Ben Coomber

Tinnitus is highly complex, diverse, and difficult to treat, in part due to the fact that the underlying causes and mechanisms remain elusive. Tinnitus is generated within the auditory brain, however, consolidating our understanding of tinnitus pathophysiology is difficult due to the diversity of reported effects and the variety of implicated brain nuclei. Here, we focus on the inferior colliculus, a midbrain structure that integrates the vast majority of ascending auditory information and projects via the thalamus to the auditory cortex. The IC is also a point of convergence for corticofugal input and input originating outside the auditory pathway. We review the evidence, from both studies with human subjects and from animal models, for the contribution the inferior colliculus makes to tinnitus. Changes in the IC, caused by either noise exposure or drug administration, involve fundamental, heterogeneous alterations in the balance of excitation and inhibition. However, differences between hearing loss-induced pathology and tinnitus-related pathology are not well understood. Moreover, variability in tinnitus induction methodology has a significant impact on subsequent neural and behavioural changes, which could explain some of the seemingly contradictory data. Nonetheless, the inferior colliculus is likely involved in the generation and persistence of tinnitus perception.

A significant challenge in tinnitus research lies in explaining how acoustic insult leads to tinnitus in some individuals, but not others. One possibility is genetic variability in the expression and function of neuromodulators – components of neural signalling that alter the balance of excitation and inhibition in neural circuits. An example is nitric oxide (NO) – a free radical and potent neuromodulator in the mammalian brain – that regulates plasticity via both presynaptic and postsynaptic mechanisms. Changes in NO have previously been implicated in tinnitus generation, specifically in the ventral cochlear nucleus (VCN). Here, we examined nitric oxide synthase (NOS) – the enzyme responsible for NO production – in the guinea pig VCN following acoustic trauma. NOS was present in most cell types – including spherical and globular bushy cells, small, medium and large multipolar cells, and octopus cells – spanning the entire extent of the VCN. The staining pattern was symmetrical in control animals. Unilateral acoustic over-exposure (AOE) resulted in marked asymmetries between ipsilateral and contralateral sides of the VCN in terms of the distribution of NOS across the cochlear nuclei in animals with behavioural evidence of tinnitus: fewer NOS-positive cells and a reduced level of NOS staining was present across the whole extent of the contralateral VCN, relative to the ipsilateral VCN. The asymmetric pattern of NOS-containing cells was observed as early as one day after AOE and was also present in some animals at 3, 7 and 21 days after AOE. However it was not until eight weeks after AOE, when tinnitus had developed, that asymmetries were significant overall, compared with control animals. Asymmetrical NOS expression was not correlated with shifts in the threshold hearing levels. Variability in NOS expression between animals may represent one underlying difference that can be linked to whether or not tinnitus develops after noise exposure.

Tinnitus is often identified in animal models by using the gap prepulse inhibition of acoustic startle (GPIAS). Impaired gap detection following acoustic over-exposure (AOE) is thought to be caused by tinnitus ‘filling in’ the gap, thus reducing its salience. This presumably involves altered perception, and could conceivably be caused by changes at the level of the neocortex, i.e. cortical reorganization. Alternatively, reduced gap detection ability might reflect poorer temporal processing in the brainstem, caused by AOE; in which case, impaired gap detection would not be a reliable indicator of tinnitus. We tested the latter hypothesis by examining gap detection in inferior colliculus (IC) neurons following AOE. Seven of nine unilaterally noise-exposed guinea pigs exhibited behavioural evidence of tinnitus. In these tinnitus animals, neural gap detection thresholds in the IC significantly increased in response to broadband noise stimuli, but not to pure tones or narrowband noise. In addition, when IC neurons were sub-divided according to temporal response profile (onset vs. sustained firing patterns), we found a significant increase in the proportion of onset-type responses after AOE. Importantly, however, gap detection thresholds were still considerably shorter than gap durations commonly used in objective behavioural tests for tinnitus. These data indicate that the neural changes observed in the IC are insufficient to explain deficits in behavioural gap detection that are commonly attributed to tinnitus. The subtle changes in IC neuron response profiles following AOE warrant further investigation.

Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise‐exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates (SFRs) and burst firing in the inferior colliculus (IC), evoked auditory brainstem responses (ABRs), and the number of neurons in the cochlear nucleus containing nitric oxide synthase (NOS). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFRs and incidences of burst firing were elevated in the IC of all noise‐exposed animals, but there were no differences between tinnitus and no‐tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral–contralateral asymmetry in NOS staining in the ventral cochlear nucleus (VCN) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS‐containing neurons on the noise‐exposed side, whereas no‐tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABRs supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus.