INTRODUCTION

 

Besides the cerebral cortex, current knowledge on migraine pathophysiology assigns an important role to both peripheral and central portions of the trigemino-vascular system. It is generally accepted that the migraine headache is associated with activation of the latter system¹. Researchers have tried to verify if the same lack of cortical habituation may exist also at the subcortical trigeminal level.

        Migraine attacks are characterized by a particular sensitivity to visual and auditory external stimuli². Some studies suggested that hypersensitivity to external  stimuli may persist between migraine attacks³. Habituation is a well – known physiological process which consists of a decreased responsiveness by repetition of the same stimuli and which may reflect an adaptive mechanism to protect against sensory over stimulation. For each sensation modality, like as for nociception, there is an interictal lack of habituation⁴. This habituation deficit concerns not only with  the cortical responses but also some brainstem reflexes such as the nociceptive blink reflex (nBR)⁵.

Studying trigeminal reflexes is a useful method for investigating the functional state of the trigeminal brain stem complex⁶. The blink reflex (BR), in particular, has been shown to be highly sensitive to changes in trigeminal activity. It was found that migraineurs have an interictal habituation deficit of the BR⁷. The nBR is elicited by a special stimulation electrode with high current density activating rather selectively Aδ fibers and has only a R2 component^8,9. While the classical blink R2 reflex habituates normally in migraine patients¹⁰, habituation of the nBR is reduced interictally¹¹.

The inherited susceptibility and environmental factors may be interrelated in migraine¹². Genetic load can be seen as determining, on the one hand, a critical threshold, and on the other hand, it may be responsible for interictal nervous system dysfunction. 

The habituation deficit of cortical evoked potentials may have a familial character and was proposed as an endophenotypic marker of migraine^13,14.

The aim of this study was to search for an abnormal habituation pattern of the nBR in healthy asymptomatic subjects who have a first degree relative affected by migraine, and to compare them with healthy volunteers and migraine patients.

 

PATIENTS AND METHODS

 

Patients

The study was done in the department of neurology, Minoufiya University Hospitals. It was approved by the local medical ethics committee and a written informed consent was taken from all subjects. It was done on 25 patients suffering from migraine without aura (MO: mean age: 23.8 years; 17 women, 8 men) according to Headache Classification Subcommittee of the International Headache Society, 2004². Exclusion criteria for patients included:

1-        Presence of any other pathology explaining the headache (either diagnosed clinically or by further investigations in the doubtful cases).

2-        Intake of prophylactic or abortive drugs for migraine on a regular basis.

3-        Intake of caffeine or alcohol containing beverages less than 4 hours before the recording.

 

The patients were compared to 52  healthy volunteers without personal history of migraine or any other  recurrent headache. They were recruited among  relatives of patients consulting our Neurology Clinic. They were separated in two groups of comparable age and sex distribution: 27 subjects without family history of migraine (HV: mean age: 24.6 years; 17 women, 10 men) , and  25 subjects  having at least one first degree relative who suffers from migraine (HV-F: mean age: 25.8 years; 16 women, 9 men).

 

Methods

The nociception-specific blink reflex was elicited according to the methods described by Kaube et al.⁸ and Katsarava et al.⁹. A custom-built planar concentric electrode  providing a high current density at low intensities was used to stimulate the supraorbital region. Recordings in patients were obtained interictally at least 2 days after the last and before the next migraine attack. With surface electrodes, we recorded bilaterally, over orbicularis oculi muscles, 10 blocks of  five  rectified EMG responses with an interblock interval (IBI) of 2 minutes. The 2-minutes IBI was chosen because it produces the most pronounced habituation in normal subjects⁹. The first sweep of each block was excluded from further analysis to avoid contamination with a startle response.

Individual pain thresholds were determined with two ascending and descending sequences of successive current intensities between 0.2 and 2mA in 0.1mA increments. Areas under the curve (AUC) of the R2 response were analyzed in each sweep off-line after demeaning, rectification and averaging between 27 and 87 ms⁵. We measured the area under the curve (the response area: RA) in µV × ms.¹⁵. Each block was analyzed separately. Mean values for each block were calculated. The data were normalized as a percentage deviation from the mean value of five consecutive sweeps.

Habituation of the nBR R2 was defined as the percentage change of the R2 area between the 1st and the 10th block of recordings. Since the study by Katasarva et al., that showed reduced nBR habituation interictally in migraineurs, was based on five responses obtained with short interstimulus intervals (ISIs)¹⁶, we also measured the amplitude change in the five sequential responses recorded in the 1st block with an ISI of 15-17 seconds.

 

Statistical Analysis

Results are presented as means ± standard deviations. Group differences in mean pain threshold and nBR latency were calculated with one-way analysis of variance (ANOVA). Habituation of the nBR responses was assessed by ANOVA for repetitive measurements with Scheffé's post hoc analysis, considering the different blocks (2 to 10) as within subject factors and the diagnostic groups (HV, MO and HV-F) as between subject factors. Results were considered significant at P<0.05.

 

RESULTS

     

No significant difference was found in mean perception or pain threshold between the three subject groups on either side of the forehead, or between the left and right side in any group. So, the mean stimulus intensities (1.5 × pain threshold) used for studying the nBR were similar between groups: 2.15±0.51 mA for HV; 2.11±0.72 mA for HV-F and 2.21±0.84 mA for MO.

Mean R2 latency was slightly shorter in migraineurs than in both groups of healthy volunteers (MO: 37.62±5.78 ms; HV: 41.81±7.45 ms; HV-F: 39.88±4.61 ms), but these differences were not significant [F(1,35) = 2.926, P = 0.10 versus HV; F(1,34) = 1.171, P = 0.29 versus HV-F] (Figure 1).

There was no significant side difference in first block nBR response area or in its habituation over 10 blocks in any of the three groups (Table 1).  The response area in the first block of stimuli was greater in healthy controls than in migraineurs  or healthy volunteers with an affected first degree relative, but this difference did not reach statistical significance [F (1,35) = 1.564, P = 0.22 versus MO; F(1,33) = 0.826, P = 0.39; (Table 1).

 

 

Figure 1. Comparison among the groups

regarding the mean R2 latency.

 

Table 1. R2 response area in the first block of averaged responses (mV_ms).

 

 

In HV there was a strong habituation with an amplitude decrease exceeding 50% between the first and the 10th block of five averagings. This contrasted with a less than 30% habituation in the MO [F(1,35) = 13.323, P = 0.001 versus HV] and HV-F [F(1,32) = 4.71, P = 0.049 versus HV] groups (Table 2).

Habituation steadily increased in successive blocks in all the three groups of subjects up to the 10th block of stimuli. The difference in the degree of nBR RA habituation between healthy volunteers and the other two groups, however, was already significant in the second block of five averagings: 25.2% habituation in HV, –8.9% (i.e. potentiation) in HV-F [F(1,33) = 7.810, P = 0.010 versus HV] and 1.9% habituation in MO [F(1,35) = 5.151, P = 0.037 versus HV]. Habituation of the R2 response area of ipsi- and contralateral nBR in 10 blocks of five averagings (interstimulus interval: 15–17 ms; interblock interval: 2 min) expressed as percentage of the 1st block.

Table  2. Habituation of the R2 response area in the last  block of averaging relative to the 1st block (%).

 

 

        A positive intra-individual correlation was found between attack frequency and habituation in MO (r = 0.598; P = 0.010).  Single response areas within the 1st block of stimuli and their habituation in individual subjects greatly varied. There was nonetheless a significant reduction in habituation between the first and fifth response in the HV-F group. For instance, on the ipsilateral side the amplitude change was -37.5% (potentiation) in HV-F, compared to +42.1% (habituation) in HV [F(1,33) = 4.760; P = 0.04]. Habituation was also lower in MO (30.5%) than in HV, but this difference was not significant [F(1,35) = 0.811; P = 0.45].

 

DISCUSSION

     

Several studies have searched for different biochemical and neurophysiological abnormalities that  are able to explain the permanent perpetuation of the migraine attacks, which, if present, should also be detectable in the pain-free period, representing underlying dysfunctions. Patients with migraine were observed to show an increased cortical bioelectrical activity with respect to normal subjects. Early investigators observed increased amplitudes of visual responses evoked by light flashes or by pattern-reversal stimulation in migraineurs between attacks. However, the question arose whether this excessive increase in amplitude could be due to an insufficient habituation and whether the latter could be a more general abnormality in processing incoming information in migraineurs brain¹⁶.       

The results of this study showed that habituation of the nBR is significantly reduced interictally in migraineurs compared to healthy volunteers, and this was in line with those reported by Katsarava et al.¹¹. The intrablock habituation values were smaller in migraineurs than in healthy volunteers, but this difference was not significant, possibly because the standard deviations were too large and groups too small. The difference in the habituation of nBR response area between patients and healthy volunteers was significant as early as the 2nd block of averages. It increased with repetition of stimuli and tended to become maximal in the 10th block, a time at which habituation was found to be maximal in normal subjects⁹. Di Clemente et al. found that the first nBR response had a tendency to be lower in migraineurs than in healthy subjects. This observation was inconsistent with an abnormality involving trigeminal nucleus sensitization and rather suggested that the reflex could be hypoexcitable in-between attacks^5,17. The question of hypo- or hyperexcitability is still debated regarding the pathophysiology of interictal habituation deficit observed in migraineurs¹⁸. The habituation of the blink reflex is reduced interictally in migraine patients during short ^7,11. as well as long time courses^5,17.

Few correlations have been found between neurophysiological results and frequency of migraine attacks. Our results showed positive intra-individual correlation between attack frequency and habituation in MO.  In another study, it was found that in episodic migraine, the habituation deficit of BR decreased with increasing attack frequency which suggested that it was unlikely to be due to trigeminal sensitization^5,17. This does not seem to be the case in chronic migraine patients who displayed a lower degree of blink reflex habituation when studied outside an attack¹⁹. Additionally, de Tommaso et al.  studied laser-evoked cortical responses and proved that the habituation deficit  found interictally in migraineurs was positively correlated with attack frequency ²⁰ . In a magnetoencephalographic recording of somatosensory evoked potentials, the amplitude increase in migraineurs was linked to the frequency of attacks ²¹.

All these results are in contrast with our finding of a negative correlation between the habituation deficit on the nBR and attack frequency. It could, however, be related to the fact that nBR short-term habituation ¹¹, parallel to habituation of evoked cortical potentials²², normalizes during the attack period. The patients with high-attack frequencies may be at greater risk of being recorded in closer vicinity to an attack.

The classical R2 is essentially normal interictally, but it is less influenced by the warning of the stimulus in migraine ¹⁰ and, at short IBI, its habituation was found reduced in migraineurs who developed an attack within 3 days after the recording⁷. The rather low nBR amplitude interictally in migraineurs, contrasts with the 680% nBR RA increase reported during the migraine attack²³. This may reflect ictal sensitization of spinal trigeminal nucleus neurons²⁴. The low nBR amplitude did not favor such sensitization and rather suggested that the R2 interneurons and circuit could be hypoexcitable in-between migraine attacks. Lack of habituation might be a consequence of reduced serotoninergic transmission^25,26. leading to a decreased preactivation level.

The pathophysiology of this habituation deficit may be related to an altered serotoninergic transmission. The serotoninergic system plays an important role in the endogenous pain control system and has been implicated in migraine pathophysiology  ²⁵ . Strong intensity dependence of auditory evoked potentials in migraine habituation pattern tends to normalize with fluoxetine prophylaxis which is a serotonin re – uptake inhibitor²⁷.      

This study showed that asymptomatic subjects with a first degree migrainous relative gave the same nBR abnormalities as patients with full-blown migraine between attacks. Compared to healthy volunteers without a family history of migraine, they tended to have smaller first block nBR response areas and reduced nBR habituation. Their degree of habituation was intermediate between that of healthy controls who habituated more and that of migraineurs who habituated less, but the difference was  significant respective to the former, but not to the latter. Healthy subjects at risk also had a significant reduction of habituation within the 1st block of five responses, which differed from the findings in migraineurs.

Some migraine phenotypes appear to be complex genetic disorders, where additive genetic effects (susceptibility genes) and environmental factors are interrelated ²⁸. Various gene polymorphisms may be more prevalent in migraineurs than in controls. Although certain rare migraine subtypes such as familial hemiplegic migraine are monogenic diseases, there is increased evidence that the common forms of migraine are polygenic multifactorial diseases, where the genotype determines a migraine threshold which is modulated by internal (e.g. hormonal) and environmental factors^28-30.

The link between genetic determinants and abnormal information processing may exist in migraine³¹. One of the migraine interictal electrophysiological abnormalities is a marked intensity dependence of auditory evoked cortical potentials (IDAP), which is obtained after stimulations of increasing intensities (25).  The IDAP habituation was investigated in 20 pairs of migraineurs, i.e. parents and their children. Children tended to have more abnormal values than parents³².

Another interictal abnormality tested was the contingent negative variation (CNV). It is a slow cortical potential related to higher mental functions, used to study habituation in migraine. Its early component showed that habituation was markedly decreased or even abolished in patients affected by migraine without aura between attacks ³³.  Siniatchkin et al, observed strong correlations according to the amplitude and habituation of the early CNV component (iCNV) between children suffering from migraine and their parents with migraine and between young migraineurs and their healthy parents who have a positive family history of migraine ³². Moreover, lack of habituation of the iCNV was found in asymptomatic subjects with a positive family history of migraine, defined ‘‘at risk”, and the amplitude of the iCNV correlated significantly with the relative number of subjects suffering from migraine in the family ³⁴.  The same observation was present with nociceptive blink reflex in a group of healthy asymptomatic subjects having a 1st degree relative affected by migraine ⁵.

The previous studies and our results raise the possibility that subjects with a familial predisposition for migraine may present a presymptomatic neurophysiological abnormality in response habituation, i.e. the same habituation deficit as migraine patients. A longitudinal follow-up study may be conducted for healthy subjects at high risk and to compare the genotypes. This may help to determine which factors such as personality traits, life events, environment or co-morbidity can protect subjects with a family history of migraine against developing migraine.

 

[Disclosure: Author reports no conflict of interest]

 

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