NIHRDataInsights/HRCSData huggingface dataset:
Title: Deafness and Hearing Problems
Funder: Department of Health and Social Care

Abstract:  Consolidate existing strengths in early-phase trials in medical devices and complex interventions  Intensify capacity across NHS ENT/Audiology for clinical trials, with clearly defined pathways to impact via engagement with stakeholders. Objectives: Short-term: 1. Establish a network of participating NHS sites agreeing to recruit into all proposed trials, especially for new patient cohorts. 2. Create the evidence base to confirm gaps in knowledge necessary for leveraging funding for proposed phase-2 (efficacy) trials (assessing existing complex interventions (hearing aids, combination devices, cochlear implants, assistive listening and e-health technologies) addressing NHS priorities in adults/children. 3. Deliver the necessary feasibility work to underpin these trials. Medium-term: 1. Generate adequate outcome tools (national recommendations) for all above proposed phase-2 (efficacy) trials. 2. Generate successful applications for phase-2 trials from feasibility studies. 3. Expand existing health psychology collaborations focusing on personalised self-management (Health Behaviour Change model, COM-B, for optimising use of innovative technologies of hearing loss, and to solve barriers in primary care that limit efficacy of self-management of tinnitus). Long-term: 1. Deliver phase-2 trials, creating the evidence base for the clinical efficacy of treatments for three of the most common hearing-related conditions: i) otitis media with effusion, ii) sensorineural hearing loss, and iii) tinnitus. 2. Create evidence-based guidelines on improving hearing-related communication in people with dementia living in care homes. 3. Develop a clinically informative pre/ post-operative prognostic/ monitoring objective measurement for speech understanding in babies and young children. 4. Validated novel neuroimaging markers for hearing loss and sensorineural plasticity. 5. Trained cohort of future hearing translational researchers.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: EAR;NEUROLOGICAL
Title: Deciphering the molecular heterogeneity of spiral ganglion neurons by single-cell gene expression profiling.
Funder: Medical Research Council

Abstract: In both noise and age related hearing impairment synapses degeneration precedes hair cell loss and threshold shift. Understanding why subtypes of synapses and their corresponding type I spiral ganglion neurons (SGNI) die requires the knowledge of genes that are expressed in individual neurons and that contribute to their differential vulnerability to noise. Our main goal in this study is to determine identity-specific molecular profiles and define genes that distinguish SGNI subtypes. My laboratory is now in a unique position to make these discoveries. We have recently generated and used a transgenic mouse with the unique feature of fluorescently labeled SGNIs to sort single neurons. Single cell gene-expression profiling was used to distinguish and to characterize different SGNI subtypes. Our pilot studies demonstrate feasibility of our approach. We have identified specific, potential marker genes that specifically label distinct subpopulations of presumptive low and high threshold neurons. We will select validated and highly differentially expressed genes to generate subtype-specific reporter mice that will also allow us to conditionally eliminate presumptive low and high threshold SGNI. These mouse models will be utilized to address physiologically important questions such as 1) what are the molecular and cell biological differences in physiologically distinct SGNI subgroups? & 2) what are the mechanisms underlying differential vulnerability of low versus high threshold SGNI to noise trauma? Using cutting edge technologies and the opportunity to work with world experts in the field at the Sheffield University & MRC Harwell, I am confident that we will contribute to the identification of genetic factors involved in the cochlear response to aging and/or noise trauma. Knowledge of these mechanisms is essential for devising early diagnostic, intervention and/or treatments for auditory synaptopathy, and consequently for age-related and noise- induced hearing loss.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL
Title: DEVELOPING ELECTROPHYSIOLOGICAL MEASURES OF BRAIN ACTIVITY TO OPTIMISE COCHLEAR IMPLANT OUTCOMES
Funder: Medical Research Council

Abstract: There are over 700,000 severe-to-profound hearing-impaired listeners with cochlear implants (CIs) worldwide and over 15,000 in the UK. CIs are life changing devices that restore hearing and give many individuals the opportunity to function in the hearing world. They provide a useable signal to the auditory system that enables young children to dramatically improve their developmental trajectory for speech and language acquisition. Despite being considered one of the most successful interventions in modern medicine, there is a huge amount of variation in CI hearing outcomes, in both child and adult CI users. The aim of this research is to reduce variability in outcomes, and to improve performance to be closer to normal hearing even in highly performing individuals. To do so, we explore four man themes: variations in cortical responses to CI stimulation, how they relate to functional measures of hearing, and their shaping by ascending auditory inputs; brain adaptation and cross-modal reorganization following implant activation; evaluating if re-mapping based on cortical responses improves functional outcomes of hearing; and measuring neural indicators of binaural integration from bilateral implants. We will employ electrophysiology techniques using electroencephalography (EEG) to objectively determine auditory capabilities of cochlear implant (CI) users and brain changes occurring following implant activation. Specific measures will look at electrode discrimination, within-channel modulation rate discrimination and between ear inter-aural time differences, inter-aural level differences. We will make use of responses to guide CI re-mapping. We will relate responses with psychophysical scores and speech perception data. The findings will provide clinicians with tools to inform re-mapping and training interventions and, with the support of industry the implementation of important procedures, into clinical practice.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: EAR;NEUROLOGICAL
Title: Cortical determinants of human auditory cognition
Funder: Medical Research Council

Abstract: Behavioural measures of pre-language auditory cognition will be developed that can account for the ability of subjects to hear speech in noise (SiN). This follows pilot work establishing that prototype non-speech auditory figure-ground (AFG) and auditory working memory (AFM) tests predict SiN independently of the audiogram. New tests will use stimuli that are closer to the spectrotemporal structure of speech. fMRI at 3T will seek brain bases for the correlation between the non-speech behavioural measures and SiN. The work will test for common changes in BOLD activity in auditory regions as a function of task difficulty for AFG and SiN and for AWM and SiN. The work will also seek evidence for a common system for AFG and SiN and for AWM and SiN using modelling to identify common effects of the tasks on effective connectivity within and between auditory areas. fMRI at 3T on the AWM system will test the involvement of the hippocampus in AWM and in active tracking tasks. If the 3T experiments are successful, further work at 7T will allow more sensitive measurement of BOLD changes within subareas during the same tasks and more precise definition of time series to allow modelling of effective connectivity within and between auditory areas. Neurophysiological recordings from neurosurgical patients will measure local field potentials (LFPs) to seek brain bases for the correlation between non-speech behavioural measures and SiN. Two groups of case studies with ten subjects each will be carried out to assess brain activity in auditory cortex during AFG and SiN tasks, and to assess activity in the network including auditory cortex, inferior frontal cortex and hippocampus during auditory working memory. Single unit recordings will be carried out from hippocampus and parahippocampus during AWM and auditory tracking tasks to seek human units that allow auditory computation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EAR;NEUROLOGICAL
Title: Characterizing the effects of hearing loss and hearing aids on the neural code for music
Funder: Medical Research Council

Abstract: Despite its central role in our society, music is largely ignored in hearing research and audiology. We know remarkably little about how music is processed by the auditory system; in fact, there has never been a large-scale single-unit study of neural responses to music. This ignorance has important practical consequences: distorted music perception is a common problem for people with hearing loss and current hearing aids, which are designed for speech, often provide little benefit. Without a detailed understanding of the neural coding of music, it is not clear how the performance of hearing aids for music can be improved. We will use in vivo electrophysiology to study the neural code for music, using gerbils with noise-induced cochlear damage of varying severity as a model for different levels of sensorineural hearing loss. Our novel methods for large-scale recordings will allow us to record from hundreds of individual neurons simultaneously to comprehensively characterize the neural code at the single neuron and network level. We will make recordings in the central nucleus of the inferior colliculus (IC) while presenting music from a wide range of genres (in addition to speech and tones) at different sound intensities with and without a hearing aid to isolate the effects of decreased audibility, supra-threshold hearing deficits, and hearing aid processing. We will provide both quantitative and qualitative descriptions of the neural code for music under all conditions, evaluate the relative importance of spectral and temporal properties, and relate our results to real-world listening through a large-scale survey of hearing aid users. Given that our preliminary results reveal striking differences between the neural code for music with and without hearing loss, we expect the results of the project to have a major impact both on our understanding of the auditory processing of music and on the design of music-specific assistive listening devices.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL
Title: Restoring the sense of sound: deep-learning based compensation strategies for the electro-neural transmission of sound by cochlear implants
Funder: Medical Research Council

Abstract: Over 800,000 severe-to-profound hearing-impaired individuals use a cochlear implant (CI) worldwide. Compromised speech perception in noisy environments is a major problem for CI users and can have a negative impact on their quality of life and mental health. Noise-reduction algorithms, that process the corrupted speech signal before being presented, have produced some benefits for CI users but they still struggle in even moderate levels of noise and there remains considerable variability in the benefits across CI users. I will develop a compensation strategy to overcome the limitations of previous approaches by taking into account CI-specific and user-specific effects. The compensation strategy consists of a computational model to simulate the electro-neural transmission of CIs and a machine-learning algorithm trained to reduce the noise component of a speech-in-noise signal. I will develop the strategy in three stages: (I) by incorporating a computational model of the CI processing, (II) by incorporating a computational model of the electrode-nerve interface and (III) by adjusting these models with user-specific parameters measured with electro-physiological and psycho-physical tests. Each stage will be used to generate training data for a noise-reduction algorithm based on deep recurrent neural networks. Hereby, real-world speech and noise recordings will be processed by the computational model to generate labels for the supervised training of the neural networks. Listening experiments will be performed with CI users to evaluate the strategy and its effect on the perception of speech in noise by measuring speech reception thresholds and quality ratings. If successful, the strategy could be integrated into the external speech processor of a cochlear implant without the need for surgical re-implantation. This CI-specific approach has the potential to overcome the current limitations and to provide benefits for CI users.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.3 MEDICAL DEVICES
Health categories: EAR;NEUROLOGICAL
Title: Control of cochlear amplification by cellular and acellular elements of the mammalian cochlea
Funder: Medical Research Council

Abstract: The prime objective of this research proposal is to understand the complex electromechanical functional in vivo relationships between cellular and noncellular elements of the organ of Corti in the mammalian cochlea, control of energy production by the outer hair cells and flow of energy in the active healthy and impaired cochleae as an essential basis for restoring hearing function. We will make in vivo microelectrode recordings from single sensory cells in guinea pigs to determine the timing of hair cell excitatory input relative to responses of other cochlear structures. Furthermore, we will investigate the importance of tectorial membrane viscoelastic properties in normal cochlear function. Outcomes from these investigations are essential for understanding the mechanisms of cochlear frequency tuning. We will express channelrhodopsins in Deiters cells in mice and selectively excite them with light to determine the mechanisms by which Deiters' cells regulate outer hair cell sensitivity, operating point and the longitudinal flow of energy in the cochlear partition. We will characterise the ionic conductances of Deiters cells and their contribution to organ of Corti electrical impedance, which is essential for understanding the basis of cochlear amplification at high frequencies. Through predictive modelling, based on in vivo and in vitro experimental measurements, further insight will be gained into the functional significance of interaction between sensory cells, their supporting cell cages, and extracellular matrixes of the basilar and tectorial membranes. This detailed understanding of functional relationship between different elements of the organ of Corti is necessary to fully exploit the exciting, evolving, possibilities for hearing restoration through repair and regeneration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL
Title: The influence of individual differences in brain rhythms on speech perception with and without age-related hearing loss
Funder: Medical Research Council

Abstract: The aim of this research is to identify intrinsic brain rhythms that influence speech comprehension in the population, and that can be non-invasively enhanced to improve comprehension in individuals with mild to moderate hearing loss. My previously developed spectral fingerprinting approach uses resting-state magnetoencephalography (MEG) to disentangle rhythmic activity into spectral modes. MEG allows for a better spatial resolution than electroencephalography (EEG), but it is expensive and less feasible for large-scale use. We will therefore first analyse the match between EEG and MEG spectral fingerprints. We will then study which brain rhythms predict challenging speech comprehension, and which are particularly useful for individuals with hearing loss in a population sample. Using resting-state EEG recordings, we will model individual brain rhythm profiles. Comprehension will be tested in 3 parametrically modulated tasks: noisy speech (signal-to-noise ratio), rapid speech (speech compression rate), and interrupted speech (number of interruptions), and modelled with psychometric Weibull functions. We will also use transcranial magnetic stimulation (TMS) to pilot the enhancement of speech-related brain rhythms to improve speech comprehension. A target rhythm will be chosen based on the effect size and its suitability for TMS in the population study. The rTMS protocol is determined based on the frequency and location of the rhythm. Speech-in-noise comprehension will be compared before and after TMS. Last, we will develop a free MATLAB toolbox to analyse individual and group brain rhythm profiles based on continuous EEG/MEG data. To do this, we will use extensive commenting throughout the project. The findings of this work will contribute to a comprehensive, mechanistic understanding of how brain rhythms affect comprehension. They will also provide a "roadmap" of possible routes to improve speech perception by non-invasively enhancing brain rhythms.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EAR;NEUROLOGICAL
Title: Genetics, pathobiology and treatment of age-related hearing loss
Funder: Medical Research Council

Abstract: Age-related hearing loss (ARHL) is the most common sensory deficit experienced by the elderly. It is a complex disease that is not fully understood, but the onset and progression is influenced by environmental factors and genetic susceptibility. Moreover, a recent Lancet Commission on Dementia (Livingston et al, 2017) identifies midlife peripheral hearing loss as the highest individual risk factor for dementia, and this is pertinent as ARHL is the most prevalent sensory deficit within the population (affects >30% of individuals older than 55-years). Through the use of mouse models my team and I will: validate the involvement of genes in ARHL causation; identify critical molecular and cellular processes occurring in the aging mammalian ear; determine the pathobiology associated with disease progression, something that is not possible in humans; and, assess the mechanistic links underlying cognitive decline associated with peripheral hearing loss. In order to elaborate upon the genetics and pathobiology of ARHL my research will use a multi-pronged approach involving both forward- and reverse-genetics approaches: - Characterization of novel late-onset hearing loss models identified from the Harwell Aging Screen - Validation and characterization of candidate ARHL genes arising from large-scale, human cohort studies - Investigation of novel age-related hearing phenodeviant mouse models generated as part of the IMPC programme Once validated, these genes and their associated molecular pathways will be assessed for their potential to be targeted as a means to ameliorate, or rescue, age-related auditory decline. Together this increased knowledge will lay the foundations necessary for developing therapeutic strategies to ameliorate progressive hearing loss, and potentially reduce dementia incidence.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL
Title: How does audiovisual binding help listening?
Funder: Wellcome Trust

Abstract: While we can deploy auditory spatial attention independently of gaze direction, we typically look at sound sources of interest. Our recent research suggests that when human listeners can see a visual stimulus whose size changes in time with amplitude changes of a sound source, this sound becomes easier to separate from competing sounds. Furthermore, listeners are more sensitive to changes in features of the sound that are not predicted by the visual stimulus, such as its timbre or pitch, suggesting that the visual and auditory streams are bound into an audiovisual object. We observed neural correlates of this effect in auditory cortex of ferrets, and identified a specific visual cortical field as providing critical input to auditory cortex. Here, we will address outstanding questions: Firstly, we will record neural activity simultaneously across multiple auditory cortical fields and the visual cortical fields that innervate them while ferrets perform the behavioural task our human listeners performed. I hypothesise that functional connectivity between early auditory and visual cortex is critical for audiovisual binding. Secondly, we will develop optogenetic approaches in the ferret animal model in order to dissect the neural circuit that underlies the integration of visual information in auditory cortex.

Lay abstract: We perceive the world through multiple senses. Our recent work shows that being able to see a sound source, such as someone’s mouth movements, can help us to hear that sound amongst others more effectively. We went on to determine that seeing a stimulus can change the way in which sound is processed in the auditory cortex. While the auditory cortex is specialized for the processing of sound, a considerable proportion of neurons here are influenced by light. However, we're not clear why that should be and what advantage it offers. In this proposal we will ask where such visual responses originate and how they are able to influence the processing of sound. Our goal is to learn how the brain combines auditory and visual information, and how this helps listening. In the future we hope to use this information to develop strategies to rehabilitate those with hearing loss.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: EAR;NEUROLOGICAL
Title: Pathological ensembles in the auditory thalamocortical circuit following acoustic trauma
Funder: Medical Research Council

Abstract: We aim to identify neural correlates of phantom auditory perception (tinnitus) at the level of neuronal circuits. By using a massively parallel extracellular recording technique and a behavioural approach in awake rats, we will determine relationships between tinnitus and abnormal neural population activity in the auditory thalamocortical circuit. Tinnitus is the perception of sound in the absence of auditory stimuli. Tinnitus is persistent in ~10% of the general population. In ~2%, it causes severe impairment of the quality of lives. Given the strong association between tinnitus and ageing, the impact of tinnitus on society will likely get worse. However, treatment options remain limited and it is still elusive how tinnitus is generated. At least two mechanisms in the central nervous system have been proposed to underlie tinnitus: abnormalities in spontaneous neural activity and reorganization of tonotopic maps. The pathological activity has been identified across the auditory pathway and even in limbic areas, suggesting abnormal interactions between distributed circuits. Here we will address two issues: first, previous animal neurophysiological studies have been done under anaesthesia where tinnitus is unlikely present. Second, little is known about how tinnitus is associated with functional interactions in the auditory thalamocortical circuit, which has long been implicated in auditory perception. Specifically, we will test the hypothesis that tinnitus is associated with pathological neural population activity in the auditory thalamocortical circuit. We will assess behavioural correlates of tinnitus in rats following acoustic trauma. Then we will monitor neural population activity in the auditory thalamocortical circuit of head-restrained, awake rats. The results of our proposal will provide insights into the mechanisms of tinnitus at the neural circuit level. This proposal contributes to both sensory neuroscience and human health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL