Abstract
INTRODUCTION
It is widely accepted that the cerebral cortex, brainstem and the trigeminovascular system are involved in the pathophysiology of migraine, but their specific functions and the sequence of activation are still unknown. For example, almost all studies have shown a deficit of habituation in migraineurs during repetitive stimulation of evoked potentials (1–6). However, it is not clear whether this is a result of an increase or a decrease in preactivation levels, e.g. a change of cortical excitability compared with unaffected individuals. A number of authors (7–13) are in favour of an increased preactivation level in migraineurs, referring among other things to lower phosphene thresholds compared with healthy subjects. Other researchers assume a decreased cortical preactivation level, focusing on the ‘ceiling theory’ (1, 3, 4, 14–16). Most recent studies add another piece of the puzzle to our understanding. What becomes clear is that we need more—and better data to settle the argument regarding cortical excitability levels in migraineurs.
Abstract
The aim of the study was to clarify whether phosphene thresholds (PTs) change over time and whether these thresholds possibly relate to a migraine attack. Antal et al. (17) investigated patients with migraine (n = 9 with aura; n = 7 without aura) and control subjects (n = 16) using transcranial magnetic stimulation (TMS) and a longitudinal design (five stimulations during a 10-week-period). The study showed no significant differences in PTs between migraineurs and healthy subjects. However, PTs in migraineurs tended to be lower and the minimum threshold values were smaller (not significant) in migraineurs with aura than in patients without aura and in controls. Interestingly, the PTs had a higher range in migraineurs than in healthy subjects and the standard deviation of PTs in migraineurs was significantly increased. No differences were seen in PTs from the first to the last stimulation in controls and migraineurs without aura. Patients with aura showed significantly lower PTs in the third, fourth and fifth session compared with the first session. Four patients suffered a migraine attack 1 day after the measurement of PTs. Compared with PTs during the other measurements in the headache-free interval, PTs before the attack were either remarkably high or exceptionally low. This result points to higher variability of PTs in migraineurs than in healthy subjects and underlies the hypothesis that migraineurs show an imbalance of cortical excitability, especially shortly before the onset of an attack.
Statement
Antal et al. (17) found that migraineurs, and particularly migraineurs with aura, showed a higher variability of PTs over time than unaffected controls. In addition, migraineurs showed shortly before the onset of an attack either very high or very low thresholds, pointing to a cortical imbalance. Averaged values of PTs seem not to be reliable parameters to quantify cerebral excitability in migraineurs because of the significantly higher standard deviation compared with healthy controls. Furthermore, measuring PTs only once will not produce valid data in migraineurs because of the considerable changes over time, which are exaggerated towards a migraine attack.
Consequently, previous studies investigating PTs at only one time point have come to controversial results, supporting either increased (7–12) or decreased (1, 15) cortical preactivation levels. Others have found no differences between migraineurs and controls (18). The study by Antal et al. quite nicely shows that PTs are highly inconsistent over time and that differences in earlier studies may be due to a low signal-to-noise ratio. In particular, the prominent high or low PTs shortly before the onset of an attack confirm this assumption. The high invariability of PTs in migraineurs compared with subjects points to the hypothesis that a dysfunction of the inhibitory system causes an imbalance of the cortical excitability level in migraineurs. This imbalance could be due to impaired inhibition (9, 19), although conflicting results exist (20, 21). Nevertheless, earlier studies using PTs have to be seen in the light of the present study.
Abstract
Chadaide et al. (13) have investigated influences of transcranial direct current stimulation (tDCS) on migraineurs (n = 16; migraineurs with aura = 9, migraineurs without aura = 7 and healthy volunteers = 9). They stimulated the subjects and patients either anodally (excitability effect), cathodally (inhibitory effect) or using sham stimulation over the occipital cortex for 10 min. They compared TMS-elicited baseline PTs (before stimulation) with those measured 10 min after tDCS. The initial PTs tended to be lower in migraineurs; however, this difference did not reach statistical significance. Anodal stimulation increased cortical excitability (lower thresholds) in all groups. The largest effect was seen in migraineurs with aura. Cathodal stimulation had the opposite effect solely in healthy subjects, leading to increased thresholds (t = −3.29; P < 0.01), whereas there was no significant effect in migraineurs (neither in migraineurs with nor without aura). The authors suggest that excitability changes could be influenced by tDCS in migraineurs and healthy subjects differently.
Discussion
The aim of this study (13) was to evaluate the excitability of the occipital cortex in migraineurs. The authors have shown excitability changes after repetitive tDCS. tDCS is transcranially administered through electrodes over the scalp and is thought to modulate cortical excitability by changing the potential of cell membranes due to anodal (facilitatory effect) or cathodal stimulation (inhibitory effect). Earlier studies have demonstrated that tDCS induces excitability changes immediately during and after a session of stimulation (22–25). The present study has evaluated for the first time changes in cortical excitability before and after repetitive DCS in migraineurs. As anodal stimulation increased cortical excitability in all groups, but cathodal stimulation had the opposite effect solely in healthy subjects, this study would favour the hypothesis that the migraineur's brain is hyperexcitable, probably due to impaired inhibition. However, the authors did not find a significant difference between migraineurs and unaffected controls at baseline levels. Furthermore, PTs as a measure of cortical excitability are dependent on endogen rhythms (17) and should be seen with caution. The present study circumvented this obstacle by using the migraineurs as their own controls. It seems that tDCS is a very interesting instrument to investigate the migrainous cycle as well as medication effects.
Abstract
Chronicle et al. (26) have demonstrated functional changes in the visual cortex in migraineurs with aura. They used the TMS technique, termed magnetic suppression of perceptual accuracy (MSPA), using a standardized protocol in which computer-presented letter targets were followed by a single magnetic pulse delivered over the occiput. MSPA performance measures response accuracy and is usually U-shaped. This was indeed the case in healthy controls and migraineurs without aura; however, migraineurs with aura exhibited flattened profiles. This suggests that it is more difficult for migraineurs with aura to suppress perception of simple targets by a TMS pulse over the occipital cortex compared with controls. Previous studies have indicated that the U-shape of the normal MSPA function is due to preferential activation of inhibitory neurons. A flattened profile such as in migraineurs with aura points towards cortical hyperexcitability, which was interpreted as attenuated cortical inhibition in migraine with aura (27, 28).
Discussion
Early TMS studies investigating the visual cortex mainly focused on phosphenes induction. Some authors postulated reduced PTs compared with controls (7, 10), others demonstrated opposite effects (1, 15). As discussed by Antal et al., PTs in migraineurs are highly susceptible over time, pointing to a general dysexcitability (17).
In the present investigation, Chronicle et al. (26) used the MSPA technique. This technique is able to evaluate the extent to which perception of simple letter stimuli is suppressed by a magnetic pulse (TMS) over the visual cortex. Previous studies have shown that MSPA is a safe and objective measure of cortical excitability, which is reliable over time (29). In the present investigation Chronicle et al. (26) have demonstrated shallower MSPA profiles in migraineurs with aura, pointing to a cortical hyperexcitability probably due to disturbed inhibitory circuits. Recent studies have also examined MSPA and demonstrated flattened profiles in migraineurs compared with controls (9, 12).
However, a single-point measurement is insufficiently valid, and longitudinal measurements are crucial for our understanding of the physiology and pathophysiology of these systems.
Commentary of the authors
Studies investigating the cortical excitability level in migraineurs have yielded controversial results, probably due to methodological differences (30). In addition, it is likely that cortical excitability levels change over time because of various endogene and environmental related influences, especially shortly before the ictal state (17). Most researchers have investigated outcome parameters such as PTs only once and produced averaged data (4, 7, 8, 15). Consequently, conflicting results are not surprising and, if based solely on these data, a discussion about an increased or reduced preactivation level in migraineurs is questionable. It seems more likely that an imbalance of the cortical excitability level per se is a pivotal pathogenic function of migraine, which is in turn affected by intrinsic and external aspects. It is very likely that the cortical preactivation level in migraineurs oscillates between high and low excitability. The controversial results highlight the importance of longitudinal studies using objective outcome parameters to shed light on the fascinating mechanism of cortical dysexcitability in migraineurs.