Auditory Research publications

The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

Myosin VI（MYO6） is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

Listening to speech in noisy environments is challenging and effortful. Factors like the signal-to-noise ratio (SNR), the spatial separation between target speech and noise interferer(s), and possibly also the listener's age might influence perceived listening effort (LE). This study measured and modeled the effect of the spatial separation of target speech and interfering stationary speech-shaped noise on the perceived LE and its relation to the age of the listeners. Reference ranges for the relationship between subjectively perceived LE and SNR for different noise azimuths were established. For this purpose, 70 listeners with normal hearing and from three age groups rated the perceived LE using the Adaptive Categorical Listening Effort Scaling method (ACALES, Krueger et al., 2017a) with speech from the front and noise from 0°, 90°, 135°, or 180° azimuth. Based on these data, the spatial release from listening effort (SRLE) was calculated. The noise azimuth had a strong effect on SRLE, with the highest release for 135°. The binaural speech intelligibility model (BSIM2020, Hauth et al., 2020) predicted SRLE very well at negative SNRs, but overestimated for positive SNRs. No significant effect of age was found on the respective subjective ratings. Therefore, the reference ranges were determined independently of age. These reference ranges can be used for the classification of LE measurements. However, when the increase of the perceived LE with SNR was analyzed, a significant age difference was found between the listeners of the youngest and oldest group when considering the upper range of the LE function.

Alpha synuclein (α-Syn) is a small synaptic protein expressed within the central nervous system (CNS). α-Syn has been implicated in the pathogenesis of Parkinson’s disease (PD), and current theory suggests that α-Syn over-expression may lead to some of the CNS changes seen in PD, but the precise function of α-Syn remains elusive. α-Syn has also been identified in the auditory system and it is predominantly localized to the efferent auditory synapses below outer hair cells. In these studies, we studied a transgenic mouse model over-expressing α-Syn to investigate whether over-expression of α-Syn leads to pathologic changes within the cochlea. In the cochleae of wild-type (WT) mice, immunofluorescence using an anti-α-Syn antibody revealed strong labeling only in the base of outer hair cells. In contrast, in mice over-expressing α-Syn, there was robust staining in cells throughout the organ of Corti. Auditory brainstem responses (ABR) showed significant threshold elevations and a significant decrease of the ABR wave I amplitude in the transgenic mice as compared to WT mice. No significant differences were seen between WT and transgenic mice in hair cell counts, morphology or distortion product otoacoustic emissions. Following noise exposure, WT mice demonstrated an ABR threshold shift of 10-20dB whereas transgenic mice showed no significant threshold shift, suggesting a protective effect of α-Syn over-expression against noise-induced hearing loss. Together, these studies demonstrate that α-Syn over-expression causes a mild hearing loss and a protective effect against noise damage with no apparent damage to the cochlear hair cells. These findings suggest that the hearing loss seen with α-Syn over-expression occurs more centrally, while the mechanism of noise protection with over-expression remains unknown.

Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise‐induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin‐ and neomycin‐induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin‐1 (Fer‐1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer‐1 on tert‐butyl hydroperoxide (TBHP)‐induced hair cell damage in vitro in cochlear explants and HEI‐OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis‐inducing factor mitochondria‐associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer‐1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer‐1 significantly alleviated noise‐induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer‐1 significantly reduced noise‐ and TBHP‐induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer‐1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer‐1 exerted its protective effects by scavenging of ROS and inhibition of TfR1‐mediated ferroptosis and P53‐AIFM2 signaling pathway‐mediated apoptosis. Our findings suggest that Fer‐1 is a promising drug for treating NIHL because of its ability to inhibit noise‐induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.

The inflammasome is a multiprotein oligomer in the cell cytoplasm and is part of the innate immune system. It plays a crucial role in the pathological process of noise-induced hearing loss (NIHL). However, the mechanisms of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in NIHL have not been clearly demonstrated. In this study, miniature pigs were exposed to white noise at 120 dB(A) and auditory brainstem response measurements were used to measure their hearing function. Immunofluorescence staining, confocal laser scanning microscopy, western blot assay, and quantitative reverse transcription-polymerase chain reaction were used to analyze inflammasome-related protein distribution and expression. NLRP3, interleukin-1β, interleukin-18, and cleaved-caspase-1 were highly expressed in the cochlea after 120 dB(A) white noise exposure. Our findings suggest that NLRP3-inflammasomes in the cochlea may be activated after acoustic trauma, which may be an important mechanism of noise-induced hearing loss.

Recent studies have established significant anatomical and functional connections between visual areas and primary auditory cortex (A1), which may be important for cognitive processes such as communication and spatial perception. These studies have raised two important questions: First, which cell populations in A1 respond to visual input and/or are influenced by visual context? Second, which aspects of sound encoding are affected by visual context? To address these questions, we recorded single-unit activity across cortical layers in awake mice during exposure to auditory and visual stimuli. Neurons responsive to visual stimuli were most prevalent in the deep cortical layers and included both excitatory and inhibitory cells. The overwhelming majority of these neurons also responded to sound, indicating unimodal visual neurons are rare in A1. Other neurons for which sound-evoked responses were modulated by visual context were similarly excitatory or inhibitory but more evenly distributed across cortical layers. These modulatory influences almost exclusively affected sustained sound-evoked firing rate (FR) responses or spectrotemporal receptive fields (STRFs); transient FR changes at stimulus onset were rarely modified by visual context. Neuron populations with visually modulated STRFs and sustained FR responses were mostly non-overlapping, suggesting spectrotemporal feature selectivity and overall excitability may be differentially sensitive to visual context. The effects of visual modulation were heterogeneous, increasing and decreasing STRF gain in roughly equal proportions of neurons. Our results indicate visual influences are surprisingly common and diversely expressed throughout layers and cell types in A1, affecting nearly one in five neurons overall.

Noise‐induced hearing loss (NIHL) has always been an important occupational hazard, but the exact etiopathogenesis underlying NIHL remains unclear. Herein, we aimed to find metabolic biomarkers involved in the development of NIHL based on a mouse model using a gas chromatography coupled with mass spectrometry (GC‐MS) metabolomics technique. We showed that the auditory brainstem response (ABR) thresholds at the frequencies of 4, 8, 12, 16, 24, and 32 kHz were all significantly elevated in the noise‐exposed mice. Noise could cause outer hair cell (OHC) loss in the base of the cochlea. A total of 17 differential metabolites and 9 metabolic pathways were significantly affected following noise exposure. Spermidine acting as an autophagy modulator was found to be 2.85‐fold higher in the noise‐exposed group than in the control group and involved in β ‐alanine metabolism and arginine and proline metabolism pathways. Additionally, we demonstrated that LC3B and Beclin1 were expressed in the spiral ganglion neurons (SGNs), and their mRNA levels were increased after noise. We showed that SOD activity was significantly decreased in the cochlea of noise‐exposed mice. Further experiments suggested that SOD1 and SOD2 proteins in the SGNs were all decreased following noise exposure. The upregulation of spermidine may induce LC3B‐ and Beclin1‐mediated autophagy in the cochlear hair cells (HCs) through β ‐alanine metabolism and arginine and proline metabolism and be involved in the NIHL. ROS‐mediated oxidative damage may be a pivotal molecular mechanism of NIHL. Taken together, spermidine can be regarded as an important metabolic marker for the diagnosis of NIHL.

Outer hair cell (OHC) degeneration is a major cause of progressive hearing loss and presbycusis. Despite the high prevalence of these disorders, targeted therapy is currently not available. Methods: We generated a mouse model harboring Kcnq4W276S/+ to recapitulate DFNA2, a common genetic form of progressive hearing loss accompanied by OHC degeneration. After comprehensive optimization of guide RNAs, Cas9s, vehicles, and delivery routes, we applied in vivo gene editing strategy to disrupt the dominant-negative allele in Kcnq4 and prevent progressive hearing loss. Results:In vivo gene editing using a dual adeno-associated virus package targeting OHCs significantly improved auditory thresholds in auditory brainstem response and distortion-product otoacoustic emission. In addition, we developed a new live-cell imaging technique using thallium ions to investigate the membrane potential of OHCs and successfully demonstrated that mutant allele disruption resulted in more hyperpolarized OHCs, indicating elevated KCNQ4 channel activity. Conclusion: These findings can facilitate the development of targeted therapies for DFNA2 and support the use of CRISPR-based gene therapy to rectify defects in OHCs.

Speech recognition in rooms requires the temporal integration of reflections which arrive with a certain delay after the direct sound. It is commonly assumed that there is a certain temporal window of about 50–100 ms, during which reflections can be integrated with the direct sound, while later reflections are detrimental to speech intelligibility. This concept was challenged in a recent study by employing binaural room impulse responses (RIRs) with systematically varied interaural phase differences (IPDs) and amplitude of the direct sound and a variable number of reflections delayed by up to 200 ms. When amplitude or IPD favored late RIR components, normal-hearing (NH) listeners appeared to be capable of focusing on these components rather than on the precedent direct sound, which contrasted with the common concept of considering early RIR components as useful and late components as detrimental. The present study investigated speech intelligibility in the same conditions in hearing-impaired (HI) listeners. The data indicate that HI listeners were generally less able to “ignore” the direct sound than NH listeners, when the most useful information was confined to late RIR components. Some HI listeners showed a remarkable inability to integrate across multiple reflections and to optimally “shift” their temporal integration window, which was quite dissimilar to NH listeners. This effect was most pronounced in conditions requiring spatial and temporal integration and could provide new challenges for individual prediction models of binaural speech intelligibility.

We tested whether sensitivity to acoustic spectrotemporal modulations can be observed from reaction times for normal-hearing and impaired-hearing conditions. In a manual reaction-time task, normal-hearing listeners had to detect the onset of a ripple (with density between 0–8 cycles/octave and a fixed modulation depth of 50%), that moved up or down the log-frequency axis at constant velocity (between 0–64 Hz), in an otherwise-unmodulated broadband white-noise. Spectral and temporal modulations elicited band-pass filtered sensitivity characteristics, with fastest detection rates around 1 cycle/oct and 32 Hz for normal-hearing conditions. These results closely resemble data from other studies that typically used the modulation-depth threshold as a sensitivity criterion. To simulate hearing-impairment, stimuli were processed with a 6-channel cochlear-implant vocoder, and a hearing-aid simulation that introduced separate spectral smearing and low-pass filtering. Reaction times were always much slower compared to normal hearing, especially for the highest spectral densities. Binaural performance was predicted well by the benchmark race model of binaural independence, which models statistical facilitation of independent monaural channels. For the impaired-hearing simulations this implied a “best-of-both-worlds” principle in which the listeners relied on the hearing-aid ear to detect spectral modulations, and on the cochlear-implant ear for temporal-modulation detection. Although singular-value decomposition indicated that the joint spectrotemporal sensitivity matrix could be largely reconstructed from independent temporal and spectral sensitivity functions, in line with time-spectrum separability, a substantial inseparable spectral-temporal interaction was present in all hearing conditions. These results suggest that the reaction-time task yields a valid and effective objective measure of acoustic spectrotemporal-modulation sensitivity.

How we distinguish multiple simultaneous stimuli is uncertain, particularly given that such stimuli sometimes recruit largely overlapping populations of neurons. One commonly proposed hypothesis is that the sharpness of tuning curves might change to limit the number of stimuli driving any given neuron when multiple stimuli are present. To test this hypothesis, we recorded the activity of neurons in the inferior colliculus while monkeys made saccades to either one or two simultaneous sounds differing in frequency and spatial location. Although monkeys easily distinguished simultaneous sounds (~90% correct performance), the frequency selectivity of inferior colliculus neurons on dual‐sound trials did not improve in any obvious way. Frequency selectivity was degraded on dual‐sound trials compared to single‐sound trials: neural response functions broadened and frequency accounted for less of the variance in firing rate. These changes in neural firing led a maximum‐likelihood decoder to perform worse on dual‐sound trials than on single‐sound trials. These results fail to support the hypothesis that changes in frequency response functions serve to reduce the overlap in the representation of simultaneous sounds. Instead, these results suggest that alternative possibilities, such as recent evidence of alternations in firing rate between the rates corresponding to each of the two stimuli, offer a more promising approach.

The auditory nerve (AN) of the inner ear is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of peripheral AN fibers are myelinated by glial cells. The integrity of myelin and the glial‐associated paranodal structures at the node of Ranvier is critical for normal AN activity and axonal survival and function in the central auditory nervous system. However, little is known about the node of Ranvier's spatiotemporal development in the AN, how the aging process (or injury) affects the activity of myelinating glial cells, and how downstream alterations in myelin and paranodal structure contribute to AN degeneration and sensorineural hearing loss. Here, we characterized two types of Ranvier nodes—the axonal node and the ganglion node—in the mouse peripheral AN, and found that they are distinct in several features of postnatal myelination and age‐related degeneration. Cellular, molecular, and structure–function correlations revealed that the two node types are each critical for different aspects of peripheral AN function. Neural processing speed and synchrony is associated with the length of the axonal node, while stimulus level‐dependent amplitude growth and action potentials are associated with the ganglion node. Moreover, our data indicate that dysregulation of glial cells (e.g., satellite cells) and degeneration of the ganglion node structure are an important new mechanism of age‐related hearing loss.

Background In aminoglycoside-induced hearing loss, damage to spiral ganglion neurons (SGNs) accelerates gradually after the acute outer hair cell death, accompanied by macrophage infiltration and cytokine release. Pyroptosis plays a critical role in neurodegenerative diseases. Here, we explored the potential role of pyroptosis in SGN degeneration. Methods C57BL/6J mice were randomly divided into a kanamycin plus furosemide group and saline control group. Auditory functions were evaluated by auditory brainstem response tests conducted before treatment and at 1, 5, 15, and 30 days after treatment. HCs and SGNs were assessed for morphological alterations. SGNs were subjected to RNA sequencing and mRNA and protein analyses of NLRP3 inflammasome-related molecules. Macrophage activation was evaluated based on morphological and mRNA alterations. The effect of NLRP3 inhibition on SGN survival after kanamycin treatment was evaluated in organ explant cultures treated with Mcc950, a specific inhibitor of the NLRP3 inflammasome. Results Kanamycin and furosemide administration led to irreversible deterioration of the auditory brainstem response threshold, accompanied by acute loss of outer hair cells and gradually progressive loss of inner hair cells. SGNs showed a progressive decrease in quantity, as well as swelling and membrane rupture, at 15 and 30 days. RNA sequencing of SGNs showed that inflammation and immune-related responses were significantly upregulated, as was the expression of the inflammasome-related gene NLRP3. During 30 days of kanamycin exposure, the canonical pyroptosis pathway was constantly activated in SGNs. Activation and infiltration of microglia-like cells/macrophages, and increased production of cytokines, hallmarks of neuroinflammation, were also observed. Mcc950 significantly ameliorated SGN degeneration by inhibiting NLRP3 expression and promoting release of interleukins 1β and 18. Conclusions Pyroptosis causes cell death during aminoglycoside-induced SGN degeneration. Activation of the NLRP3 inflammasome leads to a cascade of inflammatory events in SGNs. Inhibition of the NLRP3 inflammasome significantly alleviates SGN damage, suggesting that it could serve as a new molecular target for the treatment of aminoglycoside-induced SGN degeneration.

A bstract Sound localization and identification are challenging in acoustically rich environments. The relation between these two processes is still poorly understood. As natural sound-sources rarely occur exactly simultaneously, we wondered whether the auditory system could identify (“what”) and localize (“where”) two spatially separated sounds with synchronous onsets. While listeners typically report hearing a single source at an average location, one study found that both sounds may be accurately localized if listeners are explicitly being told two sources exist. We here tested whether simultaneous source identification (one vs. two) and localization is possible, by letting listeners choose to make either one or two head-orienting saccades to the perceived location(s). Results show that listeners could identify two sounds only when presented on different sides of the head, and that identification accuracy increased with their spatial separation. Notably, listeners were unable to accurately localize either sound, irrespective of whether one or two sounds were identified. Instead, the first (or only) response always landed near the average location, while second responses were unrelated to the targets. We conclude that localization of synchronous sounds in the absence of prior information is impossible. We discuss that the putative cortical ‘what’ pathway may not transmit relevant information to the ‘where’ pathway. We examine how a broadband interaural correlation cue could help to correctly identify the presence of two sounds without being able to localize them. We propose that the persistent averaging behavior reveals that the ‘where’ system intrinsically assumes that synchronous sounds originate from a single source. S ignificance S tatement It is poorly understood whether identification (‘what’) of sounds and their localization (‘where’) are inter-related, or independent neural processes. We measured sound-localization responses towards synchronous sounds to examine potential coupling of these processes. We varied the spatial configurations of two sounds and found that although identification improved considerably with larger spatial separation, their localization was unaffected: responses were always directed towards the average location. This shows absence of mutual coupling of information between the ‘what’ and ‘where’ streams in the auditory system. We also show how broadband interaural correlation could explain the improved identification results, without affecting localization performance, and explain how the persistent spatial averaging could be understood from strong internal priors regarding sound synchronicity.

High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction of excitotoxicity. Glutamate excitotoxicity is associated with failure in the maintenance of calcium homeostasis, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Valproic acid (VPA) is widely used for the management of bipolar disorder, epilepsy, and migraine headaches, and is known to regulate NMDA receptor activity. In this study, we examined the beneficial effects of VPA in a salicylate-induced tinnitus model in vitro and in vivo. Cells were pretreated with VPA followed by salicylate treatment. The expression levels of NMDA receptor subunit NR2B, phosphorylated cAMP response element-binding protein—an apoptosis marker, and intracellular levels of ROS were measured using several biochemical techniques. We observed increased expression of NR2B and its related genes TNFα and ARC, increased intracellular ROS levels, and induced expression of cleaved caspase-3. These salicylate-induced changes were attenuated in the neuronal cell line SH-SY5Y and rat cortical neurons after VPA pretreatment. Together, these results provide evidence of the beneficial effects of VPA in a salicylate-induced temporary hearing loss and tinnitus model.

Significance The human voice contains information about a speaker's identity and emotional state. How the brain processes the human voice remains largely unknown. We recorded electrocorticographic signals from intracranial electrodes implanted in epilepsy patients while they listened to different categories of voice and nonvoice sounds. We identified several spatially distinct “voice patches” in the temporal lobe that exhibited preferences for human voices. Further analyses suggested that the voice patches are functionally connected, and form a dual-directional hierarchical network for voice processing. This study provides clear evidence to demonstrate the existence of an interconnected “voice patch system” in the human brain, which is analogous to the face patch system of primate visual cortex, suggesting similar cortical architectures for processing faces and voices.

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo . In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here, we ask what the behavioral relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioral role to offset responses. By combining in vivo electrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generated de novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.

Prevailing theories of the neural basis of at least a subset of individuals with autism spectrum disorder (ASD) include an imbalance of excitatory and inhibitory neurotransmission. These circuitry imbalances are commonly probed in adults using auditory steady-state responses (ASSR, driven at 40 Hz) to elicit coherent electrophysiological responses (EEG/MEG) from intact circuitry. Challenges to the ASSR methodology occur during development, where the optimal ASSR driving frequency may be unknown. An alternative approach (more agnostic to driving frequency) is the amplitude-modulated (AM) sweep in which the amplitude of a tone (with carrier frequency 500 Hz) is modulated as a sweep from 10 to 100 Hz over the course of ∼15 s. Phase synchrony of evoked responses, measured via intra-trial coherence, is recorded (by EEG or MEG) as a function of frequency. We applied such AM sweep stimuli bilaterally to 40 typically developing and 80 children with ASD, aged 6–18 years. Diagnoses were confirmed by DSM-5 criteria as well as autism diagnostic observation schedule (ADOS) observational assessment. Stimuli were presented binaurally during MEG recording and consisted of 20 AM swept stimuli (500 Hz carrier; sweep 10–100 Hz up and down) with a duration of ∼30 s each. Peak intra-trial coherence values and peak response frequencies of source modeled responses (auditory cortex) were examined. First, the phase synchrony or inter-trial coherence (ITC) of the ASSR is diminished in ASD; second, hemispheric bias in the ASSR, observed in typical development (TD), is maintained in ASD, and third, that the frequency at which the peak response is obtained varies on an individual basis, in part dependent on age, and with altered developmental trajectories in ASD vs. TD. Finally, there appears an association between auditory steady-state phase synchrony (taken as a proxy of neuronal circuitry integrity) and clinical assessment of language ability/impairment. We concluded that (1) the AM sweep stimulus provides a mechanism for probing ASSR in an unbiased fashion, during developmental maturation of peak response frequency, (2) peak frequencies vary, in part due to developmental age, and importantly, (3) ITC at this peak frequency is diminished in ASD, with the degree of ITC disturbance related to clinically assessed language impairment.