Jinsheng Zhang(a)(b), Zhenlong Guan(a)(c), Virginia Ramachandran(a)(b), Jonathan
Dunford(a), Christopher Lam(a), Michael Seidman(d), Kost Elisevich(d), Susan M.
Bowyer(a,d) and Quan Jiang(d)
(a) Dept of Otolaryngology-Head and Neck Surgery & Neurology, Wayne State University School of Medicine, 4201 Saint Antoine, Detroit, Michigan 48201
(b) Dept of Communication Sciences & Disorders, Wayne State University College of Liberal Arts & Sciences, 60 Farnsworth St., Detroit, Michigan 48202
(c) Dept of Zoology, Hebei Normal University College of Life Science, Shijiazhuang, Hebei 050016, P.R. China
(d) Henry Ford Health System, Dept of Otolaryngology-Head and Neck Surgery & Neurology, 2799 West Grand Boulevard Detroit, MI 48202

The accumulated evidence from the past decade of investigation supports the notion that tinnitus generally results from hyperactivity in the central auditory system and involves activation of certain non-auditory pathways. Following sound exposure or administration of salicylate and quinine, it has been reported that hyperactivity develops in the dorsal cochlear nucleus (DCN), inferior colliculus (IC), and auditory cortex (AC). Using the same conditions that induce tinnitus, it has been found that there is an increase in the number of Fos-positive neurons in certain auditory and non-auditory structures, which include the locus coeruleus, lateral parabrachial nucleus, certain subregions of the hypothalamus, and amygdala. In combination with behavioral methods, it has been reported that the sound exposure condition that causes animals to develop tinnitus also induces hyperactivity and increases c-Fos expression in certain auditory and non-auditory brain regions.

This suggests that the hyperactivity and increases in c-Fos expression in those structures may represent neural substrates of tinnitus. It is conceivable that modulation or suppression of the hyperactivity and increased c-Fos expression may be an effective way of treating tinnitus.
We electrically stimulated the primary AC to investigate the modulatory effects of cortical electrical stimulation (CES) on tinnitus-related activity in both auditory and non-auditory structures. The rationale of stimulating the AC is that clinical CES or transcranial magnetic stimulation of certain areas of the primary AC in humans can mitigate the perception of tinnitus (Seidman et al. submitted, De Ridder et al. 2006;

Richter et al. 2006; Londero et al. 2006; Langguth et al., 2006). Anatomically, the AC has direct projections to a number of auditory and non-auditory structures. In our recent study, we used adult rats and Syrian hamsters to electrophysiologically investigate the modulatory effects of CES on neural activity in the DCN and IC. We also performed c-fos immunocytochemistry and examined the effects of CES on c-
Fos expression in several auditory and non-auditory structures. The stimulation was single charge-balanced biphasic electrical pulses (40 ms wide), delivered at intensities of 0-50 mA and at a rate of 100 pps. Our preliminary results showed stimulation of the right AC induced onset suppression, residual inhibition and excitation in the left DCN, but with a higher incidence of suppression. We also found that CES affected neural activity in the right IC. In experiments using c-fos immunocytochemistry,
we observed that CES induced changes in the number of Fos-positive
neurons in some structures including decreased Fos-labeling in the left DCN and right amygdala. The results suggest that stimulation of certain areas of the CES may have modulatory effects on neural activity at the brainstem level. The results also suggest that CES may have activated the pathways between the limbic and auditory systems, possibly modulating neural activity that is involved in tinnitus perception. Possible mechanisms will be discussed.