Variability of the blink reflex in patients with migraine

Background and purposeSensitization of brainstem trigeminal nuclei and activation of the trigeminovascular system are thought to play an important role in migraine. The blink reflex has become a valuable tool for investigating trigeminal nerve function. The aim of the study was to assess the differences in electrophysiological examinations of the trigeminal nerve (blink reflex) in a group of patients with migraine in comparison with a healthy control group.Material and methodsThe examination was conducted among 58 patients. Patients were diagnosed in the Polyclinic or hospitalized in the Department of Neurology of Warsaw Medical University in Bielański Hospital. The study group included 29 patients suffering from migraine (diagnosed according to the International Classification of Headache Disorders, 2^nd edition) and 29 patients without headaches served as controls. All patients underwent neurological examination and magnetic resonance imaging to identify organic disorders. The blink reflex was tested among all patients in accordance with electrophysiological laboratory standards.ResultsThe latency of the R1 response was significantly shorter among patients with migraine. The latency of R2 and R2’ responses was similar in patients and controls. A significant inverse correlation was observed between latency of R2 and R2’ responses and frequency of migraine attacks.ConclusionsThe inverse correlation between the frequency of attacks and the latency of R2 and R2’ responses of the blink reflex confirms the abnormal eaxcitability induced by the high frequency of migraine attacks.     

Expression of ASIC3 in the Trigeminal Nucleus Caudalis Plays a Role in a Rat Model of Recurrent Migraine

Acid-sensing ion channel 3 (ASIC3) is abundant in the trigeminal nervous system and is most sensitive to a slight pH decrease. Recent studies have indicated that ASIC3 in the peripheral trigeminal ganglia is likely involved in the pathogenesis of migraine pain. However, it is unclear whether this receptor plays a role in recurrent migraine, namely, migraine chronicity. Here, we aimed to investigate the role of ASIC3 in an animal model of recurrent migraine (RM). In this study, we established a rat model of RM through repeated administration of inflammatory soup (IS) onto the dura. Then, we tested the mechanical pain thresholds of the face and hindpaws by von Frey filaments. qRT-PCR, Western blot and immunofluorescence labelling were used to detect the expression and localization of ASIC3 in the trigeminal nucleus caudalis (TNC). The protein levels of calcitonin gene-related peptide (CGRP), its receptor component receptor activity modifying protein 1 (RAMP1) and c-Fos were analysed following treatment with the ASIC3 inhibitor APETx2 and activator 2-guanidine-4-methylquinazoline (GMQ). We found decreased pain thresholds after repeated dural inflammatory stimulation, which suggested the establishment of an RM model. Based on this model, we observed elevated expression of ASIC3 in the TNC group compared to that in the Sham group. ASIC3 was primarily expressed in neurons but not in astrocytes of the TNC. Moreover, APETx2 attenuated tactile allodynia and significantly decreased the expression of c-Fos, CGRP and RAMP1, while GMQ aggravated these effects compared to those observed in the IS + vehicle group. These findings indicate a critical role of ASIC3 channels in the pathophysiology of RM, and ASIC3 might represent a potential therapeutic target to prevent the progression of migraine.     

The blink reflex in "chronic migraine".

OBJECTIVES: Activation of the trigeminovascular system and sensitisation of brainstem trigeminal nuclei are thought to play an important role in migraine. The aim of this study was to investigate the blink reflex and its habituation in patients with "chronic migraine". METHODS: We studied 35 patients suffering from "chronic migraine" (IHS classification criteria) outside and during a spontaneous attack, and 35 control subjects. An EMG device with a specific habituation test program was used to elicit and record blink reflex responses and to randomly repeat stimulations at different time intervals so as to induce habituation. RESULTS: The R(1) and R(2) latencies, amplitudes and areas of the basal blink reflex were similar in patients studied both outside and during an attack as well as in control subjects, whereas the blink reflex habituation responses were markedly reduced in patients studied outside an attack. The percent changes in the R(2) areas from the baseline values, obtained when stimuli were delivered at time intervals of 10, 5, 4, 3, 2 and 1s, were statistically different (p<0.01-p<0.001) from those of the same patients studied during a migraine attack and of those of control subjects. There was a significant correlation between decreased habituation of the blink reflex and a higher frequency of attacks. The stimulus intensities of the blink reflex (multiples of the detection threshold intensities) were significantly lower (p<0.001) on the side affected, or more severely affected, by headache in patients studied during a migraine attack. CONCLUSIONS: The decreased habituation of the blink reflex outside an attack reflects abnormal excitability in "chronic migraine", which normalizes during the attacks. The inverse correlation between the frequency of attacks and habituation responses confirms the abnormal excitability induced by the high frequency of attacks. Central sensitisation mechanisms (allodynia) may explain the lower detection thresholds observed on the side affected by headache in patients during the attacks. SIGNIFICANCE: The blink reflex and its habituation may help shed light on the subtle neurophysiological changes that occur in migraine patients between and during attacks.     

Electroacupuncture at Fengchi (GB20) inhibits calcitonin gene-related peptide expression in the trigeminovascular system of a rat model of migraine

Most migraine patients suffer from cutaneous allodynia; however, the underlying mechanisms are unclear. Calcitonin gene-related peptide(CGRP) plays an important role in the pathophysiology of migraine, and it is therefore, a potential therapeutic target for treating the pain. In the present study, a rat model of conscious migraine, induced by repeated electrical stimulation of the superior sagittal sinus, was established and treated with electroacupuncture at Fengchi(GB20)(depth of 2–3 mm, frequency of 2/15 Hz, intensity of 0.5–1.0 m A, 15 minutes/day, for 7 consecutive days). Electroacupuncture at GB20 significantly alleviated the decrease in hind paw and facial withdrawal thresholds and significantly lessened the increase in the levels of CGRP in the trigeminal ganglion, trigeminal nucleus caudalis and ventroposterior medial thalamic nucleus in rats with migraine. No CGRP-positive cells were detected in the trigeminal nucleus caudalis or ventroposterior medial thalamic nucleus by immunofluorescence. Our findings suggest that electroacupuncture treatment ameliorates migraine pain and associated cutaneous allodynia by modulating the trigeminovascular system ascending pathway, at least in part by inhibiting CGRP expression in the trigeminal ganglion.     

Migraine-update--current concepts of migraine pathogenesis]

The pathophysiology of migraine still remains unclear. However, abundant evidence in support of the view that migraine as an illness of the central nervous system has been accumulated. First, the hyperexitability in the brain is recognized even in the stage between attacks in migraineurs according to findings of transcranial magnetic stimulation techniques, MRI-BOLD studies or 31P SPECT examinations. Second, cortical spreading depression originating in the occipital cortex is more likely to be related to the aura. Third, sensitization of the trigeminal nerve system is substantially involved in process of headache pain in migraine. Fourth, clonic dysfunction of the priaqueductal gray matter in the brain stem may underlie the migraine pathogenesis. Thus, current concept of susceptibility of migraine is attributed to certain dysfunction of the deep brain structures such as the brain stem rather than the blood vessels in the brain or dura mater.     

The PACAP receptor: A novel target for migraine treatment

The origin of migraine pain has not yet been clarified, but accumulating data point to neuropeptides present in the perivascular space of cranial vessels as important mediators of nociceptive input during migraine attacks. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in sensory trigeminal neurons and may modulate nociception at different levels of the nervous system. Human experimental studies have shown that PACAP-38 infusion induces marked dilatation of extracerebral vessels and delayed migraine-like attacks in migraine patients. PACAP selectively activates the PAC₁ receptor, which suggests a possible signaling pathway implicated in migraine pain. This review summarizes the current evidence supporting the involvement of PACAP in migraine pathophysiology and the PAC₁ receptor as a possible novel target for migraine treatment.     

Short latency trigemino-sternocleidomastoid response in patients with migraine

OBJECTIVE: To investigate the central trigeminal circuits in migraine patients. MATERIALS AND METHODS: Short latency responses can be recorded in sternocleidomastoid (SCM) muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex was investigated in 20 healthy subjects, in 20 patients suffering from migraine with aura (MWA) and in 20 patients suffering from migraine without aura (MWOA) during and between the attacks. RESULTS: The trigemino-cervical responses were bilaterally abnormal in 17 patients with MWA and 15 patients with MWOA during the headache attacks, in 11 patients with MWA and in 10 patients with MWOA during the interictal period. In the patients with normal trigemino-cervical responses during the pain-free phase the triptan was significantly more effective at relieving headache. CONCLUSIONS: Our findings further support and emphasise the role of the trigeminal system in the pathogenesis of migraine. The bilateral location of the abnormalities suggests a centrally located dysfunction. Therefore, the trigemino-cervical reflex is sensitive in disclosing a disturbed brainstem activity and may be an index of neuronal activity in the human brainstem; moreover their assessment may help as valuable prognostic tool for predicting the efficacy of triptans therapy.     

Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus?

OBJECTIVE: To investigate trigeminal sensory processing in patients with migraine using a novel "nociception-specific" blink reflex. METHODS: Seventeen patients with unilateral migraine headache were studied within 6 hours of onset. Blink reflexes were elicited with a standard stimulating electrode (standard blink reflex) and concentric stimulating electrode (nociception-specific blink reflex) during the acute migraine attack, after treatment with IV lysine acetylsalicylate (1,000 mg) or oral zolmitriptan (5 mg) and interictally. RESULTS: After standard stimulation, no differences were detected for the R1 and R2 onset latencies and areas under the curve (AUC) between the different time points and the headache and nonheadache side. Nociception-specific stimulation revealed a shortening of R2 onset latencies (44.3 +/- 5.4 ms for headache side vs 48.9 +/- 5.8 ms for nonheadache side) during the acute migraine attack compared with the headache-free interval (49.8 +/- 5.3 vs 49.8 +/- 4.5 ms). The AUC of the R2 increased on the headache side by 680% and on the nonheadache side by 230% compared with the headache-free interval. Drug treatment parallel to pain relief increased the onset latencies (zolmitriptan: 48.0 +/- 8.2 ms for headache side vs 52.3 +/- 7.6 ms for nonheadache side; lysine acetylsalicylate: 48.0 +/- 5.0 ms for headache side vs 51.2 +/- 5.6 ms for nonheadache side) and reduced the AUC of R2 (zolmitriptan by 45% and lysine acetylsalicylate by 48%). CONCLUSION: The data suggest temporary sensitization of central trigeminal neurons during acute migraine attacks.     

Defeating migraine pain with triptans: a race against the development of cutaneous allodynia

For many migraine patients, triptan therapy provides complete pain relief in some attacks but not in others. Here, we tested whether the success of triptan therapy is hindered in the presence of cutaneous allodynia (pain resulting from a nonnoxious stimulus to normal skin), a phenomenon we previously described develop gradually during the course of the migraine attack in more than 70% of patients. We studied migraine patients repeatedly on three visits to the clinic: in the absence of migraine (baseline), within the first hour of one attack, or at 4 hours from onset of another attack. Presence or absence of allodynia was determined based on differences between migraine and baseline pain thresholds to mechanical and thermal stimulation of periorbital skin. In 31 patients, we studied 34 migraine attacks that were associated with allodynia at the time of triptan treatment and 27 attacks that were not. Within 2 hours of triptan treatment, patients were rendered pain-free in 5 of 34 (15%) of allodynic attacks versus 25 of 27 (93%) of nonallodynic attacks. Treating migraine attacks 1 hour (early) or 4 hours (late) after the onset of pain was equally ineffective in inducing a pain-free state in the presence of allodynia, and equally effective in the absence of allodynia. For patients susceptible to allodynia during the attack, triptan therapy was by far more likely to provide complete pain relief if administered before rather than after the establishment of cutaneous allodynia. Patients who never developed allodynia were highly likely to be rendered pain-free by triptan therapy anytime after the onset of pain. We conclude that the probability of consistent pain-free outcome increases drastically if triptan therapy is vigilantly timed to precede any signs of cutaneous allodynia.     

Sensitization of trigeminal nociception specific for migraine but not pain of sinusitis

Trigeminal pain processing was studied in 14 patients with unilateral migraine attacks and 14 age- and sex-matched patients with comparable unilateral headache from frontal sinusitis. Using a nociception-specific blink reflex method (nBR), a facilitation of nBR responses predominantly on the headache side was observed in migraine, but not in sinusitis. The facilitation of trigeminal nociception may be specific for migraine rather than a consequence of peripheral pain such as frontal sinusitis.     

The role of glutamate and its receptors in migraine

Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system. Its receptors are classified into ionotropic receptors, which are ion channels and include NMDA, AMPA and kainate receptors, named after the agonists that selectively bind to them, and metabotropic receptors, which are G-protein coupled receptors. The trigeminal system is considered to play a key role in migraine pathophysiology, trafficking pain signals from the head and face to the trigeminal nucleus caudalis. The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies. Animal studies include experiments of cortical spreading depression, studies of c-fos protein expression in trigeminal nucleus caudalis, studies of plasma protein extravasation and electrophysiological studies. Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms. In the future, efforts should be made to further investigate the role of glutamate in migraine pathogenesis and, subsequently, in migraine treatment.     

The autonomic nervous system and the regulation of arterial tone in migraine

Abnormal regulation of the large cranial arteries seems to play a significant role in the mechanisms of migraine pain. Thus, vasodilatation of extra- and intracranial conductance arteries has been described both during spontaneous migraine attacks and during experimentally provoked vascular headaches. The regulation of the diameter of these arteries is complex and involves autonomic, trigeminovascular, endothelial and humoral mechanisms. Studies concerned with the function of the autonomic nervous system in migraine suggest that a mild parasympathetic dysfunction may be present. Cerebral arteries in migraineurs are hypersensitive to nitric oxide, which may induce migraine attacks. As the enzyme responsible for nitric oxide synthesis is present in parasympathetic nerve endings around cerebral arteries, this supports a role for the parasympathetic nervous system in migraine. In addition, vasoactive transmitters released from perivascular trigeminal nerve endings may be implicated. Several of these aspects are closely linked to the presumed mechanisms of action of modern migraine therapeutics.     

Decreased habituation of the R2 component of the blink reflex in migraine patients.

OBJECTIVE: Activation of the trigemino-vascular system as well as of brainstem trigeminal nuclei are thought to play an important role in migraine. The aim of this study was to investigate the habituation phenomenon of the blink reflex in 30 headache-free migraine patients and 30 control subjects. METHODS: An electromyographic device with a specific habituation test program was used to elicit and record blink reflex responses on both the right and left sides, and to randomly repeat the stimulations at different time intervals in order to induce habituation. RESULTS: Whereas the R1 and R2 latencies, amplitudes and areas in the basal assessment were similar in patients and control subjects, the blink reflex habituation responses were markedly reduced in migraine patients who had a migraine attack within 72 h after testing (group A). In these patients, the differences between the R2 areas, obtained when stimuli were delivered at subsequent time intervals ranging between 10-5, 5-4, 4-3 and 3-2 s, were statistically different (P<0.001) from those of the patients who had a migraine attack after a longer time interval (group B) and control subjects. CONCLUSIONS: Our data suggest that the brainstem pathways involved in the blink reflex may be activated in the premonitory phase of migraine attacks, probably through mechanisms that involve dopaminergic function.     

Positron emission tomographic studies of migraine

Due to technical constraints and randomness of migraine attacks, studies using PET are scarce. Nevertheless, these studies have given new insights into migraine pathogenesis. One of the main facts revealed by PET studies is that posterior cerebral hypoperfusion accompanying migraine auras could also be present in migraine attacks without aura. This hypoperfusion is probably due to an increase of intrinsic vasoconstrictive tone in the cerebral circulation. Using PET within 6 hours after the onset of a spontaneous migraine attack, significant activations of brainstem (midbrain and pons) and of hypothalamus, persisting after headache relief by sumatriptan have been shown. These structures could play the role of migraine attack generators, modulating intrinsic vascular tone and central pain transmission.     

Nociceptive R3 reflex in relapsing-remitting multiple sclerosis patients.

Pain in multiple sclerosis (MS) patients has only recently been recognised as a genuine symptom of this disease. It is important to determine whether this pain is the consequence of another symptom of MS or whether it is due to a demyelinating lesion affecting pain pathways. A close relationship has been found between the R3 component of the blink reflex and the pain threshold. The aim of this work was to carry out an objective evaluation of the nociceptive system in MS patients by means of the R3 component of the blink reflex. The study was performed on 20 healthy volunteers and on 20 clinically defined relapsing-remitting MS patients with EDSS not > 3.5, normal R1 and R2 components of the blink-reflex, personal and family anamnesis negative for migraine and trigeminal neuralgia; the patients were not taking drugs at the time of the test. A significant difference was found, between healthy volunteers and patients, for R3 threshold, pain threshold and R3 latency.     

Implications of Transient Receptor Potential Cation Channels in Migraine Pathophysiology

Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive,abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potential(TRP) channels, which transduce noxious stimuli into pain signals, are expressed in trigeminal ganglion neurons and brain regions closely associated with the pathophysiology of migraine. In the trigeminal ganglion,TRP channels co-localize with calcitonin gene-related peptide, a neuropeptide crucially implicated in migraine pathophysiology. Many preclinical and clinical data support the roles of TRP channels in migraine. In particular,activation of TRP cation channel V1 has been shown to regulate calcitonin gene-related peptide release from trigeminal nerves. Intriguingly, several effective antimigraine therapies, including botulinum neurotoxin type A, affect the functions of TRP cation channels. Here, we discuss currently available data regarding the roles of major TRP cation channels in the pathophysiology of migraine and the therapeutic applicability thereof.     

Cutaneous allodynia in patients with episodic migraine

Cutaneous allodynia may be observed in patients with migraine and this reflects the central sensitization of the trigeminal neurons. We aimed to investigate the frequency of cutaneous allodynia in patients with episodic migraine and to compare clinical characteristics of migraine patients with and without allodynia. One hundred and eighty-six consecutive patients with episodic migraine attacks were prospectively included in the study. The cutaneous allodynia symptoms that occurred during headache attacks were documented using a questionnaire for assessing cephalic and extracephalic cutaneous allodynia. One hundred and fourteen patients (61.3 %) were observed to develop allodynia during migraine attacks and the ratio of the female gender was found higher among the patients with allodynia (p < 0.001). Migraine disease duration was longer (p = 0.004) and accompanying nausea and phonophobia were more common (p = 0.003 and p = 0.005, respectively) in the patients with allodynia. Menstrually related migraine was found to be associated with both allodynia (p = 0.049) and its severity (p = 0.003). The results of present study revealed that cutaneous allodynia was rather frequent in episodic migraine, particularly in patients having longer disease duration. Higher frequency of allodynia in women and its association with menstrually related migraine may be related to the effects of hormonal factors on cutaneous pain thresholds and central sensitization. Association of nausea and phonophobia with allodynia may be interpreted as the common pathways are shared in the development of these symptoms.     

Ghrelin is expressed in trigeminal neurons of female mice in phase with the estrous cycle

Several disorders mediated by the trigeminal nerve including migraine and temporomandibular disorder (TMD) are more common in women than in men, and painful attacks are often linked to the menstrual cycle. Estrogen receptors in trigeminal neurons may be involved in regulating neuronal function, causing changes in sensitivity that contribute to these attacks. In a previous study, we demonstrated that expression of specific neuropeptides including galanin and neuropeptide Y in trigeminal ganglia of female rodents varies with the estrous cycle. In this study, we examined expression of the orexigenic peptide ghrelin in trigeminal ganglia of cycling female mice. RT-PCR studies demonstrated that ghrelin mRNA is upregulated by over 5-fold at the high estrogen stages of the cycle, proestrus and early estrus over the levels expressed at the low estrogen stage of the cycle, diestrus. Double-labeling immunohistochemical studies and cell size measurements were conducted to identify the phenotype of neurons in trigeminal ganglia containing ghrelin. Ghrelin was present in trigeminal neurons containing peripherin, a marker of neurons with unmyelinated axons, in trigeminal neurons binding IB4, a marker of nonpeptidergic nociceptors, in trigeminal neurons containing neurofilament H, a marker of neurons with myelinated axons, and in trigeminal neurons containing the neuropeptide calcitonin gene-related peptide (CGRP). Ghrelin-positive neurons averaged 25.6 microm in diameter, but included neurons in all the size ranges except the smallest peripherin-positive neurons. Thus, nearly all of the major populations of trigeminal neurons including peptidergic and nonpeptidergic nociceptors contain ghrelin. These studies suggest that ghrelin, a multifunctional peptide, may contribute to the mechanism linking orofacial pain syndromes in females, including temporomandibular disorder and migraine, to cyclical hormonal changes.     

Unilateral cranial autonomic symptoms in patients with migraine

The aim of this study is to investigate the frequency of unilateral cranial autonomic symptoms during migraine attacks, and to compare the clinical characteristics of migraine patients with and without unilateral cranial autonomic symptoms. One hundred and eighty-six consecutive patients with episodic migraine attacks were prospectively included. Cranial autonomic symptoms of the patients occurred during headache, frequency, duration, severity and character of headache, disease duration, presence of aura, laterality of headache, accompanying symptoms, relation of migraine attacks with menstruation, lesions detected on magnetic resonance images, and family history of migraine were recorded. The patients with and without unilateral cranial autonomic symptoms during headache were compared in terms of above-mentioned parameters. Seventy-seven (41.4 %) patients were observed to develop unilateral cranial autonomic symptoms during migraine attack. Disease duration was longer in the patients with unilateral cranial autonomic symptoms than in those without (p = 0.045). Headache was unilateral in 83.1 % of the patients with unilateral cranial autonomic symptoms (p = 0.001). Pure menstrual or menstrually related migraine attacks were more common in the patients with unilateral cranial autonomic symptoms (p = 0.043) and is thought that menstruation-related hormonal factors might have a triggering role on the trigeminal-autonomic reflex pathway. The longer disease duration in patients with unilateral cranial autonomic symptoms might be associated with the activation of pathophysiological mechanisms that cause cranial autonomic symptoms in time. Frequent unilateral pain in migraine patients with unilateral cranial autonomic symptoms is likely to indicate that the development of autonomic symptoms may share common mechanisms with the pathogenesis of trigeminal autonomic cephalalgias.     

Inter-critical and critical excessive daily sleepiness in episodic migraine patients

The objective of this study was to determine the relationship between sleepiness and migraine in the intercritical period and to evaluate the time course of critical drowsiness during the attacks. One hundred patients fulfilling IHCD 2nd (2004) criteria for migraine without aura were compared to 100 healthy subjects. Habitual excessive daily sleepiness, evaluated by means of Epworth Sleepiness Scale, was not more frequent in patients with episodic migraine than in controls (12% migraineurs vs. 8% controls, NS). The analysis of critical sleepiness by means of Stanford Sleepiness Scale (SSS) revealed a beginning of sleepiness increase before the attack onset, starting 12 h before, a peak of SSS values at the migraine attack onset and then a gradual decrease to reach baseline values only 12–24 h later. Moreover, patients responding to symptomatic drugs showed a greater and faster decrease of critical sleepiness in comparison with non-responder migraineurs; this finding allows excluding the role of medications in promoting critical somnolence and together with critical drowsiness time-course supports the hypothesis that vigilance impairment could be related to migraine pathogenesis.