Publications using the PA5

Sound harmonicity is foundational in complex auditory stimuli like music and vocalizations but it remains unclear how such spectrally complex stimuli are processed in the auditory cortex (ACtx). Subregions of the auditory cortex process are thought to process harmonic stimuli differently, and secondary ACtx (A2) layer (L) 2/3 is believed to be the most selective. Selective responses to sound features in ACtx are thought to emerge hierarchically starting from A1 L4. Since the spectral complexity of harmonic stacks can range from two to more than ten components, harmonic selectivity and sensitivity might also arise hierarchically across layers and areas. We studied responses to simple and complex harmonic stacks across A1 L4, A1 L2/3, and A2 L2/3 in adult mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HN) responding only to harmonic stacks but not to their pure-tone components in all areas at similar proportions. HNs showed non-linear processing of component tones with onset-responsive HNs showing greater nonlinearity, which decreased with harmonic complexity. Co-tuned HNs in A1 L4 exhibited the highest signal correlation, regardless of harmonic complexity. A1 L4 HNs also showed the lowest noise correlation with other neurons. Moreover, A1 L4 HNs achieve robust spectral integration and harmonic sensitivity by receiving diverse inputs and maintaining high signal correlation, ensuring independent, strong responses to harmonic stimuli. Therefore, harmonic sensitivity is present in A1 L4 and is not a unique feature of A2. Thus, tuning to complex spectral sounds is a fundamental property of ACtx and is already established in A1 L4. Significance statement Harmonics are essential in auditory perception, influencing how we process complex sounds like music and speech. This study reveals that neurons in the primary auditory cortex (A1) and secondary auditory cortex (A2) integrate simple and complex harmonic structures with distinct mechanisms of neuronal recruitment. A1 L4 harmonic-sensitive neurons (HNs) demonstrated strong, independent responses through high signal correlation and minimal noise correlation, suggesting a robust mechanism for spectral integration. Our results show that harmonic relationships are already extracted at the input layers of A1, and that HNs show non-linear facilitative integration. Thus, tuning to sounds of complex spectral contents might be a fundamental processing function of the auditory cortex and is already established in A1 L4, which receives major thalamic inputs.

The insular cortex is involved in a wide range of auditory functions in the mammalian brain. We studied the organization and basic response properties of auditory neurons in the insular cortex and adjacent areas by recording responses to sound stimuli in anesthetized female rats. Auditory neurons were present in an insulo-parietal auditory field that spans the boundary between the posterior insula, particularly in the granular insular cortex, and the ventral part of the adjacent nonprimary somatosensory fields. Confirming previous reports, neurons in this field had narrow tuning and were preferentially tuned to relatively low frequencies (<16 kHz). Intriguingly, auditory units in this field displayed shorter minimal latencies than units in the primary auditory cortex, as well as weaker sensitivity to deviance. These results establish the existence of a rapid auditory information stream with distinct properties through the insulo-parietal cortex that may parallel the pathway through the primary and anterior auditory fields.

Purpose Best practices in audiology recommend assessing speech understanding in noisy environments, especially for those with communication difficulties. Speech-in-noise (SiN) assessments such as the QuickSIN are used for validating signal processing in hearing aids (HAs) and are linked to HA satisfaction. This project seeks to enhance QuickSIN test efficiency by applying recent advancements in automatic speech recognition (ASR) technologies. Method Twenty-three adults with sensorineural hearing loss were fitted bilaterally with Unitron Moxi HAs and were administered the QuickSIN test in low and high reverberation environments. Testing was performed with two different HA programs: an omnidirectional program and a fixed directional microphone program. QuickSIN sentences were presented from 0° azimuth and competing babble from either 0°, laterally from 90° or 270°, or simultaneously from 90°, 180°, and 270° azimuths. Participants’ verbal responses to QuickSIN stimuli were scored by an audiologist and were recorded in parallel for offline transcription and scoring by ASR models from Amazon, Microsoft, NVIDIA, and Picovoice. The ASR-derived QuickSIN scores were compared to the corresponding audiologist-derived scores. Results Repeated Measures ANOVA results revealed that all ASR models overestimated the QuickSIN scores across most test conditions. Bland-Altman analyses showed that the Amazon ASR model had the least bias and the narrowest range for the limits of agreement, in comparison to the manual scoring by an experienced audiologist. Conclusions Some ASR models, such as Amazon, demonstrated performance comparable to that of an audiologist in automatically scoring QuickSIN tests. However, further refinements are necessary to increase the robustness of the ASR models in scoring low SNR loss test conditions.

Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is a leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 knockout (KO) rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 KO rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of stimulus bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiological recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. Together, these findings indicate that cortical hyperexcitability in Fmr1 KO rats may act to preserve signal-to-noise ratios and signal detection threshold at the expense of sound sensitivity and fine feature discrimination, highlighting a potential mechanistic locus for a range of auditory behavioral phenotypes in FXS.

Analyzing the functional connectivity of the brain is an enormous challenge, as deciphering functional connectivity requires knowledge of functional responses and connections. One promising strategy is analyzing the spatial pattern of activity correlations across cell populations. In the primary auditory cortex (A1), cells respond to different sound features. On the large scale, there exists a tonotopic map, which is fractured at the small scale, raising the question of whether functional connections are spatially ordered or disordered. To test whether functional connectivity on a local and a global scale is also disordered, we first designed a robust statistical model to estimate parameters and test for the significance of the estimated correlation maps. We developed an inference method that allows efficient model fitting and statistical testing to project the correlation maps to 2D space. We then performed in vivo two-photon calcium imaging in layer 2/3 of A1 with pure tones (PT) or a combination of two tones (TT; harmonically related or not). We found that the spatial patterns of signal correlations (SCs) depend on the type of sound stimuli that were presented. The functional 2D maps of PT-driven SCs are more restricted to local neurons than TT signal correlations which showed more global textures. 2D SC patterns for harmonic stimuli showed spatially distinct relationships. TT SCs revealed spatially precise functional connectivity between harmonically related neurons. Thus, even though the frequency preference of neighboring neurons in A1 is functionally diverse, the functional connection pattern of these neurons is functionally precise and harmonically related.

Background: Acoustic trauma is a common cause of acute sensorineural hearing loss associated with tinnitus; however, the underlying molecular mechanisms remain unclear. Extracellular signal-regulated kinase 2 (ERK2), a member of the mitogen-activated protein kinase family, is crucial in cellular signaling, especially in the nervous system, where it helps regulate neuroprotection, neurogenesis, and neuronal plasticity. ERK2 is activated in the cochlea by acoustic stimuli and plays a protective role in cochlear hair cells (HCs), which are the primary sensory receptors for hearing. However, the significance of ERK2 expression in HCs associated with development and etiology of tinnitus is largely unexplored. Methods: To investigate the role of ERK2 in tinnitus development, the gap detection test (GAP) was used to evaluate HC-specific ERK2-conditional knockout mice (HC-E2CKO) exposed to moderate acoustic stimuli. Results: Both control and HC-E2CKO mice showed normal prepulse inhibition levels (<0.6) before and after auditory damage, indicating normal functioning of sensorimotor gating pathways, excluding gross sensorimotor deficits. This confirmed that the animals were eligible for the GAP. HC-E2CKO mice showed a transient increase in the GAP ratio, indicating tinnitus development, 1 week after noise exposure, although the hearing threshold was not significantly elevated. The GAP ratio returned to normal after 2 weeks. In contrast, control mice did not exhibit elevation in hearing threshold and the GAP ratio remained normal. Conclusion: Our findings suggest that ERK2 in the inner ear plays a role in tinnitus onset or perception after acoustic stress, potentially through inhibitory mechanisms.

Electroanalytical methods are used to understand, modify, and control bionic devices. Bionic devices can record or stimulate cells to understand and/or control normal or abnormal biological processes. These devices contain electrodes that transduce electrical current within the electrical circuit into ionic current within a tissue. Despite the similarity between electroanalysis and electrophysiology, there remains a poor understanding of the relationship between the two techniques, including their methodology and theory. This paper investigates the electrochemical and acute electrophysiological recording performance of neural electrodes. A range of behaviors is achieved by modifying electrodes with the conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) doped with chondroitin sulfate, dextran sulfate, or para ‐toluene sulfonate. The results support previous studies showing that increased electrode area reduced total impedance below the Maxwell–Wagner relaxation frequency and thermal noise while increasing the signal‐to‐noise ratio and neural spike count. The results allowed novel investigation of relative contributions of biological and electrode properties to electrophysiological performance, with increased electrode area having a larger impact on neural population within recording range rather than reducing thermal noise. The utility of measuring electrode impedance for predicting electrophysiological performance is mainly for an indirect measure of electrode area. The results provide insight into noise sources from electrophysiological recordings and limitations in cable theory in neuroscience.

Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar ( Melopsittacus undulatus ) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.

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.

Background: Xeroderma pigmentosum (XP) is caused by impaired DNA repair of UV-induced dipyrimidine-photoproducts. XP cells also show impaired repair/removal of ROS or oxidative DNA lesions caused by UV or 4-nitroquinolline 1-oxide (4NQO). Gene profiling indicated that inflammatory response-related genes are significantly upregulated after UV exposure in XP-A model mice. Objective: Since XP cells are in the state of oxidative stress and inflammation, we aimed to search for therapeutic agents from anti-oxidants/anti-inflammatory drugs, that potentially improve XP symptoms. Methods: Several antioxidants were examined for reducing 4NQO-induced oxidative cytotoxicity or UV-induced oxidative DNA damage in XP-A cells. Among them, we focused on melatonin and evaluated its improving effect for Xpa-deficient MEF on UV-induced cytotoxicity and ROS production, and for Xpa-deficient mice on UV-induced skin tumorigenesis and auditory brainstem responses as one of the neurological symptoms. Results: Melatonin and nicotinamide attenuated 4NQO-induced oxidative cytotoxicity. UV-induced intracellular ROS production and cytotoxicity were improved by melatonin for Xpa-deficient MEF. Finally, the administration of melatonin mitigated UV-induced skin inflammation and tumorigenesis and suppressed hearing deterioration in Xpa-deficient mice. Conclusion: Our results show that melatonin could alleviate XP symptoms through its anti-inflammatory and antioxidant properties.

Auditory neuropathies affect the spiral ganglion neurons of the auditory nerve or their synapses with the sensory hair cells, distorting the sound information transmitted from the ear to the brain. Deciphering the underlying pathophysiological mechanisms remains challenging owing to the diversity of spiral ganglion neuron subtypes and associated central auditory circuits. An auditory neuropathy mechanism is unraveled by investigating the origin of auditory hyperexcitability in a mouse model for hereditary congenital deafness. Otogl encodes the large Otogelin‐like protein, which is related to secreted epithelial mucins and is implicated in the mechanical stimulation of cochlear outer hair cells. Heterozygous Otogl +/− mutant mice display auditory hyperexcitability, highlighted by their susceptibility to audiogenic seizures induced by loud sounds. It is shown that Otogl is transiently expressed in a subpopulation of spiral ganglion neurons during cochlear development. Despite their apparently normal hearing, Otogl +/− mice display poor activation of the spiral ganglion neurons processing loud sounds and an elevation of the activation threshold of the middle the ear muscle reflex that attenuates loud sounds. The findings reveal how a neuropathy affecting spiral ganglion neurons specialized in loud sound processing and associated with the middle the ear muscle reflex can manifest itself as auditory hyperexcitability.

CRISPR-Cas13 systems have therapeutic promise for the precise correction of point mutations in RNA. Using adenosine deaminase acting on RNA (ADAR) effectors, A-I base conversions can be targeted using guide RNAs (gRNAs). We compare the Cas13 effectors PspCas13b and Cas13bt3 for the repair of the gene USH2A , a common cause of inherited retinal disease and Usher syndrome. In cultured cells, we demonstrate up to 80% efficiency for the repair of the common c.11864 G > A and its murine equivalent c.11840 G > A, across different gRNAs and promoters. We develop and characterize a mouse model of Usher syndrome carrying the c.11840 G > A mutation designed for the evaluation of base editors for inherited retinal disease. Finally, we compare Cas13 effectors delivered via AAV for the repair of Ush2a in photoreceptors. Mean RNA editing rates in photoreceptors across different constructs ranged from 0.32% to 2.04%, with greater efficiency in those injected with PspCas13b compared to Cas13bt3 constructs. In mice injected with PspCas13b constructs, usherin protein was successfully restored and correctly localized to the connecting cilium following RNA editing. These results support the development of transcriptome targeting gene editing therapies for retinal disease.

Cricket song recognition is thought to evolve through modifications of a shared neural network. However, the species Anurogryllus muticus has an unusual recognition pattern that challenges this view: females respond to both normal male song pulse periods and periods twice as long. Of the three minimal models tested, only a single-neuron model with an oscillating membrane could explain this unusual behavior. A minimal model of the cricket's song network reproduced the behavior after adding a mechanism that, while present in the full network, is not crucial for song recognition in other species. This shows how a shared neural network can produce diverse behaviors and highlights how different computations contribute to evolution. Our results also demonstrate how nonlinear computations can lead to rapid behavioral changes during evolution because small changes in network parameters can lead to large changes in behavior.

Introduction Perceived loudness is challenging to study in non-human animals. However, reaction time to an acoustic stimulus is a useful behavioral proxy for the assessment of perceived loudness. Understanding the effect of sound frequency and level on perceived loudness would improve prediction and modeling of anthropogenic noise impacts on marine mammals. Methods In this study, behavioral hearing tests conducted with two killer whales were analyzed to capture conditioned vocal response latency, which is the time between the onset of the acoustic signal and the onset of the response (i.e., reaction time). Results The results showed that vocal reaction times decreased with increasing sensation level (i.e., sound pressure level above the baseline hearing threshold), while the effect of frequency on reaction time varied between the subjects. Reaction time as a function of sound duration is described, and equal-latency contours are presented. Discussion The data suggest that vocal reaction time decreases with increasing sensation level, therefore supporting the use of reaction time as a proxy for loudness perception in killer whales.

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.

We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering the neurotoxin, kainic acid, to the intact round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid–structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently suggest that active outer hair cells in the tail region of cochlear traveling waves drive cochlear fluid circulation.

Binaural speech intelligibility in rooms is a complex process that is affected by many factors including room acoustics, hearing loss, and hearing aid (HA) signal processing. Intelligibility is evaluated in this paper for a simulated room combined with a simulated hearing aid. The test conditions comprise three spatial configurations of the speech and noise sources, simulated anechoic and concert hall acoustics, three amounts of multitalker babble interference, the hearing status of the listeners, and three degrees of simulated HA processing provided to compensate for the noise and/or hearing loss. The impact of these factors and their interactions is considered for normal-hearing (NH) and hearing-impaired (HI) listeners for sentence stimuli. Both listener groups showed a significant reduction in intelligibility as the signal-to-noise ratio (SNR) decreased, and showed a reduction in intelligibility in reverberation when compared to anechoic listening. There was no significant improvement in intelligibility for the NH group for the noise suppression algorithm used here, and no significant improvement in intelligibility for the HI group for more advanced HA processing algorithms as opposed to linear amplification in either of the two acoustic spaces or at any of the three SNRs.

Speech intelligibility declines with age and sensorineural hearing damage (SNHL). However, it remains unclear whether cochlear synaptopathy (CS), a recently discovered form of SNHL, significantly contributes to this issue. CS refers to damaged auditory-nerve synapses that innervate the inner hair cells and there is currently no go-to diagnostic test available. Furthermore, age-related hearing damage can comprise various aspects (e.g., hair cell damage, CS) that each can play a role in impaired sound perception. To explore the link between cochlear damage and speech intelligibility deficits, this study examines the role of CS for word recognition among older listeners. We first validated an envelope-following response (EFR) marker for CS using a Budgerigar model. We then applied this marker in human experiments, while restricting the speech material’s frequency content to ensure that both the EFR and the behavioral tasks engaged similar cochlear frequency regions. Following this approach, we identified the relative contribution of hearing sensitivity and CS to speech intelligibility in two age-matched (65-year-old) groups with clinically normal ( n = 15, 8 females) or impaired audiograms ( n = 13, 8 females). Compared to a young normal-hearing control group ( n = 13, 7 females), the older groups demonstrated lower EFR responses and impaired speech reception thresholds. We conclude that age-related CS reduces supra-threshold temporal envelope coding with subsequent speech coding deficits in noise that cannot be explained based on hearing sensitivity alone.

This study investigates how selective auditory attention influences the lexical speech segmentation process to phonemes and words in a two competing speaker scenario. Using electroencephalography recordings from 20 participants, we applied temporal response function analysis to distinguish attention-driven neural activity to phoneme and word onsets for the attended and ignored speech stream separately. Our results reveal distinct attention effects for phoneme and word onsets. Phoneme onsets elicited significant selective attention effects at an early (18–94 ms, P1), middle (186–252 ms, P2), and late (302–382 ms, N2) time window. In contrast, word onsets showed attention effects only at a middle (192–280 ms, P2) and late (348–386 ms, N2) time window, occurring slightly later than phoneme-related effects. Prediction accuracy analyses demonstrated stronger model performance for the attended speech stream across all models, with notable improvements in prediction accuracy from a word model to a phoneme model to a combined word and phoneme model. These findings are in accordance with both hierarchical and parallel processing frameworks, where selective attention enhances lexical segmentation for attended speech, improving prediction accuracy. Early attention effects observed for phoneme onsets underscore their role in low-level speech processing, while late attention effects for word onsets may reflect higher level processing. This study highlights the importance of selective attention in neural speech tracking and provides insights into auditory processing mechanisms underlying speech comprehension in complex acoustic environments.

Two adaptations of the Single-Interval Adjust-Matrix Yes-No (SIAM-YN) task, designed to increase the efficiency of absolute threshold estimation, are described. The first, the SIAM Twin Track (SIAM-TT) task, consists of two interleaved tracks of the standard SIAM-YN that are run in the same trial with a single response. The second new task modifies the binary SIAM-YN task by using a six-point rating-scale (SIAM-Rating). In Experiment 1, data from three tasks estimating absolute thresholds were obtained using a 10-ms tone, the 2-IFC up-down procedure, SIAM-YN task, and the SIAM-TT task. The data support the use of the SIAM-TT as an alternative to the conventional two-interval and one-interval (SIAM-YN) tasks when used to estimate absolute thresholds. By presenting two interleaved SIAM-YN tracks on a single experimental trial, the SIAM-TT task possesses greater efficiency alongside its signal-detection tradition which confers less response bias. Similarly, in Experiment 2, which compared the 2-IFC adaptive, SIAM-YN, and SIAM-Rating tasks, there was no main effect of task upon threshold estimates. The findings replicate previous studies supporting the validity and efficiency of the SIAM-YN task, and extends the SIAM-YN toolbox to efficiently facilitate the generation of psychometric functions (the SIAM-TT task) and Receiver Operating Characteristic Curves (the SIAM-Rating task).