This study tested the hypothesis that tinnitus relates to increased, asymmetric activity in auditory processing areas of the temporal cortex. It is unique among other studies in its attempt to compare PET scans obtained before and after active and sham 1-Hz rTMS treatment. We discuss first the effect of rTMS on perception of tinnitus loudness and then turn to comparisons of PET scans before and after stimulation. A week-long course of active, low-frequency rTMS led to a significant reduction in VARL ratings for both ears by the end of the treatment week. Sham stimulation had no effect on tinnitus loudness ratings for either ear; however, a significant carryover effect of active stimulation was observed into the sham treatment week for those subjects who received active treatment first. This carryover effect was most pronounced for the ear contralateral to treatment, where, in general, treatment effects were observed to be the strongest. Because the carryover effect of active stimulation was assessed at the end of the week of sham stimulation, it is apparent that tinnitus remained significantly reduced for a minimum of two weeks in those subjects who received active stimulation first.
Individual subjects could be classified as either treatment responders or nonresponders. Forty-three percent of subjects were classified as responders, experiencing at least a 33% reduction in tinnitus loudness from baseline. The remaining 57% of subjects did not report marked changes in tinnitus perception following rTMS. More patients in this sample received treatment over the right than left temporal lobe, but active treatment of either hemisphere could produce a treatment responder. These results converge with previous studies of tinnitus, which show that rTMS improves tinnitus in approximately 50% of patients, across studies and laboratories, following stimulation of either the left or right hemisphere.21
The rate of improvement in this study might have been lower than 50% simply because of sampling or because our method of defining a treatment responder is conservative. We think this classification scheme has advantages over questionnaires that assess tinnitus generally because it focuses directly on changes in perception of tinnitus loudness and this is what we aimed to achieve in applying 1-Hz rTMS as a treatment. Although scores improved on the TSI following treatment, the change was not significant despite rather large improvements in tinnitus loudness. Therefore the VARL appears to have better sensitivity for detecting rTMS-induced perceptual changes in tinnitus than a questionnaire like the TSI.
PET asymmetries were of limited use in targeting rTMS. Asymmetries were accessible to rTMS in only 61% of subjects. As a result, our initial attempt to target rTMS using PET scans evolved into a decision flow chart that targeted the superior posterior temporal lobe opposite the ear with loudest tinnitus when PET asymmetries were not accessible and to target the left temporal lobe as a default. Our experience is apparently consistent with that of other studies that used PET to guide rTMS treatment for tinnitus. A recent review concluded that PET-guided targeting is no more effective than simply placing the coil over the left temporal cortex.14
In fact, it may not even be advantageous to target the left rather than the right temporal lobe as we observed a positive response to rTMS associated with targeting treatment over the secondary auditory cortex (i.e., Brodmann area 22) in either hemisphere.
A comparison of PET scans before and after treatment did not support the hypothesis that 1-Hz rTMS improves tinnitus by decreasing neural activity in auditory processing areas of the treated hemisphere. Comparing activity in the ROIs of the patient’s scans before and after treatment lacked a specific relationship either to the site of rTMS delivery, to treatment outcome, or even to active stimulation. Whereas a significant decrease in activity beneath the site of stimulation was observed following active rTMS, similar changes could be observed in control ROIs that did not receive stimulation. Further, change in tinnitus perception was not significantly correlated with change in PET activity at the site of stimulation or any other site. Finally, effect sizes observed for three ROIs following sham stimulation were larger than those observed in association with active stimulation. It is important to note that one of these four subjects received active stimulation the week prior to sham stimulation, and so carryover effects of active treatment are likely for this person; however, the remaining three subjects received sham stimulation first and none was classified as a treatment responder.
Limitations in our method might have hindered our ability to find changes in brain activation associated with changes in tinnitus. For example, the NeuroQ program limited our analysis to predefined ROIs. We could not, for example, examine ROIs involving limbic structures that might influence emotional aspects of tinnitus. A more powerful and targeted analysis of the PET data might have yielded different results. Additionally, we compared PET scans obtained at rest, which can be influenced by factors other than rTMS-induced changes in tinnitus. Also, acquisition of the second PET scan was timed to coincide with the last day of treatment. This strategy; however, may not be optimal because in some patients there may be a delay between the end of treatment and the time before tinnitus perception improves.35
In the remainder of the discussion, we compare our study to the only other treatment study of tinnitus, to our knowledge, that used functional imaging as an outcome measure following sham and active rTMS.
Marcondes et al.35
examined the effects of 1-Hz rTMS over the left temporo-parietal cortex in patients with tinnitus with no hearing impairment using single-photon emission computed tomography (SPECT) obtained at baseline and two weeks following treatment. Sham (n=9) and active rTMS (n=10) were compared using a parallel treatment design. Active stimulation improved tinnitus as measured with the Tinnitus Handicap Inventory and a VARL. Sham did not. Analysis of SPECT scans showed reductions of neural activity in the inferior temporal lobes of both hemispheres (below the site of stimulation) and increased activity in the right uncus and cingulate gyrus in association with active rTMS. Increased activity in the left middle temporal gyrus, the cingulate gyrus bilaterally, and in the right insula was observed after sham stimulation.
Even though the Marcondes study differs from the current study in subject selection, design, imaging technique, and delay of the follow-up scan; the two studies are similar in failing to support a connection between rTMS-induced change in tinnitus perception and change in neural activity within auditory processing regions of the temporal cortex. Instead, after active stimulation, Marcondes et al. found changes in ROIs with an unclear relationship to tinnitus perception and, after sham stimulation, changes that were perhaps even harder to interpret. In light of the observation that neuroimaging does not improve the efficacy of rTMS for tinnitus over non-guided coil placement,14
one has to question how sensitive these imaging techniques are to states of cortical activity associated with tinnitus perception. If one accepts that they are sensitive, then the simple hypothesis that rTMS decreases tinnitus by inhibiting excessive neural activity within auditory processing regions of the temporal lobe is probably incorrect.