We examined different approaches to rTMS treatment for tinnitus to determine whether they could increase either the response rate or duration of treatment effects. Study 1 compared the effects of stimulating homologous regions of both hemispheres using 1 Hz rTMS. Whereas previous studies compared right and left hemisphere stimulation in parallel groups of subjects (Khedr, et al., 2010
); study one is unique in using a within subjects design to study treatment responders and non-responders. Results indicated that treating the opposite hemisphere tends to replicate the initial treatment effect, both positive and negative, without converting a non-responder to a responder (or vice versa). If anything, stimulating the opposite hemisphere might have aggravated tinnitus loudness and annoyance temporarily among the non-responders, but tinnitus eventually returned to baseline in all cases. Treating both hemispheres sequentially, however, could be a useful approach for treatment responders as stimulation to both are likely to improve tinnitus.
Study two is also unique for comparing different frequencies of stimulation at the same site within responders and non-responders. In general, patients who responded positively to 1 Hz rTMS over temporal cortex also responded positively to 10 Hz stimulation, and patients who failed to respond to 1 Hz rTMS also failed to respond to 10 Hz stimulation. One exception is the patient who was not included in the analysis because he could not be unambiguously classified as a treatment responder. This patient generally failed to report any changes in tinnitus perception from baseline during the week of 1 or 10 Hz rTMS treatment but he did report a strong positive response the week following 10 Hz stimulation. Another exception was that 10 Hz stimulation may have been more beneficial than 1 Hz for ratings of tinnitus annoyance and possibly loudness. Several limitations of our study might account for this finding. One and ten Hz treatment always occurred in the same order, so the added benefit of 10 Hz treatment could represent a cumulative rather than frequency dependent effect. The period separating treatments was as short as 11 days in one subject, so carry forward effects of 1 Hz treatment could be present. Finally, the sample size was small, so it is uncertain whether the large effect size would be replicated in a larger sample. Alternatively, 10 Hz stimulation might have greater potency than 1 Hz stimulation for some patients. Several findings are consistent with this interpretation. First, we observed during maintenance treatment that 1 Hz stimulation appeared to work better for some subjects and that 10 Hz stimulation worked better for others even though all of the patients responded positively to both low and high frequency stimulation. Second, a similar observation has been reported in a maintenance treatment study of depression that delivered high frequency stimulation over prefrontal cortex (O’Reardon, et al., 2005
). One patient who had a suboptimal response to 10 Hz rTMS subsequently responded to 20 Hz stimulation. Frequency dependent responses to rTMS treatment for depression have also been reported, within subjects, in group studies (Kimbrell, et al., 1999
; Speer, et al., 2000
). Finally, a group study that compared tinnitus patients who received different frequencies of rTMS found that 1, 10 and 25 Hz stimulation could all decrease tinnitus but that 10 Hz stimulation may have had greater potency (Khedr, et al., 2008
). These findings are important because they suggest that a patient who fails to respond to one frequency of stimulation may respond to another. As outlined below, these findings are also important for theoretical reasons.
Finding that 1 and 10Hz rTMS can have similar, long term treatment effects on tinnitus challenges our understanding of how rTMS induces a treatment effect. Whereas immediate effects of rTMS, which last seconds to minutes after stimulation, appear to be frequency dependent (George, et al., 2002
), treatment effects which lasts for weeks and months may not. A frequency dependent model, however, is not adequate to explain how low and high frequencies of rTMS induce similar rather than opposite behavioral effects on tinnitus perception. A more appropriate model will need to account for how different frequencies of rTMS can have similar rather than opposite behavioral effects.
Study three is the only study, to our knowledge, that applied maintenance rTMS in a series of patients with tinnitus; however, the findings replicate those of studies using maintenance rTMS for other psychiatric and neurological disorders. Maintenance treatment, at both 1 and 10 Hz, was well tolerated and effective for persons who responded positively to an initial course of treatment. The effect of maintenance treatment was additive over a standard course of treatment and the benefits were sustained over time. On average, subjects requested additional maintenance treatment every two to three months; however, we recommend that future clinical trials incorporate fixed treatment schedules, perhaps once per month, with fixed observation periods between treatment that are sufficiently long (e.g., 3–4 weeks) to determine if maintenance treatment has additive and sustained benefits over time. We found, as well, that unilateral maintenance treatment was beneficial for tinnitus perception bilaterally even though ratings were consistently lower for the ear ipsilateral rather than contralateral to stimulation (tinnitus was typically worse for the contralateral ear at the start of the study).
Our studies share the limitations of other open label trials. Lacking subject and experimenter blinds, these studies may be biased toward finding positive results. Lacking controls, these studies cannot be considered conclusive but can only show feasibility. Although we attempted to recruit equal numbers of subjects who either responded or did not respond positively to rTMS, selection biases could still be present as subjects elected to participate in further experiments after receiving rTMS. Finally, a combination of selection bias and a small sample size could exaggerate findings if subjects are not truly representative of the target population. These concerns can only be resolved by conducting larger, controlled trials - a view expressed in nearly every manuscript on maintenance rTMS. Limitations notwithstanding, our pilot studies indicate that future controlled, clinical trials would benefit from defining treatment responders and non-responders, empirically, in order to learn if subtypes of patients exist who may be more or less likely to respond to rTMS. The efficacy of rTMS could then be examined in light of these subtypes. Future trials would also benefit from incorporating within-subject designs that comparing the efficacy of different frequencies of rTMS for tinnitus. Our data suggests that patients may respond differently to different frequencies of stimulation. For example, tinnitus duration might interact with stimulation frequency as indicated in one study (De Ridder, D. et al., 2005
). Finally, future clinical trials can improve the treatment potential of rTMS by focusing on ways to increase treatment duration. Maintenace rTMS may be particularly useful in this regard for patients who respond to an initial course of active rTMS. Our maintenance treatment study parallels other maintenance treatment studies with regard to the ambiguity over how maintenance treatment should be applied. There is no uniformity. Most studies applied several sessions per week either as a response to symptom relapse [see for example (Fitzgerald, Paul B. et al., 2006
)] or as a regularly scheduled treatment that might maintain the benefit of previous treatments. We chose 3 sessions per week, as needed, because this schedule appeared sufficient to replicate the treatment effect and because we wanted to learn how often retreatment would be necessary. We think the advantages of a relapse treatment approach are that fewer applications of rTMS are required and that the maintenance schedule can be individually tailored. Disadvantages of this approach, however, are that subjects tend to “put off” retreatment, which may make maintenance less effective, and it is difficult to evaluate treatment efficacy when schedules are not consistent across subjects. Alternatively, regularly scheduled maintenance treatments may have the advantages of greater efficacy by not allowing symptoms to return to a previous level, by better monitoring due to regular patient contact, and by ease of analyzing outcome. Our experience suggests that retreating patients several times a week, e.g., every 3 to 6 weeks, may be a reasonable starting point for maintenance treatment in tinnitus.