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Year : 2021  |  Volume : 38  |  Issue : 2  |  Page : 105-110

Changes in the blink reflex during migraine with aura and the inter-attack period

1 Department of Neurology, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Department of Clinical Neurophysiology, Department of Neurology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
3 Department of Clinical Neurophysiology, Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

Date of Submission27-Sep-2020
Date of Decision18-Jan-2021
Date of Acceptance18-Jan-2021
Date of Web Publication13-May-2021

Correspondence Address:
Mehlika Panpalli Ates
Department of Neurology, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ziraat Mah. Sehit Omer Halisdemir Street No: 20, F Block, 5. Floor, Neurology Clinic, Diskapi, Ankara 06110
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_176_20

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Introduction: This study aimed to investigate the possible excitability changes in the trigeminovascular system based on blink reflex (BR) in patients experiencing migraine and to compare migraine aura attacks and attack-free period. Materials and Methods: A total of 56 patients diagnosed with migraine headache with aura and 20 healthy individuals without migraine were evaluated electrophysiologically using the BR test. The BR test was repeated twice in patients with migraines during attacks with aura and attack-free period. Results: During the migraine attack with aura, R1 latencies were shorter, and R2 latencies were longer than in the interictal period. Likewise, R1 latencies were shorter, and R2 latencies were longer, in the interictal period compared to normal values obtained in the control group. Conclusion: The detected BR abnormalities have been thought to be able to reflect migraine-related dysfunction in the brainstem and trigeminovascular connections. Significance: It has been concluded that the detected BR abnormalities might reflect migraine-related dysfunction in the brainstem and trigeminovascular connections, indicating increased neuronal excitability in migraine.

Keywords: Blink reflex, hyperexcitability, migraine aura, trigeminovascular system

How to cite this article:
Ates MP, Ferik S, Pektezel LD, Guven H, Comoğlu SS. Changes in the blink reflex during migraine with aura and the inter-attack period. Neurol Sci Neurophysiol 2021;38:105-10

How to cite this URL:
Ates MP, Ferik S, Pektezel LD, Guven H, Comoğlu SS. Changes in the blink reflex during migraine with aura and the inter-attack period. Neurol Sci Neurophysiol [serial online] 2021 [cited 2021 Sep 18];38:105-10. Available from: http://www.nsnjournal.org/text.asp?2021/38/2/105/315948

  Introduction Top

The trigeminovascular system (TVS) is known to play a primary role in the pathophysiology of migraine, which has been suggested to be a primary neuronal process in which the cerebral cortex is hyperexcitable. The neuronal depolarization induced by the hyperexcitable cerebral cortex and the resulting cortical spreading depression (CSD) wave has been held responsible for the formation of the aura and activation of the TVS in migraine.[1]

Brainstem structures have been suggested to be activated during a migraine attack and the brainstem can be the generator of migraine, which has been supported by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies.[2] Sensitization of TVS has been shown to be responsible for pain in the initial phase of migraine.[1],[3],[4] Peripheral sensitization of trigeminal neurons reveals characteristic throbbing pain in migraine.[5],[6]

Blink reflex (BR) is an objective electrophysiological method that examines the reflex responses obtained by the trigeminal nerve and analyzes brainstem and subcortical structures function. The afferent branch of BR is the ophthalmic division of the trigeminal nerve, and the efferent branch is the facial nerve. Ipsilateral early (R1) and bilateral late (R2) responses are obtained at the stimulated area. Synapses between the main sensory nucleus of the trigeminal nerve and the ipsilateral facial nerve motor nucleus on the same side play a role in the R1 response. The entire reflex arc is located in the pons and is not associated with a clinically recognizable response. R2 responses are mediated multisynaptic pathways between the nucleus of the spinal tract of the trigeminal nerve and both ipsilateral and contralateral facial nerve motor nuclei. The R2 records can be used to assess the excitability of the brainstem reticular formation and corticoreticular pathways and are observed clinically as bilateral blinking. The R2 component is modulated by segmental and suprasegmental mechanisms and provides information about the excitability of brainstem interneurons and functions related to synaptic transition at the brainstem level and affected by the abnormalities at different levels of the brain.[7],[8]

The BR abnormalities have been reported in patients with migraine; however, evaluations have been made frequently during the interictal period and there are limited data on BR changes during migraine attacks.[9],[10],[11] This study aimed to evaluate BR in patients experiencing migraine with aura during aura attack and interictal period and to compare their BR with healthy individuals.

  Materials and Methods Top


We prospectively recruited 56 consecutive patients with migraine with aura according to the International Classification of Headache Disorder III-beta criteria who were followed in the neurology outpatient clinic.[12]

Patients with migraine were evaluated using file records, headache diaries, and face-to-face interviews. The study was conducted only with female patients and control group to eliminate the contradictions that could have been arisen from possible differences in reflex stimulation thresholds. It is known that some of the migraine attacks are associated with menstrual period and females may have some cortical excitability changes during this period. Therefore, all subjects included in the study were female, and none were in their menstrual period. A total of 56 patients experiencing an episodic migraine with only visual aura, whose duration of disease was 1 to 7 years and attack frequency was ≤15, were included in the study as the patient group and a total of 20 healthy volunteers without migraine or other types of primary and secondary headache were included in the study as the control group. The menstrual cycle and female sex hormones can have significant effects on migraine aura sex hormones differences. It has been reported that estrogen increases susceptibility to CSD, while testosterone has the opposite effect.[13],[14] Patients whose every attack were not accompanied by aura were also included in the study; however, evaluations were made only during attacks with aura, and interictal periods.

The exclusion criteria were the presence of any neurological disease other than migraine, Bell's palsy history, facial nerve and/or trigeminal nerve lesion, hemifacial spasm, primary or secondary headaches other than migraine, prophylactic treatment due to migraine in the last 2 months or excessive drug use, a medication known to cause headaches or affecting the central nervous system, lesion in the brainstem or brain lesion associated with another neurological disease in brain magnetic resonance imaging, polyneuropathy, diabetes mellitus, thyroid disease, chronic alcohol use, Vitamin B12 and folic acid deficiency or use of Vitamin B12 and folic acid supplement, and eye disorder that would affect the BR assessment. The control group included individuals without primary and secondary headache, with similar exclusion criteria.

Blink reflex

In the migraine patients included in the study, the BR examination was performed twice during the migraine attack with aura and in the interictal period. The conditions of not receiving any symptomatic treatment during the attack and having no pain complaints about 72 h minimum for the interictal period were sought. A visual Analog Scale was used to assess the severity of the pain during the attack. Healthy controls were also evaluated with BR.

The BR test was applied in our electrophysiology laboratory by the specialist and experienced personnel. An electroneuromyography (Neuropack MEB-9200K, Nihon Kohden Co., Tokyo, Japan) device with a BR test program was used to elicit and record BR responses and to randomly repeat stimulations at different time intervals. Kimura's method was used in the BR examination.[15] Patients were lied down in a quiet and warm room with their eyes slightly closed and surface recording electrodes were placed in the lower lateral direction of the bilateral orbicularis oculi muscle. Reference electrodes were placed bilaterally on the root of the nose. The ground electrode was placed around the arm. Square-wave negative single pulses lasting 0.2 ms were transmitted by a constant current isolation unit. The filter settings used were 50–3000 Hz, sensitivity of 200 μV/division, and analysis time of 200 ms. The BR test was repeated twice in patients with migraine. During a migraine attack, the supraorbital nerve was stimulated with a cathode bar electrode placed on the supraorbital foramen on the painful side, then it was stimulated on the other side. It was tested bilaterally in the interictal phase and on both occasions. Ipsilateral and contralateral responses were recorded. Stimulus intensity was 0.2 ms. The nerve was stimulated randomly and without informing the patient, with stimulation intervals of 20–30 s to avoid habituation. A total of 10 responses were recorded in both the groups. Latency and amplitudes of the R1 component (right R1 [RR1], left R1 [LR1]) and RR2 ipsilateral (RR2i and LR2 ipsilateral [LR2i]) and RR2 contralateral (RR2c and LR2 contralateral [LR2c]) latencies of the R2 component were recorded. R1 amplitude was measured peak to peak.

The study was carried out according to the Helsinki Declaration and was approved by the Institutional Local Ethics Committee (2014-15/05). All patients participating in the study provided written informed consent.

Statistical analysis

Statistical analysis was carried out using an Statistical Package for the Social Sciences (SPSS®) 22.0 (IBM Corp., Armonk, NY, USA) for Windows and Mac OS X. Shapiro-Wilk test was used to test the hypothesis of normality. Numeric data were presented as mean ± standard deviation and nominal data were presented as percentage (%). Student's t-test for paired and unpaired data was used for the statistical analysis within and between the groups in the basal assessment of the BR. Pearson's correlation test and Spearman rank correlation coefficient were used respectively for parametric and nonparametric data to assess any correlations between the neurophysiological and clinical parameters. P < 0.05 were accepted as statistically significant.

  Results Top

The study included a total of 56 female patients and 20 female healthy individuals; the mean age of the patient and control groups was 28.9 ± 6.95 years (18–41) and 28.1 ± 6.9 years (18–41), respectively (P = 0.668). The mean attack frequency of the patients in the last 3 months was 4.7 ± 3.3 (1–15) days/month. While the attack frequency was ≥4/month in 36 patients (64.3%), it was <4/month in 20 patients (35.7%). The pain was always unilateral in 44 patients (78.6%) and bilateral in 12 patients (21.4%) (being more dominant on one side). Twenty-one (47.7%) of the patients with unilateral pain reported that the pain was on the right side, whereas 23 (52.3%) reported that the pain was on the left side [Table 1].
Table 1: Demographic and clinical characteristics of patients

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The BR results of patients with migraine (during the attack and interictal period) and the control group are shown in [Table 2].
Table 2: Comparison of blink reflex test results between groups

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During the migraine attack with aura, the RR1 latencies were shorter than those in the interictal period and of the control group (P = 0.000 and P = 0.000, respectively). LR1 latencies were shorter than those in the interictal period and of the control group (P = 0.000 and P = 0.000, respectively). The RR2i latencies were longer than those in the interictal period and of the control group (P = 0.000 and P = 0.000, respectively). The RR2c latencies were longer than those in the interictal period and of the control group (P = 0.000 and P = 0.005, respectively). The LR2i latencies were longer than those in the interictal period and of the control group (P = 0.000 and P = 0.000, respectively). The LR2c latencies were longer than those in the interictal period and of the control group (P = 0.036 and P = 0.009, respectively). Furthermore, RR1 and LR1 amplitudes were found to be larger than those in the control group during migraine attacks with aura (P = 0.017 and P = 0.000, respectively) [Table 2].

During the interictal period, compared to the control group, the RR1 and LR1 latencies were shorter (P = 0.000 and P = 0.000, respectively), RR2i and RR2c latencies were longer (P = 0.012 and P = 0.048, respectively), and LR2i and LR2c latencies were longer (P = 0.017 and P = 0.019, respectively). Furthermore, no statistically significant difference was found between the migraine group and the control group in terms of RR1 and LR1 amplitudes in the interictal period (P = 0.052 and P = 0.212, respectively) [Table 2].

When the correlation of migraine duration and attack frequency with the RR1, LR1, RR2i, RR2c, LR2i, and LR2c latencies were examined; only a mild negative correlation was observed between the duration of disease and right RR1 latency (P = 0.038, ρ: 0.277). Disease duration has not any influence on the other findings. No statistically significant correlation was observed between attack frequency and BR latencies.

  Discussion Top

The results of the present study have demonstrated that brainstem dysfunction develops in patients with migraines and it is demonstrated by electrophysiological changes reflected in BR results. These changes have been shown to be more pronounced during the migraine attack than in the attack-free period; however, functional abnormality in the brainstem continues in the patients with migraines during the attack-free period.

In the present study, patients with migraine have been observed to have shorter R1 and longer R2 latencies during an attack with aura and interictal period compared to the control group, suggesting that the sensitivity and excitability of trigeminal afferents in the brain of patients with migraine increase, whereas central cortical inhibition decreases. This may have arisen as a response to the sensitization of neurons in the cutaneous nociceptive afferent arc or trigeminal nucleus. Changes in R2 latency are due to polysynaptic transition in the brainstem which includes the pons, lateral medulla, and reticular formation and excitability of the interneurons. Possible central hyperactivity in migraine also leads to a change in the excitability of brainstem interneurons. In the present study, the change in R2 latency during the attacks has reflected the excitability of the interneurons, suggesting that the stimulation threshold of the brain is lower in patients with migraine, particularly during a migraine attack with aura, considering the short R1 latency. To sum up, shortened R1 latencies may reflect the hyperexcitability in migraine and prolonged R2 latencies may reflect impairment in the modulation of pain.[16] The BR takes afferents from the cortex through the different areas of the brainstem. Possible central hyperactivity in migraine also leads to a change in the excitability of brainstem interneurons.

Shortening in R1 latencies, which is more prominent during migraine attack with aura, but also continues in the interictal period, has shown that the stimulation threshold of the brainstem is lower in patients suffering from migraine and has supported the view that brains with migraine are hyperexcitable.[17]

The involvement of the TVS in migraine pathogenesis has been demonstrated in previous animal experiments and it has been suggested that the brainstem may be a “migraine generator” in PET and fMRI studies.[2]

Pain is thought to occur with the TVS being affected directly or indirectly.[18]

The brains of individuals suffering from migraines are thought to be different from those who are not suffering from migraine headaches in terms of organization and function. To the best of our knowledge, this is the first study in the literature that evaluates the BR responses of patients suffering from migraines during attacks with aura. The BR responses of the same patient, which were measured during migraine attacks with aura and interictal periods, were compared with the healthy volunteers.

In another study, in which 43 migraine patients with aura and 31 healthy controls were compared using the standard BR technique, no difference was reported between the patient group and the control group in terms of R1 latencies, but the R2 latencies of the patient group were found to be significantly longer than the control group.[19] These findings have been interpreted as objective evidence of the fact that trigeminal afferents or polysynaptic transition are affected in the brainstem of patients suffering from migraine headache.

It has been thought that trigeminal sensitization can continue subclinically, also during the attack-free (interictal) period.

Some previous studies have reported that BR measurements were normal except for migraine attacks, R2 amplitude and area changes were corrected by the sumatriptan treatment, and there was a temporary dysfunction in the trigeminal system in the presence of migraine headache.[20] However, R2 amplitudes were not evaluated in the present study. These changes suggested that excitability was permanently affected.

The measurements reported in this study have been reported in previous studies of migraine patients. However, the results of this study potentially are valuable, in part because as it is the first study to use a paired design (each patient tested twice, ictal and interictal).

In light of these data, it can be said that there is an increase in the cortical sensitization and even excitability in the presence of migraine headache, or central inhibitory mechanisms may be impaired, and a brain with migraine headache goes through different excitability periods namely ictal and interictal, which may be responsible for the pathophysiological mechanisms of migraine.

In the literature, CSD associated with migraine visual aura has been reported to initiate the cortical and meningeal event compatible with the development of headache by activating trigeminovascular afferents.[21],[22],[23]

In this study, we did not find a relationship between reflex change and pain side. This may be attributed to the fact that there has been no numerical statistical difference between patients with right-sided pain, left-sided pain, and pain on both sides, causing the migraine patient group to be homogeneous. Another reason is that vascular theory may be effective. Headache may occur on the same side following a visual or somatosensory aura on the right or left side, although cerebral blood flow changes are in the opposite hemisphere. However, migraine is known to be associated with a stimulating period that will not be compatible with the vascular or ischemic hypothesis in 60% of patients. This stimulating period consists of mood changes, thirst, desire to overeat, excessive yawning, and dizziness. Special tomographic blood flow measurement techniques have shown that the oligemia period during the migraine aura originates from an occipital pole and proceeds toward the hemisphere on the same side at a speed of 3–4 mm/min. Although the brainstem and hypothalamic generators have been held responsible, the origin of the migraine attack is still unknown.[2],[24],[25],[26],[27],[28],[29] CSD activates the trigeminal neurons and also may trigger the activations of meningeal trigeminal termination and TVS, causing the headache.[30] The CSD has been reported to be a primary neuronal phenomenon that occurs in the human cortex and is the result of reduced metabolic requirements of the cortical circulation of the migraine aura.[21] In the study, headache occurred on the same side following the visual aura on one side. In light of these data, it can be said that aura or migraine facilitates stimulation as it can change brain excitability compared to normal individuals, it increases the action potential and causes responses with earlier latency, longer duration, and larger amplitude by ensuring (or maybe by enhancing) the depolarization of the axon membrane.

The limitation of this study is that the amplitude and area of late components (R2) occurring during the BR test are not investigated or evaluated. Essentially, the purpose of selecting only female patients was to eliminate the difference that may arise from gender differences. On the other hand, in this article, the gender selection may be a limitation of the study. When future studies are conducted on the male gender, we can understand how similar or different they are from our findings.

The BR R1 latencies have been seen to be shortened, whereas R2 latencies are prolonged in patients with migraine during an attack with aura and interictal period compared to the control group. The shortening of R1 latencies may reflect the hyperexcitability in migraine, while the prolongation of R2 latencies may indicate an impairment in the modulation of pain.

Understanding the pathophysiology of migraine is of great importance in choosing the best treatment method.

  Conclusions Top

The BR test results have shown that there is a correlation between the brainstem and the TVS in patients with migraine and excitability is increased in patients suffering from migraine.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2]


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