Animal models that recapitulate human disease are proving to be an invaluable tool in the identification of novel disease-associated genes. These models can improve our understanding of the complex genetic mechanisms involved in disease and provide a basis to guide therapeutic strategies to combat these conditions. We have identified a novel mouse model of non-syndromic sensorineural hearing loss with linkage to a region on chromosome 18. Eeyore mutant mice have early onset progressive hearing impairment and show abnormal structure of the sensory epithelium from as early as 4 weeks of age. Ultrastructural and histological analyses show irregular hair cell structure and degeneration of the sensory hair bundles in the cochlea. The identification of new genes involved in hearing is central to understanding the complex genetic pathways involved in the hearing process and the loci at which these pathways are interrupted in people with a genetic hearing loss. We therefore discuss possible candidate genes within the linkage region identified in eeyore that may underlie the deafness phenotype in these mice. Eeyore provides a new model of hereditary sensorineural deafness and will be an important tool in the search for novel deafness genes.

Human MYO7A mutations can cause a variety of conditions involving the inner ear. These include dominant and recessive non-syndromic hearing loss and syndromic conditions such as Usher syndrome. Mouse models of deafness allow us to investigate functional pathways involved in normal and abnormal hearing processes. We present two novel mouse models with mutations in the Myo7a gene with distinct phenotypes. The mutation in Myo7a(I487N/I487N) ewaso is located within the head motor domain of Myo7a. Mice exhibit a profound hearing loss and manifest behaviour associated with a vestibular defect. A mutation located in the linker region between the coiled-coil and the first MyTH4 domains of the protein is responsible in Myo7a(F947I/F947I) dumbo. These mice show a less severe hearing loss than in Myo7a(I487N/I487N) ewaso; their hearing loss threshold is elevated at 4 weeks old, and progressively worsens with age. These mice show no obvious signs of vestibular dysfunction, although scanning electron microscopy reveals a mild phenotype in vestibular stereocilia bundles. The Myo7a(F947I/F947I) dumbo strain is therefore the first reported Myo7a mouse model without an overt vestibular phenotype; a possible model for human DFNB2 deafness. Understanding the molecular basis of these newly identified mutations will provide knowledge into the complex genetic pathways involved in the maintenance of hearing, and will provide insight into recessively inherited sensorineural hearing loss in humans.

The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the residual spiral ganglion neurons. These neurons, however, undergo progressive degeneration after hearing loss, marked initially by peripheral fibre retraction and ultimately culminating in cell death. This research aims to use gene therapy techniques to both hold and reverse this degeneration by providing a sustained and localised source of neurotrophins to the deafened cochlea. Adenoviral vectors containing green fluorescent protein, with or without neurotrophin-3 and brain derived neurotrophic factor, were injected into the lower basal turn of scala media of guinea pigs ototoxically deafened one week prior to intervention. This single injection resulted in localised and sustained gene expression, principally in the supporting cells within the organ of Corti. Guinea pigs treated with adenoviral neurotrophin-gene therapy had greater neuronal survival compared to contralateral non-treated cochleae when examined at 7 and 11 weeks post injection. Moreover; there was evidence of directed peripheral fibre regrowth towards cells expressing neurotrophin genes after both treatment periods. These data suggest that neurotrophin-gene therapy can provide sustained protection of spiral ganglion neurons and peripheral fibres after hearing loss.

BACKGROUND: Studies using vocoders as acoustic simulators of cochlear implants have generally focused on simulation of speech understanding, gender recognition, or music appreciation. The aim of the present experiment was to study the auditory sensation perceived by cochlear implant (CI) recipients with steady electrical stimulation on the most-apical electrode. METHODOLOGY/PRINCIPAL FINDINGS: Five unilateral CI users with contralateral residual hearing were asked to vary the parameters of an acoustic signal played to the non-implanted ear, in order to match its sensation to that of the electric stimulus. They also provided a rating of similarity between each acoustic sound they selected and the electric stimulus. On average across subjects, the sound rated as most similar was a complex signal with a concentration of energy around 523 Hz. This sound was inharmonic in 3 out of 5 subjects with a moderate, progressive increase in the spacing between the frequency components. CONCLUSIONS/SIGNIFICANCE: For these subjects, the sound sensation created by steady electric stimulation on the most-apical electrode was neither a white noise nor a pure tone, but a complex signal with a progressive increase in the spacing between the frequency components in 3 out of 5 subjects. Knowing whether the inharmonic nature of the sound was related to the fact that the non-implanted ear was impaired has to be explored in single-sided deafened patients with a contralateral CI. These results may be used in the future to better understand peripheral and central auditory processing in relation to cochlear implants.

BACKGROUND: Recently two major manufacturers of hearing aids introduced two distinct frequency-lowering techniques that were designed to compensate in part for the perceptual effects of high-frequency hearing impairments. The Widex "Audibility Extender" is a linear frequency transposition scheme, whereas the Phonak "SoundRecover" scheme employs nonlinear frequency compression. Although these schemes process sound signals in very different ways, studies investigating their use by both adults and children with hearing impairment have reported significant perceptual benefits. However, the modifications that these innovative schemes apply to sound signals have not previously been described or compared in detail. METHODS: The main aim of the present study was to analyze these schemes'technical performance by measuring outputs from each type of hearing aid with the frequency-lowering functions enabled and disabled. The input signals included sinusoids, flute sounds, and speech material. Spectral analyses were carried out on the output signals produced by the hearing aids in each condition. CONCLUSIONS: The results of the analyses confirmed that each scheme was effective at lowering certain high-frequency acoustic signals, although both techniques also distorted some signals. Most importantly, the application of either frequency-lowering scheme would be expected to improve the audibility of many sounds having salient high-frequency components. Nevertheless, considerably different perceptual effects would be expected from these schemes, even when each hearing aid is fitted in accordance with the same audiometric configuration of hearing impairment. In general, these findings reinforce the need for appropriate selection and fitting of sound-processing schemes in modern hearing aids to suit the characteristics and preferences of individual listeners.

OBJECTIVE: To test the influence of multiple factors on cochlear implant (CI) speech performance in quiet and in noise for postlinguistically deaf adults, and to design a model of predicted auditory performance with a CI as a function of the significant factors. STUDY DESIGN: Retrospective multi-centre study. METHODS: Data from 2251 patients implanted since 2003 in 15 international centres were collected. Speech scores in quiet and in noise were converted into percentile ranks to remove differences between centres. The influence of 15 pre-, per- and postoperative factors, such as the duration of moderate hearing loss (mHL), the surgical approach (cochleostomy or round window approach), the angle of insertion, the percentage of active electrodes, and the brand of device were tested. The usual factors, duration of profound HL (pHL), age, etiology, duration of CI experience, that are already known to have an influence, were included in the statistical analyses. RESULTS: The significant factors were: the pure tone average threshold of the better ear, the brand of device, the percentage of active electrodes, the use of hearing aids (HAs) during the period of pHL, and the duration of mHL. CONCLUSIONS: A new model was designed showing a decrease of performance that started during the period of mHL, and became faster during the period of pHL. The use of bilateral HAs slowed down the related central reorganization that is the likely cause of the decreased performance.

A significant fraction of newly implanted cochlear implant recipients use a hearing aid in their non-implanted ear. SCORE bimodal is a sound processing strategy developed for this configuration, aimed at normalising loudness perception and improving binaural loudness balance. Speech perception performance in quiet and noise and sound localisation ability of six bimodal listeners were measured with and without application of SCORE. Speech perception in quiet was measured either with only acoustic, only electric, or bimodal stimulation, at soft and normal conversational levels. For speech in quiet there was a significant improvement with application of SCORE. Speech perception in noise was measured for either steady-state noise, fluctuating noise, or a competing talker, at conversational levels with bimodal stimulation. For speech in noise there was no significant effect of application of SCORE. Modelling of interaural loudness differences in a long-term-average-speech-spectrum-weighted click train indicated that left-right discrimination of sound sources can improve with application of SCORE. As SCORE was found to leave speech perception unaffected or to improve it, it seems suitable for implementation in clinical devices.

OBJECTIVE: Multi-centre collaborative study to develop and refine the design of a prototype thin perimodiolar cochlear implant electrode array and to assess feasibility for use in human subjects. STUDY DESIGN: Multi-centre temporal bone insertion studies. MATERIALS AND METHODS: The modiolar research array (MRA) is a thin pre-curved electrode that is held straight for initial insertion with an external sheath rather than an internal stylet. Between November 2006 and February 2009, six iterations of electrode design were studied in 21 separate insertion studies in which 140 electrode insertions were performed in 85 human temporal bones by 12 surgeons. These studies aimed at addressing four fundamental questions related to the electrode concept, being: (1) Could a sheath result in additional intra-cochlear trauma? (2) Could a sheath accommodate variations in cochlea size and anatomies? (3) Could a sheath be inserted via the round window? and (4) Could a sheath be safely removed once the electrode had been inserted? These questions were investigated within these studies using a number of evaluation techniques, including X-ray and microfluoroscopy, acrylic fixation and temporal bone histologic sectioning, temporal bone microdissection of cochlear structures with electrode visualization, rotational tomography, and insertion force analysis. RESULTS: Frequent examples of electrode rotation and tip fold-over were demonstrated with the initial designs. This was typically caused by excessive curvature of the electrode tip, and also difficulty in handling of the electrode and sheath. The degree of tip curvature was progressively relaxed in subsequent versions with a corresponding reduction in the frequency of tip fold-over. Modifications to the sheath facilitated electrode insertion and sheath removal. Insertion studies with the final MRA design demonstrated minimal trauma, excellent perimodiolar placement, and very small electrode dimensions within scala tympani. Force measurements in temporal bones demonstrated negligible force on cochlear structures with angular insertion depths of between 390 and 450°. CONCLUSION: The MRA is a novel, very thin perimodiolar prototype electrode array that has been developed using a systematic collaborative approach. The different evaluation techniques employed by the investigators contributed to the early identification of issues and generation of solutions. Regarding the four fundamental questions related to the electrode concept, the studies demonstrated that (1) the sheath did not result in additional intra-cochlear trauma; (2) the sheath could accommodate variations in cochlea size and anatomies; (3) the sheath was more successfully inserted via a cochleostomy than via the round window; and (4) the sheath could be safely removed once the electrode had been inserted.

Friedreich ataxia (FRDA) is an autosomal recessive disease characterised by neurodegeneration and cardiomyopathy that is caused by an insufficiency of the mitochondrial protein, frataxin. Our previous studies described the generation of FRDA induced pluripotent stem cell lines (FA3 and FA4 iPS) that retained genetic characteristics of this disease. Here we extend these studies, showing that neural derivatives of FA iPS cells are able to differentiate into functional neurons, which don't show altered susceptibility to cell death, and have normal mitochondrial function. Furthermore, FA iPS-derived neural progenitors are able to differentiate into functional neurons and integrate in the nervous system when transplanted into the cerebellar regions of host adult rodent brain. These are the first studies to describe both in vitro and in vivo characterization of FA iPS-derived neurons and demonstrate their capacity to survive long term. These findings are highly significant for developing FRDA therapies using patient-derived stem cells.

The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness.

BACKGROUND: Infants born <30 weeks' gestation are at increased risk of long term neurodevelopmental problems compared with term born peers. The predictive value of neurobehavioural examinations at term equivalent age in very preterm infants has been reported for subsequent impairment. Yet there is little knowledge surrounding earlier neurobehavioural development in preterm infants prior to term equivalent age, and how it relates to perinatal factors, cerebral structure, and later developmental outcomes. In addition, maternal psychological wellbeing has been associated with child development. Given the high rate of psychological distress reported by parents of preterm children, it is vital we understand maternal and paternal wellbeing in the early weeks and months after preterm birth and how this influences the parent-child relationship and children's outcomes. Therefore this study aims to examine how 1) early neurobehaviour and 2) parental mental health relate to developmental outcomes for infants born preterm compared with infants born at term. METHODS/DESIGN: This prospective cohort study will describe the neurobehaviour of 150 infants born at <30 weeks' gestational age from birth to term equivalent age, and explore how early neurobehavioural deficits relate to brain growth or injury determined by magnetic resonance imaging, perinatal factors, parental mental health and later developmental outcomes measured using standardised assessment tools at term, one and two years' corrected age. A control group of 150 healthy term-born infants will also be recruited for comparison of outcomes. To examine the effects of parental mental health on developmental outcomes, both parents of preterm and term-born infants will complete standardised questionnaires related to symptoms of anxiety, depression and post-traumatic stress at regular intervals from the first week of their child's birth until their child's second birthday. The parent-child relationship will be assessed at one and two years' corrected age. DISCUSSION: Detailing the trajectory of infant neurobehaviour and parental psychological distress following very preterm birth is important not only to identify infants most at risk, further understand the parental experience and highlight potential times for intervention for the infant and/or parent, but also to gain insight into the effect this has on parent-child interaction and child development.

BACKGROUND: The term 'specific language impairment' (SLI), in use since the 1980s, describes children with language impairment whose cognitive skills are within normal limits where there is no identifiable reason for the language impairment. SLI is determined by applying exclusionary criteria, so that it is defined by what it is not rather than by what it is. The recent decision to not include SLI in DSM-5 provoked much debate and concern from researchers and clinicians. AIMS: To explore how the term 'specific language impairment' emerged, to consider how disorders, including SLI, are generally defined and to explore how societal changes might impact on use the term. METHODS & PROCEDURES: We reviewed the literature to explore the origins of the term 'specific language impairment' and present published evidence, as well as new analyses of population data, to explore the validity of continuing to use the term. OUTCOMES & RESULTS AND CONCLUSIONS & IMPLICATIONS: We support the decision to exclude the term 'specific language impairment' from DSM-5 and conclude that the term has been a convenient label for researchers, but that the current classification is unacceptably arbitrary. Furthermore, we argue there is no empirical evidence to support the continued use of the term SLI and limited evidence that it has provided any real benefits for children and their families. In fact, the term may be disadvantageous to some due to the use of exclusionary criteria to determine eligibility for and access to speech pathology services. We propose the following recommendations. First, that the word 'specific' be removed and the label 'language impairment' be used. Second, that the exclusionary criteria be relaxed and in their place inclusionary criteria be adopted that take into account the fluid nature of language development particularly in the preschool period. Building on the goodwill and collaborations between the clinical and research communities we propose the establishment of an international consensus panel to develop an agreed definition and set of criteria for language impairment. Given the rich data now available in population studies it is possible to test the validity of these definitions and criteria. Consultation with service users and policy-makers should be incorporated into the decision-making process.