Maladaptive plasticity in tinnitus--triggers, mechanisms and treatment

Abstract

Tinnitus is a phantom auditory sensation that reduces quality of life for millions of people worldwide, and for which there is no medical cure. Most cases of tinnitus are associated with hearing loss caused by ageing or noise exposure. Exposure to loud recreational sound is common among the young, and this group are at increasing risk of developing tinnitus. Head or neck injuries can also trigger the development of tinnitus, as altered somatosensory input can affect auditory pathways and lead to tinnitus or modulate its intensity. Emotional and attentional state could be involved in the development and maintenance of tinnitus via top-down mechanisms. Thus, military personnel in combat are particularly at risk owing to combined risk factors (hearing loss, somatosensory system disturbances and emotional stress). Animal model studies have identified tinnitus-associated neural changes that commence at the cochlear nucleus and extend to the auditory cortex and other brain regions. Maladaptive neural plasticity seems to underlie these changes: it results in increased spontaneous firing rates and synchrony among neurons in central auditory structures, possibly generating the phantom percept. This Review highlights the links between animal and human studies, and discusses several therapeutic approaches that have been developed to target the neuroplastic changes underlying tinnitus.

Figure 1

A. Schematic describing the GPIAS assay for tinnitus. A startle stimulus (black) is inserted into a background noise without a gap (no gap; top row) and with a gap (middle and lower rows; 50 msec. gap, 50 ms before the startle sound) are presented to the animal. Each trial consists of a continuous 60 dB background sound (grey bar) with a 10 msec., 115 dB startle pulse embedded (black bar). The guinea pig startles in response to the startle stimulus, with the amplitude of the response shown by the height of each arrow. In animals without tinnitus, the gap suppresses the startle response (middle row). In animals with tinnitus, the gap is filled by the tinnitus (pink) and the startle response shows less reduction relative to the no gap startle response (white arrow). B–F. Gaussian-mixture model analysis partitions the normalized startle distribution into normal and tinnitus distributions. B. Histogram of the normalized startle distribution (white line) partitioned into two distributions: no evidence for tinnitus (black bars) and evidence for tinnitus (red bars). C. The probability distributions of normalized startle values belonging to the tinnitus or non-tinnitus distributions. D. Histogram of the partitioned distribution of post-exposure normalized startle observations for sham animals. E. Histogram of the partitioned distribution of normalized startle observations for baseline (pre-exposure) observations from sham and exposed animals. F. Histogram of the partitioned distribution of post-exposure normalized startle observations from exposed animals. The percentage of observations placed into the tinnitus group is shown on each panel in D–F. Adapted from ([41]).

Figure 2

Simplified representation of auditory and non-auditory pathways discussed in this article and revealed by functional imaging studies to be involved in aspects of tinnitus. Blue identifies principal structures in the auditory pathway commencing with the cochlear nucleus (CN) and projecting through the inferior colliculus (IC) to the thalamus and auditory cortex (A1, primary auditory cortex A2; secondary auditory cortex; AAC, anterior auditory field). Return projections to the thalamus (these projections more numerous than forward projections) and subcortical structures in the auditory pathway are represented by a thickened arrow. Output from auditory pathways distributes to several major nonauditory regions of the brain, here simplified by their putative functional roles in normal information processing as identified by neuroscience research (see color code). Prominent structures involved in memory and emotion include the parahippocampal gyrus, amygdala, and limbic region including the insula (yellow). Participating in attention and consciousness (green) are the anterior and posterior cingulate regions, orbitofrontal cortex, prefrontal cortex (dorsomedial and ventromedial divisions), the subcallosal region (nucleus accumbens), and posterior partietal cortex including the precuneus. Sensori-motor pathways (red) include somatosensory ganglia, brainstem somatosensory pathways, primary and secondary somatosensory cortex, and the cerebellum. In this summary diagram connections among these regions are portrayed by arrows, but the connections among them are densely parallel and reciprocal mediated by cortico-cortico projections directly or via the thalamus as well as by multisensory interactions that occur in subcortical auditory structures discussed in the article. A2, secondary auditory cortex; AAC, anterior auditory field; A1, primary auditory cortex; IC, inferior colliculus; CN, cochlear nucleus.

Figure 3. Mechanisms of tinnitus initiation in the dorsal cochlear nucleus

A. Schematic of DCN circuitry showing the principal output neurons, fusiform cells and inhibitory interneurons, the cartwheel cells. Electrical stimulation and recording locations are shown in spinal trigeminal nucleus (Sp5) and DCN for measuring StDP. The thirty two-channel recording electrodes (black) spanned the tonotopic axis of the DCN. Short current pulses delivered via a bipolar stimulating electrode (brown) placed into Sp5 activated parallel-fiber inputs to DCN that activate fusiform cells subsequent to granule-cell activation. Tones were delivered through calibrated, hollow ear bars. Ca - cartwheel cell; Fu - fusiform cell; Gr - granule cell; St – Stellate cell; IC - inferior colliculus; Sp5 - spinal trigeminal nucleus; a.n.f - auditory nerve fiber; p.f - parallel fiber. ET- Exposed with tinnitus; ENT – exposed without tinnitus. B. Cartoon of the locations of the recording and stimulating electrodes relative to the animal’s head. C. Bimodal plasticity of spontaneous firing rates (SFR) shifts from predominantly Hebbian in shams (where somatosensory preceding auditory produces facilitation at 20 ms) to anti-Hebbian rules in guinea pigs with tinnitus (facilitation now seen when auditory precedes somatosensory stimulation at −20 ms) and suppressive at all pairing intervals in guinea pigs without tinnitus. Mean timing rules are shown for SFRs for units from Sham (gray), ENT (pink), and ET (red) guinea pigs. Cartoon inset at top represents the relative order of Sp5 and sound stimuli. The brown vertical line indicates the Sp5 stimulation, and the sinusoid represents the tone stimulus. Mean timing rules were computed for all measurements from DCN fusiform cell units. Error bars indicate SEM. Adapted from ([41]). D. Putative molecular mechanisms underlying changes in StDP, SFR and synchrony of DCN principal output neurons (fusiform cells) in initiating tinnitus. Noise over-exposure triggers auditory nerve fiber (ANF) deafferentation or neuropathy leading to alterations in the DCN circuitry via the following processes: Synaptic changes include decreased glycinergic (Gly), GABAergic, and increased glutamatergic (Glu) neurotransmission; intrinsic cellular changes include NMDA receptor (NMDA-R), voltage-gated potassium channel (Kv), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel properties. Each of these processes has been shown to affect one or more tinnitus phenotypes in DCN: increased SFR, increased neural synchrony, and inverted STDP.