Tinnitus Research Workshop

The NIDCD held a workshop to bring together key people currently doing clinical and basic research in central mechanisms and treatments in tinnitus and others who are outside the field of tinnitus research, but who do work that might be relevant to the field. The workshop also included patients with tinnitus and related co-morbid conditions who were asked to present their work, discuss their findings and give advice to the NIDCD about potential new opportunities for tinnitus research and research training. The workshop panel was composed of a diverse group of experts. The workshop was organized by Lynn Luethke, Ph.D., Division of Scientific Programs, NIDCD/NIH, co-sponsored by the Office on Dietary Supplements/NIH, and was chaired by Richard Salvi, Ph.D., State University of New York, Buffalo.

The meeting began at 8:30 a.m. with opening remarks from NIDCD director James Battey, Jr., M.D., Ph.D., who welcomed the panelists and attending guests. Dr. Luethke then made opening remarks, stating the background and goals for the workshop. She informed the group that this workshop was not intended to develop a consensus statement or a prioritized list of recommendations, but was more an educational forum with some specific questions to answer. Those questions included: 1) Are there unique opportunities for new collaborative efforts across relevant fields to advance research for understanding the central mechanisms and treatments of tinnitus? If so, what are the major opportunities for and impediments to such research? 2) What are some obvious immediate opportunities for high-payoff research in tinnitus? 3) What are some longer-term efforts that should be pursued? 4) We need to attract students, postdocs, and new investigators to collaborate with tinnitus researchers. What are training needs/opportunities? Following the brief opening remarks, Dr. Salvi chaired and moderated the meeting.

The program agenda was specifically designed for a diverse group of scientists, clinicians, and patients to come together, share their research interests, and discuss the questions posed. Each speaker was given a 20-45 minute time slot that included some time for questions. Periods for discussion were also built into the agenda. Following the concluding remarks of the last speaker, a general discussion period was held to discuss the questions posed. The input was also accepted following the meeting. Common themes emerged and are highlighted below. The workshop adjourned at 12:30 p.m. on December 6, 2005.

Summaries of Responses to Questions Posed to Workshop Participants

There were many responses to each question and input was not limited to the workshop panel, but was solicited from all participants and attendees at the meeting. Several responses overlapped and were identified as short-term opportunities by some and as long-term opportunities by other responders. Such responses were placed into one or both categories, with some modifications as appropriate. The NIDCD plans to pursue some of these excellent suggestions and hopes that others find this document useful.

1) Are there unique opportunities for new collaborative efforts across relevant fields to advance research for understanding the central mechanisms and treatments of tinnitus? If so, what are the major opportunities for and impediments to such research? There was consensus that there are unique opportunities for new collaborative efforts in this area. Some of the opportunities identified include:

• Develop a consortium of government (including military), academic and industrial partners to foster research and development of products to meet the needs of those with tinnitus.
• Clinicians and researchers in tinnitus should partner with those in the industry to understand the unique needs of the industry as the industry tries to target drug and product development.
• NIDCD should develop initiatives with other Institutes and Centers within NIH regarding a “higher-level” view of tinnitus as a symptom of a neurological disease rather than just a localized hearing disease.
• Develop centers of excellence for tinnitus research and have these centers share resources with people around the country.
• Foster collaborations between labs focused on the auditory component of tinnitus and labs interested in mechanisms underlying attentional control and emotional responses to sensory stimuli. These efforts would help to bridge the gap between the study of auditory aspects of tinnitus and studies of the emotional and attentional aspects of tinnitus.
• Foster collaborations between labs studying the cortex and those studying the brainstem to facilitate an understanding of what the different levels of the auditory system contribute to tinnitus.
• Create mechanisms to support translational work both from “bench to bedside” and from “bedside to bench.”
• Create ways to encourage multidisciplinary approaches to tinnitus (e.g., combine tinnitus research with pain, memory, and consciousness research).
• Focus on international collaborations, recognizing unique opportunities for research that cannot be conducted in the United States and the unique contributions of international researchers in tinnitus research.
• Recruit senior scientists/scholars with interest and motivation to rigorously review the literature and propose redefinitions of various aspects of the field of tinnitus research.
• Target efforts for high-risk/high-yield proposals involving collaborative investigator teams that may be optimal for the economy of effort and cross-fertilization of complementary pools of expertise.
• Mobilize a managed, multidisciplinary effort, following the Defense Advanced Research Project Agency (DARPA) model, to achieve a phased set of milestones (and health care deliverables) toward mitigating the effects of tinnitus. The plan should include parallel basic and translational research.
• Expand treatment of tinnitus beyond the fields of audiology and otolaryngology, to include expertise from psychology, psychiatry, and pain treatment.
• Continue to have workshops like the current one to keep a regular focus on tinnitus.

Some impediments to such research include:

• Lack of funding.
• Difficult to get grants reviewed favorably because review committees tend to be risk-averse and are seldom interdisciplinary.
• Different cultures/languages/needs of the various potential partners across academia, industry, government, private practice, non-profits, etc.
• Current mechanisms often make across-institution collaborations more costly and more administratively “burdensome.”
• Not enough large centers exist with both basic auditory neuroscience and clinical expertise for “in the hallway” discussions which often foster new ideas for research.

2) What are some obvious immediate opportunities for high-payoff research in tinnitus?

• Conduct research on promising therapies using electrical stimulation in the auditory system (at all levels) and/or in non-auditory areas that might contribute to tinnitus.
• Conduct an in-depth review of the literature on tinnitus to better understand the needs and opportunities for research, as well as to develop treatment guidelines to support the use of various treatment modalities for patients.
• Develop objective measures of tinnitus (including those that characterize the variety of phenotypes seen in clinical practice).
• Develop low-cost measures of tinnitus assessment and treatment so that clinical and research centers have easy and affordable ways of diagnosing tinnitus and treating patients.
• Initiate studies to refine the phenotypic characterization of tinnitus.
• Use multiple animal models to establish methods such as high-throughput analyses of transcripts and proteins to identify the genomic and proteomic changes in cell processes in different brain structures. These studies would generate longer-term projects to understand the pathophysiology of tinnitus.
• Develop better animal models (including a primate model of tinnitus) to better predict which drugs and devices will work in humans.
• Develop awake-behaving animal models to eliminate the confounding effects of anesthetics.
• Build on existing animal models to further elucidate mechanisms of tinnitus (including the neurochemical/molecular correlates of tinnitus and related disturbances in the CNS).
• Develop animal models that allow for the assessment of tinnitus-evoked reactions as “a problem” versus just the perception of tinnitus.
• Develop animal models that separate the effects of hearing loss from tinnitus (similarly, recognition of the high prevalence of decreased sound tolerance in tinnitus and assuring that tinnitus research is not affected by hyperacusis).
• Support research to understand the pathophysiological differences between different forms of tinnitus (e.g., white noise, pure-tone, unilateral, bilateral).
• Expand imaging studies to include lower brainstem structures and include new techniques and/or combinations of techniques.
• Develop guidelines for clinicians who work with patients with cochlear implants and tinnitus to optimize both hearing and reduction of tinnitus.
• Contact sponsors of current clinical trials in associated CNS disease areas to see if questions about tinnitus or other aspects of tinnitus could be addressed in those trials.
• Study patients who have had their tinnitus treated successfully.
• Initiate or support pharmacological studies to better define the various sub-groups of patients with tinnitus and target therapies to those sub-groups.
• Initiate studies to identify neural connections between auditory, pain, and limbic pathways.
• Encourage publishing negative results (especially for clinical trials).
• Develop a research program geared toward the prevention of hearing loss and tinnitus in the military.
• Have relevant existing research programs ‘add’ tinnitus research to their programs.
• Test the effects of acoustic manipulations that might activate pathways that can modulate activity shown to contribute to tinnitus.
• Develop better drug-delivery technologies.

3) What are some longer-term efforts that should be pursued?

• Identify and understand individual variability among tinnitus patients to define the various sub-groups, determine the size of the various sub-groups, and determine the etiology for each sub-group.
• Characterize tinnitus phenotypes using psychoacoustic measures, imaging technologies, or other means.
• Determine factors that predispose a patient to be bothered by tinnitus.
• Study the time course of development of tinnitus to better understand the underlying mechanisms.
• Determine if animal models of tinnitus are necessary for preclinical studies of therapeutics in humans.
• Study all aspects of tinnitus in children (almost no research has been done on tinnitus in children).
• Initiate clinical trials of promising pharmacologic or behavioral or other therapies for tinnitus.
• Identify where in the central nervous system (including non-auditory areas) tinnitus is produced.
• Understand the different mechanisms of action for the various types of tinnitus so that therapeutics can be better targeted to the different types of tinnitus.
• Develop in vitro cell-based assays for drug testing.
• Identify useful markers on relevant cells associated with tinnitus (both genetic and protein surface) that can be used to target these cells (then agents might be developed targeting such cells specifically to reduce side effects resulting from drug exposure to non-diseased cells).
• Study chemoprotective (e.g., antioxidants) agents or other means (e.g., education) to prevent tinnitus.
• Study the relation of the limbic and autonomic nervous systems to tinnitus.
• Initiate prospective epidemiologic studies to determine the factors that induce the onset of tinnitus.
• Elucidate the genetic factors that contribute to tinnitus.
• Understand the molecular and cellular bases of tinnitus (including the role of apoptosis).
• Extend holistic view to examine tinnitus as a subset of larger classes of phenomena such as reactions to deafferentation or sensitivity to pain/irritation.
• Support studies of the emotional reaction to tinnitus within the context of emotion theory (e.g., responding with anxiety vs. defensive anger).
• Evaluate the benefits of complementary and alternative methods to treat tinnitus.

4) We need to attract students, postdocs, and new investigators to collaborate with tinnitus researchers. What are training needs/opportunities?

• Increase funding for training at all levels (pre- and post-doctoral, clinical, basic science) targeted to tinnitus or tinnitus-related research.
• Convince talented investigators with rigorous training in other disciplines to obtain equally rigorous training in the auditory sciences and, conversely, to convince auditory scientists with an interest in tinnitus to obtain rigorous training in the other related disciplines.
• Support training opportunities that don’t require huge adjustments to existing training programs.
• Include more information about tinnitus in neuroscience/neurology educational programs.
• Require more training on tinnitus in all audiology and otolaryngology training programs.
• Organize and sponsor more meetings, symposia, workshops, or retreats that have tinnitus as a theme.
• Sponsor annual or biennial short course for fellow medical students in neurobiology and otology that focuses on tinnitus (perhaps in conjunction with an existing meeting).
• Develop a non-grant research award program to recognize outstanding contributions to the field of tinnitus research.
• Support supplements to existing NIH grants to train students and post-doctoral fellows in tinnitus research.
• Develop better educational materials to be distributed at a variety of national and international meetings.
• Develop strategies to better define and measure tinnitus so that more researchers will be attracted to the field.
• Create visiting fellowships to bring tinnitus researchers together, as well as to foster cross-disciplinary interactions.
• Design a targeted K22-type research career transition award or shorter-term program similar to the K18 for retooling investigators in new techniques, coupled with a targeted small grant program.
• Develop a field of “behavioral otoneurology.”

References