Abstract
We used transcranial magnetic stimulation (TMS) with a figure-of-eight coil to excite motor and visual V1-V2 cortices in patients suffering from migraine without (MO) (n = 24) or with aura (MA) (n = 13) and in healthy volunteers (HV) (n = 33). Patients who had a migraine attack within 3 days before or after the recordings were excluded. All females were recorded at mid-cycle.
Single TMS pulses over the occipital cortex elicited phosphenes in 64% of HV, 63% of MO and 69% of MA patients. Compared with HV, the phosphene threshold was significantly increased in MO (P = 0.001) and in MA (P = 0.007), but there was no difference between the two groups of migraineurs. The motor threshold tended to be higher in both migraine groups than in HV, but the differences were not significant. In conclusion, this study shows that two-thirds (64.86%) of patients affected by either migraine type present an increased phosphene threshold in the interictal period, which suggests that their visual cortex is hypoexcitable.
Keywords
Introduction
There is increasing evidence in favour of an interictal dysfunction of the cerebral cortex in the common forms of migraine with and without aura (1). The precise causes of this dysfunction are not known, but likely to be heterogeneous, as the underlying genetic predisposition to migraine depends on a combination of various susceptibility genes (2, 3).
Following the seminal observation by Golla and Winter (4) of increased photic EEG driving in patients with migraine, the reactivity of electrocortical activity to visual stimuli has been assessed with a number of different methods. That migraine patients may have cortical hyperexcitability between attacks was suggested by several studies of the visual system showing increased amplitudes of visual evoked potentials (5, 6), more intense illusions to grating patterns (7, 8), faster low-level performance on psycho-physical visual tests (9) and hypersensitivity to environmental light stimuli (10). It has been postulated that interictal hyperexcitability of the visual cortex could be partly responsible for the migrainous aura by favouring spreading depression (11), and that it might be a consequence of selective damage to inhibitory GABA-ergic interneurones by recurrent hypoxaemia during migraine attacks (12).
The above-mentioned methods, however, are not able to assess directly cortical excitability to single stimuli, and other psycho-physical studies of the visual system came to an opposite conclusion (13). In studies of cortical evoked potentials to repeated stimulation, decreased habituation (or dishabituation), not increased amplitude, is the main finding and correlates with small responses to single or low numbers of stimuli (14, 15).
Transcranial magnetic stimulation (TMS) appears to be an interesting, non-invasive tool to assess cortical excitability in migraineurs. TMS of the motor cortex produces an electromyographic response in muscle (MEP), which can easily be recorded and measured (16, 17). By contrast, activation of the visual cortex by TMS has up to now chiefly been assessed by asking subjects if they experience phosphenes, a highly subjective method. Increased excitability may manifest itself in the motor cortex as a lowered threshold and/or an increased MEP amplitude (18), and in the visual cortex as a lowered threshold for eliciting phosphenes and/or an increased prevalence of TMS-induced phosphenes. High motor and phosphene thresholds and decreased phosphene prevalence would indicate hypoexcitability.
TMS studies of the visual cortex in migraine have produced contradictory results. We have reported that prevalence of phosphenes induced by TMS over visual cortices V1-V2 was decreased in migraine with aura (MA) patients (56%) compared with healthy volunteers (HV) (89%), which would favour hypoexcitability (19). By contrast, Aurora et al. (20) in a patient group comprising many subjects with attacks induced by visual stimuli found a high phosphene prevalence in migraineurs (100%), but an usually low prevalence (27%) in healthy controls. In another study (21) there was a non-significant trend for reduced phosphene prevalence in patients while the prevalence in controls was 94%. Phosphene thresholds were found reduced in migraine patients compared with healthy volunteers in three studies (20–22), but not in ours (19). In a study of visual area V5 (23) thresholds for magnetophosphenes were also lower in migraineurs compared with healthy controls.
By contrast with those of visual cortices, TMS studies of the motor cortex provide no indication for hyperexcitability in migraine: motor thresholds were normal in three (19, 20, 24) and even increased in two studies (25, 26).
The discrepancies between studies of magnetophosphenes may have several explanations. There are, on the one hand, important technical differences related to the stimulator device and the coil used. Magstim° 200 generates a monophasic pulse, the Cadwell° a biphasic one. The outer diameter of the circular coil is different: 130 mm in Áfra et al.'s and Mulleners et al.'s, 95 mm in Aurora et al.'s study. A figure-of-eight coil with an outer diameter of 90 mm was used by Werhahn et al. over the motor cortex. The maximum stimulator output was different between all these studies. On the other hand, there may be patient- and disease-related variables. For instance, patients with visually triggered attacks were over-represented only in one study. In most studies there was no control for occurrence of an attack after the recordings. This is a crucial variable, since it is well established that dramatic changes occur in evoked cortical responses up to 24 h before the migraine attack (27–29). In females cortical excitability varies over the ovarian cycle (30), a variable not considered in previous studies.
Against this background, we found it worthwhile to reappraise the results of our first TMS study of the V1-V2 visual cortex (19) by using a magnetic coil with a more focal output (figure-of-eight), a larger number of subjects, a strict control for absence of personal as well as family history of migraine in the healthy volunteer group and for the menstrual cycle in females, as well as blinding of the examiner for the diagnostic subtype of migraine.
Subjects and methods
Subjects
Seventy subjects were studied: 37 out-patients with migraine recruited from a specialized headache clinic (28 females and nine males, mean age 30.3 ± 10.1 years) and 33 healthy volunteers (18 females, and 15 males, mean age 25.5 ± 6.6 years) with no personal or familial history of headache. They were devoid of any other neurological, ophthalmological or systemic disorder and had no personal or family history of epilepsy (31). Patients had between one and eight attacks per month and their migraine history ranged from 4 to 30 years. None of them had received prophylactic anti-migraine treatment within the 3 months preceding the study. All subjects were naive to TMS. All the recordings were made during the headache-free interval, at least 3 days before and after an attack. The date of the last attack was verified by history; absence of an attack within the next 3 days by a telephone call given 4 days after the recordings. To minimize variations of cortical excitability due to hormonal variations (30), females were recorded at mid-cycle, i.e. 12–16 days after the first day of menses. According to the criteria of the International Headache Society Classification 1988 (32), 24 patients had exclusively migraine without aura (MO, code 1.1), 13 MA (code 1.2). Oral informed consent was obtained from all subjects and the study was approved by the Ethics Committee of the Faculty of Medicine, University of Liège, Belgium.
Transcranial magnetic stimulation
We used a Magstim Rapid° magnetic stimulator (Magstim Co. Ltd, Whitland, Dyfed, UK) connected to a double 7.0-cm figure-of-eight-shaped coil with a maximum stimulator output of 1.2 T.
To determine the motor and phosphene thresholds, a single pulse TMS of 100 µs duration was delivered. The investigator (V.B.) who performed the stimulation was blinded to the diagnostic subtype of migraine.
Motor threshold
The motor threshold (MT) was defined as the lowest intensity (expressed as a percentage of maximal stimulator output) able to produce an electromyographic (EMG) response in the first dorsal interosseous (FDI) muscle of the right hand of at least 50 µV peak-to-peak amplitude in at least five of 10 trials. The coil was placed at the optimal position over the left motor cortex for eliciting an EMG response in the right FDI. MT was determined at rest. Stimulation was initially applied at 40% of stimulator output and increased by 1% steps.
Phosphene threshold
The phosphene threshold (PT) was defined as the lowest intensity (expressed as a percentage of maximal stimulator output) able to evoke phosphenes in at least three out of five trials. The coil was placed on the inion-nasion line in a vertical position with the handle pointing upward and its inferior border 1 cm above the inion. The subjects were blindfolded in a dark room. As this may change visual cortex excitability after 40–45 min (33), the total duration of blindfolding was limited to 10–15 min. They were asked to pay attention to any visual manifestation, which appeared after each magnetic pulse. Stimulation was initially applied at 40% of stimulator output. The intensity of the stimulation was increased by 5% steps until the subject reported phosphenes. The threshold was then finely turned by increasing and decreasing the intensity by 1% steps. In patients who did not report phosphenes at the 100% intensity level, the procedure was repeated with the coil placed 1 or 2 cm above and/or below, right and/or left to the initial position before accepting the absence of phosphenes. With the coil positions used here, previous studies have shown that single magnetic stimuli are unable to induce eye movement or direct activation of the retina or optic nerve, which could be responsible for non-cortically induced phosphenes.
Statistical analyses
Means ± SD were calculated for motor and phosphene thresholds in each group of subjects. MT and PT were compared between groups with
Results
Phosphene prevalence
Phosphene prevalence was similar among groups (P = 0.81). Single TMS pulses over the occipital cortex elicited phosphenes in 21 out of 33 healthy subjects (63.63%), 15 out of 24 subjects in the MO group (62.5%), and nine out of 13 in the MA group (69.23%) (Fig. 1).
Phosphene prevalence (%; mean ± SD) in the three subject groups
Phosphene threshold
Most subjects described phosphenes as short-lasting flashes or lines in the centre of the visual field. In HV the mean threshold for phosphene production was 68.61 ± 12.49% of maximal stimulator output (range 18–87%). In MO patients it was 84.53 ± 12.57% (range 65–100%) and in MA patients 84.25 ± 12.52% (range 59–100%). The PT was significantly different between groups (P = 0.0012). The PT of HV was significantly lower than that of both groups of migraineurs (P = 0.001 MO vs. HV; P = 0.007 MA vs. HV). PT was not different between the two migraine groups (P = 0.96) (Fig. 2).
Motor (▪) and phosphene (□) thresholds in percentage of maximal stimulator output (mean ± SD) in healthy volunteers (HV, n = 33), migraine without (MO, n = 24)) and migraine with aura (MA, n = 13). ∗P < 0.001 vs. MO, P < 0.007 vs. MA.
Motor threshold
The mean TMS threshold to activate the right first dorsal interosseous muscle at rest was 57.85 ± 7.60% of maximal stimulator output (range 30–74%) for HV, 59.58 ± 9.56% (range 45–81%) for MO patients and 62.62 ± 6.68% (range 53–72%) for MA patients. The motor threshold thus tended to be higher in both migraine groups compared with HV, but the differences were not significant (Fig. 2).
There was no significant correlation between MT and PT (P = 0.81). Mean MT was similar in subjects who reported phosphenes and in those who did not.
Discussion
In this study approximately one-third of subjects, be they healthy volunteers or migraineurs, had no phosphenes elicited by single transcranial magnetic pulses of the occipital cortex with a figure-of-eight coil and a maximal stimulator output of 1.2 T. There was no significant difference in TMS-induced phosphene prevalence between subject groups. When phosphenes were produced by TMS, the average threshold intensity to elicit them was significantly higher in migraine patients between attacks than in HV, but it was not different between migraine with and without aura. The average threshold to elicit a motor response tended to be higher in both migraine groups compared with HV, but this difference did not reach statistical significance.
Although their exact generator remains a matter of debate, phosphenes elicited by brief, intense magnetic pulses directed to the occipital area of the brain are probably due to activation of the visual cortex and/or of subcortical sites such as the optic radiations adjacent to the posterior tip of the lateral ventricles (21). The prevalence rates of TMS-induced phosphenes we found in our study are similar to those reported by others (21, 22). They differ, however, from those found by Aurora et al. (20) which were higher in migraineurs, and from those reported in a previous publication from our group (19) which were lower in MA patients. Contrasting with our present finding of a significantly higher PT in both groups of migraineurs, Aurora et al. (20) and Mulleners et al. (21) reported a significantly lower PT in migraineurs. In a recent study where TMS was applied laterally over visual area V5 (23), thresholds for magnetophosphenes were also lower in migraine patients. Results of the latter study are difficult to compare with all previous studies in which midline occipital TMS was used.
Some of these discrepancies could be due to methodological differences, which may be device- and/or patient-dependent. With rare exceptions (23, 24) where a 90-mm figure-of-eight coil was used to stimulate the cortex, all published studies have used circular coils of different sizes. The two types of coils differ substantially, since a figure-of-eight coil produces a focal stimulation under the centre of the coil while a circular coil causes diffuse stimulation of the underlying cortical area (34, 35). It is thus likely that a larger cortical area is stimulated with the circular coils, which may be of importance for anatomical reasons. Compared with the hand motor area, which is situated on the lateral surface of the cortex, the greater part of the primary visual cortex is indeed buried on the medial surface of the occipital lobe. Despite variations in precise location between individuals, the hand motor area is likely to vary more in medio-lateral and anterio-posterior directions whilst the primary visual cortex tends to vary more in depth (36). These differences in size and orientation of the two cortical areas, as well as their cytoarchitectural particularities and variations in thickness of the overlying skull, will affect the TMS intensity required to reach threshold.
It must be pointed out that in those studies reporting reduced magnetophosphene thresholds (20, 23, 37, 38), subjects who reported no phosphenes were not taken into account for the threshold calculations. As a matter of fact, if one assumes that subjects without phosphenes have at least a 100% threshold, a recalculation of the figures in Mulleners et al.'s paper (21) will, for instance, increase the mean phosphene threshold in the MO group from 46 to 55, in the MA group from 47 to 60.2, while in the HV group it would increase only from 66 to 68. Needless to say, the differences between groups would lose statistical significance after such recalculations.
With regard to patient selection, one must keep in mind that dramatic changes of evoked cortical responses, and thus of cortical excitability, occur 24 h before and during the attack (27–29). While occurrence of the last attack before the recording can be checked by history, occurrence of an attack within 24 h after the recording has to be controlled by other means such as telephone calls. The latter was done in no other study besides ours. Other patient-related factors cannot be excluded. In Aurora et al.'s and Battelli et al.'s studies (20, 23) there was a surprisingly low prevalence of TMS-elicited phosphenes in the control group (3/11 and, respectively, 4/16), contrasting with all previous studies conducted in normal subjects which report a prevalence of phosphenes between 60% and 80% (36, 39–41). In previous groups of control subjects considered to be healthy, migraine patients could have been excluded. This was unlikely in our study, since we took care to exclude from the control group subjects with a personal or family history of migraine. Preponderance of patients who had visually triggered attacks might also explain why Aurora et al. (20) found such an extreme phosphene prevalence (100%) in their migraine population. Finally, cortical excitability fluctuates with hormonal variations during the menstrual cycle (30). These hormonal influences were neglected in all studies except ours, where all recordings in females were made at mid-cycle.
Although phosphenes are highly subjective and variable, interictal reduction of PT in migraineurs was taken as evidence for increased excitability of the visual cortex (20). A recent study from our group adds supplementary evidence to the concept that hyperexcitability per se is not characteristic of the visual cortex in migraineurs between attacks. We have shown that 1 Hz repetitive TMS over the occipital cortex during 15 min is able to induce in HV a potentiation, i.e. amplitude increase, of pattern reversal (PR)-visual evoked potentials, precisely the abnormality found in migraine, and that 10 Hz rTMS in migraineurs transforms the abnormal PR-VEP potentiation into normal habituation. As 1 Hz rTMS is known to inhibit the underlying cortex and 10 Hz rTMS to activate it, these results indicate that in migraineurs between attacks the visual cortex has a decreased, and not an increased, level of preactivation excitability (42).
The precise mode of activation of corticospinal neurones by TMS of the motor cortex is still a matter of debate. Evidence exists for trans-synaptic activation via excitatory interneurones (43, 44) as well as for a direct depolarization of the initial axonal segment (45, 46). In both cases the transmembrane potential of the target cells at the time of stimulation should be a crucial variable. With the notable exception of one study (18), the consistent finding of motor cortex TMS was reduced interictal motor cortex excitability in various forms of migraine: unilateral or bilateral MA (19, 25), menstrual MO (47), familial hemiplegic migraine (FHM) (18). In our study, motor thresholds at rest tended to be higher in both MO and MA, but the difference with HV was not significant. Together with the above abnormalities, the finding of prolonged central motor conduction times in FHM (26) may suggest a permanent dysfunction of corticospinal pathways in that particular group of migraine patients, possibly reflecting ischaemic brain damage secondary to calcium channel dysfunction (48). In another very recent study, Werhahn et al. (24) found no significant motor threshold differences between controls and MA or FHM patients. As mentioned by others (19, 38), there seems to be little correlation in the same individual between visual and motor cortices, indicating that both are worth being studied in migraine.
In conclusion, we have confirmed in our laboratory setting that TMS activates less visual cortex in migraineurs than in healthy volunteers, which suggests that both migraine with and without aura are associated interictally with a reduced cortical excitability. Considering the variability of results based on the detection of phosphenes after TMS of the visual cortex, it seems preferable in future studies to replace this subjective measure by a more objective one, e.g. visual evoked potentials or metabolic changes assessed by functional neuroimaging methods.
Footnotes
Acknowledgements
This study was supported by grant no. 3.4523.00 from the Belgian Fund for Medical Research (Brussels) and grant no. 125 from the Migraine Trust (London, UK) to J.S. V.B. is the recipient of a Clinical Fellowship of the International Headache Society.