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The Effect of rTMS on Auditory Processing in Adults with Chronic, Bilateral Tinnitus: A Placebo-Controlled Pilot Study
Brain Stimulation xxx (2013) 1e8
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Original Research
The effect of rTMS on auditory processing in adults with chronic, bilateral tinnitus: A placebo-controlled pilot study Caroline H.S. Barwood a, *, Wayne J. Wilson a, Alicja N. Malicka a, Bradley McPherson b, David Lloyd a, Katherine Munt a, Bruce E. Murdoch a a b
School of Health and Rehabilitation Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia Division of Speech and Hearing Sciences, The University of Hong Kong, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 September 2012 Received in revised form 28 January 2013 Accepted 28 January 2013 Available online xxx
Background: On the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated the use of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as a potential modulator of this hyperactivity. While these investigations show promise, investigations to date have neglected to consider the possible effect of 1 Hz rTMS on other functions of the auditory cortex of these individuals, such as auditory processing. Objective/hypothesis: This placebo-controlled pilot study aimed to determine whether 1 Hz rTMS applied to the primary auditory cortex (PAC), specifically Brodmann Area 41 (BA41), of adults with chronic, bilateral tinnitus would influence their auditory processing abilities. Methods: Eight participants with bilateral, chronic tinnitus were randomized to receive a 10-day course of neuronavigationally guided active rTMS (n ¼ 4) or placebo rTMS (n ¼ 4) treatment applied to a focal region of the left PAC (BA41). Participants’ auditory processing was measured using Time Compressed Reverberant Speech and three-pair Dichotic Digits (DD). Their tinnitus was measured using the Tinnitus Handicap Inventory (THI) and a psychoacoustic measure of tinnitus perception. All outcome measures were administered at baseline (1 week prior to rTMS), 1 week, 1, 2 and 3 months post-rTMS. Results: All four participants in the active rTMS (A) group, and none of the participants in the sham (placebo) rTMS (S) group, showed improved auditory processing scores at multiple assessment points post-stimulation, with the group differences in median normalized gain scores reaching significance at the 5% level from 1 week or 1 month post-stimulation onwards. Three of the four participants in the active rTMS (A) group, and none of the participants in the sham rTMS (S) group, showed improved tinnitus scores at multiple assessment points post-stimulation, with some of the group differences in median normalized gain scores reaching significance at the 5% level. Conclusions: The results of this preliminary study suggest that 1 Hz rTMS applied to the PAC (BA41) has the capacity to improve both auditory processing and tinnitus perception in some adults with chronic, bilateral tinnitus. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Transcranial magnetic stimulation rTMS Tinnitus Hearing Auditory cortex Auditory processing
Introduction On the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated methods to modulate this hyperactivity using low frequency repetitive transcranial magnetic stimulation (rTMS). Low frequency rTMS (1 Hz) entails repeatedly discharging a transduction coil on the scalp, to induce a very short lasting (w50 ms) magnetic field (reaching peak Financial disclosures: All authors of this manuscript have no conflict of interest to declare. * Corresponding author. Tel.: þ61 7 3365 6162; fax: þ61 7 3365 1877. E-mail address: [email protected] (C.H.S. Barwood). 1935-861X/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2013.01.015
strengths of 1e2.5 T). Low frequency magnetic pulses are suggested to modulate action potentials in brain regions underlying the coil [1,2] with evidence available to suggest that it may inhibit the generation of action potentials [1]. Early suggestions offered by Eichhammer et al. [3], Langguth et al. [4] and Kleinjung et al. [5] advocating for the use of 1 Hz rTMS as a therapeutic tool for tinnitus have catalyzed a range of studies, incorporating sham-controlled, sham-controlled crossover, parallel, open and multiple active group designs. In general, these investigations have applied 600e2000 rTMS stimuli per day over 5e10 days, at intensities ranging from 100% to 120% of motor threshold. Neural targets have included maximal PET activation areas in the temporal cortex, the left auditory cortex, the left
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Table 1 Biographical information on the eight [7] participants recruited into the study. Participant
Age Gender Handedness Tinnitus e Tinnitus e lateralization duration (years)
Tinnitus e quality Hearing thresholds (air conduction)
Bilateral e left ear louder
Noise
20
Bilateral
Tone
L
25
Bilateral e left ear louder
Tone
M M
R R
1 30
Bilateral e left ear louder Bilateral e left ear louder
Tone Tone
29
F
R
15
Bilateral e left ear slightly louder Tone
39 52
F M
R R
5 15
Bilateral Bilateral
Active rTMS 1 (A1) 46
F
R
1
Active rTMS 2 (A2) 40
M
R
Active rTMS 3 (A3) 41
F
Active rTMS 4 (A4) 34 Sham 1 (S1) 58 Sham 2 (S2) Sham 3 (S3) Sham 4 (S4)
temporoparietal cortex and/or the left dorsolateral prefrontal cortex. A range of target localization techniques have been employed across some of these investigations including stereotactic neuronavigation and the 10e20 EEG system. The outcomes of these collective studies show significant improvements in the tinnitus reported by the test participants (on questionnaires and/or psychoacoustic measures) for periods ranging from <2 weeks to 6 months post-stimulation. Despite positive indications across these investigations, outcome variability in individual participants remains high [5e7]. While the above studies suggest that 1 Hz rTMS may remediate tinnitus symptoms in some individuals, none of these studies considered the potential effect of 1 Hz rTMS on other auditory functions. In the case of the auditory cortex, a common target for 1 Hz rTMS in individuals with tinnitus, this includes a range of skills that encompass auditory processing mechanisms. The American Speech-Language-Hearing Association (ASHA) [8] lists these skills as including sound localization and lateralization; auditory discrimination; auditory pattern recognition; temporal aspects of audition, including temporal integration, temporal discrimination (e.g., temporal gap detection), temporal ordering, and temporal masking; auditory performance in competing acoustic signals (including dichotic listening); and auditory performance with degraded acoustic signals. Given that all of these skills are essential for everyday communication, the application of rTMS techniques for the purpose of treating tinnitus symptoms must to be balanced with any effects (adverse or otherwise) that it might impose on auditory processing abilities. To the authors’ knowledge, only two studies to date have examined the effect on auditory processing of 1 Hz rTMS applied to the auditory cortex. In the first study, Andoh and Zatorre [9] observed improved response times on a melody discrimination task in females but not males subsequent to 1 Hz rTMS targeting left Heschl’s gyrus. In the second study, Andoh and Paus [10] observed improved response times on word recognition tasks in their participants following 1 Hz rTMS targeting the left temporoparietal area. As both of the aforementioned studies examined healthy participants only, the reported improvements in auditory processing cannot easily be generalized to persons with tinnitus. However, these investigations do provide evidence to support modulation auditory processing in the healthy brain. The present study aimed to determine the effect on auditory processing of 1 Hz rTMS applied to the primary auditory cortex (PAC) (specifically, Brodmann Area 41 [BA41]) in adults with chronic, bilateral tinnitus. It is hypothesized that in light of the observed improvements in auditory processing reported in healthy participants post-rTMS, individuals with tinnitus may demonstrate
Tone Tone
R e mild loss at 16 000 Hz only L e mild loss at 8000 and 16 000 Hz only R e mild to moderately severe loss, above 3000 Hz R & L e mild sloping to moderate loss, above 4000 Hz R e mild loss at 14 000 and 16 000 Hz only L e mild loss at 10 000e14 000 Hz only R & L e mild to moderately severe loss, above 4000 Hz R e mild to moderately severe loss, above 6000 Hz L e mild to moderately severe loss, above 3000 Hz R e moderate to severe loss, above 4000 Hz L e mild to moderately severe loss, above 9000 Hz R & L e hearing thresholds within normal limits R & L e hearing thresholds within normal limits
improvements in auditory processing abilities up to 2 months poststimulation. Methods Ethical clearance Ethical clearance was granted from The University of Queensland Medical Research Ethical Review (MREC) board. All participants gave informed consent to participate in this research and all procedures conformed to the Declaration of Helsinki. Participants Table 1, shows the biographical information, and Fig. 1 shows audiograms for the eight participants recruited into the study through an open advertisement on the staff information system at The University of Queensland. All participants had bilateral tinnitus of at least 1 year duration; no self-reported neurological or psychological conditions; normal hearing thresholds up to and including 3000 Hz with normal hearing thresholds or hearing losses ranging from mild to severe above 3000 Hz, in accordance with the Goodman classification system [11]. In addition, participants had normal middle ear compliance (tympanograms showing static compliance 0.2 ml and tympanic peak pressure between 100 and þ50 daPa, as per Jerger [12]); normal distortion product otoacoustic emissions from 500 to 3000 Hz according to Hall [13]. These audiometric results remained stable for all participants throughout the study. With respect to eligibility to receive rTMS, participants had no history of seizures or epilepsy, neurological disorders, brain injury, cardiac pacemakers, metal implants or implanted medication pumps and were not taking mood altering medications (e.g., antidepressants or neuroepileptic medications) [2,14,15]. Seven participants were right handed and one was left handed, as measured using the Edinburgh Handedness Inventory [16]. The participants were randomly assigned (using a randomized list of numbers) to the active rTMS (A, n ¼ 4) or sham (S, n ¼ 4) group and were blinded to the stimulation condition (i.e., a singleblind, randomized method). Protocol Overview Each participant underwent assessment and treatment in the following order: neuroimaging; basic audiological assessment; auditory processing assessment; tinnitus assessment; rTMS
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Auditory processing assessment
Figure 1. The participant audiograms for those in the active rTMS (A) group (above) and sham (S) group (below).
treatment; and auditory processing and tinnitus re-assessments at 1 week, 1 month and 3 months post-rTMS.
All participants completed the auditory processing assessments in sound-treated booths using a commercially available, calibrated audiometer (Interacoustics Clinical Audiometer AC40) coupled to a compact disc player (Interacoustics Clinical Audiometer AC40, AN-9204 DVPH). These assessments consisted of two, pre-recorded tests: Time-compressed and Reverberant Speech (TCRS) and threepair Dichotic Digits (DD) from the Wilson and Strousse CD “Tonal and Speech Materials for Auditory Perceptual Assessment, Disc 2.0” [19]. Both ears in each participant were tested. For the TCRS testing, 25 filtered NU-6 words from the filtered NU-6 wordlists (male speaker with the carrier phrase “say the word” and each stimulus word compressed 45% and reverberated 0.3 s were played at 50 dB HL (dial setting) to the test ear only and the participant was asked to repeat each stimulus word as it was played. Each ear was assessed separately. The first five words were used as practice, leaving the remaining 20 words to be scored at 5% for each word correctly repeated. The 25 words played to each ear were counterbalanced across test occasions. ASHA [8] reported that TCRS assesses the auditory process of performance with degraded signals. For the DD testing, 20 pairs of number (1e10, excluding 7) triplets (male speaker and interval between digits from 500 ms to 700 ms with an interstimulus interval of 5 s) were played at 50 dB HL (dial setting) so that for each pair, one number triplet was played to one ear at the same time as the second number triplet was played to the other ear. This resulted in the first number in the first triplet being played to one ear at the same time as the first number in the second triplet being played to other ear, and the same for the second and third numbers in each triplet. Both ears were assessed simultaneously. A score of 0.83% was awarded for each number correctly repeated (regardless of order). ASHA [8] reported that DD assesses the auditory process of dichotic listening (particularly binaural integration).
Tinnitus assessment Neuroimaging The neuroimaging protocol consisted of a 3-T structural magnetic resonance imaging (MRI) scan with the following acquisition parameters: TR ¼ 19 ms, TE ¼ 4.92 ms, matrix size ¼ 256 256, number of slices ¼ 128, and slice thickness ¼ 2 mm. A computerized MRI visualization and analysis system [17] was then employed to visually mark target areas (BA41 and the motor hand knob) with a crosshair. This software program permitted a Talairach transformation of each subject’s brain, generating voxel and Talairach co-ordinates in reference to general neuroanatomical landmarks and Brodmann Area.
Basic audiological assessment All participants completed the basic audiometric assessments in sound-treated booths using commercially available, calibrated audiometric equipment (Interacoustics Clinical Audiometer AC40, Zodiac 901 Middle Ear Analyzer, and Otodynamics ILO292 USB-I Echoport running ILOv6 for Windows [file version 6.40.26.0]). This assessment included obtaining pure tone audiometry thresholds (air conduction only) at 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, 8000, 9000, 10 000, 11 000, 12 500, 14 000 and 16 000 Hz [18], tympanometry using a standard 226 Hz probe tone [12], and distortion product otoacoustic emissions at 1/3 octave frequencies from 500 Hz to 4000 Hz.
All information and data regarding each participant’s tinnitus was collected using a questionnaire and a psychoacoustic measure of tinnitus sensation level in accordance with the current consensus for tinnitus patient assessment and treatment outcome measurement [20]. The questionnaire utilized was the Tinnitus Handicap Inventory (THI) [21]. This questionnaire has support for its repeated use within short intervals and its validity and reliability for measuring tinnitus outcomes [21,22], although its sensitivity for measuring treatment outcomes has been challenged [23]. The psychoacoustic measure of tinnitus perception was a loudness-matching task, which included pitch matching, to enable loudness matching at the frequency associated with pitch of tinnitus. The tests were run using a personal computer (PC) and Matlab Software (version 7.0.1a) with a custom written M-file. The PC was equipped with an external 24-bit sound card (E-MU 0204) and Sennheiser HD600 headphones (which offered a broad frequency response with low distortion). The stimuli were corrected for the frequency response characteristic of the headphones (corrections were measured for individual frequencies and included in M-file). This system was calibrated by requesting a 60 dB SPL output at 1000 Hz, measured using a Brüel & Kjær Type 2250B hand-held analyzer (a Class 1 sound level meter under IEC 61672-1 [24]) with a Brüel & Kjær Type 4153 Artificial Ear fitted with a 1/2” microphone. The analyzer and the microphone were calibrated yearly by the Brüel & Kjær laboratories in Sydney,
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Australia, and a Brüel & Kjær Type 4231 sound level calibrator was used to check their status before and after testing. Tinnitus loudness required the participant to wear the headphones and follow instructions presented on the computer screen to complete an automated tinnitus pitch-matching procedure based on the binary method of Henry et al. [25]. This involved an adaptive, two-alternative forced choice (2AFC) procedure chosen because it is more reliable than manual methods and is one of the most reliable automated methods for pitch matching [25,26]. The matching signal was always presented to the right ear. This was due to the fact that all participants reported tinnitus in both ears with some reporting their tinnitus to be worse in their left ear, and the use of contralateral stimulation has been reported to be less challenging than ipsilateral stimulation for pitch matching [27,28]. The procedure began with successive presentations of a 1000 Hz pure tone and a narrow-band noise (NBN) (10% of signal frequency bandwidth) at a comfortable listening level to which each participant was asked to indicate which sound most closely resembled the sound quality of their tinnitus. This selection determined the type of sounds (pure tones or NBNs) used in the remainder of the procedure for that participant. The initial tinnitus loudness matching was then performed using pure tone or NBN signals at 250, 500, 1000, 2000, 4000, 6000, 8000, 10 000, 12 000, 14 000 and 16 000 Hz. For each run at each frequency the participant was presented with a signal and was required to respond if the signal was louder or softer than the participant’s tinnitus. The participant’s description of the matching signal was used to increase (if the signal was described as being softer than the tinnitus) or decrease (if the signal was described as being louder than the tinnitus) the level of the next presentation in 5 dB steps until a reversal point was obtained. Each time a reversal point was reached, the step size was reduced by half and the presentations continued until a final 1 dB step size was reached. The final levels at each frequency were then used to interpolate equal loudness levels for tinnitus matching stimuli ranging from 250 to 16 000 Hz [29]. Following the initial tinnitus loudness matching described above, tinnitus pitch-matching commenced with the sequential presentation of two loudness-matched tones or NBNs (at a comfortable loudness) with center frequencies of 3180 and 4000 Hz. Participants were first instructed to select the tone/NBN whose pitch was closest to the predominant pitch of their tinnitus. Based on the participant’s response, the frequency of the next presentation was increased (if the signal was described as being of lower pitch than the tinnitus) or decreased (if the signal was described as being of higher pitch than the tinnitus) in half-octave steps until six reversal points were obtained. From this frequency, the process was then repeated using 1/3 octave steps until five reversal points were obtained. The matched frequency of each participant’s tinnitus was calculated as an average of the frequencies of the last three reversals of the 1/3 octave step part of the run. The highest frequency for this process was 16 000 Hz, which resulted in 12 000 Hz being the highest frequency that could be matched to a participant’s tinnitus using this process. The pitchmatching procedure was repeated three times in an attempt to improve its accuracy [30] and the average of these three measures was taken as the final tinnitus pitch-matched frequency for that participant. Following the tinnitus pitch matching, the final tinnitus loudness matching was performed at the tinnitus pitch-matched frequency only, using the loudness matching protocol described above. This value was recorded as the tinnitus matching loudness level in dB SPL. Each participant’s hearing threshold in dB HL in their right ear at the frequency matching the tinnitus pitch was then converted to dB SPL (using the recommended reference equivalent sound pressure levels in a coupler complying with IEC
Figure 2. The target area for the rTMS: the primary auditory cortex (Brodmann Area 41) in the left hemisphere.
60318 [30]) and this value was subtracted from his or her tinnitus matching loudness level in dB SPL to give each participant’s final psychoacoustic measure of tinnitus perception in dB SL (decibels sensation level: the number of dB the tinnitus was judged to be above each participant’s hearing threshold at the pitch-matched frequency of that participant’s tinnitus). rTMS protocol For the treatment group, low frequency (1 Hz) rTMS was applied to each participant for w33 min per day (2000 pulses) over 10 sessions (MondayeFriday, within two consecutive weeks) at 110% of resting motor threshold (RMT) as defined by Eichhammer et al. [3]. A Magstim Rapid2 stimulator and a figure of eight, 70 mm diameter rTMS coil was utilized to administer rTMS (Magstim, UK). Participants received no other treatment for their tinnitus during participation in this study. The rTMS coil was placed over the marked region of interest on the MRI scan on the interface of a StealthStation TreonÓ (Medtronic, USA, Minneapolis, Minnesota) neuronavigational system (Medtronic, USA). The TMS target was BA41. On the acquired structural MRI scan, this was marked on the anatomical boundary of Heschel’s gyrus, in the medial aspect [3]. Fig. 2 shows the marked target BA41 on a participant’s structural MRI. The coil was held by hand and position relative to the head was maintained using real-time feedback from the stereotactic guidance system, the StealthStation Treon. For the sham group, low frequency (1 Hz) rTMS was applied in exactly the same manner described for the treatment group, with the exception that the coil was a sham coil that presented a sound only with no magnetic pulse administered at each stimulus event. Motor threshold attainment The RMT attainment for the stimulation protocol described above was determined using a hand muscle. The TMS coil (bi-phasic
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stimulation, 70 mm) was placed on the motor “hot spot” for the first dorsal interosseous (FDI) muscle in the left hand (i.e., the knob within pre-central gyrus) in the contralateral hemisphere as determined by MRI marking and StealthStation software. Motor evoked potentials (MEPs) were then elicited via TMS and surface EMG recorded from FDI via Ag/AgCl electrodes (1 cm in diameter), positioned over the belly of the muscle and the metacarpophalangeal joint of the index finger, respectively. The ground electrode was attached over a bony prominence on a distal region of the radius. The coil was positioned tangentially to the skull above the left primary motor cortex with the handle pointing backward and laterally at an angle of about 45 to the sagittal plane inducing an electrical current in the brain tissue with a posteriorelateral to anterioremedial direction roughly perpendicular to the central sulcus. This current orientation is known to be optimal for evoking a motor response in the contralateral hand [31]. The location and orientation to which the stimulus was applied (at suprathreshold intensity) consistently yielded maximal MEPs in the contralateral FDI muscle. RMT was defined as the minimum stimulus intensity eliciting five responses of about 50 mV out of 10 consecutive trials (50% successful MEPS) in the relaxed contralateral FDI [32]. Trials commenced with a suprathreshold value and subsequent TMS intensities were decreased in steps of 2% until no reliable MEPs were recorded. For the present study stimulation was applied at 110% of the RMT attained [3]. Participant stimulation intensities in the present investigation ranged between 35 and 60% of maximum stimulator output. All participants tolerated rTMS well and completed the 10 days of stimulation. Data collection The following data were collected from each participant at each point of assessment post-rTMS treatment: 1) Auditory processing measures: the raw scores for the right (R) and left (L) ears for the TCRS and DD tests, and; 2) Tinnitus measures: the total score from the THI and the psychoacoustic measure of tinnitus perception in dB SL obtained from the psychoacoustic measures. Data analysis All participant scores on each auditory processing and tinnitus measure at each of the assessment points (baseline and post-rTMS treatment) were plotted and the Mann Whitney U statistic was used to test for differences between the active (A) and sham (S) group scores on each measure at each assessment point. Difference scores (post-test score pre-test score) were calculated for the participants on each of the auditory processing and tinnitus measures. These difference scores were then converted to normalized gain scores. For the auditory processing scores, the normalized gain score ¼ (post-test score pre-test score)/ (maximum possible score pre-test score). For the tinnitus scores, the normalized gain score ¼ (post-test score pre-test score)/ (minimum possible score pre-test score). This method was employed because normalized gain scores have been shown to reduce the bias caused by outliers [33]. The median normalized gain scores were plotted and the Mann Whitney U statistic was used to test for differences between the active (A) and sham (S) group normalized gain scores on each measure at each assessment point. All Mann Whitney U analyses were performed using IBM SPSS Statistics 20 (release 20.0.0.) [34] at the 5% level. Results For the auditory processing measures, the performance of each participant at each assessment point was within two standard
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deviations (2 SD) of the mean performances of healthy adult participants (with hearing thresholds within normal limits from 250 Hz to 8000 Hz) reported by Wilson et al. [35] for the TCRS test and Strouse and Wilson [36] for the DD test, with the following exceptions: participant S1 performed marginally below 2 SD on TCRSL at each assessment, participant S2 performed below 2 SD on DDR and DDL at each assessment, participant A1 performed below 2 SD on DDL at the baseline and week one assessments, and participant A4 performed below 2 SD on DDR at the baseline assessment. Fig. 3 shows each participant’s raw scores, and the active rTMS (A) and sham (S) groups’ median normalized gain scores, for each auditory processing measure at each assessment point. All four participants in the active rTMS (A) group, and none of the participants in the active rTMS (A) group, showed improved auditory processing scores at >1 assessment point post-stimulation. The normalized gains for these improvements ranged from 0.10 to 1.00. Significant (P < 0.05) differences were observed between the median normalized gain scores of the active rTMS and sham groups from 2 months post-stimulation onward for TCRSR, TCRSL and DDR scores, and at 3 months post-stimulation for DDL (not shown in Fig. 2). Significant (P < 0.05) differences were also observed between the median normalized gain scores of the active rTMS and sham groups from 1 week post-stimulation onward for TCRSR and DDR scores, from 1 month post-stimulation onward for TCRSL scores, and at 1 and 3 months post-stimulation for DDL scores. For all significant differences, the active rTMS group performed better than the sham group. For the tinnitus measures at baseline, participants S2 and A2 had THI scores in the no handicap range, participants S1, S3, S4, A3 and A4 had THI scores in the mild handicap range, and participant A1 had a THI score in the moderate handicap range, according to Hanscomb [37]. Fig. 4 shows each participant’s raw score, and the active rTMS (A) and sham (S) groups’ median normalized gain scores, for each tinnitus measure at each assessment point. Three participants (A1, A3 and A4) in the active rTMS (A) group, and no participants in the sham (S) group, showed improved THI scores at >1 assessment point post-stimulation of the seven points or more reported by Zeman et al. [38] as being the minimum required for participants to perceive an improvement in their tinnitus. The normalized gains for these improvements ranged from 0.04 to 0.80. Three participants (A1, A2 and A3) in the active rTMS (A) group showed reduced dB SL values for their tinnitus at >1 assessment point post-stimulation, with the normalized gains for these improvements ranging from 0.25 to 0.88. Only one of these participants (A3) subjects showed an absolute reduction of >10 dB. Two participants in the active rTMS group, A1 and A4, reported complete amelioration of the tinnitus in their right ears (the ear contralateral to the PAC targeted by the active rTMS stimulation) from 1 month post-rTMS stimulation onward. Participant A1 maintained this effect at the 3 month post-rTMS assessment, while participant A4 reported this effect had subsided by the 3 month post-rTMS assessment. Significant (P < 0.05) differences were observed between the median raw scores of the active rTMS and sham groups at baseline for the tinnitus levels in dB SL (with the active rTMS group reporting greater dB SL values for their tinnitus than the sham group: not shown in Fig. 2). Significant (P < 0.05) differences were also observed between the median normalized gain scores at 1 month post-stimulation for the tinnitus levels in dB SL (with the active rTMS group reporting lower dB SL values than the sham group), and from 1 week onwards for the THI score (with the active rTMS group reporting lower handicap scores than the sham group). For all significant differences, the active rTMS group performed better than the sham group. There was no evidence of a placebo effect in the sham group with all of their raw scores on the auditory processing and tinnitus
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Figure 3. Plots of each participant’s scores (left; participant A1 ¼ diamond, A2 ¼ asterisk, A3 ¼ circle, A4 ¼ triangle, S1 ¼ inverted triangle, S2 ¼ star, S3 ¼ square and S4 ¼ hexagon), and each group’s median normalized gain scores (right) on the auditory processing measures at each assessment point. The asterisks above the baseline corrected median scores (right) indicate significant differences between the active rTMS (A) and sham (S) groups at those assessment points.
measures remaining stable (differing by less than 5% from assessment point to assessment point) across all assessment points. Discussion The results of this preliminary study suggest that the application of 1 Hz rTMS to the PAC (BA41) may improve elements of auditory
processing in adults with chronic, bilateral tinnitus. This is evidenced by improvements in TCRS and DD test scores at multiple assessment points post-stimulation, in all four participants in the active rTMS (A) group and none of the participants in the sham (S) group, and the resulting group differences observed despite the limited sample size. The observed improvements did not appear to require the auditory processing abilities be below normal limits
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Figure 4. Plots of each participant’s scores (left), and each group’s median normalized gain scores (right) on the tinnitus measures at each assessment point. The symbols are as per Fig. 3.
prior to stimulation, with only two of the participants in the active rTMS (A) group showing this feature on only one test of auditory processing each at baseline. The potentially confounding effect on auditory processing of the peripheral hearing losses present in some participants should be noted, although this was mitigated by factors such as repeated measures design, the mild nature of these losses in the speech frequency range, and reports that mild cochlear hearing losses have only a minimal effect on DD test performance [17]. Overall, the improvements in auditory processing observed in this investigation support similar reports of improved auditory processing (reduced response times on melody discrimination and word recognition tasks) following 1 Hz rTMS in healthy participants [9,10]. The present results provided less clarity on the benefits for tinnitus of applying 1 Hz rTMS to the PAC (BA41) in these adults. While all four participants in the active rTMS (A) group showed reduced dB SL values for their tinnitus post-stimulation, only one of these subjects showed what was considered to be a substantial absolute reduction (>10 dB) in this value. As a result, the group differences for this variable only reached significance at the 1 month assessment point post-stimulation. These results could have been due to a floor effect resulting from the baseline tinnitus dB SL values being <20 dB SL for seven of the eight participants. The THI findings were more substantial, with three out of the four participants in the active rTMS (A) group, and none of the participants in the sham (S) group, showing improved THI scores poststimulation of the seven points or more reported by Zeman et al. [37] as being the minimum required for participants to perceive an improvement in their tinnitus. Consequently, the group differences for this variable reached significance at all post-stimulus assessment points. The complete amelioration of the tinnitus in the right ears (the ear contralateral to the PAC targeted by the active rTMS
stimulation) of two of the participants in the active rTMS (A) group also supports the use of this treatment in some individuals, although this effect had subsided in one of these participants by 3 months post-stimulation. Overall, these results were consistent with a growing number of reports suggesting 1 Hz rTMS could be employed as an efficacious treatment in some persons with tinnitus [5e7,39e46]. While the results of the present investigation are encouraging, they are limited by a small sample size, the potentially confounding effect of the peripheral hearing losses on the auditory processing measures and an inability to generalize the results beyond this sample of participants, tests and protocols. Furthermore, the present tinnitus outcomes should be treated with added caution due to the possible floor effect noted on the tinnitus measures. Despite these limitations, the results of this investigation warrant further research into the potential benefits of rTMS on auditory processing in adults with chronic, bilateral tinnitus and indeed, individuals with specific deficits in auditory processing.
Acknowledgements The authors acknowledge and thank the staff of the Center for Advanced Imaging, The University of Queensland, for their assistance with neuroimaging procedures. This research was supported by a donation from the Estate of Dulcie Rose Gardner.
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[26] Henry JA, Flick CL, Gilbert A, Ellingson RM, Fausti SA. Comparison of manual and computer-automated procedures for tinnitus pitch-matching. Journal of Rehabilitation Research and Development 2004;41:121e38. [27] Goodwin PE, Johnson RM. The loudness of tinnitus. Acta Oto-Laryngologica 1980;90:353e9. [28] Henry JA, Flick CL, Gilbert AM, Ellingson RM, Fausti SA. Reliability of tinnitus loudness matches under procedural variation. Journal of the American Academy of Audiology 1999;19:502e20. [29] Vernon JA, Meikle MB. Tinnitus masking: unresolved problems. In: Evered D, Lawrenson G, editors. CIBA foundation symposium 85. Tinnitus. London: Pitman; 1981. p. 239e56. [30] Tyler RS, Conrad-Armes D. Tinnitus pitch: a comparison of three measurement methods. British Journal of Audiology 1983;17:101e7. [31] Mills KR, Boniface SJ, Schubert M. Magnetic brain stimulation with a double coil: the importance of coil orientation. Electroencephalography and Clinical Neurophysiology 1992;85:17e21. [32] Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalography and Clinical Neurophysiology 1994;91(2):79e92. [33] Hake RR. Interactive-engagement versus traditional methods: a six-thousandstudent survey of mechanics test data for introductory physics courses. American Journal of Physics 1998;66(1):64e74. [34] SPSS for Windows (version 15.0.0.). Chicago: SPSS Inc; 2006. [35] Wilson RH, Preece JP, Salamon DL, Sperry JL, Bornstein SP. Effects of time compressed and time compression plus reverberation on the intelligibility of Northwestern University Auditory Test No. 6. Journal of the American Academy of Audiology 1994;5:269e77. [36] Strouse A, Wilson RH. Recognition of one-, two-, and three-pair dichotic digits under free and directed recall. Journal of the American Academy of Audiology 1999;10:557e71. [37] Hanscomb L. Analysis of responses to individual items on the Tinnitus Handicap Inventory according to severity of tinnitus handicap. American Journal of Audiology 2006;15:102e7. [38] Zeman F, Koller M, Figueiredo R, Aazevedo A, Rates M, Coelho C, et al. Tinnitus Handicap Inventory for evaluating treatment effects: which changes are clinically relevant? Otolaryngology e Head and Neck Surgery 2011;145: 282e7. [39] Rossi S, De Capua A, Ulivelli M, Bartalini S, Falzarano V, Filippone G, et al. Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study. Journal of Neurology, Neurosurgery, and Psychiatry 2007;78(8):857e63. [40] Smith JA, Mennemeier M, Bartel T, Chelette KC, Kimbrell T, Triggs W, et al. Repetitive transcranial magnetic stimulation for tinnitus: a pilot study. Laryngoscope 2007;117(3):529e34. [41] Khedr EM, Rothwell JC, Ahmed MA, Awad EM, Galal O. Cortical excitability and transcallosal inhibition in chronic tinnitus: transcranial magnetic study. Neurophysiologie Clinique/Clinical Neurophysiology 2008; 38(4):243e8. [42] Langguth B, Kleinjung T, Frank E, Landgrebe M, Sand P, Dvorakova J, et al. High-frequency priming stimulation does not enhance the effect of lowfrequency rTMS in the treatment of tinnitus. Experimental Brain Research 2008;184(4):587e91. [43] Lee SL, Abraham M, Cacace AT, Silver SM. Repetitive transcranial magnetic stimulation in veterans with debilitating tinnitus: a pilot study. Otolaryngology e Head and Neck Surgery 2008;138(3):398e9. [44] Langguth B, de Ridder D, Dornhoffer JL, Eichhammer P, Folmer RL, Frank E, et al. Controversy: does repetitive transcranial magnetic stimulation/transcranial direct current stimulation show efficacy in treating tinnitus patients? Brain Stimulation 2008;1(3):192e205. [45] Marcondes RA, Sanchez TG, Kii MA, Ono CR, Buchpiguel CA, Langguth B, et al. Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study. European Journal of Neurology 2010;17(1):38e44. [46] Anders M, Dvorakova J, Rathova L, Havrankova P, Pelcova P, Vaneckova M, et al. Efficacy of repetitive transcranial magnetic stimulation for the treatment of refractory chronic tinnitus: a randomized, placebo controlled study. Neuroendocrinology Letters 2010;31(2):238e49.
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Original Research
The effect of rTMS on auditory processing in adults with chronic, bilateral tinnitus: A placebo-controlled pilot study Caroline H.S. Barwood a, *, Wayne J. Wilson a, Alicja N. Malicka a, Bradley McPherson b, David Lloyd a, Katherine Munt a, Bruce E. Murdoch a a b
School of Health and Rehabilitation Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia Division of Speech and Hearing Sciences, The University of Hong Kong, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 September 2012 Received in revised form 28 January 2013 Accepted 28 January 2013 Available online xxx
Background: On the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated the use of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as a potential modulator of this hyperactivity. While these investigations show promise, investigations to date have neglected to consider the possible effect of 1 Hz rTMS on other functions of the auditory cortex of these individuals, such as auditory processing. Objective/hypothesis: This placebo-controlled pilot study aimed to determine whether 1 Hz rTMS applied to the primary auditory cortex (PAC), specifically Brodmann Area 41 (BA41), of adults with chronic, bilateral tinnitus would influence their auditory processing abilities. Methods: Eight participants with bilateral, chronic tinnitus were randomized to receive a 10-day course of neuronavigationally guided active rTMS (n ¼ 4) or placebo rTMS (n ¼ 4) treatment applied to a focal region of the left PAC (BA41). Participants’ auditory processing was measured using Time Compressed Reverberant Speech and three-pair Dichotic Digits (DD). Their tinnitus was measured using the Tinnitus Handicap Inventory (THI) and a psychoacoustic measure of tinnitus perception. All outcome measures were administered at baseline (1 week prior to rTMS), 1 week, 1, 2 and 3 months post-rTMS. Results: All four participants in the active rTMS (A) group, and none of the participants in the sham (placebo) rTMS (S) group, showed improved auditory processing scores at multiple assessment points post-stimulation, with the group differences in median normalized gain scores reaching significance at the 5% level from 1 week or 1 month post-stimulation onwards. Three of the four participants in the active rTMS (A) group, and none of the participants in the sham rTMS (S) group, showed improved tinnitus scores at multiple assessment points post-stimulation, with some of the group differences in median normalized gain scores reaching significance at the 5% level. Conclusions: The results of this preliminary study suggest that 1 Hz rTMS applied to the PAC (BA41) has the capacity to improve both auditory processing and tinnitus perception in some adults with chronic, bilateral tinnitus. Ó 2013 Elsevier Inc. All rights reserved.
Keywords: Transcranial magnetic stimulation rTMS Tinnitus Hearing Auditory cortex Auditory processing
Introduction On the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated methods to modulate this hyperactivity using low frequency repetitive transcranial magnetic stimulation (rTMS). Low frequency rTMS (1 Hz) entails repeatedly discharging a transduction coil on the scalp, to induce a very short lasting (w50 ms) magnetic field (reaching peak Financial disclosures: All authors of this manuscript have no conflict of interest to declare. * Corresponding author. Tel.: þ61 7 3365 6162; fax: þ61 7 3365 1877. E-mail address: [email protected] (C.H.S. Barwood). 1935-861X/$ e see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2013.01.015
strengths of 1e2.5 T). Low frequency magnetic pulses are suggested to modulate action potentials in brain regions underlying the coil [1,2] with evidence available to suggest that it may inhibit the generation of action potentials [1]. Early suggestions offered by Eichhammer et al. [3], Langguth et al. [4] and Kleinjung et al. [5] advocating for the use of 1 Hz rTMS as a therapeutic tool for tinnitus have catalyzed a range of studies, incorporating sham-controlled, sham-controlled crossover, parallel, open and multiple active group designs. In general, these investigations have applied 600e2000 rTMS stimuli per day over 5e10 days, at intensities ranging from 100% to 120% of motor threshold. Neural targets have included maximal PET activation areas in the temporal cortex, the left auditory cortex, the left
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Table 1 Biographical information on the eight [7] participants recruited into the study. Participant
Age Gender Handedness Tinnitus e Tinnitus e lateralization duration (years)
Tinnitus e quality Hearing thresholds (air conduction)
Bilateral e left ear louder
Noise
20
Bilateral
Tone
L
25
Bilateral e left ear louder
Tone
M M
R R
1 30
Bilateral e left ear louder Bilateral e left ear louder
Tone Tone
29
F
R
15
Bilateral e left ear slightly louder Tone
39 52
F M
R R
5 15
Bilateral Bilateral
Active rTMS 1 (A1) 46
F
R
1
Active rTMS 2 (A2) 40
M
R
Active rTMS 3 (A3) 41
F
Active rTMS 4 (A4) 34 Sham 1 (S1) 58 Sham 2 (S2) Sham 3 (S3) Sham 4 (S4)
temporoparietal cortex and/or the left dorsolateral prefrontal cortex. A range of target localization techniques have been employed across some of these investigations including stereotactic neuronavigation and the 10e20 EEG system. The outcomes of these collective studies show significant improvements in the tinnitus reported by the test participants (on questionnaires and/or psychoacoustic measures) for periods ranging from <2 weeks to 6 months post-stimulation. Despite positive indications across these investigations, outcome variability in individual participants remains high [5e7]. While the above studies suggest that 1 Hz rTMS may remediate tinnitus symptoms in some individuals, none of these studies considered the potential effect of 1 Hz rTMS on other auditory functions. In the case of the auditory cortex, a common target for 1 Hz rTMS in individuals with tinnitus, this includes a range of skills that encompass auditory processing mechanisms. The American Speech-Language-Hearing Association (ASHA) [8] lists these skills as including sound localization and lateralization; auditory discrimination; auditory pattern recognition; temporal aspects of audition, including temporal integration, temporal discrimination (e.g., temporal gap detection), temporal ordering, and temporal masking; auditory performance in competing acoustic signals (including dichotic listening); and auditory performance with degraded acoustic signals. Given that all of these skills are essential for everyday communication, the application of rTMS techniques for the purpose of treating tinnitus symptoms must to be balanced with any effects (adverse or otherwise) that it might impose on auditory processing abilities. To the authors’ knowledge, only two studies to date have examined the effect on auditory processing of 1 Hz rTMS applied to the auditory cortex. In the first study, Andoh and Zatorre [9] observed improved response times on a melody discrimination task in females but not males subsequent to 1 Hz rTMS targeting left Heschl’s gyrus. In the second study, Andoh and Paus [10] observed improved response times on word recognition tasks in their participants following 1 Hz rTMS targeting the left temporoparietal area. As both of the aforementioned studies examined healthy participants only, the reported improvements in auditory processing cannot easily be generalized to persons with tinnitus. However, these investigations do provide evidence to support modulation auditory processing in the healthy brain. The present study aimed to determine the effect on auditory processing of 1 Hz rTMS applied to the primary auditory cortex (PAC) (specifically, Brodmann Area 41 [BA41]) in adults with chronic, bilateral tinnitus. It is hypothesized that in light of the observed improvements in auditory processing reported in healthy participants post-rTMS, individuals with tinnitus may demonstrate
Tone Tone
R e mild loss at 16 000 Hz only L e mild loss at 8000 and 16 000 Hz only R e mild to moderately severe loss, above 3000 Hz R & L e mild sloping to moderate loss, above 4000 Hz R e mild loss at 14 000 and 16 000 Hz only L e mild loss at 10 000e14 000 Hz only R & L e mild to moderately severe loss, above 4000 Hz R e mild to moderately severe loss, above 6000 Hz L e mild to moderately severe loss, above 3000 Hz R e moderate to severe loss, above 4000 Hz L e mild to moderately severe loss, above 9000 Hz R & L e hearing thresholds within normal limits R & L e hearing thresholds within normal limits
improvements in auditory processing abilities up to 2 months poststimulation. Methods Ethical clearance Ethical clearance was granted from The University of Queensland Medical Research Ethical Review (MREC) board. All participants gave informed consent to participate in this research and all procedures conformed to the Declaration of Helsinki. Participants Table 1, shows the biographical information, and Fig. 1 shows audiograms for the eight participants recruited into the study through an open advertisement on the staff information system at The University of Queensland. All participants had bilateral tinnitus of at least 1 year duration; no self-reported neurological or psychological conditions; normal hearing thresholds up to and including 3000 Hz with normal hearing thresholds or hearing losses ranging from mild to severe above 3000 Hz, in accordance with the Goodman classification system [11]. In addition, participants had normal middle ear compliance (tympanograms showing static compliance 0.2 ml and tympanic peak pressure between 100 and þ50 daPa, as per Jerger [12]); normal distortion product otoacoustic emissions from 500 to 3000 Hz according to Hall [13]. These audiometric results remained stable for all participants throughout the study. With respect to eligibility to receive rTMS, participants had no history of seizures or epilepsy, neurological disorders, brain injury, cardiac pacemakers, metal implants or implanted medication pumps and were not taking mood altering medications (e.g., antidepressants or neuroepileptic medications) [2,14,15]. Seven participants were right handed and one was left handed, as measured using the Edinburgh Handedness Inventory [16]. The participants were randomly assigned (using a randomized list of numbers) to the active rTMS (A, n ¼ 4) or sham (S, n ¼ 4) group and were blinded to the stimulation condition (i.e., a singleblind, randomized method). Protocol Overview Each participant underwent assessment and treatment in the following order: neuroimaging; basic audiological assessment; auditory processing assessment; tinnitus assessment; rTMS
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3
Auditory processing assessment
Figure 1. The participant audiograms for those in the active rTMS (A) group (above) and sham (S) group (below).
treatment; and auditory processing and tinnitus re-assessments at 1 week, 1 month and 3 months post-rTMS.
All participants completed the auditory processing assessments in sound-treated booths using a commercially available, calibrated audiometer (Interacoustics Clinical Audiometer AC40) coupled to a compact disc player (Interacoustics Clinical Audiometer AC40, AN-9204 DVPH). These assessments consisted of two, pre-recorded tests: Time-compressed and Reverberant Speech (TCRS) and threepair Dichotic Digits (DD) from the Wilson and Strousse CD “Tonal and Speech Materials for Auditory Perceptual Assessment, Disc 2.0” [19]. Both ears in each participant were tested. For the TCRS testing, 25 filtered NU-6 words from the filtered NU-6 wordlists (male speaker with the carrier phrase “say the word” and each stimulus word compressed 45% and reverberated 0.3 s were played at 50 dB HL (dial setting) to the test ear only and the participant was asked to repeat each stimulus word as it was played. Each ear was assessed separately. The first five words were used as practice, leaving the remaining 20 words to be scored at 5% for each word correctly repeated. The 25 words played to each ear were counterbalanced across test occasions. ASHA [8] reported that TCRS assesses the auditory process of performance with degraded signals. For the DD testing, 20 pairs of number (1e10, excluding 7) triplets (male speaker and interval between digits from 500 ms to 700 ms with an interstimulus interval of 5 s) were played at 50 dB HL (dial setting) so that for each pair, one number triplet was played to one ear at the same time as the second number triplet was played to the other ear. This resulted in the first number in the first triplet being played to one ear at the same time as the first number in the second triplet being played to other ear, and the same for the second and third numbers in each triplet. Both ears were assessed simultaneously. A score of 0.83% was awarded for each number correctly repeated (regardless of order). ASHA [8] reported that DD assesses the auditory process of dichotic listening (particularly binaural integration).
Tinnitus assessment Neuroimaging The neuroimaging protocol consisted of a 3-T structural magnetic resonance imaging (MRI) scan with the following acquisition parameters: TR ¼ 19 ms, TE ¼ 4.92 ms, matrix size ¼ 256 256, number of slices ¼ 128, and slice thickness ¼ 2 mm. A computerized MRI visualization and analysis system [17] was then employed to visually mark target areas (BA41 and the motor hand knob) with a crosshair. This software program permitted a Talairach transformation of each subject’s brain, generating voxel and Talairach co-ordinates in reference to general neuroanatomical landmarks and Brodmann Area.
Basic audiological assessment All participants completed the basic audiometric assessments in sound-treated booths using commercially available, calibrated audiometric equipment (Interacoustics Clinical Audiometer AC40, Zodiac 901 Middle Ear Analyzer, and Otodynamics ILO292 USB-I Echoport running ILOv6 for Windows [file version 6.40.26.0]). This assessment included obtaining pure tone audiometry thresholds (air conduction only) at 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, 8000, 9000, 10 000, 11 000, 12 500, 14 000 and 16 000 Hz [18], tympanometry using a standard 226 Hz probe tone [12], and distortion product otoacoustic emissions at 1/3 octave frequencies from 500 Hz to 4000 Hz.
All information and data regarding each participant’s tinnitus was collected using a questionnaire and a psychoacoustic measure of tinnitus sensation level in accordance with the current consensus for tinnitus patient assessment and treatment outcome measurement [20]. The questionnaire utilized was the Tinnitus Handicap Inventory (THI) [21]. This questionnaire has support for its repeated use within short intervals and its validity and reliability for measuring tinnitus outcomes [21,22], although its sensitivity for measuring treatment outcomes has been challenged [23]. The psychoacoustic measure of tinnitus perception was a loudness-matching task, which included pitch matching, to enable loudness matching at the frequency associated with pitch of tinnitus. The tests were run using a personal computer (PC) and Matlab Software (version 7.0.1a) with a custom written M-file. The PC was equipped with an external 24-bit sound card (E-MU 0204) and Sennheiser HD600 headphones (which offered a broad frequency response with low distortion). The stimuli were corrected for the frequency response characteristic of the headphones (corrections were measured for individual frequencies and included in M-file). This system was calibrated by requesting a 60 dB SPL output at 1000 Hz, measured using a Brüel & Kjær Type 2250B hand-held analyzer (a Class 1 sound level meter under IEC 61672-1 [24]) with a Brüel & Kjær Type 4153 Artificial Ear fitted with a 1/2” microphone. The analyzer and the microphone were calibrated yearly by the Brüel & Kjær laboratories in Sydney,
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Australia, and a Brüel & Kjær Type 4231 sound level calibrator was used to check their status before and after testing. Tinnitus loudness required the participant to wear the headphones and follow instructions presented on the computer screen to complete an automated tinnitus pitch-matching procedure based on the binary method of Henry et al. [25]. This involved an adaptive, two-alternative forced choice (2AFC) procedure chosen because it is more reliable than manual methods and is one of the most reliable automated methods for pitch matching [25,26]. The matching signal was always presented to the right ear. This was due to the fact that all participants reported tinnitus in both ears with some reporting their tinnitus to be worse in their left ear, and the use of contralateral stimulation has been reported to be less challenging than ipsilateral stimulation for pitch matching [27,28]. The procedure began with successive presentations of a 1000 Hz pure tone and a narrow-band noise (NBN) (10% of signal frequency bandwidth) at a comfortable listening level to which each participant was asked to indicate which sound most closely resembled the sound quality of their tinnitus. This selection determined the type of sounds (pure tones or NBNs) used in the remainder of the procedure for that participant. The initial tinnitus loudness matching was then performed using pure tone or NBN signals at 250, 500, 1000, 2000, 4000, 6000, 8000, 10 000, 12 000, 14 000 and 16 000 Hz. For each run at each frequency the participant was presented with a signal and was required to respond if the signal was louder or softer than the participant’s tinnitus. The participant’s description of the matching signal was used to increase (if the signal was described as being softer than the tinnitus) or decrease (if the signal was described as being louder than the tinnitus) the level of the next presentation in 5 dB steps until a reversal point was obtained. Each time a reversal point was reached, the step size was reduced by half and the presentations continued until a final 1 dB step size was reached. The final levels at each frequency were then used to interpolate equal loudness levels for tinnitus matching stimuli ranging from 250 to 16 000 Hz [29]. Following the initial tinnitus loudness matching described above, tinnitus pitch-matching commenced with the sequential presentation of two loudness-matched tones or NBNs (at a comfortable loudness) with center frequencies of 3180 and 4000 Hz. Participants were first instructed to select the tone/NBN whose pitch was closest to the predominant pitch of their tinnitus. Based on the participant’s response, the frequency of the next presentation was increased (if the signal was described as being of lower pitch than the tinnitus) or decreased (if the signal was described as being of higher pitch than the tinnitus) in half-octave steps until six reversal points were obtained. From this frequency, the process was then repeated using 1/3 octave steps until five reversal points were obtained. The matched frequency of each participant’s tinnitus was calculated as an average of the frequencies of the last three reversals of the 1/3 octave step part of the run. The highest frequency for this process was 16 000 Hz, which resulted in 12 000 Hz being the highest frequency that could be matched to a participant’s tinnitus using this process. The pitchmatching procedure was repeated three times in an attempt to improve its accuracy [30] and the average of these three measures was taken as the final tinnitus pitch-matched frequency for that participant. Following the tinnitus pitch matching, the final tinnitus loudness matching was performed at the tinnitus pitch-matched frequency only, using the loudness matching protocol described above. This value was recorded as the tinnitus matching loudness level in dB SPL. Each participant’s hearing threshold in dB HL in their right ear at the frequency matching the tinnitus pitch was then converted to dB SPL (using the recommended reference equivalent sound pressure levels in a coupler complying with IEC
Figure 2. The target area for the rTMS: the primary auditory cortex (Brodmann Area 41) in the left hemisphere.
60318 [30]) and this value was subtracted from his or her tinnitus matching loudness level in dB SPL to give each participant’s final psychoacoustic measure of tinnitus perception in dB SL (decibels sensation level: the number of dB the tinnitus was judged to be above each participant’s hearing threshold at the pitch-matched frequency of that participant’s tinnitus). rTMS protocol For the treatment group, low frequency (1 Hz) rTMS was applied to each participant for w33 min per day (2000 pulses) over 10 sessions (MondayeFriday, within two consecutive weeks) at 110% of resting motor threshold (RMT) as defined by Eichhammer et al. [3]. A Magstim Rapid2 stimulator and a figure of eight, 70 mm diameter rTMS coil was utilized to administer rTMS (Magstim, UK). Participants received no other treatment for their tinnitus during participation in this study. The rTMS coil was placed over the marked region of interest on the MRI scan on the interface of a StealthStation TreonÓ (Medtronic, USA, Minneapolis, Minnesota) neuronavigational system (Medtronic, USA). The TMS target was BA41. On the acquired structural MRI scan, this was marked on the anatomical boundary of Heschel’s gyrus, in the medial aspect [3]. Fig. 2 shows the marked target BA41 on a participant’s structural MRI. The coil was held by hand and position relative to the head was maintained using real-time feedback from the stereotactic guidance system, the StealthStation Treon. For the sham group, low frequency (1 Hz) rTMS was applied in exactly the same manner described for the treatment group, with the exception that the coil was a sham coil that presented a sound only with no magnetic pulse administered at each stimulus event. Motor threshold attainment The RMT attainment for the stimulation protocol described above was determined using a hand muscle. The TMS coil (bi-phasic
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stimulation, 70 mm) was placed on the motor “hot spot” for the first dorsal interosseous (FDI) muscle in the left hand (i.e., the knob within pre-central gyrus) in the contralateral hemisphere as determined by MRI marking and StealthStation software. Motor evoked potentials (MEPs) were then elicited via TMS and surface EMG recorded from FDI via Ag/AgCl electrodes (1 cm in diameter), positioned over the belly of the muscle and the metacarpophalangeal joint of the index finger, respectively. The ground electrode was attached over a bony prominence on a distal region of the radius. The coil was positioned tangentially to the skull above the left primary motor cortex with the handle pointing backward and laterally at an angle of about 45 to the sagittal plane inducing an electrical current in the brain tissue with a posteriorelateral to anterioremedial direction roughly perpendicular to the central sulcus. This current orientation is known to be optimal for evoking a motor response in the contralateral hand [31]. The location and orientation to which the stimulus was applied (at suprathreshold intensity) consistently yielded maximal MEPs in the contralateral FDI muscle. RMT was defined as the minimum stimulus intensity eliciting five responses of about 50 mV out of 10 consecutive trials (50% successful MEPS) in the relaxed contralateral FDI [32]. Trials commenced with a suprathreshold value and subsequent TMS intensities were decreased in steps of 2% until no reliable MEPs were recorded. For the present study stimulation was applied at 110% of the RMT attained [3]. Participant stimulation intensities in the present investigation ranged between 35 and 60% of maximum stimulator output. All participants tolerated rTMS well and completed the 10 days of stimulation. Data collection The following data were collected from each participant at each point of assessment post-rTMS treatment: 1) Auditory processing measures: the raw scores for the right (R) and left (L) ears for the TCRS and DD tests, and; 2) Tinnitus measures: the total score from the THI and the psychoacoustic measure of tinnitus perception in dB SL obtained from the psychoacoustic measures. Data analysis All participant scores on each auditory processing and tinnitus measure at each of the assessment points (baseline and post-rTMS treatment) were plotted and the Mann Whitney U statistic was used to test for differences between the active (A) and sham (S) group scores on each measure at each assessment point. Difference scores (post-test score pre-test score) were calculated for the participants on each of the auditory processing and tinnitus measures. These difference scores were then converted to normalized gain scores. For the auditory processing scores, the normalized gain score ¼ (post-test score pre-test score)/ (maximum possible score pre-test score). For the tinnitus scores, the normalized gain score ¼ (post-test score pre-test score)/ (minimum possible score pre-test score). This method was employed because normalized gain scores have been shown to reduce the bias caused by outliers [33]. The median normalized gain scores were plotted and the Mann Whitney U statistic was used to test for differences between the active (A) and sham (S) group normalized gain scores on each measure at each assessment point. All Mann Whitney U analyses were performed using IBM SPSS Statistics 20 (release 20.0.0.) [34] at the 5% level. Results For the auditory processing measures, the performance of each participant at each assessment point was within two standard
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deviations (2 SD) of the mean performances of healthy adult participants (with hearing thresholds within normal limits from 250 Hz to 8000 Hz) reported by Wilson et al. [35] for the TCRS test and Strouse and Wilson [36] for the DD test, with the following exceptions: participant S1 performed marginally below 2 SD on TCRSL at each assessment, participant S2 performed below 2 SD on DDR and DDL at each assessment, participant A1 performed below 2 SD on DDL at the baseline and week one assessments, and participant A4 performed below 2 SD on DDR at the baseline assessment. Fig. 3 shows each participant’s raw scores, and the active rTMS (A) and sham (S) groups’ median normalized gain scores, for each auditory processing measure at each assessment point. All four participants in the active rTMS (A) group, and none of the participants in the active rTMS (A) group, showed improved auditory processing scores at >1 assessment point post-stimulation. The normalized gains for these improvements ranged from 0.10 to 1.00. Significant (P < 0.05) differences were observed between the median normalized gain scores of the active rTMS and sham groups from 2 months post-stimulation onward for TCRSR, TCRSL and DDR scores, and at 3 months post-stimulation for DDL (not shown in Fig. 2). Significant (P < 0.05) differences were also observed between the median normalized gain scores of the active rTMS and sham groups from 1 week post-stimulation onward for TCRSR and DDR scores, from 1 month post-stimulation onward for TCRSL scores, and at 1 and 3 months post-stimulation for DDL scores. For all significant differences, the active rTMS group performed better than the sham group. For the tinnitus measures at baseline, participants S2 and A2 had THI scores in the no handicap range, participants S1, S3, S4, A3 and A4 had THI scores in the mild handicap range, and participant A1 had a THI score in the moderate handicap range, according to Hanscomb [37]. Fig. 4 shows each participant’s raw score, and the active rTMS (A) and sham (S) groups’ median normalized gain scores, for each tinnitus measure at each assessment point. Three participants (A1, A3 and A4) in the active rTMS (A) group, and no participants in the sham (S) group, showed improved THI scores at >1 assessment point post-stimulation of the seven points or more reported by Zeman et al. [38] as being the minimum required for participants to perceive an improvement in their tinnitus. The normalized gains for these improvements ranged from 0.04 to 0.80. Three participants (A1, A2 and A3) in the active rTMS (A) group showed reduced dB SL values for their tinnitus at >1 assessment point post-stimulation, with the normalized gains for these improvements ranging from 0.25 to 0.88. Only one of these participants (A3) subjects showed an absolute reduction of >10 dB. Two participants in the active rTMS group, A1 and A4, reported complete amelioration of the tinnitus in their right ears (the ear contralateral to the PAC targeted by the active rTMS stimulation) from 1 month post-rTMS stimulation onward. Participant A1 maintained this effect at the 3 month post-rTMS assessment, while participant A4 reported this effect had subsided by the 3 month post-rTMS assessment. Significant (P < 0.05) differences were observed between the median raw scores of the active rTMS and sham groups at baseline for the tinnitus levels in dB SL (with the active rTMS group reporting greater dB SL values for their tinnitus than the sham group: not shown in Fig. 2). Significant (P < 0.05) differences were also observed between the median normalized gain scores at 1 month post-stimulation for the tinnitus levels in dB SL (with the active rTMS group reporting lower dB SL values than the sham group), and from 1 week onwards for the THI score (with the active rTMS group reporting lower handicap scores than the sham group). For all significant differences, the active rTMS group performed better than the sham group. There was no evidence of a placebo effect in the sham group with all of their raw scores on the auditory processing and tinnitus
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Figure 3. Plots of each participant’s scores (left; participant A1 ¼ diamond, A2 ¼ asterisk, A3 ¼ circle, A4 ¼ triangle, S1 ¼ inverted triangle, S2 ¼ star, S3 ¼ square and S4 ¼ hexagon), and each group’s median normalized gain scores (right) on the auditory processing measures at each assessment point. The asterisks above the baseline corrected median scores (right) indicate significant differences between the active rTMS (A) and sham (S) groups at those assessment points.
measures remaining stable (differing by less than 5% from assessment point to assessment point) across all assessment points. Discussion The results of this preliminary study suggest that the application of 1 Hz rTMS to the PAC (BA41) may improve elements of auditory
processing in adults with chronic, bilateral tinnitus. This is evidenced by improvements in TCRS and DD test scores at multiple assessment points post-stimulation, in all four participants in the active rTMS (A) group and none of the participants in the sham (S) group, and the resulting group differences observed despite the limited sample size. The observed improvements did not appear to require the auditory processing abilities be below normal limits
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Figure 4. Plots of each participant’s scores (left), and each group’s median normalized gain scores (right) on the tinnitus measures at each assessment point. The symbols are as per Fig. 3.
prior to stimulation, with only two of the participants in the active rTMS (A) group showing this feature on only one test of auditory processing each at baseline. The potentially confounding effect on auditory processing of the peripheral hearing losses present in some participants should be noted, although this was mitigated by factors such as repeated measures design, the mild nature of these losses in the speech frequency range, and reports that mild cochlear hearing losses have only a minimal effect on DD test performance [17]. Overall, the improvements in auditory processing observed in this investigation support similar reports of improved auditory processing (reduced response times on melody discrimination and word recognition tasks) following 1 Hz rTMS in healthy participants [9,10]. The present results provided less clarity on the benefits for tinnitus of applying 1 Hz rTMS to the PAC (BA41) in these adults. While all four participants in the active rTMS (A) group showed reduced dB SL values for their tinnitus post-stimulation, only one of these subjects showed what was considered to be a substantial absolute reduction (>10 dB) in this value. As a result, the group differences for this variable only reached significance at the 1 month assessment point post-stimulation. These results could have been due to a floor effect resulting from the baseline tinnitus dB SL values being <20 dB SL for seven of the eight participants. The THI findings were more substantial, with three out of the four participants in the active rTMS (A) group, and none of the participants in the sham (S) group, showing improved THI scores poststimulation of the seven points or more reported by Zeman et al. [37] as being the minimum required for participants to perceive an improvement in their tinnitus. Consequently, the group differences for this variable reached significance at all post-stimulus assessment points. The complete amelioration of the tinnitus in the right ears (the ear contralateral to the PAC targeted by the active rTMS
stimulation) of two of the participants in the active rTMS (A) group also supports the use of this treatment in some individuals, although this effect had subsided in one of these participants by 3 months post-stimulation. Overall, these results were consistent with a growing number of reports suggesting 1 Hz rTMS could be employed as an efficacious treatment in some persons with tinnitus [5e7,39e46]. While the results of the present investigation are encouraging, they are limited by a small sample size, the potentially confounding effect of the peripheral hearing losses on the auditory processing measures and an inability to generalize the results beyond this sample of participants, tests and protocols. Furthermore, the present tinnitus outcomes should be treated with added caution due to the possible floor effect noted on the tinnitus measures. Despite these limitations, the results of this investigation warrant further research into the potential benefits of rTMS on auditory processing in adults with chronic, bilateral tinnitus and indeed, individuals with specific deficits in auditory processing.
Acknowledgements The authors acknowledge and thank the staff of the Center for Advanced Imaging, The University of Queensland, for their assistance with neuroimaging procedures. This research was supported by a donation from the Estate of Dulcie Rose Gardner.
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