Transcutaneous Vagus Nerve Stimulation Modulates Tinnitus-Related Beta- and Gamma-Band Activity Petteri Hyvärinen,1,2 Santeri Yrttiaho,3,4 Jarmo Lehtimäki,5 Risto J. Ilmoniemi,2 Antti Mäkitie,1 Jukka Ylikoski,5 Jyrki P. Mäkelä,4 and Antti A. Aarnisalo1 Objectives: The ability of a treatment method to interfere with tinnitusrelated neural activity patterns, such as cortical gamma rhythms, has been suggested to indicate its potential in relieving tinnitus. Therapeutic modulation of gamma-band oscillations with vagus nerve stimulation has been recently reported in epileptic patients. The aim of this study was to investigate the effects of transcutaneous vagus nerve stimulation (tVNS) on neural oscillatory patterns.

of time. Objective and acute measures of treatment effect are needed to evaluate the efficacy of emerging neurostimulation methods. In this study, we present a method combining a novel neurostimulation approach with recent advances in the search of objective markers for tinnitus. Electrophysiological studies of the brain at rest suggest that increased gamma-band (30–45 Hz) activity in various cortical regions, as reflected by the power spectral density (PSD), is a physiological marker for tinnitus (Lorenz et al. 2009; van Der Loo et al. 2009; Langguth et al. 2013). In addition, increases in beta-band activity have been reported in patients with tinnitus and in patients with auditory hallucinations (Vanneste et al. 2013; Kumar et al. 2014). Decreased alpha-band (8–12 Hz) power, especially in temporal areas, has also been found in tinnitus patients (Weisz et al. 2005). This decrease may be linked to a corresponding increase in gamma activity (Lorenz et al. 2009), which in turn may result from reduced cortical inhibition due to deprived input from the earlier stages of the auditory pathway and manifested by the reduction in alpha oscillations in the auditory system. This explanation is in-line with theories about functional and structural changes in tinnitus (Eggermont & Roberts 2004). However, the electrophysiological changes associated with tinnitus are not restricted to the auditory modality but comprise a wide network including brain areas responsible for emotions, attention, and higher-level information processing as well (Schlee et al. 2009b). Thus, studying cortical activity encompassing the whole cortical surface and pacific subregions may be required for establishing objective markers of tinnitus. Functional connections within the brain networks of tinnitus patients differ from those seen in normal-hearing control subjects. Schlee et al. (2008) compared functional coupling in normal controls and tinnitus subjects using auditory steady state responses and found differences in connections from the right parietal and right frontal regions to the anterior cingulum. In the tinnitus patients, strengths of these connections correlated with the subjective ratings of tinnitus intrusiveness. Tinnitus has also been associated with altered long-range functional connections in the resting state as indicated by weaker alpha and stronger gamma synchronization in tinnitus patients than in normal-hearing control subjects (Schlee et al. 2009a). This negative correlation between alpha and gamma coupling discriminated between tinnitus and control groups with 87% accuracy. The authors also found an effect of tinnitus duration on these networks: the left temporal cortex played a central role in the gamma-band network in patients with tinnitus duration of less than 4 years, whereas in patients with a longer history of tinnitus the gamma network spread more widely (Schlee et al. 2009a). Further support for the role of gamma-band connectivity as a marker for tinnitus comes from a transcranial direct current stimulation

Design: We calculated the power spectral density and synchrony of magnetoencephalography recordings during auditory stimulation in seven tinnitus patients and eight normal-hearing control subjects. Comparisons between subject groups were performed to reveal electrophysiological markers of tinnitus. tVNS-specific effects within each group were studied by comparing recording blocks with and without tVNS. We also investigated the correlation of each measure with individual ratings of tinnitus distress, as measured by the tinnitus handicap inventory questionnaire. Results: Tinnitus patients differed from controls in the baseline condition (no tVNS applied), measured by both cortical oscillatory power and synchronization, particularly at beta and gamma frequencies. Importantly, we found tVNS-induced changes in synchrony, correlating strongly with tinnitus handicap inventory scores, at whole-head betaband (r = −0.857, p = 0.007), whole-head gamma-band (r = −0.952, p = 0.0003), and frontal gamma-band (r = −0.952, p = 0.0003). Conclusions: We conclude that tVNS was successful in modulating tinnitus-related beta- and gamma-band activity and thus could have potential as a treatment method for tinnitus. Key words: MEG, Synchrony, Tinnitus, Transcutaneous vagus nerve stimulation. (Ear & Hearing 2015;36:e76–e85)

INTRODUCTION Tinnitus affects approximately 10 to 15% of the population to some extent, and it severely affects the quality of life in 0.5 to 2% of the population (Baguley et al. 2013; Langguth et al. 2013). However, no objective method exists for its diagnosis (Baguley et al. 2013); the existence and severity of the condition are determined by the patient’s subjective assessment (Henry et al. 2005). This limits the development of new treatment methods because changes in the tinnitus percept or the quality of life may only be measured over longer periods Department of Otorhinolaryngology–Head and Neck Surgery, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; 2 Department of Biomedical Engineering and Computational Science, Aalto University School of Science, Espoo, Finland; 3School of Medicine, University of Tampere, Tampere, Finland; 4BioMag Laboratory, HUS Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland; and 5Helsinki Ear Institute, Helsinki, Finland. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and text of this article on the journal’s Web site (www.ear-hearing.com). 1

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(tDCS) study. Gamma-band connectivity patterns predicted the treatment outcome (responders versus nonresponders) of bifrontal tDCS; the responders had higher gamma-band activity in right primary and secondary auditory cortices and right parahippocampal cortex (Vanneste et al. 2011). An increased functional connectivity within the cortex of patients with tinnitus has also been indicated between the auditory cortices and the left parahippocampal cortex in a recent functional magnetic resonance imaging (fMRI) study (Maudoux et al. 2012). Functional connectivity and synchronization are closely related, and the terms are even sometimes used interchangeably. Also oscillatory power can be interpreted as an index for the synchronous activity of a local neural assembly (Varela et al. 2001). Although the majority of studies on functional connectivity in tinnitus focus on long-range synchrony, the studies on spectral power differences between tinnitus patients and controls could be interpreted as evidence for abnormal short-range synchrony in tinnitus. This possibility is also speculated by Weisz and Obleser (2014), who go on to hypothesize that tinnitus-related increases in short-range excitation and synchronization are likely to be found at the gamma-band. Hence, indexes of functional connectivity represent a viable candidate for objective markers of tinnitus in addition to the raw oscillatory power at specific regions and frequency bands. In this study, we investigated sensor-level synchrony over the whole cortical surface and over the cortical lobes, reflecting overall synchrony and short-range synchrony of brain activity, respectively. In an animal model of tinnitus, a combination of sound and vagus nerve stimulation (VNS)—applied to the left cervical branch of the vagus nerve with a cuff electrode—might reverse maladaptive neural plasticity related to tinnitus (Engineer et al. 2011). VNS acutely influences cortical synchrony and excitability in rats (Nichols et al. 2011). VNS has also been applied to tinnitus patients. Tinnitus handicap inventory (THI) scores and the minimal masking level of the tinnitus sound were improved by VNS with an implanted device in medication-free patients, whereas those on medication did not respond to VNS (De Ridder et al. 2014). Tailored sound therapy, aimed at modulating tinnitus-associated plasticity, also improves tinnitus symptoms (Okamoto et al. 2010). The underlying mechanisms related to the treatment outcomes are, however, poorly understood. In epileptic patients with implanted devices, studies have reported a VNS-induced modulation of gamma-band synchrony (Marrosu et al. 2005; Fraschini et al. 2013). Fraschini et al. (2013) found that gamma-band desynchronization by VNS correlated with a positive clinical outcome. The link between gamma activity and tinnitus, thus, suggests that VNS could be used for modulating the tinnitus-related gamma-band activity. Transcutaneous (noninvasive) VNS (tVNS) has recently been proposed as an alternative to the traditional VNS requiring surgery. In tVNS, electrical stimulation is targeted to the auricular branch of the vagus nerve instead of the cervical branch in the neck in invasive VNS. Tragus stimulation is most successful in evoking vagus-evoked somatosensory potentials (Fallgatter et al. 2003 2005; Polak et al. 2009), although a recent study has found vagus-evoked somatosensory potentials to disappear under neuromuscular block (Leutzow et al. 2013). tVNS has been studied for its effects on pain perception (Busch et al. 2012) and in patients with epilepsy (Stefan et al. 2012) and tinnitus (Kreuzer et al. 2012; Lehtimäki et al. 2013) with moderate but promising results. No adverse effects of tVNS have been

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reported (Kreuzer et al. 2012; Lehtimäki et al. 2013). Acute effects of tVNS on the synchrony of brain spontaneous activity have not been investigated previously. Schlee et al. (2008) proposed that the ability of a therapeutic intervention to induce changes in the tinnitus network would also indicate its potential in providing relief of tinnitus awareness. We investigated the effects of tVNS on the frequency spectrum and synchrony of artifact-corrected magnetoencephalography (MEG) signals, focusing in particular on beta and gamma frequencies, which have previously been identified as plausible electrophysiological markers of tinnitus. Tracking functional changes in the human brain during electrical stimulation may be challenging because of stimulus-induced artifacts in MEG or electroencephalography (EEG). With novel MEG signal processing algorithms, the measurement of human cortical activity simultaneously with close-by electric stimulation has become possible (Taulu & Simola 2006; Medvedovsky et al. 2009; Airaksinen et al. 2011). We hypothesized that tVNS would decrease the synchrony of cortical gamma-band activity. As elevated gamma power and synchrony have been linked to tinnitus (van Der Loo et al. 2009), we further hypothesized that the degree of desynchronization would differ between tinnitus patients and the control group.

MATERIALS AND METHODS Subjects Seven tinnitus patients (two females; mean age 42 years, range 29–63 years) and eight normal-hearing control subjects (one female; mean age 26 years, range 21–33 years) participated in the study. Tinnitus type, laterality, and pitch were determined for each patient with a tinnitus profiler software (Tinnoff Inc., Helsinki, Finland). The distress caused by tinnitus was assessed with the THI questionnaire (Newman et al. 1996), which inquires about the overall effect of tinnitus on the patient’s life. THI is clear and easy to answer and suitable for clinical use. It determines the severity of tinnitus on a scale from 0 to 100. The following grading has been suggested for the interpretation of THI scores: THI 0–16: grade 1—slight; THI 18–36: grade 2—mild; THI 38–56: grade 3—moderate; THI 58–76: grade 4—severe; and THI 78–100: grade 5—catastrophic (McCombe et al. 2001). Tinnitus characteristics were determined before the experiments, and so they represent baseline values. The tinnitus ratings of the patient group are shown in Table 1. The control subjects reported no history of hearing disorders. THI scores in the control group were zero. The hearing of all subjects was tested by audiometry. For the tinnitus group, a full audiometry was completed, whereas for the control group, a screening audiometry was conducted at 20 dB hearing level (HL). The mean audiogram of the tinnitus group is shown in Figure  1. The study was approved by the Research Ethics Committee of the Helsinki University Central Hospital.

Stimuli Transcutaneous VNS  •  Electric stimulation was targeted to the left tragus of each subject using a transcutaneous vagus nerve stimulator (Tinnoff Inc.). A clip electrode with two contacts of equal size—one in contact with the medial side and one in contact with the lateral side of the tragus—was used. The stimulus was a 500 μs biphasic rectangular pulse. Stimulus intensity was set to a value just above the sensory threshold, corresponding to

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TABLE 1.   Characteristic information of the tinnitus group Subjects

Age

Tinnitus Frequency

Tinnitus Type

Tinnitus Laterality

THI Score

1 2 3 4 5 6 7 Average

47 30 40 34 51 29 63 42

1177 8000 5823 8000 5000 4000 6000 5429

Noise Narrowband noise Tone Narrowband noise Narrowband noise Narrowband noise Noise

Bilateral Varying Bilateral Right Left Left Bilateral

30 36 80 52 58 20 50 47

THI indicates tinnitus handicap inventory.

approximately 0.5 mA. During tVNS stimulation, stimuli were presented continuously at 25 Hz (“tVNS-on” condition). In the “tVNS-off ” condition, the stimulator was kept in place, but no electrical stimulation was applied. For the control group, a “tVNS-sham” stimulation of the lobulus auriculae of the left ear, innervated by the trigeminal nerve, was applied as well. Stimulation parameters were identical to those used in the tVNS-on, except for the stimulation intensity, which was readjusted just above sensory threshold (also approximately 0.5 mA). Auditory Stimuli •  Tones of 500 ms duration and 5 ms rise and decay times were delivered once every 1500 ms (1000 ms intertone interval). They were presented at 75 dB(A) (at 1 m distance) using a MEG-compatible loudspeaker (Panphonics Oy, Tampere, Finland), positioned 3 m directly in front of the subject inside the magnetically shielded room. For tinnitus patients, the tone frequency was matched to the tinnitus sensation (Table 1). For the control group, 1 kHz tones were used.

MEG Measurements and Preprocessing MEG was recorded in a magnetically shielded room (Euroshield, Eura, Finland) of the BioMag Laboratory with a 306-channel whole-head Elekta Neuromag MEG device (Elekta Oy, Helsinki, Finland). The patients were seated under the dewar and were watching a silent movie during the measurement. For each condition, a 5 min measurement block was recorded. In tVNS-on and tVNS-sham conditions, the electrical stimulation was started 1 min before the measurement and continued through the whole duration of the measurement block. Auditory stimuli were presented continuously during the recording.

Fig. 1. The mean audiogram of the tinnitus group. Error bars correspond to +1 SD (left ear) and −1 SD (right ear).

The signals were band-pass filtered from 0.1 to 200 Hz and sampled at 1 kHz. The electrical artifact produced by the tVNS stimulator was removed by preprocessing the MEG data with the spatiotemporal signal space separation (tSSS) method (Taulu & Simola 2006). The tSSS time window was 10 sec, and the subspace correlation limit was 0.8 for all subjects (Medvedovsky et al. 2009). The signal artifacts from the sensors nearest to the stimulation site were not completely removed by tSSS; consequently, signals from the left temporal area were excluded from the analysis. The artifacts were successfully removed by tSSS in other regions.

Data Analysis The analysis of the MEG signals was done using MNEPython (Gramfort et al. 2013, 2014). The spectra were divided into delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), and gamma (30–48 Hz) bands. The analyses were performed for five different combinations of gradiometers, corresponding to the following brain areas: whole-head, frontal, parietal, right temporal, and occipital. For frontal, parietal, and occipital areas, the sensor groups were bilateral (Fig. 2). The sensors above the left temporal area were excluded from analysis as explained in MEG Measurements and Preprocessing and are not part of the whole-head sensor group. Spectral Analysis  •  For all conditions, the PSD of the whole measurement was calculated for each gradiometer. The PSD was then normalized with respect to the baseline condition by dividing all values with the average PSD of the tVNS-off condition taken over all sensors and frequencies from 0.5 to 48 Hz. Finally, the arithmetic mean of the normalized PSD values within each frequency band was calculated (see Supplemental Digital Content, Appendix A, http://links.lww.com/EDE/A855). Differences in the baseline activity between the tinnitus group and the normal-hearing control group were investigated by comparing the mean PSD values of the tVNS-off condition using the Wilcoxon rank sum test. The effects of tVNS were investigated by comparing the PSDs between tVNS-off and tVNS-on conditions for both groups independently, using the Wilcoxon signed rank test. Also, the effect of sham stimulation was studied in the control group by comparing the tVNS-sham and tVNS-off conditions using Wilcoxon signed rank test. To find if tVNS induces a different effect depending on tinnitus severity, Spearman’s rank correlation coefficients between the normalized mean PSDs and THI scores were calculated for the tVNS-off condition, as well as for the difference in normalized mean PSDs between tVNS-off and tVNS-on conditions.



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Fig. 2. Illustration of the magnetoencephalographysensor layout and the different sensor selections. In each position, there are two orthogonal gradiometers, which measure the tangential gradient components of the radial components of the magnetic field. Magnetometers were not used.

Average values taken over the control group were assigned the THI value zero and were also used in the correlation analysis. Statistical significance was set at the 5% level. Synchronicity Analysis  •  The synchrony of brain activity in response to the auditory stimulation, as reflected in the sensorlevel signals, was analyzed by means of the average phase lag index (PLI) (Stam et al. 2007). PLI is a measure of phase synchronization between two signals, which takes into account the problem that two nearby sensors in EEG or MEG are likely to pick up activity from the same source and thus experience high coherence that could incorrectly be interpreted as synchrony. The PLI gets values between 0 and 1; increase in phase locking between two signals increases PLI toward 1. In other words, higher PLI reflects higher synchrony between two signals. However, signals differing in phase by multiples of 180 degree are classified as originating from a common source and are discarded (Stam et al. 2007), whereas signals with other constant values of phase lag are thought to reflect true phase synchrony between two sensors. We calculated average PLIs of all pairs of sensors in distinct sensor arrays to obtain a single value of synchrony in each brain area (Fraschini et al. 2013). Auditory evoked fields were obtained from MEG recording epochs following auditory stimulation (700 ms with a 100 ms prestimulus baseline). Noisy epochs (gradiometer threshold 4000 fT/cm, EOG threshold 150 μV) were rejected. About 150 faultless epochs were analyzed from each participant. PLIs between pairs of sensors were then computed independently for each frequency band from the poststimulus time period 0 to 600 ms of each epoch. Finally, an average PLI value reflecting overall synchrony of brain activity within each frequency band was obtained by averaging the PLIs first across all epochs and

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then across all sensor pairs (see Supplemental Digital Content, Appendix B, http://links.lww.com/EDE/A856). These average PLIs were calculated from the frontal, parietal, and right temporal sensor locations, as well as from the whole-head array (excluding the left temporal sensors). Averaged PLI values of the auditory evoked fields were compared between conditions using the Wilcoxon signed rank test. The correlation between PLI values and THI scores was studied by Spearman’s rank correlation coefficients. In the same manner as in spectral analysis, the average taken over the control group was assigned the THI value zero and was also included in the analysis. Confounding Factors  •  We also carried out post hoc tests to find out if other factors than tinnitus, such as hearing loss or age, affected the observed results. We pooled all subjects into a single group and conducted a multiple linear regression analysis, where THI scores, high-frequency (4–12 kHz) pure tone average (hf-PTA), hearing threshold at tinnitus frequency, stimulus frequency, and age were regressors. Hearing threshold at tinnitus frequency was determined for the tinnitus group directly from the audiogram. When the tinnitus frequency was not included in the audiometry, the threshold was calculated as the mean of thresholds at the two closest frequencies. For the control group, the hearing threshold at stimulus frequency, and the hf-PTA were assigned values of zero. The linear model was constructed separately for each area and frequency band displaying a significant correlation with the THI scores. Both the normalized mean PSD values and the averaged PLI values were used as the response variable. The linear model was tested for statistical significance using the F test. For cases where the F test reached significance, the regression coefficients were further tested individually using a t test, which tests the hypothesis of whether the response variable has a linear dependence on the regressor.

RESULTS Normalized Power Spectra Tinnitus Group Versus Control Group  •  The individual wholehead normalized PSDs for tinnitus and control subjects from tVNS-off condition are shown in Figure 3. The tinnitus patients had stronger normalized mean PSD of the gamma-band in the frontal areas (control group median: 0.218, tinnitus group median: 0.284; Z = −2, p = 0.049). No differences for other frequency bands between the two groups were detected in the tVNS-off condition. In control subjects, there were slight decreases between tVNS-off and tVNS-sham in frontal alpha (tVNS-off median: 1.176, tVNS-sham median: 1.060; T = 2, p = 0.03) and frontal beta (off: 0.571, on: 0.675; T = 0, p = 0.01). The grand averages of normalized PSDs for each condition are shown in Figure 4. Correlation of Normalized Power Spectra With THI Scores  •  In tVNS-off condition, THI scores correlated with the normalized mean PSD values of whole-head beta (r  =  0.738, p  =  0.037), right temporal delta (r  =  −0.738, p  =  0.037), and frontal theta (r = −0.714, p = 0.047) activities. In other words, high whole-head beta and low temporal delta and frontal theta activities were associated with more severe tinnitus. THI scores also correlated positively with the tVNS-induced change in normalized PSD values (Table 2). The strongest correlation was found in whole-head and parietal alpha (r = 0.857, p  =  0.007 in both). In addition, there were THI-correlated changes in occipital alpha, beta, and gamma bands; and in parietal areas in delta and theta bands, all correlating with THI scores

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Fig. 3. Whole-head normalized power spectral densities from individual participants (separate lines) from the control group (left figure) and the tinnitus group (right figure) in the tVNS-off condition.

positively. Of special interest is the whole-head beta, which correlated with THI scores in both the baseline condition (r = 0.738, p = 0.037) and the tVNS-induced change (r = 0.833, p = 0.01). Confounding Factors  •  The post hoc multiple linear regression model reached significance for right temporal delta normalized PSD [F(5,9) = 4.588, p = 0.023] in the baseline tVNS-off-condition and for parietal alpha [F(5,9) = 3.636, p = 0.045] in the tVNS-induced change in normalized PSD. THI was the only factor in the linear model reaching significance in the t tests both in baseline temporal delta (t = −3.385, p = 0.008) and in tVNSinduced parietal alpha change (t = 2.778, p = 0.021). Other factors did not show any linearly dependent behavior with respect to the normalized PSD values in either baseline temporal delta (hf-PTA: t = 0.814, p = 0.437; hearing threshold: t = 0.092, p = 0.929; stimulus frequency: t = 2.063, p = 0.069; age: t = −0.589, p = 0.570) or tVNS-induced parietal alpha change (hf-PTA: t  =  0.224, p = 0.827; hearing threshold: t = 0.476, p = 0.645; stimulus frequency: t = −1.165, p = 0.274; age: t = −1.808, p = 0.104).

Average PLI Tinnitus Group Versus Control Group •  The sensor-level synchronicity analysis revealed widespread differences between groups in the tVNS-off condition (Table 3).

tVNS effects differed between controls and tinnitus subjects (Fig. 5). In control subjects, the PLI of whole-head alpha activity increased during stimulation (tVNS-on median: 0.074, tVNS-off median 0.069; T = 4, p = 0.05). A tVNS-induced PLI increase was observed also in occipital alpha (on: 0.085, off: 0.075; T = 0, p = 0.012) and right temporal gamma (on: 0.064, off: 0.063; T = 3, p = 0.036) activity. In tinnitus patients, PLI of occipital theta activity decreased in response to tVNS (on: 0.077, off: 0.089; T = 1, p = 0.028). In control subjects, the average PLI in tVNS-sham condition did not differ from tVNS-off in any brain area or frequency band. Correlation of Average PLI With THI Scores •  Average PLI values in the tVNS-off condition as well as the change in PLI caused by tVNS correlated strongly with THI scores in multiple brain areas and frequency bands (Table 4). In tVNSoff, THI scores correlated most strongly with parietal beta PLI (r  =  0.881, p  =  0.004), followed by whole-head beta and gamma, parietal gamma, occipital alpha, and right temporal beta (r = 0.857, p = 0.007 for each). Even stronger correlations were found between THI scores and the tVNS-induced change in PLI in whole-head gamma and frontal gamma (r = −0.952, p = 0.0003 for both). In all cases where tVNS elicited THI-specific changes in synchrony, PLI values also correlated with THI scores in tVNS-off condition. These connections between the

Fig. 4. Whole-head grand average normalized power spectral densities (PSDs) for the control group (left figure) and the tinnitus group (right figure) in all stimulation conditions. tVNS indicates transcutaneous vagus nerve stimulation.



TABLE 2. Spearman’s rank correlation coefficients reflecting correlation between normalized power spectra values and THI scores Brain Area

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Frequency Band

Spearman’s ρ

tVNS-off vs. THI  Whole-head Beta 0.738  Right temporal Delta −0.738  Frontal Theta −0.714 tVNS-on—tVNS-off vs. THI (tVNS-induced change)  Whole-head Alpha 0.857  Whole-head Beta 0.833  Occipital Alpha 0.810  Occipital Beta 0.714  Occipital Gamma 0.762  Parietal Delta 0.714  Parietal Theta 0.738  Parietal Alpha 0.857

p 0.037 0.037 0.047 0.007 0.010 0.015 0.047 0.028 0.047 0.037 0.007

Those areas and frequency bands, in which there is correlation between THI and both the baseline normalized power spectral density (PSD) values and the tVNS-induced decrease in normalized PSD values, are shown in boldface. THI indicates tinnitus handicap inventory; tVNS, transcutaneous vagus nerve stimulation.

tVNS-induced changes and tVNS-off values are highlighted in boldface in Table 4. A general trend for elevated beta- and gamma-band synchrony in tVNS-off condition with higher THI scores was observed (Table  4). Furthermore, tVNS also modulated beta and gamma synchrony in a THI-dependent manner. Synchrony increased in subjects with mild or no tinnitus, whereas in subjects with a more severe tinnitus the synchrony decreased. Figure  6 plots average PLIs, and PLI changes against THI scores in both cases and further demonstrates the pattern described above. Confounding Factors  •  Results for the post hoc multiple linear model are shown in Supplemental Digital Content, Appendix A (http://links.lww.com/EDE/A857). In general, the model explained the results of baseline beta and gamma bands well, whereas it reached significance only for whole-head beta in the tVNS-induced change [F(5,9) = 4.040, p = 0.034]. In the baseline tVNS-off condition, both THI and hf-PTA were significant factors according to the t tests for individual factors. However, in the tVNS-induced whole head beta change, only THI reached significance. Also, the linearly dependent behavior of THI was always in the opposite direction as for the hf-PTA; a higher THI score affected the average PLI positively, whereas a higher hfPTA (worse high-frequency hearing) had a negative effect.

DISCUSSION The aim of this study was to determine the acute effects of tVNS on tinnitus-related brain activity. We found that tVNS modulates the synchrony of tone-evoked brain activity, especially at the beta and gamma bands. The magnitude of this effect correlated with the subjective evaluations of tinnitus distress, as measured by the THI questionnaire. We also found trends in brain activity patterns, in-line with previous results from tinnitus patients and normal-hearing control subjects. We did not study the effects of tVNS on the tinnitus percept itself because we did not expect to see any changes in subjective measures of, for example, tinnitus loudness or disturbance during the 6 min of stimulation. No studies currently exist about the effects of tVNS on EEG or MEG spectra. Invasive VNS has been studied for its effects on spontaneous brain activity, and it has been found to modulate connectivity and synchrony especially at gamma frequencies (Marrosu et al. 2005; Fraschini et al. 2013). We found tVNSinduced changes in sensor-level measures of synchrony that correlated with individual assessments of tinnitus severity. This effect was most pronounced at the beta- and gamma-frequency bands. These results show a VNS-like effect for tVNS, and thus further support the feasibility of transcutaneously stimulating the vagal system. Although it is not possible to make conclusions regarding the underlying neural mechanisms of tVNS based on our data, there is evidence from fMRI studies for the involvement of vagal afferents in tVNS (Kraus et al. 2007 2013). A tentative framework for explaining the currently observed effect of tVNS could be based on a mediating pathway through the GABAergic system. The positive outcome of chronic VNS therapy in epileptic patients has been linked to the upregulation of GABA(A) receptors (Marrosu et al. 2003). GABAergic activity has further been found to modulate oscillations in the gamma frequencies (Wendling et al. 2002), and increased gamma-band synchrony has been related to degraded GABAergic inhibition (Traub et al. 2003). Brozoski et al. (2012) also uncovered alterations in GABAergic and glutaminergic structures of subcortical auditory nuclei in an animal model of tinnitus. Previous studies have found a relationship between increased synchronous brain activity and tinnitus (Bowyer et al. 2008; van Der Loo et al. 2009; Schlee et al. 2009a; Zhang et al. 2010). Our results also support this link. Group-level comparisons of baseline activity in tVNS-off condition revealed higher beta- and gamma-band synchrony in tinnitus patients compared with controls. Frontal gamma power was also higher in tinnitus patients than in the control group when no tVNS was applied, in-line with previous research (van Der Loo et al. 2009). We were

TABLE 3.   Average PLIs between the tinnitus group and the control group in the transcutaneous vagus nerve stimulation (tVNS)-off condition Brain Area Whole-head Frontal Frontal Parietal Occipital Occipital Right temporal Right temporal

Frequency Band

Tinnitus Group Median

Control Group Median

Z

p

Gamma Beta Gamma Gamma Delta Gamma Beta Gamma

0.072 0.072 0.071 0.073 0.089 0.071 0.077 0.071

0.061 0.062 0.061 0.061 0.073 0.063 0.066 0.063

−2.2 −1.97 −2.08 −2.08 −2.31 −2.2 −2.08 −2.31

0.028 0.049 0.037 0.037 0.021 0.028 0.037 0.021

Only those areas and frequency bands are shown where the p value of the Wilcoxon rank sum test was less than 0.05.

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Fig. 5. Bar chart illustrating the changes in average phase lag index (PLI) values compared with transcutaneous vagus nerve stimulation (tVNS)-off condition. Only those areas and frequency bands are shown, where the p value of the Wilcoxon signed rank test was below 0.05. Error bars correspond to ±1 SD.

unable to show group-level differences in alpha activity between tinnitus patients and the control group, although a link connecting loss of alpha power to tinnitus symptoms has been reported (Weisz et al. 2005). Decreased alpha power has also been linked to increased gamma synchrony in tinnitus patients (Lorenz et al. 2009). However, these studies investigated resting-state activity, whereas our study included auditory stimuli. Auditory stimulation has been found to modulate alpha oscillations (Lehtelä et al. 1997; Müller & Weisz 2012). Thus, our findings, together with previous results, suggest that the tinnitus-related decrease in alpha power can only be observed in resting-state recordings and not during auditory stimulation. In addition to the group-level differences, we were able to show activity patterns that correlated with the patients’ subjective assessments of tinnitus-related distress. Patients with more severe tinnitus had stronger synchrony than normal-hearing controls and patients with less severe tinnitus in the baseline, tVNS-off, TABLE 4.  Spearman’s rank correlation coefficients reflecting correlation between PLI values and THI scores Brain Area

Frequency Band

Spearman’s ρ

tVNS-off vs. THI  Whole-head Delta 0.786  Whole-head Beta 0.857  Whole-head Gamma 0.857  Frontal Beta 0.810  Frontal Gamma 0.810  Parietal Beta 0.881  Parietal Gamma 0.857  Occipital Alpha 0.857  Occipital Beta 0.786  Occipital Gamma 0.786  Right temporal Beta 0.857  Right temporal Gamma 0.714 tVNS-on—tVNS-off vs. THI (tVNS-induced change)  Whole-head Beta −0.857  Whole-head Gamma −0.952  Frontal Gamma −0.952  Parietal Gamma −0.762  Right temporal Beta −0.786

p 0.021 0.007 0.007 0.015 0.015 0.004 0.007 0.007 0.021 0.021 0.007 0.047 0.007 0.0003 0.0003 0.028 0.021

Those areas and frequency bands, in which there is correlation between THI and both the PLI values in tVNS-off as well as the tVNS-induced decrease in PLI, are shown in boldface. THI indicates tinnitus handicap inventory; tVNS, transcutaneous vagus nerve stimulation.

condition. This pattern could mostly be seen at beta and gamma frequencies and additionally on occipital alpha and whole-head delta, where PLI values in the tVNS-off condition also correlated strongly with THI scores. In parallel, beta and gamma-band activities are more prominent with patients having complex auditory phantoms than patients with tinnitus (Vanneste et al. 2013; Kumar et al. 2014). Moreover, in addition to the above baseline measures, we found tVNS-induced decreases in beta and gamma synchrony, which depended on the severity of tinnitus. Specifically, tVNS had a stronger desynchronizing effect at beta and gamma frequencies in subjects with high level of synchronous activity in the same frequency bands. In normal-hearing control subjects and in patients with less severe tinnitus, tVNS had an opposite effect of promoting synchrony on alpha and gamma bands. However, despite baseline correlations between tinnitus severity and occipital alpha and whole-head delta, no THI-specific tVNS effects were found in these measures. Because correlation does not imply causality, we wanted to assure ourselves that the observed THI-related results were not caused by confounding factors—hearing loss, stimulus parameters, or age—and conducted post hoc tests using a multiple linear regression model. These tests revealed that stimulus frequency or age did not affect the observed results. However, THI, hf-PTA, and hearing threshold at tinnitus frequency could be regarded as plausible factors affecting the baseline PLI measures. The hearing threshold reached significance only barely for the beta-band results, whereas there seemed to be strong support for the results of beta and gamma bands depending on both THI and hf-PTA. Remarkably, the two factors received opposing coefficient signs in the linear model, suggesting that they affected the PLI measure in opposite directions; higher THI increasing the baseline synchrony and higher hf-PTA decreasing it. Schlee et al. (2008) reported similar results where long-range synchronization measures correlated with tinnitus intrusiveness. However, they did not find any association between synchrony and average hearing loss or hearing threshold at the stimulus frequency. In their study, Schlee et al. used a 37.1 Hz amplitude-modulated tone to elicit an auditory steady state response. This frequency is within the gamma band, where there was no dependency between the hearing thresholds and synchronization in our results, either. As for the overall presence and level of hearing loss, the differences in results are likely to be explained by the frequency range in which hearing loss is examined. The audiometry in our study included higher



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Fig. 6. Scatter plots illustrating the correlation of tinnitus handicap inventory (THI) scores with gamma-band baseline synchrony (left) and the transcutaneous vagus nerve stimulation (tVNS)-induced change in synchrony (right). The data point at THI value zero represents the mean value taken over the whole control group. PLI indicates phase lag index.

frequencies, and the PTA was calculated for the frequency range from 4 to 12 kHz, whereas Schlee et al. used frequencies from 250 to 8 kHz. As opposed to the results in the baseline condition, the tVNS-induced change in synchrony was not associated with hearing loss. The model reached significance only for the strongest correlation in tVNS-induced whole-head beta change, and THI was the only factor reaching significance in the t tests. Thus, these post hoc tests give further support for our observations of tinnitus-related effects of tVNS at beta frequencies. When interpreting the results, particular attention has to be given to the areas and frequency bands where both tinnitusspecific patterns in the tVNS-off condition and a tVNS-induced effect were observed. The analysis of normalized mean PSD values reveals that for the whole-head beta, both baseline activity and its tVNS-induced change correlate with the THI scores. Besides these PSD-based findings, additional markers of tinnitus were found in the average PLI values. Group-level analyses show that occipital delta synchronization in tinnitus subjects is higher than in controls in tVNS-off condition but decreases approximately to the same level with controls when tVNS is applied. However, occipital delta synchronization in the tVNSoff condition did not correlate with THI scores; this measure may represent a more general aspect of tinnitus common to all tinnitus patients but not present in normal-hearing subjects. THIdependent patterns of beta and gamma frequencies were widely spread over all brain areas. Whole-head beta correlated with THI scores in both baseline measures and the tVNS-induced changes in them. Interestingly, in these cases, both baseline measures had a positive correlation with THI scores, but the tVNS-induced changes behaved differently: PSD change showing positive correlation and PLI change experiencing negative correlation. Thus, in subjects with worse tinnitus, tVNS increased beta power while decreasing its synchrony globally. Strongest correlation with

THI scores was found for the tVNS-induced change in wholehead and frontal gamma frequencies. Another observation evident from results linking PLI values with THI scores is that there are less THI-specific tVNS effects on synchrony than there are THI-specific synchrony patterns in the tVNS-off condition. One explanation could be that tVNS only affects some parts of a larger tinnitus network. According to Vanneste and De Ridder (2012), different brain areas are responsible for different aspects of tinnitus and they form multiple functionally connected subnetworks. For example, tinnitus loudness and distress may be independent aspects, coded by separate networks. It is also possible that the observed differences between tinnitus and control groups or the tVNS-induced changes cannot be directly explained by tinnitus but could as well be caused by tinnitus-related comorbidity such as anxiety or depression. The presence or acuteness of such conditions was not assessed in this study, and thus, no conclusions can be made about their role in the observed phenomena. This study focused on the acute effects of tVNS, whereas the majority of research related to both tinnitus and VNS has studied long-term effects. Although no direct conclusions can be made on the effectiveness of tVNS as a method for tinnitus treatment on the basis of the results presented here, they indicate tVNSinduced modulation in cortical activity and synchrony related to tinnitus and provide a good starting point in designing future experiments. A working hypothesis for the action of VNS as a treatment for epilepsy is its ability to desynchronize ongoing brain activity (Jaseja 2010). In conditions such as epilepsy and tinnitus, there is increased synchronous activity related to the condition; VNS could be used to reduce the aberrant activity. Thus, targeting of VNS and tVNS could be measured objectively by monitoring the VNS-induced desynchronization by means of EEG or MEG.

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The effects of neurostimulation generally depend on the duration of applied stimulation. When VNS is used for treating epilepsy, stimulation is typically presented for 30 sec, followed by 5 min of no stimulation (DeGiorgio et al. 2005); this adds up to 130 min of stimulation per day. In a pain perception study by Busch et al. (2012), tVNS was applied continuously for 1 hr, leading to an increase in mechanical pain threshold and a reduction in mechanical pain sensitivity. De Ridder et al. (2013) achieved lasting effects on tinnitus distress and loudness in some patients after a 4 week treatment period where VNS tone pairing was given 2.5 hr daily, with VNS presented for 0.5 sec every 30 sec. They conducted spectral EEG measurements, but their findings cannot be directly compared with ours because of major differences in the analysis time period, as well as in the way of delivering the VNS and auditory stimuli. The duration of stimulation used in our experiments was 6 min, and the 5 min MEG recording was started after 1 min of tVNS. In this time, we were able to observe tVNS-induced changes in brain activity, reflected by measures of both spectral power and synchrony. Thus, our results show that tVNS causes acute changes in brain activity, observable already in 6 min. It is not known whether the effect described here is constant or cumulates during stimulation. Future studies should include comparison between different durations of stimulation to address this question. The external electrical activity of the stimulation device, not genuine changes in brain activity, could interfere with the results. This interpretation is difficult to justify, as both increases and decreases were observed in all measures. For example, if the changes in synchrony were indeed caused by the stimulator, one would likely expect an increase in synchrony in all subjects because the device operates in a highly synchronous manner. In contrast, the effect of stimulation was different between control and tinnitus patients. Furthermore, sham stimulation, applied for the control group, had only a weak effect on the normalized spectrum at frontal alpha and beta and no effect on the measures of synchrony. We acknowledge that a clear limitation of this study is the small number of subjects and that results therefore need to be interpreted with caution. Future studies should also aim at relating the phenomena described here to possible changes in the tinnitus percept and distress, in-line with that reported by Vanneste et al. (2011) on tDCS.

CONCLUSIONS We studied the effects of tVNS on brain activity patterns in tinnitus patients and normal-hearing controls, finding tVNSinduced changes in beta- and gamma-band synchrony that correlated strongly with individual THI scores. Thus, tVNS was successful in modulating tinnitus-related beta- and gammaband synchrony. This motivates further research into the use of tVNS both as a therapeutic treatment method and as a diagnostic tool for tinnitus.

ACKNOWLEDGMENTS The work of P.H. was supported by grants from the Paulo Foundation and the Research Foundation of Helsinki University of Technology. The authors declare no other conflicts of interest. Address for correspondence: Petteri Hyvärinen, P.O. Box 220, FI-00029 HUS, Helsinki, Finland. E-mail: [email protected] Received March 10, 2014; accepted September 29, 2014.

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Transcutaneous vagus nerve stimulation modulates tinnitus-related beta- and gamma-band activity.

The ability of a treatment method to interfere with tinnitus-related neural activity patterns, such as cortical gamma rhythms, has been suggested to i...
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