What's the buzz? The neuroscience and the treatment of tinnitus

Abstract

Tinnitus is a pervasive public health issue that affects ∼15% of the United States population. Similar estimates have also been shown on a global scale, with similar prevalence found in Europe, Asia, and Africa. The severity of tinnitus is heterogeneous, ranging from mildly bothersome to extremely disruptive. In the United States, ∼10-20% of individuals who experience tinnitus report symptoms that severely reduce their quality of life. Due to the huge personal and societal burden, in the last 20 yr a concerted effort on basic and clinical research has significantly advanced our understanding and treatment of this disorder. Yet, neither full understanding, nor cure exists. We know that tinnitus is the persistent involuntary phantom percept of internally generated nonverbal indistinct noises and tones, which in most cases is initiated by acquired hearing loss and maintained only when this loss is coupled with distinct neuronal changes in auditory and extra-auditory brain networks. Yet, the exact mechanisms and patterns of neural activity that are necessary and sufficient for the perceptual generation and maintenance of tinnitus remain incompletely understood. Combinations of animal model and human research will be essential in filling these gaps. Nevertheless, the existing progress in investigating the neurophysiological mechanisms has improved current treatment and highlighted novel targets for drug development and clinical trials. The aim of this review is to thoroughly discuss the current state of human and animal tinnitus research, outline current challenges, and highlight new and exciting research opportunities.

Keywords: channels; drug development; hearing loss; synapses; tinnitus.

Graphical abstract

FIGURE 1.

Hearing loss is the most common cause of tinnitus. A: death or dysfunction of cochlear hair cells. B: loss of ribbon synapses. C: hyperexcitability of type II afferents. D: death or dysfunction of auditory nerve fibers. OHC, outer hair cell; IHC, inner hair cell.

FIGURE 2.

Causes of tinnitus.

FIGURE 3.

The Dorsal Cochlear Nucleus and Tinnitus Mechanisms. Tinnitus mice display increased spontaneous firing of fusiform cells (FC). This is due to enhanced intrinsic excitability due to a shift in the voltage dependence of KCNQ2/3 channels. Adapted from Ref. , with permission from Proceedings of the National Academy of Sciences of the USA. Additional contributors are reductions in GABAergic and glycinergic signaling and aberrant spike timing-dependent plasticity (STDP)-like plasticity. Tinnitus-related changes are depicted in red. CWC, cartwheel cells.

FIGURE 4.

Thalamocortical dysrhythmia in tinnitus. A: peripheral deafferentation causes a reduction of input from the peripheral auditory system that is sent to the medial geniculate body (MGB). B: hyperpolarization and decreased excitatory input to the thalamic neurons causes the firing mode to switch from tonic to burst firing due to de-inactivation of T-type calcium channels. C: as a result of the switch to burst firing, low-frequency oscillations are generated and propagated to the auditory cortex. D: low-frequency oscillations in the deafferented area of cortex leads to a reduction of inhibition to adjacent columns generating high frequency oscillations (Edge effect).

FIGURE 5.

Auditory cortex and tinnitus mechanisms. A: increased spontaneous firing rate (SFR). B: increased neural synchrony. C: tonotopic map reorganization. Adapted from Ref. , with permission from Proceedings of the National Academy of Sciences of the USA. D: increased response gain. Tinnitus-related changes are depicted in red. CF, characteristic frequency.

FIGURE 6.

Circuit diagram detailing the proposed frontostriatal gating theory of tinnitus. The circuit by which the negative perception of tinnitus and the neuromodulatory inputs may affect the gating of auditory percepts is depicted in yellow. The proposed mechanism by which ventromedial prefrontal cortex (vmPFC) gates auditory perception via the GABAergic the thalamic reticular nucleus (TRN) is depicted in blue. Tinnitus-related changes are depicted in red. scACC, subcallosal anterior cingulate cortex.

FIGURE 7.

Conclusions. Brain regions and neural correlates of tinnitus (purple), mechanistic underpinnings (green), and preclinical drug development (yellow). TRN, thalamic reticular nucleus; vmPFC, ventromedial prefrontal cortex; STDP, spike timing-dependent plasticity. TCD, thalamocortical dysrhythmia hypothesis; IC, inferior colliculus; mGluR, metabatropic glutamate receptor.