Temporo-insular enhancement of EEG low and high frequencies in patients with chronic tinnitus.
From: BMC Neurosci. 2010 Mar 24;11(1):40. [Epub ahead of print]
Tinnitus is an auditory phantom perception, reported subjectively as a tone and/or a noise, in the absence of an external stimulus. Approximately 5-15 % of the general population experience tinnitus. In 1-3% of the general population the tinnitus affects the quality of life, involving sleep disturbance, work impairment and psychological distress. The underlying physiological mechanisms that lead to phantom sensation are still being explored. In most cases, tinnitus is accompanied by an audiometrically measurable hearing loss, and even in a majority of those cases with normal audiograms abnormal outer or inner hair-cell function has been reported correlating with the presence of tinnitus.
Contemporary views of tinnitus emphasize the role of the central auditory system. Studies in anaesthetized animals suggest enhanced firing rate and /or synchronized firing to be a necessary neurophysiological mechanism underlying tinnitus. A reduction of tinnitus intensity in patients has been correlated to reduction of delta band power.
Alterations in spontaneous central neuronal activity patterns after peripheral deafferentations have recently been proposed to be essential in the genesis of tinnitus. A relevance for peripheral deafferentation has also been proposed in the field of neurogenic pain, which prompted some authors to envisage that a similar mechanism might be at the source of tinnitus and neurogenic pain. Peripheral deafferentation leads to thalamic deactivation, which in turn disrupts normal thalamocortical interaction, thus leading to the appearance of tinnitus. The effects of an abnormal thalamocortical interaction can be analysed at the cortical level using magnetoencephalogram or electroencephalogram. This sequential view integrates both the induction in the periphery and the generation at the thalamocortical level of tinnitus. In the following, the authors refer to a mechanism that focuses on thalamocortical interplay. First evidence for this mechanism in tinnitus was the finding of low-threshold calcium spike bursts in the medial thalamus. 50% of neuronal activity in the medial thalamus (central lateral nucleus, central lateral nucleus) was characterized as low-threshold calcium spike bursts. Low-threshold calcium spike bursts displayed a delta/theta rhythmicity, with a mean interburst discharge rate of 4 Hz. low-threshold calcium spikes have been described intracellularly in in vitro and in vivo experiments and have been related to a state of membrane hyperpolarization. In tinnitus this would be a consequence of auditory deprivation caused by peripheral damage.
The central lateral nucleus is part of the medial thalamus, is diffusely connected to wide cortical areas and is thought to serve as a non-specific amplifier of thalamocortical activity. The thalamocortical loop constitutes an important component contributing to the rhythmicity of scalp electroencephalogram and magnetoencephalogram. The 4 Hz discharge rate of thalamic low-threshold calcium spike bursts may be supposed to attract the thalamocortical system into low electroencephalogram frequencies, a proposition which is at the base of this and other studies. Thus analyzing spectral features of continuously recorded electroencephalogram offers a window for the investigation of abnormal thalamocortical interplay in tinnitus patients. Surprisingly, even though spontaneous activity has been a frequent research target in animal models of tinnitus, studies in humans have been rare. A few studies have looked at the resting oscillatory electroencephalogram/magnetoencephalogram in tinnitus patients as compared to healthy controls. In a resting electroencephalogram study of patients with severe tinnitus as compared to healthy controls a significant increase of Z-score power over the frequency ranges from 0.5 to 22 Hz was reported, which was dominant in fronto-temporal electrodes. Another electroencephalogram study described an increase and decrease of average total power in female and male patients as compared to healthy controls, respectively. A further study of spontaneous brain activity reported temporal and fronto-temporal changes (increases and decreases) of relative power in individuals with severe tinnitus. Most recently, an magnetoencephalogram study found an increase and decrease of delta and alpha power respectively in tinnitus patients as compared to healthy controls.
Further studies emphasized the relevance of gamma (> 40 Hz) activity to the pathophysiology of tinnitus. The aforementioned findings have been incongruous, showing both increase and decrease in different frequency band power. Therefore the characteristic of different frequency bands remains an ongoing debate in the pathogenesis of tinnitus. Otherwise, attempts to study tinnitus in humans have focused on the use of designs that measure neurophysiological responses to sounds or experimental manipulations that enhance or reduce the perceived loudness. In a recent experiment of that kind, Kahlbrock and Weisz found transient reductions of tinnitus intensity following the offset of a masker (so-called residual inhibition, residual inhibition), accompanied by significant reduction in the delta frequency band. These changes were specific to a masker inducing residual inhibition and not observed with maskers that do not.
In light of the high variability of results we still lack sufficient knowledge of the anomalies of the resting electroencephalogram state in tinnitus patients, and the localization of cortical generators at the source of the observed power excesses has not been investigated in detail.
In the present study, the authors use power spectrum analysis and source localization of electroencephalogram data to identify cortical regions with changes in the underlying spontaneous activity patterns in individuals with tinnitus under both conditions eyes closed and eyes open as compared to healthy controls.
The authors findings can be added to the microphysiological and magnetoencephalographic evidence for a thalamocortical dysrhythmic process at the source of tinnitus, characterised by a low frequency overproduction in thalamocortical loops.
This study on chronic tinnitus shows power enhancement of the spontaneous electroencephalogram activity, and localizes corresponding cortical generators of this dysrhythmic activity. Our most striking finding in the electroencephalogram spectra of the patient group is the delta and theta electroencephalogram power enhancement. An increase of cortical activity is in line with a previous magnetoencephalogram report of excess power in the whole frequency range for positive symptoms and an increase of delta in tinnitus patients compared to healthy controls. It is at variance with an earlier report. This variance may be due to 1) the size of the patient groups and/or the selection of patients, and 2) the specific choice of frequency bands entering the statistical analysis. The authors analysis is less likely to be biased in this respect, since Z-values are calculated for each frequency point. Concerning the statistics for band powers, the authors have corrected for multiple comparisons using false discovery rate, yielding more potent statistical inference to this study.
The general increase in power in delta, theta and beta frequency ranges is confirmed if individual electrodes are analysed. This increase is generalized for theta and delta, and limited to fronto-centro-parietal sites in the beta domain. An increase of alpha is also found in the eyes open condition, localized on similar areas as delta and theta and indicating thus a participation of this frequency band in the thalamocortical dysrhythmia tinnitus process. An increase in low and high frequencies is in line with the concept of thalamocortical dysrhythmia and may reflect the outspoken and chronic thalamocortical dysrhythmia involvement of our patient group. This may explain the differences with the study of Weisz et al., where only delta increase and a reduction of alpha were observed. Reduction of delta band power and theta band power after neurofeedback speaks for a causal relevance of slow oscillation increase in tinnitus. In an magnetoencephalogram case study, Llinas et al. obtained a general (delta to beta) spectral power reduction after tinnitus masking.
In the delta, theta, alpha and beta bands, the cortical generators of excess electroencephalogram power were located in dominantly left auditory (Brodmann area) temporo-parietal, insular posterior, cingulate anterior and parahippocampal cortical areas. Such a localization is in accordance with data from metabolic studies and speaks for a dysrhythmic co-involvement of associative and paralimbic areas in the pathogenesis of tinnitus, which is consistent with their topographic and functional vicinity with the auditory system. Many other studies pointed out the involvement of associative/paralimbic areas and the importance of reactive emotional factors in tinnitus has been repeatedly reported, as well as reciprocal involvement of auditory and associative/paralimbic areas. The authors observe a dominance on the left side for both thalamocortical dysrhythmia and tinnitus. At the time, the authors can only speculate that this observation is related to cognitive/emotional factors, e.g. the relevance of the non-acceptance of, and related frustration about, the presence of tinnitus. This non-acceptance may be viewed as primarily conceptual, i.e. left-side dominant.
Following the proposition of Llinas of a central relevance of thalamocortical interaction in the genesis of hemispheric function and encouraged by earlier finding of strong thalamocortical coupling, the authors propose here an interpretation of results in the framework of thalamocortical dysrhythmia. This thalamocortical concept for neurogenic pain, abnormal movements, epilepsy, tinnitus and neuropsychiatric disorders was proposed on the basis of experimental, and clinical evidence in the mentioned diseases. It may be characterized by the following sequential set of events:
(1) A lesion leads to deafferentation of excitatory inputs on thalamic relay cells and initiates the tinnitus syndrome. The deafferentation of excitatory inputs results in disfacilitation and cell membrane hyperpolarization.
(2) In the hyperpolarized state, deinactivation of calcium T-channels causes thalamic relay neurons to fire low-threshold calcium spike bursts at delta/theta frequency.
(3) Bursting thalamic relay neurons exert a rhythmic influence on thalamocortical loops in the delta/theta frequency band. Thalamic and cortical areas are densely and reciprocally interconnected. The tight functional coupling between thalamus and cortex is confirmed by the high theta coherence between the two. This coupling is sustained by thalamocorticothalamic and also by thalamoreticulothalamic and corticoreticulothalamic recurrent projections. The tendency of the thalamocortical network to maintain a given functional modality reinforces the hyperpolarized state over time.
(4) Divergent thalamocortical, corticothalamic and reticulothalamic projections provide the anatomical substrate for diffusion of low frequency activity to an increasing number of neighbouring thalamocortical loops.
(5) After recruitment of a sufficiently large number of thalamocortical loops, excess delta/theta power becomes measurable. Increased low-frequency oscillations also occur during sleep and cognitive tasks, where they are considered as normal. It is the continuous, widespread and state-independent overproduction of slow rhythms in the awake brain that characterizes thalamocortical dysrhythmia.
(6) The final step towards the production of tinnitus is related to the reciprocal cortico-cortical inhibition mediated by GABrodmann areaergic interneurons, which is a general feature of cortical organization (Fig. 6C). thalamocortical modules in delta/theta mode exert less collateral inhibition on neighboring modules, which are thereby overactivated in high (beta/gamma) frequencies. This event has been termed “edge effect”. The concept is inspired by the effect of lateral inhibition in the retina. It has also been considered in the periphery of the auditory system. The asymmetrical inhibition between a low frequency cortical area and neighbouring high frequency domains provides a ring of reduced inhibition onto, and thus activation of, the cortex surrounding this low frequency area. Support for such an effect was first provided by the increased interfrequency covariation between theta and beta ranges in magnetoencephalogram. Recently, the increase of high frequency activation around a core of theta modules could be demonstrated in a slice preparation.
Plasticity mechanisms have been proposed to be at the base of the appearance of tinnitus. The following observations speak however for the necessity of at least another mechanism. The presence of a deficit after a damage to the auditory system and the induction of plastic mechanisms are both seen to happen in all deafferentation situations, whereas tinnitus, quite like neurogenic pain, develops and maintains itself along years only in a small (less than 10%) percentage of all deafferented subjects. Plastic map reorganizations, as argued by Weisz and collaborators, certainly contribute to the new post-lesional situation, but cannot satisfactorily explain the emergence and maintenance of tinnitus.
Accumulating evidence from electroencephalogram and magnetoencephalogram studies underscores the fact that conceptual and emotional activations increase hemispheric theta activity. The electroencephalogram source localization data confirm other studies demonstrating the coactivation of cortical auditory and associative/paralimbic areas. This provides a substrate for a role of mental functions in the reactive modulation of neurogenic (i.e. due to auditory deafferentation) tinnitus and the generation of psychogenic tinnitus. Indeed, a top-down activation of the divergent corticothalamic projection from associative/paralimbic onto auditory areas, when strong and long-lasting enough to cause sustained thalamic overinhibition, might be at the source of an increase of theta production and, thus, of an amplification of neurogenic tinnitus mechanisms. It may even be at the origin of psychogenic tinnitus. One of the most deleterious conceptual/emotional dynamics is, in this experience, frustration and non-acceptance of the disease-related health impairment. The conceptual and practical consequences of these considerations are obvious and have a wide range of implications for the therapeutic support of neurogenic and psychogenic tinnitus patients. These include the recognition of a dual origination of tinnitus (neurogenic and psychogenic), in body and mind, respectively, but the existence of a common thalamocortical mechanism for both.
Source: Temporo-insular enhancement of EEG low and high frequencies in patients with chronic tinnitus
