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We used PET to map brain regions responding to changes in tinnitus loudness in four patients who could alter tinnitus loudness by performing voluntary oral facial movements (OFMs). Cerebral blood flow was measured in four patients and six controls at rest, during the OFM, and during stimulation with pure tones. OFM-induced loudness changes affected the auditory cortex contralateral to the ear in which tinnitus was perceived, whereas unilateral cochlear stimulation caused bilateral effects, suggesting a retrocochlear origin for their tinnitus. Patients, compared with controls, showed evidence for more widespread activation by the tones and aberrant links between the limbic and auditory systems. These abnormal patterns provide evidence for cortical plasticity that may account for tinnitus and associated symptoms. Although audiologic symptoms and examinations of these patients were typical, the unusual ability to modulate tinnitus loudness with an OFM suggests some caution may be warranted in generalizing these findings.

Age-related hearing loss (AHL), known as presbycusis, is a universal feature of mammalian aging and is the most common sensory disorder in the elderly population. The molecular mechanisms underlying AHL are unknown, and currently there is no treatment for the disorder. Here we report that C57BL/6J mice with a deletion of the mitochondrial pro-apoptotic gene Bak exhibit reduced age-related apoptotic cell death of spiral ganglion neurons and hair cells in the cochlea, and prevention of AHL. Oxidative stress induces Bak expression in primary cochlear cells, and Bak deficiency prevents apoptotic cell death. Furthermore, a mitochondrially targeted catalase transgene suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Oral supplementation with the mitochondrial antioxidants ␣-lipoic acid and coenzyme Q 10 also suppresses Bak expression in the cochlea, reduces cochlear cell death, and prevents AHL. Thus, induction of a Bak-dependent mitochondrial apoptosis program in response to oxidative stress is a key mechanism of AHL in C57BL/6J mice.aging ͉ antioxidant ͉ cochlea ͉ oxidative stress ͉ presbycusis A ge-related hearing loss (AHL), also known as presbycusis, is characterized by an age-dependent decline of auditory function associated with loss of sensory hair cells, spiral ganglion (SG) neurons, and stria vascularis cells in the cochlea of the inner ear (1, 2). Hair cells and SG neurons do not regenerate in mammals, and loss of these long-lived cochlear cells leads to permanent hearing impairment. AHL affects more than 40% of people greater than 65 years of age in the United States (1, 2) and is projected to afflict more than 28 million Americans by 2030 (1, 3

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Sensorineural hearing loss induced by noise or ototoxic drug exposure reduces the neural activity transmitted from the cochlea to the central auditory system. Despite a reduced cochlear output, neural activity from more central auditory structures is paradoxically enhanced at suprathreshold intensities. This compensatory increase in the central auditory activity in response to the loss of sensory input is referred to as central gain enhancement. Enhanced central gain is hypothesized to be a potential mechanism that gives rise to hyperacusis and tinnitus, two debilitating auditory perceptual disorders that afflict millions of individuals. This review will examine the evidence for gain enhancement in the central auditory system in response to cochlear damage. Further, it will address the potential cellular and molecular mechanisms underlying this enhancement and discuss the contribution of central gain enhancement to tinnitus and hyperacusis. Current evidence suggests that multiple mechanisms with distinct temporal and spectral profiles are likely to contribute to central gain enhancement. Dissecting the contributions of these different mechanisms at different levels of the central auditory system is essential for elucidating the role of central gain enhancement in tinnitus and hyperacusis and, most importantly, the development of novel treatments for these disorders.

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The CBA mouse shows little evidence of hearing loss until late in life, whereas the C57BL/6 strain develops a severe and progressive, high-frequency sensorineural hearing loss beginning around 3-6 months of age. These functional differences have been linked to genetic differences in the amount of hair cell loss as a function of age; however, a precise quantitative description of the sensory cell loss is unavailable. The present study provides mean values of inner hair cell (IHC) and outer hair cell (OHC) loss for CBA and C57BL/6 mice at 1, 3, 8, 18, and 26 months of age. CBA mice showed little evidence of hair cell loss until 18 months of age. At 26 months of age, OHC losses in the apex and base of the cochlea were approximately 65% and 50%, respectively, and IHC losses were approximately 25% and 35%. By contrast, C57BL/6 mice showed approximately a 75% OHC and a 55% IHC loss in the base of the cochlea at 3 months of age. OHC and IHC losses increased rapidly with age along a base-to-apex gradient. By 26 months of age, more than 80% of the OHCs were missing throughout the entire cochlea; however, IHC losses ranged from 100% near the base of the cochlea to approximately 20% in the apex.

High doses of salicylate, the anti-inflammatory component of aspirin, induce transient tinnitus and hearing loss. Systemic injection of 250 mg/kg of salicylate, a dose that reliably induces tinnitus in rats, significantly reduced the sound evoked output of the rat cochlea. Paradoxically, salicylate significantly increased the amplitude of the sound-evoked field potential from the auditory cortex (AC) of conscious rats, but not the inferior colliculus (IC). When rats were anesthetized with isoflurane, which increases GABA-mediated inhibition, the salicylate-induced AC amplitude enhancement was abolished, whereas ketamine, which blocks N-methyl-D-aspartate receptors, further increased the salicylate-induced AC amplitude enhancement. Direct application of salicylate to the cochlea, however, reduced the response amplitude of the cochlea, IC and AC, suggesting the AC amplitude enhancement induced by systemic injection of salicylate does not originate from the cochlea. To identify a behavioral correlate of the salicylate-induced AC enhancement, the acoustic startle response was measured before and after salicylate treatment. Salicylate significantly increased the amplitude of the startle response. Collectively, these results suggest that high doses of salicylate increase the gain of the central auditory system, presumably by down-regulating GABA-mediated inhibition, leading to an exaggerated acoustic startle response. The enhanced startle response may be the behavioral correlate of hyperacusis that often accompanies tinnitus and hearing loss. Published by Elsevier Ltd on behalf of IBRO. Keywordssalicylate; tinnitus; hyperacusis; auditory cortex; inferior colliculus; GABA A challenging question for tinnitus research is to identify the neural generator(s) in the cochlea and/or central auditory system (CAS) of tinnitus. Although the phantom sound of tinnitus is commonly induced by noise exposure or ototoxic drugs, increasing evidence suggests that noise and drug-induced cochlear damage that reduces the output of the cochlea induces a plethora of functional changes in the CAS. In many cases of cochlear damage, the CAS appears to increase its gain to compensate for the reduced sensorineural input from the cochlea. An excessive increase in central gain may give rise to the phantom sound of tinnitus under quiet conditions, as well as an intolerance to loud sounds (hyperacusis) (Gerken, 1996;Salvi et al., 2000;Eggermont and Roberts, 2004 which has been linked to chronic tinnitus in humans (Goldstein and Shulman, 1996;Nelson and Chen, 2004). Chronic tinnitus and hyperacusis in humans are most often associated with cochlear damage induced by aging, noise or ototoxic drugs. The salicylate-induced pathology provides a reversible and highly reliable method to investigate how the CAS adjusts due to insult as well as the possible neural correlates of tinnitus and hyperacusis.Previous studies have shown that acoustic trauma which damages hair cells in the cochlea causes an enhancement in sound-evoked activity in the cochlear ...