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Electric field navigated transcranial magnetic stimulation for chronic tinnitus: A pilot study a
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Hanna Sahlsten , Johan Isohanni , Jorma Haapaniemi , Jaakko Salonen , Janika Paavola , e
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Eliisa Löyttyniemi , Reijo Johansson & Satu K. Jääskeläinen a
Department of Ear, Nose and Throat, Satakunta Central Hospital, Pori, Finland
b
Medical School, University of Turku, Turku, Finland
c
Department of Ear, Nose and Throat, Turku University Hospital, Turku, Finland
d
Department of Clinical Neurophysiology, Turku University Hospital and University of Turku, Turku, Finland e
Department of Biostatistics, University of Turku, Turku, Finland Published online: 18 Jun 2015.
To cite this article: Hanna Sahlsten, Johan Isohanni, Jorma Haapaniemi, Jaakko Salonen, Janika Paavola, Eliisa Löyttyniemi, Reijo Johansson & Satu K. Jääskeläinen (2015): Electric field navigated transcranial magnetic stimulation for chronic tinnitus: A pilot study, International Journal of Audiology To link to this article: http://dx.doi.org/10.3109/14992027.2015.1054041
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International Journal of Audiology 2015; Early Online: 1–11
Original Article
Electric field navigated transcranial magnetic stimulation for chronic tinnitus: A pilot study
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Hanna Sahlsten*, Johan Isohanni†, Jorma Haapaniemi‡, Jaakko Salonen‡, Janika Paavola#, Eliisa Löyttyniemi$, Reijo Johansson‡ & Satu K. Jääskeläinen# *Department of Ear, Nose and Throat, Satakunta Central Hospital, Pori, Finland, †Medical School, University of Turku, Turku, Finland, ‡Department of Ear, Nose and Throat, Turku University Hospital, Turku, Finland, #Department of Clinical Neurophysiology, Turku University Hospital and University of Turku, Turku, Finland and $Department of Biostatistics, University of Turku, Turku, Finland
Abstract Objective: Repetitive transcranial magnetic stimulation (rTMS) has shown potential in reducing tinnitus symptoms. We evaluated effects of electric field (E-field) navigated rTMS targeted neuroanatomically according to tinnitus pitch. Design: In this open methodological pilot study, the patients received E-field navigated 1-Hz rTMS in daily treatment sessions to the left superior temporal gyrus, targeted according to tonotopic representation of their individual tinnitus pitch. Patients rated their tinnitus intensity and annoyance with a numeric rating scale (NRS) from 0 to 10 at the baseline and after each rTMS session. They also rated their global impression of change (scale ⫺ 3 to ⫹ 3) after the treatment. Study sample: Thirteen patients (mean age 53 years; 10 men, 3 women) with chronic, intractable tinnitus. Results: The mean intensity was 7.1 (SD 1.8) at the baseline, decreasing to 4.5 (SD 2.2) after the rTMS (p ⬍ 0.0001). The mean annoyance 7.0 (SD 1.8) at the baseline decreased to 4.0 (SD 2.4) after the treatment (p ⬍ 0.0001). Intensity diminished at least 30% in 8/13 patients and annoyance in 9/13 patients. A total of 10/13 patients felt subjective benefit from the treatment. Conclusions: These preliminary observations suggest that E-field-rTMS may improve the current treatment options for intractable tinnitus.
Key Words: Tinnitus; electric field navigated; transcranial magnetic stimulation Tinnitus is defined as a perception of sound in the absence of external stimuli. It affects approximately 10–15% of the population, and approximately 80% of tinnitus patients do not require clinical intervention (Henry et al, 2005). However, some people suffer from disabling tinnitus causing insomnia, anxiety, and distress in daily life. Severe tinnitus can even lead to suicide, especially when combined with depression (Dobie, 2003). No curative therapy for tinnitus exists, and the current treatment strategies aim at improving the patient’s ability to cope with the symptoms. Psychological therapies, such as counseling, cognitive behavioral therapy, and tinnitus retraining therapy may diminish tinnitus distress or improve the quality of life (Phillips & McFerran, 2010). Some patients may benefit from masking devices (Hobson et al, 2012), or hearing aids if there is a significant hearing impairment (Del Bo & Ambrosetti, 2007). No current drug treatment has been shown to cure tinnitus, but antidepressive medications such as tricyclic antidepressants and serotonin reuptake inhibitors may alleviate suffering from tinnitus, at least in patients with depression. There is not yet sufficient evidence that antidepressant drug therapy aids in improving tinnitus (Baldo et al, 2012). The exact mechanism underlying tinnitus is still unknown, although various hypotheses explain the development and
aggravation of tinnitus (Seidman et al, 2010). Tinnitus is thought to be a perception caused by abnormal hyperactivity generated within the auditory cortex and auditory brainstem nuclei as a result of cortical deafferentation and functional reorganization following damage to the cochlea (Henry et al, 2014). In addition, abnormal activity in non-auditory areas such as the frontal lobes, the limbic system, and the cerebellum has been found in neuroimaging studies on tinnitus patients (Leaver et al, 2011). Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique based on the electromagnetic induction of an electric field in the brain by means of magnetic pulses given to the scalp. When TMS pulses are applied repetitively (rTMS), they can modulate cortical excitability, by increasing or decreasing it via long-term potentiation (LTP) or long-term depression (LTD) like effects (Siebner et al, 2003). TMS pulses given at low frequencies (ⱕ 1 Hz) decrease cortical excitability. This forms the basis for using low frequency rTMS to treat chronic tinnitus patients whose auditory cortex is hyperactive (Plewnia et al, 2007). During the past decade, rTMS has been successfully and safely used for the treatment of various clinical entities including chronic neuropathic pain and major depression (Rossi et al, 2009; Lefaucheur et al, 2014). There are several studies on the treatment of
Correspondence: Hanna Sahlsten, Satakunnan keskussairaala, Korvatautien poliklinikka, Sairaalantie 3, 28500 Pori, Finland. E-mail: [email protected] (Received 15 December 2014 ; accepted 18 May 2015) ISSN 1499-2027 print/ISSN 1708-8186 online © 2015 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society DOI: 10.3109/14992027.2015.1054041
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Abbreviations
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cMAP DLPF E-field GIC MEP MRI NRS PTA RMT rTMS STG V/m
Compound muscle action potential Dorsolateral prefrontal cortex Electric field Global impression of change Motor evoked potential Magnetic resonance image Numeric rating scale Pure tone average Resting motor threshold Repetitive transcranial magnetic stimulation Superior temporal gyrus Volts per metre (E-field strength)
tinnitus with rTMS, with so far rather modest effect sizes in 20 original placebo-controlled studies with at least 10 tinnitus patients (Lefaucheur et al, 2014). The effects of rTMS treatment seem to vary widely between patients (Langguth et al, 2008), and tinnitus reduction after rTMS is usually partial and temporary, but may last for up to six months. Repeated sessions of low-frequency rTMS to the temporoparietal cortex have been investigated as a treatment for tinnitus with promising, yet moderate effects (Rossi et al, 2007; Plewnia et al, 2007; Khedr et al, 2008; Anders et al, 2010; Marcondes et al, 2010; Mennemeier et al, 2011; Zhe et al, 2012). However, in some studies, rTMS was no more effective than sham stimulation (Piccirillo et al, 2013; Hoekstra et al, 2013; Langguth et al, 2014). Based on the current evidence, a group of European experts recently justified a Level C recommendation (“possible efficacy”) for the use of rTMS for tinnitus (Lefaucheur et al, 2014). However, most of the previous studies have not applied navigated TMS, and there are no studies utilizing real time electric field (E-field) navigation for anatomically precise targeting of rTMS treatment. Moreover, the treatment targets and stimulation protocols have varied widely between the studies (Theodoroff et al, 2013; Lefaucheur et al, 2014). The goal of this open methodological pilot study was to evaluate the feasibility and effects of precise E-field navigation according to individual neuroanatomy and tinnitus pitch reflected in the tonotopy of the auditory cortex (see Figure 1 (a), and Purves et al, 2004) in patients with long history of severe, intractable, and disabling tinnitus. In addition, the influence of several factors related to stimulation protocol on the treatment results was evaluated.
Materials and Methods Patients The study was performed according to the Declaration of Helsinki. Information concerning the trial was given to all patients, and they all gave their informed spoken consent; attending was completely voluntary and the patients were free to discontinue the treatment at anytime. Inclusion criterion was severe (intensity at least 5/10 on the NRS scale), chronic (duration at least one year), otherwise intractable, and disabling tinnitus that severely interfered with daily life activities. Exclusion criteria were epilepsy and any contraindication, like metallic intracorporeal appliances, to MR imaging. Previous tinnitus treatments included repeated counseling with ENT-specialist and psychologist or psychiatrist, medication trials with anti-depressants and betahistine, but these had not been successful. Consecutive patients fulfilling the criteria and willing to participate in this open methodological pilot study were recruited from the Ear, Nose and Throat
(ENT) department of the Turku University Hospital during a period from autumn 2011 to spring 2013. Only one patient had to be rejected from the pilot study due to previous brain tumor surgery. This study took place at the department of clinical neurophysiology and was undertaken to serve as a pilot for a prospective randomized controlled trial on navigated therapeutic rTMS for chronic tinnitus. Thirteen patients (three women, ten men) aged 30–73 years (mean age 53 years) participated in the study. Eight of the thirteen patients had bilateral tinnitus and the remaining five patients had more lateralized tinnitus. Only two patients had normal hearing, and the other patients had variable sensorineural hearing deficit, predominantly in the high frequency range. Eight patients suffered from depression and eight patients used prescription medication affecting the central nervous system (Table 1). None of the patients had previously been treated with rTMS. Table 1 shows the demographic data, tinnitus and hearing characteristics, medications, and head MRI findings.
Evaluation scales All the patients suffered from intractable tinnitus, but the actual tinnitus intensity and annoyance varied among the patients. A numeric rating scale (NRS) from 0 to 10 was used to evaluate the severity of the tinnitus. Zero (0) represented the situation with no tinnitus or no annoyance and ten (10) was the worst possible tinnitus intensity or annoyance the patients could imagine. If a patient declared two numbers, for example 6–7, the value was registered as 6.5. NRS was obtained before the start of the treatment: the patients were asked to give a value for the average tinnitus intensity and annoyance level for the previous week. In addition, the patients evaluated tinnitus intensity and annoyance immediately before and after each rTMS session, in the evening and the following morning after the session (tinnitus diary). As there were missing values in the symptom diaries, the mean NRS values at baseline before the start of the treatment series, and daily assessments after the first four (three in one patient) treatment sessions (immediately or in the evening of the treatment day), as well as at the end of the whole treatment series right after the last rTMS session were chosen for statistical analyses, as they were available for the patients. A reduction of 30% or more on a NRS value was considered to be a clinically significant change, as it is a commonly used cut-off point also in more recent randomized controlled trials on pain treatment (Dworkin et al, 2008). In addition, other possible effects, like lateralization of tinnitus, changes in tinnitus frequency or quality, and possible side-effects were registered. The global impression of change scale (GIC scale ⫺ 3 to ⫹ 3, in which ⫺ 3 means very much worse than before the treatment and ⫹ 3 very much better than before the treatment and 0 is no change) was used after the serial rTMS treatment to define the subjective benefit of the treatment. One patient had difficulties in self-rating the tinnitus intensity and annoyance in the evening and the following morning. One patient was not able to evaluate tinnitus immediately after the treatment because the tinnitus was not discernible due to the sound generated by the TMS device. The tinnitus intensity may fluctuate during the day, and this may have caused some additional variability in this small group of patients. After this prospective trial, the data on long-term effects was collected retrospectively through the electronic patient archives as they were available.
rTMS First, all patients underwent a 3-tesla magnetic resonance image (MRI) of the head for a three dimensional reconstruction of the head for the navigated TMS system before the treatment.
E-field navigated TMS for tinnitus
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The TMS equipment was an electric field (E-field) navigated NBS System 4.0 (manufactured by Nexstim Ltd, Helsinki, Finland). It uses an infrared camera tracking unit together with specific head-trackers and a digitizing pen to mark anatomical landmarks on the patient’s head. This allows the matching of the MRI image based head model to the external anatomical landmarks on the patient’s head. In addition, the NBS System uses a spherical model to mathematically estimate induced electric field within the brain. Together with the known coil location (via infrared tracking) and electric parameters, the NBS system is capable of visualizing the induced E-field in real time during stimulation and estimating the strength of the E-field in Volts per metre at the stimulation target. The E-field and its “hot spot” (the site of maximal electric field strength) are shown on the peeled MRI head image on the computer screen allowing the user to control the cortical target and the direction of the electric current vector during stimulation (Figure 1, b). This “hot spot” has been shown to have an anatomical accuracy of a few millimetres, corresponding to the accuracy of direct intraoperative cortical electric stimulation (Picht et al, 2011). A figure-of-eight coil giving biphasic magnetic pulses was used for measuring the resting motor threshold, and for giving the rTMS treatment. During the treatment, the coil was fixed in the correct position by a coil holder and the patient’s head was stabilized on the chair with a neck/head brace. The stability of the positioning was monitored throughout the treatment session in real time from the computer screen by a medical doctor or a nurse specialized in clinical neurophysiology and TMS techniques; if the centre of the induced E-field moved away from the set target more than 3 mm, the stimulation was paused and the coil readjusted. During the first session, the resting motor threshold (RMT) was measured at the right M1 cortex representing the left hand thenar muscles as described earlier (Valmunen et al, 2009). Self-adhesive surface electrodes were used to record the compound muscle action potential (cMAP). The “hot spot” at M1 was located by moving the coil at right angles against the central sulcus until the optimal site and coil orientation producing maximum cMAP was found. The RMT was determined by delivering single TMS pulses at the optimal coil position with automatically up-and-down varying intensities given by the NBS System software used to obtain an estimate of the RMT. RMT is thus defined as the lowest intensity (% of maximum device output) capable of eliciting a small (⬎ 50 μV) cMAP in at least 50% of the trials. The number of stimulation pulses required for the NBS software algorithm to determine the RMT value ranged between 7 and 20. The RMT estimation was done at least two times, and if there was a larger than 2% discrepancy in these two values, a third trial was done. The mean of the measured values was used as the RMT for rTMS treatment. The number of rTMS treatment sessions, the exact location, and the number of pulses were individually tailored for the patients (Table 2). The number of the treatment sessions in this pilot study varied between 3 and 15. The first patients, Figure 1. (a) upper illustration. The exact location of the treatment coil was adjusted according to the known tonotopy of the auditory cortex where higher frequencies are represented posteriorly and lower frequencies anteriorly. The pitch of the tinnitus at the baseline determined the initial target location along the anterior-posterior axis on the superior temporal gyrus (STG). (b) lower illustration. The red arrow in the figure shows the induced electric field vector on the cortical target site at the left STG. The exact stimulation spot (“hot spot”) is at the border of the red and the blue arrows. The brightness of the arrow reflects the optimal tangential position of
the coil. The calculated electric field on the cortex is also shown numerically as V/m (not shown in the figure). It was possible to use several stimulation targets on the STG: the most anterior one was situated close to the posterior end of the sulcus centralis (for lower pitch tinnitus) and the most posterior one was situated 2–3 cm more posteriorly (for high pitch tinnitus). The “hotspot” of stimulation was moved forwards or backwards on the STG during consecutive sessions according to the achieved results (diminution of intensity and changes in the pitch of tinnitus).
49/M 53/M
39/F 30/F 65/M
65/M
73/F
61/M
62/M
35/M 51/M
41/M 59/M
1 2
3 4 5
6
7
8
9
10 11
12 13
healthy depression, high blood pressure healthy multiple sclerosis, pain on the left side
depression, neck/back pain healthy
migraine, facial pain, high blood pressure
depression, hand injury depression, rheumatoid arthritis depression depression, headache depression, rheumatoid arthritis depression, personality disorder, high blood pressure
Major illnesses
no medications P, C
no medications C, S
no medications
P, C, D, S
P, C, S
S
C, D no medications P, C, D, S
C, D P, C, D
arachnoidea cyst signal changes in the white matter
venous angioma normal
mild leucoaraiosis, minor infarction mild ischemic degeneration, lacunar infarction mild leucoaraiosis normal
normal mild leucoaraiosis normal normal mild atrophy
Head 3 D MRI
no mild, hf
mild R severe
mild, hf
mild, hf
mild, hf
moderate
no mild, hf mild, hf
mild, hf mild, hf
Hearing loss
normal 6/16
21/18 75/4
13/9
14/18
20/24
58/63
0/1 18/24 19/25
20/11 21/25
PTA (500–4000 Hz) R/L
3 6
several 4
10
2
20
several
1 3 10
1.5 3.5
Duration of tinnitus (years)
BIL BIL
BIL R
BIL
high high
high and low high high
low
L⬎R
medium
R⬎L
high
high high medium
R⬎L L⬎R BIL
BIL
medium high
Pitch of tinnitus
BIL BIL
Location of tinnitus
5 8
8 6
5
7
10
9.5
9.5 5 6
6.5 6.5
Tinnitus intensity (NRS 0–10)
3 8
8 6
6
7
10
9
7 5 6
8 8
Tinnitus annoyance (NRS 0–10)
M ⫽ male, F ⫽ female, PTA (500–4000 Hz) ⫽ pure tone average of 500–4000 Hz (the exact values were not available for patient 12, but in patient files the hearing test was described as normal); BIL ⫽ bilateral, R ⫽ right, L ⫽ left, hf ⫽ high frequency, NRS ⫽ numeric rating scale
Age/sex
Patient
Medication: P ⫽ pain, C ⫽ central nervous, D ⫽ anti-depressant, S ⫽ somatic
Table 1. Patient demographics and tinnitus characteristics at the baseline before the rTMS treatment.
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4 H. Sahlsten et al.
49
30
25
52
41
57 35 46
36
44 36 50
2
3
4
5
6
7 8 9
10
11 12 13
12 5 9
10
8 15 10
13
4
3
4
4
10
Number of sessions
2000 3000 2000, 2500, 30007
2000
3000 2000 2000
1800
1800
1800
1800
24000 15000 25500
20000
24000 30000 20000
23400
7200
5400
7200
7200
22800
1800, 30001
1800
Total amount of pulses/ patient
Pulses/ session
Intensity of stimulation (%) 110 110 110 110 110 90–100 90–100 90–110 90–100 100 100 100 100
Location of stimulation* STG sin ↑2 STG sin ↑ STG sin ↓↑3 STG sin ↑ STG sin ↑ STG sin ↑4 STG sin ↑ STG sin ↑ STG sin ↑ STG sin ↑5 STG sin ↑6 STG sin ↑ STG sin ↑8 80–116 74–84 80–103
58–82
78–110 50–75 59–91
62–83
70–110
45–57
58–91
97–124
66–84
E-field (V/m)
⫺ 17 ⫺ 50 ⫺ 63
⫺ 38
⫺ 13 0 ⫺ 80 ⫺ 63
⫺ 20 ⫺ 43 ⫺ 67
⫺ 11
⫺ 33
⫺ 20 ⫺ 43 ⫺ 60
⫺ 26
⫺ 33
⫺ 100
⫺ 29
⫺ 37 ⫺ 40
⫺ 38
⫺ 75
Change (%) in tinnitus annoyance
⫺ 23
⫺ 69
Change (%) in tinnitus intensity
0 ⫹2 ⫹2
-
0 ⫹1 ⫹2
⫹1
⫹1
⫹2
⫹1
⫹2
⫹2
GIC
slightly lower and milder slightly lower milder lower
slightly milder higher and milder higher and milder
lower and milder
diverse into lower tunes/disappear milder
creakier
softer
lower
Change in tinnitus quality
moved to the right moved slightly to the right no change no change moved slightly to the right moved slightly to the right no change no change no change
moved to the right moved to the right moved more to the right centralized
Change in tinnitus location
4, still annoying 6, less than before 6, less than before
9, still annoying
3, still annoying 2, still annoying no data
3, still annoying
15, still annoying
6, have returned
7, still annoying
10, increased
2, less than before
Symptoms at follow-up (months)
RMT ⫽ resting motor threshold, STG ⫽ superior temporal gyrus, E-field ⫽ induced electric field during the sessions in volts per metre, GIC ⫽ global impression of change, scale ⫺ 3 to ⫹ 3 (for patient number 10, the data was missing) *The arrow indicates the direction of the active E-field on the superior temporal gyrus (STG). ¹During the last four sessions, the number of pulses was 3000. ²Once treatment was given on the right STG. During two sessions, a combined treatment attempt on the left dorsolateral prefrontal cortex (DLPF) for depression (10 Hz, 100% RMT, 1000 pulses). ³During the first session, the active E-field arrow pointed downward and caused slight hypomanic symptoms. 4During the last eight sessions, the stimulation of the right DLPF for depression (10 Hz, 90% RMT, 1800 pulses) was combined in the treatment. 5During sessions 7, 8, 9 and 10 the treatment was applied both on the right and left side. 6In every session, the stimulation of the left DLPF for depression (10 Hz, 90% RMT, 3000 pulses) was combined in the treatment. 7During the first session 2000 pulses were given, otherwise 3000 pulses, except once 2500 pulses. 8In every session, the stimulation of the right primary motor cortex (M1) hand representation area for pain (10 Hz, 90% RMT, 1500–2000 pulses) was combined in the treatment.
35
1
Patient
RMT (%)
Table 2. The rTMS stimulation protocols and results at the end of the serial treatment.
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E-field navigated TMS for tinnitus 5
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with whom we mainly tested the hypothesis of tonotopical targeting, received shorter serial treatments, whereas towards the end of the study period, the patients received longer series from 8 to 15 repeated sessions that are currently acknowledged to be more efficient in clinical practice. The rTMS sessions were given on consecutive days apart from weekends. Each rTMS stimulation session consisted of 1800–3000 pulses at 1 Hz given to the left superior temporal gyrus (STG) at 90–110% of RMT. Left side was chosen based on previous literature mostly indicating that stimulation of the left auditory area is efficient irrespective of the tinnitus location (Burger et al, 2011; Lehner et al, 2012), although there exists some contradictory evidence as well (Kim et al, 2014). In one patient, the right STG was additionally treated during the last three sessions because of prominent lateralization of the originally bilateral tinnitus during the treatment. On clinical grounds, four patients received combination treatments: three patients to the dorsolateral prefrontal cortex for depression, and one to the primary motor cortex because of neuropathic pain. The intensity was lowered from 110/100% to 90% in four patients due to annoying contractions in facial muscles with higher intensities. Patients used ear plugs during the rTMS treatment. The induced E-field was directed upwards orthogonally against the edge of the STG, with the centre of the “hotspot” on the gyrus and the red active arrow (i.e. the direction of the induced E-field) pointing upwards (except for one patient during the first session when the arrow was pointing downwards), see Figure 1 (b). The induced and mathematically estimated E-field on the brain cortex varied between 45–124 V/m between the patients and the sessions. As the different pitches are tonotopically represented within the auditory cortex: high tones are represented on the more posterior and lower tones anterior parts (Purves et al, 2004; also Figure 1, a); we hypothesized that targeting rTMS treatment to the representation area roughly corresponding to the perceived tinnitus pitch would more specifically inhibit the cortical hyperexcitability, and alleviate the tinnitus more efficiently. Thus, we targeted the more posterior regions of the auditory cortex when the tinnitus was high pitch (the more posterior point in Figure 1, b), and when the pitch lowered during the treatment, we gradually moved forwards by 0.5–1 cm steps to the more anterior target points (as shown in Figure 1, b). Consequently, there were several stimulation targets on the STG: the most anterior one was situated close to the posterior end of the central sulcus (for lower pitch tinnitus) and the most posterior one was situated 2–3 cm backwards (for very high pitch tinnitus). Table 2 shows the exact treatment protocols and locations used in each patient.
Statistical analysis The descriptive statistics for intensity and annoyance values are presented as mean and standard deviations (SD). Intensity and annoyance were found to be normally distributed when tested with the Shapiro-Wilk test, and by visual evaluation for each time point separately. A hierarchical linear mixed-model with a compound symmetry covariance matrix was conducted. This repeated measures analysis of variance method evaluated whether a change in the patients’ selfreported ratings for intensity and annoyance of tinnitus occurred during the consecutive treatment days. In the model, only a timeeffect describing within subject change was used, no other factors were included because of the small sample size. In addition, paired t-tests were done to evaluate the change in the perceived tinnitus
intensity and annoyance at the baseline before rTMS and at the end of the serial treatment. Fisher’s exact test was used to evaluate the influence of co-morbid conditions (depression, hearing loss, chronic pain) to the treatment efficacy. Spearman correlations were studied between tinnitus intensity, tinnitus annoyance, GIC score, and total number of rTMS pulses, patient age, and duration of symptoms. All analyses were performed as two-tailed and with a significance level set at 0.05. Analyses were performed using IBM SPSS statistics, version 22 (SPSS Inc., Chicago, USA) and SAS System, version 9.3 for Windows (SAS Institute Inc., Cary, USA).
Results The mean intensity of tinnitus decreased during the rTMS treatment (F (5,59) ⫽ 10.13, p ⬍ 0.0001). The mean intensity at the baseline was 7.1 (SD 1.8) and it decreased to 4.5 (SD 2.2) after the treatment (p ⬍ 0.0001). The tinnitus intensity decreased on average 39% (95% interval of confidence from ⫺ 53% to ⫺ 25%). Similarly, the annoyance caused by tinnitus decreased during the treatment (F (5,59) ⫽ 8.19, p ⬍ 0.0001). The mean annoyance caused by tinnitus in daily life was 7.0 (SD 1.8) at the baseline and 4.0 (SD 2.4) after the treatment series (p ⬍ 0.0001). The annoyance of tinnitus decreased on average 45% (95% interval of confidence from ⫺ 60% to ⫺ 29%). At least a 30% reduction in tinnitus intensity occurred in 8/13 (62%) patients and in annoyance in 9/13 (69%) patients. See Table 2 for the total amount of rTMS pulses per patient, individual decreases (%) in tinnitus intensity and annoyance, other qualitative changes in tinnitus and the long-term effects. The values of tinnitus intensity and annoyance in each individual patient before the rTMS treatment, after the first four rTMS sessions, and at the end of the treatment are shown in Figure 2. The mixed model estimated means are additionally shown in Figure 2 as thicker red lines. The patients rated their tinnitus in the evening after the treatment (tinnitus diary), but in some patients (numbers 2, 4, 5 and 6) one or two of the evening values were missing and therefore, the NRS values immediately after the rTMS session were used instead. Figure 2 shows that the mean tinnitus intensity and annoyance decreased starting immediately after the first rTMS session, and thereafter the decrease was continuous and rather linear. Figure 3 shows the rather uniform decreasing trend of individual assessments of tinnitus intensity and annoyance from the baseline to the end of the serial treatments. In addition to intensity and annoyance, rTMS treatment influenced the location and the pitch of tinnitus. Seven out of thirteen patients noted that their bilateral tinnitus had lateralized to the right after the rTMS series given to the left STG (Table 2). In addition, 10/13 patients reported that their tinnitus sound had transformed. This transformation varied among the patients; the tinnitus altered into lower, softer, or sharper sounds, or broke down into different spectral components with lower intensity. According to the GIC scale (patients’ own estimates of the treatment efficacy at the end of the treatment), 10/13 (77%) patients felt they had benefitted from the treatment: six patients reported GIC ⫹ 2, and four patients reported GIC ⫹ 1. Two patients felt they had not benefitted of the treatment (GIC 0), although they had a slight reduction in tinnitus intensity or annoyance according to NRS ratings. For one patient, the GIC was missing, but he also had a mild reduction in tinnitus intensity and a significant (⬎ 30%) reduction in tinnitus annoyance according to NRS ratings (see Table 2 for details).
E-field navigated TMS for tinnitus
(a)
10
Patient 1
9
Patient 2
7
Patient 3
Tinnitus intensity in NRS (0-10)
8 7
Patient 4 7,1
Patient 5 Patient 6
6
5,7
5,5
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Figure 2. The effect of rTMS on patient’s self-rated tinnitus intensity (a, upper graph) and annoyance (b, lower graph) as the score on the eleven-point numeric rating scale (0–10) at the baseline, after the first four rTMS sessions, and at the end of the whole rTMS treatment. The mean intensity of tinnitus (F (5,59) ⫽ 10.13, p ⬍ 0.0001) and the annoyance caused by tinnitus decreased during the treatment (F (5,59) ⫽ 8.19, p ⬍ 0.0001). The estimated mean values from the repeated measures ANOVA statistical model are shown as a thick red line (standard error of mean for intensity was 0.61 and 0.64 for annoyance).
The duration of the tinnitus, the age or sex of the patients, and the total number of TMS pulses given were not significantly associated with the efficacy of the rTMS treatment. Furthermore, co-morbidities (depression, chronic pain, hearing deficit) did not seem to influence the rTMS treatment results. Short-term follow-up information was received from five patients, and they reported that the full effect of the treatment had lasted from two days to up to six days. Long-term effects were collected from the patient archives as available. After a few months, 12 patients still had tinnitus: among those, one patient reported more intense tinnitus symptoms, and three patients
felt the tinnitus was less severe than before the treatment. No long-term data was available for one patient (see Table 2 for individual details). There were no major side effects, such as epileptic seizures, but mild side effects were encountered in 4/13 patients. Three patients suffered from painful facial muscle contractions during the stimulation and their stimulation intensity was therefore lowered from 110–100% to 90% of RMT, after which they were able to continue the treatment. There was only one drop-out; one patient noticed that her migraine got worse during rTMS treatment and she stopped the treatment after eight sessions.
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Figure 3. The effect of rTMS on each patient’s self-rated tinnitus intensity (a, upper graph) and annoyance (b, lower graph) in NRS scores at the baseline and after the serial rTMS treatment. The mean intensity of tinnitus decreased from 7.1 (SD 1.8) before the start of the rTMS treatment to 4.5 (SD 2.2) after the serial rTMS treatment (p ⬍ 0.0001). The tinnitus intensity decreased on average by 39% (95% interval of confidence from ⫺ 53% to ⫺ 25%). The mean value of annoyance in daily life caused by tinnitus was 7.0 (SD 1.8) at the baseline and 4.0 (SD 2.4) after the treatment series (p ⬍ 0.0001). The annoyance of tinnitus decreased on average 45% (95% interval of confidence from ⫺ 60% to ⫺ 29 %).
Clinical vignette
Discussion
Patient number 13 in Tables 1 and 2 was a 59-year old man who suffered from multiple sclerosis, left spastic hemiparesis, and central neuropathic pain (face, upper and lower extremities on the left side). He had suffered from bilateral high pitch tinnitus and high frequency sensorineural hearing deficit for six years. All were chronic, severe, disabling, and treatment resistant conditions. See Table 2 for rTMS treatment protocol. The patient rated his tinnitus intensity 8, annoyance 8, and pain intensity 9, interference 8 by NRS (0–10) before the treatment. After the first week of the treatment (five sessions) the tinnitus intensity and annoyance had decreased to 4 and 4, and the pain had vanished (NRS 0), also his spasticity was better. After the serial treatment (nine sessions) he rated his tinnitus as 3 and 3 and his global impression of change was ⫹ 2. In addition, his pain and spasticity were absent and he had been able to leave out neuropathic pain and muscle-relaxing medications. He also experienced a significant improvement in sleep. After six months he still felt better than before the treatment. At this time, he rated his tinnitus intensity as 6/10 on NRS scale and annoyance as 5/10. His pain intensity (NRS 3) and spasticity (NRS 1) were still almost absent and he was able to continue without medications.
The results of this small open pilot study imply that it may be possible to reduce patients’ tinnitus symptoms with E-field navigated rTMS. However, the effects are temporary, especially with shorter treatment series. There are many studies on rTMS for tinnitus with rather modest clinical effects and very variable rTMS protocols (Kleinjung et al, 2005; Rossi et al, 2007; Anders et al, 2010; Marcondes et al, 2010; Piccirillo et al, 2011, 2013). As most of the randomized controlled trials so far carry methodological limitations, currently only level C recommendation has been given for the use of rTMS in tinnitus patients (Lefaucheur et al, 2014). To our knowledge, this is the first study that has used an E-field navigated TMS device for tinnitus treatment, aiming for more accurate anatomical and tonotopical targeting at the auditory cortex with rTMS. These preliminary results suggest that individually tailored targeting of the treatment might, in fact, improve efficacy of rTMS treatment, but properly controlled comparative studies in larger patient groups are surely needed to confirm these promising preliminary observations. The preliminary therapeutic impact of rTMS in this open pilot study seems to be somewhat larger than in previous studies using rTMS for tinnitus. Rossi et al (2007) conducted a study using rTMS
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E-field navigated TMS for tinnitus targeted both navigated and according to the 10–20 international EEG system, and found at least 25 % improvement of tinnitus intensity in 8/14 patients. Mennemeier et al (2011) carried out a study with positron emission tomography (PET) navigated rTMS on the temporal cortex, and found 43% of the patients to be responders, experiencing at least a 33% drop in tinnitus loudness. These two studies were randomized and placebo controlled, and that may partly explain the difference in the therapeutic impact compared to our open pilot study, where placebo effect is presumably considerable. However, it is also possible that E-field navigation, allowing precise control of the stimulus target on the centre of the STG, with the induced electric field vector at optimal orthogonal angle against the edge of the gyrus, partly improved the effects observed in this methodological pilot study. These potential benefits remain to be verified in future randomized controlled trials. The rTMS frequency, number of given pulses, number of sessions, stimulation intensity (% RMT), and stimulation target were predominantly equal to those in the previous studies (Rossi et al, 2007; Khedr et al, 2008; Anders et al, 2010; Marcondes et al, 2010; Piccirillo et al 2011), but some of our patients had only a few stimulation sessions (the number of sessions per patient varied from 3 to 15). It is worth noting though, that even a short treatment series could induce remarkable shortterm effects in our very severe and chronic tinnitus patients with psychiatric co-morbidity. Based on the GIC scale alone, 77% of the patients benefitted from the treatment, which is more than in most previous studies. The small number of patients and the lack of placebo control may partly explain this finding. Two patients reported GIC 0; despite slight reduction of tinnitus intensity and annoyance (20%) in one of them. The discrepancies between subjective appraisal of benefit and NRS scores underline the need for multimodal assessment of rTMS treatment results as different outcome measures elucidate distinct aspects of possible therapeutic effects. Most of the patients felt the effect of the rTMS treatment for several days after the end of the treatment, but the long-term effects were not systemically followed in this open methodological pilot study. After six months, two patients reported by e-mail or phone that they still had less severe tinnitus than before and were satisfied with their present situation. At six months, our clinical vignette (patient 13) still had 25% reduction in tinnitus intensity and 38% reduction in tinnitus annoyance. His central neuropathic pain was also still reduced 67% compared to baseline, supporting the level A recommendation for the use of rTMS treatment in neuropathic pain (Lefaucheur et al, 2014). This patient illustrates the feasibility of rTMS treatment in tinnitus patients with co-morbidities, as several different disorders can be treated during the same session with rTMS. In the studies of Plewnia et al (2007) and Rossi et al (2007), the effect of rTMS lasted up to two weeks, but there are reports in the literature of lasting therapeutic effects for up to six months after longer serial treatments (5–10 sessions of rTMS) (Kleinjung et al, 2005; Marcondes et al, 2010), or even longer lasting effects (Burger et al, 2011). It has been suggested that long duration of tinnitus (De Ridder et al, 2005; Khedr et al, 2008), hearing loss (Kleinjung et al, 2007), and patient’s old age may decrease the efficacy of rTMS treatment (Langguth et al, 2008): it seems that rTMS is more effective in younger patients and in patients with shorter tinnitus duration. On the other hand, Lehner et al (2012) stated in their study that there are no good demographic or clinical predictors for the treatment outcome. In this small pilot study with no standardized examination protocol, it is not possible to evaluate the potential effects of those
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parameters properly, but no significant associations were found in this group. It is worth noting though, that our patients represented the most severe edge of tinnitus symptomatology with rather severe co-morbid psychiatric problems (among them, one suicide attempt), and even senior citizens who benefitted from the treatment. There are several limitations in this open methodological pilot study evaluating the best targets and stimulation protocols for precise E-field navigated rTMS in tinnitus patients. This was not a randomized or placebo-controlled trial and the number of patients was small, which makes the results only preliminarily promising. It is notable, as stated earlier, that rTMS was no more effective than sham stimulation in some recent studies (Piccirillo et al, 2013; Hoekstra et al, 2013; Langguth et al, 2014). With an open design, the true effects are always superimposed on placebo effect, which probably contributes to the present, rather promising results with E-field navigation as well. In addition, patients’ diagnoses were heterogeneous: 11/13 patients had hearing loss, 8/13 patients had co-morbid depression, and 8/13 patients used prescription medicines affecting the central nervous system. However, this patient group may well represent clinically relevant patients with severe intractable chronic tinnitus who would really need new treatment options. The E-field navigated rTMS device proved to be practical. The main advantage was that it showed in real time the exact “hot spot” on the patient’s 3D MRI image as well as the direction of the electric field induced at that spot, and all this information could be followed online during the treatment and saved on the computer. It was easy to keep the protocol constant or alter it, for example by changing the stimulation spot according to the alterations in tinnitus sound and the known tonotopy of the auditory cortex. There are still many questions to be answered considering the treatment of tinnitus with rTMS. Stimulation can be targeted with an accuracy of a few millimetres (Schönfeldt-Lecuona et al, 2005; Picht et al, 2011), but the optimal location and side for the stimulation still remain uncertain (Langguth et al, 2010). In a recent study, daily treatment with 1-Hz rTMS at the temporoparietal junction either ipsilaterally or contralaterally to the side of the tinnitus had significant beneficial effects irrespective of the laterality of stimulation (Kim et al, 2014). Additional studies should be performed to evaluate the optimal locations and protocols for the stimulation. Lee et al (2013) showed by positron emission tomography in healthy subjects that 1-Hz rTMS of the temporal cortex causes not only focal alteration, but also cortico-cortical modulation with widespread functional changes in brain networks via long-range neural connections. In addition, more information is needed to define the role of stimulation of multiple cortical targets, including non-auditory areas, on the efficacy of rTMS in tinnitus (Lehner et al, 2013; Park et al, 2013), as well as the protocols for possible maintenance therapy with rTMS. In general, the rTMS treatment results are characterized by high inter-individual variability (Langguth et al, 2008). In the literature it has been implied that the val/met polymorphism of the brain derived neurotrophic factor (BDNF) gene may cause individual differences in the effect of rTMS by altering the synaptic plasticity (Hoogendam et al, 2010). Just recently it has been discovered that variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation (Jääskeläinen et al, 2014). Further studies are thus needed to investigate the role of genotype variation on the individual therapeutic effects of rTMS. The results of this open methodological pilot study are encouraging and possibly somewhat better than in previous studies considering that the patients in this study had very severe, intractable, chronic tinnitus and other complex co-morbidities. Hence, randomized and
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placebo-controlled studies with adequate sample sizes should be performed to investigate the impact of E-field navigation on improving the efficacy of rTMS in tinnitus patients.
Acknowledgements This study was supported by Finnish governmental University Hospital grants (EVO). We thank Mrs. Elizabeth Nyman for checking the language of this article and Mr. Sami Sahlsten for IT assistance. Declaration of interest: The authors report no conflicts of interest.
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Electric field navigated transcranial magnetic stimulation for chronic tinnitus: A pilot study a
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Hanna Sahlsten , Johan Isohanni , Jorma Haapaniemi , Jaakko Salonen , Janika Paavola , e
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Eliisa Löyttyniemi , Reijo Johansson & Satu K. Jääskeläinen a
Department of Ear, Nose and Throat, Satakunta Central Hospital, Pori, Finland
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Medical School, University of Turku, Turku, Finland
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Department of Ear, Nose and Throat, Turku University Hospital, Turku, Finland
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Department of Clinical Neurophysiology, Turku University Hospital and University of Turku, Turku, Finland e
Department of Biostatistics, University of Turku, Turku, Finland Published online: 18 Jun 2015.
To cite this article: Hanna Sahlsten, Johan Isohanni, Jorma Haapaniemi, Jaakko Salonen, Janika Paavola, Eliisa Löyttyniemi, Reijo Johansson & Satu K. Jääskeläinen (2015): Electric field navigated transcranial magnetic stimulation for chronic tinnitus: A pilot study, International Journal of Audiology To link to this article: http://dx.doi.org/10.3109/14992027.2015.1054041
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International Journal of Audiology 2015; Early Online: 1–11
Original Article
Electric field navigated transcranial magnetic stimulation for chronic tinnitus: A pilot study
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Hanna Sahlsten*, Johan Isohanni†, Jorma Haapaniemi‡, Jaakko Salonen‡, Janika Paavola#, Eliisa Löyttyniemi$, Reijo Johansson‡ & Satu K. Jääskeläinen# *Department of Ear, Nose and Throat, Satakunta Central Hospital, Pori, Finland, †Medical School, University of Turku, Turku, Finland, ‡Department of Ear, Nose and Throat, Turku University Hospital, Turku, Finland, #Department of Clinical Neurophysiology, Turku University Hospital and University of Turku, Turku, Finland and $Department of Biostatistics, University of Turku, Turku, Finland
Abstract Objective: Repetitive transcranial magnetic stimulation (rTMS) has shown potential in reducing tinnitus symptoms. We evaluated effects of electric field (E-field) navigated rTMS targeted neuroanatomically according to tinnitus pitch. Design: In this open methodological pilot study, the patients received E-field navigated 1-Hz rTMS in daily treatment sessions to the left superior temporal gyrus, targeted according to tonotopic representation of their individual tinnitus pitch. Patients rated their tinnitus intensity and annoyance with a numeric rating scale (NRS) from 0 to 10 at the baseline and after each rTMS session. They also rated their global impression of change (scale ⫺ 3 to ⫹ 3) after the treatment. Study sample: Thirteen patients (mean age 53 years; 10 men, 3 women) with chronic, intractable tinnitus. Results: The mean intensity was 7.1 (SD 1.8) at the baseline, decreasing to 4.5 (SD 2.2) after the rTMS (p ⬍ 0.0001). The mean annoyance 7.0 (SD 1.8) at the baseline decreased to 4.0 (SD 2.4) after the treatment (p ⬍ 0.0001). Intensity diminished at least 30% in 8/13 patients and annoyance in 9/13 patients. A total of 10/13 patients felt subjective benefit from the treatment. Conclusions: These preliminary observations suggest that E-field-rTMS may improve the current treatment options for intractable tinnitus.
Key Words: Tinnitus; electric field navigated; transcranial magnetic stimulation Tinnitus is defined as a perception of sound in the absence of external stimuli. It affects approximately 10–15% of the population, and approximately 80% of tinnitus patients do not require clinical intervention (Henry et al, 2005). However, some people suffer from disabling tinnitus causing insomnia, anxiety, and distress in daily life. Severe tinnitus can even lead to suicide, especially when combined with depression (Dobie, 2003). No curative therapy for tinnitus exists, and the current treatment strategies aim at improving the patient’s ability to cope with the symptoms. Psychological therapies, such as counseling, cognitive behavioral therapy, and tinnitus retraining therapy may diminish tinnitus distress or improve the quality of life (Phillips & McFerran, 2010). Some patients may benefit from masking devices (Hobson et al, 2012), or hearing aids if there is a significant hearing impairment (Del Bo & Ambrosetti, 2007). No current drug treatment has been shown to cure tinnitus, but antidepressive medications such as tricyclic antidepressants and serotonin reuptake inhibitors may alleviate suffering from tinnitus, at least in patients with depression. There is not yet sufficient evidence that antidepressant drug therapy aids in improving tinnitus (Baldo et al, 2012). The exact mechanism underlying tinnitus is still unknown, although various hypotheses explain the development and
aggravation of tinnitus (Seidman et al, 2010). Tinnitus is thought to be a perception caused by abnormal hyperactivity generated within the auditory cortex and auditory brainstem nuclei as a result of cortical deafferentation and functional reorganization following damage to the cochlea (Henry et al, 2014). In addition, abnormal activity in non-auditory areas such as the frontal lobes, the limbic system, and the cerebellum has been found in neuroimaging studies on tinnitus patients (Leaver et al, 2011). Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique based on the electromagnetic induction of an electric field in the brain by means of magnetic pulses given to the scalp. When TMS pulses are applied repetitively (rTMS), they can modulate cortical excitability, by increasing or decreasing it via long-term potentiation (LTP) or long-term depression (LTD) like effects (Siebner et al, 2003). TMS pulses given at low frequencies (ⱕ 1 Hz) decrease cortical excitability. This forms the basis for using low frequency rTMS to treat chronic tinnitus patients whose auditory cortex is hyperactive (Plewnia et al, 2007). During the past decade, rTMS has been successfully and safely used for the treatment of various clinical entities including chronic neuropathic pain and major depression (Rossi et al, 2009; Lefaucheur et al, 2014). There are several studies on the treatment of
Correspondence: Hanna Sahlsten, Satakunnan keskussairaala, Korvatautien poliklinikka, Sairaalantie 3, 28500 Pori, Finland. E-mail: [email protected] (Received 15 December 2014 ; accepted 18 May 2015) ISSN 1499-2027 print/ISSN 1708-8186 online © 2015 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society DOI: 10.3109/14992027.2015.1054041
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Abbreviations
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cMAP DLPF E-field GIC MEP MRI NRS PTA RMT rTMS STG V/m
Compound muscle action potential Dorsolateral prefrontal cortex Electric field Global impression of change Motor evoked potential Magnetic resonance image Numeric rating scale Pure tone average Resting motor threshold Repetitive transcranial magnetic stimulation Superior temporal gyrus Volts per metre (E-field strength)
tinnitus with rTMS, with so far rather modest effect sizes in 20 original placebo-controlled studies with at least 10 tinnitus patients (Lefaucheur et al, 2014). The effects of rTMS treatment seem to vary widely between patients (Langguth et al, 2008), and tinnitus reduction after rTMS is usually partial and temporary, but may last for up to six months. Repeated sessions of low-frequency rTMS to the temporoparietal cortex have been investigated as a treatment for tinnitus with promising, yet moderate effects (Rossi et al, 2007; Plewnia et al, 2007; Khedr et al, 2008; Anders et al, 2010; Marcondes et al, 2010; Mennemeier et al, 2011; Zhe et al, 2012). However, in some studies, rTMS was no more effective than sham stimulation (Piccirillo et al, 2013; Hoekstra et al, 2013; Langguth et al, 2014). Based on the current evidence, a group of European experts recently justified a Level C recommendation (“possible efficacy”) for the use of rTMS for tinnitus (Lefaucheur et al, 2014). However, most of the previous studies have not applied navigated TMS, and there are no studies utilizing real time electric field (E-field) navigation for anatomically precise targeting of rTMS treatment. Moreover, the treatment targets and stimulation protocols have varied widely between the studies (Theodoroff et al, 2013; Lefaucheur et al, 2014). The goal of this open methodological pilot study was to evaluate the feasibility and effects of precise E-field navigation according to individual neuroanatomy and tinnitus pitch reflected in the tonotopy of the auditory cortex (see Figure 1 (a), and Purves et al, 2004) in patients with long history of severe, intractable, and disabling tinnitus. In addition, the influence of several factors related to stimulation protocol on the treatment results was evaluated.
Materials and Methods Patients The study was performed according to the Declaration of Helsinki. Information concerning the trial was given to all patients, and they all gave their informed spoken consent; attending was completely voluntary and the patients were free to discontinue the treatment at anytime. Inclusion criterion was severe (intensity at least 5/10 on the NRS scale), chronic (duration at least one year), otherwise intractable, and disabling tinnitus that severely interfered with daily life activities. Exclusion criteria were epilepsy and any contraindication, like metallic intracorporeal appliances, to MR imaging. Previous tinnitus treatments included repeated counseling with ENT-specialist and psychologist or psychiatrist, medication trials with anti-depressants and betahistine, but these had not been successful. Consecutive patients fulfilling the criteria and willing to participate in this open methodological pilot study were recruited from the Ear, Nose and Throat
(ENT) department of the Turku University Hospital during a period from autumn 2011 to spring 2013. Only one patient had to be rejected from the pilot study due to previous brain tumor surgery. This study took place at the department of clinical neurophysiology and was undertaken to serve as a pilot for a prospective randomized controlled trial on navigated therapeutic rTMS for chronic tinnitus. Thirteen patients (three women, ten men) aged 30–73 years (mean age 53 years) participated in the study. Eight of the thirteen patients had bilateral tinnitus and the remaining five patients had more lateralized tinnitus. Only two patients had normal hearing, and the other patients had variable sensorineural hearing deficit, predominantly in the high frequency range. Eight patients suffered from depression and eight patients used prescription medication affecting the central nervous system (Table 1). None of the patients had previously been treated with rTMS. Table 1 shows the demographic data, tinnitus and hearing characteristics, medications, and head MRI findings.
Evaluation scales All the patients suffered from intractable tinnitus, but the actual tinnitus intensity and annoyance varied among the patients. A numeric rating scale (NRS) from 0 to 10 was used to evaluate the severity of the tinnitus. Zero (0) represented the situation with no tinnitus or no annoyance and ten (10) was the worst possible tinnitus intensity or annoyance the patients could imagine. If a patient declared two numbers, for example 6–7, the value was registered as 6.5. NRS was obtained before the start of the treatment: the patients were asked to give a value for the average tinnitus intensity and annoyance level for the previous week. In addition, the patients evaluated tinnitus intensity and annoyance immediately before and after each rTMS session, in the evening and the following morning after the session (tinnitus diary). As there were missing values in the symptom diaries, the mean NRS values at baseline before the start of the treatment series, and daily assessments after the first four (three in one patient) treatment sessions (immediately or in the evening of the treatment day), as well as at the end of the whole treatment series right after the last rTMS session were chosen for statistical analyses, as they were available for the patients. A reduction of 30% or more on a NRS value was considered to be a clinically significant change, as it is a commonly used cut-off point also in more recent randomized controlled trials on pain treatment (Dworkin et al, 2008). In addition, other possible effects, like lateralization of tinnitus, changes in tinnitus frequency or quality, and possible side-effects were registered. The global impression of change scale (GIC scale ⫺ 3 to ⫹ 3, in which ⫺ 3 means very much worse than before the treatment and ⫹ 3 very much better than before the treatment and 0 is no change) was used after the serial rTMS treatment to define the subjective benefit of the treatment. One patient had difficulties in self-rating the tinnitus intensity and annoyance in the evening and the following morning. One patient was not able to evaluate tinnitus immediately after the treatment because the tinnitus was not discernible due to the sound generated by the TMS device. The tinnitus intensity may fluctuate during the day, and this may have caused some additional variability in this small group of patients. After this prospective trial, the data on long-term effects was collected retrospectively through the electronic patient archives as they were available.
rTMS First, all patients underwent a 3-tesla magnetic resonance image (MRI) of the head for a three dimensional reconstruction of the head for the navigated TMS system before the treatment.
E-field navigated TMS for tinnitus
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The TMS equipment was an electric field (E-field) navigated NBS System 4.0 (manufactured by Nexstim Ltd, Helsinki, Finland). It uses an infrared camera tracking unit together with specific head-trackers and a digitizing pen to mark anatomical landmarks on the patient’s head. This allows the matching of the MRI image based head model to the external anatomical landmarks on the patient’s head. In addition, the NBS System uses a spherical model to mathematically estimate induced electric field within the brain. Together with the known coil location (via infrared tracking) and electric parameters, the NBS system is capable of visualizing the induced E-field in real time during stimulation and estimating the strength of the E-field in Volts per metre at the stimulation target. The E-field and its “hot spot” (the site of maximal electric field strength) are shown on the peeled MRI head image on the computer screen allowing the user to control the cortical target and the direction of the electric current vector during stimulation (Figure 1, b). This “hot spot” has been shown to have an anatomical accuracy of a few millimetres, corresponding to the accuracy of direct intraoperative cortical electric stimulation (Picht et al, 2011). A figure-of-eight coil giving biphasic magnetic pulses was used for measuring the resting motor threshold, and for giving the rTMS treatment. During the treatment, the coil was fixed in the correct position by a coil holder and the patient’s head was stabilized on the chair with a neck/head brace. The stability of the positioning was monitored throughout the treatment session in real time from the computer screen by a medical doctor or a nurse specialized in clinical neurophysiology and TMS techniques; if the centre of the induced E-field moved away from the set target more than 3 mm, the stimulation was paused and the coil readjusted. During the first session, the resting motor threshold (RMT) was measured at the right M1 cortex representing the left hand thenar muscles as described earlier (Valmunen et al, 2009). Self-adhesive surface electrodes were used to record the compound muscle action potential (cMAP). The “hot spot” at M1 was located by moving the coil at right angles against the central sulcus until the optimal site and coil orientation producing maximum cMAP was found. The RMT was determined by delivering single TMS pulses at the optimal coil position with automatically up-and-down varying intensities given by the NBS System software used to obtain an estimate of the RMT. RMT is thus defined as the lowest intensity (% of maximum device output) capable of eliciting a small (⬎ 50 μV) cMAP in at least 50% of the trials. The number of stimulation pulses required for the NBS software algorithm to determine the RMT value ranged between 7 and 20. The RMT estimation was done at least two times, and if there was a larger than 2% discrepancy in these two values, a third trial was done. The mean of the measured values was used as the RMT for rTMS treatment. The number of rTMS treatment sessions, the exact location, and the number of pulses were individually tailored for the patients (Table 2). The number of the treatment sessions in this pilot study varied between 3 and 15. The first patients, Figure 1. (a) upper illustration. The exact location of the treatment coil was adjusted according to the known tonotopy of the auditory cortex where higher frequencies are represented posteriorly and lower frequencies anteriorly. The pitch of the tinnitus at the baseline determined the initial target location along the anterior-posterior axis on the superior temporal gyrus (STG). (b) lower illustration. The red arrow in the figure shows the induced electric field vector on the cortical target site at the left STG. The exact stimulation spot (“hot spot”) is at the border of the red and the blue arrows. The brightness of the arrow reflects the optimal tangential position of
the coil. The calculated electric field on the cortex is also shown numerically as V/m (not shown in the figure). It was possible to use several stimulation targets on the STG: the most anterior one was situated close to the posterior end of the sulcus centralis (for lower pitch tinnitus) and the most posterior one was situated 2–3 cm more posteriorly (for high pitch tinnitus). The “hotspot” of stimulation was moved forwards or backwards on the STG during consecutive sessions according to the achieved results (diminution of intensity and changes in the pitch of tinnitus).
49/M 53/M
39/F 30/F 65/M
65/M
73/F
61/M
62/M
35/M 51/M
41/M 59/M
1 2
3 4 5
6
7
8
9
10 11
12 13
healthy depression, high blood pressure healthy multiple sclerosis, pain on the left side
depression, neck/back pain healthy
migraine, facial pain, high blood pressure
depression, hand injury depression, rheumatoid arthritis depression depression, headache depression, rheumatoid arthritis depression, personality disorder, high blood pressure
Major illnesses
no medications P, C
no medications C, S
no medications
P, C, D, S
P, C, S
S
C, D no medications P, C, D, S
C, D P, C, D
arachnoidea cyst signal changes in the white matter
venous angioma normal
mild leucoaraiosis, minor infarction mild ischemic degeneration, lacunar infarction mild leucoaraiosis normal
normal mild leucoaraiosis normal normal mild atrophy
Head 3 D MRI
no mild, hf
mild R severe
mild, hf
mild, hf
mild, hf
moderate
no mild, hf mild, hf
mild, hf mild, hf
Hearing loss
normal 6/16
21/18 75/4
13/9
14/18
20/24
58/63
0/1 18/24 19/25
20/11 21/25
PTA (500–4000 Hz) R/L
3 6
several 4
10
2
20
several
1 3 10
1.5 3.5
Duration of tinnitus (years)
BIL BIL
BIL R
BIL
high high
high and low high high
low
L⬎R
medium
R⬎L
high
high high medium
R⬎L L⬎R BIL
BIL
medium high
Pitch of tinnitus
BIL BIL
Location of tinnitus
5 8
8 6
5
7
10
9.5
9.5 5 6
6.5 6.5
Tinnitus intensity (NRS 0–10)
3 8
8 6
6
7
10
9
7 5 6
8 8
Tinnitus annoyance (NRS 0–10)
M ⫽ male, F ⫽ female, PTA (500–4000 Hz) ⫽ pure tone average of 500–4000 Hz (the exact values were not available for patient 12, but in patient files the hearing test was described as normal); BIL ⫽ bilateral, R ⫽ right, L ⫽ left, hf ⫽ high frequency, NRS ⫽ numeric rating scale
Age/sex
Patient
Medication: P ⫽ pain, C ⫽ central nervous, D ⫽ anti-depressant, S ⫽ somatic
Table 1. Patient demographics and tinnitus characteristics at the baseline before the rTMS treatment.
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4 H. Sahlsten et al.
49
30
25
52
41
57 35 46
36
44 36 50
2
3
4
5
6
7 8 9
10
11 12 13
12 5 9
10
8 15 10
13
4
3
4
4
10
Number of sessions
2000 3000 2000, 2500, 30007
2000
3000 2000 2000
1800
1800
1800
1800
24000 15000 25500
20000
24000 30000 20000
23400
7200
5400
7200
7200
22800
1800, 30001
1800
Total amount of pulses/ patient
Pulses/ session
Intensity of stimulation (%) 110 110 110 110 110 90–100 90–100 90–110 90–100 100 100 100 100
Location of stimulation* STG sin ↑2 STG sin ↑ STG sin ↓↑3 STG sin ↑ STG sin ↑ STG sin ↑4 STG sin ↑ STG sin ↑ STG sin ↑ STG sin ↑5 STG sin ↑6 STG sin ↑ STG sin ↑8 80–116 74–84 80–103
58–82
78–110 50–75 59–91
62–83
70–110
45–57
58–91
97–124
66–84
E-field (V/m)
⫺ 17 ⫺ 50 ⫺ 63
⫺ 38
⫺ 13 0 ⫺ 80 ⫺ 63
⫺ 20 ⫺ 43 ⫺ 67
⫺ 11
⫺ 33
⫺ 20 ⫺ 43 ⫺ 60
⫺ 26
⫺ 33
⫺ 100
⫺ 29
⫺ 37 ⫺ 40
⫺ 38
⫺ 75
Change (%) in tinnitus annoyance
⫺ 23
⫺ 69
Change (%) in tinnitus intensity
0 ⫹2 ⫹2
-
0 ⫹1 ⫹2
⫹1
⫹1
⫹2
⫹1
⫹2
⫹2
GIC
slightly lower and milder slightly lower milder lower
slightly milder higher and milder higher and milder
lower and milder
diverse into lower tunes/disappear milder
creakier
softer
lower
Change in tinnitus quality
moved to the right moved slightly to the right no change no change moved slightly to the right moved slightly to the right no change no change no change
moved to the right moved to the right moved more to the right centralized
Change in tinnitus location
4, still annoying 6, less than before 6, less than before
9, still annoying
3, still annoying 2, still annoying no data
3, still annoying
15, still annoying
6, have returned
7, still annoying
10, increased
2, less than before
Symptoms at follow-up (months)
RMT ⫽ resting motor threshold, STG ⫽ superior temporal gyrus, E-field ⫽ induced electric field during the sessions in volts per metre, GIC ⫽ global impression of change, scale ⫺ 3 to ⫹ 3 (for patient number 10, the data was missing) *The arrow indicates the direction of the active E-field on the superior temporal gyrus (STG). ¹During the last four sessions, the number of pulses was 3000. ²Once treatment was given on the right STG. During two sessions, a combined treatment attempt on the left dorsolateral prefrontal cortex (DLPF) for depression (10 Hz, 100% RMT, 1000 pulses). ³During the first session, the active E-field arrow pointed downward and caused slight hypomanic symptoms. 4During the last eight sessions, the stimulation of the right DLPF for depression (10 Hz, 90% RMT, 1800 pulses) was combined in the treatment. 5During sessions 7, 8, 9 and 10 the treatment was applied both on the right and left side. 6In every session, the stimulation of the left DLPF for depression (10 Hz, 90% RMT, 3000 pulses) was combined in the treatment. 7During the first session 2000 pulses were given, otherwise 3000 pulses, except once 2500 pulses. 8In every session, the stimulation of the right primary motor cortex (M1) hand representation area for pain (10 Hz, 90% RMT, 1500–2000 pulses) was combined in the treatment.
35
1
Patient
RMT (%)
Table 2. The rTMS stimulation protocols and results at the end of the serial treatment.
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E-field navigated TMS for tinnitus 5
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H. Sahlsten et al.
with whom we mainly tested the hypothesis of tonotopical targeting, received shorter serial treatments, whereas towards the end of the study period, the patients received longer series from 8 to 15 repeated sessions that are currently acknowledged to be more efficient in clinical practice. The rTMS sessions were given on consecutive days apart from weekends. Each rTMS stimulation session consisted of 1800–3000 pulses at 1 Hz given to the left superior temporal gyrus (STG) at 90–110% of RMT. Left side was chosen based on previous literature mostly indicating that stimulation of the left auditory area is efficient irrespective of the tinnitus location (Burger et al, 2011; Lehner et al, 2012), although there exists some contradictory evidence as well (Kim et al, 2014). In one patient, the right STG was additionally treated during the last three sessions because of prominent lateralization of the originally bilateral tinnitus during the treatment. On clinical grounds, four patients received combination treatments: three patients to the dorsolateral prefrontal cortex for depression, and one to the primary motor cortex because of neuropathic pain. The intensity was lowered from 110/100% to 90% in four patients due to annoying contractions in facial muscles with higher intensities. Patients used ear plugs during the rTMS treatment. The induced E-field was directed upwards orthogonally against the edge of the STG, with the centre of the “hotspot” on the gyrus and the red active arrow (i.e. the direction of the induced E-field) pointing upwards (except for one patient during the first session when the arrow was pointing downwards), see Figure 1 (b). The induced and mathematically estimated E-field on the brain cortex varied between 45–124 V/m between the patients and the sessions. As the different pitches are tonotopically represented within the auditory cortex: high tones are represented on the more posterior and lower tones anterior parts (Purves et al, 2004; also Figure 1, a); we hypothesized that targeting rTMS treatment to the representation area roughly corresponding to the perceived tinnitus pitch would more specifically inhibit the cortical hyperexcitability, and alleviate the tinnitus more efficiently. Thus, we targeted the more posterior regions of the auditory cortex when the tinnitus was high pitch (the more posterior point in Figure 1, b), and when the pitch lowered during the treatment, we gradually moved forwards by 0.5–1 cm steps to the more anterior target points (as shown in Figure 1, b). Consequently, there were several stimulation targets on the STG: the most anterior one was situated close to the posterior end of the central sulcus (for lower pitch tinnitus) and the most posterior one was situated 2–3 cm backwards (for very high pitch tinnitus). Table 2 shows the exact treatment protocols and locations used in each patient.
Statistical analysis The descriptive statistics for intensity and annoyance values are presented as mean and standard deviations (SD). Intensity and annoyance were found to be normally distributed when tested with the Shapiro-Wilk test, and by visual evaluation for each time point separately. A hierarchical linear mixed-model with a compound symmetry covariance matrix was conducted. This repeated measures analysis of variance method evaluated whether a change in the patients’ selfreported ratings for intensity and annoyance of tinnitus occurred during the consecutive treatment days. In the model, only a timeeffect describing within subject change was used, no other factors were included because of the small sample size. In addition, paired t-tests were done to evaluate the change in the perceived tinnitus
intensity and annoyance at the baseline before rTMS and at the end of the serial treatment. Fisher’s exact test was used to evaluate the influence of co-morbid conditions (depression, hearing loss, chronic pain) to the treatment efficacy. Spearman correlations were studied between tinnitus intensity, tinnitus annoyance, GIC score, and total number of rTMS pulses, patient age, and duration of symptoms. All analyses were performed as two-tailed and with a significance level set at 0.05. Analyses were performed using IBM SPSS statistics, version 22 (SPSS Inc., Chicago, USA) and SAS System, version 9.3 for Windows (SAS Institute Inc., Cary, USA).
Results The mean intensity of tinnitus decreased during the rTMS treatment (F (5,59) ⫽ 10.13, p ⬍ 0.0001). The mean intensity at the baseline was 7.1 (SD 1.8) and it decreased to 4.5 (SD 2.2) after the treatment (p ⬍ 0.0001). The tinnitus intensity decreased on average 39% (95% interval of confidence from ⫺ 53% to ⫺ 25%). Similarly, the annoyance caused by tinnitus decreased during the treatment (F (5,59) ⫽ 8.19, p ⬍ 0.0001). The mean annoyance caused by tinnitus in daily life was 7.0 (SD 1.8) at the baseline and 4.0 (SD 2.4) after the treatment series (p ⬍ 0.0001). The annoyance of tinnitus decreased on average 45% (95% interval of confidence from ⫺ 60% to ⫺ 29%). At least a 30% reduction in tinnitus intensity occurred in 8/13 (62%) patients and in annoyance in 9/13 (69%) patients. See Table 2 for the total amount of rTMS pulses per patient, individual decreases (%) in tinnitus intensity and annoyance, other qualitative changes in tinnitus and the long-term effects. The values of tinnitus intensity and annoyance in each individual patient before the rTMS treatment, after the first four rTMS sessions, and at the end of the treatment are shown in Figure 2. The mixed model estimated means are additionally shown in Figure 2 as thicker red lines. The patients rated their tinnitus in the evening after the treatment (tinnitus diary), but in some patients (numbers 2, 4, 5 and 6) one or two of the evening values were missing and therefore, the NRS values immediately after the rTMS session were used instead. Figure 2 shows that the mean tinnitus intensity and annoyance decreased starting immediately after the first rTMS session, and thereafter the decrease was continuous and rather linear. Figure 3 shows the rather uniform decreasing trend of individual assessments of tinnitus intensity and annoyance from the baseline to the end of the serial treatments. In addition to intensity and annoyance, rTMS treatment influenced the location and the pitch of tinnitus. Seven out of thirteen patients noted that their bilateral tinnitus had lateralized to the right after the rTMS series given to the left STG (Table 2). In addition, 10/13 patients reported that their tinnitus sound had transformed. This transformation varied among the patients; the tinnitus altered into lower, softer, or sharper sounds, or broke down into different spectral components with lower intensity. According to the GIC scale (patients’ own estimates of the treatment efficacy at the end of the treatment), 10/13 (77%) patients felt they had benefitted from the treatment: six patients reported GIC ⫹ 2, and four patients reported GIC ⫹ 1. Two patients felt they had not benefitted of the treatment (GIC 0), although they had a slight reduction in tinnitus intensity or annoyance according to NRS ratings. For one patient, the GIC was missing, but he also had a mild reduction in tinnitus intensity and a significant (⬎ 30%) reduction in tinnitus annoyance according to NRS ratings (see Table 2 for details).
E-field navigated TMS for tinnitus
(a)
10
Patient 1
9
Patient 2
7
Patient 3
Tinnitus intensity in NRS (0-10)
8 7
Patient 4 7,1
Patient 5 Patient 6
6
5,7
5,5
5,2
5
Patient 7 4,7
4,5
4
Patient 9 Patient 10
3
Patient 11
2
Patient 12
1
Patient 13
0
Mean (estimated)
Baseline
After 1. session
After 2. session
After 3. session
After 4. session
End of treatment
Time
(b)
10
Patient 1
9
Patient 2 Patient 3
Tinnitus annoyance in NRS (0-10)
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Patient 8
8 Patient 4
7
7,0
Patient 5 Patient 6
6,1
6
5,4
5
Patient 7
5,4 4,7
4
Patient 8 4,0
Patient 9 Patient 10
3
Patient 11
2
Patient 12
1
Patient 13
0 Baseline
After 1. session
After 2. session
After 3. session
After 4. session
End of treatment
Mean (estimated)
Time
Figure 2. The effect of rTMS on patient’s self-rated tinnitus intensity (a, upper graph) and annoyance (b, lower graph) as the score on the eleven-point numeric rating scale (0–10) at the baseline, after the first four rTMS sessions, and at the end of the whole rTMS treatment. The mean intensity of tinnitus (F (5,59) ⫽ 10.13, p ⬍ 0.0001) and the annoyance caused by tinnitus decreased during the treatment (F (5,59) ⫽ 8.19, p ⬍ 0.0001). The estimated mean values from the repeated measures ANOVA statistical model are shown as a thick red line (standard error of mean for intensity was 0.61 and 0.64 for annoyance).
The duration of the tinnitus, the age or sex of the patients, and the total number of TMS pulses given were not significantly associated with the efficacy of the rTMS treatment. Furthermore, co-morbidities (depression, chronic pain, hearing deficit) did not seem to influence the rTMS treatment results. Short-term follow-up information was received from five patients, and they reported that the full effect of the treatment had lasted from two days to up to six days. Long-term effects were collected from the patient archives as available. After a few months, 12 patients still had tinnitus: among those, one patient reported more intense tinnitus symptoms, and three patients
felt the tinnitus was less severe than before the treatment. No long-term data was available for one patient (see Table 2 for individual details). There were no major side effects, such as epileptic seizures, but mild side effects were encountered in 4/13 patients. Three patients suffered from painful facial muscle contractions during the stimulation and their stimulation intensity was therefore lowered from 110–100% to 90% of RMT, after which they were able to continue the treatment. There was only one drop-out; one patient noticed that her migraine got worse during rTMS treatment and she stopped the treatment after eight sessions.
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H. Sahlsten et al.
Tinnitus intensity in NRS (0-10)
(a)
10
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 13 Mean
9 8 7 6 5 4 3 2 1 0
(b) Tinnitus annoyance in NRS (0-10)
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Intensity at baseline
Intensity after the serial rTMS
10
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 13 Mean
9 8 7 6 5 4 3 2 1 0 Annoyance at baseline
Annoyance after the serial rTMS
Figure 3. The effect of rTMS on each patient’s self-rated tinnitus intensity (a, upper graph) and annoyance (b, lower graph) in NRS scores at the baseline and after the serial rTMS treatment. The mean intensity of tinnitus decreased from 7.1 (SD 1.8) before the start of the rTMS treatment to 4.5 (SD 2.2) after the serial rTMS treatment (p ⬍ 0.0001). The tinnitus intensity decreased on average by 39% (95% interval of confidence from ⫺ 53% to ⫺ 25%). The mean value of annoyance in daily life caused by tinnitus was 7.0 (SD 1.8) at the baseline and 4.0 (SD 2.4) after the treatment series (p ⬍ 0.0001). The annoyance of tinnitus decreased on average 45% (95% interval of confidence from ⫺ 60% to ⫺ 29 %).
Clinical vignette
Discussion
Patient number 13 in Tables 1 and 2 was a 59-year old man who suffered from multiple sclerosis, left spastic hemiparesis, and central neuropathic pain (face, upper and lower extremities on the left side). He had suffered from bilateral high pitch tinnitus and high frequency sensorineural hearing deficit for six years. All were chronic, severe, disabling, and treatment resistant conditions. See Table 2 for rTMS treatment protocol. The patient rated his tinnitus intensity 8, annoyance 8, and pain intensity 9, interference 8 by NRS (0–10) before the treatment. After the first week of the treatment (five sessions) the tinnitus intensity and annoyance had decreased to 4 and 4, and the pain had vanished (NRS 0), also his spasticity was better. After the serial treatment (nine sessions) he rated his tinnitus as 3 and 3 and his global impression of change was ⫹ 2. In addition, his pain and spasticity were absent and he had been able to leave out neuropathic pain and muscle-relaxing medications. He also experienced a significant improvement in sleep. After six months he still felt better than before the treatment. At this time, he rated his tinnitus intensity as 6/10 on NRS scale and annoyance as 5/10. His pain intensity (NRS 3) and spasticity (NRS 1) were still almost absent and he was able to continue without medications.
The results of this small open pilot study imply that it may be possible to reduce patients’ tinnitus symptoms with E-field navigated rTMS. However, the effects are temporary, especially with shorter treatment series. There are many studies on rTMS for tinnitus with rather modest clinical effects and very variable rTMS protocols (Kleinjung et al, 2005; Rossi et al, 2007; Anders et al, 2010; Marcondes et al, 2010; Piccirillo et al, 2011, 2013). As most of the randomized controlled trials so far carry methodological limitations, currently only level C recommendation has been given for the use of rTMS in tinnitus patients (Lefaucheur et al, 2014). To our knowledge, this is the first study that has used an E-field navigated TMS device for tinnitus treatment, aiming for more accurate anatomical and tonotopical targeting at the auditory cortex with rTMS. These preliminary results suggest that individually tailored targeting of the treatment might, in fact, improve efficacy of rTMS treatment, but properly controlled comparative studies in larger patient groups are surely needed to confirm these promising preliminary observations. The preliminary therapeutic impact of rTMS in this open pilot study seems to be somewhat larger than in previous studies using rTMS for tinnitus. Rossi et al (2007) conducted a study using rTMS
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E-field navigated TMS for tinnitus targeted both navigated and according to the 10–20 international EEG system, and found at least 25 % improvement of tinnitus intensity in 8/14 patients. Mennemeier et al (2011) carried out a study with positron emission tomography (PET) navigated rTMS on the temporal cortex, and found 43% of the patients to be responders, experiencing at least a 33% drop in tinnitus loudness. These two studies were randomized and placebo controlled, and that may partly explain the difference in the therapeutic impact compared to our open pilot study, where placebo effect is presumably considerable. However, it is also possible that E-field navigation, allowing precise control of the stimulus target on the centre of the STG, with the induced electric field vector at optimal orthogonal angle against the edge of the gyrus, partly improved the effects observed in this methodological pilot study. These potential benefits remain to be verified in future randomized controlled trials. The rTMS frequency, number of given pulses, number of sessions, stimulation intensity (% RMT), and stimulation target were predominantly equal to those in the previous studies (Rossi et al, 2007; Khedr et al, 2008; Anders et al, 2010; Marcondes et al, 2010; Piccirillo et al 2011), but some of our patients had only a few stimulation sessions (the number of sessions per patient varied from 3 to 15). It is worth noting though, that even a short treatment series could induce remarkable shortterm effects in our very severe and chronic tinnitus patients with psychiatric co-morbidity. Based on the GIC scale alone, 77% of the patients benefitted from the treatment, which is more than in most previous studies. The small number of patients and the lack of placebo control may partly explain this finding. Two patients reported GIC 0; despite slight reduction of tinnitus intensity and annoyance (20%) in one of them. The discrepancies between subjective appraisal of benefit and NRS scores underline the need for multimodal assessment of rTMS treatment results as different outcome measures elucidate distinct aspects of possible therapeutic effects. Most of the patients felt the effect of the rTMS treatment for several days after the end of the treatment, but the long-term effects were not systemically followed in this open methodological pilot study. After six months, two patients reported by e-mail or phone that they still had less severe tinnitus than before and were satisfied with their present situation. At six months, our clinical vignette (patient 13) still had 25% reduction in tinnitus intensity and 38% reduction in tinnitus annoyance. His central neuropathic pain was also still reduced 67% compared to baseline, supporting the level A recommendation for the use of rTMS treatment in neuropathic pain (Lefaucheur et al, 2014). This patient illustrates the feasibility of rTMS treatment in tinnitus patients with co-morbidities, as several different disorders can be treated during the same session with rTMS. In the studies of Plewnia et al (2007) and Rossi et al (2007), the effect of rTMS lasted up to two weeks, but there are reports in the literature of lasting therapeutic effects for up to six months after longer serial treatments (5–10 sessions of rTMS) (Kleinjung et al, 2005; Marcondes et al, 2010), or even longer lasting effects (Burger et al, 2011). It has been suggested that long duration of tinnitus (De Ridder et al, 2005; Khedr et al, 2008), hearing loss (Kleinjung et al, 2007), and patient’s old age may decrease the efficacy of rTMS treatment (Langguth et al, 2008): it seems that rTMS is more effective in younger patients and in patients with shorter tinnitus duration. On the other hand, Lehner et al (2012) stated in their study that there are no good demographic or clinical predictors for the treatment outcome. In this small pilot study with no standardized examination protocol, it is not possible to evaluate the potential effects of those
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parameters properly, but no significant associations were found in this group. It is worth noting though, that our patients represented the most severe edge of tinnitus symptomatology with rather severe co-morbid psychiatric problems (among them, one suicide attempt), and even senior citizens who benefitted from the treatment. There are several limitations in this open methodological pilot study evaluating the best targets and stimulation protocols for precise E-field navigated rTMS in tinnitus patients. This was not a randomized or placebo-controlled trial and the number of patients was small, which makes the results only preliminarily promising. It is notable, as stated earlier, that rTMS was no more effective than sham stimulation in some recent studies (Piccirillo et al, 2013; Hoekstra et al, 2013; Langguth et al, 2014). With an open design, the true effects are always superimposed on placebo effect, which probably contributes to the present, rather promising results with E-field navigation as well. In addition, patients’ diagnoses were heterogeneous: 11/13 patients had hearing loss, 8/13 patients had co-morbid depression, and 8/13 patients used prescription medicines affecting the central nervous system. However, this patient group may well represent clinically relevant patients with severe intractable chronic tinnitus who would really need new treatment options. The E-field navigated rTMS device proved to be practical. The main advantage was that it showed in real time the exact “hot spot” on the patient’s 3D MRI image as well as the direction of the electric field induced at that spot, and all this information could be followed online during the treatment and saved on the computer. It was easy to keep the protocol constant or alter it, for example by changing the stimulation spot according to the alterations in tinnitus sound and the known tonotopy of the auditory cortex. There are still many questions to be answered considering the treatment of tinnitus with rTMS. Stimulation can be targeted with an accuracy of a few millimetres (Schönfeldt-Lecuona et al, 2005; Picht et al, 2011), but the optimal location and side for the stimulation still remain uncertain (Langguth et al, 2010). In a recent study, daily treatment with 1-Hz rTMS at the temporoparietal junction either ipsilaterally or contralaterally to the side of the tinnitus had significant beneficial effects irrespective of the laterality of stimulation (Kim et al, 2014). Additional studies should be performed to evaluate the optimal locations and protocols for the stimulation. Lee et al (2013) showed by positron emission tomography in healthy subjects that 1-Hz rTMS of the temporal cortex causes not only focal alteration, but also cortico-cortical modulation with widespread functional changes in brain networks via long-range neural connections. In addition, more information is needed to define the role of stimulation of multiple cortical targets, including non-auditory areas, on the efficacy of rTMS in tinnitus (Lehner et al, 2013; Park et al, 2013), as well as the protocols for possible maintenance therapy with rTMS. In general, the rTMS treatment results are characterized by high inter-individual variability (Langguth et al, 2008). In the literature it has been implied that the val/met polymorphism of the brain derived neurotrophic factor (BDNF) gene may cause individual differences in the effect of rTMS by altering the synaptic plasticity (Hoogendam et al, 2010). Just recently it has been discovered that variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation (Jääskeläinen et al, 2014). Further studies are thus needed to investigate the role of genotype variation on the individual therapeutic effects of rTMS. The results of this open methodological pilot study are encouraging and possibly somewhat better than in previous studies considering that the patients in this study had very severe, intractable, chronic tinnitus and other complex co-morbidities. Hence, randomized and
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placebo-controlled studies with adequate sample sizes should be performed to investigate the impact of E-field navigation on improving the efficacy of rTMS in tinnitus patients.
Acknowledgements This study was supported by Finnish governmental University Hospital grants (EVO). We thank Mrs. Elizabeth Nyman for checking the language of this article and Mr. Sami Sahlsten for IT assistance. Declaration of interest: The authors report no conflicts of interest.
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