ATA-Funded Research

The following four* grants were selected by ATA's Scientific Advisory Committee in March 2012 and approved for funding by the ATA Board of Directors in April 2012.
 

 

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
connectivity."
 

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 1^st 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 1^st 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)."

 

 

*Note: Dr. Langguth's proposal was evaluated by a special subcommittee of the ATA Scientific Advisory Committee and approved by the ATA Board of Directors in June 2012. This grant was graciously funded by an ATA member.