Single unit hyperactivity and bursting in the auditory thalamus of awake rats directly correlates with behavioural evidence of tinnitus.

Tinnitus is an auditory percept without an environmental acoustic correlate. Contemporary tinnitus models hypothesize tinnitus to be a consequence of maladaptive plasticity-induced disturbance of excitation-inhibition homeostasis, possibly convergent on medial geniculate body (MGB, auditory thalamus) and related neuronal networks. The MGB is an obligate acoustic relay in a unique position to gate auditory signals to higher-order auditory and limbic centres. Tinnitus-related maladaptive plastic changes of MGB-related neuronal networks may affect the gating function of MGB and enhance gain in central auditory and non-auditory neuronal networks, resulting in tinnitus. The present study examined the discharge properties of MGB neurons in the sound-exposure gap inhibition animal model of tinnitus. MGB single unit responses were obtained from awake unexposed controls and sound-exposed adult rats with behavioural evidence of tinnitus. MGB units in animals with tinnitus exhibited enhanced spontaneous firing, altered burst properties and increased rate-level function slope when driven by broadband noise and tones at the unit's characteristic frequency. Elevated patterns of neuronal activity and altered bursting showed a significant positive correlation with animals' tinnitus scores. Altered activity of MGB neurons revealed additional features of auditory system plasticity associated with tinnitus, which may provide a testable assay for future therapeutic and diagnostic development.

Is GABA neurotransmission enhanced in auditory thalamus relative to inferior colliculus?

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central auditory system. Sensory thalamic structures show high levels of non-desensitizing extrasynaptic GABAA receptors (GABAARs) and a reduction in the redundancy of coded information. The present study compared the inhibitory potency of GABA acting at GABAARs between the inferior colliculus (IC) and the medial geniculate body (MGB) using quantitative in vivo, in vitro, and ex vivo experimental approaches. In vivo single unit studies compared the ability of half maximal inhibitory concentrations of GABA to inhibit sound-evoked temporal responses, and found that GABA was two to three times (P < 0.01) more potent at suppressing MGB single unit responses than IC unit responses. In vitro whole cell patch-clamp slice recordings were used to demonstrate that gaboxadol, a δ-subunit selective GABAAR agonist, was significantly more potent at evoking tonic inhibitory currents from MGB neurons than IC neurons (P < 0.01). These electrophysiological findings were supported by an in vitro receptor binding assay which used the picrotoxin analog [(3)H]TBOB to assess binding in the GABAAR chloride channel. MGB GABAARs had significantly greater total open chloride channel capacity relative to GABAARs in IC (P < 0.05) as shown by increased total [(3)H]TBOB binding. Finally, a comparative ex vivo measurement compared endogenous GABA levels and suggested a trend towards higher GABA concentrations in MGB than in IC. Collectively, these studies suggest that, per unit GABA, high affinity extrasynaptic and synaptic GABAARs confer a significant inhibitory GABAAR advantage to MGB neurons relative to IC neurons. This increased GABA sensitivity likely underpins the vital filtering role of auditory thalamus.

Desensitizing nicotinic agents normalize tinnitus-related inhibitory dysfunction in the auditory cortex and ameliorate behavioral evidence of tinnitus.

Tinnitus impacts between 10-20% of the population. Individuals most troubled by their tinnitus have their attention bound to and are distracted by, their tinnitus percept. While numerous treatments to ameliorate tinnitus have been tried, no therapeutic approach has been clinically accepted. The present study used an established condition-suppression noise-exposure rat model of tinnitus to: (1) examine tinnitus-related changes in nAChR function of layer 5 pyramidal (PNs) and of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1) and (2) examine how the partial desensitizing nAChR agonists, sazetidine-A and varenicline, can act as potential therapeutic agents in the treatment of tinnitus. We posited that tinnitus-related changes in layer 5 nAChR responses may underpin the decline in attentional resources previously observed in this animal model (Brozoski et al., 2019). In vitro whole-cell patch-clamp studies previously revealed a significant tinnitus-related loss in nAChR-evoked excitatory postsynaptic currents from A1 layer 5 PNs. In contrast, VIP neurons from animals with behavioral evidence of tinnitus showed significantly increased nAChR-evoked excitability. Here we hypothesize that sazetidine-A and varenicline have therapeutic benefits for subjects who cannot divert their attention away from the phantom sound in their heads. We found that sazetidine-A or varenicline normalized tinnitus-related reductions in GABAergic input currents onto A1 layer 5 PNs. We then tested sazetidine-A and varenicline for the management of tinnitus using our tinnitus animal model. Subcutaneous injection of sazetidine-A or varenicline, 1 h prior to tinnitus testing, significantly decreased the rat's behavioral evidence of tinnitus in a dose-dependent manner. Collectively, these results support the need for additional clinical investigations of partial desensitizing nAChR agonists sazetidine-A and varenicline for the treatment of tinnitus.

Effect of tinnitus retraining therapy on the loudness and annoyance of tinnitus: a controlled trial.

OBJECTIVES: Subjective tinnitus is the sensation of hearing a sound in the absence of an external stimulus. Although an estimated 30 million Americans experience chronic tinnitus, only a small percentage are significantly bothered by the sensation. However, this population is currently in need of effective therapy that reduces the impact of tinnitus. Tinnitus retraining therapy has been promoted as an effective intervention for treating chronic bothersome tinnitus from any etiology. The aim of this study was to compare the effect of tinnitus retraining therapy on the loudness and annoyance of tinnitus with a control group. DESIGN: Subjects with subjective, stable, bothersome, chronic tinnitus, and normal to near-normal hearing in the speech frequencies (average pure-tone thresholds for 0.5, 1, 2, and 4 kHz ≤ 30 dB HL) were recruited to participate in a study for the effect of tinnitus retraining therapy (TRT) on the loudness and annoyance of their tinnitus. Participants were assigned to either the TRT arm or a control arm, with assignment balanced between groups by tinnitus severity. After baseline evaluation, participants received acoustic stimulation devices and 3 mos of individual counseling. An integrated computerized test battery of questionnaires and psychophysical procedures were used to evaluate participants at 6, 12, and 18 mos after enrollment. The primary outcome measure was the change in total score on the tinnitus handicap inventory. Secondary outcome measures were change in global tinnitus impact on a tinnitus experience questionnaire, subjective tinnitus loudness rating, and tinnitus loudness objectively measured using a psychophysical matching procedure. RESULTS: Both TRT and general counseling without additional sound therapy are effective in reducing the annoyance and impact of tinnitus. The largest effect on overall tinnitus handicap was observed in the TRT participants, with an effect size of 1.13. However, a clinically significant effect was also observed in the control group, with an effect size of 0.78. CONCLUSIONS: Individuals with moderate to severe tinnitus, without hearing loss in the speech frequency range, benefit from treatment with either TRT or general counseling. The global improvement in tinnitus handicap with TRT accrues over an 18-mo period and seems to be a robust and clinically significant effect.

Animal Models of Tinnitus: A Review.

Animal models have significantly contributed to understanding the pathophysiology of chronic subjective tinnitus. They are useful because they control etiology, which in humans is heterogeneous; employ random group assignment; and often use methods not permissible in human studies. Animal models can be broadly categorized as either operant or reflexive, based on methodology. Operant methods use variants of established psychophysical procedures to reveal what an animal hears. Reflexive methods do the same using elicited behavior, for example, the acoustic startle reflex. All methods contrast the absence of sound and presence of sound, because tinnitus cannot by definition be perceived as silence.

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.

Gabapentin.

Several lines of evidence suggest that loss of central inhibition after deprivation of input from the ear (peripheral deafferentation) may be one cause of chronic tinnitus. Aging and acoustic trauma, the two most common causes of peripheral damage to the auditory system, each decrease input to central auditory structures. Loss of input to tonic inhibitory systems would release excitatory structures from inhibitory regulation. The increased activity resulting may be interpreted by more rostral structures in the auditory pathway as tinnitus. Down-regulation of gamma-amino butyric acid (GABA), a major inhibitory neurotransmitter of the central auditory pathway, is a potential mechanism for the loss of inhibition. Both animal studies and human clinical trials implicate loss of inhibition, and specifically loss of GABA function, in the development of acoustic trauma-induced tinnitus.

Vigabatrin, a GABA transaminase inhibitor, reversibly eliminates tinnitus in an animal model.

Animal models have facilitated basic neuroscience research investigating the pathophysiology of tinnitus. It has been hypothesized that partial deafferentation produces a loss of tonic inhibition in the auditory system that may lead to inappropriate neuroplastic changes eventually expressed as tinnitus. The pathological down-regulation of gamma-amino butyric acid (GABA) provides a potential mechanism for this loss of inhibition. Using an animal model previously demonstrated to be sensitive to treatments that either induce or attenuate tinnitus, the present study examined the effect of the specific GABA agonist vigabatrin on chronic tinnitus. It was hypothesized that vigabatrin would decrease the evidence of tinnitus by restoring central inhibitory function through increased GABA availability. Vigabatrin has been demonstrated to elevate central GABA levels (Mattson et al. 1995). Tinnitus was induced in rats using a single 1-h unilateral exposure to band-limited noise, which preserved normal hearing in one ear. Psychophysical evidence of tinnitus was obtained using a free-operant conditioned-suppression method: Rats lever-pressed for food pellets and were trained to discriminate between the presence and absence of sound by punishing lever pressing with a mild foot shock (0.5 mA; 1 s) at the conclusion of randomly introduced silent periods (60 s) inserted into background low-level noise. Additional random insertion of pure tone and noise periods of variable intensity enabled the derivation of psychophysical functions that reflected the presence of tinnitus with features similar to 20-kHz tones. Vigabatrin was chronically administered via drinking water at 30 and 81 mg kg-1 day-1, with each dose level tested over 2 weeks, followed by a 0-mg washout test. Vigabatrin completely and reversibly eliminated the psychophysical evidence of tinnitus at both doses. Although vigabatrin has serious negative side effects that have prevented its clinical use in the USA, it is nevertheless a potentially useful tool in unraveling tinnitus pathophysiology.

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.

Acoustic injury and TRPV1 expression in the cochlear spiral ganglion.

Acoustic trauma not only produces temporary and permanent hearing loss but is a common cause of chronic tinnitus. Recent work indicated a possible role for the transient receptor potential channel vanilloid subfamily type 1 (TRPV1) in modulating the effects of cochlear injury. In our research, we investigated the effects of acoustic damage on TRPV1 expression in spiral ganglion neurons of adult rats. After exposing them unilaterally to noise, we extracted cochleas and processed the spiral ganglion for TRPV1 expression at four posttrauma intervals (2 hours, 24 hours, 12 days, and 16.9 months). We measured TRPV1 immunodensity in the apical, middle, and basal turns of the cochlea. We found a significant interaction (p = .039) between posttrauma interval and regional cochlear receptor expression: For survival intervals between 24 hours and 2 weeks, TRPV1 density increased in all cochlear regions; at the longest survival interval (16.9 months), TRPV1 density was dramatically reduced in the basal region. We also psychophysically tested the long-survival subjects, which showed evidence of 20-kHz tonal tinnitus. These results suggest that TRPV1 may participate after cochlear injury in a signal cascade that is responsible for the neuroplastic events leading to tinnitus and hyperacusis.

The effect of tinnitus retraining therapy on chronic tinnitus: A controlled trial.

OBJECTIVES: The goal of this study was to compare treatment outcomes for chronic bothersome tinnitus after Tinnitus Retraining Therapy (TRT) versus standard of care treatment (SC) and to determine the longevity of the effect over an 18-month period. STUDY DESIGN: A randomized controlled trial comparing TRT to SC for chronic tinnitus. METHODS: Adults with subjective, stable, bothersome chronic tinnitus associated with hearing loss amenable to aural rehabilitation with hearing aids were recruited. The Tinnitus Handicap Inventory (THI) was the primary outcome measure and the Tinnitus Functional Index (TFI) the secondary outcome measure of tinnitus severity and impact. Data were collected at screening, entry (0 months), and 6, 12, and 18 months after the beginning of treatment, using an integrated digitized suite of evaluation modules. TRT consisted of directive counseling and acoustic enrichment using combination hearing aids and sound generators; SC consisted of general aural rehabilitation counseling and hearing aids. RESULTS: Significant improvement in tinnitus impact occurred after both TRT and SC therapy, with a larger treatment effect obtained in the TRT group. Lasting therapeutic benefit was evident at 18 months in both groups. THI initial scores were unstable in 10% of enrolled participants, showing moderate bidirectional fluctuation between screening and baseline (0 month) assessment. CONCLUSION: Adults with moderate to severe tinnitus and hearing loss amenable to amplification, benefit from either TRT or SC treatment when combined with hearing aid use. TRT benefit may exceed that of SC. The global improvement in tinnitus severity that accrued over an 18-month period appeared to be robust and clinically significant. LEVEL OF EVIDENCE: I.

Specific subcortical structures are activated during seizure-induced death in a model of sudden unexpected death in epilepsy (SUDEP): A manganese-enhanced magnetic resonance imaging study.

Sudden unexpected death in epilepsy (SUDEP) is a major concern for patients with epilepsy. In most witnessed cases of SUDEP generalized seizures and respiratory failure preceded death, and pre-mortem neuroimaging studies in SUDEP patients observed changes in specific subcortical structures. Our study examined the role of subcortical structures in the DBA/1 mouse model of SUDEP using manganese-enhanced magnetic resonance imaging (MEMRI). These mice exhibit acoustically-evoked generalized seizures leading to seizure-induced respiratory arrest (S-IRA) that results in sudden death unless resuscitation is rapidly instituted. MEMRI data in the DBA/1 mouse brain immediately after acoustically-induced S-IRA were compared to data in C57 (control) mice that were exposed to the same acoustic stimulus that did not trigger seizures. The animals were anesthetized and decapitated immediately after seizure in DBA/1 mice and after an equivalent time in control mice. Comparative T1 weighted MEMRI images were evaluated using a 14T MRI scanner and quantified. We observed significant increases in activity in DBA/1 mice as compared to controls at previously-implicated auditory (superior olivary complex) and sensorimotor-limbic [periaqueductal gray (PAG) and amygdala] networks and also in structures in the respiratory network. The activity at certain raphe nuclei was also increased, suggesting activation of serotonergic mechanisms. These data are consistent with previous findings that enhancing the action of serotonin prevents S-IRA in this SUDEP model. Increased activity in the PAG and the respiratory and raphe nuclei suggest that compensatory mechanisms for apnea may have been activated by S-IRA, but they were not sufficient to prevent death. The present findings indicate that changes induced by S-IRA in specific subcortical structures in DBA/1 mice are consistent with human SUDEP findings. Understanding the changes in brain activity during seizure-induced death in animals may lead to improved approaches directed at prevention of human SUDEP.

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 rat's 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.

Marking multi-channel silicon-substrate electrode recording sites using radiofrequency lesions.

Silicon-substrate multi-channel electrodes (multiprobes) have proven useful in a variety of electrophysiological tasks. When using multiprobes it is often useful to identify the site of each channel, e.g., when recording single-unit activity from a heterogeneous structure. Lesion marking of electrode sites has been used for many years. Electrolytic, or direct current (DC) lesions, have been used successfully to mark multiprobe sites in rat hippocampus [Townsend G, Peloquin P, Kloosterman F, Hetke JF, Leung LS. Recording and marking with silicon multichannel electrodes. Brain Res Brain Res Protoc 2002;9:122-9]. The present method used radio-frequency (rf) lesions to distinctly mark each of the 16 recording sites of 16-channel linear array multiprobes, in chinchilla inferior colliculus. A commercial radio-frequency lesioner was used as the current source, in conjunction with custom connectors adapted to the multiprobe configuration. In vitro bench testing was used to establish current-voltage-time parameters, as well as to check multiprobe integrity and radio-frequency performance. In in vivo application, visualization of individual-channel multiprobe recording sites was clear in 21 out of 33 sets of collicular serial-sections (i.e., probe tracks) obtained from acute experimental subjects, i.e., maximum post-lesion survival time of 2h. Advantages of the rf method include well-documented methods of in vitro calibration as well as low impact on probe integrity. The rf method of marking individual-channel sites should be useful in a variety of applications.

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. STUDY DESIGN: Prospective, placebo-controlled, single-blind clinical trial. METHODS: Pure-tone audiograms and personal histories were used to categorize tinnitus etiology as either secondary to acoustic trauma or not associated with acoustic trauma. Participants were restricted to those with moderate to severe tinnitus for at least 1 year. All participants received gabapentin in a graduated ascending-descending dose series extending over 20 weeks (peak dose of 2,400 mg/d). RESULTS: There was a significant improvement in tinnitus annoyance for the trauma group (P = .05). Other subjective aspects of tinnitus were not significantly affected in either group. Between-subject variability of therapeutic response was considerable. Nevertheless, in consideration of subjective loudness ratings, 4 of 19 nontrauma participants and 6 of 20 trauma participants showed an improvement of 20% or better. In consideration of psychoacoustic loudness estimates, 3 of 19 nontrauma and 6 of 20 trauma participants showed an improvement of 20 dB HL or greater. Evenly dividing each group into high and low responders revealed significant improvement in loudness at 1,800 and 2,400 mg/day for the trauma high-response subgroup (P = .007). No significant improvement was obtained for other subgroups. CONCLUSION: Gabapentin is effective in reducing subjective and objective aspects of tinnitus in some individuals, with the best therapeutic response obtained in individuals with associated acoustic trauma.

Animal models of tinnitus.

Presented is a thematic review of animal tinnitus models from a functional perspective. Chronic tinnitus is a persistent subjective sound sensation, emergent typically after hearing loss. Although the sensation is experientially simple, it appears to have central a nervous system substrate of unexpected complexity that includes areas outside of those classically defined as auditory. Over the past 27 years animal models have significantly contributed to understanding tinnitus' complex neurophysiology. In that time, a diversity of models have been developed, each with its own strengths and limitations. None has clearly become a standard. Animal models trace their origin to the 1988 experiments of Jastreboff and colleagues. All subsequent models derive some of their features from those experiments. Common features include behavior-dependent psychophysical determination, acoustic conditions that contrast objective sound and silence, and inclusion of at least one normal-hearing control group. In the present review, animal models have been categorized as either interrogative or reflexive. Interrogative models use emitted behavior under voluntary control to indicate hearing. An example would be pressing a lever to obtain food in the presence of a particular sound. In this type of model animals are interrogated about their auditory sensations, analogous to asking a patient, "What do you hear?" These models require at least some training and motivation management, and reflect the perception of tinnitus. Reflexive models, in contrast, employ acoustic modulation of an auditory reflex, such as the acoustic startle response. An unexpected loud sound will elicit a reflexive motor response from many species, including humans. Although involuntary, acoustic startle can be modified by a lower-level preceding event, including a silent sound gap. Sound-gap modulation of acoustic startle appears to discriminate tinnitus in animals as well as humans, and requires no training or motivational manipulation, but its sensitivity, reliability, mechanism, and optimal implementation are incompletely understood. While to date animal models have significantly expanded the neuroscience of tinnitus, they have been limited to examining sensory features. In the human condition, emotional and cognitive factors are also important. It is not clear that the emotional features of tinnitus can be further understood using animal models, but models may be applied to examine cognitive factors. A recently developed model is described that reveals an interaction between tinnitus and auditory attention. This research suggests that effective tinnitus therapy could rely on modifying attention to the sensation rather than modifying the sensation itself. This article is part of a Special Issue entitled .

Clinical trials supported by the Tinnitus Research Consortium: Lessons learned, the Southern Illinois University experience.

The Tinnitus Research Consortium funded three clinical trials investigating treatments for chronic bothersome tinnitus at Southern Illinois University School of Medicine. The trials were designed to measure the subjective changes in tinnitus distress using standardized questionnaires and objective changes in tinnitus loudness using psychophysical matching procedures. The results of the first two trials have been published and are summarized here. The first trial investigated the effect of gabapentin on the loudness and annoyance of tinnitus in adults with chronic bothersome tinnitus with and without a history of acoustic trauma. A small but significant number of subjects reported decreased tinnitus annoyance that corresponded with a decrease in objective measures of tinnitus loudness during active drug treatment with a washout effect during placebo treatment. The second trial compared the effect of tinnitus retraining therapy (TRT) on adults with normal to near-normal hearing and chronic bothersome tinnitus to treatment with general counseling without acoustic enrichment. Significant improvements in tinnitus severity, but not in objective psychometric measures of tinnitus loudness, occurred in both treatment groups, however a greater effect was observed in the TRT group compared with the control group. The third trial is nearing completion and investigates the long-term results of tinnitus retraining therapy on chronic bothersome tinnitus in adults with hearing loss. Significant lessons and observations on conducting tinnitus clinical trials were learned from these three trials. The challenges of recruiting and retaining study participants is discussed. More importantly, the reliability and stability of the Tinnitus Handicap Inventory (THI) over long intervals is presented. The implications of this variability for the design and interpretation of future tinnitus studies is discussed. This article is part of a Special Issue entitled .

Cochlear structure and function after round window application of ototoxins.

Topical round window application of ototoxic agents has been a useful method for studying ototoxicity and hearing loss in the mammalian cochlea. For example, species-specific differences in cochlear susceptibility to damage have been documented using this technique. Carboplatin has been characterized in the literature as a selective inner hair cell (IHC) toxin in chinchillas, while cisplatin has been characterized as a selective outer hair cell (OHC) toxin. The present experiment quantified dose-dependent damage to cochlear hair cells in the chinchilla after a single direct round window application of either cisplatin or carboplatin. Detailed cytocochleograms were obtained for the entire cochlear duct, for a range of doses, along with auditory brainstem response thresholds. In agreement with the literature, although there was variability, at the lowest concentrations tested (2 and 3 mg/ml), carboplatin produced substantial IHC damage with no OHC damage. In contrast, the effects of cisplatin were more variable, and contrary to published reports, across the range of doses producing OHC damage, IHC damage was always observed. Limitations of direct round window ototoxin treatments are discussed, in addition to their potential application in the study of 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.

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.