Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study

Background

Chronic tinnitus is a disabling, almost untreatable, condition, usually accompanied by psychiatric distress. In patients with complex neuropsychiatric diseases, such as chronic pain, with which tinnitus shares pathophysiological similarities, placebo effects may be pronounced. Moreover, it may be difficult to distinguish actual repetitive transcranial magnetic stimulation (rTMS) induced clinical benefits beyond placebo effects in neuropsychiatric patients.

Methods

16 patients with chronic tinnitus underwent a randomised, double blind, crossover, placebo controlled trial of 1 Hz rTMS (120% of motor threshold; 1200 stimuli/day for 5 days) of the left temporoparietal region. Patients were screened for psychiatric comorbidity; additionally, anxiety and depression were monitored throughout the study. Moreover, an original placebo rTMS procedure produced the same activation of ipsilateral face muscles (a condition which may per se change the subjective rating of tinnitus) as the real rTMS.

Results

There were 8 out of 14 responders. Two patients dropped out for transient worsening of tinnitus. Active rTMS induced an overall significant, but transient, improvement (35% of the basal score) of subjective tinnitus perception that was independent of either tinnitus laterality or mood or anxiety changes. No correlations were found between response to rTMS and tinnitus duration, initial subjective score or patient age. When asked after the study was over, 71.4% of patients failed to identify the temporal sequence of the real or sham rTMS interventions.

Conclusion

The beneficial effects of rTMS on tinnitus are independent of mood changes. Moreover, they appear in the context of an original placebo stimulation designed to more closely replicate the somatic sensation of active stimulation. Because of the limited temporal duration of the clinical benefit, these neuromodulatory effects could be mediated by transient functional changes taking place in the neural circuits underlying tinnitus processing.Tinnitus is a subjective auditory perception of sounds or noise, not triggered by external auditory stimuli, which affects millions of people.¹ It is estimated that in 1–3% of the general population tinnitus becomes chronic and sufficiently intrusive to interfere with the patient''s quality of life, mainly because of psychiatric distress, including sleep disturbances, thereby leading to work impairment.² Pharmacological and physical/behavioural treatments in severe cases are generally unsatisfactory.³Experimental data based on transection of⁴ or drug effects on⁵ the cochlear nerve, and in vivo human brain imaging studies,^6,7,8 converge in suggesting that tinnitus could be associated with maladaptive plastic brain reorganisations, taking place at multiple brain levels following—and thereafter being maintained independently by—an initial cochlear dysfunction.⁹ Functional brain changes associated with tinnitus showed hyperactivity of discrete temporoparietal regions, including both the primary auditory cortex (AC)^10,11,12,13 and the secondary, or associative, AC.^{7,11,14,15,16,17,18} More comprehensive views on the generation and maintenance of tinnitus indicate involvement of a broader neural network, most likely including the primary and associative AC (although it is difficult to disentangle the relative contribution of these two areas by positron emission tomography (PET) scans¹⁹), part of the limbic system,¹⁷ the anterior cingulated cortex¹⁸ and higher order processing areas.^20,21More direct evidence for the key role played by the AC in the perception/elaboration of tinnitus comes from studies with repetitive transcranial magnetic stimulation (rTMS), a technique that transiently modulates/disrupts the brain function of the targeted area(s) in several perceptive, motor and cognitive domains²²: high‐frequency rTMS (ie, 10 Hz or more for 2 s or less) applied on the scalp overlying the hyperactive left AC produced an intense, short lived tinnitus attenuation (see table 1​1).^16,12,23,24 Although these studies were not designed to “treat” tinnitus, they demonstrate that the AC is definitely involved in the expression of tinnitus. Interestingly, high frequency rTMS has been applied successfully to produce transient clinical benefits in other deafferentation induced disorders, such as chronic neurogenic pain,^25,26 which shares pathophysiological similarities with tinnitus in terms of maladaptive plastic changes at the cortical level.²⁷Table 1 Full papers on repetitive transcranial magnetic stimulation studies (single case reports are not considered) in chronic tinnitus

	Plewnia 200216	Eichhammer 200339	Kleinjung 200513	De Ridder 200523
No of patients	14	3	14	114
Treatment duration	Single application	5 days	5 days	Single application
rTMS frequency/length of the train/No of stimuli	10 Hz for 3 s (30 pulses)	1 Hz (2000 stimuli/day)	1 Hz (2000 stimuli/day)	1, 3, 5, 10, 20 Hz (200 pulses each)
Stimulus intensity (% of RMT)	120%	110%	110%	90%
Coil type	Figure‐of‐eight	Figure‐of‐eight	Figure‐of‐eight	Circular non‐focal
Individual neuronavigation	No	PET guided	PET guided	fMRI guided in 10
Target brain area	Temporoparietal (halfway between C3/T5 or C4/T6) and Pz	PAC	Hyperactive PAC	Unspecified coil positioning “on the AC” in 104
Controlled study	TMS delivered on additional 11 scalp positions	Double blind (placebo TMS with a sham coil)	Double blind (placebo TMS with a sham coil)	Sham with the coil at 90°. Unspecified blindness
Crossover	No	Yes	Yes	No
Percentage of responders	57%	2/3 patients	78.6%	53% with active, 63% with sham (but significantly more with active rTMS)
Duration of effects after the last rTMS application	Seconds	One week	Up to 6 months	Unspecified, presumably seconds
Correlations between rTMS and clinical characteristics	—	Responders had hyperactive PAC	Initial tinnitus grading and symptom duration negatively influenced rTMS response	High frequency better for acute tinnitus; low frequency better for chronic tinnitus

Open in a separate window

	Plewnia 200617	Plewnia 200618	Langguth 200640	Fregni 2006 24
No of patients	9	6 (retested after17)	28	7
Treatment duration	Single application	20 consecutive working days	10 consecutive working days	Single application
rTMS frequency/length of the train/No of stimuli	1 Hz for 5, 15 or 30 min (300, 900 or 1800 pulses)	1 Hz for 30 min/day (1800 pulses/day)	1 Hz for 33.3 min/day (2000 pulses/day)	3 trains 10 Hz for 3 s (30 pulses each)
Stimulus intensity (% of the RMT)	120%	120%	110%	120%
Coil type	Figure‐of‐eight	Figure‐of‐eight	Figure‐of‐eight	Figure‐of‐eight
Individual neuronavigation	PET guided	PET guided	No	No
Target brain area	Hyperactive BA 39 or 22	Hyperactive BA 39 or 22	Left PAC, determined on 10‐20 EEG system	Left temporoparietal (halfway between C3/T5 and Pz)
Controlled study	Double blind (sham delivered on the lower occiput)	Double blind (sham delivered on the lower occiput)	No	Yes, sham coil. Unspecified blindness. Additional scalp positions stimulated
Crossover	Yes	Yes	No	No
Percentage of responders	75%	83.3%	67.8%	42%
Duration of effects after the last rTMS application	Up to 30 min, dose dependent	2 weeks	Up to 13 weeks	Less than 5 min
Correlations between rTMS and clinical characteristics	Previous tinnitus duration negatively influenced rTMS response	Hyperactivity of the ACC predicted the response to rTMS	Not reported	Responders had less hearing loss

Open in a separate windowAC, auditory cortex; ACC, anterior cingulate cortex; BA, Brodman Area; C3, C4, C5, C6, Pz, electrode positions according to the International 10‐20 EEG system; fMRI, functional MRI; PAC, primary auditory cortex; PET, positron emission tomography; RMT, resting motor threshold; rTMS, repetitive transcranial magnetic stimulation.Medline search updated on 30 October 2006 (keywords: tinnitus, TMS or rTMS). Only peer reviewed international journals are taken into account.When rTMS is applied at a low frequency (ie, 1 Hz or less) for longer periods of time (tens of minutes, eventually with daily applications), or as continuous theta burst stimulation,^28,29 it induces relatively long lasting inhibitory changes in cortical excitability, probably mediated by long term synaptic depression, that can be associated with transient beneficial effects on clinical manifestations of neuropsychiatric disorders characterised by regional cortical hyperactivity³⁰ as painful dystonia related axial spasms³¹ or obsessive–compulsive disorders.³² Moreover, slow rTMS of the left temporoparietal region significantly attenuated auditory hallucinations in schizophrenia,^{33,34,35,36,37} the most relevant finding in view of rTMS application in chronic tinnitus. Previous studies of rTMS of temporoparietal regions at 1 Hz in patients with chronic tinnitus (see table 1​1)^{13,17,18,38,39,40} generally reported a considerable subjective improvement, occasionally lasting up to 6 months,¹³ with a dose dependency of rTMS induced beneficial effects.¹⁷Despite the fact that psychiatric comorbidity, such as mood or anxiety disorders, are relevant in chronic tinnitus sufferers,² this aspect has not been taken into account in previous controlled rTMS studies. Most importantly, there is agreement that the applied placebo conditions were suboptimal^41,42,43: this is because active rTMS of the temporoparietal regions may elicit strong activation of ipsilateral muscles supplied by the facial nerve, not reproduced by previous placebo rTMS conditions, but possibly influencing per se perception of tinnitus (see later in the discussion). We present a randomised, double blind, crossover, placebo controlled trial of daily 1 Hz rTMS on chronic tinnitus in which eventual mood changes were also monitored. Moreover, an original placebo condition is introduced, which minimises the possibility of subject awareness of the active or sham rTMS. This is relevant for at least two reasons: (i) patients with tinnitus are known to exhibit a particularly strong placebo response⁴⁴; (ii) it may be difficult to distinguish the actual rTMS induced clinical benefit beyond a placebo effect in neuropsychiatric patients,^45,46 including those with chronic pain²⁶ or tinnitus.^3,43