ReviewTinnitus: Models and mechanisms
Highlights
► This article reviews behavioral and physiological models of tinnitus developed over the past decade. ► The principal themes that have emerged from studies conducted in these models will also be reviewed. ► Emphasis is placed on the neural correlates of acute and chronic forms of tinnitus. ► The role of plasticity and other mechanisms in the induction of tinnitus-related changes in neural activity will also be reviewed.
Introduction
For many years, the search for tinnitus mechanisms was a highly speculative endeavor, with few clues concerning the underlying pathologies other than those derived from clinical and psychoacoustic observations. Some important new ground was broken in the late 1970s and early 1980s with studies examining stimulus driven and spontaneous activity in the auditory nerves and ventral cochlear nucleus of animals treated with inducers of tinnitus such as noise or ototoxic drugs (Liberman and Kiang, 1978, Liberman and Dodds, 1984; Evans and Borerwe, 1982; Evans et al., 1981, Dallos and Harris, 1978, Salvi and Ahroon, 1983, Lonsbury-Martin and Martin, 1981). However, these manipulations were found to have either little effect on or to weaken spontaneous activity in ways that seemed more related to hearing loss than tinnitus. Further complicating the picture were clinical reports showing that most tinnitus patients who undergo eighth nerve transections continue to experience their tinnitus, often in a worsened condition (Dandy, 1941, House and Brackman, 1981, Gardner, 1984). Experimental approaches were needed to reconcile these findings with the common notion that tinnitus is largely a problem of the auditory periphery.
A major turning point came in the latter half of the 1980s and early 1990s with the introduction of the first animal models of the acute form of tinnitus (Jastreboff and Sasaki, 1986, Jastreboff et al., 1988, Jastreboff, 1990, Chen and Jastreboff, 1995). These models, which were developed in rodents treated with sodium salicylate, demonstrated experimentally that animals can experience tinnitus and that the observed ‘phantom auditory percepts’ are associated with alterations of neural activity in the central auditory system quite different from those related to hearing loss. The field received additional impetus in the late-1990s and early 2000s with the first animal models of chronic tinnitus (Chen et al., 1999, Kaltenbach and McCaslin, 1996, Kaltenbach et al., 2004, Zhang and Kaltenbach, 1998, Eggermont and Kenmochi, 1998, Seki and Eggermont, 2003, Brozoski et al., 2002, Heffner and Harrington, 2002). Such studies were based on experiments conducted in rats, hamsters and cats variously exposed to intense sound and examined weeks to months after exposure.
Since that time, there has been a steady crescendo of interest in using animal models to elucidate mechanisms of tinnitus. This reflects increased study at multiple levels, including the auditory periphery, the auditory CNS and non-auditory areas of the brain. Models have now been developed in several species for studying mechanisms of tinnitus in vivo and in vitro, and for studying acute and chronic forms of tinnitus. These studies have ushered in a new era of tinnitus investigation that has resulted in a number of important new concepts on the biological basis of tinnitus. Despite a late start, the formal study of tinnitus in animals is fast becoming comparable to the study of other related sensory disorders in animals, such as neuropathic pain and phantom limb, which have had much longer histories.
This article will begin with a brief summary of the types of models that have been developed. This will be followed by a review of what has been learned from these models, what some of the challenges that have been confronted by these studies, and what problems need to be addressed to move animal research closer to an effective treatment for tinnitus. This review will focus on the auditory component of tinnitus rather than the emotional and attentional aspects of tinnitus.
Section snippets
Types of animal models of tinnitus
Animal models of tinnitus published to date can be classified in two general categories. Behavioral models are concerned with the measure of tinnitus percepts in animals. These models allow examination of the psychophysical attributes of those percepts, how such percepts are induced, and ultimately, provide opportunities to test potential new approaches to tinnitus treatment. Physiological models are concerned with changes in the nervous system that underlie tinnitus. They seek to identify,
Behavioral models
There is general agreement among behavioral studies that manipulations which cause tinnitus in humans, also cause animals to experience tinnitus. This has been shown using different behavioral paradigms, different species (rat, chinchilla, hamster and mouse) and different inducers of tinnitus (salicylate, quinine and noise) (Jastreboff et al., 1994; Bauer et al., 1999, Lobarinas et al., 2004, Guitton et al., 2003, Rüttiger et al., 2003, Heffner and Harrington, 2002, Brozoski et al., 2002,
The problem of correlating physiological and behavioral evidence for tinnitus
Ultimately, the case that changes in physiology are linked to tinnitus rests on the ability to show a relationship between the observed activity changes and the percept of tinnitus based on behavioral measures. As just reviewed, there is good evidence that exposure conditions that cause putative tinnitus-producing changes in spontaneous activity (hyperactivity, increased neural synchrony, increased bursting activity) also cause animals to experience tinnitus. This concurrence is a strong
Summary and the future of animal research on tinnitus
The last decade has seen a major transformation in the way we think about the biological basis of tinnitus. The traditional view that chronic tinnitus was exclusively an auditory disorder originating in the ear has been largely supplanted. The contemporary view is that although tinnitus may be triggered by injury to the ear, the neural generators are most readily found centrally and while the neural generators may be primarily auditory, non-auditory centers often participate. Studies of
Acknowledgements
This work was supported by R01 DC009097.
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