Research Project 1, Marseille, France
New approaches to assess the psychoacoustic properties of tinnitus and differentiate tinnitus sub-types
The global goal of the thesis is to create new psychophysical tools to study, characterize and/or treat tinnitus and hyperacusis. My first project consists in creating a new assessment and outcome tool for hyperacusis. To do so, I created a database of pleasant and unpleasant natural sounds which I will present to a hyperacusic population and a normal population. Their goal will be to judge them on a pleasant to unpleasant visual analog scale. Hyperacusic sufferers will be recruited in collaboration with the Claireval clinic in Marseille. With the data, we will identify differences between and within populations. Dimensionality reduction techniques, like multiple factorial analyses, will be used to identify possible clusters of populations. The tool will be designed with an interactive interface for possible use by clinicians. Moreover, I will further elaborate and test residual inhibition protocols previously designed by our team. Other collaborations include the design of a new hyperacusis questionnaire and observation of tinnitus-related EEG modulations.
Research Project 2, Copenhagen, Denmark
Characterization of supra-threshold listening deficits in listeners with tinnitus
Tinnitus describes the perception of a phantom sound in the absence of acoustic stimulation. The severity reaches from subtle annoyance to extreme cases with severe implications on everyday life. The possible mechanisms underlying tinnitus are manyfold and not yet clearly understood. Because tinnitus is often reported in connection with hearing impairment, understanding the interplay between hearing impairment and tinnitus will provide important information about the underlying mechanisms. This Ph.D. project focuses on the specific case of tinnitus sufferers with audiological normal hearing, to avoid misleading results coming from the grouping of subjects with different acoustic profiles. In these listeners, the tinnitus was often initiated by noise trauma. It has recently been shown in animal models that excessive noise exposure can lead to permanent changes in the inner ear without affecting sensitivity to sound, commonly referred to as “cochlear synaptopathy”, or “hidden hearing loss” (since no increase in the hearing threshold can be assessed). Making use of recent insights within cochlear synaptopathy, behavioral outcome measures will be combined with novel approaches based on non-invasive electrophysiology, imaging and computational modeling to quantify the presence of tinnitus in these listeners. The hypothesis that cochlear synaptopathy could be one of the feasible causes of tinnitus comes from the suppositions that both the phenomena are related to deafferentation and consequential central gain effect. Deafferentation is related to the decrease of afferent connections with the nerve cells and “Central gain” means that the central auditory pathways can generate hyperactivity to compensate for this loss of information. This hyperactivity is thought to be a possible driving cause of tinnitus. Finding a connection between tinnitus and cochlear synaptopathy will provide important insights toward the development of better diagnosis and treatment methods.
Research Project 3, Erlangen, Germany
Neural markers of sustained perception: Clinical diagnostics for acute and chronic subjective tinnitus
The research project will investigate the tinnitus-related neural activity patterns in tinnitus patients and healthy subjects with acutely induced phantom sound percepts by detailed analysis of multichannel MEG/EEG recordings. In particular, the ‘attractor-like’ dynamics of spatiotemporal activity patterns associated with the emergence and disappearance of subjective tinnitus will be described using novel statistics and compared to the respective local field potential (LPF) and spike recordings in auditory cortex of animal models for tinnitus in a companion project (ESR12). We expect the spatiotemporal cortical activation patterns to differ significantly between different perceptual states: By comparing patterns related to the perception of pure tones with different pitches with those measured during the perception of tinnitus it will be possible to provide an objective, physiological marker for the tinnitus percept in general, as well as an estimate of the perceived tinnitus pitch, rather than being reliant on subjective questionnaires. The results of this translational approach will extend our understanding of the physiological basis of subjective tinnitus and provide objective, diagnostic markers for its characterization, both in animal research and clinical therapy.
Researc Project 4, Groningen, The Netherlands
Relating a behavioral model and brain activity in mice by fMRI
Punitkumar received his Diploma’s degree in Biomedical Engineering from Gujarat Technological University, India (2011-2014); and his Master’s degree in Biomedical Technologies from Eberhard Karls University of Tübingen, Germany (2015-2018). His Master’s thesis was focused on resting-state functional MRI in the rodent at 14 Tesla: technical developments and application to Alzheimer’s models (2017-2018: Centre d’Imagerie Biomédicale, EPFL, Switzerland). He joined TIN-ACT group in 2018 as a Marie Curie early stage researcher at University Medical Center Groningen, Netherland under the supervision of Prof. Dr. Pim van Dijk, Dr. Sonja Pyott and Drs. Ing. Kees van de Kolk. His Ph.D. research is focused on relating a behavioral model and brain activity in mice by fMRI.
This TIN-ACT project is based on the hypothesis that tinnitus is caused by a maladaptive response of the brain to hearing loss. Main objectives are to test this hypothesis by (1) development and optimization of behavioral measurements to assess tinnitus in mice; (2) development of MR spectroscopy (MRS) and functional MRI (fMRI) protocols to measure neurotransmitter levels and functional responses in mice brain, respectively; (3) optimization and comparison of neurotransmitter levels and functional responses between control and tinnitus induced mouse models; (4) correlation between MRI results and behavioral indicators of tinnitus; and (5) cross-validation of mice MRI results by comparison of MRI results those already obtained in human. In summary, the main goal of this project is to develop mouse model of tinnitus, support by both behavioral and MRI testing.
Research Project 5, Berlin, Germany
Biomarkers of tinnitus-related distress in chronic tinnitus patients
This research project investigates the characteristics of stress-related changes in patients with chronic tinnitus. The main aim of the project is to determine the presence of biomarkers that reflect tinnitus-related distress in adults. The presence and kinetics of biomarkers will be studied using biological samples obtained from a large group of chronic tinnitus patients. Prospective relationships between biomarkers, psychological status (depression, anxiety, insomnia) and tinnitus severity and associated distress will be investigated. The expected results include the identification of biomarkers that correlate with psychometric measures of tinnitus-related distress and that are sensitive to psychological treatment responses. Moreover, the severe (decompensated) and less severe (compensated) forms of chronic tinnitus are expected to show a distinct pattern of biomarker expression. The identification of such biomarkers might potentially be used to improve clinical care of tinnitus patiënts.
Research Project 6, Marseille, France
Investigating the neurophysiological mechanisms of the Zwicker tone
Tinnitus is an auditory perception of varying intensity and pitch without the presence of external stimuli. Tinnitus is a symptom and can be the result of various causes including exposure to loud noise, hearing loss due to aging, or high-dose of salicylate. Tinnitus can have a significant impact on a patient’s quality of life. Still, the neural mechanisms of tinnitus are unclear. The Zwicker tone is a transient auditory perception that can be triggered by a broadband noise con¬taining a spectral gap. It is an auditory illusion perceived after the stimulus presentation and during silence. The pitch of this phantom perception corresponds approximately to the center of the spectral gap of the inducer. The Zwicker tone can be interpreted as a model of transient tinnitus due to their similarities. Indeed, both central tinnitus and the Zwicker tone can be induced by a “spectral gap”, the missing frequency band being the hearing loss frequency region for tinnitus. Moreover, the pitch of the two percepts corresponds to the missing frequency band. Assuming that the Zwicker tone mimics tinnitus sub-type resulting from sensory input discontinuities, we will investigate its neural mechanisms in animals using the cortical recording (multi-unit activity and local field potential). Overall, our project is aimed at understanding further the mechanisms of tinnitus.
Research Project 7, Nottingham, United Kingdom
Selecting evidence-based measures to assess core outcome domains for sound-based interventions for chronic subjective tinnitus in adults
My project aims to establish an evidence-based standard for how the core outcome domains for sound-based interventions for chronic subjective tinnitus in adults should be measured. The core outcomes identified from the COMiT’ID study for sound-based interventions will be used. These are the ability to ignore, concentration, quality of sleep, sense of control and tinnitus intrusiveness. The process will first identify existing instruments for each of the core domains and second will gather information on each instrument’s psychometric properties. The evidence will then be synthesized and evaluated to inform recommendations for the instrument with the “best” supporting evidence. Gaps in evidence will be highlighted and which will inform recommendations for developing a new tool where necessary. The overall ambition for my project is to use this standardized measure across sound-based interventions for comparison, for example between hearing aids, cochlear implants, and sound algorithms.
Research Project 8, Groningen, The Netherlands
Focused fMRI and brainstem evoked response audiometry to probe the brainstem mechanism in tinnitus
In this research project, I will focus on attaining an informative tonotopy of the human brainstem, particularly the inferior colliculus as a prominent subcortical auditory region, in tinnitus patients. Comparing the function of the brainstem in the tinnitus group with the normal hearing group may reveal a tonotopic reorganization in the diseased subjects, as the animal experiments have already reported that. The data acquisition in this project will be accomplished by fMRI. Thanks to the dense vascular network in the brain, the hemodynamic response in each region is strongly associated with the activity in the same area. However, due to the miniature size of the inferior colliculus, the conventional fMRI cannot return informative results. Thus, an advanced zoom-technique in MRI by Siemens will be employed to achieve functional images with higher resolution in different small subcortical areas. By applying several sound stimulations with different frequencies to the subject, the fMRI scanner acquires high-resolution activity map of the subcortical auditory region. This experiment will be combined with Brainstem Evoked Response Audiometry (BERA) to elevate the accuracy of the fMRI result by correlating the outcomes of both data acquisition methods.
Research Project 9, Nottingham, United Kingdom
Measuring the brain’s neurochemistry in tinnitus and hearing loss using non-invasive Magnetic Resonance Spectroscopy
“This project is focused on measuring alterations of the brain’s neurochemistry in tinnitus and hearing loss using non-invasive Magnetic Resonance Spectroscopy (MRS). This is an innovative approach to make use of advanced neurotransmitter MRI technology (MEGA-PRESS detection of γ-aminobutyric acid [GABA] and Glutamate [Glu]. Applying these advanced techniques both at 3T and in selected cases at 7T will allow important novel understanding of adaptive and maladaptive brain processes associated with tinnitus and hearing loss. GABA is thought to be crucial in maintaining the balance between excitation and inhibition. Decreases in GABA production and signaling are known to contribute to hyperexcitable states such as epileptic seizures. Glu is the most prevalent excitatory neurotransmitter. Damage to the inner hair cells of the cochlea causes the release of excessive Glu and the phenomenon of excitotoxicity (animal studies). Sedley and colleagues at the University of Newcastle showed a decrease in GABA in tinnitus, unrelated to the degree of hearing loss. But they used a 3T scanner and could not measure Glu. We intend to use 3T and 7T and special sequences to improve metabolite differentiation and extend the study to the dynamic assessment of GABA changes during auditory stimulations. Results will indicate whether subsequent pharmacological targeting of GABA/GLU synapses has the potential to alleviate tinnitus symptoms.”
Research Project 10, Groningen, The Netherlands
Biophysical mechanisms of the imbalance between excitation and inhibition in tinnitus
The project “Biophysical mechanisms of the imbalance between excitation and inhibition in tinnitus” will explore mechanisms leading to altered neural activity in central auditory pathways in tinnitus. Electrophysiological and imaging studies from both humans and animals have shown that tinnitus is accompanied by increased spontaneous firing rates of neurons in the central auditory system. However, the molecular and cellular mechanisms underlying these changes in spontaneous activity are not fully understood.
The aim of the present project is to identify molecules involved in changed neuronal excitability. Animal models with noise-induced hearing loss with and without tinnitus will be used to elucidate how damage to the peripheral auditory system alters the balance between excitation and inhibition in auditory brain areas. An initial focus of this project will be to examine the role of chloride ion homeostasis in regulating neuronal excitability via GABAergic signaling. Although in the mature brain GABA acts as an inhibitory neurotransmitter, its effect depends on the transmembrane chloride ion gradient of the postsynaptic neuron. In this project, the hypothesis that changes in chloride ion homeostasis switch GABA activity from inhibition to excitation will be tested. This work will require a combination of behavioral assessments of tinnitus as well as molecular and electrophysiological techniques.
Additional work will aim to more generally identify the molecular mechanisms underlying altered excitability along the length of the auditory pathway. Overall, this project will identify the molecular mechanisms underlying tinnitus generation and, thereby, indicate novel approaches to treat and prevent tinnitus.
Research Project 11, Berlin, Germany
Stress-induced changes in the animal auditory system
Emotional stress is a common aspect of life. Clinical evidence suggests that there is a link between tinnitus and stress. The main aim of this research project is to determine the quantitative and qualitative changes occurring in the auditory system of animals upon exposure to experimental stress. These changes are measured on the functional level using evoked auditory brainstem responses (ABR), Distorted Product Otoacoustic Emissions (DPOAE) and on the protein expression and localization levels using the Western blot and immunohistochemistry. Strain-dependent (Wistar and Lewis rats) differences of the auditory response to emotional stress, already suggested a possible role of genetic background as a factor influencing tinnitus resilience. In the present project, we will focus on studying possible changes occurring in the auditory system of Fisher 344 rats. We expect to determine, which proteins are affected by stress in the auditory pathway and which cells produce these proteins. Finally, by comparing the three rat strains (Wistar, Lewis, and Fischer), we will investigate the correlation between lower and higher levels of target proteins in the auditory brain and the functional performance of auditory system. The difference between rat strains might provide different models for testing therapeutic tinnitus interventions that might in the future be applied in the clinical practice.
Research Project 12, Erlangen, Germany
Neural markers of sustained perception: Animal model for acute and transient subjective tinnitus
High-doses of salicylate reliably induces transient tinnitus in humans as well as in animal models as tested with several different behavioral paradigms. A second way to induce the phantom sound of tinnitus is noise exposure (trauma), also investigated with several different testing methods. I will investigate if salicylate induced tinnitus shares a common mechanism of development with the noise trauma-induced phantom percept. In particular, I will characterize the effect of the salicylate on auditory brainstem response (ABR), gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and auditory cortex recordings and will compare these results with previous studies from noise trauma. The neurophysiological data will be analyzed with both the common statistical analysis and with the multidimensional cluster statistics (MSC) to analyze multichannel sustained recordings. With this last methods, I will be able to analyze stimulus-specific spatiotemporal activity patterns to see if they are significantly different from each other and from possible phantom percepts.
Research Project 13, Copenhagen, Denmark
Exploring innovative hearing aid techniques for tinnitus treatment
Currently, no routine treatment exists for tinnitus patients, despite the fact that an estimated 10-15 % of the adult population suffer from the perception of phantom sounds. The difficulties in implementing a routine treatment is in part due to large individual variabilities and in part due to the many tinnitus comorbidities seen in patients such as stress, insomnia, and depression. The current project investigates the use of sound therapy as a treatment for tinnitus. The aim is to develop improved methods for the management of tinnitus by means of combination hearing aids that provide both standard hearing aid and sound therapy. Certain forms of sound therapy have shown long-term improvements in tinnitus patients, but there are still large intra-individual variabilities in treatment outcomes. The project addresses this issue by investigating acute sound therapy induced changes in tinnitus-related distress using psycho- and electrophysiological markers. These acute changes will also be related to the long-term tinnitus improvement, which in the future will allow us to optimize the individual treatment parameters based on the acute response. Furthermore, it has been hypothesized that more advanced hearing aid processing approaches based on more complex features of the hearing profile, can be more successful in normalizing the cause of tinnitus. Therefore, it will be investigated whether these more complex hearing aid settings can provide long-term tinnitus improvements to patients, that otherwise don’t benefit from the treatment.
Research Project 14, Marseille, France
Developing customized acoustic stimulation to improve tinnitus
My interest in tinnitus emerged from the lack of treatment for this debilitating condition. During my research project, I will be working on developing a personalized acoustic stimulation that aims at reversing the maladaptive plasticity in the auditory cortex resulting in this symptom; by stimulating at the frequency of the hearing loss and restoring sensory input. In fact, following the offset of an appropriate masking stimulus, tinnitus may remain suppressed for a short period of time (typically less than one minute). This phenomenon is known as residual inhibition. Recently developed in the laboratory, an acoustic sequence made of pulsed stimuli has been demonstrated to induce residual inhibition (Fournier et al., 2018). The idea behind my project is to customize this pulsed signal for each patient using psychoacoustic measures and thus, to maximize the balance between the depth and the duration of residual inhibition and listening comfort. In this perspective, we will test a large sample of patients (recruited in collaboration with the IMERTA clinic in Marseille) to determine the short-term and long-term effects of this personalized acoustic stimulation on tinnitus. If after a short-time exposition (one/two sessions of 30 minutes approximately), this pulsed signal is effective at achieving lasting residual inhibition, it could be used by the patient during tinnitus crisis or before going to bed (similar to taking a pill before or during a headache). It would also be relevant to explore if a long-term exposition to this acoustic stimulation, for several hours during weeks will help in reducing tinnitus loudness, extending residual inhibition duration, or even suppressing tinnitus permanently.
Research Project 15, Belgium & Utrecht, The Netherlands
Tinnitus management through electrical stimulation in cochlear implant users
My name is Kelly Assouly. I studied Health Science engineering at Télécom Physique Strasbourg, in France. With a master thesis at the EPFL –Switzerland- in relation to the development of an innovative nerve stimulation device, I received an MCs degree of Micro and Nanoelectronics from the University of Strasbourg in 2018. During the years of study, I specialized in Innovative Therapies and had the chance to participate to neuroscience clinical research projects such as the Brain & Mindfulness project in the CRNL in France and the Walk Again project in the AASDAP, Brazil. My main research interests are the electrical stimulation of the nerve, cochlear implant technology, and clinical trials. Started in November 2018 when I joined Cochlear Technology Centre in Belgium as well as the University Medical Center of Utrecht, in the Netherlands. During my Ph.D., I will work on tinnitus management through electrical stimulation in cochlear implant users. Within the Tin-ACT project, we will conduct a randomized controlled clinical trial at the UMC Utrecht in order to evaluate the performance of cochlear implants as a potential treatment for tinnitus. For this purpose, I will implement personalized tinnitus suppression algorithms integrated in the cochlear implant processor. The goal will be to evaluate and further develop a therapeutic protocol to suppress tinnitus for cochlear implant users.
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