Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus
Introduction
Over the past decade, there has been increasing evidence that the dorsal cochlear nucleus (DCN) plays an important role in the etiology of tinnitus. This structure was first implicated as a source of tinnitus-generating signals in studies conducted in hamsters (Kaltenbach et al., 1996, Kaltenbach et al., 1998; Kaltenbach and McCaslin, 1996). These and several more recent investigations in the same species (Kaltenbach and Afman, 2000; Kaltenbach et al., 2000, Kaltenbach et al., 2004) showed that neurons become hyperactive in the DCN following exposure to intense sound. The hyperactivity was originally observed as increases in spontaneous activity at the multiunit level, although more recent studies have demonstrated sound exposure-induced hyperactivity in the DCN at the single unit level (Brozoski et al., 2002). Evidence for intense sound-induced hyperactivity in the DCN has now been observed in four other species, including rats (Zhang and Kaltenbach, 1998), chinchillas (Brozoski et al., 2002), gerbils (Wallhausser-Franke et al., 2003) and mice (Kaltenbach et al., 2001) suggesting that it may be a general phenomenon across species.
It is not yet known whether intense noise-exposure causes hyperactivity to develop in the DCN of humans. However, several studies have implicated the DCN as an important component involved in the modulation of tinnitus in humans. Soussi and Otto (1994) reported that tinnitus loudness could be negatively modulated by applying electrical stimuli directly to the DCN surface. In 6 out of 7 patients, stimulation of the DCN resulted in decreasing the loudness of tinnitus or eliminating it altogether. A role of the DCN in the modulation of tinnitus has also been inferred from studies of patients with somatic tinnitus. In these patients, tinnitus percepts can be modulated by certain manipulations of the head and neck (Levine, 1999; Levine et al., 2003). An interesting aspect of this modulation is that in cases with unilateral tinnitus the modulatory effect was described as always coming from the ear ipsilateral to the side of the somatic manipulation (Levine, 1999). It was hypothesized that the DCN is a structure that may underlie somatically modulated tinnitus because it integrates auditory with mainly ipsilateral rather than contralateral somatosensory pathways (El-Kashlan and Shore, 2004; Weinberg and Rustioni, 1987; Young et al., 1995; Wright and Ryugo, 1996). More recent studies showing that stimulation of the trigeminal nerve or ganglion can modulate spontaneous activity of DCN cells, including fusiform cells, is consistent with this hypothesis (Kanold and Young, 2001; Shore, 2004).
Evidence that hyperactivity in the DCN represents a source of tinnitus-generating signals comes from studies in which electrophysiological recordings from the DCN were complemented by behavioral tests for tinnitus. These studies suggest that noise-exposure conditions which cause hyperactivity in the DCN also cause animals to develop tinnitus-like percepts (Bauer, 2003; Bauer and Brozoski, 2001; Brozoski et al., 2002; Heffner and Harrington, 2002). Moreover, when behavioral and electrophysiological tests were conducted in the same animals, a significant correlation was found between the level of activity in the DCN and the behavioral evidence for tinnitus (Kaltenbach et al., 2004). A correlation, however, does not prove a cause and effect relationship. It is possible that both DCN hyperactivity and tinnitus result from hearing loss, and yet be causally unrelated to each other. However, this explanation was cast in doubt by Brozoski et al. (2002) who exposed chinchillas to low levels of sound (80 dB SPL) and succeeded in demonstrating that both hyperactivity in the DCN and behavioral evidence of tinnitus were induced in chinchillas even after recovery from temporary hearing loss.
In the present study, we sought additional evidence that tinnitus and DCN hyperactivity are related. We set out to determine whether hyperactivity and related phenomena in the DCN might show similar patterns of plasticity as those that are characteristic of tinnitus. This search requires comparison of data from neurophysiological, anatomical and neurochemical studies of the DCN with the features of tinnitus that have been cited as evidence for plasticity. The term ‘plasticity’ is used in many ways in the literature and there is no universal agreement on its definition. We apply the term at the physiological level to refer to short and long-term secondary changes in neuronal sensitivity or excitability that result from alterations or manipulations of synaptic input. Changes in excitability commonly reflect changes at the synaptic level, but may also arise from changes in membrane properties. It is reasonable to suppose that both types of change begin with alterations in the expression of related genes. This definition thus encompasses changes that are triggered by alterations of input, either pathological or normal, but which go beyond the primary changes that would be expected based on the passive properties of neurons, such as immediate elevations of response thresholds due to a failure of peripheral receptor function. The term ‘plasticity’ can also be useful at the psychophysical level. In the present discussion, we will apply the term in reference to both the process by which tinnitus is induced as well as the changes in tinnitus percepts that are experienced over time, either spontaneously without obvious cause, or as a result of experimental manipulations of input. It is assumed that the plastic features of tinnitus are the perceptual manifestations of the plastic changes in neural excitability. Thus, it is reasonable to expect that if DCN hyperactivity contributes to the percepts of tinnitus, we should expect to find numerous parallels between the plastic features of tinnitus, or what we will refer to hereinafter as tinnitus plasticity, and DCN plasticity. The purpose of this paper is to examine this issue in detail.
Section snippets
Plasticity of tinnitus
The literature describes a wealth of psychophysical attributes of tinnitus that can be considered hallmarks of plasticity. Not only is the process by which tinnitus is induced thought to involve plasticity, the post-induction perceptual features of tinnitus can change spontaneously over time or be modulated by certain manipulations of sensory input. To facilitate this discussion, we have categorized various forms of tinnitus plasticity into four types, based on the kinds of events that trigger
DCN plasticity and hyperactivity
We now turn to the issue of whether there are any known properties of DCN organization and function that might serve as underlying correlates of the plastic features of tinnitus that have just been reviewed. Focus on the DCN is justified here because the hyperactivity that develops in this structure after acoustic injury has been found to be associated with tinnitus percepts (see Section 1). If the DCN contributes to the generation of tinnitus, then it is natural to expect that the various
DCN plasticity and the search for a final common path for tinnitus
The search for a final common path underlying tinnitus has been complicated by the multiple forms of tinnitus, the numerous potential mechanisms that have been proposed, and by evidence for the involvement of many brain areas. While our focus on the DCN might be viewed as an oversimplification of this search, it should be apparent from the foregoing analysis that the DCN possesses many characteristics that one would expect of a major center for the generation of tinnitus and its various forms
Summary and conclusion
This article has reviewed various forms of plasticity that characterize tinnitus, including its induction by injuries and hearing loss, its fluctuant behavior over time, its changes in psychophysical attributes following use of non-traumatic acoustic maskers, and its modulations that occur with certain somatic manipulations. Each of these forms of plasticity has one or more parallels that can be found at the neuronal level in the DCN. These parallels lend further support to the hypothesis that
Acknowledgements
Much of the work reviewed in this paper was supported by grants from the National Institute of Deafness and Other Communication Disorders (R01 DC03258) and by the Tinnitus Research Consortium.
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