Trajectories of Hearing From Childhood to Adulthood.

OBJECTIVES: The Dunedin Multidisciplinary Health and Development Study provides a unique opportunity to document the progression of ear health and hearing ability within the same cohort of individuals from birth. This investigation draws on hearing data from 5 to 13 years and again at 45 years of age, to explore the associations between childhood hearing variables and hearing and listening ability at age 45. DESIGN: Multiple linear regression analyses were used to assess associations between childhood hearing (otological status and mid-frequency pure-tone average) and (a) age 45 peripheral hearing ability (mid-frequency pure-tone average and high-frequency pure-tone average), and (b) age 45 listening ability (listening in spatialized noise and subjective questionnaire on listening experiences). Sex, childhood socioeconomic status, and adult IQ were included in the model as covariates. RESULTS: Peripheral hearing and listening abilities at age 45 were consistently associated with childhood hearing acuity at mid-frequencies. Otological status was a moderate predicting factor for high-frequency hearing and utilization of spatial listening cues in adulthood. CONCLUSIONS: We aim to use these findings to develop a foundational model of hearing trajectories. This will form the basis for identifying precursors, to be investigated in a subsequent series of analyses, that may protect against or exacerbate hearing-associated cognitive decline in the Dunedin Study cohort as they progress from mid-life to older age.

Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

The developmental journey of therapies targeting purine receptors: from basic science to clinical trials.

Since the discovery of ATP as an extracellular signalling molecule in 1972, purinergic signalling, mediated by extracellular purines and pyrimidines has been identified in virtually all mammalian tissues and is implicated in regulating fundamental cellular processes. In recent years, there has been an increasing focus on the pathophysiology and potential therapeutic interventions based on purinergic signalling. A vast range of compounds targeting purine receptors are in clinical development, and many more are in preclinical studies, which highlights the fast growth in this research field. As a tribute to Professor Geoffrey Burnstock's legacy in purinergic signalling, we present here a brief review of compounds targeting purine receptors that are in different stages of clinical trials. The review highlights the 50-year journey from basic research on purinergic receptors to clinical applications of therapies targeting purine receptors.

Diagnostic and management plan concordance across advanced audiologists, paediatric audiologists and non-specialist ENT doctors.

OBJECTIVE: To compare the concordance of advanced audiologists (AA), junior doctors (JD) and paediatric audiologists (PA) with an Ear, Nose and Throat (ENT) specialist on the diagnosis and management of children with middle ear or hearing concerns. DESIGN: A clinical equivalence (concordance) study. STUDY SAMPLE: Three AAs, five JDs, three PAs and one ENT specialist asynchronously reported diagnoses and management plans for ten, online paediatric cases consisting of video-otoscopic images and clinical findings. RESULTS: For medical diagnosis, significant agreement with the ENT specialist was observed at moderate and near-perfect levels for two AAs (k = 0.561 and 0.815), moderate levels for four JDs (k = 0.5 to 0.603) and near-perfect level for one PA (k = 0.815). For management decisions, significant agreement with the ENT specialist was observed at substantial (k = 0.636) and near-perfect (k = 0.818) levels for two AAs, and at a moderate level (k = 0.538) for one PA. Within group inter-rater agreement for management plans was substantial for AAs and JDs, and moderate for PAs. CONCLUSIONS: For children with middle ear disease or hearing concerns, AAs, JDs and PAs showed similar levels of agreement with an ENT specialist on diagnosis, but AAs were more likely than JDs or PAs to agree with an ENT specialist on management.

Parental satisfaction with an advanced audiology-led triage service in paediatric ENT outpatient clinics.

OBJECTIVE: The advanced audiology-led service is designed to triage and manage children who are referred to Ear Nose and Throat (ENT) outpatient services with middle ear or hearing concerns. This service has resulted in shorter waiting times for children to receive ENT treatment, and improved ENT capacity. The aim of this study was to explore parental satisfaction with the advanced audiology-led ENT service and to determine if there were cultural or process factors affecting satisfaction. DESIGN: Prospective cross-sectional study using a modified Visit-Specific Satisfaction Questionnaire (VSQ-9) survey. STUDY SAMPLE: One hundred and thirteen parents of children consecutively attending a first appointment in the advanced audiology-led service recruited between October 2016 and October 2017. RESULTS: There were a total of 100 valid responses (rate of 88.5%). The survey showed high levels of satisfaction. Satisfaction scores were significantly higher for items related to interactions with the audiologist compared to items related to waiting times. There were no differences in satisfaction across cultural groups. Parents were equally satisfied with the service whether their child was managed independently by the audiologist or required another appointment for medical input. CONCLUSIONS: The advanced audiology-led service had high levels of satisfaction from parents attending with their children.

Purinergic Signalling in the Cochlea.

The mammalian cochlea is the sensory organ of hearing with a delicate, highly organised structure that supports unique operating mechanisms. ATP release from the secretory tissues of the cochlear lateral wall (stria vascularis) triggers numerous physiological responses by activating P2 receptors in sensory, supporting and neural tissues. Two families of P2 receptors, ATP-gated ion channels (P2X receptors) and G protein-coupled P2Y receptors, activate intracellular signalling pathways that regulate cochlear development, homeostasis, sensory transduction, auditory neurotransmission and response to stress. Of particular interest is a purinergic hearing adaptation, which reflects the critical role of the P2X2 receptor in adaptive cochlear response to elevated sound levels. Other P2 receptors are involved in the maturation of neural processes and frequency selectivity refinement in the developing cochlea. Extracellular ATP signalling is regulated by a family of surface-located enzymes collectively known as "ectonucleotidases" that hydrolyse ATP to adenosine. Adenosine is a constitutive cell metabolite with an established role in tissue protection and regeneration. The differential activation of A1 and A2A adenosine receptors defines the cochlear response to injury caused by oxidative stress, inflammation, and activation of apoptotic pathways. A1 receptor agonism, A2A receptor antagonism, and increasing adenosine levels in cochlear fluids all represent promising therapeutic tools for cochlear rescue from injury and prevention of hearing loss.

A High-Fat Diet Induces Low-Grade Cochlear Inflammation in CD-1 Mice.

There is growing evidence for a relationship between gut dysbiosis and hearing loss. Inflammatory bowel disease, diet-induced obesity (DIO), and type 2 diabetes have all been linked to hearing loss. Here, we investigated the effect of a chronic high-fat diet (HFD) on the development of inner ear inflammation using a rodent model. Three-week-old CD-1 (Swiss) mice were fed an HFD or a control diet for ten weeks. After ten weeks, mouse cochleae were harvested, and markers of cochlear inflammation were assessed at the protein level using immunohistochemistry and at the gene expression level using quantitative real-time RT-PCR. We identified increased immunoexpression of pro-inflammatory biomarkers in animals on an HFD, including intracellular adhesion molecule 1 (ICAM1), interleukin 6 receptor α (IL6Rα), and toll-like-receptor 2 (TLR2). In addition, increased numbers of ionized calcium-binding adapter molecule 1 (Iba1) positive macrophages were found in the cochlear lateral wall in mice on an HFD. In contrast, gene expression levels of inflammatory markers were not affected by an HFD. The recruitment of macrophages to the cochlea and increased immunoexpression of inflammatory markers in mice fed an HFD provide direct evidence for the association between HFD and cochlear inflammation.

Can an advanced audiology-led service reduce waiting times for paediatric ear nose and throat outpatient services?

AIM: Children with middle ear disease often experience lengthy delays waiting for outpatient paediatric ear nose and throat (ENT) services. This study aimed to investigate whether an alternative service delivery model using audiologists working in an expanded scope of practice reduced waiting times for children to access such services. METHODS: A total of 131 children consecutively referred to a large ENT outpatient service in Queensland, Australia, for middle ear and hearing concerns were prospectively allocated to either a standard ENT service or an advanced audiology (AA)-led service. Waiting times and attendance rates were collected and compared between the two patient groups. RESULTS: The median waiting time from referral to first offered appointment was 96 days for children in the AA-led service versus 417.5 days for children in the standard ENT service. Seventy-nine percent of children in the AA-led service attended their first offered appointment versus 61% in the standard ENT service. For children receiving grommets, the median waiting time from initial referral to grommet insertion was 226 days for children in the AA-led service versus 627 days for children in the standard ENT service. CONCLUSION: The AA-led service was an effective alternative pathway to reduce waiting times for children referred to ENT services with middle ear and hearing concerns.

Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics.

The sense of hearing enables us to enjoy sounds and music and engage with other people [...].

The Link between Gut Dysbiosis Caused by a High-Fat Diet and Hearing Loss.

This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood-labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.

Istradefylline Mitigates Age-Related Hearing Loss in C57BL/6J Mice.

Age-related hearing loss (ARHL) is the most common sensory disorder among older people, and yet, the treatment options are limited to medical devices such as hearing aids and cochlear implants. The high prevalence of ARHL mandates the development of treatment strategies that can prevent or rescue age-related cochlear degeneration. In this study, we investigated a novel pharmacological strategy based on inhibition of the adenosine A2A receptor (A2AR) in middle aged C57BL/6 mice prone to early onset ARHL. C57BL/6J mice were treated with weekly istradefylline (A2AR antagonist; 1 mg/kg) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4-32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies) were evaluated at 6, 9, and 12 months of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells. Cognitive function was assessed using the Morris water maze and the novel object recognition test, and the zero maze test was used to assess anxiety-like behaviour. Weekly injections of istradefylline attenuated ABR threshold shifts by approximately 20 dB at mid to high frequencies (16-32 kHz) but did not improve ABR suprathreshold responses. Istradefylline treatment improved hair cell survival in a turn-dependent manner, whilst the cognitive function was unaffected by istradefylline treatment. This study presents the first evidence for the rescue potential of istradefylline in ARHL and highlights the role of A2AR in development of age-related cochlear degeneration.

The inaugural World Report on Hearing: From barriers to a platform for change.

The inaugural World Report on Hearing was recently published by the World Health Organisation, and outlines the burden of hearing loss, and strategies to overcome this through preventative and public health approaches. Here, we identify barriers to wide-scale adoption, including historic low prioritisation of hearing loss against other public health needs, a lack of a health workforce with relevant training, poor access to assistive technology, and individual and community-level stigma and misunderstanding. Overcoming these barriers will require multi-sector stakeholder collaboration, involving ear and hearing care professionals, patients, communities, industry and policymakers.

Effectiveness and Safety of Advanced Audiology-Led Triage in Pediatric Otolaryngology Services.

OBJECTIVES: Expansion of the scopes of practice of allied health practitioners has the potential to improve the efficiency and cost-effectiveness of healthcare, given the identified shortages in medical personnel. Despite numerous examples in other allied health disciplines, this has yet to be applied to pediatric Audiology. This study aimed to investigate the effectiveness and safety of using audiologists with advanced training to independently triage children referred to otolaryngology (ORL) services, and compare the subsequent use of specialist resources, and postoperative grommet care to a standard medical ORL service. DESIGN: One hundred twenty children consecutively referred to a large ORL outpatient service in Queensland, Australia, for middle ear and hearing concerns were prospectively allocated to either the ORL service or Advanced Audiology-led service. Demographic and clinical data were extracted from electronic medical records and compared between the two services. Clinical incidents and adverse events were recorded for the Advanced Audiology-led service. RESULTS: Approximately half of all children referred to ORL for middle ear or hearing concerns were discharged without requiring any treatment, with the remaining half offered surgical treatment. The Advanced Audiology-led model increased the proportion of children assessed by ORL that proceeded to surgery from 57% to 82% compared with the standard medical ORL model. Children followed up by the audiologists after grommet insertion were more likely to be discharged independently and at the first postoperative review appointment compared with the standard medical ORL service. There were no reports of adverse events or long-term bilateral hearing loss after discharge by the Advanced Audiology-led service. CONCLUSIONS: These findings indicate that an Advanced Audiology-led service provides a safe and effective triaging model for the independent management of children not requiring treatment, and children requiring routine postoperative grommet review, and improves the effective use of specialist resource compared with the standard medical ORL service.

Regulator of G Protein Signalling 4 (RGS4) as a Novel Target for the Treatment of Sensorineural Hearing Loss.

We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the "post-exposure" treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6-8 weeks) were exposed to traumatic noise (110 dBSPL, 8-16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.

Resistance to neomycin ototoxicity in the extreme basal (hook) region of the mouse cochlea.

Aminoglycoside ototoxicity results in permanent loss of the sensory hair cells in the mammalian cochlea. It usually begins at the basal turn causing high-frequency hearing loss. Here we describe previously unreported resistance of hair cells to neomycin ototoxicity in the extreme basal (hook) region of the developing cochlea of the C57BL/6 mouse. Organ of Corti explants from mice at postnatal day 3 were incubated (37 °C, 5% CO2) in normal culture medium for 19.5 h prior to and after exposure to neomycin (1 mM, 3 h). To study neomycin uptake in the hair cells, cochlear explants were incubated with Neomycin Texas-red (NTR) conjugate. As expected, exposure to neomycin significantly reduced the survival of inner (IHC) and outer hair cells (OHC). IHC survival rate was high in the apical segment and low in the basal segment. OHC were well preserved in the apical and hook regions, with substantial OHC loss in the basal segment. The NTR uptake study demonstrated that the high survival rate in the extreme basal turn OHC was associated with low NTR uptake. Treatment with a calcium chelator (BAPTA), which disrupts the opening of mechanoelectrical (MET) transduction channels, abolished or reduced NTR uptake in the hair cells throughout the cochlea. This confirmed the essential role of MET channels in neomycin uptake and implied that the transduction channels could be impaired in the hook region of the developing mouse cochlea, possibly as a result of the cadherin 23 mutation responsible for the progressive deafness in C57BL/6 mice.

Characterisation of cochlear inflammation in mice following acute and chronic noise exposure.

Oxidative stress has been established as the key mechanism of the cochlear damage underlying noise-induced hearing loss, however, emerging evidence suggests that cochlear inflammation may also be a major contributor. This study aimed to improve our understanding of the cochlear inflammatory response associated with acute and chronic noise exposure. C57BL/6 mice were exposed to acute traumatic noise (100 dBSPL, 8-16 kHz for 24 h) and their cochleae collected at various intervals thereafter, up to 7 days. Using quantitative RT-PCR and immunohistochemistry, changes in expression levels of proinflammatory cytokines (TNF-α, IL-1ß), chemokines (CCL2) and cell adhesion molecules (ICAM-1) were studied. All gene transcripts displayed similar dynamics of expression, with an early upregulation at 6 h post-exposure, followed by a second peak at 7 days. ICAM-1 immunoexpression increased significantly in the inferior region of the spiral ligament, peaking 24 h post-exposure. The early expression of proinflammatory mediators likely mediates the recruitment and extravasation of inflammatory cells into the noise-exposed cochlea. The occurrence of the latter expression peak is not clear, but it may be associated with reparative processes initiated in response to cochlear damage. Chronic exposure to moderate noise (90 dBSPL, 8-16 kHz, 2 h/day, up to 4 weeks) also elicited an inflammatory response, reaching a maximum after 2 weeks, suggesting that cochlear damage and hearing loss associated with chronic environmental noise exposure may be linked to inflammatory processes in the cochlea. This study thus provides further insight into the dynamics of the cochlear inflammatory response induced by exposure to acute and chronic noise.

ATP-gated ion channels mediate adaptation to elevated sound levels.

The sense of hearing is remarkable for its auditory dynamic range, which spans more than 10(12) in acoustic intensity. The mechanisms that enable the cochlea to transduce high sound levels without damage are of key interest, particularly with regard to the broad impact of industrial, military, and recreational auditory overstimulation on hearing disability. We show that ATP-gated ion channels assembled from P2X2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise. In mice null for the P2RX2 gene (encoding the P2X2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed. ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X2 receptors on epithelial cells lining the endolymphatic compartment. This purinergic signaling is supported by significantly greater noise-induced suppression of distortion product otoacoustic emissions derived from outer hair cell transduction and decreased suprathreshold auditory brainstem response input/output gain in WT mice compared with P2RX2-null mice. At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption. P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells. These data indicate that a significant component of TTS represents P2X2 receptor-dependent purinergic hearing adaptation that underpins the upper physiological range of hearing.

Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.

Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea. Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in a second family with the same phenotype. The mutation was absent from more than 7,000 controls. P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP-stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling. Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability. P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults. Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood. Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise.

Properties of ATP-gated ion channels assembled from P2X2 subunits in mouse cochlear Reissner's membrane epithelial cells.

In the cochlea, Reissner's membrane separates the scala media endolymphatic compartment that sustains the positive endocochlear potential and ion composition necessary for sound transduction, from the scala vestibuli perilymphatic compartment. It is known that with sustained elevated sound levels, adenosine 5'-triphosphate (ATP) is released into the endolymph and ATP-gated ion channels on the epithelial cells lining the endolymphatic compartment shunt the electrochemical driving force, contributing to protective purinergic hearing adaptation. This study characterises the properties of epithelial cell P2X(2)-type ATP-activated membrane conductance in the mouse Reissner's membrane, which forms a substantial fraction of the scale media surface. The cells were found to express two isoforms (a and b) of the P2X(2) subunit arising from alternative splicing of the messenger RNA (mRNA) transcript that could contribute to the trimeric subunit assembly. The ATP-activated conductance demonstrated both immediate and delayed desensitisation consistent with incorporation of the combination of P2X(2) subunit isoforms. Activation by the ATP analogue 2meSATP had equipotency to ATP, whereas α,ß-meATP and adenosine 5'-diphosphate (ADP) were ineffective. Positive allosteric modulation of the P2X(2) channels by protons was profound. This native conductance was blocked by the P2X(2)-selective blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and the conductance was absent in these cells isolated from mice null for the P2rX2 gene encoding the P2X(2) receptor subunit. The activation and desensitisation properties of the Reissner's membrane epithelial cell ATP-gated P2X(2) channels likely contribute to the sensitivity and kinetics of purinergic control of the electrochemical driving force for sound transduction invoked by noise exposure.