Auditory Hypersensitivity Research Articles

Assessment of auditory hypersensitivity in children and adolescents with Autism Spectrum Disorder: integrative review

Introduction: Individuals with Autism Spectrum Disorder may present impairments in communication, behavior, social interaction and changes in sensory processing with atypical responses to information from the senses, such as auditory hypersensitivity. Objective: to describe the methods of evaluating auditory hypersensitivity used in babies, children and/or adolescents with Autism Spectrum Disorder, through an integrative review. Data Synthesis: The study was carried out with the PVO strategy, in the months of October and November 2023, with the search key: “Infant” OR “Child” OR “Adolescent” AND “Autism Spectrum Disorder” AND “Hyperacusis” OR “ Hyperacuses” OR "Hearing” in 11 databases. Results: 7,071 studies were identified, after reading titles and abstracts, 59 were selected, 30 of which were duplicates and 29 were read in full. In the end, 10 articles were included. The majority of studies carried out audiological exams followed by a questionnaire, with the Sensory Profile questionnaire being the most common and the Otoacoustic Emissions, Brainstem Auditory Evoked Potential and Immittance Tests being the most common. The sounds that cause the most discomfort are: sounds of strong intensity in general, such as, vacuum cleaner and hairdryer. The most common emotional reaction was crying and physical reactions, covering the ears and running away. Conclusion: It was noticed that the majority of studies reported in this review demonstrate that for the investigation of auditory hypersensitivity, it can be both questionnaires and hearing exams were used in children and adolescents with auditory hypersensitivity, making it necessary to carry out more studies on the subject to standardize an assessment for auditory hypersensitivity.

Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism.

Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in four genetic lines relevant to autism: fmr1, mecp2, scn1lab and cntnap2. In free-swimming behavioral tests, we found each line had a unique profile of auditory hypersensitivity and/or delayed habituation. Combining the optical transparency of larval zebrafish with genetically encoded calcium indicators and light-sheet microscopy, we then observed brain-wide activity at cellular resolution during auditory habituation. As with behavior, each line showed unique alterations in brain-wide spontaneous activity, auditory processing, and adaptation in response to repetitive acoustic stimuli. We also observed commonalities in activity across our genetic lines that indicate shared circuit changes underlying certain aspects of their behavioral phenotypes. These were predominantly in regions involved in sensory integration and sensorimotor gating rather than primary auditory areas. Overlapping phenotypes include differences in the activity and functional connectivity of the telencephalon, thalamus, dopaminergic regions, and the locus coeruleus, and excitatory/inhibitory imbalance in the cerebellum. Unique phenotypes include loss of activity in the habenula in scn1lab, increased activity in auditory regions in fmr1, and differences in network activity over time in mecp2 and cntnap2. Comparing these distinct but overlapping brain-wide auditory networks furthers our understanding of how diverse genetic factors can produce similar behavioral effects through a range of circuit- and network-scale mechanisms.

SCN2A-linked myelination deficits and synaptic plasticity alterations drive auditory processing disorders in ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by complex sensory processing deficits. A key unresolved question is how alterations in neural connectivity and communication translate into the behavioral manifestations seen in ASD. Here, we investigate how oligodendrocyte dysfunction alters myelin plasticity and neuronal activity, leading to auditory processing disorder associated with ASD. We focus on the SCN2A gene, an ASD-risk factor, to understand its role in myelination and neural processing within the auditory nervous system. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes in Scn2a conditional knockout mice, highlighting the cellular consequences engendered by Scn2a deletion in oligodendrocytes. The results reveal a nuanced interplay between oligodendrocytes and axons, where Scn2a deletion causes alterations in the intricate process of myelination. This disruption instigates changes in axonal properties, presynaptic excitability, and synaptic plasticity at the single cell level. Furthermore, oligodendrocyte-specific Scn2a deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity. Our findings reveal a novel pathway linking myelin deficits to synaptic activity and sensory abnormalities in ASD.

Hyperacusis questionnaire and event-related potential correlation in migraine patients

This study aims to investigate auditory hypersensitivity and cortical function in migraine patients using the Hyperacusis Questionnaire and the Event-Related Potential (ERP) technique. The study analyzes alterations in the latency and amplitude of the event-related potentials MMN and P300 components. The findings contribute to a better understanding of the physiological relationship between migraine and auditory hypersensitivity. Seventeen migraine patients were admitted to the outpatient clinic of the Department of Otorhinolaryngology-Head and Neck Surgery at Peking University People’s Hospital from June 2023 to September 2023. Nineteen matched healthy subjects were also selected. All participants underwent the pure tone audiometry and the auditory brainstem response test to determine hearing thresholds, the Hyperacusis Questionnaire, the Tinnitus Handicap Inventory, and an ERP examination. The Oddball classical paradigm was used as the stimulation task, and electroencephalography signals were recorded synchronously. The scores of the Hyperacusis Questionnaire, latency and amplitude of MMN and P300 component were compared between the migraine group and the control group, and their correlation was analyzed. The latency of MMN at the Fz and Cz sites in migraine patients was significantly shorter than that in the control group (P < 0.05), and the amplitudes were significantly higher than those in the control group (P < 0.05). The variances in latency and amplitude of P300 at Cz and Pz sites in migraine patients were not statistically significant when compared with the control group. (P > 0.05). The Hyperacusis Questionnaire was negatively correlated with MMN latency, with a correlation coefficient of − 0.374 (P = 0.025), and positively correlated with MMN amplitude, with a correlation coefficient of 0.378 (P = 0.023). There was no significant similarity between the Hyperacusis Questionnaire and P300 latency and amplitude (P > 0.05). Overall, auditory hypersensitivity was enhanced in individuals with migraines compared to healthy individuals, leading to faster information processing, while there may be less impairment in cognitive function.

Frontal Cortex Hyperactivation and Gamma Desynchrony in Fragile X Syndrome: Correlates of Auditory Hypersensitivity.

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.

Cortical determinants of loudness perception and auditory hypersensitivity.

Parvalbumin-expressing inhibitory neurons (PVNs) stabilize cortical network activity, generate gamma rhythms, and regulate experience-dependent plasticity. Here, we observed that activation or inactivation of PVNs functioned like a volume knob in the mouse auditory cortex (ACtx), turning neural and behavioral classification of sound level up or down over a 20dB range. PVN loudness adjustments were "sticky", such that a single bout of 40Hz PVN stimulation sustainably suppressed ACtx sound responsiveness, potentiated feedforward inhibition, and behaviorally desensitized mice to loudness. Sensory sensitivity is a cardinal feature of autism, aging, and peripheral neuropathy, prompting us to ask whether PVN stimulation can persistently desensitize mice with ACtx hyperactivity, PVN hypofunction, and loudness hypersensitivity triggered by cochlear sensorineural damage. We found that a single 16-minute bout of 40Hz PVN stimulation session restored normal loudness perception for one week, showing that perceptual deficits triggered by irreversible peripheral injuries can be reversed through targeted cortical circuit interventions.

Auditory Encoding of Natural Speech at Subcortical and Cortical Levels Is Not Indicative of Cognitive Decline.

More and more patients worldwide are diagnosed with dementia, which emphasizes the urgent need for early detection markers. In this study, we built on the auditory hypersensitivity theory of a previous study-which postulated that responses to auditory input in the subcortex as well as cortex are enhanced in cognitive decline-and examined auditory encoding of natural continuous speech at both neural levels for its indicative potential for cognitive decline. We recruited study participants aged 60 years and older, who were divided into two groups based on the Montreal Cognitive Assessment, one group with low scores (n = 19, participants with signs of cognitive decline) and a control group (n = 25). Participants completed an audiometric assessment and then we recorded their electroencephalography while they listened to an audiobook and click sounds. We derived temporal response functions and evoked potentials from the data and examined response amplitudes for their potential to predict cognitive decline, controlling for hearing ability and age. Contrary to our expectations, no evidence of auditory hypersensitivity was observed in participants with signs of cognitive decline; response amplitudes were comparable in both cognitive groups. Moreover, the combination of response amplitudes showed no predictive value for cognitive decline. These results challenge the proposed hypothesis and emphasize the need for further research to identify reliable auditory markers for the early detection of cognitive decline.

Improvement of symptoms in children with autism by TOMATIS training: a cross-sectional and longitudinal study.

Autism spectrum disorder (ASD) is a neurological condition that is marked by deficits in social interaction, difficulty expressing oneself, lack of enthusiasm, and stereotypical conduct. The TOMATIS training method is an effective music therapy for children with ASD for its individually developed programs to improve behavioral deficits. The research employed both longitudinal and crosssectional designs. In the cross-sectional study, the experimental group showed significant improvement in symptoms after TOMATIS training compared to the control group of children with ASD. The results validated the effect of TOMATIS treatment for ASD-related deficits, including perceptual-motor, attentional, social, and emotional issues. ASD's auditory hypersensitivity hampers social information processing, but TOMATIS enhances cochlear frequency selectivity, aiding in capturing relevant auditory stimuli. In addition, the longitudinal study confirmed these findings, which proved TOMATIS training effective in clinically treating ASD. This study focused on audiometric indicators and behavioural improvement, elucidating the mechanisms behind the training's success. Behavioral improvements might stem from TOMATIS' frequency selectivity, reshaping auditory organ-cortical feedback loops to filter interference and focus on valid information.

Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice

There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

Electrophysiological evidence for increased auditory crossmodal activity in adult ADHD.

Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by core symptoms of inattention, and/or impulsivity and hyperactivity. In order to understand the basis for this multifaceted disorder, the investigation of sensory processing aberrancies recently reaches more interest. For example, during the processing of auditory stimuli comparable low sensory thresholds account for symptoms like higher distractibility and auditory hypersensitivity in patients with ADHD. It has further been shown that deficiencies not only exist on an intramodal, but also on a multimodal level. There is evidence that the visual cortex shows more activation during a focused auditory task in adults with ADHD than in healthy controls. This crossmodal activation is interpreted as the reallocation of more attentional resources to the visual domain as well as deficient sensory inhibition. In this study, we used, for the first time, electroencephalography to identify a potential abnormal regulated crossmodal activation in adult ADHD. 15 adult subjects with clinically diagnosed ADHD and 14 healthy controls comparable in age and gender were included. ERP components P50, P100, N100, P200 and N200 were measured during the performance of a unimodal auditory and visual discrimination task in a block design. Sensory profiles and ADHD symptoms were assessed with inattention as well as childhood ADHD scores. For evaluating intramodal and crossmodal activations, we chose four EEG channels for statistical analysis and group-wise comparison. At the occipital channel O2 that reflects possible crossmodal activations, a significantly enhanced P200 amplitude was measured in the patient group. At the intramodal channels, a significantly enhanced N200 amplitude was observed in the control group. Statistical analysis of behavioral data showed poorer performance of subjects with ADHD as well as higher discrimination thresholds. Further, the correlation of the assessed sensory profiles with the EEG parameters revealed a negative correlation between the P200 component and sensation seeking behavior. Our findings show increased auditory crossmodal activity that might reflect an altered stimulus processing resource allocation in ADHD. This might induce consequences for later, higher order attentional deployment. Further, the enhanced P200 amplitude might reflect more sensory registration and therefore deficient inhibition mechanisms in adults with ADHD.

The Shank3-InsG3680(+/+) mouse model of autism spectrum disorder displays auditory avoidance in a novel behavioral test.

Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, repetitive behaviors, and sensory alterations, with auditory hypersensitivity being one of the most commonly reported sensory-perceptual abnormalities. Several candidate genes for involvement in this disorder have emerged from patient studies, including SHANK3, a gene that encodes a protein (SHANK3) in the postsynaptic density of excitatory synapses. Previous work has shown that mutant mice carrying a human ASD mutation in the Shank3 gene (InsG3680) exhibit repetitive behaviors and social interaction deficits, indicating important construct and face validity for this genotype as an animal model of ASD. To further address whether these mice also present auditory sensory-perceptual alterations, we developed a novel behavioral test in which mice can choose between different soundscapes. Our results reveal that, in comparison to wild-type mice, Shank3 mutants display a strong behavioral preference toward silent regions of the arena. These data suggest that Shank3- mutant mice might express an auditory hypersensitivity phenotype, further adding to the face validity of this genotype as an animal model of ASD.

Cochlear Nucleus Transcriptome of a Fragile X Mouse Model Reveals Candidate Genes for Hyperacusis.

Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity. RNA was isolated from cochlear nuclei of Fmr1-KO and WT mice. Using next-generation sequencing (RNA-seq), the transcriptomes of Fmr1-KO mice and WT mice (n = 3 each) were compared and analyzed using gene ontology programs. We identified 270 unique, differentially expressed genes between Fmr1-KO and WT cochlear nuclei. Upregulated genes (67%) are enriched in those encoding secreted molecules. Downregulated genes (33%) are enriched in neuronal function, including synaptic pathways, some of which are ideal candidate genes that may contribute to hyperacusis. The loss of FMRP can affect the expression of genes in the cochlear nucleus that are important for neuronal signaling. One of these, Kcnab2, which encodes a subunit of the Shaker voltage-gated potassium channel, is expressed at an abnormally low level in the Fmr1-KO cochlear nucleus. Kcnab2 and other differentially expressed genes may represent pathways for the development of hyperacusis. Future studies will be aimed at investigating the effects of these altered genes on hyperacusis. N/A Laryngoscope, 134:1363-1371, 2024.

SoundFields: A Virtual Reality Home-Based Intervention for Auditory Hypersensitivity Experienced by Autistic Children

Previous studies have shown that autistic people often display atypical responses when processing sensory information, with particular prevalence within the auditory domain. Often provoked by common everyday sounds, auditory hypersensitivity can result in self-regulatory fear responses. This can be potentially harmful to autistic individuals and the people around them and is associated with greater occurrence of anxiety, depression, and poorer overall quality of life in the autistic population. Rather than a physiological causation, the literature suggests that hypersensitivity to sound is likely to be caused by how auditory stimuli are processed in the brain. This paper reports a home-based digital intervention aimed to address auditory hypersensitivity in autistic children. Developed as an interactive virtual reality game, the system integrates exposure-based therapy techniques into game mechanics and delivers target auditory stimuli to the player rendered via binaural-based spatial audio. The performance of the platform was evaluated in a 10-week feasibility study, during which children (n = 7) engaged weekly with the game during a 30 min session. Following this period, a comparison of pre- and post-study measurements showed a decrease in sensitivity for five participants, with qualitative feedback highlighting an increase in tolerance towards real-world stimuli and challenging environments. These results provide initial support for SoundFields as a home-based intervention targeting auditory hypersensitivity experienced by autistic children.

The Multi-Modal Evaluation of Sensory Sensitivity (MESSY): assessing a commonly missed symptom of acquired brain injury

Objective: Sensory hypersensitivity is common after acquired brain injury. Since appropriate diagnostic tools are lacking, these complaints are overlooked by clinicians and available literature is limited to light and noise hypersensitivity after concussion. This study aimed to investigate the prevalence of sensory hypersensitivity in other modalities and after other types of brain injury. Method: We developed the Multi-Modal Evaluation of Sensory Sensitivity (MESSY), a patient-friendly questionnaire that assesses sensory sensitivity across multiple sensory modalities. 818 neurotypical adults (mean age = 49; 244 male) and 341 chronic acquired brain injury patients (including stroke, traumatic brain injury, and brain tumour patients) (mean age = 56; 126 male) completed the MESSY online. Results: The MESSY had a high validity and reliability in neurotypical adults. Post-injury sensory hypersensitivity (examined using open-ended questions) was reported by 76% of the stroke patients, 89% of the traumatic brain injury patients, and 82% of the brain tumour patients. These complaints occurred across all modalities with multisensory, visual, and auditory hypersensitivity being the most prevalent. Patients with post-injury sensory hypersensitivity reported a higher sensory sensitivity severity on the multiple-choice items of the MESSY as compared to neurotypical adults and acquired brain injury patients without post-injury sensory hypersensitivity (across all sensory modalities) (effect sizes (partial eta squared) ranged from .06 to .22). Conclusions: These results show that sensory hypersensitivity is prevalent after different types of acquired brain injury as well as across several sensory modalities. The MESSY can improve recognition of these symptoms and facilitate further research.

0996 A New Insomnia Phenotype: Coronasomnia Misophonia Syndrome

Abstract Introduction Misophonia is a complex neuropsychiatric phenomenon characterized by an intense selective auditory hypersensitivity to auditory stimuli accompanied by emotional intolerance consisting of anger, anxiety, and frustration. We report on four subjects who presented with significant sleep onset insomnia coinciding with the mandated stay-at-home order in March 2020. All patients reported unique and specific irritability and aversion to sounds in their proximal environment - the misophonic trigger (MT). While a previous study reported on the capacity of misophonia to emerge during venerable periods of confinement, we report a series of four patients in whom misophonia was a unique precipitant of insomnia, a “misophonic response” accompanied by hypervigilance and insomnia. Our findings support the consideration of a unique insomnia phenotype - Coronasomnia Misophonia Syndrome (CMS). Report of case(s) Subject A is a 29-year-old female with a history of OCD and mild insomnia (MT: humming refrigerator). Subject B is a 31-year-old female with a history of delayed sleep phase disorder in her teenage years (MT: husband’s breathing). Subject C is a 36-year-old male with well-controlled sleep-onset insomnia (MT: electric humming from walls). Subject D is a 46-year-old male with well-controlled depression (MT: carotid pulsation transmitted through his pillow). All but one patient had reasonable improvement with mindfulness therapy combined with systematic desensitization. Subject A improved after pharmacological modification of OCD therapy. Conclusion Our case series supports CMS as a unique insomnia phenotype coinciding with social isolation during the COVID-19 pandemic. The MT might have served as a precipitant through classical conditioning. Desensitization with mindfulness therapy was helpful, but the presence of comorbid OCD led to a refractory course supporting pervasive sensory processing in this patient. Our data highlights the need for more dedicated investigation for MT in patients presenting with insomnia during times of confinement and unprecedented anxiety. Additional data is needed to support our observation and investigate the potential psychophysiological mechanism, particularly the proposed alteration in auditory processing in response to the MT in healthy and psychiatric cohorts. Support (if any)

Initial Outcomes of the Safe and Sound Protocol on Patients with Adult Autism Spectrum Disorder: Exploratory Pilot Study.

Sensory impairments are common features of autism spectrum disorder (ASD) and are associated with its social impairments. However, there is no established treatment for these impairments in adults with ASD. The Safe & Sound Protocol (SSP) is a listening program designed to improve social communication skills by reducing auditory hypersensitivity. We investigated the effectiveness of the SSP for adults with ASD. We administered the SSP to six participants with ASD aged 21-44 years old, and the effects were assessed using the Social Responsiveness Scale, Second Edition (SRS-2). Secondary outcomes were assessed using the Center for Epidemiological Studies Depression Scale (CES-D), State-Trait Anxiety Inventory (STAI), WHO Quality of Life 26 (WHOQOL-BREF), and Adolescent/Adult Sensory Profile (A/ASP). In this study, only the Social Awareness scale of the SRS-2 Family-Report showed a significant improvement after the intervention. In addition, it was significantly correlated with physical health of WHOQOL-BREF (r = -0.577, p = 0.012), state and trait anxiety of STAI (r = 0.576, p = 0.012; r = 0.708, p = 0.00009, respectively), and CES-D (r = 0.465, p = 0.05). In conclusion, the SSP has a partial effect on social impairments in adults with ASD, specifically on the Social Awareness subscale of the SRS-2.

How Classroom Acoustic Conditions May Impact Autistic Students: A Review

Data about the prevalence of autism worldwide diverge across different censuses. However, with the growing availability of diagnostic assessments, the number of diagnosed autistic persons has been increasing over the years and, with that, also the need for accommodations. One differentiating characteristic of autistic persons compared to those who are not is a hypo- or hypersensitive response to any sensory input, usually referred to as sensory processing disorder. Here we focus on auditory hypersensitivity. In room acoustics, and more specifically in the field of classroom acoustics, it is known that the design of indoor spaces affects speech intelligibility and comprehension for people regardless of their neurological condition, which is essential in learning environments. For autistic persons, high levels of reverberation and background noise may lead to a sensory overload. This situation could be ameliorated with the use of assistive technology or adequate acoustic design. In this paper we present a literature review regarding the impacts of room acoustics on autistic people, how it can be used as an accessibility tool, and propose ideas for work to be done to better identify and resolve acoustic issues for autistic persons in classrooms.

Classification of cases of auditory hypersensitivity due to ASD with a focus on mechanism

Classification of cases of auditory hypersensitivity due to ASD with a focus on mechanism

Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice

Fragile XSyndrome (FXS) is a leading known genetic cause of Autism Spectrum Disorders (ASD) and intellectual disability. A consistent and debilitating phenotype of FXS is sensory hypersensitivity that manifests strongly in the auditory domain and may lead to delayed language and high anxiety. The mouse model of FXS, the Fmr1 KO mouse, also shows auditory hypersensitivity, an extreme form of which is seen as audiogenic seizures (AGS). The midbrain inferior colliculus (IC) is critically involved in generating audiogenic seizures and IC neurons are hyper-responsive to sounds in developing Fmr1 KO mice. Serotonin-1A receptor (5-HT1A) activation reduces IC activity. Therefore, we tested whether 5-HT1A activation is sufficient to reduce audiogenic seizures in Fmr1 KO mice. A selective and post-synaptic 5-HT1A receptor biased agonist, 3-Chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin-1-yl] methanone (NLX-101, 0.6, 1.2, 1.8 or 2.4 mg/kg, i.p.) was administered to Fmr1 KO mice 15 min before seizure induction. Whereas the 0.6 mg/kg dose was ineffective in reducing seizures, the 1.2, 1.8 and 2.4 mg/kg doses of NLX-101 dramatically reduced seizures and increased mouse survival. Treatment with a combination of NLX-101 and 5-HT1A receptor antagonists prevented the protective effects of NLX-101, indicating that NLX-101 acts selectively through 5-HT1A receptors to reduce audiogenic seizures. NLX-101 (1.8 mg/kg) was still strongly effective in reducing seizures even after repeated administration over 5 days, suggesting an absence of tachyphylaxis to the effects of the compound. Together, these studies point to a promising treatment option targeting post-synaptic 5-HT1A receptors to reduce auditory hypersensitivity in FXS, and potentially across autism spectrum disorders.

The Use of Binaural Based Spatial Audio in the Reduction of Auditory Hypersensitivity in Autistic Young People.

Individuals diagnosed with autism spectrum disorder (ASD) are characterised as experiencing impairments in social-emotional interaction and communication, alongside frequently displaying repetitive behaviours and interests. Further to this, they are often described as experiencing difficulties in processing sensory information, with particular prevalence within the auditory modality. Provoked by common environmental sounds, auditory hypersensitivity can result in self-regulatory fear responses. Rather than a physiological pain reaction, literature suggests that these hypersensitivities are resulting through irrational fear of the sounds. This investigation evaluates the use of binaural based spatial audio as a rendering technique for delivering realistic simulations of averse stimuli within a virtual reality (VR) exposure based computer game intervention for auditory hypersensitivity in autism. Over multiple experimental sessions, 20 autistic participants experiencing auditory hypersensitivity were exposed to either spatial audio or stereo renders of target stimuli during the intervention. Measurements of self-reported emotions displayed significant reductions in associated negative emotional reactions to target stimuli for all participants. However, significant improvements were experienced by those listening to spatial audio simulations. Moreover, tracked voluntary interactions with exposure based game-mechanics increased as the study progressed. Providing further evidence of increased tolerance towards averse auditory stimuli.