Tinnitus, the perception of ringing or buzzing in the absence of an acoustic stimulus, is a significant problem in the United States and is of specific concern for the military personnel. For the second consecutive year tinnitus is again the number one compensated disability with more than $1.2 billion paid in disability benefits in 2010. From training to deployment and combat activity, the military population is constantly exposed to acoustic trauma from weapons fire, tracked and non-tracked vehicles, airplanes and helicopters as well as bombs and grenades. Since tinnitus often results from exposure to loud noise, military personnel are at high risk of developing tinnitus. There is currently no cure for tinnitus. In order to develop appropriate pharmacological interventions, metrics that can be used as indicators of tinnitus attenuation are critically needed. Several studies report increased neuronal activity in the inferior colliculus (I) as a result of tinnitus. This suggests that monitoring neuronal activity in IC neurons may provide a useful biomarker for the diagnosis of tinnitus. A novel non-invasive method for assessment of neuronal activity is manganese enhanced MRI (MEMRI). Our group and others have used MEMRI to evaluate neuronal activity in auditory neurons (Yu et al., 2007; Brozoski et al. 2007; Holt et al., 2010). Although tinnitus sufferers often report loud, sustained or impulse noise exposure as a trigger for their tinnitus, many people with tinnitus do not sustain a permanent hearing loss. Thus, the biomarker for tinnitus needs to be apparent regardless of hearing status or method of tinnitus generation. Our proposed studies use several models of tinnitus (PTS-permanent threshold shift tone; TTS-temporary threshold shift tone; and SAFTS-small arms fire threshold shift noise) and build on our previous report suggesting that increased neuronal activity in the IC identified by MEMRI may be a reliable diagnostic marker for tinnitus. Having the capability of definitively associating a specific biomarker with the perception of tinnitus allows for testing the efficacy of pharmacological intervention. We have recently shown that tinnitus results in differential expression of voltage gated calcium channel (CaV) genes. Furthermore, our preliminary studies have shown that pharmacological administration of CaV blockers prior to the generation of tinnitus greatly reduced the perception of tinnitus. Therefore we will use two metrics, tinnitus perception and increased spontaneous neuronal activity in the IC, as indicators of tinnitus and assessment of these two metrics will be used as a method for evaluation of drugs proposed for pharmacological interventions. The research proposed in this application offers a path both to objective diagnosis of tinnitus and therapeutic interventions.

Public Health Relevance

The Department of Veterans Affairs (VA) recently reported that tinnitus is the number-one service connected disability for Global War on Terror Veterans for the second year in a row. Currently there are no broadly effective pharmacological agents used for the treatment of tinnitus. Crucial for development and testing of pharmacological interventions is identification of a biomarker that is reliably correlated with the perception of tinnitus. Since changes in neuronal activity in the inferior colliculus (IC) has often been correlated with the perception of tinnitus e propose that monitoring neuronal activity in IC neurons may provide a useful biomarker for the diagnosis of tinnitus. Our most recent data suggest that voltage gated calcium channel blockers may prove effective in the attenuation of tinnitus perception. Therefore we propose that increased neuronal activity in the IC is an indicator of tinnitus perception and that decreases in the perception of tinnitus and spontaneous neuronal activity can be used as a metrics for evaluation of drugs proposed for pharmacological intervention.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Sensory Systems & Communication Disorders (RRD3)
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John D Dingell VA Medical Center
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Muca, Antonela; Standafer, Emily; Apawu, Aaron K et al. (2018) Tinnitus and temporary hearing loss result in differential noise-induced spatial reorganization of brain activity. Brain Struct Funct 223:2343-2360
Subramanian, Madhan; Holt, Avril G; Mueller, Patrick J (2014) Physical activity correlates with glutamate receptor gene expression in spinally-projecting RVLM neurons: a laser capture microdissection study. Brain Res 1585:51-62
Cacace, Anthony T; Brozoski, Tom; Berkowitz, Bruce et al. (2014) Manganese enhanced magnetic resonance imaging (MEMRI): a powerful new imaging method to study tinnitus. Hear Res 311:49-62