Divergent Auditory Nerve Encoding Deficits Between Two Common Etiologies of Sensorineural Hearing Loss.

Speech intelligibility can vary dramatically between individuals with similar clinically defined severity of hearing loss based on the audiogram. These perceptual differences, despite equal audiometric-threshold elevation, are often assumed to reflect central-processing variations. Here, we compared peripheral-processing in auditory nerve (AN) fibers of male chinchillas between two prevalent hearing loss etiologies: metabolic hearing loss (MHL) and noise-induced hearing loss (NIHL). MHL results from age-related reduction of the endocochlear potential due to atrophy of the stria vascularis. MHL in the present study was induced using furosemide, which provides a validated model of age-related MHL in young animals by reversibly inhibiting the endocochlear potential. Effects of MHL on peripheral processing were assessed using Wiener-kernel (system identification) analyses of single AN fiber responses to broadband noise, for direct comparison to previously published AN responses from animals with NIHL. Wiener-kernel analyses show that even mild NIHL causes grossly abnormal coding of low-frequency stimulus components. In contrast, for MHL the same abnormal coding was only observed with moderate to severe loss. For equal sensitivity loss, coding impairment was substantially less severe with MHL than with NIHL, probably due to greater preservation of the tip-to-tail ratio of cochlear frequency tuning with MHL compared with NIHL rather than different intrinsic AN properties. Differences in peripheral neural coding between these two pathologies-the more severe of which, NIHL, is preventable-likely contribute to individual speech perception differences. Our results underscore the need to minimize noise overexposure and for strategies to personalize diagnosis and treatment for individuals with sensorineural hearing loss.SIGNIFICANCE STATEMENT Differences in speech perception ability between individuals with similar clinically defined severity of hearing loss are often assumed to reflect central neural-processing differences. Here, we demonstrate for the first time that peripheral neural processing of complex sounds differs dramatically between the two most common etiologies of hearing loss. Greater processing impairment with noise-induced compared with an age-related (metabolic) hearing loss etiology may explain heightened speech perception difficulties in people overexposed to loud environments. These results highlight the need for public policies to prevent noise-induced hearing loss, an entirely avoidable hearing loss etiology, and for personalized strategies to diagnose and treat sensorineural hearing loss.

Perfidious synaptic transmission in the guinea-pig auditory brainstem.

The presence of 'giant' synapses in the auditory brainstem is thought to be a specialization designed to encode temporal information to support perception of pitch, frequency, and sound-source localisation. These 'giant' synapses have been found in the ventral cochlear nucleus, the medial nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus. An interpretation of these synapses as simple relays has, however, been challenged by the observation in the gerbil that the action potential frequently fails in the ventral cochlear nucleus. Given the prominence of these synapses it is important to establish whether this phenomenon is unique to the gerbil or can be observed in other species. Here we examine the responses of units, thought to be the output of neurons in receipt of 'giant' synaptic endings, in the ventral cochlear nucleus and the medial nucleus of the trapezoid body in the guinea pig. We found that failure of the action-potential component, recorded from cells in the ventral cochlear nucleus, occurred in ~60% of spike waveforms when recording spontaneous activity. In the medial nucleus of the trapezoid body, we did not find evidence for action-potential failure. In the ventral cochlear nucleus action-potential failures transform the receptive field between input and output of bushy cells. Additionally, the action-potential failures result in "non-primary-like" temporal-adaptation patterns. This is important for computational models of the auditory system, which commonly assume the responses of ventral cochlear nucleus bushy cells are very similar to their "primary like" auditory-nerve-fibre inputs.

Endoscopic Ear Surgery for External Auditory Canal Cholesteatoma.

BACKGROUND: Treatment of external auditory canal cholesteatoma (EACC) has been a question of debate. To our knowledge and according to a systematic review of endoscopic ear surgery (EES) in 2015, this study describes for the first time the technique and outcome by solely transcanal EES for EACC. STUDY METHOD: Retrospective case series, level of evidence IV. METHODS: Between October 2014 and December 2016, nine patients with unilateral EACC have been treated by EES. Using a bimanual technique, canaloplasty has been performed using tragal perichondrium, cartilage, or artificial bone. Symptoms, signs, and reconstruction technique have been assessed and the primary endpoint: healing time was compared with benchmark values in the literature. RESULTS: During the 26 months study period all of our nine Naim stage III EACCs were successfully treated by EES with median healing time of 23.8 days. EACC limited to the external auditory canal (Naim stage III) represented an ideal target for EES minimizing tissue damage and thus median healing time compared with retroauricular (42-56 d) or endaural (59 d) surgical techniques. DISCUSSION: Shorter healing time helped to reduce skepticism toward a surgical treatment of EACC from the patient's perspective. Moreover, EES relied on reduced bulky equipment, dressing time, and complex maintenance compared with microscopic techniques. CONCLUSION: Transcanal endoscopic surgery is a valid treatment option for EACC up to Naim stage III. Moreover, the described procedure fosters in our eyes the teaching of our residence to get familiar with the basic steps of EES.

Suppression Measured from Chinchilla Auditory-Nerve-Fiber Responses Following Noise-Induced Hearing Loss: Adaptive-Tracking and Systems-Identification Approaches.

The compressive nonlinearity of cochlear signal transduction, reflecting outer-hair-cell function, manifests as suppressive spectral interactions; e.g., two-tone suppression. Moreover, for broadband sounds, there are multiple interactions between frequency components. These frequency-dependent nonlinearities are important for neural coding of complex sounds, such as speech. Acoustic-trauma-induced outer-hair-cell damage is associated with loss of nonlinearity, which auditory prostheses attempt to restore with, e.g., "multi-channel dynamic compression" algorithms.Neurophysiological data on suppression in hearing-impaired (HI) mammals are limited. We present data on firing-rate suppression measured in auditory-nerve-fiber responses in a chinchilla model of noise-induced hearing loss, and in normal-hearing (NH) controls at equal sensation level. Hearing-impaired (HI) animals had elevated single-fiber excitatory thresholds (by ~ 20-40 dB), broadened frequency tuning, and reduced-magnitude distortion-product otoacoustic emissions; consistent with mixed inner- and outer-hair-cell pathology. We characterized suppression using two approaches: adaptive tracking of two-tone-suppression threshold (62 NH, and 35 HI fibers), and Wiener-kernel analyses of responses to broadband noise (91 NH, and 148 HI fibers). Suppression-threshold tuning curves showed sensitive low-side suppression for NH and HI animals. High-side suppression thresholds were elevated in HI animals, to the same extent as excitatory thresholds. We factored second-order Wiener-kernels into excitatory and suppressive sub-kernels to quantify the relative strength of suppression. We found a small decrease in suppression in HI fibers, which correlated with broadened tuning. These data will help guide novel amplification strategies, particularly for complex listening situations (e.g., speech in noise), in which current hearing aids struggle to restore intelligibility.

Neural Segregation of Concurrent Speech: Effects of Background Noise and Reverberation on Auditory Scene Analysis in the Ventral Cochlear Nucleus.

Concurrent complex sounds (e.g., two voices speaking at once) are perceptually disentangled into separate "auditory objects". This neural processing often occurs in the presence of acoustic-signal distortions from noise and reverberation (e.g., in a busy restaurant). A difference in periodicity between sounds is a strong segregation cue under quiet, anechoic conditions. However, noise and reverberation exert differential effects on speech intelligibility under "cocktail-party" listening conditions. Previous neurophysiological studies have concentrated on understanding auditory scene analysis under ideal listening conditions. Here, we examine the effects of noise and reverberation on periodicity-based neural segregation of concurrent vowels /a/ and /i/, in the responses of single units in the guinea-pig ventral cochlear nucleus (VCN): the first processing station of the auditory brain stem. In line with human psychoacoustic data, we find reverberation significantly impairs segregation when vowels have an intonated pitch contour, but not when they are spoken on a monotone. In contrast, noise impairs segregation independent of intonation pattern. These results are informative for models of speech processing under ecologically valid listening conditions, where noise and reverberation abound.

Pharyngo-cutaneous fistula complicating laryngectomy in the chemo-radiotherapy organ-preservation epoch.

Pharyngo-cutaneous fistula is a serious complication of laryngectomy, with a significant associated morbidity and mortality. The oncologic success of organ-preservation protocols with radiotherapy or chemo-radiotherapy for laryngeal carcinoma means laryngectomy is increasingly reserved for surgical salvage in the event of persistent or recurrent disease. A retrospective review of fistula incidence after laryngectomy in 171 patients in a UK tertiary referral centre over the last decade was conducted to identify trends in this complication in the epoch of non-surgical organ preservation. The overall fistula incidence following laryngectomy is 29.2% (50/171). Fistula incidence following salvage total laryngectomy is significantly higher than after primary total laryngectomy [19/51 (37.3%) vs. 8/47 (17.0%), χ2 = 5.02, p = 0.03]. There is no significant effect of prior treatment on fistula incidence following laryngo-pharyngectomy or pharyngo-laryngo-oesophagectomy [14/39 (35.9%) vs. 9/27 (33.3%), χ2 = 0.05, p = 0.83]. Prophylactic vascularised tissue flaps to reinforce the pharyngeal suture line may reduce fistula incidence and fistula severity in salvage total laryngectomy.

Preventing pharyngo-cutaneous fistula in total laryngectomy: a systematic review and meta-analysis.

OBJECTIVES/HYPOTHESIS: Concurrent chemoradiotherapy is the gold-standard nonsurgical organ-preservation treatment for advanced laryngeal carcinoma. Total laryngectomy (TL) is increasingly reserved for surgical salvage. Salvage surgery is associated with more complications than primary surgery. A systematic review and meta-analysis was undertaken to establish the impact of organ preservation protocols on pharyngo-cutaneous fistula incidence following TL, and to synthesize evidence on the role of "onlay" prophylactic tissue flaps in reducing this complication in salvage TL. DATA SOURCES: The English language literature (January 1, 2000, to September 1, 2013) was searched, using PUBMED and EMBASE databases, for the terms "laryngectomy" and "fistula." Of 522 studies identified from database searches, 33 were included in the quantitative synthesis. REVIEW METHODS: Studies reporting fistula incidence following primary TL (PTL), salvage TL (STL), and STL with "onlay" flap-reinforced pharyngeal closure were included. Data were extracted by the first author (M.S.). Meta-analysis of fistula incidence was performed. RESULTS: PTL fistula incidence is 14.3% (95% CI 11.7-17.0), STL 27.6% (23.4-31.8), and STL with flap-reinforced closure 10.3% (4.6-15.9). Chemoradiotherapy is associated with a pooled fistula incidence of 34.1% (22.6-45.6), compared to 22.8% (18.3-27.4) for radiotherapy alone. Relative risk of fistula is 0.566 (0.374-0.856, P = 0.001) for STL with flap-reinforced closure compared to STL alone. The number needed to treat (NNT) to prevent one fistula is 6.05. CONCLUSION: Prophylactic flaps used in an "onlay" technique reduce fistula incidence in STL. Chemoradiotherapy increases fistula incidence more than radiotherapy alone. Prophylactic flaps should be offered in salvage cases after failed chemoradiation protocols.

Reverberation impairs brainstem temporal representations of voiced vowel sounds: challenging "periodicity-tagged" segregation of competing speech in rooms.

The auditory system typically processes information from concurrently active sound sources (e.g., two voices speaking at once), in the presence of multiple delayed, attenuated and distorted sound-wave reflections (reverberation). Brainstem circuits help segregate these complex acoustic mixtures into "auditory objects." Psychophysical studies demonstrate a strong interaction between reverberation and fundamental-frequency (F0) modulation, leading to impaired segregation of competing vowels when segregation is on the basis of F0 differences. Neurophysiological studies of complex-sound segregation have concentrated on sounds with steady F0s, in anechoic environments. However, F0 modulation and reverberation are quasi-ubiquitous. We examine the ability of 129 single units in the ventral cochlear nucleus (VCN) of the anesthetized guinea pig to segregate the concurrent synthetic vowel sounds /a/ and /i/, based on temporal discharge patterns under closed-field conditions. We address the effects of added real-room reverberation, F0 modulation, and the interaction of these two factors, on brainstem neural segregation of voiced speech sounds. A firing-rate representation of single-vowels' spectral envelopes is robust to the combination of F0 modulation and reverberation: local firing-rate maxima and minima across the tonotopic array code vowel-formant structure. However, single-vowel F0-related periodicity information in shuffled inter-spike interval distributions is significantly degraded in the combined presence of reverberation and F0 modulation. Hence, segregation of double-vowels' spectral energy into two streams (corresponding to the two vowels), on the basis of temporal discharge patterns, is impaired by reverberation; specifically when F0 is modulated. All unit types (primary-like, chopper, onset) are similarly affected. These results offer neurophysiological insights to perceptual organization of complex acoustic scenes under realistically challenging listening conditions.

Zenker's diverticulum complicating achalasia: a 'cup-and-spill' oesophagus.

A 72-year-old woman presented with long-standing gastro-oesophageal reflux, regurgitation of swallowed food and worsening cervical dysphagia. Fluoroscopic barium oesophagography revealed a posterolateral pharyngeal pouch (Zenker's diverticulum (ZD)) complicating a 'cup and spill' oesophageal deformity with a smoothly tapered segment at the gastro-oesophageal junction. CT and high-resolution manometry confirmed that the underlying abnormality was a massively dilated oesophagus with aperistalsis and pan-oesophageal pressurisation, consistent with a diagnosis of oesophageal achalasia (type II). She underwent endoscopic stapled diverticulotomy, with good symptomatic relief. We discuss the aetiology of ZD, its management and the association here with oesophageal achalasia.

Neurometric amplitude-modulation detection threshold in the guinea-pig ventral cochlear nucleus.

Amplitude modulation (AM) is a pervasive feature of natural sounds. Neural detection and processing of modulation cues is behaviourally important across species. Although most ecologically relevant sounds are not fully modulated, physiological studies have usually concentrated on fully modulated (100% modulation depth) signals. Psychoacoustic experiments mainly operate at low modulation depths, around detection threshold (∼5% AM). We presented sinusoidal amplitude-modulated tones, systematically varying modulation depth between zero and 100%, at a range of modulation frequencies, to anaesthetised guinea-pigs while recording spikes from neurons in the ventral cochlear nucleus (VCN). The cochlear nucleus is the site of the first synapse in the central auditory system. At this locus significant signal processing occurs with respect to representation of AM signals. Spike trains were analysed in terms of the vector strength of spike synchrony to the amplitude envelope. Neurons showed either low-pass or band-pass temporal modulation transfer functions, with the proportion of band-pass responses increasing with increasing sound level. The proportion of units showing a band-pass response varies with unit type: sustained chopper (CS) > transient chopper (CT) > primary-like (PL). Spike synchrony increased with increasing modulation depth. At the lowest modulation depth (6%), significant spike synchrony was only observed near to the unit's best modulation frequency for all unit types tested. Modulation tuning therefore became sharper with decreasing modulation depth. AM detection threshold was calculated for each individual unit as a function of modulation frequency. Chopper units have significantly better AM detection thresholds than do primary-like units. AM detection threshold is significantly worse at 40 dB vs. 10 dB above pure-tone spike rate threshold. Mean modulation detection thresholds for sounds 10 dB above pure-tone spike rate threshold at best modulation frequency are (95% CI) 11.6% (10.0-13.1) for PL units, 9.8% (8.2-11.5) for CT units, and 10.8% (8.4-13.2) for CS units. The most sensitive guinea-pig VCN single unit AM detection thresholds are similar to human psychophysical performance (∼3% AM), while the mean neurometric thresholds approach whole animal behavioural performance (∼10% AM).

Equivalent-rectangular bandwidth of single units in the anaesthetized guinea-pig ventral cochlear nucleus.

Frequency-tuning is a fundamental property of auditory neurons. The filter bandwidth of peripheral auditory neurons determines the frequency resolution of an animal's auditory system. Behavioural studies in animals and humans have defined frequency-tuning in terms of the "equivalent-rectangular bandwidth" (ERB) of peripheral filters. In contrast, most physiological studies report the Q [best frequency/bandwidth] of frequency-tuning curves. This study aims to accurately describe the ERB of primary-like and chopper units in the ventral cochlear nucleus, the first brainstem processing station of the central auditory system. Recordings were made from 1020 isolated single units in the ventral cochlear nucleus of anesthetized guinea pigs in response to pure-tone stimuli which varied in frequency and in sound level. Frequency-threshold tuning curves were constructed for each unit and estimates of the ERB determined using methods previously described for auditory-nerve-fibre data in the same species. Primary-like, primary-notch, and sustained- and transient-chopper units showed frequency selectivity almost identical to that recorded in the auditory nerve. Their tuning at pure-tone threshold can be described as a function of best frequency (BF) by ERB = 0.31 * BF(0.5).

Appendiceal mucinous adenocarcinoma presenting as an enterocutaneous fistula in an incisional hernia.

A 68-year-old woman with a history of bone-graft harvesting from the right iliac crest presented with an incisional hernia and abscess at the graft donor site. Following incision and drainage of the abscess, CT demonstrated an enterocutaneous fistula between the appendix and bone-graft incision with appendicitis assumed to be the original cause of the abscess. At laparoscopy, the appendix was adherent to the hernia sac with mucinous material at the superficial orifice of the fistula site but not in the peritoneal cavity. Laparoscopic appendicectomy with fistula track excision was performed. Histological evaluation confirmed a well-to-moderately differentiated mucinous adenocarcinoma arising on a background of dysplastic villous adenoma. Tumour extended along the fistula track to involve the surface skin. A laparoscopic right hemicolectomy, lymph node dissection and wide local excision of the fistula track were carried out at a second procedure. Final histology confirmed pT4N1 tumour with clear resection margins.

Ambiguous pitch and the temporal representation of inharmonic iterated rippled noise in the ventral cochlear nucleus.

Neural coding of the pitch of complex sounds is vital for animals' ability to communicate and to perceptually organize natural acoustic scenes. Harmonic complex sounds typically have a well defined pitch corresponding to their fundamental frequency, whereas inharmonic sounds can exhibit pitch ambiguity: their pitch can have more than one value. Iterated rippled noise (IRN), a common "pitch stimulus," is generated from broadband noise by a cascade of delay-and-add steps, with the delayed noise phase-shifted by varphi degrees. By varying varphi, the (in)harmonicity, and therefore the pitch ambiguity, of IRN can be manipulated. Recordings were made from single-units in the ventral cochlear nucleus of anesthetized guinea pigs in response to IRN and complex tones, systematically varying the inharmonicity. In their all-order interspike interval distributions, primary-like and chopper units tuned within the phase-locking range of best frequencies represent the waveform temporal fine structure (which varies with varphi). In contrast, those units tuned to higher frequencies represent the temporal-envelope modulation (independent of varphi). We show a temporal representation of ambiguous pitch for IRN and complex tones based on responses to the stimulus fine structure. Within the dominance region for pitch this representation follows the predictions of classic human behavioral experiments and provides a unifying contribution to possible neuro-temporal explanations for the pitch shift and pitch ambiguity associated with many inharmonic sounds.

Perceptual organization of sound begins in the auditory periphery.

Segmenting the complex acoustic mixture that makes a typical auditory scene into relevant perceptual objects is one of the main challenges of the auditory system [1], for both human and nonhuman species. Several recent studies indicate that perceptual auditory object formation, or "streaming," may be based on neural activity within the auditory cortex and beyond [2, 3]. Here, we find that scene analysis starts much earlier in the auditory pathways. Single units were recorded from a peripheral structure of the mammalian auditory brainstem, the cochlear nucleus. Peripheral responses were similar to cortical responses and displayed all of the functional properties required for streaming, including multisecond adaptation. Behavioral streaming was also measured in human listeners. Neurometric functions derived from the peripheral responses predicted accurately behavioral streaming. This reveals that subcortical structures may already contribute to the analysis of auditory scenes. This finding is consistent with the observation that species lacking a neocortex can still achieve and benefit from behavioral streaming [4]. For humans, we argue that auditory scene analysis of complex scenes is probably based on interactions between subcortical and cortical neural processes, with the relative contribution of each stage depending on the nature of the acoustic cues forming the streams.

Reverberation challenges the temporal representation of the pitch of complex sounds.

Accurate neural coding of the pitch of complex sounds is an essential part of auditory scene analysis; differences in pitch help segregate concurrent sounds, while similarities in pitch can help group sounds from a common source. In quiet, nonreverberant backgrounds, pitch can be derived from timing information in broadband high-frequency auditory channels and/or from frequency and timing information carried in narrowband low-frequency auditory channels. Recording from single neurons in the cochlear nucleus of anesthetized guinea pigs, we show that the neural representation of pitch based on timing information is severely degraded in the presence of reverberation. This degradation increases with both increasing reverberation strength and channel bandwidth. In a parallel human psychophysical pitch-discrimination task, reverberation impaired the ability to distinguish a high-pass harmonic sound from noise. Together, these findings explain the origin of perceptual difficulties experienced by both normal-hearing and hearing-impaired listeners in reverberant spaces.

The temporal representation of the delay of dynamic iterated rippled noise with positive and negative gain by single units in the ventral cochlear nucleus.

Spike trains were recorded from single units in the ventral cochlear nucleus of the anaesthetised guinea-pig in response to dynamic iterated rippled noise with positive and negative gain. The short-term running waveform autocorrelation functions of these stimuli show peaks at integer multiples of the time-varying delay when the gain is +1, and troughs at odd-integer multiples and peaks at even-integer multiples of the time-varying delay when the gain is -1. In contrast, the short-term autocorrelation of the Hilbert envelope shows peaks at integer multiples of the time-varying delay for both positive and negative gain stimuli. A running short-term all-order interspike interval analysis demonstrates the ability of single units to represent the modulated pitch contour in their short-term interval statistics. For units with low best frequency (approximate < or = 1.1 kHz) the temporal discharge pattern reflected the waveform fine structure regardless of unit classification (Primary-like, Chopper). For higher best frequency units the pattern of response varied according to unit type. Chopper units with best frequency approximate > or = 1.1 kHz responded to envelope modulation; showing no difference between their response to stimuli with positive and negative gain. Primary-like units with best frequencies in the range 1-3 kHz were still able to represent the difference in the temporal fine structure between dynamic rippled noise with positive and negative gain. No unit with a best frequency above 3 kHz showed a response to the temporal fine structure. Chopper units in this high frequency group showed significantly greater representation of envelope modulation relative to primary-like units with the same range of best frequencies. These results show that at the level of the cochlear nucleus there exists sufficient information in the time domain to represent the time-varying pitch associated with dynamic iterated rippled noise.

The time course of recovery from suppression and facilitation from single units in the mammalian cochlear nucleus.

The responses to two identical, consecutive pure tone stimuli with varying inter-stimulus intervals (delta ts) were measured for 89 neurons in the cochlear nucleus of the anaesthetised guinea pig. We observed two main effects; either a decrease (suppression) or an increase (facilitation) in response to the second tone followed by an exponential recovery. Response behaviour correlated with the unit type; primary-like, primary-like with notch and transient-chopper units showed a recovery from suppression that was very similar to that already reported in the auditory nerve. For chopper units the strength of the adaptation was correlated with the units regularity of spike discharge; sustained chopper (CS) units showed less suppression than transient choppers. Onset units showed complete suppression at short delta ts. Pause/Build (PB) units responded with increased activity to the second tone. In contrast to previous studies in the cochlear nucleus the recovery from suppression or facilitation was well described by a single exponential function, enabling us to define a recovery time constant and a maximum suppression/facilitation. There appeared to be a hierarchy in the time constant of recovery with PB and CS units showing the longest recovery times and onset units showing the shortest.

The cellular repair of the brain in Parkinson's disease--past, present and future.

Damage to the central nervous system was once considered irreparable. However, there is now growing optimism that neural transplant therapies may one day enable complete circuit reconstruction and thus functional benefit for patients with neurodegenerative conditions such as Parkinson's disease (PD), and perhaps even those with more widespread damage such as stroke patients. Indeed, since the late 1980s hundreds of patients with Parkinson's disease have received allografts of dopamine-rich embryonic human neural tissue. The grafted tissue has been shown to survive and ameliorate many of the symptoms of the disease, both in the clinical setting and in animal models of the disease. However, practical problems associated with tissue procurement and storage, and ethical concerns over using aborted human fetal tissue have fuelled a search for alternative sources of suitable material for grafting. In particular, stem cells and xenogeneic embryonic dopamine-rich neural tissue are being explored, both of which bring their own practical and ethical dilemmas. Here we review the progress made in neural transplantation, both in the laboratory and in the clinic with particular attention to the development of stem cell and xenogeneic tissue based therapy.