Kenneth S. Henry

Diminished temporal coding with sensorineural hearing loss emerges in background noise

Behavioral studies in humans suggest that sensorineural hearing loss (SNHL) decreases sensitivity to the temporal structure of sound, but neurophysiological studies in mammals provide little evidence for diminished temporal coding. We found that SNHL in chinchillas degraded peripheral temporal coding in background noise substantially more than in quiet. These results resolve discrepancies between previous studies and help to explain why perceptual difficulties in hearing-impaired listeners often emerge in noisy situations.

The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury

In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2α was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-α (TNF-α), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-α. Furthermore, the effects of TNF-α on phosphorylated eIF2α, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.

Vocally correlated seasonal auditory variation in the house sparrow (Passer domesticus).

SUMMARY Songbirds exhibit seasonal plasticity in a broad variety of behavioral and morphological traits associated with reproduction. Changes in song production are well described while changes in song reception are not. In the present study, we test for seasonal variation in auditory processing of the house sparrow (Passer domesticus L.) using auditory brainstem responses (ABRs) to tone bursts. We measured amplitude and latency of the first ABR peak in spring, summer and autumn at stimulus frequencies from 0.8 to 6.4 kHz and intensity levels from 24 to 80 dB SPL. ABR thresholds were determined at each frequency using cross-correlation. Amplitude was greater in spring than in autumn at frequencies from 3.2 to 6.4 kHz whereas latency and thresholds exhibited no seasonal variation. The results indicate an increase in the number or temporal synchrony of responses from peripheral auditory neurons during the early breeding season. Changes in peripheral auditory processing may enhance temporal coding of the fine structure and envelope of song; thereby, improving assessment of encoded information in both sexes (e.g. individual identity and dominance status) and auditory feedback during song production in males. Peripheral auditory changes may be mediated by reproductive hormones, and could involve changes in hair cell density on the basilar papilla. Our results suggest that peripheral auditory processing of songbirds changes seasonally in parallel with other behavioral and morphological traits, such as song production.

Schwann Cell LRP1 Regulates Remak Bundle Ultrastructure and Axonal Interactions to Prevent Neuropathic Pain

Trophic support and myelination of axons by Schwann cells in the PNS are essential for normal nerve function. Herein, we show that deletion of the LDL receptor-related protein-1 (LRP1) gene in Schwann cells (scLRP1−/−) induces abnormalities in axon myelination and in ensheathment of axons by nonmyelinating Schwann cells in Remak bundles. These anatomical changes in the PNS were associated with mechanical allodynia, even in the absence of nerve injury. In response to crush injury, sciatic nerves in scLRP1−/− mice showed accelerated degeneration and Schwann cell death. Remyelinated axons were evident 20 d after crush injury in control mice, yet were largely absent in scLRP1−/− mice. In the partial nerve ligation model, scLRP1−/− mice demonstrated significantly increased and sustained mechanical allodynia and loss of motor function. Evidence for central sensitization in pain processing included increased p38MAPK activation and activation of microglia in the spinal cord. These studies identify LRP1 as an essential mediator of normal Schwann cell–axonal interactions and as a pivotal regulator of the Schwann cell response to PNS injury in vivo. Mice in which LRP1 is deficient in Schwann cells represent a model for studying how abnormalities in Schwann cell physiology may facilitate and sustain chronic pain.

Songbirds tradeoff auditory frequency resolution and temporal resolution

Physical tradeoffs may in some cases constrain the evolution of sensory systems. The peripheral auditory system, for example, performs a spectral decomposition of sound that should result in a tradeoff between frequency resolution and temporal resolution. We assessed temporal resolution in three songbird species using auditory brainstem responses to paired click stimuli. Temporal resolution was greater in house sparrows (Passer domesticus) than Carolina chickadees (Poecile carolinensis) and white-breasted nuthatches (Sitta carolinensis), as predicted based on previous observations of broader auditory filters (lower frequency resolution) in house sparrows. Furthermore, within chickadees, individuals with broader auditory filters had greater temporal resolution. In contrast to predictions however, temporal resolution was similar between chickadees and nuthatches despite broader auditory filters in chickadees. These results and the results of a model simulation exploring the effect of broadened auditory filter bandwidth on temporal resolution in the auditory periphery strongly suggest that frequency resolution constrains temporal resolution in songbirds. Furthermore, our results suggest that songbirds have greater temporal resolution than some mammals, in agreement with recent behavioral studies. Species differences in temporal resolution may reflect adaptations for efficient processing of species-specific vocalizations, while individual differences within species may reflect experience-based developmental plasticity or hormonal effects.

Noise-induced hearing loss increases the temporal precision of complex envelope coding by auditory-nerve fibers

While changes in cochlear frequency tuning are thought to play an important role in the perceptual difficulties of people with sensorineural hearing loss (SNHL), the possible role of temporal processing deficits remains less clear. Our knowledge of temporal envelope coding in the impaired cochlea is limited to two studies that examined auditory-nerve fiber responses to narrowband amplitude modulated stimuli. In the present study, we used Wiener-kernel analyses of auditory-nerve fiber responses to broadband Gaussian noise in anesthetized chinchillas to quantify changes in temporal envelope coding with noise-induced SNHL. Temporal modulation transfer functions (TMTFs) and temporal windows of sensitivity to acoustic stimulation were computed from 2nd-order Wiener kernels and analyzed to estimate the temporal precision, amplitude, and latency of envelope coding. Noise overexposure was associated with slower (less negative) TMTF roll-off with increasing modulation frequency and reduced temporal window duration. The results show that at equal stimulus sensation level, SNHL increases the temporal precision of envelope coding by 20–30%. Furthermore, SNHL increased the amplitude of envelope coding by 50% in fibers with CFs from 1–2 kHz and decreased mean response latency by 0.4 ms. While a previous study of envelope coding demonstrated a similar increase in response amplitude, the present study is the first to show enhanced temporal precision. This new finding may relate to the use of a more complex stimulus with broad frequency bandwidth and a dynamic temporal envelope. Exaggerated neural coding of fast envelope modulations may contribute to perceptual difficulties in people with SNHL by acting as a distraction from more relevant acoustic cues, especially in fluctuating background noise. Finally, the results underscore the value of studying sensory systems with more natural, real-world stimuli.

Auditory brainstem responses predict auditory nerve fiber thresholds and frequency selectivity in hearing impaired chinchillas.

Noninvasive auditory brainstem responses (ABRs) are commonly used to assess cochlear pathology in both clinical and research environments. In the current study, we evaluated the relationship between ABR characteristics and more direct measures of cochlear function. We recorded ABRs and auditory nerve (AN) single-unit responses in seven chinchillas with noise-induced hearing loss. ABRs were recorded for 1-8 kHz tone burst stimuli both before and several weeks after 4 h of exposure to a 115 dB SPL, 50 Hz band of noise with a center frequency of 2 kHz. Shifts in ABR characteristics (threshold, wave I amplitude, and wave I latency) following hearing loss were compared to AN-fiber tuning curve properties (threshold and frequency selectivity) in the same animals. As expected, noise exposure generally resulted in an increase in ABR threshold and decrease in wave I amplitude at equal SPL. Wave I amplitude at equal sensation level (SL), however, was similar before and after noise exposure. In addition, noise exposure resulted in decreases in ABR wave I latency at equal SL and, to a lesser extent, at equal SPL. The shifts in ABR characteristics were significantly related to AN-fiber tuning curve properties in the same animal at the same frequency. Larger shifts in ABR thresholds and ABR wave I amplitude at equal SPL were associated with greater AN threshold elevation. Larger reductions in ABR wave I latency at equal SL, on the other hand, were associated with greater loss of AN frequency selectivity. This result is consistent with linear systems theory, which predicts shorter time delays for broader peripheral frequency tuning. Taken together with other studies, our results affirm that ABR thresholds and wave I amplitude provide useful estimates of cochlear sensitivity. Furthermore, comparisons of ABR wave I latency to normative data at the same SL may prove useful for detecting and characterizing loss of cochlear frequency selectivity.

Distorted Tonotopic Coding of Temporal Envelope and Fine Structure with Noise-Induced Hearing Loss.

People with cochlear hearing loss have substantial difficulty understanding speech in real-world listening environments (e.g., restaurants), even with amplification from a modern digital hearing aid. Unfortunately, a disconnect remains between human perceptual studies implicating diminished sensitivity to fast acoustic temporal fine structure (TFS) and animal studies showing minimal changes in neural coding of TFS or slower envelope (ENV) structure. Here, we used general system-identification (Wiener kernel) analyses of chinchilla auditory nerve fiber responses to Gaussian noise to reveal pronounced distortions in tonotopic coding of TFS and ENV following permanent, noise-induced hearing loss. In basal fibers with characteristic frequencies (CFs) >1.5 kHz, hearing loss introduced robust nontonotopic coding (i.e., at the wrong cochlear place) of low-frequency TFS, while ENV responses typically remained at CF. As a consequence, the highest dominant frequency of TFS coding in response to Gaussian noise was 2.4 kHz in noise-overexposed fibers compared with 4.5 kHz in control fibers. Coding of ENV also became nontonotopic in more pronounced cases of cochlear damage. In apical fibers, more classical hearing-loss effects were observed, i.e., broadened tuning without a significant shift in best frequency. Because these distortions and dissociations of TFS/ENV disrupt tonotopicity, a fundamental principle of auditory processing necessary for robust signal coding in background noise, these results have important implications for understanding communication difficulties faced by people with hearing loss. Further, hearing aids may benefit from distinct amplification strategies for apical and basal cochlear regions to address fundamentally different coding deficits. SIGNIFICANCE STATEMENT Speech-perception problems associated with noise overexposure are pervasive in todays society, even with modern digital hearing aids. Unfortunately, the underlying physiological deficits in neural coding remain unclear. Here, we used innovative system-identification analyses of auditory nerve fiber responses to Gaussian noise to uncover pronounced distortions in coding of rapidly varying acoustic temporal fine structure and slower envelope cues following noise trauma. Because these distortions degrade and diminish the tonotopic representation of temporal acoustic features, a fundamental principle of auditory processing, the results represent a critical advancement in our understanding of the physiological bases of communication disorders. The detailed knowledge provided by this work will help guide the design of signal-processing strategies aimed at alleviating everyday communication problems for people with hearing loss.

Neural correlates of behavioral amplitude modulation sensitivity in the budgerigar midbrain

Amplitude modulation (AM) is a crucial feature of many communication signals, including speech. Whereas average discharge rates in the auditory midbrain correlate with behavioral AM sensitivity in rabbits, the neural bases of AM sensitivity in species with human-like behavioral acuity are unexplored. Here, we used parallel behavioral and neurophysiological experiments to explore the neural (midbrain) bases of AM perception in an avian speech mimic, the budgerigar (Melopsittacus undulatus). Behavioral AM sensitivity was quantified using operant conditioning procedures. Neural AM sensitivity was studied using chronically implanted microelectrodes in awake, unrestrained birds. Average discharge rates of multiunit recording sites in the budgerigar midbrain were insufficient to explain behavioral sensitivity to modulation frequencies <100 Hz for both tone- and noise-carrier stimuli, even with optimal pooling of information across recording sites. Neural envelope synchrony, in contrast, could explain behavioral performance for both carrier types across the full range of modulation frequencies studied (16-512 Hz). The results suggest that envelope synchrony in the budgerigar midbrain may underlie behavioral sensitivity to AM. Behavioral AM sensitivity based on synchrony in the budgerigar, which contrasts with rate-correlated behavioral performance in rabbits, raises the possibility that envelope synchrony, rather than average discharge rate, might also underlie AM perception in other species with sensitive AM detection abilities, including humans. These results highlight the importance of synchrony coding of envelope structure in the inferior colliculus. Furthermore, they underscore potential benefits of devices (e.g., midbrain implants) that evoke robust neural synchrony.

Midbrain Synchrony to Envelope Structure Supports Behavioral Sensitivity to Single-Formant Vowel-Like Sounds in Noise

Vowels make a strong contribution to speech perception under natural conditions. Vowels are encoded in the auditory nerve primarily through neural synchrony to temporal fine structure and to envelope fluctuations rather than through average discharge rate. Neural synchrony is thought to contribute less to vowel coding in central auditory nuclei, consistent with more limited synchronization to fine structure and the emergence of average-rate coding of envelope fluctuations. However, this hypothesis is largely unexplored, especially in background noise. The present study examined coding mechanisms at the level of the midbrain that support behavioral sensitivity to simple vowel-like sounds using neurophysiological recordings and matched behavioral experiments in the budgerigar. Stimuli were harmonic tone complexes with energy concentrated at one spectral peak, or formant frequency, presented in quiet and in noise. Behavioral thresholds for formant-frequency discrimination decreased with increasing amplitude of stimulus envelope fluctuations, increased in noise, and were similar between budgerigars and humans. Multiunit recordings in awake birds showed that the midbrain encodes vowel-like sounds both through response synchrony to envelope structure and through average rate. Whereas neural discrimination thresholds based on either coding scheme were sufficient to support behavioral thresholds in quiet, only synchrony-based neural thresholds could account for behavioral thresholds in background noise. These results reveal an incomplete transformation to average-rate coding of vowel-like sounds in the midbrain. Model simulations suggest that this transformation emerges due to modulation tuning, which is shared between birds and mammals. Furthermore, the results underscore the behavioral relevance of envelope synchrony in the midbrain for detection of small differences in vowel formant frequency under real-world listening conditions.