INTRODUCTION

           Migraine is a very common disorder, the cause of which is still unknown. Abnormal cortical excitability has been suggested to play an important role as a possible factor predisposing to the spontaneous, cortical spreading depression that has been suggested to represent the pathophysiological basis of the migraine with aura¹. It was proposed that there could be a generalized interictal hyperexcitablity of the cerebral cortex in migraine, more pronounced in visual areas because of its neural density². By contrast, other psychophysical tests of the visual system thought to reflect hypoexcitability of the visual cortex³. To assess cortical excitability in a more direct way, transcranial magnetic stimulation (TMS) seems a tool of choice, as it can explore none invasively excitatory and inhibitory neurons in visual and motor cortex. It has been recently applied to test visual cortical excitability by measuring phosphene threshold (the minimum TMS intensity needed to evoke phosphenes. The prevalence and/or threshold data of phosphenes induced by single pulse TMS of the visual cortex are controversy, some favoring increased^4,5,  and others decreased interictal excitability⁶. The aim of this work was to study the motor and visual cortical excitability in migraineurs between attacks.

MATERIALS AND METHODS

Subjects:

Twenty-eight patients with migraine, 18 were migraineurs with visual aura (MA) and 10 were migraineurs without aura (MO) compared to 20 healthy volunteers. The mean age of migraineurs was 33.7+6.9 and 30.5+7.8 in control group, no significant difference between the two groups. Ten patients out of the 28 migrainers had common migraine and 18 had symptoms always located on the same side (unilateral migraine). In migraineurs 17 patients were males and 10 were females. The mean duration of illness was 49.07±46.8 months, duration of each attack was 25.0±69.5 hours and frequency of attacks were 1.6±0.62 per week.

Patients were consecutively recruited from the Headache Outpatients Service of the Neurology Department at Assiut University Hospital. Diagnosis of migraine with or without aura was made on the basis of a clinical interview using the diagnostic criteria of the Headache Classification Committee of the International Headache Society⁷. Patients and controls were not taking any drug; non-of the control subjects had a family history of migraine. Migraineurs were examined interictally at least 3 days before (checked by history) or after an attack (checked by telephone calls). To avoid unspecific effects on cortical excitability, female subjects (patients and controls) were not tested pre or during menstrual phase.

The local ethical committee of Assiut University Hospital approved the study. Written informed consent was obtained from all of the subjects.

Preparation

The subjects were seated in a comfortable chair and instructed to be as relaxed as possible. Electromyography (EMG) recordings from the contralateral abductor digiti minimi (ADM) muscle were acquired with silver-silver chloride surface electrodes, using a muscle belly-tendon setup, with a 3-cm diameter circular ground placed on the wrist. A Dantec keypoint EMG was utilized to collect the signal (Dantec, Skovlunde, Denmark). EMG parameters included a bandpass of 20-1000 Hz, and a recording time window of 200 ms. TMS was delivered using a figure-of-eight coil, with each coil wing having a 9-cm outer diameter. The coil was hand held in place by paying attention to keep orientation and position constant. Single pulse was applied using Maglite-r25 magnetic stimulator (Dantec, Skovlunde, Denmark).

Determination of resting motor threshold

First, we determined the optimal scalp location for stimulation defined as scalp position from which TMS evoked MEPs of greatest amplitude in the ADM. We used constant suprathreshold stimulus intensity, as the figure of eight coil was systematically moved in 1-cm steps to determine the scalp position from where TMS evoked MEPs of maximum peak-to-peak amplitude in the target muscle. The coil was positioned tangentially to the scalp and oriented so that the induced electrical currents would flow approximately perpendicular to the central sulcus, at a 45 angle from the midsagittal line⁸. Then, single pulse TMS was delivered to the optimal location starting at suprathreshold intensity and decreased in steps of 2% of the stimulator output. Relaxation and EMG signals were monitored for 20 ms prior to stimulation. The rMT was defined, as the minimal intensity required eliciting MEPs of 50 UV peak-to peak amplitude, in 5 out of 10 consecutive trails⁹.

Cortical silent period

The duration of the transcranially postexcitatory cortical silent period (CSP) was determined for both hemispheres during isometric voluntary contraction of the contralateral ADM. The participants were asked to perform a 10% maximum voluntary flexion of the thumb. EMG signal was played through a loud speaker as a feedback to the subjects. Voluntary contraction started several seconds before TMS. Stimuli were delivered not closer than one every 15-second to avoid fatigue. Sex magnetic stimuli were applied at intensity 125% of resting motor threshold. The EMG traced were rectified and averaged the length of the silent period was determined from the onset of the transcranially evoked response to the recurrence of at least 50% of EMG background activity.

MEP input-output curves:

TMS was applied over the right and then over the left hemisphere while 2 responses were recorded at each of a range of different stimulus intensities. Stimulus intensity was increased in steps of 10% of the individual rMT (from 110% to 150% rMT). MEP size was measured peak-to-peak in signal trails and averages were calculated for each of the different levels of intensity.

Phosphene threshold:

The optimal point to induced phosphenes was determined by mapping procedure. The session started with the coil placed on the midline 2-4 cm above the inion, after wards, the coil was shifted laterally to both sides. To induce phosphenes, a single magnetic stimulation was used; it began at an intensity of 100% of maximal stimulator output until phosphenes were obtained. Stimulation intensity was then fine-tuned to less than 100% to determine the threshold at which phosphenes could just visualized. This intensity was defined as the phosphene threshold (PT). Repeated determinations of the perception of the phosphenes and constant response had to be obtained.

Statistical analysis:

Comparisons between migraineurs and controls were made by means of an unpaired t-test (for rMT, and phosphenes values) and ANOVA for repeated measures (for the input –output curve). Pearson's correlation coefficient test was used to study correlations between PT, rMT and clinical parameters. Fisher's exact t-test was used to compare the proportion of subjects reporting phosphenes in patients and controls.

RESULTS

There was significant decreased rMT (36.8+8.8) in migraineurs patients (those with MA and MO) compared with control group (46.5+7.4) (P value < 0.0001), while no significant differences between migraineurs with MA (34.7+8.8) compared to MO  (40.7+7.7) (figure 1).

There was significant shortened duration of CSP in migraineurs (74.1+36.7 )(those with MA and MO) compared with the control group (98.5+28.4 ) P value < 0.0001, while no significant differences between migraineurs with aura (75.8+36.6) compared to without aura (71.4+38.7) (figure2).

But no significant difference between migraineurs (MA and MO) and control  in input output curve, despite the rapid increased in amplitude of MEP parallel to increased intensity of stimulation in migraineurs compared with control group (figure 3).

In-group of unilateral migraine (18 patients), there was no significant differences between migrainous side and none migranious side in rMT, in input –output curve. However there was shortened duration of CSP in migrainous side (58.5+22.7) compared with none migranious side (81.7+40.5) (P < 0.05).

The prevalence of phosphene was higher in migraineurs than control group, 24/ 28 (85.1 %), (17/ 18 in MA and 7/ 10 in MO) in migraineurs and 15 / 20, (75%) in control group. There was a significant negative correlation between duration of illness and phosphene threshold (P = 0.02).

There was significant decreased PT (P< 0.05) in migraineurs patients (those with MA and MO) (63.08+13.5) compared with the control group (72.0+10.8), with no significant differences between migraineurs with MA (62.5+12.8) and those MO (64.5+15.8) (figure 4).

Fig. (1): Resting motor threshold in patients and control groups. Values correspond to stimulator power expressed as means + SE%.

Fig. (2): Duration of cortical silent period during voluntary muscle contraction migraineurs with aura, without aura and control group. Data correspond to the duration of contralateral silent period expressed as mean+SE.

Fig. (3): Input-output curve of the primary motor cortex in migraineurs with aura, without aura and control group. Data correspond to the amplitude of MEP expressed as mean+SE.

Fig. (4): Phosphene threshold in patients groups and control group. Values correspond to stimulator power expressed as means+SE%.

DISCUSSION

The first study of motor cortex TMS in migraine was published in 1992¹⁰. In the present study, we investigated migraine patients with or without auras, unilateral and common migraine, compared with control group. The use of patients with unilateral migraine to allowed us to use the other side as additional control for this group. On the basis of our results, there was significant reduction in rMT in migraineurs patients with and without aura compared with control group, which may suggest hyperexcitability of motor cortex in migraineurs patients. This result was in agreement with the results of Van der Kamp et al.¹¹. They found that there was an increased MEP amplitudes and reduced rMT between attacks of patients with MA or MO.  While Maertens de Noordhout et al.¹⁰, and Afra et al.⁶, reported a reduction of interictal motor cortex excitability in unilateral and bilateral migraine with aura. The same results were reported by Bettucci et al.¹², in menstrual migraineurs patients without aura. We observed that rMT was significantly decreased in affected cortical side in patients with unilateral migraine compared to control group and unaffected side. Contrasting to our findings, Schoenen et al.¹³, reported that a significant increased MT on the affected cortical side of patients with migraine with auras compared to normal subjects or to the unaffected side. The differences between laboratories may be explained by different methodology, which may be device and patients dependent.

There was significant reduction in CSP migraineurs (those with and without aura) compared with control group. While there was no significant differences between migraineurs with aura compared to those without aura. These results suggest that the hyperexcitability of the motor cortex is a consequence of failure of interneuronal inhibitory circuit. Our results were agreement with Aurora et al.¹⁴, as they found that, cortical silent period was significantly shorter in MA patients than in controls. While Afra et al.¹⁵, Werhahn et al.¹⁶ reported normal silent period in MA or MO patients.

On the other hand the prevalence of phosphene was higher in migraineurs than control group especially in patients with visual aura. Beside this result there was significant reduction in phosphene threshold (PT) in migraineurs (with and without aura) compared with control group suggesting hyperexcitability of visual cortex.

These results were agreement with many investigators; Aurora et al.¹⁷ reported high prevalence of magnetophosphenes in migraine with aura patients between attacks (11/11 MA compared to 3/11 normal subjects). Similar prevalence differences (100% in MA, 47% in controls) were reported by Brighina et al.¹⁸. Aurora et al.^17,19 reported that, phosphene threshold was much lower in MA patients than controls. Battelli et al.²⁰, concluded that PHT for occipital TMS were lower in migraine with aura or without aura than in healthy subjects. Others failed to find significant differences between migraineurs and healthy subjects in phosphenes thresholds for TMS of the primary visual cortex¹⁸. Interestingly, in the latter study phosphene threshold tended also to be higher in MA (71.04%) and MO (74.2%) than in control (62.5%).

An opposite results were obtained by Afra et al.⁶, they reported that the prevalence of phosphenes was significantly lower in MA patients than in controls (10/18 versus 17/19), while no difference were found between controls and MO patients (18/22). Others reported the same results as regarded PHT²¹. Bohotin et al.²², reported that no difference in PHT between different groups. It has been suggested that the increased visual cortex excitability observed in migraine patients could be the expression of a reduced inhibition consequent upon the deficiency of GABA-mediated circuits^23,24.

There is evidence from experiments in animal models that GABAergic neurons are selectively damaged by a short period of hypoxia²⁵, and that repeated episodes of cortical spreading depression can cause selective suppression of GABAergic inhibitory function²⁶. Interesting data about the role of deficiency of GABA-mediated inhibition in the pathophysiology of migraine come also from observation of the efficacy of sodium valproate, a central GABA agonist, as a migraine prophylactic.

Several factors may explain the resting state of hyperexcitable cortical neurons between migraine attacks-brain damage, mitochondrial dysfunction, damage caused metabolic imbalance, ischemic changes, or a genetic factor may play an important role²⁰.

Although there is a large variability reported between laboratories on this subject⁵, our data seem to support the concept of an increased visual cortical excitability in migraine as a result of failure of inhibitory circuits. This was documented by decreased cortical silent period.

Our finding favors the hypothesis² of a permanent cortical hyperexcitability in migraine. This excitability changes seem to result from dysfunction of cortical inhibitory interneurones, as documented by decreased cortical silent period in migraineurs with or without aura compared to control group.

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