Thomas J. Brozoski

Gap detection deficits in rats with tinnitus: a potential novel screening tool.

The study describes a novel method for tinnitus screening in rats by use of gap detection reflex procedures. The authors hypothesized that if a background acoustic signal was qualitatively similar to the rats tinnitus, poorer detection of a silent gap in the background would be expected. Rats with prior evidence of tinnitus at 10 kHz (n = 14) exhibited significantly worse gap detection than controls (n = 13) when the gap was embedded in a background similar to their tinnitus. No differences between tinnitus and control rats were found with 16 kHz or broadband noise backgrounds, which helped to rule out explanations related to hearing loss or general performance deficits. The results suggest that gap detection reflex procedures might be effective for rapid tinnitus screening in rats.

Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma.

A longstanding hypothesis is that tinnitus, the perception of sound without an external acoustic source, is triggered by a distinctive pattern of cochlear hair cell (HC) damage and that this subsequently leads to altered neural activity in the central auditory pathway. This hypothesis was tested by assessing behavioral evidence of tinnitus and spontaneous neural activity in the inferior colliculus (IC) after unilateral cochlear trauma. Chinchillas were assigned to four cochlear treatment groups. Each treatment produced a distinctive pattern of HC damage, as follows: acoustic exposure (AEx): sparse low‐frequency inner hair cell (IHC) and outer hair cell (OHC) loss; round window cisplatin (CisEx): pronounced OHC loss mixed with some IHC loss; round window carboplatin (CarbEx): pronounced IHC loss without OHC loss; control: no loss. Compared with controls, all experimental groups displayed significant and similar psychophysical evidence of tinnitus with features resembling a 1‐kHz tone. Contralateral IC spontaneous activity was elevated in the AEx and CisEx groups, which showed increased spiking and increased cross‐fiber synchrony. A multidimensional analysis identified a subpopulation of neurons more prevalent in animals with tinnitus. These units were characterized by high bursting, low ISI variance, and within‐burst peak spiking of approximately 1,000/sec. It was concluded that cochlear trauma in general, rather than its specific features, leads to multiple changes in central activity that underpin tinnitus. Particularly affected was a subpopulation ensemble of IC neurons with the described unique triad of features.

Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model.

Subjective tinnitus is a common and often debilitating disorder that is difficult to study because it is a perceptual state without an objective stimulus correlate. Studying tinnitus in humans is further complicated by the heterogeneity of tinnitus quality, severity, and associated hearing loss. As a consequence, the pathophysiology of tinnitus is poorly understood and treatments are often unsuccessful. In the present study, an animal psychophysical model was developed to reflect several features of tinnitus observed in humans. Chronic tinnitus was induced in rats by a single intense unilateral exposure to noise. The tinnitus was measured using a psychophysical procedure, which required the animals to discriminate between auditory test stimuli consisting of tones, noise, and 0 dB. Tinnitus was indicated by a frequency-specific shift in discrimination functions with respect to control subjects not exposed to noise. The psychophysical consequences of the noise exposure were best explained by a tinnitus hypothesis and could not be explained easily by other consequences of noise exposure such as hearing loss. The qualitative features of the tinnitus were determined and related to the duration of noise exposure and the associated cochlear trauma. The tinnitus was found to persist and intensify over 17 months of testing. Finally, the tinnitus was reversibly attenuated by treatment with gabapentin, a GABA agonist. It was concluded that this model reflected several features of human tinnitus, such as its tonality and persistence, and could be useful as a screen for potential therapeutics as well as a tool to help unravel the pathophysiology of the disorder of phantom auditory perception.

Central neural activity in rats with tinnitus evaluated with manganese-enhanced magnetic resonance imaging (MEMRI)

The pathophysiology of tinnitus, the perception of sound in the absence of acoustic stimulation, is largely unknown, although several lines of research implicate long-term neuroplastic loss of inhibition. The evidence to date suggests that the neuroplastic alterations are likely to be found in multiple brain structures. The present study used manganese-enhanced magnetic resonance imaging (MEMRI) to assess the pattern of neural activity in the central auditory pathway of rats with psychophysical evidence of chronic acoustic-exposure-induced tinnitus. Manganese, an activity-dependent paramagnetic contrast agent, accumulates in active neurons through voltage-gated calcium channels, primarily at synapses, and serves as both a structural and functional indicator. Comparison images were obtained from normal subjects exposed to external tinnitus-like sound, and from tinnitus subjects treated with vigabatrin, a GABA agonist shown to eliminate the psychophysical evidence of tinnitus in rats. MEMRI indicated: (1) In rats with evidence of tinnitus, activity was generally elevated in the auditory brainstem, with significant elevation in the cerebellar paraflocculus, the posterior ventral cochlear nucleus, and the inferior colliculus; in general forebrain structures showed decreased activity, although MEMRI may be a less sensitive indicator of forebrain activity than brainstem activity; (2) in normal rats exposed to a tinnitus-like sound, a similar pattern of elevated brainstem activity and decreased forebrain activity was evident, with the notable exception of the paraflocculus, where artificial tinnitus had no effect and (3) vigabatrin, decreased brainstem activity to control levels, in rats with prior evidence of tinnitus, and decreased forebrain activity to below control levels. It was concluded that chronic tinnitus in rats is associated with focal activity elevation in the auditory brainstem and increased activity in the paraflocculus that may be unique to tinnitus.

The effect of dorsal cochlear nucleus ablation on tinnitus in rats.

A growing body of evidence implies that the dorsal cochlear nucleus (DCN) plays an important role in tinnitus. To test the hypothesis that the rostral output of the DCN is necessary for the experience of chronic tinnitus, the dorsal DCN and the dorsal acoustic stria of rats with psychophysical evidence of tinnitus was ablated. If the DCN plays a necessary role in the generation of chronic tinnitus, ablating the DCN should decrease the evidence of tinnitus in subjects previously shown to have tinnitus. Contrary to prediction, bilateral dorsal DCN ablation did not significantly (n=11, p=0.707) affect the psychophysical evidence of tinnitus, and ipsilateral dorsal DCN ablation appeared to increase the evidence of tinnitus (n=9, p=0.018) compared to pre-ablation performance. It was concluded that the DCN does not act as a simple feed-forward source of chronic tinnitus. Alternative hypotheses were considered, among them that elevated DCN activity following acoustic trauma triggers persistent pathological changes distributed across more than one level of the auditory system. In addition to serving as a trigger, the DCN may also modify the experience of tinnitus, since the evidence of tinnitus was enhanced by ipsilateral DCN ablation.

Inhibitory Neurotransmission in Animal Models of Tinnitus: Maladaptive Plasticity

Tinnitus is a phantom auditory sensation experienced by up to 14% of the United States population with a smaller percentage experiencing decreased quality of life. A compelling hypothesis is that tinnitus results from a maladaptive plastic net down-regulation of inhibitory amino acid neurotransmission in the central auditory pathway. This loss of inhibition may be a compensatory response to loss of afferent input such as that caused by acoustic insult and/or age-related hearing loss, the most common causes of tinnitus in people. Compensatory plastic changes may result in pathologic neural activity that underpins tinnitus. The neural correlates include increased spontaneous spiking, increased bursting and decreased variance of inter-spike intervals. This review will examine evidence for chronic plastic neuropathic changes in the central auditory system of animals with psychophysically-defined tinnitus. Neurochemical studies will focus on plastic tinnitus-related changes of inhibitory glycinergic neurotransmission in the adult dorsal cochlear nucleus (DCN). Electrophysiological studies will focus on functional changes in the DCN and inferior colliculus (IC). Tinnitus was associated with increased spontaneous activity and altered response properties of fusiform cells, the major output neurons of DCN. Coincident with these physiologic alterations were changes in glycine receptor (GlyR) subunit composition, its anchoring/trafficking protein, gephyrin and the number and affinity of membrane GlyRs revealed by receptor binding. In the IC, the primary afferent target of DCN fusiform cells, multi-dimensional alterations in unit-spontaneous activity (rate, burst rate, bursting pattern) were found in animals with behavioral evidence of chronic tinnitus more than 9 months following the acoustic/cochlear insult. In contrast, immediately following an intense sound exposure, acute alterations in IC spontaneous activity resembled chronic tinnitus-related changes but were not identical. This suggests that long-term neuroplastic changes responsible for chronic tinnitus are likely to be responsible for its persistence. A clear understanding of tinnitus-related plasticity in the central auditory system and its associated neurochemistry may help define unique targets for therapeutic drug development.

Effect of Gabapentin on the Sensation and Impact of Tinnitus

Objectives/Hypothesis: This study evaluated the effectiveness of gabapentin in treating chronic tinnitus in two populations: participants with tinnitus with associated acoustic trauma and participants with tinnitus without associated acoustic trauma. The hypothesis was that gabapentin would decrease both subjective and objective features of tinnitus in the trauma group but would be less effective in the nontrauma group.

Primary afferent dendrite degeneration as a cause of tinnitus

Chronic tinnitus affects millions of people, but the mechanisms responsible for the development of this abnormal sensory state remain poorly understood. This study examined the type and extent of cochlear damage that occurs after acoustic trauma sufficient to induce chronic tinnitus in rats. Tinnitus was evaluated by using a conditioned suppression method of behavioral testing. Cochlear damage was assessed 6 months after acoustic trauma. There was minimal loss of inner and outer hair cells in the exposed cochleas of subjects demonstrating evidence of tinnitus. However, a significant loss of large‐diameter fibers in the osseous spiral lamina of exposed cochleas of trauma subjects was observed. The significance of this finding in the context of a model of tinnitus is discussed.

The Cerebellum as a Novel Tinnitus Generator

The role of the cerebellum in auditory processing is largely unknown. Recently it was shown that rats with psychophysical evidence of tinnitus had significantly elevated neural activity in the paraflocculus of the cerebellum (PFL), as indicated by functional imaging. It was further shown that PFL activity was not elevated in normal rats listening to a tinnitus-like sound. This suggests that plastic changes in the PFL may underpin chronic tinnitus, i.e., it may serve as a tinnitus generator. Using a rat model of acoustic trauma-induced tinnitus, the role of the cerebellum was further examined in a series of experiments:The PFL was surgically ablated in animals with established tinnitus; the PFL was surgically ablated in animals before induction of tinnitus; the PFL was reversibly inactivated by chronic lidocaine infusion into the subarcuate fossa of animals with established tinnitus. It was found that PFL ablation eliminated established tinnitus without altering auditory discrimination. Similar to the ablation results, PFL inactivation with lidocaine reversibly eliminated existing tinnitus. In contrast however, PFL ablation before tinnitus induction attenuated, but did not completely eliminate, tinnitus. In a rat model of noise-induced chronic tinnitus, the cerebellar PFL may serve as a sufficient but non-obligatory generator of tinnitus.

Targeting inhibitory neurotransmission in tinnitus

Tinnitus perception depends on the presence of its neural correlates within the auditory neuraxis and associated structures. Targeting specific circuits and receptors within the central nervous system in an effort to relieve the perception of tinnitus and its impact on ones emotional and mental state has become a focus of tinnitus research. One approach is to upregulate endogenous inhibitory neurotransmitter levels (e.g., glycine and GABA) and selectively target inhibitory receptors in key circuits to normalize tinnitus pathophysiology. Thus, the basic functional and molecular properties of two major ligand-gated inhibitory receptor systems, the GABA(A) receptor (GABA(A)R) and glycine receptor (GlyR) are described. Also reviewed is the rationale for targeting inhibition, which stems from reported tinnitus-related homeostatic plasticity of inhibitory neurotransmitter systems and associated enhanced neuronal excitability throughout most central auditory structures. However, the putative role of the medial geniculate body (MGB) in tinnitus has not been previously addressed, specifically in terms of its inhibitory afferents from inferior colliculus and thalamic reticular nucleus and its GABA(A)R functional heterogeneity. This heterogeneous population of GABA(A)Rs, which may be altered in tinnitus pathology, and its key anatomical position in the auditory CNS make the MGB a compelling structure for tinnitus research. Finally, some selective compounds, which enhance tonic inhibition, have successfully ameliorated tinnitus in animal studies, suggesting that the MGB and, to a lesser degree, the auditory cortex may be their primary locus of action. These pharmacological interventions are examined in terms of their mechanism of action and why these agents may be effective in tinnitus treatment. This article is part of a Special Issue entitled: Tinnitus Neuroscience.