We studied a typical and heterogeneous group of patients with tinnitus, as evidenced by a range of ages, the presence or absence of overt hearing loss, tinnitus aetiology, distress, duration and laterality. Similarly heterogeneous across patients, though without any systematic relationship with these factors, were the frequency bands and directions of oscillatory power change in non-auditory cortical regions. The Supplementary material
provides further interpretation of these findings and their relevance to the study of tinnitus and other perceptual situations, in which a similar degree of heterogeneity might be found. Despite this marked heterogeneity, subjects consistently demonstrated correlations, at individual level,
between perceived tinnitus intensity and the strength of localized auditory cortex gamma oscillations in the residual inhibition and residual excitation conditions.
In the context of residual inhibition, auditory cortex gamma positively correlated with tinnitus intensity (i.e. decreased during residual inhibition). Residual inhibition is achieved by a transient and partial normalization of the deafferentation of auditory thalamus that leads to the generation of tinnitus. Our finding of increased delta/theta power in the auditory cortex of six subjects, with increased tinnitus intensity in the context of residual inhibition, was in keeping with this model (increases might also have existed in the other subjects, but did not reach statistical significance). As the presence of tinnitus is known to be associated with increased auditory cortex gamma, these findings are to be expected. However, they do not shed any further light on the role that auditory cortex gamma actually plays with respect to tinnitus. If auditory cortex gamma were the cornerstone and driving force behind the perception of tinnitus (as proposed in the theory of thalamocortical dysrhythmia) then it would be expected to decrease along with tinnitus decreases in residual inhibition. However, if auditory cortex gamma were an inhibitory force in tinnitus, it would also be expected to decrease in residual inhibition, during which the tinnitus drive to inhibition decreases.
In the context of residual excitation, auditory cortex gamma negatively correlated with tinnitus intensity (i.e. decreased during residual excitation). This finding is incompatible with any theory based on auditory cortex gamma as a driving force behind tinnitus (or as a driving force behind perception in general) and demands a reconsideration of what its role might be. Unlike residual inhibition, residual excitation cannot primarily operate at the level of the auditory periphery or thalamus, in which case the same relationship between tinnitus intensity and auditory cortex gamma should be demonstrated as in residual inhibition (i.e. increasing auditory cortex gamma power during excitation associated with increasing low-frequency power as a reflection of increased thalamocortical input). Rather, with increasing tinnitus intensity, we found decreasing gamma power and no change in delta or theta band power during residual excitation. It is also unlikely that it is primarily a top–down process from higher cortical areas, as our results showed extra-auditory cortical power changes in only a minority of residual excitation subjects, with no consistency between these. The consistent reduction in auditory cortex gamma oscillatory power in residual excitation suggests a local basis in auditory cortex, with modification of gamma oscillations as its fundamental mechanism.
Based on our experimental findings, we propose that auditory cortex gamma oscillations suppress, rather than cause, the perception of tinnitus. Our present data are insufficient to establish the mechanism by which this inhibitory process operates. However, our results are fully explicable by existing knowledge derived from the study of gamma oscillations at a local circuit level. We therefore offer a speculative model to explain how gamma oscillations might inhibit the perception of tinnitus, and how these oscillations might be disrupted to give rise to residual excitation. illustrates this model in the context of a simplified auditory pathway during spontaneous tinnitus, residual inhibition and residual excitation (both during and after masker presentation). In spontaneous tinnitus, cochlear dysfunction reduces thalamic inputs in the affected parts of the tonotopic axis. This thalamic deafferentation gives rise to regions of spontaneous low-frequency spiking activity. This in turn projects to auditory cortex in approximately the inverse tonotopic configuration to the thalamic input (i.e. areas of weak thalamic input give rise to strong thalamic outputs). Stimulated tonotopic regions in auditory cortex exert lateral inhibitory influences over neighbouring regions; as the thalamocortical input is broad, these lateral inhibitory connections are relatively balanced. There is strong evidence that gamma oscillations are driven by inhibitory interneurons and constitute a process of mutual inhibition whereby excitatory neurons are rhythmically and synchronously inhibited at gamma frequencies (Wang and Rinzel, 1992
; Bartos et al., 2007
). Furthermore, evidence from primary visual cortex indicates that increased gamma oscillations are associated with reduced firing rates of principal excitatory neurons, the authors proposing activation of a neuron’s suppressive surround as a mechanism for these phenomena (Gieselmann and Thiele, 2008
). Similar work has also shown that gamma oscillations occur most strongly in response to large stimuli spanning multiple receptive fields and that selective attention towards a particular receptive field both reduces gamma oscillations and increases neuronal firing rates (Chalk et al., 2010
). Modelling of cholinergic attentional mechanisms suggests that acetylcholine acts to increase lateral inhibition and reduce lateral excitation (Deco and Thiele, 2011
Figure 4 Model of the cause and role of auditory cortex gamma oscillations in the suppression of tinnitus. A simplified schematic of the auditory pathway (A) in association with tinnitus, during silence (i.e. no external auditory stimuli), (B) in the context of (more ...)
Based on these findings, we postulate that gamma oscillations are facilitated by activation of neighbouring tonotopic regions in the context of reciprocally balanced lateral inhibition, and that these oscillations act to mutually inhibit the firing rates of excitatory neurons. We also propose that in attentional states, imbalances in lateral inhibition lead to certain tonotopic regions ‘winning out’, which is associated with a reduction in gamma oscillation-mediated mutual inhibition. In tinnitus, we suggest that an area of auditory cortex spanning multiple tonotopic regions is chronically stimulated, and these regions are subject to relatively balanced lateral inhibition. These conditions lead to strong mutual inhibition via gamma oscillations that are synchronous across a relatively wide region of cortex and thus strongly detectable externally. Functionally, these oscillations attenuate the representation of a broad and information-poor input to auditory cortex, and are facilitated by its relative homogeneity and low recruitment of attentional mechanisms. In the case of residual inhibition, the difference is that the thalamic inputs are partially normalized. There is thus a weaker thalamocortical input, which results in gamma-mediated mutual inhibition that is less pronounced than in spontaneous tinnitus. In the case of residual excitation, the thalamic and thalamocortical inputs return to baseline after cessation of the masker, and the primary mechanism is a disruption of the gamma oscillations. Presentation of an auditory stimulus narrower in spectrum than the region of deafferentation may result in an imbalance of lateral inhibition at the edge frequencies of the stimulus (edge frequencies strongly inhibit their neighbours and are in turn only weakly inhibited). Once the stimulus has ended, the imbalance in lateral inhibition temporarily persists. This imbalance is perpetuated by the continued (albeit weaker) input at masker frequencies due to thalamocortical projections. It could also be promoted by cholinergic activity, either at a purely local level, or involving the action of the basal forebrain cholinergic system that mediates both stimulus-driven and top–down attention (Sarter et al., 2005
). The imbalance of lateral inhibition disrupts gamma oscillations around these stimulus edge frequencies, leading to an overall pattern of gamma oscillations that is reduced in magnitude from baseline, and occurring incontiguously (due to anatomical discontinuity and/or phase dys-synchrony). The effect of this gamma disruption is a release from inhibition of neuronal activity and therefore strengthened projection to higher perceptual areas.
Regardless of our model’s correctness, the finding that auditory cortex gamma oscillations are an inhibitory process in tinnitus is an important one; cortical gamma oscillations are known to be generated by the action of gamma-aminobutyric acidergic interneurons (Candin et al., 2009
) and to be influenced in vivo
by local concentration of gamma-aminobutyric acid (Muthukumaraswamy et al., 2009
). These factors are potentially amenable to pharmacological manipulation, and therefore a correct understanding of their role with respect to tinnitus is important for therapeutic exploitation. If our assertion is correct that cholinergic mechanisms influence gamma oscillations in tinnitus, then this might represent a further possible avenue of pharmacological intervention. Our findings suggest that auditory cortex gamma oscillations are not generators of tinnitus, but rather an intrinsic control mechanism that exerts tonic suppression of the phantom auditory percept, and might be augmented to therapeutic effect.