The hunt for hidden hearing loss in humans: From preclinical studies to effective interventions

Many individuals experience hearing problems that are hidden under a normal audiogram. This not only impacts on individual sufferers, but also on clinicians who can offer little in the way of support. Animal studies using invasive methodologies have developed solid evidence for a range of pathologies underlying this hidden hearing loss (HHL), including cochlear synaptopathy, auditory nerve demyelination, elevated central gain, and neural mal-adaptation. Despite progress in pre-clinical models, evidence supporting the existence of HHL in humans remains inconclusive, and clinicians lack any non-invasive biomarkers sensitive to HHL, as well as a standardized protocol to manage hearing problems in the absence of elevated hearing thresholds. Here, we review animal models of HHL as well as the ongoing research for tools with which to diagnose and manage hearing difficulties associated with HHL. We also discuss new research opportunities facilitated by recent methodological tools that may overcome a series of barriers that have hampered meaningful progress in diagnosing and treating of HHL.Australian GovernmentDepartment of Health & AgeingMinistry of Science and Innovation, Spain (MICINN) Spanish GovernmentAndalucia European Regional Development Fund PID2020-119073GB-I00 B-TIC-382-UGR2

The minimum monitoring signal-to-noise ratio for off-axis signals and its implications for directional hearing aids

The signal-to-noise ratio (SNR) benefit of hearing aid directional microphones is dependent on the angle of the listener relative to the target, something that can change drastically and dynamically in a typical group conversation. When a new target signal is significantly off-axis, directional microphones lead to slower target orientation, more complex movements, and more reversals. This raises the question of whether there is an optimal design for directional microphones. In principle an ideal microphone would provide the user with sufficient directionality to help with speech understanding, but not attenuate off-axis signals so strongly that orienting to new signals was difficult or impossible. We investigated the latter part of this question. In order to measure the minimal monitoring SNR for reliable orientation to off-axis signals, we measured head-orienting behaviour towards targets of varying SNRs and locations for listeners with mild to moderate bilateral symmetrical hearing loss. Listeners were required to turn and face a female talker in background noise and movements were tracked using a head-mounted crown and infrared system that recorded yaw in a ring of loudspeakers. The target appeared randomly at ± 45, 90 or 135° from the start point. The results showed that as the target SNR decreased from 0 dB to −18 dB, first movement duration and initial misorientation count increased, then fixation error, and finally reversals increased. Increasing the target angle increased movement duration at all SNRs, decreased reversals (above −12 dB target SNR), and had little to no effect on initial misorientations. These results suggest that listeners experience some difficulty orienting towards sources as the target SNR drops below −6 dB, and that if one intends to make a directional microphone that is usable in a moving conversation, then off-axis attenuation should be no more than 12 dB

Perceptual and physiological measures of auditory selective attention in normal-hearing and hearing-impaired listeners

Human listeners can direct top-down spatial auditory attention to listen selectively to one sound source amidst competing sounds. However, many listeners with hearing loss (HL) have trouble on tasks requiring selective auditory attention; even listeners with normal hearing thresholds (NHTs) differ in this ability. Selective attention depends on both top-down executive control and coding fidelity of the peripheral auditory system. Here we explore how low-level sensory perception and high-level attentional modulation interact to contribute to auditory selective attention for listeners with NHTs and HL. In the first study, we designed a paradigm to allow simultaneous measurement of envelope following responses (EFRs), onset event-related potentials (ERPs), and behavioral performance. We varied conditions to alter the degree to which the bottleneck limiting behavior was due to the coding of fine stimulus details vs. top-down control of attentional focus. We found attention modulated ERPs, from cortex, but not EFRs from the brainstem. Importantly, when coding fidelity limited the task, EFRs but not ERPs correlated with behavior; conversely, when sensory cues for segregation were robust, individual behavior correlated with both EFR strength and strength of attentional modulation of cortical responses. In the second study, we explored how HL affects control of auditory selective attention. Listeners with NHTs or with HL identified a simple melody presented simultaneously with two competing melodies, each from different spatial locations. Compared to NHT listeners, HL listeners both performed more poorly and showed less robust attentional modulation of cortical ERPs. While both groups showed some cortical suppression of distracting streams, this modulation was weaker in HL listeners, especially when spatial separation between attended and distracting streams was small. In the final study, we compared temporal coding precision in listeners with NHT and HL using both behavioral and physiological measures. We found that listeners with HL are more sensitive than listeners with NHT to amplitude modulation in both measures. Within the NHT listener group, we found a strong correlation between behavioral and electrophysiological measurements, consistent with cochlear synaptopathy. Overall, these studies demonstrate that everyday communication abilities depend jointly on both low-level differences in sensory coding and high-level ability to control attention

2019 Graduate Medical Education Research Day Compendium

Anyone engaged in research knows that the process can be daunting. Add the rigors of training in a graduate medical education program to this, and it might seem all but impossible to accomplish anything meaningful. However, the individuals highlighted in our 2019 Graduate Medical Education Research Day Compendium were able to overcome those odds. Their abstracts are showcased here and their efforts to advance the collective knowledge in their respective fields are commendable. We thank these Resident and Fellow Physicians and all who have supported them in their endeavors to reach this point with their research. Most of all, we encourage their great work to continue in the spirit of intellectual curiosity that will lead everyone into a better tomorrow

Tinnitus

Tinnitus is a prevalent experience and, for those who are troubled by it, it can be debilitating. Risk factors include hearing loss, ototoxic medication, head injury and depression, and at presentation the possibility of otologic disease and of anxiety/depression should be considered. Effective drug treatments have proven elusive, though this is a vibrant theme in tinnitus research. Surgical intervention for any otological pathology associated with tinnitus may be effective for that condition, but the tinnitus may persist. Presently available treatments include the provision of hearing aids when a hearing loss is identified (even when mild or unilateral), wide band sound therapy and counselling. In some patients, cognitive behavioural therapy (CBT) is indicated though availability of tinnitus specific CBT is limited in the UK. Of these treatments the evidence base is strongest for a combination of sound therapy and CBT based counselling, though clinical trials are constrained by the heterogeneity of the tinnitus patient population. Research into mechanisms of tinnitus and effective treatments now abounds, and progress is keenly anticipated

Cochlear neuropathy and the coding of supra-threshold sound

Many listeners with hearing thresholds within the clinically normal range nonetheless complain of difficulty hearing in everyday settings and understanding speech in noise. Converging evidence from human and animal studies points to one potential source of such difficulties: differences in the fidelity with which supra-threshold sound is encoded in the early portions of the auditory pathway. Measures of auditory subcortical steady-state responses (SSSRs) in humans and animals support the idea that the temporal precision of the early auditory representation can be poor even when hearing thresholds are normal. In humans with normal hearing thresholds (NHTs), paradigms that require listeners to make use of the detailed spectro-temporal structure of supra-threshold sound, such as selective attention and discrimination of frequency modulation (FM), reveal individual differences that correlate with subcortical temporal coding precision. Animal studies show that noise exposure and aging can cause a loss of a large percentage of auditory nerve fibers (ANFs) without any significant change in measured audiograms. Here, we argue that cochlear neuropathy may reduce encoding precision of supra-threshold sound, and that this manifests both behaviorally and in SSSRs in humans. Furthermore, recent studies suggest that noise-induced neuropathy may be selective for higher-threshold, lower-spontaneous-rate nerve fibers. Based on our hypothesis, we suggest some approaches that may yield particularly sensitive, objective measures of supra-threshold coding deficits that arise due to neuropathy. Finally, we comment on the potential clinical significance of these ideas and identify areas for future investigation

Hearing in dementia: defining deficits and assessing impact

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain and are therefore predicted to damage hearing function early and profoundly. Here I present evidence for this proposition, based on structural and functional features of auditory brain organisation that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between ‘peripheral’ and ‘central’ hearing dysfunction, and recently characterised auditory signatures of canonical neurodegenerative dementias (Alzheimer’s disease and frontotemporal dementia). In chapter 3, I examine pure tone audiometric thresholds in AD and FTD syndromes and explore the functional interplay between the auditory brain and auditory periphery by assessing the contribution of auditory cognitive factors on pure tone detection. In chapter 4, I develop this further by examining the processing of degraded speech signals, leveraging the increased importance of top-down integrative and predictive mechanisms on resolving impoverished bottom-up sensory encoding. In chapter 5, I use a more discrete test of phonological processing to focus in on a specific brain region that is an early target in logopenic aphasia, to explore the potential of auditory cognitive tests as disease specific functional biomarkers. Finally, in chapter 6, I use auditory symptom questionnaires to capture real-world hearing in daily life amongst patients with dementia as well as their carers and measure how this correlates with audiometric performance and degraded speech processing. I call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory ‘cognitive stress tests’ and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity

EVALUATION OF AUDITORY CORTICAL PLASTICITY FROM FIRST AMPLIFICATION TO ONE YEAR OF HEARING AID USE: THE RELATIONSHIP BETWEEN AIDED CORTICAL AUDITORY EVOKED POTENTIALS (ACAEPs) AND SPEECH PERCEPTION OUTCOMES AMONG HEARING-IMPAIRED ADULT PATIENTS

Over the last decade, aided cortical auditory evoked potentials (ACAEPs) have continued to be a focus of interest due to the lack of adequate tools to objectively assess cortical auditory activity in response to amplified stimuli. The majority of authors have investigated the direct relationship between behavioral thresholds and ACAEPs and the evolution of ACAEP waves among children with sensorineural hearing loss (SNHL) undergoing rehabilitation. In contrast, scarce data are available regarding changes in ACAEPs over time in adult hearing aid users, particularly in relation to speech perception outcomes. The main goal of this project was to investigate the relationship between ACAEPs and speech perception capability over time in post-lingual SNHL adult patients who were first-time hearing aid users. We hypothesized that, in patients with better speech understanding, a modification of the P1-N1-P2 complex could be expected as a result of neuroplastic changes due to hearing aid amplification. A longitudinal prospective clinical study was conducted on 72 new hearing aid users suffering from symmetrical, sloping SNHL. Patients were assessed at three different time points: baseline (T0), 6 months after the initial assessment (T6), and 12 months after the initial assessment (T12). All the participants went through the same evaluation protocol, which included pure-tone audiometry, speech audiometry tests, ACAEPs recorded with two different stimuli (1000 Hz and 2000 Hz) and questionnaires assessing hearing aid benefit. Analysis of amplitude values at the three different time points demonstrated an increasing tendency for all waves in both experimental conditions (p<0.01). Latencies seemed to become shorter from T0 to T12 for each wave and in the case of 1 kHz and 2 kHz stimuli. (p<0.05). Linear regression analysis found that only P2 amplitude showed a statistically significant increase in its variation while matrix sentence test (MST) and speech intellection threshold (SIT) decreased in both experimental conditions, even when the analysis was adjusted for age and daily hearing aid use (p<0.05). The data collected in this study provide new evidence regarding the relationship between ACAEPs and the speech recognition capability of adults who are new hearing aid users. In both experimental conditions, we observed larger P2 amplitude in patients with better speech perception outcomes. It should be underlined that, even though P2 may reflect auditory processing beyond sensation, its increase could be an expression of neural activity associated with the acquisition process driven by exposure to sounds and speech. The observation that P2 amplitude tended to improve as SIT and MST scores decreased might be, in the future, a further object of investigation to assess its reliability as a marker of speech perception improvement; it may assist hearing aid dispensers and audiologists as a source of feedback in the evaluation of listening benefits in hard-to-test patients

Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current trends in Diagnosis and Management with a focus on Novel Medical Therapies

Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are distinct single gene disorders, which share a predisposition to formation of benign nervous system tumours due to loss of tumour suppressor function. Since identification of the genes encoding NF1 and NF2 in the early 1990s, significant progress has been made in understanding the biological processes and molecular pathways underlying tumour formation. As a result, identifying safe and effective medical approaches to treating NF1 and NF2-associated tumours has become a focus of clinical research and patient care in recent years. This thesis presents a comprehensive discussion of the complications of NF1 and NF2 and approaches to treatment, with a focus on key tumours in each condition. The significant functional impact of these disorders in children and young adults is illustrated, demonstrating the need for coordinated care from experienced multidisciplinary teams. Response of the first Australian patients offered novel medications under careful prospective monitoring for safety and efficacy, is described. The approach to treatment trials including principles of patient selection, rationale for candidate medication choices, and identification of appropriate outcome measures are outlined. Treatment response is assessed utilizing multiple criteria including radiologic response, functional status and patient reported outcomes. Tumours considered include plexiform neurofibromas in NF1, treated with the protein tyrosine kinase inhibitor imatinib, with limited benefit. In NF2, vestibular schwannomas were treated using the vascular endothelial growth factor inhibitor bevacizumab, showing definite benefit in a proportion of patients. Refinements in the clinical approach to NF-associated tumours are discussed, considering results from this early experience. Optimizing tumour surveillance prior to intervention, identifying the most potent yet tolerable agents for use, determining when medical therapy should be utilized in concert with surgical and other approaches, and establishing ways of stratifying individual risk of disease complications and likelihood of treatment benefit, remain important questions for the future