Transcranial magnetic stimulation tinnitus clinical trials 07,ear keloid home remedies vinegar,sinus infection mayo clinic 401k - Tips For You

08.04.2015
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The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at time of review. Chronic tinnitus is associated with neuroplastic changes in auditory and non-auditory cortical areas.
Tinnitus is the perception of sound in the absence of a corresponding external auditory stimulus. But although increasing knowledge about tinnitus generation has been revealed by neuroscientific research during the last decades, the pathophysiology of tinnitus is still incompletely understood and there exists no well established causally oriented treatment (Langguth et al., 2013). Due to these limitations, it is important to collect and combine information from different methods in order to obtain an elaborate knowledge about the neuronal correlates of chronic tinnitus. Here, we investigated the effects of single sessions of low-frequency rTMS over the left and right temporal and prefrontal cortices on oscillatory brain activity.
Patients with chronic bilateral tinnitus, who had consulted the multidisciplinary Tinnitus Clinic of the University of Regensburg, were included in the study.
Twenty four patients with chronic tinnitus were included in the study, but only the data of 20 patients could be analyzed. Pulses were delivered with a Medtronic system (Medtronic, USA) and a passive-cooled figure of eight coil (MCF B-65). After recording, EEG data were filtered with a high-pass filter of 1 Hz and a low-pass filter of 45 Hz and segmented into epochs of 2 s skipping the first and last two segments of the recording.
After preprocessing which was done with EEGLAB (Delorme and Makeig, 2004), data were converted into Fieldtrip format (Oostenveld et al., 2011) for power spectrum analysis. Even if the pathophysiology of tinnitus remains incompletely understood, there is growing agreement that dysfunctional neuroplastic processes in the brain are involved.
Tinnitus is a very frequent clinical condition, which is often associated with a lesion of the peripheral auditory system, such as presbycusis, Meniere's disease, noise trauma, sudden deafness, or drug-related ototoxicity [9,10]. The notion that rTMS is safe and well tolerated by patients within a range of parameters defined according to a consensus on a safety guideline [33] is proven by an extensive body of data.
Several studies with single sessions of rTMS have been performed to transiently disrupt tinnitus perception (Table 1). In recent years, an increasing number of studies on rTMS for the treatment of tinnitus have been published (Table 2). New insights into neurobiology of chronic tinnitus suggested that functional abnormalities are not limited to temporal and temporoparietal cortical areas but can occur in brain areas used for attentional and emotional processing, such as the dorsolateral prefrontal cortex. Because tinnitus is a subjective phantom perception of sound, it represents a condition that is susceptible for placebo effects. Though some studies demonstrated effects that outlasted the stimulation period by 3, 4, or 6 months [16,52,53], others were not able to observe longer-lasting effects [44,50]. In most studies, validated tinnitus questionnaires and visual analog scales serve as primary outcome measurement, owing to the lack of objective parameters.
Just recently, a case report showed that using maintenance rTMS to manage chronic tinnitus is feasible [57]. The high variability of treatment results, which is encountered in all studies, confirms the concept of the biological heterogeneity of tinnitus.
In summary, the results from an increasing number of studies using rTMS show that treatment of tinnitus with this method is promising.
AbstractIntroduction: Some forms of tinnitus are considered to be auditory phantom phenomena related to reorganization and hyperactivity of the auditory central nervous system.
Forty-six patients with narrow band noise or white noise tinnitus, which is unilateral or predominantly perceived as coming from one side, are included in the study. De Ridder D, Verstraeten E, Van der Kelen K, De Mulder G, Sunaert S, Verlooy J, Van de Heyning P, Moller A. Correspondence to: Dirk De Ridder, Dept of Neurosurgery, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience.
About 10 years ago, repetitive transcranial magnetic stimulation (rTMS) of auditory and prefrontal cortex was introduced as potential treatment for tinnitus. Here, we suggest the use of another method which might overcome some of the above mentioned limitations: combined measurements of transcranial magnetic stimulation (TMS) and EEG to investigate differences between people with and without tinnitus in the reaction to magnetic stimulation. We concentrated on effects of 1 Hz rTMS as there is most clinical evidence for 1 Hz stimulation in chronic tinnitus. Subjects with history or presence of severe and relevant somatic, neurologic, or mental disorders were not included.
In addition participants answered questions with respect to demographic and tinnitus-related characteristics, usage of psychoactive substances, and handedness (Oldfield, 1971). Measurements were done on the same weekday and at the same time except in two cases in the patient and in two cases in the control group. Study procedures with single sessions of repetitive transcranial magnetic stimulation (rTMS) and measurement with resting state electroencephalography (EEG). Randomization was guided by the rationale to stimulate one frontal, one temporal, and one parietal (=sham) cortical site per session (Figure 1), resulting in 24 possible combinations for the first session. Three patients did not complete both sessions and data of one patient could not be analyzed because of a high amount of artifacts in the EEG recordings. Demographic, tinnitus-related, and measurement-related data of the patient and control group.
Each stimulation protocol consisted of 200 pulses applied with 1 Hz at 60% stimulator output lasting about 3 min and 20 s. Sixty two equidistant electrodes that were mounted in an elastic cap (EasyCap, Germany) were referenced to FCz during recording. Thereafter segments were visually inspected for distinct and visible aberrations from the overall recording to identify muscle artifacts (short high frequency oscillations), single channels with low signal-to-noise ratio (zero line in the EEG, main hums, or not smooth trajectories), or other large amplitude physiological artifacts (movement artifacts). For power analyses we used the minimal number of available epochs of each measurement (all subjects and all conditions) and therefore chose the first 79 epochs of each measurement. Transcranial Magnetic Stimulation: A New Diagnostic and Therapeutic Tool for Tinnitus Patients. Repetitive transcranial magnetic stimulation (rTMS) is a potent tool for modifying neural activity at the stimulated area and at a distance along functional anatomical connections.
However, there is increasing agreement that deafferentation-induced neuroplastic processes in the brain are also critically involved in the pathophysiology of tinnitus [11,12]. Most rTMS treatment studies applied lowfrequency rTMS in long trains of 1,200-2,000 pulses repeatedly over 5-10 days. They reported moderate-but significant-effects after active stimulation with high interindividual variability. A recently published study demonstrated a more pronounced long-term effect of a combined treatment protocol of rTMS applied to the temporal and dorsolateral prefrontal cortex as compared to an exclusive stimulation of the temporal cortex [46]. Evaluation of treatment efficacy requires adequate methodology for control of nonspecific treatment effects. The number of daily sessions may be an important issue to achieve sustained results in tinnitus patients [54], as already seen in other TMS applications, such as depression [55] and auditory hallucinations [56]. In a patient in that study, tinnitus could be reduced each time it recurred using one to three maintenance sessions, and finally it remained stable on a low level after the third stimulation series.
Theta, alpha and beta burst transcranial magnetic stimulation: brain modulation in tinnitus. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool capable of modulating human brain activity, using single pulse or burst stimuli. Some forms of tinnitus are considered to be auditory phantom phenomena [1] similar to central neuropathic pain [2] related to reorganization [3, 4] and hyperactivity [5, 6] of the auditory central nervous system. All participants undergo both burst and tonic rTMS of the auditory cortex at two separate dates.
Our data demonstrate that it is not possible to suppress this kind of tinnitus by tonic rTMS. The resulting changes in tinnitus loudness are interpreted in the context of rTMS induced activity changes (neuroplasticity).
The rationale of this approach is that the way how the brain reacts to a specific stimulation protocol differs between people with and without tinnitus.
However, treatment effects are only small and individually highly variable (Langguth et al., 2012). Intake of psychotropic medication, participating in rTMS interventions within 1 year before the present study and wearing metal implants were further exclusion criteria.
Furthermore, hearing level was measured with a standard audiogram using frequencies ranging from 125 Hz to 8 kHz (Madsen Midimate 622D; GN Otometrics, Denmark).
At each session three rTMS protocols were tested and four EEG recordings (before and after each rTMS intervention) were done. In the second session the contralateral stimulation (sham stimulation was unchanged for both measurements) sites were stimulated in the same order as in the first session. Stimulation intensity was set to a fixed value of 60% stimulator output and not adjusted to the individual motor threshold as stimulation was done through the EEG cap hampering exact motor threshold measurements.
After the fast fourier transformation using a hanning window (Fieldtrip parameters mtmfft and hanning) the power spectrum of each channel, condition, and subject was normalized by dividing the power of each frequency bin by the mean power of the whole power spectrum. In a second step, we substracted the baseline-corrected data of the sham condition from the baseline-corrected data for the different active conditions (stimulation site specific changes minus sham-induced change). Depending on stimulation parameters, cortical networks can be functionally disturbed or modulated in their activity. This method, called transcranial magnetic stimulation (TMS), was much less painful than transcranial electrical stimulation.
Figure eight-shaped coils are more focal, with a maximum current at the intersection of the two round components [2].
In particular, phenomenological analogies with phantom limb pain suggest that chronic tinnitus as an auditory phantom perception might be the correlate of maladaptive attempts at cortical reorganization owing to distorted sensory input from a peripheral lesion [13].
After 2-4 weeks of daily prefrontal rTMS, there was no sign of structural magnetic resonance imaging changes [34], no significant changes in auditory thresholds, and no significant EEG abnormalities [35]. Even if the quantity of improvement varied across studies, a stable statistically significant improvement of tinnitus complaints could be observed.
Another combined treatment protocol consisting of a 6-Hz priming stimulation prior to 1-Hz rTMS of the temporal cortex resulted also in a reduction in tinnitus severity.
Most controlled studies published thus far have used placebo treatment in crossover designs. The positive effect of this maintenance stimulation could also be confirmed by reduced cerebral metabolism in PET imaging after treatment. Several rTMS studies indicate that treatment response depends on tinnitus duration, with better outcome for shorter duration [37,44,52,53]. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Characteristics of tinnitus and etiology of associated hearing loss: A study of 123 patients. Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: A PET study with [ 18 F]deoxyglucose. Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus.
The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus-first results from a PET study.
The functional neuroanatomy of tinnitus: Evidence for limbic system links and neural plasticity. Dose-dependent attenuation of auditory phantom perception (tinnitus) by PET-guided repetitive transcranial magnetic stimulation. Salicylate and quinine selectively increase spontaneous firing rates in secondary auditory cortex.
Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations.
Neuronavigated transcranial magnetic stimulation and auditory hallucinations in a schizophrenic patient: Monitoring of neurobiological effects.


Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Risk and safety of repetitive transcranial magnetic stimulation: Report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Lack of significant changes on magnetic resonance scans before and after 2 weeks of daily prefrontal transcranial magnetic stimulation for depression. Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychological functioning, electroencephalogram and auditory threshold in depressed patients. Transcranial magnetic stimulation for tinnitus: Influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Transient tinnitus suppression induced by repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: A randomised, controlled pilot study.
Transcranial magnetic stimulation for the treatment of tinnitus: A new coil positioning method and first results.
Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: A pilot study. High-frequency priming stimulation does not enhance the effect of lowfrequency rTMS in the treatment of tinnitus.
Design of a placebo-controlled, randomized study of the efficacy of repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus. Neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: A short case series. Effect of daily repetitive transcranial magnetic stimulation for treatment of tinnitus: Comparison of different stimulus frequencies. Temporoparietal transcranial magnetic stimulation for auditory hallucinations: Safety, efficacy and moderators in a fifty patient sample.
Maintenance repetitive transcranial magnetic stimulation can inhibit the return of tinnitus. In reference to: Maintenance repetitive transcranial magnetic stimulation can inhibit the return of tinnitus. Repetitive transcranial magnetic stimulation in veterans with debilitating tinnitus: A pilot study. Recently it has been shown that stimulation of specific regions of the human brain can alter (suppress) tinnitus in some patients [7, 8]. All patients who experience a tinnitus suppression during either tonic or burst rTMS or both sessions also undergo a sham stimulation: the presence of a placebo effect is tested by placing the coil perpendicular to the auditory cortex at the frequencies that yield maximal tinnitus suppression rates both for tonic and burst rTMS. Tinnitus suppression was better in all patients with burst rTMS than tonic rTMS, therefore further analyses are done on burst data only.
This could be due the simple fact that burst neuromodulation is more powerful than tonic neuromodulation or to a differential effect of burst and tonic stimulation on the lemniscal and extralemniscal auditory system. Here, we investigate the effect of single rTMS sessions on oscillatory power to probe the capacity of rTMS to interfere with tinnitus-specific cortical plasticity.
Decreased output from the cochlea leads to neuroplastic changes along the auditory pathway including changes of the spontaneous firing rate, evoked activity and tonotopic reorganization.
Nevertheless we have to be aware that each of these methods has both strengths and weaknesses. We aimed at testing if this procedure can be used (1) as marker for altered neuroplasticity in chronic tinnitus (pre- to post-rTMS effects); and (2) as indicator for rTMS induced tinnitus loudness reduction.
The control group was recruited by advertisements and matched for age, sex, handedness, education, and hearing level. The TMS motor threshold was assessed with the EEG cap on the head at the beginning of each session. The 24 possible combinations were randomized before study begin for the patient and control group separately.
We measured 20 healthy controls which were comparable to the patients for age, sex, handedness, education, and hearing level. Nevertheless, motor threshold was determined in each participant by beginning the search for the hot spot in the area of C3 followed by stepwise adjustment of the stimulation intensity.
The data excluding electrodes with low signal-to-noise ratio (maximum of five per measurement) was then subjected to an infomax independent component analysis in order to identify artifact components.
These baseline- and sham-controlled data of patients and controls were compared in an unpaired t-test using a non-parametric permutation test (Fieldtrip parameter montecarlo) with 1000 iterations and a cluster correction to control for alpha inflation due to multiple testing of 63 electrodes. The technique can alleviate tinnitus by modulating the excitability of neurons in the auditory cortex.
For TMS, a brief (100-300 µsec), high-current pulse is produced in an insulated coil of wire that is placed above the skull over the region of particular interest.
Owing to the strong decline of the magnetic field with increasing distance from the coil, direct stimulation effects are limited to superficial cortical areas. Support for this model comes from magnetoencephalography studies showing reorganization of the auditory cortex as reflected by a shift in the tonotopic map of the auditory cortex contralateral to the tinnitus [14].
Adverse auditory effects, such as hearing loss or auditory hallucinations, have not been reported to date after temporal rTMS.
Differences in study design, stimulation parameters, and patient population render a further comparison of results difficult.
After active treatment, a significant decrease in the tinnitus score [43] could be observed, whereas sham treatment showed no effect.
An easier applicable technique is the coil localization according to the 10-20 EEG coordinate system, which was described by Langguth et al.
Therefore, carryover effects and missed effects owing to limited observation periods cannot be entirely excluded. Therefore, functional imaging might represent an important objective marker of treatment effects in the future. On the basis of findings, it is tempting to conclude that the degree of maladaptive neuroplastic changes in auditory and nonauditory brain structures may depend on tinnitus duration. This might be owing to the relatively low number of daily stimuli (600 per day) used in this investigation [59]. Auditory cortex stimulation can be performed with a strong impulse of magnetic field that induces an electrical current in the brain (transcranial magnetic stimulation (TMS)) or with implanted electrodes [7, 8]. Of the participants, 14 (30,4 %) demonstrated no placebo effect on both tonic and burst rTMS, 9 (19,6%) did have a placebo suppression, and 23 (50%) showed no suppressive response to either burst nor tonic rTMS. To assess differences in tinnitus suppression between genders, an independent sampled t-test was performed with burst rTMS stimulation as dependent variable and gender as grouping variable. The difference in the effect of single pulses and bursts on tinnitus may be explained by the fact that burst stimulation is more powerful in activating the cerebral cortex than tonic stimulation [11-14].
We measured 20 patients with bilateral chronic tinnitus and 20 healthy controls comparable for age, sex, handedness, and hearing level with a 63-channel electroencephalography (EEG) system.
As tinnitus is continuously perceived in most cases, resting state measurements were assumed to be best suited to identify the neuronal correlates of tinnitus. TMS-EEG studies enable the measurement of neural reactivity (TMS evoked activity after single pulses) and of neuroplasticity (resting state measurements before and after short repetitive transcranial magnetic stimulation (rTMS) interventions) free of cognitive confounders. The rational of this approach is to reduce putative over-activation and hyper-connectivity in chronic tinnitus (Eichhammer et al., 2003).
Concerning the first question we hypothesized that neuroplastic effects of rTMS over temporal and frontal brain areas will differ between tinnitus patients and controls.
The study was approved by the Ethics Committee of the University of Regensburg (12-101-0216). Motor threshold was defined as the minimal stimulation intensity at which visible muscle twitches of the fingers of the right hand were obtained in at least five out of ten pulses.
The signals were digitized at a rate of 500 Hz (BrainAmp DC, Vision Recorder, Brain Products, Germany). Horizontal and vertical eye movement artifact components were removed and the remaining components were back-projected to the EEG signal space.
For the baseline and sham conditions the two available measurements (one from session 1, one from session 2) were averaged. In other words we calculated the following t-test for each stimulation site: patients [(verum-baseline)-(sham-baseline)] vs. It is assumed that TMS decreases the hyperexcitability that is associated with some forms of tinnitus.
The strong current in the coil results in a magnetic field (1.5-2 Tesla) with lines of flux passing perpendicularly to the plane of the coil. Whereas single magnetic pulses do not seem to have longer-lasting effects, the application of multiple pulses in rhythmic sessions, called repetitive TMS (rTMS), can have effects that outlast the stimulation period. Functional imaging studies demonstrated that tinnitus is associated with neuroplastic alterations in the central auditory system and associated areas.
The risk of highintensity and high-frequency rTMS-induced epileptic seizures that had been reported in individual cases has been largely reduced since the introduction of safety guidelines [33].
When stimulation was administered to the left temporoparietal cortex-corresponding to the area of the secondary auditory cortex-a significant transient reduction of tinnitus was observed in 57% of the participants. In the latter study, functional magnetic resonance imaging with an acoustic paradigm was used for target detection within the auditory cortex.
At 6 months after treatment, 57% of patients reported a remarkable, sustained reduction in tinnitus.
However, all results have to be considered as preliminary, owing to the small sample sizes, the methodological heterogeneity, and the high variability of results. Methods: rTMS is performed both in tonic and burst mode in 46 patients contralateral to the tinnitus side, at 5, 10 and 20 Hz. Repetitive TMS (rTMS) is a non-invasive tool that makes it possible to selectively and safely stimulate specific regions of the human brain. To assess differences in distress caused by tinnitus depending on the side (left or right) an independent sampled t­-test was performed with Tinnitus Questionnaire (TQ) score as dependent variable and tinnitus side as grouping variable.
This may be related to the fact that burst activation requires less temporal integration to reach the threshold of a neuron and bursts may activate neurons that are not activated by tonic stimulations (unmasking dormant synapses) [2].A second hypothetical explanation could be that only burst stimulation is capable of modifying the function of the extralemniscal (nonspecific or non-classical) system, the neurons of which are known to fire in bursts [20, 21]. Educational level, intelligence, depressivity and hyperacusis were controlled for by analysis of covariance. However, in most of the EEG-, MEG-, PET- and fMRI-resting state studies perceptual, attentional and cognitive processes during the measurement were not specified. All participants gave written informed consent after a comprehensive explanation of the procedures. In all participants, educational years, hyperacusis, depressivity and intelligence were recorded and considered in the statistical analysis. In most cases the motor threshold was ≤60% stimulator output with the exception of one patient in session one and another patient in session two. For the sham condition (single blinded; patients were not informed about a placebo stimulation) the back-side of the passive cooled coil was put over the electrode position CPz with the handle pointing backwards. Finally, the data was carefully visually inspected a second time for any remaining artifacts. A growing number of studies demonstrate reduction of tinnitus after repeated sessions of low-frequency rTMS and indicate that rTMS might represent a new promising approach for the treatment of tinnitus.
An electric field is induced perpendicularly to the magnetic field, resulting in neuronal depolarization of the underlying brain area. Positron emission tomography (PET) investigations showed abnormal asymmetry in the auditory cortices of tinnitus patients with higher levels of spontaneous neuronal activity on the left side, irrespective of tinnitus laterality [15-17].
Mild adverse effects, such as physical discomfort on the skull during stimulation or transient headache after stimulation, are reported by approximately 10% of stimulated patients. The clinical validation of this coil-positioning method resulted in a significant reduction of tinnitus severity after 10 sessions of 1-Hz rTMS. Deprivation from auditory input is assumed to result in deafferentation-induced neuroplastic changes in the central auditory system that might represent the crucial step in the development of subjective tinnitus. Replication of data must be performed in multicenter trials with a large number of patients and long-term follow-up before further conclusions can be drawn [48]. The electrical current induced in brain tissue by a strong single pulse magnetic field can temporarily excite or inhibit neuronal activity depending on the stimulation parameters [9]. Since the rTMS machine generates a clicking sound on each magnetic pulse delivery, using only results from placebo negative patients prevents the possible influence of sound from the rTMS masking the tinnitus.


Pearson's correlations were performed to assess significant correlations between variables. Tonic or single spike firing is the main firing mode of neurons in the tonotopically organized lemniscal auditory system [20-22].
Different rTMS protocols were tested: Left and right temporal and left and right prefrontal cortices were each stimulated with 200 pulses at 1 Hz and with an intensity of 60% stimulator output. Repetitive TMS (rTMS; rhythmic repetition of single pulses at specific frequencies or with specific protocols) induces prolonged changes for up to 2 h which can be measured by resting state EEG before and after the intervention (Thut and Pascual-Leone, 2010). Thereafter the data was re-referenced to an average reference, the online-reference FCz was reconstructed, and electrodes with signal loss were interpolated.
Single sessions of high-frequency rTMS over the temporal cortex have been successful in reducing the intensity of tinnitus during the time of stimulation and could be predictive for treatment outcome of chronic epidural stimulation using implanted electrodes. Low-frequency ( 1 Hz) rTMS has been repeatedly shown to result in a decrease in cortical excitability [3,4] and is considered to produce long-term synaptic depression, which diminishes the efficiency of intercellular links. Other studies revealed additional changes in the middle temporal and temporoparietal regions as well as activation in frontal and limbic areas [18-22]. As there is no study so far comparing different coil-positioning strategies with treatment outcome, the optimum coil localization is still a matter of debate. Besides the sham coil system [16,49], which mimics the sound of the active coil without producing a magnetic field, an angulation of an active coil tilted 45 degrees [50] or 90 degrees [51] to the skull surface or stimulation of nonauditory brain areas [22,44] has been described. For that reason, chronic hearing impairment might attenuate rTMS effects by continuously triggering neuroplastic changes in central auditory structures.
Further research is needed for a clear definition of subgroups of patients who benefit most from rTMS.
Results: In 5 patients, maximal tinnitus suppression is obtained with theta, in 2 with alpha and in 7 with beta burst stimulation. So far it has only been possible to suppress pure tone tinnitus whereas narrow band or white noise tinnitus remains unaffected by such stimulation [7, 10].As burst firing is a more powerful activator of the cortex than tonic firing [11-14] it may be expected that burst rTMS is more powerful in suppressing abnormal activity perceived as tinnitus than tonic rTMS.
The rTMS is performed as a part of a continuing clinical protocol for selection of candidates for implantation of permanent electrodes for electrical stimulation of the auditory cortex for treatment for tinnitus [7, 8] the multidisciplinary tinnitus clinic of the University Hospital of Antwerp, Belgium. Burst firing has been found to occur normally in neurons in the non-tonotopically organized extralemniscal auditory system [20-22]. Stimulation of central parietal cortex with 6-fold reduced intensity (inverted passive-cooled coil) served as sham condition.
Resting state studies assume that the tinnitus percept and the related neural changes are constant over time. Because most available studies have been performed with small sample sizes and show only moderate effect sizes and high interindividual variability of treatment effects, further development of the technique is needed before it can be recommended for use in clinical routine. High-frequency (5-20 Hz) rTMS results in an increase in excitability [5] and therefore might generate long-term potentiationlike effects [6].
Electrophysiological studies in animal models of tinnitus have shown an increase of firing rate and neuronal synchrony in both the lemniscal and extralemniscal systems [23-25]. Only patients in whom tinnitus could be suppressed by an intravenous lidocaine bolus were included. Finding an optimal control condition for treatment studies is also difficult, owing to limitations in blinding of patient and operator to different stimulus conditions and owing to the fact that TMS itself results in auditory and somatosensory stimulation in addition to the actual brain site-specific effect. In this context, short trains of high-frequency rTMS seem to have a promising potential to select patients for surgical implantation of cortical electrodes. Recently it has become possible to deliver stimulations that consist of bursts of magnetic impulses (burst rTMS) [15].
All prospective participants undergo a complete audiological, ENT and neurological investigation to rule out possible treatable causes for their tinnitus. Some cells in the ventral medial geniculate body (MGBv) of the thalamus can fire in both modes depending on their membrane potential [23, 24].
In a recent analysis a substantial variability of oscillatory brain activity during the measurements was reported (Schlee et al., 2014). To sum up, combined TMS-EEG studies enable the measurement of TMS evoked activity after single pulses (neural reactivity) and of changes in resting state activity from before to after a single sessions of rTMS (neuroplasticity).
After each stimulation protocol tinnitus patients were asked to rate the loudness change of their tinnitus on a percentage scale. Interestingly, these features of rTMS effects are similar to those of direct electrical cortical stimulation in animal studies [4,7]. Electroencephalography (EEG) and magnetoencephalography studies in humans have demonstrated that tinnitus is associated with reduced alpha and increased gamma activity in the contralateral auditory cortex [26,27].
The large sample allowed the establishment of a statistical relationship between optimum tinnitus suppression, optimum stimulation frequency, and tinnitus duration.
Still far from being obvious is determining which stimulation parameters, such as frequency, intensity, and coil localization, account for optimum treatment outcome.
Non-clinical studies have shown that short bursts of high-frequency (50 Hz) magnetic impulses repeated at 5 Hz (the frequency of the theta rhythm in the EEG) produce a controllable, consistent, long-lasting and powerful effect on motor [15, 16] and visual cortex [17] by suppressing excitatory circuits [16].In this paper we describe that burst rTMS at frequencies of the EEG theta (5 Hz), alpha (10 Hz) and beta (20 Hz) rhythms applied to the auditory cortex can temporarily suppress narrow band noise or white noise tinnitus.
Tinnitus matching is performed by presenting sounds to the ear in which the tinnitus is not perceived, and both tinnitus pitch and tinnitus intensity (above hearing threshold) are matched to the perceived tinnitus.
In a depolarized state they fire in a tonic mode, in a hyperpolarized state they fire in burst mode. The order of rTMS protocols was randomized over two sessions with 1 week interval in between. An alternative approach to resting state is to measure, whether the brain’s reaction to an external stimulus differs in tinnitus patients as compared to healthy controls. For the present study we used TMS-EEG to investigate alterations of neuroplasticity in tinnitus. Based on these findings together with numerous findings of increased temporal and prefrontal activity and connectivity in chronic tinnitus (for review, see De Ridder et al., 2011, 2014), we deduced the hypothesis that tinnitus loudness reductions are associated with reductions in gamma power. In addition, for brief periods after stimulation, rTMS can block or inhibit a brain function and create a transient functional lesion in the immediate poststimulation period [8].
As rTMS has the ability to modulate cortical activity focally, there was a rationale to assume that TMS could interfere with cortical hyperexcitability and, therefore, influence the tinnitus sensation. The amount of tinnitus suppression was correlated positively with stimulation frequency and negatively with tinnitus duration, indicating the potential of TMS as a diagnostic tool for differentiating pathophysiologically distinct forms of chronic tinnitus. Single sessions of low-frequency (1 Hz) rTMS with the coil navigated to these activated areas resulted in tinnitus reduction lasting up to 30 minutes in six of eight patients.
The monitoring of rTMS effects with electrophysiological and neuroimaging methods might contribute to a better understanding of neurobiological mechanisms that underlie the clinical effects. Technical investigations include MRI of the brain and posterior fossa, pure tone and speech audiometry, Auditory Brainstem Response (ABR) and tympanometry.
During alertness, neurons in the MGBv encode sound signals by firing action potentials in a tonic mode. Analyses on electrode level showed that people with and without tinnitus differed in their response to left temporal and right frontal stimulation. Moreover, we expected that the increased connectivity of frontal and auditory areas in tinnitus will result in remote rTMS effects in the tinnitus group. On the basis of these multiple effects, TMS is now widely used as a research tool to study the physiology and pathophysiology of the brain.
Moreover, repeated applications of rTMS might represent a potential treatment by producing longer-lasting modulation of cortical activity. This approach has already been successfully used as a screening method to select patients for surgical implantation of cortical electrodes [38,39]. Assessment of tinnitus loudness is analysed by Visual Analogue Scale (VAS) while tinnitus severity is analysed by the Tinnitus Questionnaire[18] (TQ). When these neurons fire in burst, connections to other parts of the central nervous system may be opened through unmasking dormant synapses [2]. In tinnitus patients left temporal rTMS decreased frontal theta and delta and increased beta2 power, whereas right frontal rTMS decreased right temporal beta3 and gamma power. As these effects can outlast the time of stimulation, the technique was considered to be potentially useful for the therapy of disorders with cortical dysfunction [2].
The rationale was confirmed by promising results obtained by the use of rTMS as a therapeutic tool in various neurological and psychiatric conditions, in which increased cortical activity as underlying pathophysiology is assumed [28-32]. Patients responding to this type of rTMS with a shortlasting suppression of tinnitus perception were considered as good surgical candidates for permanent electrical stimulation of the auditory cortex.
Discussion: Burst rTMS can be used clinically, not only theta burst, but also alpha and beta burst. Externally applied burst stimuli may have the same effect.There are indications that the extralemniscal auditory system is abnormally involved in tinnitus [25]. If a tinnitus-like sound is used for stimulation it is a challenge to exactly measure the pitch and volume of the tinnitus (Hoare et al., 2014). Furthermore, animal studies demonstrate that both tonic [26, 27] and burst [28, 29] firing are increased in the lemniscal and extralemniscal system respectively under conditions that are assumed to mimic tinnitus in humans. Therefore, increased activation of the burst-firing non-tonotopic extralemniscal pathways may lead to perception of tinnitus of noise character, whereas increased activation of the tonic firing tonotopic lemniscal system may produce pure tone tinnitus.
This is the first study to show tinnitus-related alterations of neuroplasticity that were specific to stimulation site and oscillatory frequency.
Other studies contrasted conditions where patients were instructed to distract or to focus on their tinnitus by using cognitive tasks (Andersson et al., 2006). In some patients only alpha or beta burst rTMS is capable of suppressing tinnitus, and theta burst not.
The intensity of the magnetic stimulation is slowly increased until a clear contraction is observed in the contralateral thenar muscle. The fact that bursts may activate neurons that are not activated by tonic stimulations [2] may explain why neural activity in the extralemniscal pathways cannot be suppressed by tonic stimulation but only by burst stimulation.The second hypothesis is supported by the finding that patients who perceive their tinnitus having a low centered pitch respond better to burst stimulation than higher pitches. The observed effects can be interpreted within the thalamocortical dysrhythmia model assuming that slow waves represent processes of deafferentiation and that high frequencies might be indicators for tinnitus loudness. Results obtained with such techniques are confounded by activation related to the cognitive effort. The coil is then moved to a location over the auditory cortex contralateral to the side to where the patients refer their tinnitus (5-6 cm in above the entrance of auditory meatus on straight line to the vertex).
Neurons in the nuclei of the ascending auditory pathways that are tuned to low frequency sounds generally have wider tuning curves than neurons tuned to high frequency sounds. Moreover our findings confirm the role of the left temporal and the right frontal areas as relevant hubs in tinnitus related neuronal network. With the intensity of the stimulation set at 90% of the motor threshold, the site of maximal tinnitus suppression is determined using 1 Hz stimulation.
This means that auditory cortex cells processing low pitch sounds are less frequency specific than those processing high pitch sounds, and thus respond more like a non-tonotopic system in general.
Our results underscore the value of combined TMS-EEG measurements for investigating disease related changes in neuroplasticity.
Moreover these techniques are limited by invasiveness or low prevalence of such kind of patients, respectively (Lanting et al., 2009). When tinnitus suppression is noted that patient is asked to estimate the decrease in tinnitus in percentage using the VAS.
The tonotopic organization of Heschl's gyrus (primary auditory cortex) in humans demonstrates [4, 30-32] neural generators for low frequency sounds more laterally, and higher pitch sounds more medially. The procedure is repeated with stimulations at 5 Hz (= theta frequency), followed by 10 Hz (= alpha frequency) and 20 Hz (= beta frequency), each stimulation session consisting of 200 pulses.
This could lead to the suggestions that low frequency tinnitus, generated more superficially, might be reached easier with rTMS than higher pitched tinnitus, which is presumably generated deeper in the Silvian valley. When tinnitus suppression is induced by rTMS the patient is asked to notify when the tinnitus has returned back to baseline, i.e.
Finally we found that in this study left sided tinnitus is perceived as more distressing than right sided tinnitus.
For each patient the tonic and burst rTMS frequency that yield maximal tinnitus suppression was compared. This is in accordance with published epidemiological data that show that people suffering left sided tinnitus complain more from tinnitus than people with right sided tinnitus [36].



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