Introduction
Abnormal cortical excitability is an intriguing piece in the puzzle of migraine pathogenesis. While strong data support increase in activity or excitability in the cerebral cortex measured in visual and motor areas of patients with migraine (MP), there is also evidence that decreased excitability leading to decreased preactivation and lack of habituation to afferent stimuli is migraine’s biological signature [
1‐
4]. Inconsistencies between these mixed results have not yet been resolved.
A widely used, powerful, and non-invasive tool to evaluate cortical excitability in humans is transcranial magnetic stimulation (TMS) (for a review, see [
5]). In MP, visual and corticospinal or cortico-cortical excitabilities to TMS have been found to be increased, decreased, or normal, compared to control subjects without migraine (CS) [
1‐
4,
6,
7]. The debate was therefore not settled by these studies probably because, in all of them, only single measures of excitability were performed in MP and CS. Interestingly, variability of visual cortical excitability measured once a day on different days is greater in MP than in CS [
7,
8]. This finding raises the important point that increased fluctuation, rather than mere increase or decrease in excitability, may be a marker of abnormal neuronal function in migraine. However, whether this phenomenon is restricted to the visual cortex in MP, and whether it occurs within a day or over several days, is unknown.
In contrast to the conflicting evidence regarding cortical excitability to TMS, a well-recognized feature in MP is the abnormal responsiveness to external stimuli such as environmental light [
9]. It is known that light deprivation (LD) modulates visual [
10,
11] and motor cortex (M1) [
12] excitability to TMS. Effects of LD on M1 excitability in MP have not been described.
This is the first study to compare variability of motor cortex excitability within a day and across several days in MP and CS, before and after LD or exposure to environmental light exposure (EL). We hypothesized that: (1) variability of excitability would be greater in MP compared to CS; (2) LD would increase excitability to a greater extent in MP than in CS.
Discussion
The main result of this study was that MT increased significantly within a short period of time (less than 2 h) in MP, but remained stable in CS. This change cannot be attributed to differences in muscle relaxation, because the computer-controlled system used to trigger the magnetic stimulator insured that TMS pulses were administered only at rest, during all MT measurements. Furthermore, there were no significant between-group differences regarding cognitive impairment, anxiety, sedation, or discomfort. The lack of significant differences in MT in the CS group reported here is in agreement with previous reports involving measurements repeated seven times within 10 h [
27] and once daily on three different days [
27‐
29], indicating the stability of MT in CS.
Repetitive testing was crucial to observe this MT variability and may explain discrepant results in previous reports [
1‐
4]. It is reasonable to think that if MT is less stable in MP than in CS, differences between groups may or may not arise depending on when the punctual measurements are collected. Our results indicate that controversies about excitability to TMS in MP may partially be due to this factor.
Baseline MTs, measured before LD and EL on different days did not significantly differ in MP in our study, in contrast to phosphene thresholds that were shown to vary significantly more in MP than CS across days [
7,
8]. One plausible explanation is that fluctuation in visual cortex excitability does not necessarily parallel fluctuation in M1 excitability. Phosphene thresholds measured once a day were shown to increase, 1–2 days before migraine attacks in children, while MT measured once a day did not significantly change in the interictal period [
6]. Resting MT and phosphene thresholds were found not to correlate significantly in healthy subjects in a number of studies [
30‐
33] even though a significant correlation was found between active MT (measured during voluntary muscle contraction) and phosphene thresholds when similar thresholding procedures were employed for both measurements of excitability [
34].
Also, phosphene threshold is known to be more variable than MT across and within subjects [
7,
8,
33] and depends on subjective responses, while MT relies on objective determination of MEPs. Finally, the use of different types of stimulators and coils limit result comparability between our results and those of studies that evaluated phosphene thresholds in MP and CS.
The magnitude of change in MT in the MP group was small (mean around 2%) but significant. MT is a fairly stable TMS measure that can change significantly after brain lesions, such as stroke or amyotrophic lateral sclerosis [
35,
36], or administration of drugs that interfere on ionic channels or on NMDA receptors [
16]. On average, MT increases in 2–10% after administration of antagonists of sodium and calcium channels [
16,
37‐
41] and decreases in 2.7–6.7% after administration of the NMDA antagonist ketamine [
42]. Therefore, the magnitude of change in MT even after administration of these drugs is relatively small. Considering that no overt structural lesions and only subtle changes in brain excitability would be expected in migraine, we obviously did not anticipate large shifts in MT in MP.
The significant increase in MT observed over a short period of time in MP may reflect abnormal function of ionic channels [
1,
3], because MT can be significantly increased by antagonists of sodium and calcium channels [
16] and for this reason is considered a marker of ion channel excitability in the motor cortex. Furthermore, mutations of neuronal ionic channels have been identified in rare, familial forms of migraine [
43‐
45]. Neurons with these mutations can be hypoexcitable and hyperexcitable at different points in time, i.e., their excitability is more variable than in non-mutated neurons [
46]. Hence, increased variability in neuronal excitability due to abnormal function of ionic channels is a candidate explanation to our findings of greater drifts in MT in MP, compared to CS.
Motor thresholds depend not only on the activity of ion channels of motor cortical neurons [
16,
27], but is also influenced by other factors: corticospinal fiber orientation, distance between the coil and the motor cortex, technique of measurement (coil positioning, type of coil or magnetic stimulator), excitability of spinal motor neurons, and possibly by attention, hormonal fluctuations, and fatigue. None of these other factors explain our findings.
First, within-subject comparisons were performed in MT measurements and, therefore, corticospinal fiber orientation was constant. Second, stimulation technique, including the number of stimuli for MT determination, was comparable in all TMS sessions. Although we did not use neuronavigation, it is unlikely that such an approach would have provided a different explanation because a previous report demonstrated no significant differences in MT measured with or without neuronavigation [
47]. Third, all experiments were performed in the afternoon and in the same phase of the menstrual cycle in each participant, and subjective states were comparable between the two MP and CS groups. Fourth, no between-group differences were found in M responses (data not shown), arguing against spinal mechanisms.
In contrast with MT results, there were no significant differences between groups with regard to SICI or MEP/M ratios. MEP/M ratios were significantly lower under a condition of less cognitive demand (rest in the dark in the LD session), consistent with previous reports [
19,
48]. A limitation to interpretation of these findings is the extreme heterogeneity in SICI and MEP/M ratios within and across subjects. This was not unexpected given the reports about variability of these measures in CS [
10,
19,
49].
Motor thresholds were reported to remain unchanged while MEP amplitudes were reported to increase and SICI to decrease after 30 min of LD compared to baseline EL measured in a different experimental session in CS [
12]. In contrast, LD had no significant effects on SICI or on MEP/M ratios in CS or in MP in our study. The reason behind this discrepancy between studies is likely the difference in experimental designs: measurements were performed once in each session in the study of Leon-Sarmiento et al. [
12], at baseline in the EL session and after 30 min of LD in the LD session. In our study, CS and MP remained at rest for 30 min during exposure to environmental light in the EL session, and without exposure to light in the LD session. Measurements were performed before and after LD and EL. Rest influences baseline activity in the brain. The magnitude of the “rest” condition may have exceeded effects of LD on MT, therefore obscuring any possible effects of this intervention compared to EL.
Another question that arises from our research is whether there is a correlation between the degree of fluctuation in excitability and clinical features (number, duration, severity of attacks, use of prophylactic drugs, gender, and pain during TMS). Most studies on single measurements of MT excluded data from patients having migraine attacks at intervals ranging from 1 week to 24 h before and/or after experiments. This was based on pseudo-normalization of neurophysiological measures performed with various techniques other than TMS [
1‐
4]. However, there is no demonstration that results of these tests mirror excitability measured with TMS. Furthermore, the hypothesis that migraine attacks influence MT failed to be confirmed in children [
6] and has not been formally tested in adults. Future studies should include greater sample sizes, provide detailed information of migraine attacks for prolonged periods, and perform more than one MT measurement, within a day and across days.
One exciting, possible application of TMS in a paroxysmal disorder such as migraine is to define surrogate end points for responsiveness to specific therapeutic interventions. In patients with epilepsy, seizure control after 1 year of treatment with antiepileptic drugs can be predicted from early increase in MT and intracortical inhibition measured with TMS after several weeks of treatment [
50]. It is possible that change or rate of change in MT may be useful markers to predict responsiveness of MP to pharmacological or non-pharmacological interventions. Moreover, TMS itself has been suggested to be a potential novel non-pharmacological intervention to treat MP, due to beneficial effects reported after single-pulse stimulation of the visual cortex in patients with migraine with aura [
51,
52]. If TMS is to be used to predict clinical improvements, then MT and fluctuation in MT are candidate measurements. More studies are necessary to define whether TMS can be an adjuvant tool to stratify patients for specific therapeutic strategies.
Although our study encompassed patients with migraine without aura, with aura, and chronic migraine, we were able to find significant differences between M1 excitability in MP, compared to CS. Whether variability in MT differs in different types of migraine or according to severity of this condition is a matter to be addressed in future studies. In addition, whether it predisposes to migraine attacks or is a consequence of them remains a difficult question.
The results presented here show for the first time that fluctuation in MT is greater in MP compared to CS. Fluctuation in excitability over hours or days in MP is an issue that, until now, has been relatively neglected and is important to understanding contradictory findings of previous studies that performed single measures of excitability. Many reasons may underlie the stability of electric activity in cortical neurons, such as the types, quantity, and activity of ionic channels and the relative strengths of inhibitory and excitatory synaptic inputs [
53]. Adding fluctuation in cortical excitability to the complex equation of brain electrical dynamics in migraine will reconcile conflicting results, which may be useful to enlighten the pathogenesis underlying this condition.