: In this comparative analysis, we explored the rate, severity, and specific symptoms of TMS-related adverse effects (AEs) between sp/ppTMS and TBS in subjects between ages 6 and 18 years.Method: Data from 165 participants from 2009-2014 were analyzed. Assessment of AEs was performed based on baseline and post-TMS administration of a symptom-based questionnaire that rated AEs on a 5-level ordinal scale (minimal, mild, moderate, marked, severe). AE rates and severity were compared using Chi Square or Fisher’s Exact Test depending on data characteristics.Result: Overall, no seizures or severe-rated AEs were reported by 165 pediatric participants. The rate of AE in all TBS sessions was 10.5% (n=76, 95% CI: 4.7 - 19.7%), whereas the rate of AE in all sp/ppTMS sessions was 12.4% (n=89, 95% CI: 6.3 - 21.0%). There was no statistical difference in AE rates between TBS and sp/ppTMS (p=0.71). In all sp/ppTMS and TBS sessions, 20 subjects reported a total of 35 AEs, among these 31 (~88.6%) were rated as minimal or mild. There was no difference in the severity of AE between TBS and sp/ppTMS (p=1.0). Only one of 76 TBS participants reported an AE rated as more than minimal/mild.Conclusion: Our comparative analysis showed that TBS appears to be as safe as sp/ppTMS in terms of AE rate and severity. This report supports further investigation of TBS in children