Psychoacoustics publications

Tinnitus is one of the most common hearing disorders affecting one-third of Americans and is defined as the buzzing or ringing sound one perceives in one or both ears in the absence of an acoustic stimulus. One objective method for tinnitus screening in rodents is gap prepulse inhibition of the acoustic startle reflex (GPIAS), a reduction in the abrupt motor response elicited by an intense auditory stimulus following a silent gap in noise. Reduced inhibition by gaps embedded in narrow-band noise is hypothesized to reflect the primary tinnitus pitch, as the tinnitus “fills-in” the gap. However, Lobarinas et al. (2013) identified a critical limitation: after acoustic trauma or hearing loss, rodents often exhibit markedly diminished acoustic startle reflexes, creating a “floor effect” where further suppression becomes undetectable even if gap perception remains intact, leading to false-positive tinnitus screening results. To address this limitation, we utilized the CBA/CaJ mouse model to assess tactile airpuff modification efficacy and employed a machine learning algorithm to classify startle responses, achieving 98% accuracy in differentiating startles from non-startles. We induced unilateral conductive hearing loss via ear plugging and found enhanced gap detection ability, contrasting with false-positive tinnitus indicators observed in rats by Lobarinas and colleagues. We also pharmacologically induced tinnitus via sodium salicylate, revealing frequency-specific alterations in gap detection patterns. Our findings suggest that differences in data analysis methodology, specifically using a machine learning algorithm to filter non-startle responses, may explain species-specific differences between mouse and rat models and significantly improve GPIAS validity as a tinnitus screening assessment tool. Highlights • Gap-startle paradigm objectively screens for tinnitus in rodent models. • Machine learning classification achieved 98% accuracy in startle detection. • Enhanced analysis resolved floor effects that previously limited paradigm validity. • Species differences explained by improved data filtering methodology.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.

Cochlear damage triggers compensatory primary auditory cortex (A1) plasticity that amplifies responses to residual sensory inputs, thereby contributing to the restoration of both cortical responsiveness to sound and perceptual sound detection threshold. However, this adaptation can become maladaptive, producing neuronal hyperactivity that contributes to tinnitus and hyperacusis. The neuromodulatory mechanisms governing these adaptive and maladaptive changes remain unknown. Here, we demonstrate that noise-induced cochlear injury triggers bidirectional synaptic zinc signaling plasticity that potentiates activity in excitatory principal neurons and parvalbumin-expressing interneurons, while suppressing activity in somatostatin-expressing interneurons. These cell-type-specific effects of synaptic zinc plasticity contribute to restoring A1 responsiveness to sound and perceptual detection thresholds, while being necessary for neural hyperactivity. Together, our findings establish synaptic zinc as a pivotal neuromodulator that shapes both adaptive and maladaptive cortical plasticity and identify a promising therapeutic target for improving perceptual recovery after cochlear damage and mitigating tinnitus and hyperacusis.

Tinnitus involves peripheral auditory damage and aberrant central plasticity, with dysregulated BDNF signaling linking injury to compensation. Yet, direct evidence connecting BDNF/AKT/mTOR pathway activation to behavioral phenotypes is limited. This study examined BDNF/AKT/mTOR expression in the inferior colliculus (IC) of sodium salicylate (SS)-induced tinnitus rats and assessed therapeutic inhibition. Rats received intraperitoneal SS, showing decreased GPIAS ratios, elevated ABR thresholds, and upregulated BDNF/TrkB/AKT/mTOR phosphorylation in the IC-changes associated with tinnitus-like behavior. Bilateral IC microinjection of BDNF siRNA or systemic rapamycin revealed that siRNA suppressed BDNF/TrkB and ameliorated tinnitus without improving hearing, while rapamycin reduced mTOR phosphorylation and partially alleviated behavior. These results first demonstrate that BDNF/AKT/mTOR upregulation in the IC contributes to tinnitus in SS rats, and its inhibition improves behavioral manifestations without reversing peripheral hearing loss.

Purpose: In anesthesia research and clinical practice, the level of consciousness is often assessed by stimulating subjects and observing their responses. It is possible that such stimulation alters the very state of consciousness being assessed. Whether this phenomenon is accompanied by specific cortical activities remains unknown. Here, we tested the effects of behavioral assessments on neuronal activity in the rat primary auditory cortex (A1) and perirhinal cortex (PrC). Methods: Neuronal spiking activity was recorded from microwire arrays targeting A1 and/or PrC in rats (n = 9), whilst presenting 40 Hz click-trains and gradually increasing infusion rates of propofol, remifentanil, ketamine or dexmedetomidine. We assessed righting reflex, pain withdrawal, whisking reflex, and corneal reflex every 12 minutes (every 360 auditory trials). We searched for significant changes in baseline firing rate and stimulus-evoked activities (where present) due to the behavioral assessments, by comparing 4 min intervals before and after the behavioral tests. Results: Out of 1004 units in 20 sessions, we found significantly elevated activity (p < 0.01) following behavioral tests in 32% and 20% of A1 auditory-responsive units and 8.6% and 5.3% of auditory-unresponsive units under propofol and dexmedetomidine, respectively, but not under remifentanil or ketamine. A higher proportion of units modulated their firing following behavioral tests in A1 compared to PrC, with median gains ranging from +0.23 to +1.06, depending on the specific response feature. Conclusion: Behavioral testing increases ongoing firing rate and responses to sounds in some cortical neurons. This increase is more prevalent in A1 than in PrC, mirroring clinical observations that patients exhibit basic responses under sedation, while complex processing, such as memory encoding, is impaired. The degree of neuronal modulation due to behavioral testing varies between anesthetic agents, mirroring their clinical phenotypes.

Perceptual entrainment and temporal prediction aid speech perception in both quiet and noisy environments. Isochronous, periodic auditory rhythmic cues facilitate neural entrainment and temporal expectations which can benefit encoding and perception of target speech. However, most studies using isochronous cues confound periodicity with predictability. To this end, we characterized how systematic changes in the acoustic dimensions of stimulus rate, target phase, periodicity, and predictably of an entraining sound precursor impact the subsequent identification of concurrent speech targets. Target concurrent vowel pairs were preceded by rhythmic woodblock cues which were either periodic-predictable (PP, isochronous rhythm), aperiodic-predictable (AP, accelerating rhythm), or aperiodic-unpredictable (AU, random rhythm). The number of pulses per rhythm was roved to further manipulate predictability. Stimuli also varied in presentation rate (2.5, 4.5, 6.5 Hz) and target speech phase (in-phase, 0°; out-of-phase, –90°, 180°) relative to the preceding entraining rhythm. We also measured participants’ musical pulse continuation and standardized speech-in-noise perception abilities. We did not observe any effects of stimulus rhythm, rate, or target phase on target speech identification accuracy. However, reaction times were slowest at the nominal speech rate (4.5 Hz) and were most disrupted by out-of-phase presentations following the PP rhythm. Double-vowel task performance was associated with stronger musical pulse continuation abilities, but not speech-in-noise perception. Our results support the notion that perceptual entrainment benefits from rhythmic cues rely on top-down processing and thus are relatively muted when stimulus predictability is unknown. Additionally, we find that individual differences in musical pulse perception may underlie benefits of rhythmic cueing on subsequent speech perception.

Hearing is the largest modifiable mid-life risk factor for Alzheimer's disease (AD), yet its link to dementia remains unclear. We identified a neurophysiological biomarker of AD risk using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to Amyloid precursor protein, AppS; male and female). Human ABRs have been proposed as a biomarker for AD and related dementias. The novel metric reported here is derived from multidimensional parametric feature extraction on the distribution statistics of repeated single-trial ABR traces. We report accurate prediction of genetic risk for AD risk in young and aged rats: AppS separate clearly from healthy humanized (AppH) in sex- and age-dependent manners. Notably, auditory learning during young adulthood shifted the AppS ABR signature towards a healthy AppH-like state that maintained over time into older age. Altogether the findings support the utility of the ABR to track disease state, progression, and effects of intervention, and point to a central neural generator of auditory dysfunction related to AD risk. ABRs could provide a very early biomarker for detection of AD risk and used to test the synergy of auditory and cognitive functions in human dementia.

Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse Fmr1 knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific Fmr1 KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Abnormal GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and abnormal behaviors in cKO mice. Blocking astrocyte GABA transport enables higher PV expression, improves EEG responses to frequency-modulated sound, and corrects aberrant exploratory behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes.

Introduction: Hearing is critical for communication and clinical evidence suggests that hearing loss can lead to poorer mental well-being including social isolation, anxiety, depression, and cognitive decline. Deaf animal models offer opportunities to investigate the impact of hearing loss on behavioral correlates of mental health while controlling for genetic variability and shared etiological factors such as environmental stressors, aging, and metabolic diseases. We previously showed that conditional deletion of Ebf1 in the inner ear causes deafness. We hypothesize that otic-specific Ebf1 knockout (KO) mice recapitulate neurobehavioral alterations experienced in congenital deafness. Methods: Slc26a9P2A-Cre and Ebf1 floxed mice were crossed previously to generate the otic-specific Ebf1 conditional KO. We measured auditory brainstem response and behavior in groups of otic-specific Ebf1 conditional KO mice and Cre-negative littermate controls (WT). We performed behavioral tests including elevated plus maze, acoustic startle, locomotor activity, forced swim, and Y-maze. Results: We found that the KO mice spend significantly less time than WT mice in the open arms of the elevated plus maze. KO mice also show significantly increased latency to enter the open arms. Acoustic startle response was decreased in KO mice vs. WT controls and pre-pulse inhibition was also reduced in the KO, consistent with elevated hearing thresholds. We found no significant differences in exploratory behavior, forced swim immobility time, or other behavioral measures examined. Conclusions: Our findings demonstrate that deaf otic-specific KO mice are indeed a model for the study of effects of hearing loss on clinically relevant behavioral correlates. Our results provide new empirical evidence that hearing loss contributes to anxiety, which is consistent with clinical evidence that anxiety is associated with hearing loss in older adults.

Purpose Measures of the human medial olivocochlear reflex (MOCR) typically rely on long duration (> 100 ms) or continuously presented broadband elicitors. MOCR gain reduction measured by otoacoustic emissions (OAE) exhibits multiple time constants, including in the hundreds of milliseconds, when elicited by broadband noise. Psychoacoustic studies of gain reduction have largely adopted these elicitor characteristics, but less is known about how broadband elicitor duration affects auditory perception. Additionally, the literature on the relationship between psychoacoustic and OAE measures of gain reduction has yielded mixed results, which is counterintuitive if both measures reflect the same mechanism. In this study, the effects of ipsilateral broadband elicitor duration were evaluated using forward masking psychoacoustic and transient-evoked OAE (TEOAE) paradigms in individuals with normal hearing (N = 19; m = 7, f = 12). Methods Ipsilateral pink broadband noise was used as the elicitor in both experiments, presented at 50 dB SPL (50–800 ms) for the psychoacoustic measures and 50 dB FPL (50–400 ms) for the TEOAE measures. Gain reduction was quantified as the change in signal threshold (2 kHz) and the change in TEOAE level (1/3rd-octave band centered at 2 kHz) with and without the presence of the elicitor. Results The average time constants for psychoacoustic and TEOAE gain reduction were similarly short (< 100 ms), with near-maximal effects observed for elicitor durations of 200 ms. However, individual comparisons of TEOAE and psychoacoustic gain reduction revealed mixed results. Potential factors contributing to this discrepancy are discussed. Conclusion The human MOCR reduces cochlear gain on relatively short time scales (< 100 ms) with ipsilateral broadband elicitors.

Noise-induced hearing loss (NIHL) is a primary contributor to tinnitus, involving mechanisms such as inflammatory damage, central sensitization, and auditory cortex remodeling. However, not all cases of tinnitus are accompanied by NIHL, and the precise relationship between the two remains incompletely understood. Phosphorylation/dephosphorylation, as a core mechanism for fine cellular regulation, influences neuronal excitability, immune responses, and disease development by modulating protein activity, signal transduction, and gene expression. We hypothesized that aberrant phosphorylation levels may alter auditory cortex neuron function, leading to pathological changes at the protein level. Leveraging auditory cortex tissue from a noise-induced tinnitus model, we systematically investigated the pathogenesis of tinnitus and its distinction from NIHL through integrated proteomic and phosphoproteomic analyses. Compared to animals with NIHL alone, the tinnitus model exhibited enhanced neuronal excitability, synaptic dysfunction, hyperactive energy metabolism, and weakened neuroprotection, with disordered membrane receptor function playing a critical role. Multi-omics analysis further revealed that tinnitus development primarily depends on phosphorylation-mediated post-translational modifications reshaping cellular function, rather than changes in protein abundance caused by alterations in gene transcription levels. Collectively, this study elucidates the physiological and cellular structural alterations in noise-induced tinnitus from the dimensions of protein expression and phosphorylation modification. It confirms that tinnitus leads to neural dysfunction through abnormal membrane receptor activity, and the characteristic proteins and phosphorylation sites identified offer novel therapeutic targets for modulating central hyperexcitability in tinnitus.

This study aimed to characterize maturation of the binaural intelligibility level difference (BILD) for school-age children in the context of speech-in-speech recognition. Children (5–17 years) and adults completed an adaptive, open-set sentence recognition task in a two-talker masker in two binaural conditions: (1) target and masker speech in-phase across the two ears, and (2) target speech presented 180° out-of-phase across the two ears and masker speech presented in-phase. Estimates of the BILD, computed as the difference score between the two binaural conditions, were mature by ten years of age, consistent with previous data on the BILD for speech-in-noise recognition.

This study compared the behavioral minimum audible angle (MAA) and the electrophysiological acoustic change complex (ACC) elicited by an azimuthal shift in sound location. To examine age effects, 63 participants with normal or near-normal hearing were divided into three age groups (Young, Mid-Aged, and Older). The stimuli were narrow bands of noise centered at 500 Hz to facilitate reliance on primarily binaural temporal cues. Putative spatial location was manipulated by means of head-related transfer functions under headphones. MAA results showed that performance was dependent on the reference location, with performance becoming poorer as the reference location shifted away from midline. The Young group had smaller MAAs than the Older group, and performance of the Mid-Age group was intermediate. Measurement of the ACC was restricted to shifts away from midline, and results showed no ACC for shifts of 4.5° and 9° but present ACCs for shifts of 13.5°, 18°, and 36°. The robustness of the ACC, as measured with the intertrial phase coherence metric, grew with increasing azimuthal shift. For shifts of 13.5° and 18°, Young participants had more robust ACCs than Older participants. Although age-related deficits were found in both the MAA and in the robustness of the ACC, no associations were observed at the individual level between MAA and ACC measures. Further work is necessary to evaluate the ACC elicited by shifts from off-midline reference locations before a firm conclusion can be reached that the ACC is not a viable objective proxy for the MAA.

The ability to recognize speakers by their voice despite acoustical variation plays a substantial role in primate social interactions. Although neurons in the macaque anterior temporal lobe (ATL) show invariance to face viewpoint, whether they also encode abstract representations of caller identity is not known. Here, we demonstrate that neurons in the voice-selective ATL of two macaques support invariant voice identity representations through dynamic population-level coding. These representations minimize neural distances across different vocalizations from the same individual while preserving distinct trajectories for different callers. This structure emerged from the coordinated activity of the broader neuronal ensemble, although a small subset of highly identity-selective neurons carried high identity information. Our findings provide a neural basis for voice identity recognition in primates and highlight the ATL as a key hub for integrating perceptual voice features into higher-level identity representations.

Introduction Tinnitus is the perception of non-meaningful sound in the absence of external stimuli. Although tinnitus behavior in animal models is associated with altered central nervous system activity, it is not currently possible to identify tinnitus using neuronal activity alone. In the mouse inferior colliculus (IC), a subpopulation of neurons demonstrates a sustained increase in spontaneous activity after a long-duration sound (LDS). Methods Here, we use the “ LDS test ” to reveal tinnitus-specific differences in sound-evoked plasticity through IC extracellular recordings and the auditory brainstem response (ABR LDS ) in CBA/CaJ mice after sound exposure and behavioral tinnitus assessment. Results Sound-exposed mice showed stronger and shorter tone-evoked responses in the IC compared to unexposed controls, but these differences were not strong predictors of tinnitus. In contrast, in the LDS test, non-tinnitus mice had a significantly stronger suppression in tone-evoked spike rate compared to tinnitus and unexposed control mice. ABR peak amplitudes also revealed robust differences between tinnitus and non-tinnitus mice, with ABR peaks from non-tinnitus mice exhibiting significantly stronger suppression in the LDS test compared to tinnitus and control mice. No significant differences were seen between cohorts in ABR amplitude, latency, wave V:I ratio, wave V:III ratio, I-V intra-peak latency, and I-VI intra-peak latency. We found high-frequency tone stimuli better suited to reveal tinnitus-specific differences for both extracellular IC and ABR recordings. Discussion We successfully used the LDS test to demonstrate that tinnitus-specific differences in sound-evoked plasticity can be shown using both multi-unit near-field recordings in the IC and non-invasive far-field recordings, providing a foundation for future electrophysiological research into the causes and treatment of tinnitus.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

The homozygous Cntnap2 knockout (KO) rat is a well-established genetic model for neurodevelopmental disorders, exhibiting core features of autism spectrum disorder (ASD), including impaired sensory processing and sensorimotor gating. Recent findings indicate that the severity of ASD-like phenotypes in Cntnap2 KO offspring is influenced by the parental genotype, with more pronounced impairments observed in KO rats bred from homozygous pairs compared to heterozygous pairs ( Cntnap2 HET). However, it is unclear to what extent this is due to in utero versus postnatal effects. We, therefore, investigated how early postnatal environmental factors, shaped by differences in parental and littermate genotypes, influence auditory processing and sensorimotor gating in Cntnap2 KO rats. To examine this, we cross-fostered Cntnap2 KO pups bred from Cntnap2 KO rats to be reared with litters of Cntnap2 HET dams. Cross-fostering Cntnap2 KO rats reversed or partially reversed delayed hearing sensitivity maturation, heightened acoustic startle responses, and deficits in prepulse inhibition of the acoustic startle response. However, cross-fostering also exacerbated deficits in the neural responsiveness and conductivity in the auditory brainstem, as well as in gap-induced prepulse inhibition of the acoustic startle response. These results emphasize the importance of considering the postnatal environment and breeding strategies in preclinical genetic models of neuropsychiatric disorders. More importantly, they also demonstrate that ASD-like traits, including alterations in brainstem sensory processing, are not strictly determined by genetic factors, but remain malleable by environmental factors during early postnatal development.

Cisplatin-induced hearing loss is a common and irreversible side effect affecting a significant proportion of cancer patients. While various strategies to mitigate this toxicity have been explored, there remains a critical need for effective treatments. A major challenge in developing new therapies is the lack of reliable animal models that accurately replicate the clinical use of cisplatin in humans, which typically involves multiple cycles of low-dose administration. Traditional models using high doses of cisplatin have resulted in high mortality and variable hearing loss, complicating the assessment of potential treatments. To address this, a multi-cycle model using lower cisplatin doses in mice was developed, providing hearing loss without mortality. However, variability in outcomes across different research groups persisted. In the present study, we optimize the multi-cycle model of cisplatin-induced ototoxicity by using clinical-grade cisplatin rather than laboratory-grade formulations. The use of clinical cisplatin ensures greater consistency, reliability, and relevance to human treatment protocols, as it adheres to the rigorous quality standards required for patient use. This new administration protocol will minimize variability across research laboratories and more accurately mimic the dosing regimens typically administered to cancer patients. Additionally, we have enhanced a zebrafish model for high-throughput screening of potential therapeutics, further improving the consistency of results. These improvements to the animal models are critical for accelerating the discovery and testing of therapies to prevent cisplatin-induced hearing loss, supporting the development of effective treatments for cancer patients undergoing cisplatin chemotherapy.

Tinnitus, a widespread condition affecting numerous individuals worldwide, remains a significant challenge due to limited effective therapeutic interventions. Intriguingly, patients using cochlear implants (CIs) have reported significant relief from tinnitus symptoms, although the underlying mechanisms remain unclear and intracochlear implantation risks cochlear damage and hearing loss. This study demonstrates that targeted intracochlear electrical stimulation (ES) in guinea pigs with noise‐induced hearing loss reversed tinnitus‐related maladaptive plasticity in the cochlear nucleus (CN), characterized by reduced auditory innervation, increased somatosensory innervation, and diminished inhibitory neural networks. Additionally, a customized extracochlear ES delivered by a newly designed extracochlear electrode array to guinea pigs with salicylate‐induced tinnitus also reversed the aforementioned maladaptive plasticity and alleviated tinnitus without causing additional cochlear damage or hearing loss. These findings suggest that CI‐delivered ES may alleviate tinnitus by reversing maladaptive CN plasticity. Additionally, the extracochlear ES strategy offers a promising tinnitus treatment with minimal risk to hearing.