In this study, the tested rTMS protocol was effective in the overall reduction in days of migraine/month, duration of migraine attack, number of analgesics taken during acute attacks, intensity of pain, and degree of disability assessed by MIDAS score 4 weeks after the sessions. In addition, we noticed that improvement even has lasted more than 1 month in five patients who were followed up to 6 months considering decreasing the effect of TMS with increasing the period post-sessions. Our results were partially consistent with those of Teepker et al. [12] who treated twenty-seven migraineurs with low-frequency rTMS (1 Hz) using the same protocol with a round coil; the study was a placebo-controlled, blinded study that resulted in a moderate and significant reduction regarding migraine attacks, days with migraine, and total hours with migraine, whereas no effects were evident for pain intensity and the use of analgesics.
This improvement in these migraine parameters can be explained by reduction in cortical excitability caused by low-frequency rTMS. Central neuronal hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. In addition, studies of the visual cortex in patients with migraine have generally concluded that migraine (particularly migraine with aura) is associated with a state of functional cortical hyperexcitability [2].
In another explanation regarding the effects of TMS in migraine, previous studies have also suggested that blood flow and metabolic changes at the stimulation site, brain-derived neurotrophic factor upregulation, improvements in synaptic plasticity, and changes in the activity of the neural circuitry of the dorsolateral prefrontal (DLPFC)-cingulate cortex, including both the DLPFC and the anterior cingulate cortex, are involved [13].
Other studies, moreover, have demonstrated that the suppressive effects of low rTMS can be propagated to other regions not directly stimulated, presumably by functional connections. For instance, low rTMS of the left primary motor cortex reduces motor evoked potentials elicited by single-pulse TMS administered to the right primary motor cortex, an effect presumably mediated by transcallosal projections [14].
The reduction in pain intensity in our study and subsequently reduction in abortive analgesics intake but not in Teepker et al.’s study may be explained by the use of figure-of-eight coil in our study while using round coil in Teepker et al.’s [12] study assuming that figure-of-eight coil is more effective than round coil as proven by Rollnik et al. [15].
In contrast to a circular coil, a figure-of-eight coil in which two coils are placed beside each other, wired such that the stimulator current rotates in opposite directions in the two coils, produces a more localized peak induced field and can decrease the uncertainty as to the site of stimulation. In fact, the area under the center of the side-by-side coils experiences approximately twice the induced electric fields that occur elsewhere in the vicinity of the coils [16].
These results are consistent with the study made by Tamura et al. who revealed that low-frequency rTMS over M1 induced earlier recovery from acute pain compared with the sham or control conditions after induction of acute pain by intradermal capsaicin injection. This modulation of pain is thought to be through modification of C-fiber pathways by slow rTMS [17].
The current study revealed non-significant difference between patients with migraine without aura and migraine with aura regarding the response to rTMS sessions. However, this may be due to the small number of the patients with migraine with aura in our study. This corresponds to the conclusion of Misra et al.’s study which cited that there is no significant difference between patients with migraine with aura and patients with migraine without aura regarding to the response to rTMS [18]. This also can be explained through that most of the neurophysiological characteristics are certainly common to migraine patients with and without aura because most patients with migraine with aura also experience migraine attacks without aura [19].
Neurokinin A plays an important role in the pathophysiology of migraine through enhancing the neurovascular inflammation mechanism being released from primary sensory neurons of the trigeminal ganglia (TG) and increasing its level during the migraine attack [20].
In this study, there was a highly significant increase in neurokinin A serum level in the patient group in comparison to the control group before rTMS sessions. However, after sessions, there was a reduction in neurokinin A serum level by about 50% in the patient group. Nevertheless, it is still higher than the control group. This may be due to the neurovascular inflammatory processes, which have long been implicated as a possible mechanism in the pathophysiology of migraine. The results also revealed a positive correlation between neurokinin A serum level and number of headache attacks, duration of individual attack, number of pills per month, pain intensity, and MIDAS score pre- as well as post-TMS treatment. These results are in agreement with Sarchielli et al.’s [21] study results where ten migraineurs were treated with rizatriptan. He assessed neurokinin A serum level before and after treatment, where he found a significant decrease in neurokinin A serum level with significant pain relief and alleviation of accompanying symptoms. Patients who did not respond to rizatriptan had less significant variations in neurokinin A serum level before and following rizatriptan administration, which indicate that neurokinin A is a good indicator for migraine improvement.
Generally, treatment of migraine by rTMS was easy to be applied and well tolerated by the patients, with minimal (e.g., mild dysesthesias and scalp discomfort) or no side effects.
Limitations of the study were the relatively small sample of migraine patients and no control group for TMS as the sham group. In addition, low-frequency TMS was used, while most studies used high-frequency TMS.
