Title Promoter Affiliations Abstract "Neural tracking of the speech envelope: unraveling the effects of listening effort, age and hearing impairment" "Tom Francart" "Research Group Experimental Oto-rhino-laryngology" "Partly due to the rapid pace of aging of the world population, it is expected that by 2050 more than 900 million people will experience hearing loss. Since adequate hearing is a prerequisite for daily life communication, hearing impairment increases the risk of social isolation and poorer physical functioning, which in turn negatively affects quality of life. Currently, hearing aids are the most used and well-known treatment for hearing impairment. Although these devices restore hearing sensitivity, adequate speech perception in noisy environments is often not achieved. Research has suggested that, next to hearing loss, age-related cognitive decline and temporal processing deficits also contribute to the speech-in-noise difficulties experienced by older adults. To provide rehabilitation strategies that overcome these difficulties, there is a need for a better understanding of the neural mechanisms underlying speech-in-noise difficulties.When we listen to natural speech, our neural activity tracks the low amplitude modulations of speech, also called the speech envelope. Recent studies have demonstrated the potential of neural envelope tracking to objectively measure speech understanding. This could provide additional information to current behavioral speech tests and improve the fitting of hearing aids as neural envelope tracking does not require active cooperation of the patient. This could be particularly useful for difficult-to-test populations such as young children, intellectually disabled persons and older adults with severe cognitive impairment such as dementia. Although this seems promising, previous studies mainly measured neural envelope tracking in a specific well-controlled population, i.e. young, normal-hearing adults. The aim of this doctoral thesis was to investigate the effects of three individual-related factors on neural envelope tracking: listening effort, age and hearing impairment.As daily life speech understanding can be challenging for both normal-hearing and hearing impaired adults, individuals can differ in the amount of allocated neural resources, also called listening effort, that they need to expend to achieve a particular level of speech understanding. This could, however, result in a confound when using neural envelope tracking to objectively measure speech understanding. In view of this, we investigated the effect of listening effort, on neural envelope tracking in young, normal-hearing listeners. Five measures were included to quantify listening effort. Our results demonstrated that different measures can reflect different aspects of effort, e.g. perceived effort versus processing load. Listening effort was not found to substantially modulate neural envelope tracking. Nevertheless, participants showed increases in envelope tracking with increasing speech understanding, suggesting that neural envelope tracking can be used as a reliable objective measure for speech understanding.With advancing age, hearing loss becomes more prevalent. To disentangle these two closely intertwined factors, we designed two studies in which we investigated neural envelope tracking in normal-hearing adults across the adult lifespan and compared the results with those of age-matched hearing impaired adults. For both normal-hearing and hearing impaired adults, neural envelope tracking was measured to sentences and a story masked by different levels of a stationary noise or competing talker. A competing talker was included to investigate the effects of hearing impairment on neural segregation of different talkers. Participants also completed two cognitive tests, measuring verbal working memory and inhibition, to investigate the interplay between cognition, age, hearing impairment and neural envelope tracking.Our results reveal that aging and hearing impairment both result in major alterations of neural envelope tracking. More specifically, envelope tracking was found to increase supralinearly with advancing age, resulting in an enhanced envelope tracking for older normal-hearing adults. This enhancement is likely to underlie the speech-in-noise difficulties experienced by older normal-hearing adults as we found that worse cognitive scores were associated with this enhancement. Hearing impaired adults showed additional enhanced envelope tracking compared to their age-matched normal-hearing peers. As we only observed this for the attended, target talker, our results suggest that in order to neurally segregate different talkers, persons with a disabling hearing loss need enhanced cortical envelope tracking to compensate for peripheral deficits. Furthermore, enhanced envelope tracking in hearing impaired adults may be caused by different neural mechanisms than those related to age since no significant relation with cognitive skills was observed. Finally, middle-aged and older normal-hearing and hearing impaired adults showed a significant increase in neural envelope tracking with increasing speech understanding similar to their young normal-hearing counterparts, highlighting the potential of neural envelope tracking to objectively measure speech understanding.In conclusion, this doctoral thesis demonstrates substantial effects of age and hearing impairment on neural envelope tracking which contribute to the current understanding of the mechanisms underlying impaired speech understanding. In addition, observing the link between speech understanding and neural envelope tracking in different populations, supports the value of neural envelope tracking in diagnostic tests, rehabilitation strategies and self-fitting hearing aids." "Hearing impairment in children with congenital cytomegalovirus: long-term follow-up and hunt for therapy." "Ingeborg Dhooge" "Department of Head and Skin" "With a reported prevalence of 7 per 1000 births, congenital cytomegalovirus (cCMV) is a frequent condition. In addition to the risk for neurodevelopmental disabilities, it is the major cause of congenital nonhereditary sensorineural hearing loss in developed countries. Hearing loss can be unilateral or bilateral and the extent varies from mild to profound. It may be present at birth or develop within the following years. Progressive and fluctuating hearing thresholds make diagnosis challenging. Current literature shows large variability in prevalence and presentation, so more long-term studies are required to describe the nature of the hearing loss. Since 2007, a multicenter Flemish CMV register collects data from children with cCMV in a prospective way. The first objective is to extensively describe the audiological follow-up until the age of 6 years in a large group of cCMV patients. The correlation of hearing phenotype with viral load and timing of seroconversion will be innovative. Systemic valganciclovir is the gold standard for symptomatic cCMV patients, although its impact on hearing remains contradictory. For our second objective, we will perform an explanatory research to estimate the effect of (val)ganciclovir on hearing outcome. The third purpose is to investigate the effect of local therapy in a mouse model, in order to avoid the current systemic side-effects. With this research project, we aim to provide a more suitable approach for cCMV associated hearing loss" "Development of allele-specific CRISPR-nuclease gene therapy for late-onset sensorineural hearing impairment in a new humanized DFGNA9 mouse model." "Rik Gijsbers" "Molecular Virology and Gene Therapy" "Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. At current, it is believed that the presence of aberrant COCH proteins in the extracellular matrix (ECM) of the inner ear leads to local cell damage resulting in progressive hearing loss. Within Belgium and the Netherlands, there are > 1000 patients affected by the P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness and balance loss. Furthermore, there are over twenty different COCH mutations identified in people from all over the world that lead to SNHL. Given the genetic nature of this disorder with highly specific mutations, as well as recent advances in CRISPR-nuclease mediated gene therapeutic approaches, there is a great opportunity to develop a successful therapeutic strategy to reduce or prevent DFNA9-induced SNHL." "Communication for Children with Hearing Impairment to optimise Language Development" "Astrid van Wieringen" "Research Group Experimental Oto-rhino-laryngology" "The World Health Assembly adopted a 2017 resolution recognising Hearing Impairment (HI) as a priority worldwide health issue. Children with HI present significant risks for language acquisition, educational achievement, socio-emotional development, and well-being. Current intervention plans fail to prepare those children for academic achievement and social participation in contemporary society where the diversity of their needs is increasing. Comm4CHILD is a consortium implementing an innovative approach for optimising the communicative skills and social inclusion of children with HI. Comm4CHILD addresses the large inter-individual heterogeneity in brain plasticity, cognitive resources, and linguistic abilities, and takes full advantage of this heterogeneity to support efficient communicative skills in children with HI. A group of 15 ESRs will be trained in research and intervention in a cross-sectoral way. ESRs individual research projects are conceptualized within three focus areas or work packages: biology (i.e. anatomical variations of the cochlea and cerebral functional reorganisation), cognition (i.e. working memory, multimodal integration in communication), and language (i.e. inter-individual differences in speech intelligibility and spelling ability). The work of the ESRs will (1) enhance mapping of the factors underlying heterogeneity, (2) advance the understanding of the predictors of linguistic communicative skills, and (3) develop new intervention methods. The ESRs will become the “paediatric hearing care entrepreneurs” of the future, thanks to the collaborations between academic, industrial, clinical, and community-based partners. The output of this unique consortium is expected to have an impact across all aspects of HI children's everyday life. Specifically, Comm4CHILD will provide a significantly improved understanding of communicative and social skills that will underpin the development of innovative future treatment and rehabilitation measures." "Development of allele-specific CRISPR-nuclease gene therapy for late-onset sensorineural hearing impairment in a new humanized DFNA9 mouse model." "Vincent Van Rompaey" "Human molecular genetics, Laboratory for Experimental Hematology (LEH), Katholieke Universiteit Leuven, Translational Neurosciences (TNW)" "Hearing impairment is the most frequent sensory deficit in the human population, affecting 440 million people worldwide, whereby loss of hearing and balance has a significant impact on quality of life and society. Hearing loss is also listed by the World Health Organization as a priority disease for research into therapeutic interventions to address public health needs. DFNA9 (DeaFNess Autosomal 9) is an autosomal dominant hearing disorder caused by a heterozygous gain-of-function mutation in the COCH gene (Coagulation Factor C Homology) and is characterized by progressive late-onset (3rd-5th decade) sensorineural hearing loss (SNHL) and deafness. At current, it is believed that the presence of aberrant COCH proteins in the extracellular matrix (ECM) of the inner ear leads to local cell damage resulting in progressive hearing loss. Within Belgium and the Netherlands, there are > 1000 patients affected by the P51S COCH mutation, who – in the current absence of a disease modifying therapy – will develop deafness and balance loss. Furthermore, there are over twenty different COCH mutations identified in people from all over the world that lead to SNHL. Given the genetic nature of this disorder with highly specific mutations, as well as recent advances in CRISPR-nuclease mediated gene therapeutic approaches, there is a great opportunity to develop a successful therapeutic strategy to reduce or prevent DFNA9-induced SNHL." "Genetic and functional studies for GRM7 and GRHL2, two genes for Age-Related Hearing Impairment." "Guy Van Camp" "Human molecular genetics" "Age-Related Hearing Impairment (ARHI), the most prevalent sensory impairment in the elderly, is a complex disease caused by environmental and genetic factors. Our laboratory recently identified two susceptibility genes for ARHI, GRHL2 and GRM7. The current project will elaborate the role of these two genes for the development of ARHI by genetic and functional studies." "Genetic and functional studies for GRHL2 and GRM7, two genes for Age-Related Hearing Impairment." "Guy Van Camp, Lut Van Laer" "Human molecular genetics" "Age-Related Hearing Impairment (ARHI), the most prevalent sensory impairment in the elderly, is a complex disease caused by environmental and genetic factors. Our laboratory recently identified two susceptibility genes for ARHI, GRHL2 and GRM7. The current project will elaborate the role of these two genes for the development of ARHI by genetic and functional studies." "Identification and characterisation of genes responsible for age-related hearing impairment." "Guy Van Camp" "Human molecular genetics" "The general aim of this project is to acquire better insights into the development of ARHI, a complex type of hearing loss. To achieve this we will firstly perform additional investigations on two recently identified ARHI susceptibility genes, GRHL2 and GRM7, using genetic and functional studies." "Development of allele-specific crispr-nuclease gene therapy for late-onset sensorineural hearing impairment in a humanized dfna9 mouse model." "Vincent Van Rompaey" "Radboud University Nijmegen, Translational Neurosciences (TNW)" "Hearing loss affects 1.57 billion people worldwide and has been listed by the World Health Organisation as a priority disease for research into therapeutic interventions. DFNA9 is the most frequent hereditary disorder in Belgium and the Netherlands causing hearing loss at 20-30 years and evolving towards deafness by 60-70 years. Currently, there is no therapy available. The aim of this project is to develop a gene therapy that can delay or stop the progression of DFNA9 in the pre-symptomatic window of opportunity. Only one of the two copies of the COCH gene (one inherited from either parent), is mutated in DFNA9 and encodes for a toxic protein that affects the aging inner ear. Our therapeutic approach is designed to specifically stop the production of this mutated COCH protein, leaving the patient only with healthy COCH proteins. Earlier research has demonstrated that one healthy COCH gene is sufficient for normal hearing. It is of vital importance that protein production from the healthy COCH gene is not affected. As mutant and healthy COCH only differ by a single nucleotide, high sensitivity and specificity is essential to specifically recognize the mutant COCH gene. To achieve this, we will adapt the genetic manipulation tool ""CRISPR-Cas9"". This project will provide insight in which approach is most suitable to safely and specifically block the production of mutant COCH proteins and will lay the foundation for continued (pre)clinical development towards clinical trials." "Optimization and pharmacokinetics of allele-specific antisense oligonucleotide therapy for late-onset sensorineural hearing impairment DFNA9." "Vincent Van Rompaey" "Laboratory for Experimental Hematology (LEH), Radboud Universitary Medical Centre, Translational Neurosciences (TNW)" "Hearing loss (HL) is a growing problem in modern society, and is associated with an increased risk for social isolation and unemployment. Although the genetic basis of adult-onset HL is still largely elusive, heritability is suggested in 30-70% of cases. Lacking curative or preventive (genetic) treatments, hearing aids and cochlear implantation (CI) can relieve part of the burden of HL. However, the majority of patients with adult-onset HL still do not experience a satisfactory improvement of their auditory function with these devices. Furthermore, the outcome of CI in adult-onset cases is often less favorable as compared to CI in congenital HL cases. DFNA9, caused by mutations in the COCH gene, is amongst the best-studied forms of dominantly-inherited adult-onset HL. The c.151C>T (p.(P51S)) mutation likely occurred many generations ago, and is now estimated to cause adult-onset progressive HL and vestibular dysfunction in >1500 Dutch and Belgian individuals. The high prevalence of this founder mutation in our cohorts presents a unique opportunity to overcome the translational obstacles in the development of novel inner ear therapeutics. The adult onset of hearing loss provides a window of opportunity for therapeutic intervention. The large cohort of patients with the exact same mutation provide enough power for future clinical trials. The dominant inheritance pattern of DFNA9 implies that only one of the two gene copies (alleles) contains a mutation. These DFNA9 mutations in the COCH gene are all well-established to result in the production of toxic cochlin proteins that interfere with the function of the healthy cochlin proteins produced from the healthy allele. As such, a treatment that can block the formation of these toxic cochlin proteins has high therapeutic potential, especially when administered in an early stage of the disease. The remaining cochlin proteins produced from the healthy allele are sufficient for normal inner ear function. Recently published antisense oligonucleotides (AONs; small strands of synthetic DNA and RNA molecules) can specifically induce the degradation of c.151C>T mutant COCH transcripts, but not COCH transcripts resulting from the healthy allele (de Vrieze et al, Molecular Therapy – Nucleic Acids, 2021). In this project, we aim to further improve the efficiency and stability of our best-performing c.151C>T AON by introducing chemical modifications, and perform a series of pre-clinical validation studies in patient-derived stem cell models and a humanized DFNA9 mouse model. These data will provide a strong foundation for a swift translation of our AON treatment to future clinical trials. As there is virtually no prior art on the use of AONs to treat inner ear disorders, our studies are designed to also provide insights in the safety and feasibility of AONs a treatment paradigm of inner ear disorders in general."