Publications using the RX6

Understanding speech in noisy, multi-talker environments is crucial for social communication but becomes increasingly challenging and frustrating as we age. Here, we simulated the acoustic challenges of multi-talker listening and found that adults over 50 years old (N = 76) recognized speech more slowly, less accurately, and less consistently than younger adults (N = 107). While peripheral hearing status accounted for average differences in speech intelligibility by age, it did not account for moment-to-moment variability in speed and accuracy - fluctuations central to the frustration experienced by older listeners in challenging environments. We hypothesized that age-related changes in brain arousal systems might account for the fluctuant “noise” in speech processing observed in older listeners. To isolate the contribution of arousal state independent of hearing status and cognitive load, we measured the pre-stimulus pupil-indexed arousal state (PPAS) immediately prior to speech onset. Older – but not younger - adults exhibited a striking inverted-U relationship between PPAS and speech recognition accuracy. Notably, pupil-indexed listening effort measured seconds later during speech encoding was not associated with trial-to-trial performance. Moreover, older adults exhibited altered arousal regulation, occupying a lower PPAS extremum not observed in younger listeners that was specifically associated with performance deficits and subjective listening difficulties reported in hearing health questionnaires. These findings show that age-related changes in central arousal states interact with peripheral hearing status to offer a more complete explanation for why older adults find speech processing in social setting so challenging. Significance Statement As we age, following a conversation in crowded environments becomes more difficult and frustrating, even when hearing tests appear normal. This study shows that variations in arousal level (measured through pre-stimulus pupil size) are tightly linked to fluctuations in the speed and accuracy of speech processing in adults over 50 years of age. Changes in arousal state regulation uniquely accounted for the moment-to-moment variations in speech intelligibility and were more closely associated with self-reported listening challenges than other conventional measures. These findings highlight the contribution of brain-wide arousal systems to real-world listening challenges and identify a straightforward measure that could be used to more comprehensively assess and potentially improve speech understanding in social settings.

In bats, which express a complex vocal repertoire and are considered vocal learners, the frontal auditory field (FAF) is supposedly placed in a frontal cortico‐striatal network for vocal–motor control. The FAF receives input from the auditory cortex (AC) and other auditory nuclei via multiple pathways. However, not much is known about the transition of information on vocalizations from the AC to the FAF. The bat AC consists of different subfields, among which the dorsal fields (dAC) are characterized by precise coding of the temporal envelope of vocalizations. The dAC should, therefore, be a major source of auditory feedback information about self‐produced or perceived vocalizations to the FAF. Our study aimed to investigate the specificity of encoding for different types of vocalizations in FAF and dAC neurons. Using extracellular recordings in anesthetized Phyllostomus discolor , we describe basic response properties in both cortical areas and compare responses to different types of prerecorded vocalizations. The specificity of encoding for different behaviorally relevant call categories and single calls was higher in dAC than in FAF neurons, both in terms of temporal firing patterns and response strength. These findings highlight the importance of the dAC in the neural network for control of vocal communication in bats.

Perception of rhythm significantly impacts various aspects of daily life, including engaging with music, discerning speech prosody nuances, and coordinating physical activities like walking and sports. Numerous studies in cognitive sciences have highlighted that human rhythmic synchronization is more precise when responding to auditory rhythmic stimuli than to visual ones when the timing cues are identical. However, deaf individuals were shown to display a heightened proficiency in synchronizing their movements with visual timing cues, outperforming hearing controls (HC). Furthermore, it was demonstrated that cochlear implant (CI) users can synchronize their movements with the rhythm of unpitched drum tones. These findings raise an important question: do CI users possess a visual synchronization advantage from their pre-implant deafness, while maintaining auditory synchronization skills comparable to those of HC? Alternatively, does the neural reorganization post-implantation negate the visual synchronization advantage acquired before the implant? This study aims to answer these questions by using a sensorimotor synchronization task to probe multisensory processing abilities in CI users. Specifically, we assessed unimodal and multimodal auditory and visual abilities in CI users compared to HC using a finger tapping synchrony task with four isochronous stimulus conditions: an auditory metronome, a visual metronome, a synchronous presentation of both the auditory and visual metronomes at the same tempo, and an asynchronous presentation of the auditory and visual stimuli at differing tempos. Synchronization to auditory stimuli surpassed synchronization to visual stimuli in both groups. CI users and HC demonstrated similar unisensory synchronization consistency within the visual and auditory conditions. While HC enhanced their consistency in the audio-visual synchronous condition compared to the unisensory visual condition, CI users did not display the same improvement. Furthermore, the interference from incongruent auditory information in the asynchronous condition was comparable in HC and CI users. This study highlights that, although pitch processing is known to be impaired in CI users, our findings suggest that rhythm processing remains relatively spared. As anticipated, CI users demonstrate similar auditory rhythmic synchronization skills to those of HC, in line with existing research. Moreover, we find that, unlike deaf individuals, CI users do not exhibit an advantage in visual rhythmic synchronization, which may be due to the relatively few CI users in the study who had early prolonged pre-implantation deafness. The observed shift in audio-visual integration among CI users suggests that post-deafness or post-implantation reorganization of their auditory cortex may impede the effective integration of temporal auditory stimulation from the implant and visual information.

Exposure to traumatic noise triggers cochlear damage and consequently causes permanent sensorineural hearing loss. However, effective treatment strategies for noise-induced hearing loss (NIHL) are lacking. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that plays a critical role in multiple physiological and pathological events. However, its role in NIHL pathogenesis remains elusive. This study revealed that SIRT1 expression in the cochlea progressively decreases in a mouse model of NIHL. Hair cell-specific knockout of SIRT1 exacerbates the noise-induced loss of outer and inner hair cell synaptic ribbons, retraction of cochlear nerve terminals, and oxidative stress, leading to more severe NIHL. Conversely, adeno-associated virus (AAV)-mediated SIRT1 overexpression effectively attenuated most noise-induced cochlear damage and alleviated NIHL. Transcriptomic analysis revealed that SIRT1 deficiency impairs glucose metabolism and inhibits antioxidant pathways in the cochlea following exposure to noise. Further investigation revealed that SIRT1 exerts an antioxidant effect, at least in part, through AMPK activation in cultured auditory HEI-OC1 cells exposed to oxidative stress. Collectively, these findings indicate that SIRT1 is essential for the maintenance of redox balance and mitochondrial function in the cochlea after traumatic noise exposure, thus providing a promising therapeutic target for NIHL treatment.

Molecular profiling of inner ear neurons has broadened the classification of the primary afferents that support neural coding for hearing and balance. To extend spatiotemporal characterization of auditory and vestibular neuron diversity, we established a transgenic reporter mouse model (Prphp-mCherry), where elements of the peripherin promoter (Prphp) drive expression of the mCherry fluorescent reporter. Type III intermediate filament protein peripherin expression is a marker for type II spiral ganglion neurons (SGN) that innervate the cochlear outer hair cells, and the small diameter 'bouton' vestibular ganglion neurons (VGN) innervating the type II vestibular hair cells. Using Nanopore genome sequencing, the integration site of the transgene construct was identified within the class III metabotropic glutamate receptor 8 gene (Grm8, chromosome 6). Use of CUBIC / PEGASOS clearing of early postnatal to adult inner ear tissues enabled in situ 3D spatial localization of a dispersed population of cochlear mCherry + ve SGN, with highest expression and density in the hook (high frequency encoding) basal region. Of these mCherry + ve SGN, type II SGN (peripherin-immunopositive) were all co-labeled in the basal region, but the majority of the overall mCherry-delineated SGN auditory subpopulation were type I SGN innervating inner hair cells. In the VGN, mCherry + ve neurons represented ~ 15% of the adult population, dispersed as a small diameter subpopulation throughout both the inferior and superior VGN regions. These findings resolve heterogeneous type I and type II cochlear SGN subpopulations, particularly in the structurally complex hook region, and further differentiate vestibular primary afferents across postnatal development.

A large body of literature has shown that sensory neurons typically exhibit adaptation to repetitive stimulation. However, adaptation alone does not account for the ability of sensory systems to remain vigilant to the environment in spite of repetitive sensory stimulation. Here, we investigated single neuron responses to sequences of sounds repeatedly delivered from a particular spatial location. Instead of inducing adaptation, repetitive stimulation evoked long-lasting and location-specific facilitation (LSF) in firing rate of nearly 90% of recorded neurons. The LSF decreased with decreasing presentation probability and diminished when sounds were randomly delivered from multiple spatial locations. Intracellular recordings showed that repetitive sound stimulation evoked sustained membrane potential depolarization. Computational modeling showed that increased arousal, not decreased inhibition, underlies the LSF. Our findings reveal a novel form of contextual modulation in the marmoset auditory cortex that may play a role in tasks such as auditory streaming and the cocktail party effect.

Transgenic mice provide unprecedented access to manipulate and visualize neural circuits; however, those on a C57BL/6 background develop progressive hearing loss, significantly confounding systems-level and behavioral analysis. While outbreeding can limit hearing loss, it introduces strain variability and complicates the generation of complex genotypes. Here, we propose an approach to preserve hearing by crossing transgenic mice with congenic B6.CAST- Cdh23 Ahl + mice, which maintain low-threshold hearing into adulthood. Widefield and two-photon imaging of the auditory cortex revealed that 2.5-month-old C57BL/6 mice exhibit elevated thresholds to high-frequency tones and widespread cortical reorganization, with most neurons responding best to lower frequencies. In contrast, Ahl+ C57BL/6 mice exhibited robust neural responses across tested frequencies and sound levels (4–64 kHz, 30–90 dB SPL) and retained low thresholds into adulthood. Our approach offers a cost-effective solution for generating complex genotypes and facilitates more interpretable systems neuroscience research by eliminating confounding effects from hearing loss.

In the mammalian cochlea, the transduction from vibrations to inner hair cell receptor currents is preceded by a stage of mechanical pre-processing that involves a rapid, strongly nonlinear compression. The mechanisms by which the cochlea realizes this dynamic compression are still poorly understood. Previous work by our group suggested that compression does not occur locally, but is realized by a cascade of weakly nonlinear elements along the cochlear partition. The resulting progressive accumulation of nonlinearity was termed the spatial buildup of compression. Here we studied mechanical compression in the basal turn of the sensitive gerbil cochlea using optical coherence tomography. We recorded vibrations at multiple positions along the length of the cochlear partition. Such longitudinal studies were virtually impossible with previous techniques. Using a tailored two-tone stimulus we quantified the spatial profile of compression. We found that the amount of compression grew gradually in an intensity-dependent fashion along our measurement stretch, as we moved apically toward the place of maximum vibration. This gradual buildup of compression was not mirrored by a gradual reduction beyond the peak. In fact the amount of compression accumulated even beyond the peak. This asymmetric pattern supports the view that mechanical compression is realized in a cascaded, distributed fashion which hinges on the traveling wave nature of cochlear vibrations.

RESUMO Objetivo Analisar o Benefício do Mascaramento Modulado (BMM) em medidas eletrofisiológicas e comportamentais em indivíduos jovens e adultos normouvintes. Método Estudo analítico observacional e transversal, com amostra final da pesquisa composta por 40 participantes, sendo 20 indivíduos de 18 a 30 anos (jovens-adultos) e 20 indivíduos de 31 a 50 anos (adultos), para realização de avaliação comportamental (Teste de reconhecimento de sentença na presença de ruído estável e modulado) e eletrofisiológica (Potencial Evocado Auditivo Cortical) para investigação do BMM. Os resultados foram analisados através do Test-t pareado e ANOVA para medidas repetidas, seguido pelo teste post-hoc de Bonferroni (p-valor <0,05). Resultados Foi identificada uma menor interferência do ruído modulado nas medidas de latência e amplitude dos componentes corticais, gerando uma redução significativa na latência de P1 e aumento da amplitude de P2 em ambos os grupos de participantes. O ruído estável gerou limiares eletrofisiológicos e comportamentais mais elevados comparado ao ruído modulado. Uma maior magnitude do BMM foi observada no grupo jovem-adulto. Conclusão Identificou-se em ambos os grupos de participantes uma menor interferência do ruído modulado no tempo de codificação da resposta auditiva neural e no processo de discriminação neural da fala. Além disso, os limiares comportamentais e eletrofisiológicos foram tipicamente mais elevados diante do ruído estável quando comparado ao ruído modulado, apontando para uma correspondência da medida do BMM entre os domínios da audição. A magnitude do BMM superior no grupo de jovens-adultos, especialmente no domínio eletrofisiológico, sugere uma maior habilidade de resolução temporal em indivíduos mais jovens.

Transitive inference allows people to infer new relations between previously experienced premises. It has been hypothesized that this logical thinking relies on a mental schema that spatially organizes elements, facilitating inferential insights. However, recent evidence challenges the need for these complex cognitive processes. To dig into the neural substrate driving TI cognitive processes, we examine the role of beta and gamma local field potential bands in the prefrontal cortex of 2 monkeys. During the inferential problem-solving period, we discover a tight link between beta and gamma bands modulation and TI complexity. This correlation diminishes its strength before initiating the motor response, indicating the chosen item. Notably, while the beta band maintains a constant relationship with TI performance throughout the trial, the gamma band shows a flexible relationship. This research highlights the role of beta and gamma interplay in cognitive computations when solving TI problems.

Noise exposure is one of the most common causes of sensorineural hearing loss. Although many studies considered inflammation to be a major contributor to noise-induced hearing loss, the process of cochlear inflammation is still unclear. Studies have found that activation of the NF-κB signaling pathway results in the accumulation of macrophages in the inner ear plays an important role in hair cell damage. In this study, tandem mass tag (TMT) technique was used to analyze the changes in basilar membrane proteome expression before and after acoustic injury. After noise exposure, the nicotinamide adenine dinucleotide (NAD) metabolism level was decreased, and the NF-κB signaling pathway was activated. The expression of CD38, the main NAD hydrolase in mammals, may directly lead to inflammation onset. Then, anakinra, an IL-1 receptor blocker, and apigenin, a CD38 inhibitor, were administered to animals to protect against noise-induced hearing loss. Our results showed that anakinra had little influence on the hearing threshold shift, while apigenin significantly reduce the threshold shift of hearing by inhibiting the expression of NF-κB and CD38 can be a promising target for protecting against noise-induced hearing loss.

Because bats emit ultrasound and listen to echoes to perceive their surroundings, presenting phantom echoes is useful for understanding their perception of echolocation. Here, we present a protocol for the real-time playback of phantom echoes, especially from approaching objects. We describe steps for presenting virtual objects using a microphone, digital signal processor, and loudspeaker to induce the escape behavior of bats. We then detail procedures for clarifying their detection algorithm for approaching objects. For complete details on the use and execution of this protocol, please refer to Yoshida et al.1.

Objective: To analyze the Benefit of Modulated Masking (BMM) on hearing in young, adult and elderly normal-hearing individuals. Methods: The sample included 60 normal-hearing individuals aged 18-75 years who underwent behavioral assessment (sentence recognition test in the presence of steady and modulated noise) and electrophysiological assessment (cortical Auditory Evoked Potential) to investigate BMM. The results were analyzed comparatively using the paired t-test and ANOVA for repeated measures, followed by the Bonferroni post-hoc test (p-value < 0.05). Results: A decrease in latencies and an increase in amplitudes of cortical components (P1-N1-P2) was observed due to noise modulation in all age groups. Modulated noise generated better auditory threshold responses (electrophysiological and behavioral), compared to steady noise. The elderly presented a higher threshold in both hearing domains, compared to the other participants, as well as a lower BMM magnitude. Conclusion: It was possible to conclude that the modulated noise generated less interference in the magnitude of the neural response (smaller latencies) and in the neural processing time (larger amplitudes) for the speech stimulus in all participants. The higher auditory thresholds (electrophysiological and behavioral) and the lower BMM magnitude observed in the elderly group, even in the face of noise modulation, suggest a lower temporal auditory performance in this population, and may indicate a deficit in the temporal resolution capacity, associated with the process of aging. Level of evidence: 3:

The goal of the present study was to determine, through a detailed study of the auditory brainstem response (ABR) waves, the possible existence of an early functional marker for the onset of presbycusis in an animal model. Toward this goal, Wistar rats were divided into four age groups: 3-month-old (3M, n = 6, control), 9-month-old (9M, n = 6), 14-month-old (14M, n = 6), and 20-month-old (20M, n = 6). ABR recordings were performed at 0.5, 1, 2, 4, 8, 16, and 32 kHz. The novel result reported here is that wave amplitudes, particularly wave II, were significantly diminished in the 9M group, even though there was no evidence of significant age-related threshold shift at that age. A significant increase in auditory thresholds with age was first detected at 14M, which further progressed at 20M, confirming our previous findings. These findings suggest that measurable alterations in ABR waves may precede age-related threshold shift and could serve as early markers to detect the onset of age-related hearing loss. Upon translation to humans, they could be used to implement early objective diagnosis, crucial to prevent or mitigate the negative consequences of presbycusis, a common, progressive, and irreversible neurodegenerative age-related disorder. This may allow, for instance, a better preservation of residual hearing, thus delaying the progression of the disease and minimizing the impact of hearing loss, ultimately improving the quality of life for those who suffer from this neurodegenerative condition.

A major challenge in neuroscience is to understand how neural representations of sensory information are transformed by the network of ascending and descending connections in each sensory system. By recording from neurons at several levels of the auditory pathway, we show that much of the nonlinear encoding of complex sounds in auditory cortex can be explained by transformations in the midbrain and thalamus. Modeling cortical neurons in terms of their inputs across these subcortical populations enables their responses to be predicted with unprecedented accuracy. By contrast, subcortical responses cannot be predicted from descending cortical inputs, indicating that ascending transformations are irreversible, resulting in increasingly lossy, higher-order representations across the auditory pathway. Rather, auditory cortex selectively modulates the nonlinear aspects of thalamic auditory responses and the functional coupling between subcortical neurons without affecting the linear encoding of sound. These findings reveal the fundamental role of subcortical transformations in shaping cortical responses.

Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg++ (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg++ administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined “antioxidation threshold”, results in unrecoverable redox imbalance with loss of otoprotectant activity.

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.

Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.

This dataset was collected to study the functional consequences of age-related hearing loss for the auditory nerve, which carries acoustic information from the periphery to the central auditory system. Using high-impedance glass electrodes, raw voltage traces and spike times were recorded from more than one thousand single fibres of the auditory nerve of young-adult, middle-aged, and old Mongolian gerbils raised in a quiet environment. The dataset contains not only responses to simple acoustic stimuli to characterize the fibres, but also to more complex stimuli, such as speech logatomes in background noise and Schroeder-phase stimuli. A software toolbox is provided to search through the dataset, to plot various analysed outcomes, and to give insight into the analyses. This dataset may serve as a valuable resource to test further hypotheses about age-related hearing loss. Additionally, it can aid in optimizing available computational models of the auditory system, which can contribute to, or eventually even fully replace, animal experiments.

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca 2+ imaging in FMR1 ( fragile X messenger ribonucleoprotein 1 ) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.