Tinnitus at the Junction of Traditional Medicine and Modern Technology.

The WHO estimated that 430 million people worldwide suffer from moderate-to-severe hearing loss [...].

Behavioral Assessment of Zwicker Tone Percepts in Gerbils.

The Zwicker tone illusion - an auditory phantom percept after hearing a notched noise stimulus - can serve as an interesting model for acute tinnitus. Recent mechanistic models suggest that the underlying neural mechanisms of both percepts are similar. To date it is not clear if animals do perceive the Zwicker tone, as up to now no behavioral paradigms are available to objectively assess the presence of this phantom percept. Here we introduce, for the first time, a modified version of the gap pre-pulse inhibition of the acoustic startle reflex (GPIAS) paradigm to test if it is possible to induce a Zwicker tone percept in our rodent model, the Mongolian gerbil. Furthermore, we developed a new aversive conditioning learning paradigm and compare the two approaches. We found a significant increase in the GPIAS effect when presenting a notched noise compared to white noise gap pre-pulse inhibition, which is consistent with the interpretation of a Zwicker tone percept in these animals. In the aversive conditioning learning paradigm, no clear effect could be observed in the discrimination performance of the tested animals. When investigating the first 33% of the correct conditioned responses, an effect of a possible Zwicker tone percept can be seen, i.e. animals show identical behavior as if a pure tone was presented, but the paradigm needs to be further improved. Nevertheless, the results indicate that Mongolian gerbils are able to perceive a Zwicker tone and can serve as a neurophysiological model for human tinnitus generation.

Preventive Effects of Ginkgo-Extract EGb 761® on Noise Trauma-Induced Cochlear Synaptopathy.

Noise trauma-induced loss of ribbon synapses at the inner hair cells (IHC) of the cochlea may lead to hearing loss (HL), resulting in tinnitus. We are convinced that a successful and sustainable therapy of tinnitus has to treat both symptom and cause. One of these causes may be the mentioned loss of ribbon synapses at the IHC of the cochlea. In this study, we investigated the possible preventive and curative effects of the Ginkgo biloba extract EGb 761® on noise-induced synaptopathy, HL, and tinnitus development in Mongolian gerbils (Meriones unguiculatus). To this end, 37 male animals received EGb 761® or placebo orally 3 weeks before (16 animals) or after (21 animals) a monaural acoustic noise trauma (2 kHz, 115 dB SPL, 75 min). Animals' hearing thresholds were determined by auditory brainstem response (ABR) audiometry. A possible tinnitus percept was assessed by the gap prepulse inhibition acoustic startle reflex (GPIAS) response paradigm. Synaptopathy was quantified by cochlear immunofluorescence histology, counting the ribbon synapses of 15 IHCs at 11 different cochlear frequency locations per ear. We found a clear preventive effect of EGb 761® on ribbon synapse numbers with the surprising result of a significant increase in synaptic innervation on the trauma side relative to placebo-treated animals. Consequently, animals treated with EGb 761® before noise trauma did not develop a significant HL and were also less affected by tinnitus compared to placebo-treated animals. On the other hand, we did not see a curative effect (EGb 761® treatment after noise trauma) of the extract on ribbon synapse numbers and, consequently, a significant HL and no difference in tinnitus development compared to the placebo-treated animals. Taken together, EGb 761® prevented noise-induced HL and tinnitus by protecting from noise trauma-induced cochlear ribbon synapse loss; however, in our model, it did not restore lost ribbon synapses.

Pharmacologic treatments in preclinical tinnitus models with special focus on Ginkgo biloba leaf extract EGb 761®.

Tinnitus is defined as the perception of sound in the absence of external acoustic stimuli. Frequent comorbidities or associated factors are depression, anxiety, concentration problems, insomnia, resignation, helplessness, headache, bruxism, or social isolation, just to name a few. Although many therapeutic approaches have already been tested with varying success, there still is no cure available for tinnitus. The search for an effective treatment has been hampered by the fact that the mechanisms of tinnitus development are still not fully understood, although several models are available and discussed in this review. Our review will give a brief overview about preclinical models, presenting the heterogeneity of tinnitus sub-types depending on the different inner ear and brain structures involved in tinnitus etiology and pathogenesis. Based on these models we introduce the different target structures and transmitter systems implicated in tinnitus development and provide an extensive overview on preclinical drug-based therapeutic approaches that have been explored in various animal models. As the special extract from Ginkgo biloba leaves EGb 761® has been the most widely tested drug in both non-clinical tinnitus models as well as in clinical trials, a special focus will be given to EGb 761®. The efficacy of terpene lactones, flavone glycosides and proanthocyanidines with their distinct contribution to the overall efficacy profile of the multi-constituent drug EGb 761® will be discussed.

Therapeutic Value of Ginkgo biloba Extract EGb 761® in an Animal Model (Meriones unguiculatus) for Noise Trauma Induced Hearing Loss and Tinnitus.

Noise induced hearing loss (NIHL) is a common disease in modern societies and may lead to maladaptations within the auditory system that finally result in subjective tinnitus. Available therapies may only alleviate the symptoms rather than restore normal hearing. In a previous study we demonstrated that the prophylactic application of Ginkgo biloba extract EGb 761® significantly reduces NIHL and tinnitus development in our Mongolian gerbil (Meriones unguiculatus) animal model. Here, we tested whether the application of EGb 761® has beneficial effects after the formation of permanent NIHL and tinnitus. To this end we monitored the therapeutic effects of EGb 761® on noise trauma-induced changes in signal processing within the auditory system of our animal model by behavioral (acoustic startle response, ASR) and electrophysiological approaches (auditory brainstem responses, ABR). We found that-in contrast to vehicle-three weeks of daily oral EGb 761® treatment (100 mg/kg body weight) led to a restoration of hearing thresholds back to pre-trauma conditions. In addition, all 9 animals that displayed behavioral signs of subjective tinnitus showed improvement, with 7 of them showing complete relief of tinnitus symptoms during the time of EGb 761® treatment. After discontinuation of EGb 761® treatment, tinnitus related behavior reappeared in all but one of these animals while auditory thresholds remained restored. A detailed analysis of ABR waves revealed that EGb 761® treatment did not simply change auditory processing back to pre-trauma conditions, but led to subtle changes of ABR wave amplitude and latency at different levels of the auditory pathway, with an overall increase of response to low stimulus intensities and a decrease at high intensities. The functional relevance of these changes may be the observed improvement of hearing thresholds while at the same time suppression of responses to high stimulus intensities may point to a global inhibitory mechanism that counteracts tinnitus.

Protective effects of Ginkgo biloba extract EGb 761 against noise trauma-induced hearing loss and tinnitus development.

Noise-induced hearing loss (NIHL) and resulting comorbidities like subjective tinnitus are common diseases in modern societies. A substance shown to be effective against NIHL in an animal model is the Ginkgo biloba extract EGb 761. Further effects of the extract on the cellular and systemic levels of the nervous system make it a promising candidate not only for protection against NIHL but also for its secondary comorbidities like tinnitus. Following an earlier study we here tested the potential effectiveness of prophylactic EGb 761 treatment against NIHL and tinnitus development in the Mongolian gerbil. We monitored the effects of EGb 761 and noise trauma-induced changes on signal processing within the auditory system by means of behavioral and electrophysiological approaches. We found significantly reduced NIHL and tinnitus development upon EGb 761 application, compared to vehicle treated animals. These protective effects of EGb 761 were correlated with changes in auditory processing, both at peripheral and central levels. We propose a model with two main effects of EGb 761 on auditory processing, first, an increase of auditory brainstem activity leading to an increased thalamic input to the primary auditory cortex (AI) and second, an asymmetric effect on lateral inhibition in AI.

Improvement of auditory discrimination learning by Ginkgo biloba extract EGb 761.

The effect of oral application of Ginkgo biloba extract EGb 761 on auditory discrimination learning in Mongolian gerbils was investigated using discrimination tasks with three different degrees of difficulty and two protocols for administration starting 2 weeks prior to or at the beginning of training. In comparison to placebo-treated controls we observed significant improvement of learning performance in EGb 761 treated gerbils in discrimination tasks of all degrees of difficulty, from the easiest to the most demanding. EGb 761 has been reported to increase the extracellular concentration of dopamine in prefrontal cortex of rats which plays a major role in the type of discrimination learning used in the present study. We, therefore, suppose that EGb 761 improves discrimination learning through its effect on the dopaminergic system.

Cortical and subcortical sides of auditory rhythms and pitches.

It is commonly assumed that different perceptual qualities arising from sensory stimuli depend on their physical nature being transformed by specific peripheral receptors, for example, colour, vibration or heat. A notable unexplained exception is the low and high repetition rates of any sound perceived as rhythm or pitch, respectively. Using auditory discrimination learning in bilaterally auditory cortex ablated animals, we demonstrate that the perceptual quality of sounds depends on the way the brain processes stimuli rather than on their physical nature. In this context, cortical and subcortical processing steps have different roles in analysing different aspects of sounds with the complete analysis accomplished not before information converges in the auditory cortex.

Auditory sensory memory for random waveforms in the Mongolian gerbil.

Mongolian gerbils (N = 21) were trained to discriminate between continuous and repeated auditory white noise. While for periods up to 40 ms of the repeated noise spectral effects make this a perceptual task, longer periods require auditory sensory memory to solve the task. Short periods (20 ms) could easily be discriminated by naive gerbils (discrimination performance, i.e. hit rate minus false alarm rate >80% after 8 days of training). Discrimination was more difficult for longer periods (100 ms: discrimination performance approximately 50% after 18 days of training). By long-term training (156 days) using an optimized training paradigm two further gerbils learned to discriminate up to a period length of 360 ms but could not proceed at 400 ms. While this falls short of human performance, it demonstrates for the first time sensory memory for random waveforms in animals.

Superposition of horseshoe-like periodicity and linear tonotopic maps in auditory cortex of the Mongolian gerbil.

The segregation of an individual sound from a mixture of concurrent sounds, the so-called cocktail-party phenomenon, is a fundamental and largely unexplained capability of the auditory system. Speaker recognition involves grouping of the various spectral (frequency) components of an individual's voice and segregating them from other competing voices. The important parameter for grouping may be the periodicity of sound waves because the spectral components of a given voice have one periodicity, viz. fundamental frequency, as their common denominator. To determine the relationship between the representations of spectral content and periodicity in the primary auditory cortex (AI), we used optical recording of intrinsic signals and electrophysiological mapping in Mongolian gerbils (Meriones unguiculatus). We found that periodicity maps as an almost circular gradient superimposed on the linear tonotopic gradient in the low frequency part of AI. This geometry of the periodicity map may imply competitive signal processing in support of the theory of "winner-takes-all".