2013 ATA-Funded Research
Ola Alsalman, University of North Carolina at Greensboro
Student Project: A Psycho Neural Endocrine Model of Tinnitus
Roadmap to a Cure Paths: A,B
"Stress can be caused by internal changes that result in homeostatic disturbance. Homeostatic reactions to stress caused by tinnitus involve the releasing of stress-related glucocorticoids hormones such as cortisol. Recent studies have exhibited evidence that glucocorticoids are not the sole actor in the generation of stress. However, regardless of the origin, persistent stress can lead to serious health conditions. Moreover, interaction between the hypothalamic-pituitary-adrenal (HPA) system and the sympathomedullary adrenal axis occurs within the hypothalamus, which also responds to stress, influencing the sympathetic and the HPA system. The long-term goal of this multi-disciplinary proposal is first, to investigate whether hypothalamic regulation of responses to stressful situations are involved in the experience of tinnitus; adult males will be stressed to determine whether those with tinnitus exhibit a differential adrenal and/or ANS response relative to those without tinnitus; second, to identify specific subcortical areas of influence on the experience of tinnitus, by measuring the circadian cycle and melatonin, stress and cortisol and alpha-amylase, and gonad hormones and progesterone; and, third, to build a neuro-endocrine-psychological (NEP) model that will permit the investigation of tinnitus as a consequence of the disruption of ANS and HPA regulation of stress. The approach is to obtain human hormone salvia samples in 10 male adults from the University of North Carolina at Greensboro (UNCG) with self-reported tinnitus before and after an induced stress activity and compare their hormone levels with those of a normal control group (n=10) without tinnitus. This will provide evidence regarding whether stress reactions are associated with tinnitus. The hypothesis is that differences between groups from baseline and the post stress might reveal that tinnitus group is more sensitive to the stressor. However, both groups may recover (30 and 60 min post test) equivalently, but the tinnitus group recovery will be more slowly.
Millions of people all around the world suffer from tinnitus. Studies have shown that of those patients who experience chronic tinnitus, 15% of the tinnitus population, the experience is often associated with distress (Lewis et al., 1994). For millions of them, the condition contributes to physical and psychological problems that adversely affect their ability to work and communicate and to their quality of life. Severe tinnitus can be an extremely handicapping and debilitating problem in adults, especially among the elderly; it is also a problem for young Americans who are increasingly exposed to environmental noise. Until recently, many hearing health care providers had little to offer tinnitus patients except to say that they should learn to live with it. However, new clinical research over the past decade has focused on tinnitus management (Jastreboff and Hazell, 1993). To date, only a few clinics dedicated to the treatment of tinnitus exist in the US. The lack of access to such support services results in reduced productivity and increased costs to those with the condition.
The research proposed focuses on the belief that one means to the discovery of tinnitus treatment is to deeply investigate the systems involved in causing the condition; that is not limited to the brain, but also includes the autonomic, and endocrinal systems. This research will involve health care providers gathering comprehensive case histories, interviews, tests, for subjects with tinnitus. Different service models have been utilized and successfully used before with patients with tinnitus, such as providing psychological counseling, or those implementing hearing testing (Givens et al., 2003), offering tinnitus retraining therapy (Jastreboff and Hazell, 1993). However, the use of a comprehensive neuro-endocrine-psychological NEP model of tinnitus has not been investigated previously, despite the need for such a model that looks into the involvement of three major systems, neurological, endocrine, and psychological, in the generation of tinnitus.
This research will help to:
1) Determine hypothalamic nuclei areas involved in the generation of tinnitus,
2) Identify specific subcortical areas of influence on the experience of tinnitus, by measuring the circadian cycle and melatonin, stress and cortisol and alpha-amylase, and gonad hormones and progesterone, and
3) Build a neuro‐endocrine‐psychological NEP model of tinnitus.
This neuro-endocrine-psychological model will have a significant impact on the clinical use of treatment options for patients with tinnitus. Although most people are able to ignore tinnitus fluctuating symptoms, the majority of tinnitus patients are bothered by their tinnitus and, as a result, have difficulty sleeping, concentrating on highly demanding tasks, and find that it affects their moods. Most, if not all of these symptoms point to some type of contribution of the neuro-endocrine-psychological system; this establishes a model that comprehensively investigates the role that each system plays in the generation of tinnitus and has a significant impact on the way tinnitus is approached and treated clinically.
The proposed research will identify different regions in the brain that are involved in the generation of tinnitus through the formation of a neuro-endocrine-psychological model NEP; this will identify areas in the brain and the hypothermic nuclei that exhibit abnormalities (path A). That will determine the role of the neural and endocrine systems that cause tinnitus and the psychological impact on tinnitus patients through the identification of the underlying mechanisms of neural and endocrinal abnormalities (path B)."
Jake Richard Carpenter-Thompson, University of Illinois at Urbana-Champaign
Student Project: The Effect of Exercise on Tinnitus Severity
Roadmap to a Cure Paths: A,C
"The long-term objective of our efforts is to identify treatment options that decrease tinnitus-related distress. Our aims are (1) to identify any existing relationship between tinnitus severity and physical activity and (2) to characterize the differences between tinnitus subjects with varying physical fitness and tinnitus severity levels using both behavior and brain imaging tools. Our hypothesis is that physical activity will be negatively correlated with tinnitus severity scores, and brain function and structure will be different between individuals with tinnitus based on fitness level. Several studies have shown fitness to be correlated with lower depression scores and improved perceived quality of life (QOL) in many populations; however, few studies have made similar connections with respect to tinnitus-related distress. Therefore, to assess the relationship between physical fitness and tinnitus severity we will conduct a two part study. First, we will distribute surveys via Survey Monkey to hundreds of individuals with tinnitus to assess the relationship between tinnitus severity and physical activity. Second, we will estimate the differential effects of fitness level and tinnitus on behavior, brain function and structure, specifically, as related to emotional processing. To assess physical fitness level, maximal oxygen uptake scores will be obtained from each subject. We will use a 3T Siemens Allegra MRI head-only scanner with a sparse sampling technique to measure brain function and brain structure with minimal scanner noise interference. The understanding attained as a result of the study will advance the understanding of the neural bases of tinnitus in general, and specifically, the effects of physical fitness.
Clinical applications of physical fitness include in-clinic exercise sessions for patients, take-home exercise program books, and consultations with professionals concerning simple self-directed exercise programs. To adopt physical fitness in the clinic, no expensive equipment or special training is needed. Simple cardiovascular workouts are available to the general public and can be easily recommended by an audiologist. Clinicians can print and disseminate the physician-approved exercise regimens recommended for older adults and inform the patients about different types of exercise to improve physical fitness. The advantage of physical fitness therapy for patients is that it is self-directed and has been shown to improve self-efficacy in older populations. Currently, clinicians in a plethora of fields including psychology, cardiology, neurology and sports medicine recommend exercise to decrease depression and psychological distress associated with a number of disorders. Clinical applications of physical fitness can be implemented in audiology clinics to alleviate tinnitus-related distress.
This research primarily fits into Path A and Path C on the roadmap to a cure. For Path A (A1, A2a,A3) we will use functional magnetic resonance imaging (fMRI) to measure changes in brain areas associated with tinnitus abnormalities will be used. Path C (C1,C2,C3a) is satisfied by testing physical fitnes s a s a therapeutic approach to treating tinnitus severity. We will use fMRI to assess the effect of physical fitness on the emotional processing network and to determine the magnitude of its therapeutic effect using structural and functional brain differences. Behavioral differences between fitness groups will also be assessed."
Berthold Langguth, M.D., Ph.D., University of Regensburg - Germany
Research Project: rTMS for the Treatment of Chronic Tinnitus: Optimization by Stimulation of the Cortical Tinnitus Network
Roadmap to a Cure Paths: B, C, D
Funded: Year 2, $50,000 (read the progress report article from the Summer 2012 Tinnitus Today)
Type: Human research study
In April 2011, our proposal “rTMS for the treatment of Tinnitus: Optimization by stimulation of the cortical Tinnitus network” was approved for funding by the ATA. In our second year our project pursues three main objectives:
- Aim 1 Is a new “multisite” rTMS treatment protocol which involves three stimulation sites more efficient for tinnitus reduction as compared to a standard rTMS protocol over the auditory cortex? (Roadmap to a Cure: path C)
- Aim 2 Is the new “multisite” rTMS treatment protocol more efficient for normalizing tinnitus-related alterations of oscillatory brain activity and connectivity as compared to a standard rTMS protocol over the auditory cortex? (Roadmap to a Cure: path B+D)
- Aim 3 Are there specific patterns of brain activity which can predict treatment response of rTMS? (Roadmap to a Cure: path D)
Our project is a two-arm randomized controlled trial. A total of 50 patients will be randomized to one of two treatment groups.Every patient will undergo an imaging procedure consisting of EEG and (f)MRI measurements in the week before the first and after the last treatment session. Additionally,psychometric assessment including the Tinnitus Handicap Inventory, the Tinnitus Questionnaire and some more questionnaires will be done at different time points, providing a detailed documentation of perceived tinnitus distress and loudness for up to three months.
Additionally, a group of 25 healthy control subjects will be assessed once (including imaging, audiogram and psychological assessment) to allow for cross-sectional comparisons between patients with tinnitus and healthy controls.Within the past months, we were able to collect pilot data in order to test a multi-site rTMS protocol with respect to its effectiveness, feasibility and safety. In this pilot study, 45 patients were treated with multi-site rTMS on ten consecutive working-days. Tinnitus severity was assessed at three time points: at baseline, after the last treatment session (day 12) and after a follow-up period of 90 days. Results were then compared with historical data from 29 patients who had been treated with a standard procedure (left temporal stimulation) in a previous
This comparison shows that both treatment protocols resulted in a similar improvement after two weeks. However, after a follow-up period of three months, the improvement of tinnitus severity remained stable in the multisite stimulation group whereas the patients receiving temporal stimulation returned to their baseline level of tinnitus severity. These pilot data suggest that multisite stimulation shows better long-term effects than temporal rTMS. Furthermore, multisite stimulation turned out to be feasible in clinical routine
and it was well tolerated by all patients. All in all, these results are very promising and highlight the need for our project which provides a randomized design and which allows for the analysis of the neural changes that come along with multi-site rTMS treatment.
Martin Schecklmann, Ph.D., University of Regensburg - Germany
Research Project: Combination of TMS and EEG: The Role of Temporal and Frontal Cortical Excitability and Plasticity in Chronic Tinnitus
Roadmap to a Cure Paths: A, B, C, D
Funded: 1-year, $50,000
Type: Human research study
Neuroscientific research indicates that temporal and frontal cortical areas are involved in tinnitus pathophysiology. Main findings come from studies with electroencephalography (EEG) and repetitive transcranial magnetic stimulation (rTMS). EEG showed altered frequency power and phase connectivity in auditory and non-auditory areas. rTMS was effective in reducing tinnitus by stimulation of the temporal, parietal, and frontal cortex. These findings and animal data indicate the relevance of deficient inhibitory processes in tinnitus. Proposed models assume hyperactivity in central auditory pathways due to deficient lateral and feed-forward inhibition within the auditory pathway together with insufficient top-down and noise cancelation processes. EEG and rTMS has their inherent limitations. EEG is measured during resting state or sound stimulating conditions revealing only correlational information. rTMS has shown to induce moderate effects with high variability and predictors for positive treatment response could not identified so far.
Here, we aim to introduce a new neuroscientific approach using the combination of two techniques (EEG and rTMS). This combination allows the investigation of basal neural processes without interference of cognitive processes. EEG will be measured before, during, and after single sessions of low-frequency rTMS of left and right temporal and prefrontal cortex in bilateral tinnitus and will be apt to measure cortical excitability and plasticity as elicited by TMS-pulse related changes in ongoing brain activity (TMS evoked potentials and oscillations) and by rTMS induced long term changes (post vs. pre rTMS). Low-frequency (1Hz) rTMS acts as inhibitory; thus, it will show the neural capability of tinnitus for inhibitory functioning. The central aims of the present research proposal are. a) Are rTMS induced neural changes in left and right temporal and prefrontal areas altered in chronic tinnitus (in contrast to healthy controls)? b) Are there differences in rTMS induced changes with respect to stimulation site (left vs. right; temporal vs. prefrontal cortex)? c) Is chronic
tinnitus a malfunction of cortical excitability or of cortical plasticity? d) Are there differences between responders and non-responders with respect to cortical excitability and plasticity? These findings will show if TMS-EEG combination measurements will be sufficient to serve as biological markers of tinnitus.
The presented study is motivated by the concept that frontal and temporal cortical areas are part of the pathophysiology of tinnitus. Within this study these very recent advances in the understanding of the neurobiological mechanisms underlying tinnitus are translated in a hypothesis-driven new assessment approach outperforming recent approaches by using combined TMS-EEG measurements.
This study directly aims at identifying tinnitus generators and the underlying neural mechanisms mirroring path A and B of the ATA’s Roadmap. Targeting frontal and temporal areas will show which area is involved in chronic tinnitus. These measurements will also shed light into the functionality of rTMS as treatment option in chronic tinnitus mirroring path C and D of the ATA’s Roadmap.
Lucien Thompson, Ph.D., University of Texas at Dallas
Research Project: Developing and Treating Tinnitus by Modulating Neuroplasticity in Hippocampus and Amygdala
Roadmap to a Cure Paths: A,B,C
Funded: Year 2, $49,659
"Tinnitus induces brain plasticity, but most research has focused upon classical auditory brain regions. Neural plasticity also occurs in limbic regions, supporting both beneficial functions like memory but also contributing significantly to pathologies like epilepsy and tinnitus. We earlier demonstrated (Goble et a/., 2009) novel and rapidly developing plasticity in firing patterns of place cells (excitatory neurons) in the hippocampus that persisted at least 24 hrs after high intensity sound exposure in our rat model of tinnitus.
In the first year of this grant we have:
1.) Better characterized the nature and time course of this plasticity of excitatory (projection) and inhibitory (local) neuron firing in the hippocampus of freely-behaving rats, with plasticity persisting > 2 weeks post-noise exposure;
2.) Compared this noise-induced neural plasticity to psychophysical (perceptual) signs of tinnitus early (immediately after noise exposure), persistently (hours to days later) and long-term (days to months later), showing that onset of hippocampal neural plasticity precedes perceptual/behavioral signs of tinnitus by more than 2 months;
3.) Shown that noise exposure is stressful, but that stress alone produces less-profound hippocampal plasticity than does tinnitus-inducing loud noise exposure;
4.) Shown that hippocampal plasticity is amygdala-dependent, i.e. blocked by temporary inactivation of the basolateral amygdala with lidocaine;
5.) Shown that D-cycloserine, a modulator of NMDA receptors, alters neuronal activity in the hippocampus of freely-behaving rats. We will complete these studies for publication, with additional critical aims to
6.) Test dose-/schedule-dependent effects of D-cycloserine to eliminate both neurophysiological and perceptual signs of tinnitus, both early after noise exposure, and also at much longer intervals, after tinnitus has been well established; and finally,
7.) Compare D-cycloserine's dose-/schedule-dependent ability to reduce or eliminate tinnitus (both the neurophysiological and psychophysical signs that we have quantified) to those of amygdala inactivation.
We work to identify neural plasticity mechanisms leading to tinnitus, then use this understanding to reduce or eliminate the disorder. The brains of rats exposed for 60 minutes to loud noise show striking plasticity. In our 1st year of ATA support, we showed that many excitatory neurons in the hippocampus, a non-classical auditory brain region, lose normal functions within minutes after intense noise exposure. They continue to exhibit aberrant activity as long as we have recorded them to date (> 2 weeks after noise exposure). Perceptual testing of these same rats show that behavioral signs of tinnitus develop more slowly, -10 weeks post-noise exposure, i.e. hippocampal plasticity precedes perceptual signs of tinnitus. If we briefly inactivate the amygdala, a stress-related region (injecting lidocaine directly into the brain after sound stimulation), we can prevent auditory-induced hippocampal plasticity. We have data showing that peripheral injections of the drug D-cycloserine (DCS) can reduce hippocampal activity. We will now test DCS as a promising treatment to prevent noise-induced hippocampal plasticity, and induce or prevent induction or maintenance of tinnitus. We will assess short- and long-term effects of DCS on both neural plasticity and on perceptual signs of tinnitus. We will also compare the efficacy of DCS (used clinically in humans at much higher doses for treatment of infectious disease) with the effects of transient amygdala inactivation to reduce or abolish signs of tinnitus.
Our research carried out in our first year of funding by the ATA encompasses aspects of Path A, Path B, and Path C of the Roadmap to a Cure. Specifically, we have: A1. identified a form of rapid onset yet persistent (>2 weeks) abnormal hippocampal plasticity induced by 60 minutes of loud noise exposure; A2a. quantitatively characterized these changes in hippocampal activity, A2b. used a behavioral pre-pulse startle paradigm to demonstrate initial absence of, and later development of, perceptual signs of tinnitus in our rat model, and to specify the precise frequency of tinnitus in each individual rat. We have: B1. shown that stress alone, as well as noise exposure, induces similar aberrant hippocampal plasticity, but that tinnitus-inducing noise exposure has a larger magnitude effect on the hippocampus; B2. shown that cortisol release post-noise exposure is enhanced, but is more significantly enhanced more by stressors; B3. shown that transient inactivation of a major stress regulating center, the basolateral amygdala (with lidocaine), prevents auditory-induced hippocampal plasticity. Finally, C1. we have shown that D-cycloserine, a drug that crosses the bloodbrain barrier, reduces hippocampal activity. We now propose to fully test this drug's dose- and schedule-dependent efficacy to reduce or eliminate neurophysiological and psychophysical signs of tinnitus in our rat model."
Pim Van Dijk, Ph.D., University Medical Center Groningen, The Netherlands
Project: Tinnitus and Tonotopic Remapping of the Auditory Cortex
Roadmap to a Cure Paths: A,B,C
Funded: Year 1, $50,000
Type: Human research study
"Several experimental tinnitus therapies aim to restore a normal tonotopic organization of the auditory cortex. However, it has never been established whether tinnitus is related to abnormalities in the cortical tonotopy. On the other hand, it is well known that hearing loss leads to reorganization of the tonotopic organization in the auditory cortex. Since tinnitus and tonotopic reorganization both are consequences of hearing loss, it has been suggested that tonotopic reorganization itself may cause tinnitus. This project will test whether tonotopic reorganization is specifically related to tinnitus. For the first time, the project uses a new state-of-the-art fMRI neuroimaging methods to robustly measure detailed tonotopic maps in subjects with hearing loss. Subjects with and without tinnitus will be tested, as well as normal hearing subjects. It is expected that hearing impaired subjects will exhibit extensive reorganization of the auditory cortex. By a comparison of subjects with and without tinnitus, it will become clear to what extent tinnitus is associated with the manifest tonotopic reorganization. The project directly tests one of the most dominant hypotheses in today’s tinnitus research. Elucidating the role of tonotopic reorganization in tinnitus will be of key importance for the development of therapies. In addition, it may provide important tools to test the effectiveness of therapies. The project will be performed in the ENT Department of the University Medical Center Groningen. This unique research environment combines scientists (clinical and basic) and clinicians in a single organizational unit.
Tinnitus is believed to be related to changes in the brain. A process referred to as tonotopic reorganization has been specifically proposed to cause tinnitus. This process may lead to an overrepresentation of particular sound frequencies in the brain, which is believed to lead to tinnitus. Today, several therapies have been proposed to restore normal tonotopy, and thereby possibly cure tinnitus. However, it has not been rigorously tested in humans with tinnitus whether tonotopic reorganization is indeed related to tinnitus. This project will directly measure tonotopy in subjects with and without tinnitus, using a state-of-the-art neuroimaging methods. If tinnitus is found to be related to tonotopic reorganization in the human brain, it will strongly stimulate the development of therapies (such a sound therapies) that aim at restoring normal tonotopic representation and thereby cure tinnitus.
This project is a step in Path A1 of the Roadmap to a Cure. It aims at identifying areas in the brain that are abnormal in tinnitus. It will measure changes in activity (subroad A2a) and may result in metrics (subroad A2b) related to tinnitus. It is also related to Path B1, where cellular populations are identified that give rise to tinnitus. The project does not directly test a therapy. However, if we show tonotopic reorganization to be directly related to tinnitus, it will directly affect Path C, the development of therapies for tinnitus."
Berthold Langguth, M.D., Ph.D., University of Regensburg
Project: Combined Transcranial Magnetic Stimulation in Treatment of Chronic Tinnitus Using Double Cone Coil
Roadmap to a Cure Paths: C,D
Funded: $50,000, 1-year project*
Type: Human research study
"It is well known that tinnitus is related to increased activity in central auditory pathways. Repetitive transcranial magnetic stimulation (rTMS) is an innovative method for locally modulating brain activity. With the idea to downregulate increased activity in the auditory cortex, rTMS has been introduced as a new treatment for tinnitus. Reduction of tinnitus by rTMS has been demonstrated in many studies, however unfortunately the over-all benefits from this treatment are only relatively small. In the last years additional brain areas have been identified, which are strongly connected with the auditory cortex in tinnitus patients. These neural networks reflect the adverse emotional reaction (i.e. the suffering caused by the sound perception) and the conscious perception of tinnitus. With the aim to attack tinnitus more efficiently we propose a new stimulation protocol using a newly developed TMS coil. The specific form of this coil allows a deeper penetration depth of the magnetic field in the brain and offers the possibility to directly modulate deeper brain structures which are known to be involved in generating feelings of suffering. We expect that this new rTMS procedure will reduce tinnitus better and in more patients than the existing procedure and will thus provide an efficient new treatment option for the many patients suffering from tinnitus.
Transcranial magnetic stimulation (TMS) has been introduced into neuroscience in 1985 by A.T. Barker (1). It consists of a technique providing a strong and focal magnetic field by a coil connected to an electrical power source. The induced magnetic field penetrates the scull easily and painlessly and leads to depolarization of neurons in mostly superficial cortical regions. It constitutes a non-invasive and well-tolerated (2) neuromodulatory approach which is known to modulate neural activity not only in directly stimulated but also functionally connected brain areas (3, 4). By repetitive TMS (rTMS) application over auditory brain areas a persisting modulation of neural activity and an alleviation of tinnitus complaints can be achieved in a subgroup of tinnitus patients (5-7). Treatment effects could be enhanced by high-frequency stimulation of the left prefrontal cortex before lowfrequency stimulation of temporo-parietal locations (8). Recent imaging studies indicate the critical involvement of the dorsal anterior cingulate cortex (dACC) in tinnitus pathophysiology. The dACC can be reached by a newly developed stimulation coil, the so-called double cone coil (DCC) (9). The angulated geometry of the double cone coil enables a deeper penetration depth of the magnetic impulse. Thus, mediofrontal stimulation with the double cone coil results in a direct influence of the dACC (9).
In the proposed study this new stimulation procedure (high frequency mediofrontal stimulation with the DCC followed by low-frequency temporoparietal stimulation targeting auditory cortical areas) will be investigated. For the assessment of the treatment effects patients will be asked to fill out a compilation of standardized and validated questionnaires. In addition, before and after the treatment consisting of 10 rTMS sessions electroencephalographic (EEG) examinations will take place. Clinical data will be stored and analyzed using the TRI Database (http://database.tinnitusresearch.org/). Data storage will be effected in a pseudonymized way, data handling and its statistical analysis will be performed according to high quality standards following a pre-defined statistical analysis plan (SAP). Additionally, clinical data will be correlated with EEG power spectra and
Jennifer Melcher, Ph.D., Massachusetts Eye & Ear, Harvard Medical School
Project: Brain Function and Attention in Tinnitus
Roadmap to a Cure Paths: A,B
Funded: $49,983 1st year of 2-year project
Type: Human research study
"The project will examine brain function during selective and involuntary attention in people with tinnitus using fMRI and a classic dichotic listening task with two novel elements:
(1) Tinnitus and non-tinnitus subjects will be matched for performance on the listening task in order to specifically image processes recruited when tinnitus subjects work to maintain normal performance. It has been hypothesized that daily “management” of tinnitus engages extra cognitive, and hence neural, resources. A first aim of this project is to identify areas of the brain that are engaged.
(2) A potent auditory distracter (the subject’s name) will be used to engage involuntary attention mechanisms. This aspect of the experimental design is motivated by a common report of tinnitus patients: that they are easily distracted or have difficulty concentrating. While it is possible that these symptoms result from the distracting tinnitus percept itself, it is equally possible that hypervigilance to the auditory domain causes people with tinnitus to be more vulnerable to hijacking of attention by any potentially salient auditory stimulus. A second aim is to examine the brain processes behind auditory distraction in tinnitus in a controlled way. We expect this project will shed light, at a physiological level, on the role of attention in tinnitus and suggest ways to inform and improve emerging attention-based tinnitus therapies
There are multiple aspects of attention controlled by different parts of the brain. For instance, we sometimes pay “selective” attention to a particular thing – someone’s voice, for instance - or ones tinnitus. The focus of attention can sometimes be controlled voluntarily or, it can be involuntarily captured, for instance by someone calling your name or, again, by tinnitus. This project begins to examine whether the brain processes of selective and involuntary attention are different in people with tinnitus and if so how. There are already researchers working on tinnitus therapies that involve attention training exercises. Our hope is that this project shows ways to improve on these therapies, perhaps by showing which aspects of attention need shoring up.
The research seeks to understand brain processes underlying the condition of tinnitus and thus intersects paths A and B in the ATA Roadmap. By working directly in people with tinnitus and on an aspect of tinnitus that is being targeted by therapies, this project also has a clear eye toward path C."
Josef Rauschecker, Ph.D., Georgetown University Medical Center
Project: Tonotopic Map Reorganization and the Effects of Frequency Discrimination Treatment in Tinnitus
Roadmap to a Cure Paths: A,C,D
Funded: $50,000 1st year of 2-year project
Type: Human research study
"Tinnitus research has shown that tinnitus is associated with changes in central auditory as well as limbic structures. However, it is unclear which of these changes, if any, cause tinnitus and which are simply byproducts of the disorder. This project tackles this problem in two ways. First, it assesses whether auditory tonotopic map distortions, thought by some to underlie the tinnitus sensation, occur only in tinnitus patients or in all cases of hearing loss. The latter finding would rule out tonotopic distortion as the ultimate cause of tinnitus. Second, the project investigates a low-cost, non-invasive web-based treatment for tinnitus and identifies areas of the brain responsible for the effectiveness of this treatment. Identifying the brain-bases of symptom improvement would reveal crucial targets for future treatments, and could be used to refine existing treatments.
Tinnitus is a common auditory disorder with largely unknown pathophysiology and no cure. It has been proposed that tinnitus results from loss of peripheral sensory input (usually due to hearing damage) and subsequent distortion of central tonotopic maps. While such distortions have been measured in animals with tinnitus and hearing loss, comparable evidence from human tinnitus patients is lacking. Moreover, none of these studies controlled for hearing loss, leaving open the question whether the observed distortions reflect a normal response to peripheral damage or a pathological process generating tinnitus. Nevertheless, the tonotopic reorganization hypothesis persists and is the theoretical basis for various “sound therapies” of tinnitus. The studies will address these issues by critically examining the relationship between tonotopic map reorganization and tinnitus, and by determining the neural sites of action for sound therapies. Aim 1 of this project uses high-resolution functional magnetic resonance imaging (fMRI) to compare tonotopic maps of tinnitus patients with those of controls matched for hearing loss. Aim 2 is to identify the neural sites of action for sound therapies of tinnitus. Frequency discrimination training is known to increase the cortical representation of trained frequencies in healthy subjects, and is thought to attenuate tinnitus by reversing tonotopic map distortions. However, while such training seems to alleviate tinnitus to some extent, its effects on tonotopic maps has not been demonstrated directly. The studies will use high-resolution fMRI to compare tonotopic maps of tinnitus patients before and after 30 days of a web-based frequency discrimination training to investigate 1) how training affects tonotopic maps, and 2) whether symptom improvement is tied to specific tonotopic map changes or to changes in limbic areas known to be altered in tinnitus. These results will help determine which changes are crucial for alleviating tinnitus, so that future treatments can be focused accordingly.
The research project overlaps with Paths A, C, and D of the Roadmap. It addresses the question of whether tonotopic map distortions occur in all cases of hearing loss, or only in tinnitus patients. While tonotopic map distortions are a proposed source of the tinnitus signal, to date there is no direct evidence that such distortions occur exclusively in tinnitus (Path A: Identification of Generators). Second, the project investigates the efficacy and neural sites of action for acoustic-behavioral therapy, which has shown some success in alleviating tinnitus. Our proposed treatment variation (specifically targeting low frequencies) has never been tested and can therefore be considered “Development of Therapy” (Path C). Finally, the combination of pre/post-treatment fMRI and treatment success measures will identify the neural sites of successful treatment, and will thus serve as a guide for further refinement of the treatment (Path D)."
Sarah Hayes, State University of New York at Buffalo
Student Research Project: Contribution of Stress to Tinnitus Generation: Role of GABAergic Inhibition
Roadmap to a Cure Path: B
Funded: 1-year student grant, $10,000
Type: Animal research study
"Although the majority of tinnitus patients suffer from hearing loss, not all individuals with hearing loss develop tinnitus. This discrepancy emphasizes the need to better understand factors that may increase the susceptibility of individuals to tinnitus generation. One such factor may be chronic stress and its effects on GABAergic inhibition. Although clinical observations and subjective reports from tinnitus patients suggest a link between stress and tinnitus, they provide only anecdotal evidence that stress may contribute to tinnitus susceptibility. Elucidation of a cause and effect relationship between stress and tinnitus generation requires a study in which both hearing loss and the level of stress are tightly controlled for; something that can only be done in an animal model. By screening for behavioral evidence of tinnitus in noise-exposed rats with or without prior exposure to chronic restraint stress, this study will determine whether stress increases the incidence of noiseinduced tinnitus. Additionally, given the known ability of chronic stress to reduce GABAergic inhibition in a number of brain regions, this proposal will be the first to investigate whether chronic stress can alter GABAerigic inhibition in the auditory pathway by quantifying protein levels of the GABAergic markers GAD65/67 and the GABAA receptor α1 subunit. Given that a loss of inhibition in the auditory pathway is believed to play a significant role in tinnitus generation, stress-induced changes in inhibition may underlie a potential mechanism in which stress can contribute to the development of tinnitus. Understanding the contribution of stress to noise-induced tinnitus may help identify individuals at increased risk for developing tinnitus and may lead to novel preventative and treatment strategies.
This proposal addresses Path B of ATA’s Roadmap to a Cure (Elucidation of Mechanisms of Tinnitus Generation). The goal of the experiments is to better understand how factors such as stress contribute to tinnitus generation by altering GABAergic inhibition along the auditory pathway. A better understanding of how stress-induced changes in GABAergic inhibition can contribute to tinnitus generation, can lead to future development of therapies to prevent and treat tinnitus (Path C, Development of Therapy)."