James A. Kaltenbach

Hyperactivity in the dorsal cochlear nucleus after intense sound exposure and its resemblance to tone-evoked activity: a physiological model for tinnitus.

Intense tone exposure induces increased spontaneous activity (hyperactivity) in the dorsal cochlear nucleus (DCN) of hamsters. This increase may represent an important neural correlate of noise-induced tinnitus, a condition in which sound, typically of very high pitch, is perceived in the absence of a corresponding acoustic stimulus. Since high pitch sounds are thought to be represented in central auditory structures by the place of activation across the tonotopic array; it is therefore possible that the high pitch of noise-induced tinnitus occurs because intense sound exposure induces a tonotopic distribution of chronic hyperactivity in the DCN similar to that normally evoked only under conditions of high frequency stimulation. To investigate this possibility we compared this tone-induced hyperactivity with the activity evoked in normal animals by presentation of a tone. This comparison revealed that the activity in the DCN of animals which had been exposed to an intense 10 kHz tone 1 month previously showed a striking similarity to the activity in the DCN of normal animals during presentation of low to moderate level tonal stimuli of the same frequency. In both test conditions similar patterns were seen in the topographic distribution of the increased activity along the tonotopic axis. The magnitude of hyperactivity in exposed animals was similar to the evoked activity in the normal DCN responding to a stimulus at a level of 20 dB SL. These results suggest that the altered DCN following intense tone exposure behaves physiologically as though it is responding to a tone in the absence of a corresponding acoustic stimulus. The relevance of these findings to noise-induced tinnitus and their implications for understanding its underlying mechanisms are discussed.

Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure

Chronic increases in spontaneous multiunit activity can be induced in the dorsal cochlear nucleus (DCN) of hamsters by intense sound exposure (Kaltenbach and McCaslin, 1996). It has been hypothesized that this hyperactivity may represent a neural code that could underlie the sound percepts of tinnitus. The goal of the present study was to determine whether hyperactivity could be demonstrated in animals that had previously been tested for tinnitus, and, if so, whether animals differing in their behavioral evidence for tinnitus also differ in their levels of spontaneous activity. The results showed not only that levels of activity in exposed animals were higher than those in control animals, but the degree to which the activity was increased was related to the strength of the behavioral evidence for tinnitus. These findings are consistent with the hypothesis that hyperactivity in the DCN may be a physiological correlate of noise-induced tinnitus.

Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus.

Tinnitus displays many features suggestive of plastic changes in the nervous system. These can be categorized based on the types of manipulations that induce them. We have categorized the various forms of plasticity that characterize tinnitus and searched for their neural underpinnings in the dorsal cochlear nucleus (DCN). This structure has been implicated as a possible site for the generation of tinnitus-producing signals owing to its tendency to become hyperactive following exposure to tinnitus inducing agents such as intense sound and cisplatin. In this paper, we review the many forms of plasticity that have been uncovered in anatomical, physiological and neurochemical studies of the DCN. Some of these plastic changes have been observed as consequences of peripheral injury or as fluctuations in the behavior and chemical activities of DCN neurons, while others can be induced by stimulation of auditory or even non-auditory structures. We show that many parallels can be drawn between the various forms of plasticity displayed by tinnitus and the various forms of neural plasticity which have been defined in the DCN. These parallels lend further support to the hypothesis that the DCN is an important site for the generation and modulation of tinnitus-producing signals.

Plasticity of spontaneous neural activity in the dorsal cochlear nucleus after intense sound exposure

Increases in multiunit spontaneous activity (hyperactivity) can be induced in the dorsal cochlear nucleus (DCN) by intense sound exposure. This hyperactivity has been observed in the hamster and rat following exposure to a 10 kHz tone at a level of 125-130 dB SPL for a period of 4 h. The present study demonstrates that the onset of this hyperactivity is not immediate, but develops in the DCN between 2 and 5 days after exposure. Mean rates of multiunit spontaneous activity increased sharply from below normal levels at day 2 to higher than normal levels at day 5. The mean magnitude of activity continued to increase more gradually over the next 6 months. During this period, changes in the distribution of hyperactivity across the tonotopic array were also noted. The hyperactivity was more broadly distributed across the DCN at the early post-exposure times (5 and 14 days) than at later post-exposure recovery times (30 and 180 days), and peak activity was found at increasingly more medial positions over this time frame. These changes over time indicate that the mechanisms leading to hyperactivity following intense sound exposure are more complex than previously realized.

Increases in spontaneous activity in the dorsal cochlear nucleus of the rat following exposure to high-intensity sound

The effects of intense sound exposure on neural activity in the dorsal cochlear nucleus (DCN) were studied in the rat. Seventeen anesthetized adult rats were exposed to a 10-kHz tone at 125-130 dB SPL for 4 h. Fourteen unexposed rats served as controls. Spontaneous activity (SA) and neural thresholds at the characteristic frequency were measured in three rows of 8-12 sites along the mediolateral, tonotopic, axis of the DCN surface 27-61 days after exposure. The results showed that intense tone exposure induced chronic increases in SA. This hyperactivity was found to be distributed broadly across the DCN with an emphasis around the 10-kHz locus and was associated with shifted response thresholds. These findings demonstrate the usefulness of the rat for studies of physiological phenomena related to noise-induced tinnitus and hearing loss.

Changes in spontaneous neural activity in the dorsal cochlear nucleus following exposure to intense sound : Relation to threshold shift

Previous studies have shown that the dorsal cochlear nucleus exhibits increased spontaneous activity after exposure to intense sound. Such increases were apparent 1-2 months after the exposure and were generally proportional to the shift in response thresholds induced by the same exposure. The purpose of the present study was to determine whether this sound-induced increase in spontaneous activity is an early event which can be observed shortly after exposure. As in previous studies, anesthetized hamsters ranging in postnatal age from 60-70 days were exposed to a 10-kHz tone at levels between 125 and 130 dB SPL for a period of 4 h. Control animals were similarly anesthetized but were not exposed to the intense tone. Exposed animals were examined in two groups, one at 30 days after exposure, the other at 2 days after exposure. Time of exposure was adjusted so that all animals were between 90 and 100 days of age when spontaneous activity was studied electrophysiologically. The results showed that the increases in spontaneous activity, which were evident at 30 days after exposure, were not observed in animals studied 2 days after exposure. This result contrasted with the effect of the intense tone exposure on neural response thresholds. That is, the shifts in response thresholds seen 2 days after exposure were similar to those observed in animals studied 30 days after exposure. These results indicate that changes in spontaneous activity reflect a more slowly developing phenomenon and occur secondarily after induction of threshold shift.

The dorsal cochlear nucleus as a participant in the auditory, attentional and emotional components of tinnitus.

The dorsal cochlear nucleus (DCN) has been modeled in numerous studies as a possible source of tinnitus-generating signals. This hypothesis was originally developed on the basis of evidence that the DCN becomes hyperactive following exposure to intense noise. Since these early observations, evidence that the DCN is an important contributor to tinnitus has grown considerably. In this paper, the available evidence to date will be summarized. In addition, the DCN hypothesis of tinnitus can now be expanded to include possible involvement in other, non-auditory components of tinnitus. It will be shown by way of literature review that the DCN has direct connections with non-auditory brainstem structures, such as the locus coeruleus, reticular formation and raphe nuclei, that are implicated in the control of attention and emotional responses. The hypothesis will be presented that attentional and emotional disorders, such as anxiety and depression, which are commonly associated with tinnitus, may result from an interplay between these non-auditory brainstem structures and the DCN. Implicit in this hypothesis is that attempts to develop effective anti-tinnitus therapies are likely to benefit from a greater understanding of how the levels of activity in the DCN are influenced by different states of activation of these non-auditory brainstem structures and vice versa.

The comparative effects of sodium thiosulfate, diethyldithiocarbamate, fosfomycin and WR-2721 on ameliorating cisplatin-induced ototoxicity

The efficacies of four agents in ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 1600 mg/kg/injection sodium thiosulfate (STS), 300 mg/kg/injection diethyldithiocarbamate (DDTC), 18 mg/kg/injection WR-2721, or 300 mg/kg/injection fosfomycin (n = 10/group). Ototoxicity was assessed electrophysiologically by auditory brainstem responses (ABRs) and anatomically by cochlear histology. The greatest auditory protection was given by STS, followed by DDTC. WR-2721 and fosfomycin did not provide any protection. All of the animals in the STS and DDTC groups survived, while some fatalities occurred in the fosfomycin, WR-2721, and cisplatin-only groups. Thus, the agents that were protective against ototoxicity were also protective against mortality. The ABRs also provided evidence of cisplatin-induced neuropathy. In summary, STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy and the hamster proved to be an excellent model of cisplatin ototoxicity.

Effects of cochlear ablation on noise induced hyperactivity in the hamster dorsal cochlear nucleus: Implications for the origin of noise induced tinnitus

Chronic increases in multiunit spontaneous activity are induced in the dorsal cochlear nucleus (DCN) following exposures to intense sound. This hyperactivity has been implicated as a neurophysiological correlate of noise induced tinnitus. However, it is not known whether this hyperactivity originates centrally, or instead, reflects an increase in the level of spontaneous input from the auditory nerve. In the present study we addressed this issue by testing whether hyperactivity, induced in the DCN by previous exposure to intense sound, persists after ipsilateral cochlear input to the DCN has been removed. To induce hyperactivity, Syrian golden hamsters were exposed under anesthesia to an intense pure tone (122-127 dB SPL at 10 kHz) for 4 h. Additional hamsters, which were anesthetized for 4 h, but not tone exposed, served as controls. Electrophysiological recordings of spontaneous activity were performed on the surface of the left DCN in animals in which the ipsilateral cochlea was either intact or ablated. The degree of cochlear removal was determined by microdissection and histologic evaluation of the cochlea after completion of each recording session. Comparisons between the levels of activity recorded in animals with and without intact cochleas revealed that the induced hyperactivity in the DCN persisted after both partial and complete cochlear ablations. These results indicate that the maintenance of hyperactivity is not dependent on input from the ipsilateral cochlea, implying that hyperactivity originates centrally.

The dorsal cochlear nucleus as a contributor to tinnitus: mechanisms underlying the induction of hyperactivity

It has been hypothesized that tinnitus percepts may arise, in part, from increases in spontaneous neural activity in the central auditory system. The DCN is the lowest central auditory nucleus where this hyperactivity is observed, and it is most prominent following exposure to intense sound or ototoxic insult. Efforts to develop effective treatments for tinnitus will probably benefit from a better understanding of the mechanisms underlying the induction of hyperactivity in the DCN. This chapter will summarize the evidence linking tinnitus to altered activity in the DCN and review some of the likely mechanisms underlying the induction of hyperactivity following injury to the ear.