Neural Correlates Of Tinnitus Research Articles

Tinnitus Correlates with Downregulation of Cortical Glutamate Decarboxylase 65 Expression But Not Auditory Cortical Map Reorganization.

Hearing loss is the biggest risk factor for tinnitus, and hearing-loss-related pathological changes in the auditory pathway have been hypothesized as the mechanism underlying tinnitus. However, due to the comorbidity of tinnitus and hearing loss, it has been difficult to differentiate between neural correlates of tinnitus and consequences of hearing loss. In this study, we dissociated tinnitus and hearing loss in FVB mice, which exhibit robust resistance to tinnitus following monaural noise-induced hearing loss. Furthermore, knock-down of glutamate decarboxylase 65 (GAD65) expression in auditory cortex (AI) by RNA interference gave rise to tinnitus in normal-hearing FVB mice. We found that tinnitus was significantly correlated with downregulation of GAD65 in the AI. By contrast, cortical map distortions, which have been hypothesized as a mechanism underlying tinnitus, were correlated with hearing loss but not tinnitus. Our findings suggest new strategies for the rehabilitation of tinnitus and other phantom sensation, such as phantom pain.SIGNIFICANCE STATEMENT Hearing loss is the biggest risk factor for tinnitus in humans. Most animal models of tinnitus also exhibit comorbid hearing loss, making it difficult to dissociate the mechanisms underlying tinnitus from mere consequences of hearing loss. Here we show that, although both C57BL/6 and FVB mice exhibited similar noise-induced hearing threshold increase, only C57BL/6, but not FVB, mice developed tinnitus following noise exposure. Although both strains showed frequency map reorganization following noise-induced hearing loss, only C57BL/6 mice had reduced glutamate decarboxylase 65 (GAD65) expression in the auditory cortex (AI). Knocking down GAD65 expression in the AI resulted in tinnitus in normal-hearing FVB mice. Our results suggest that reduced inhibitory neuronal function, but not sensory map reorganization, underlies noise-induced tinnitus.

An animal model of deep brain stimulation for treating tinnitus: A proof of concept study.

This proof-of-concept study aimed to demonstrate therapeutic effects of deep brain stimulation (DBS) on noise-induced tinnitus. Experimental animal study. After Institutional Animal Care and Use Committee approval, nine adult rats were implanted in the caudate nucleus with custom-made electrode array. The rats were exposed to noise to induce tinnitus. Auditory brainstem response was performed to evaluate hearing threshold changes. Noise-induced tinnitus and its suppression by DBS were evaluated using the gap-detection acoustic startle reflex behavioral paradigm and electrophysiological evaluation of modulatory effects on neural correlates of tinnitus. Various stimulation parameters were used to determine the most effective ones in affecting behavioral changes, along with corresponding neural activity in the caudate nucleus. The correlation between the caudate nucleus and auditory cortex also was determined. Analysis of variance with Bonferroni correction was performed to examine DBS-induced effects on behavioral evidence of tinnitus. Bursting activity, a neural marker of tinnitus, was noted to decrease compared to baseline in tinnitus (+) animals. After stimulation, spontaneous and bursting activity increased in the tinnitus (+) animals but decreased in the tinnitus (-) animals. Behavioral data suggested suppression of tinnitus after DBS. These effects lasted up to 5 days. To our knowledge, this is the first development of an animal model to test deep brain stimulation of the caudate region for the treatment of tinnitus. Deep brain stimulation of the caudate nucleus can modulate tinnitus in a rat model of tinnitus. NA. Laryngoscope, 128:1213-1222, 2018.

The auditory cortex and tinnitus – a review of animal and human studies.

Tinnitus is the sound heard in the absence of physical sound sources external or internal to the body. Tinnitus never occurs in isolation; it typically develops after hearing loss, and not infrequently for losses at the higher frequencies not tested in clinical audiology. Furthermore, tinnitus is often accompanied by hyperacusis, i.e. increased loudness sensitivity, which may reflect the central gain change in the auditory system that occurs after hearing loss. I will first review the electrophysiological findings in the thalamus and cortex pertaining to animal research into tinnitus. This will comprise the changes in tonotopic maps, spontaneous firing rates and changes in pairwise neural cross-correlation induced by tinnitus-inducing agents that are commonly used in animal experiments. These are systemic application of sodium salicylate, and noise exposure at levels ranging from those that do not cause a hearing loss, to those that only cause a temporary threshold shift, to those that cause a permanent hearing loss. Following this, I will review neuroimaging and electrophysiological findings in the auditory cortex in humans with tinnitus. The neural substrates of tinnitus derived from animal data do not apply universally, as neither hearing loss nor hyperacusis appear to be necessary conditions for tinnitus to occur in humans. Finally, I will relate the findings in humans to the predictions from animal models of tinnitus. These comparisons indicate that neural correlates of tinnitus can be studied successfully both at the level of animal models and in humans.

Multi-sensory integration in brainstem and auditory cortex

Tinnitus is the perception of sound in the absence of a physical sound stimulus. It is thought to arise from aberrant neural activity within central auditory pathways that may be influenced by multiple brain centers, including the somatosensory system. Auditory-somatosensory (bimodal) integration occurs in the dorsal cochlear nucleus (DCN), where electrical activation of somatosensory regions alters pyramidal cell spike timing and rates of sound stimuli. Moreover, in conditions of tinnitus, bimodal integration in DCN is enhanced, producing greater spontaneous and sound-driven neural activity, which are neural correlates of tinnitus. In primary auditory cortex (A1), a similar auditory-somatosensory integration has been described in the normal system (Lakatos et al., 2007), where sub-threshold multisensory modulation may be a direct reflection of subcortical multisensory responses (Tyll et al., 2011). The present work utilized simultaneous recordings from both DCN and A1 to directly compare bimodal integration across these separate brain stations of the intact auditory pathway. Four-shank, 32-channel electrodes were placed in DCN and A1 to simultaneously record tone-evoked unit activity in the presence and absence of spinal trigeminal nucleus (Sp5) electrical activation. Bimodal stimulation led to long-lasting facilitation or suppression of single and multi-unit responses to subsequent sound in both DCN and A1. Immediate (bimodal response) and long-lasting (bimodal plasticity) effects of Sp5-tone stimulation were facilitation or suppression of tone-evoked firing rates in DCN and A1 at all Sp5-tone pairing intervals (10, 20, and 40 ms), and greater suppression at 20 ms pairing-intervals for single unit responses. Understanding the complex relationships between DCN and A1 bimodal processing in the normal animal provides the basis for studying its disruption in hearing loss and tinnitus models. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Acoustic over-exposure triggers burst firing in dorsal cochlear nucleus fusiform cells

Acoustic over-exposure (AOE) triggers deafness in animals and humans and provokes auditory nerve degeneration. Weeks after exposure there is an increase in the cellular excitability within the dorsal cochlear nucleus (DCN) and this is considered as a possible neural correlate of tinnitus. The origin of this DCN hyperactivity phenomenon is still unknown but it is associated with neurons lying within the fusiform cell layer. Here we investigated changes of excitability within identified fusiform cells following AOE. Wistar rats were exposed to a loud (110 dB SPL) single tone (14.8 kHz) for 4 h. Auditory brainstem response recordings performed 3–4 days after AOE showed that the hearing thresholds were significantly elevated by about 20–30 dB SPL for frequencies above 15 kHz. Control fusiform cells fired with a regular firing pattern as assessed by the coefficient of variation of the inter-spike interval distribution of 0.19 ± 0.11 (n = 5). Three to four days after AOE, 40% of fusiform cells exhibited irregular bursting discharge patterns (coefficient of variation of the inter-spike interval distribution of 1.8 ± 0.6, n = 5; p < 0.05). Additionally the maximal firing following step current injections was reduced in these cells (from 83 ± 11 Hz, n = 5 in unexposed condition to 43 ± 6 Hz, n = 5 after AOE) and this was accompanied by an increased firing gain (from 0.09 ± 0.01 Hz/pA, n = 5 in unexposed condition to 0.56 ± 0.25 Hz/pA, n = 5 after AOE). Current and voltage clamp recordings suggest that the presence of bursts in fusiform cells is related to a down regulation of high voltage activated potassium currents.In conclusion we showed that AOE triggers deafness at early stages and this is correlated with profound changes in the firing pattern and frequency of the DCN major output fusiform cells. The changes here described could represent the initial network imbalance prior to the emergence of tinnitus.

Electrical Stimulation of the Cochlea to Reduce Tinnitus.

This article reviews possible neural correlates of tinnitus, including an increase in rate, a decrease in rate, periodic activity, synchronous activity across neurons, and an edge between active and inactive neurons. We make some suggestions regarding how electrical current might alter these patterns of neural activity. For example, if tinnitus were represented with periodic neural activity, then electrical stimulation would need to disrupt this periodicity. Some cases of cochlear electrical stimulation are reviewed that show the tinnitus can be reduced or eliminated with cochlear electrical stimulation although it varies across individuals. Finally, after summarizing some key observations, we suggest some next steps to bring this into a clinical application.

Electrical Modulation of Tinnitus-Related Activity

Tinnitus is the conscious experience of sound without an external acoustic source. Many years of research effort have contributed to a better understanding of the mechanisms underlying tinnitus, including the neural correlates of tinnitus. Our laboratory has been investigating the modulatory effects of somatosensory and cortical electrical stimulation on the neural correlates of tinnitus in auditory and nonauditory structures. These aspects of tinnitus suppression research are explored in an effort to stimulate further studies and to promote the development of effective strategies in the management of tinnitus through electrical stimulation.

Development of hyperactivity after hearing loss in a computational model of the dorsal cochlear nucleus depends on neuron response type

Cochlear damage can change the spontaneous firing rates of neurons in the dorsal cochlear nucleus (DCN). Increased spontaneous firing rates (hyperactivity) after acoustic trauma have been observed in the DCN of rodents such as hamsters, chinchillas and rats. This hyperactivity has been interpreted as a neural correlate of tinnitus. In cats, however, the spontaneous firing rates of DCN neurons were not significantly elevated after acoustic trauma. Species-specific spontaneous firing rates after cochlear damage might be attributable to differences in the response types of DCN neurons: In gerbils, type III response characteristics are predominant, whereas in cats type IV responses are more frequent. To address the question of how the development of hyperactivity after cochlear damage depends on the response type of DCN neurons, we use a computational model of the basic circuit of the DCN. By changing the strength of two types of inhibition, we can reproduce salient features of the responses of DCN neurons. Simulated cochlear damage, which decreases the activity of auditory nerve fibers, is assumed to activate homeostatic plasticity in projection neurons (PNs) of the DCN. We find that the resulting spontaneous firing rates depend on the response type of DCN PNs: PNs with type III and type IV-T response characteristics may become hyperactive, whereas type IV PNs do not develop increased spontaneous firing rates after acoustic trauma. This theoretical framework for the mechanisms and circumstances of the development of hyperactivity in central auditory neurons might also provide new insights into the development of tinnitus.