Called Cefaly, the Belgian-made device is the first to win FDA approval for migraine prevention and is also the first transcutaneous electrical nerve stimulation (TENS) system OK’d for any type of pain prevention, as opposed to acute treatment, the agency said.

The device is battery-powered and worn around the head, with the actual TENS stimulator centered on the forehead just above the eyes. It delivers a small, steady current to trigeminal nerve branches. Patients will be instructed to use the device once daily for a maximum of 20 minutes. It is approved for adults only.

Approval was based primarily on the PREMICE trial, in which 67 adult patients were randomized to wear either the Cefaly device or a nonfunctional sham. When turned on, the device typically causes a tingling sensation, but the trial investigators sought to maintain blinding by not asking participants what it felt like and by trying to keep them from talking with each other.

Patients assigned to the real device showed a decline from baseline of about two headache days per month, compared with no change in the control group. A responder analysis showed that 38% of patients receiving stimulation had at least a 50% reduction in monthly headache days, compared with 12% of the control group.

The Cefaly device was previously approved in Europe and Canada. The device’s manufacturer, STX-Med of Herstal, Belgium, submitted results of a patient satisfaction survey conducted among more than 2,000 users in Europe, indicating that most regular users believed they had experienced “very significant improvement” and only 4% reported adverse effects.

Across the entire respondent group, including those who only used the device infrequently or not at all, 54% reported substantial improvement.

Complaints about the device included dislike of the tingling sensation, sleepiness during the treatment sessions, and headache following the sessions, the FDA said. None of the reported adverse effects were considered serious.

Numerous TENS devices are already marketed for pain treatment.

White matter brain lesions appeared 68% more often in migraineurs with aura than in those without migraine; a trend for 34% elevated risk of white matter in migraine patients without aura didn’t reach significance, Messoud Ashina, MD, PhD, of the Danish Headache Center at Glostrup Hospital in Copenhagen, and colleagues found.

Clinically-silent infarct-like abnormalities and brain volume changes also correlated with migraine, they reported online in Neurology.

However, it’s still not clear how these changes arise or whether they have any clinical significance, the group cautioned. “Traditionally, migraine has been considered a benign disorder without long-term consequences for the brain,” they noted.

MRI imaging to exclude secondary causes of headache often turns up such abnormalities that worry both neurologists and patients, the group noted.

“Patients with white matter abnormalities can be reassured,” they recommended. “Patients with infarct-like lesions should be evaluated for stroke risk factors. Volumetric MRI remains a research tool.”

Eli Feen, MD, a neurologist at Saint Louis University in St. Louis, agreed with the researchers on evaluating stroke risk factors in patients with infarct-like brain lesions on MRI. But he suggested it should be done regardless of migraine status, and instead be based on age and the prevalence of stroke.

“What is reassuring is that when we look at the brain MRI of a migraine patient, we don’t have to be concerned about the lesions or abnormalities of the white matter suggesting something more malignant,” he said in an interview.

Without knowing the true clinical significance of the findings, clinicians should focus on making sure that migraine is taken seriously and treated properly, commented Emily Rubenstein Engel, MD, associate director of the Dalessio Headache Center at Scripps Clinic in San Diego.

“It is a disease that can — and should — be managed well, so that patients are minimally symptomatic and have minimal injury to their brain,” she said in an email to MedPage Today.

But while there’s growing evidence that migraineurs are at slightly elevated stroke risk overall, there’s no evidence that preventing migraine reduces that risk, argued Andrew Charles, MD, director of the headache research and treatment program at the University of California Los Angeles.

“Patients with migraine, particularly those with aura along with their migraine attacks, should work to reduce other stroke risk factors like high blood pressure, high cholesterol, and smoking,” he suggested in an email to MedPage Today.

The meta-analysis included six population-based studies and 13 clinic-based studies that looked for MRI abnormalities in migraineurs from 1989 through 2013.

The prevalence of white matter abnormalities ranged from 4% to 59% across the studies.

Pooled analysis of the four that reported on this measure indicated an odds ratio of 1.68 for migraine with aura compared with no-migraine controls (95% CI 1.07-2.65).

The odds of white matter lesions was 1.34 for migraine without aura but missed statistical significance (95% CI 0.96-1.87).

One of the studies, CAMERA-2, suggested no link between white matter abnormality progression and anti-migraine therapy; another indicated no increased risk of stroke, heart attack, or cardiovascular death with triptan medication.

“While this result is reassuring, robust conclusions are limited due to confounding by indication,” Ashina’s group cautioned.

For silent infarct-like lesions, the likelihood across two pooled studies was 44% higher for migraineurs with aura than without aura (P=0.04), but no statistically significant association emerged for either compared with controls.

“It is unclear whether silent infarct-like lesions predispose to or are associated with development of clinical stroke,” the researchers pointed out.

Also, whereas infarct-like lesions are associated with cognitive decline and dementia in the elderly, CAMERA-2 and another study didn’t show a link to cognitive decline in migraine and other severe types of headache, they added.

Theories are that these lesions could represent a combination of episodic focal brain under-perfusion or a manifestation of hypertensive small-vessel disease.

Of the nine studies that looked at brain volume, seven indicated reduced grey matter density in brain regions in migraineurs compared with controls. Another study indicated increased grey matter density in the periaqueductal gray (a region involved in pain processing) and the dorsolateral pons regions only in migraine with aura.

“Additional longitudinal studies are needed to determine the differential influence of migraine without and with aura, to better characterize the effects of attack frequency and to assess longitudinal changes in brain structure and function,” the group concluded.

Limitations included heterogeneity in patient samples, selection criteria, headache characteristics, test methodology, timing, and data interpretation, as well as the possibility of residual or unmeasured confounding and unclear directionality of associations.

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation.

Ashina reported being an associate editor of Cephalalgia and a consultant or scientific adviser for Autonomic Technologies, Allergan, Amgen, and Alder.

The results are significant in terms of understanding the neurobiology of migraine and could have future implications for drug treatment, said study author Peter James Goadsby, MD, PhD, professor, neurology, and director, Headache Program, University of California at San Francisco, and president, International Headache Society.

“This is an important step in solidifying our ideas that migraine is fundamentally a disorder of the brain, not a disorder of structures outside the brain,” said Dr. Goadsby. “We were able to address the question that people have wondered about for many, many years, that is, what is the degree to which pain is driving the initial symptomatology — and we got clear answers to that.”

Dr. Goadsby and his colleagues won the Harold G. Wolff Lecture Award for this research during the 2013 International Headache Congress (IHC).

Subtle Symptoms

Premonitory symptoms of migraine can include yawning, neck discomfort, nausea, thirst, photophobia, phonophobia, craving sweet or savory foods, and mood swings. It’s not clear what proportion of patients with migraine experience these early symptoms, which are often quite subtle, Dr. Goadsby said. Estimates vary widely, from about a third to 80%.

In the past, this symptomatology has not received much medical attention, said Dr. Goadsby. Physicians might not ask about premonitory symptoms because this information doesn’t influence their diagnosis.

In years gone by, people used to think of migraine as a disorder of the blood vessels. In more recent times, the view has been that migraine is a reaction to pain stimuli. “I think our new research suggests that this is just not true,” said Dr. Goadsby.

Using nitroglycerin, a well-documented trigger for migraine, researchers induced premonitory symptoms in patients who have migraine without aura. Instead of waiting for headache onset to begin scanning the patients’ brains, as has been done in the past, researchers did the scanning during the premonitory phase. Eight patients had at least 1 premonitory scan without pain.

“Before this, all the imaging of migraine has been during the headache and the question has risen as to the degree to which what’s happening in the brain is just a response to pain, or is something more fundamental, a part of the process of the migraine,” said Dr. Goadsby. “By studying the premonitory symptoms, you get rid of that question because these patients don’t have any pain.”

Neuronal Activation

Researchers used H₂ ¹⁵O (radioactive water) to measure regional cerebral blood flow as a surrogate marker for neuronal activation.

They found that compared with baseline scans, there was activation in several key areas, including the hypothalamus, an area involved in low-level regulation of sleep, appetite, mood, and fluids. “It seems likely that the hypothalamus is pivotal in the onset of migraine,” commented Dr. Goadsby.

Other structures that were activated included the midbrain, around the periaqueductal grey, which has been shown to be active during a migraine attack, and an area in the pons that past migraine imaging has also shown to be active.

“This shows you the areas of the brain that are involved at the earliest in the attack,” said Dr. Goadsby.

Scans of the 8 patients plus another 2 patients experiencing photophobia symptoms, again before they felt any pain, showed activation in the visual cortex. “This suggests that the photophobia experience can be dissected away from the pain experience,” said Dr. Goadsby.

Similarly, scans of patients experiencing nausea had activation of an area of the medulla that includes nausea and vomiting centers. “So it’s entirely plausible that those areas are activated by the migraine process and that’s why nausea and vomiting are so common in migraine; it’s not simply a response to the pain,” said Dr. Goadsby.

“It was thought that nausea and pain were highly linked, but that doesn’t seem to necessarily be the case,” he added.

Dr. Goadsby hopes the research will “shift thinking” to consider migraine as a brain disorder, but he stressed that this should not lessen the importance of the pain that migraine patients suffer.

The research could have ramifications for treatment in that the most obvious target would be the brain, but developing targeted therapies that don’t have adverse effects could be challenging.

“From a big picture treatment perspective, this says to me that we probably won’t get away with developing drugs that don’t get into the brain to have substantial effects on migraine prevention,” said Dr. Goadsby.

He noted that to date, the best proven migraine prevention therapies are anticonvulsant drugs, tricyclic antidepressants, and the β-blocker propranolol, all of which affect the brain. This, he said, is consistent with the theory that migraine is a disorder of the brain.

Original Article

The unbalanced levels of the neurotransmitters (dopamine and noradrenaline) and neuromodulators (eg, tyramine, octopamine, and synephrine) in the synaptic dopaminergic and noradrenergic clefts of the pain matrix pathways may activate, downstream, the trigeminal system that releases calcitonin gene-related peptide. This induces the formation of an inflammatory soup, the sensitization of first trigeminal neuron, and the migraine attack. In view of this, we propose that migraine attacks derive from a top-down dysfunctional process that initiates in the frontal lobe in a hyperexcitable and hypoenergetic brain, thereafter progressing downstream resulting in abnormally activated nuclei of the pain matrix.

Introduction

Migraine is a disabling condition characterized by unilateral headache pain, pulsating in quality and lasting 4–70 hours, accompanied by photo-, phono-, osmo-phobia, nausea, and vomiting. Aura may precede the migraine attacks in about 30% of patients and, in some patients, occurs as an isolated symptom.^[1] The etiology of migraine is still not completely understood. This is because of the multiple complex symptomatology characteristic of migraine (headache attacks and psychiatric, neurologic, and sympathetic symptoms) and difficulty in unifying these characteristics into one or more interelated pathophysiological processes.

A pathophysiological hypothesis that may reconcile with the proteiform symptomatology of migraine has been proposed by Welch. According to this hypothesis, migraine is a multifactorial (ie, biological and psychological) biobehavioral disorder^[2] in which the crisis is a response to stressful agents within an hyperexcitable brain.^[3] Genetic mutations and/or polymorphisms of genes, yet to be determined, that regulate neuronal mitochondrial energy, neurotransmitter metabolism, and ion channels in the central nervous system (CNS) are considered the main biological factors.^[4] Menstrual cycle, pregnancy, lifestyle, diet, anxiety, chronic stress, etc, are among the main psychological factors.^[5] Once the migraine threshold is primed, the frequency of the attacks depends on the type of stress and anomalies in the metabolism of neurotransmitters and neuromodulators that regulate the synapses of cortical, antinociceptive (antinociceptic system [ANS]), and sympathetic neurons.^[6]

In the CNS, glutamic acid and aspartic acid are the main excitatory neurotransmitters, whereas gamma aminobutyric acid (GABA) is the inhibitory neurtransmitter.^[7] The balance between these 2 systems constitutes the frame in which the other circuitries regulate the functions of the human brain. It has been hypothesized that anomalies in the metabolism of glutamate and GABA, together with those that govern pain and vegetative functions, such as serotonin (5-HT), dopamine (DA), and noradrenaline (NE), constitute the phenotypical biochemical causes of the migraine.^[8]

Recent evidence also supports the old notion that elusive amines, such as tyramine (tyr) and octopamine (Oct), play a role in migraine pathogensis.^[9] These amines, together with DA and NE, are products of two different metabolic pathways of tyrosine. Tyrosine hydroxylase generates 3,4-dihydroxyphenylalanine (DOPA), DA, and NE, with the last 2 compounds requiring the action of DOPA decarboxylase and dopamine β-hydroxylase (Dβ-H) enzymes, respectively. The alternative pathway, tyrosine decarboxylase, synthetizes tyr, Oct, and synephrine, with Oct and synephrine requiring in addition Dβ-H and phenylethanolamine-N-methyltransferase (PNMT) enzyme activities^[10] (see the Figure). Although the hypothesis that tyr and Oct may contribute to pathogenesis of migraine was proposed several decades ago,^[11] the recent discovery of a new class of G-protein-coupled receptors with high affinity for these amines in rodents and humans has fuelled ever-increasing scientific interest. The trace amine receptors (TAARs) are found in various tissues and organs, including specific brain areas such as the rhinencephalon, limbic system, amygdala, hypothalamus, extrapyramidal system, and locus coeruleus.^[12] This and other evidence has led to the suggestion that tyr and/or Oct behave as neurotransmitters and neuromodulators via TAARs and other receptors (eg, catecholaminergic receptors), respectively, contributing to physiology of noradrenergic and dopaminergic synaptic transmission in the ANS.^[13]

We hereby summarize briefly the results, mainly generated from our laboratory, that support a role for biochemical alterations of different neurotransmitters and neuromodulators in the pathophysiology of migraine. Based on this evidence, we propose that future research efforts aiming to comprehend the pathophysiological relevance of neuromodulators, such as trace amines, in the CNS, have the potential to provide for new, more effective, treatment options for migraine.

Excitatory Amino Acids and Aura

The aura constitutes the clinical phenotype of migraine with aura. The hypothesis that aura is a clinical counterpart of a cortical phenomena derives from the observation of Lashley’s own visual phenomena.^[14] The speed of the scotomata on the visual field, 3 mm/minute, and the fundamental studies of Olesen and his group on cerebral blood flow (CBF), in patients during their auras, have substantially demonstrated that the spreading depression (SD) of Leao is the neurophysiological cortical event of the aura symptomology. In these human experiments, the positive scotomata (visual scintillations and/or paresthesia) is concomitant to a brief increase in blood flow, and the negative symptoms to a reduced flow (oligemia) that propagates at the speed of 3 mm/minute on the occipital cortex.^[15] Studies with functional magnetic resonance imaging (MRI), during spontaneous aura, have confirmed that the first phase of the aura is accompanied with a brief focal occipital increase in the brain oxygen-level dependent (BOLD) signal that propagates at the same velocity of SD on the occipital cortex, followed by a longer lasting decrease and impaired BOLD response to functional activation.^[3] The clinical picture and the features derived from CBF and functional MRI (fMRI) studies suggest that the positive and negative signs of the aura may be caused, as in SD, by a burst of activity followed by suppression of neuronal cortical activity.

We hypothesized that neuronal hyperexcitability constitutes the functional prerequisite of the occurrence of the aura.^[3] An array of biochemical, neurophysiological, and pharmacological data in humans support this hypothesis. Glutamate, released from neurons and glia, is the main excitatory neurotransmitter in the CNS. Anomalous levels of glutamic acid determine SD in animal experiments and ingestion of glutamate-rich food provokes, in predisposed subjects, migraine attacks.^[16,17] To date, it is almost impossible to directly measure glutamate levels in the human brain. Platelets, however, have constituted a valid model to study glutamate metabolism because these cells display glutamate-related components similar to those of the neurons. A number of studies, conducted in the last 2 decades, have demonstrated that the levels of glutamic and aspartic acids are significantly more elevated in platelets, plasma, and CSF of migraine patients, particularly in those with aura.^[18–20]

Occurrence of CNS hyperexicitability in migraine is also supported by neurophysiological studies employing transcranial magnetic stimulation (TMS). Stimulation with TMS of the occipital lobe in migraine with aura patients determines the appearance of a higher number of phosphenes in comparison with control and migraine without aura sufferers.^[21] These same results were also found stimulating the motor areas and measuring the resting motor threshold and the silent period.^[22] Although the authors suggest that these response abnormalities are due to a reduced inhibitory cortical tone,^[23] the possibility that an increase in glutamate levels in the CNS plays a major role in pathogenesis of the aura is supported by ^[31]pNMR studies and pharmacological evidences employing lamotrigine. In comparison with control subjects, the levels of magnesium, measured with ^[31]pNMR, are significantly lower in the brain of migraine patients, particularly during the painful attacks.^[24] Magnesium is a unique compound known to block glutamate-dependent SD.^[25] Lamotrigine is an antiepileptic drug useful in the prevention of partial and generalized seizures as well. It acts by blocking voltage-sensitive channels leading to an inhibition of neuronal glutamate release.^[26] Based on these pharmacodynamic characteristics, we conducted an open pilot study aiming to assess the effects of lamotrigine in migraine with aura. Twenty-five migraine patients with high frequency of aura attacks (at least 2 auras/month) were treated for 2 months. There was a dramatic reduction in the aura frequency and duration in the treated patients. Thereafter, a number of studies have confirmed the efficacy of lamotrigine in the prevention of auras.^[27,28] The specificity of this drug for the prophylaxis of the migraine aura is stressed by the inefficacy of lamotrigine in the reduction of migraine without aura attacks^[29] and the capacity of lamotrigine, in contrast to valproate, to block the SD-induced by potassium cloride (KCl) on the rat occipital cortex.^[30]

Elusive Amines, Premonitory Symptoms, and Migraine Attack

The modalities by which stressful agents within the brain may cause the painful attacks in migraine is not known; however, according to the theory put forth by Welch, the first pathophysiological event may occur in the orbitofrontal part of the frontal lobe and, thereafter, downstream to the limbic, amygdale, and hypothalamic-connected areas of the CNS. Although still partly speculative, an increasing body of clinical, biochemical, and functional studies now support this theory. Migraine attacks are, very often, preceded by premonitory symptoms, such as hyperosmia, yawning, mood changes, anxiety, food craving, sexual excitement, fatigue, and emotional lability, which last from minutes to days.^[31,32] These symptoms are considered markers of activation of the above-mentioned brain areas, and, therefore, it is logical to attribute the first phase of the migraine attacks within these areas.^[33] Further support also derives from evidences showing that, in these same brain areas, TAARs and dopamine receptors are abundantly distributed. The activation of these receptors is likely reflected in the high levels of dopamine and elusive amines found in plasma and platelets of migraine without aura sufferers during headache-free periods.^[34,35]

Catecholamines, Elusive Amines, and the Migraine Attack

After the premonitory symptoms in migraine, the painful phase occurs. One current hypothesis considers the head pain a consequence of trigeminal activation. This determines release of the neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), in the trigemino-vascular system.^[36] Both peptides stimulate platelets, leukocytes, and endothelium to secrete an inflammatory soup (5-HT, adenosine diphosphate [ADP], platelet-activating factor, nitric oxide [NO], interleukins, etc) that sensitizes the first-order neuron of the trigeminal system and, after minutes or hours, the second, by an early gene-related process in the nucleus.^[37]

The pathophysiological process that underlies trigeminal activation is a debated question. One hypothesis, derived from studies performed in animal models, suggests that the wave of the SD on the occipital cortex stimulates the nerve endings of the trigeminal system surrounding the pial vessels. This stimulation determines a trigeminal antidromic reflex resulting in the release of CGRP and SP in the dura mater head circulation. CGRP has been long suggested to be important in the occurrence of headache attacks because of its capability to interact with circulating cells and to determine neurogenic inflammation. CGRP stimulates platelets, white cells, and endothelium to synthesize NO. NO is considered a diffusible neurotransmitter in the CNS and, as such, may play a role in the release of glutamate and diffusion of SD on the cortex. In the circulation, it is a potent vasodilatator. NO, while dilatating the vessel wall, stretches the trigeminal endings innervating the wall, already sensitized by the inflammatory soup, and determines the migraine attack.^[38]

Another hypothesis, and not mutually exclusive, is that the activation of the trigeminal system is a result of abnormal pain processing initiating in the frontal lobe and, thereafter, progressing downstream to the connected pain centers.^[2,39] In support of this hypothesis is a functional fMRI study showing that inhibition of the orbito-frontal cortex, an important pain inhibitory cortex area, occurs in chronic migraine when the pain subsides.^[40] Also, evidence from fMRI and PET studies have shown activation of the red nucleus, extrapyramidal system, and nuclei behind the aqueduct of the brain stem before and during migraine attacks,^[41,42] all parts of the descending centers of the pain matrix. The modalities and the characteristics of the activation of these nuclei, however, are not known.

We hypothesized that abnormal levels of elusive amines and catecholaminergic neurotransmitters such as DA and NE, all products of tyrosine metabolism, play an important role in the pathophysiology of migraine attacks.^[34] As mentioned previously, TAARs are located in the rhinencephalon, limbic system, amygdala, hypothalamus, extrapyramidal system, and locus coeruleus. These areas are important parts of the pain matrix that modulates the pain threshold.^[39] The functions of the pain matrix neurons are mainly regulated by synapses that utilize DA and NE as neurotransmitters. Intriguingly, the highest levels of Oct are found in the same brain regions.^[43] Oct acts, in the same synaptic clefts, as a neuromodulator. A neuromodulator is a chemical released from a neuron that causes no change in the excitability of the postsynaptic cells in the absence of a neurotransmitter. The released neuromodulator acts to modify the action (increase or decrease) of a coexisting neurotransmitter.^[14] Thus, one possible physiologic role Oct is to regulate, together with other neurotransmitters, DA and NE synapses in the centers that regulate the pain threshold. As hypothesized by Welch, it is possible that, in the particular metabolic circumstances such as that associated with migraine, there occurs an abnormality in the metabolism of tyrosine toward increased synthesis of products of the decarboxylase pathway, resulting in increased synthesis of tyr, Oct, and synephrine in association with a decrease of NE. In support of this, we recently demonstrated that there occur higher levels of circulating Oct and synephrine along with increased levels of DA in migraine without aura (MwoA) patients, in comparison with healthy controls subjects.^[44] The higher levels of DA are suggestive of a reduction in dopamine Dβ-H enzyme activity. Reduced Dβ-H enzyme activity^[45] and reduced NE levels have been reported in migraine without aura patients.^[46] Also, more recently, a polymorphism in the gene that encodes for Dβ-H protein has been identified.^[47] All these results support the possibility that complex abnormalities in the metabolism of tyrosine-related pathways occurs in migraine patients, resulting in possible derangement in neurotransmitters and neuromodulators. If the same biochemical anomalies found in the circulation of migraine sufferers are present in the synaptic clefts innervating the pain matrix, an unphysiologic balance between neuromodulators (Oct and synephrine) and neurotransmitters (DA and NE) the intra-synaptic milieu should be expected. Possible pathological consequences include abnormal function of the hypothalamus,^[33] the sympathetic system with related autonomic symptoms, reported in migraine patients (eg, orthostatic blood pressure changes, anomalies of pupillary control, and vertigo),^[48] and the ANS nuclei, with downstream activation of the trigeminal nucleus, CGRP release in the encephalic circulation and head pain. Another possibility is that cortical SD may direct activate second-order trigeminovascular neurons, as recently suggested by Lambert et al^[49] employing animal models. However, the biochemical pathway(s) involved in this process is (are) still unknown.

Biochemical Tryptophan Anomalies and Painful Attacks

The main product of tryptophan hydroxylase is serotonin (5-HT), whereas tryptamine is the neuromodulator that derives from the decarboxylase product of tryptophan. The involvement of 5-HT in migraine was hypothesized more than 50 years ago when F. Sicuteri demonstrated the occurrence of significantly elevated levels in urine of 5-hydroxyindoleacetic acid, stable metabolite of 5-HT, during migraine attacks.^[50] Since this, numerous studies have attempted to clarify the possible biochemical anomalies of 5-HT in migraine, mainly utilizing platelets as a model of serotonergic neurons. Studies from our laboratory have shown that the levels of platelet 5-HT fluctuate in female migraine sufferers differently from those in healthy woman in the different phases of the menses and, more importantly, the levels of the indole decrease significantly in the luteal phase in menstrual migraine before the painful attacks.^[51,52] The reason why the levels of 5-HT drop before the attack is not known. However, it is possible to conceive that there may occur a biochemical shift of tryptophan metabolism toward decarboxylation rather than hydroxylation, therein favoring an increase in the synthesis of tryptamine and a reduction in the synthesis 5-HT, respectively, in the synaptic clefts of neurons of the ANS nuclei of the brain stem.

GABA and Migraine

GABA is the main inhibitory neurotransmitter in the CNS. GABA plays an important role in the modulation of pain threshold. The antiepileptic drugs valproate and topiramate, the most efficacious drugs in preventing migraine without aura attacks, are potent GABAergic agonists.^[53] Other than this, however, direct evidence for a role of GABA-related abnormalities in migraine is very scarce. One study has shown that plasma levels of GABA are not detectable during migraine attacks, but after this phase, its plasma levels increase, suggesting that activation of the GABAergic pathways is necessary to end the pain crisis.^[54]

Mitochondrial Energy, Metabolic Shifts, and Migraine

An increasing number of studies suggest that migraine sufferers display a reduction in the metabolism of cellular energy in different tissues, including brain. The first line of evidence in support of this is the platelet anomalies. Platelets of migraineurs display elevated free intracytosolic calcium levels^[55] and abnormal high number of dense bodies together with increased levels of serotonin within these organelles.^[56] These abnormalities are accompanied by a reduction in dense body secretion when platelets are stimulated by collagen.^[57] The reason for the accumulation of dense bodies and the impaired secretion in response to agonists may be due to a decrease of multiple enzymatic activities found in the mitochondria of platelets of MWoA and migraine with aura (MWA) patients.^[58] The same mitochondrial energy defect(s) has (have) been demonstrated in brain and muscle in ^[31]pNMR spectroscopy studies in different types of headache patients.^[59]

The synthesis of neurotransmitters is energy dependent. A shift of tyrosine metabolism leading to increased levels of trace amines in migraine may depend on energy defects. This hypothesis is supported by a study of these amines in CSF of early postmortem subjects. In the first hours after death, the levels of tyr, Oct, and synephrine increase dramatically suggesting that when the brain energy fails, the activity of tyrosine decarboxylase prevails.^[60] Also, deposition of free radicals in brain stem structures of migraine patients may contribute to mitochondrial energy decline in these patients. The accumulation of iron ions is proportional to the frequency of attacks, being greatest in chronic migraine wherein the attacks may occur every day.^[61] It is known that deposition of iron ions deteriorate the surface of mitochondria and reduce the efficiency of the respiratory chain and the neuronal energy substrates. Thus, it is probable that the deposition of iron radicals may progressively favor tyrosine metabolism along the decarboxylation pathway and deteriorate the neurotransmission of the pain matrix.

Conclusion

All of the above results provide for a functional framework in which anomalies in different biochemical pathways together act in determining migraine. Although many steps remain speculative, future biochemical studies should be focused on the study of the functional role of the TAARs alone and together with other neuromodulators, in particular, those affecting serotoninergic (eg, tryptamine) and dopaminergic (phenylethylamine and phenylethanolamine) neurotransmission, in the CNS of patients with migraine and, possibly, in adequately stressed animal models. Also, eventual effects of elusive amines on ion channels present on sensory neurons, the activation of which are associated with allodynia and hyperalgesia, as well as their interaction with TAARs should be questioned. Some genes recently implicated in migraine (eg, TRPM8 and KCNK18) are, intriguingly, predominantly expressed in trigeminal and dorsal root ganglia, a finding suggestive of an important role in the initiation of the headache attack.^[62]

Another important point in need of clarification is the nature of the energy failure in migraine and the relationship between this failure and the metabolic alterations of the strategic amino acid parents of the dopaminergic and serotoninergic CNS circuitries. Studies on possible mutations or polymorphisms in genes that regulate the decarboxylase enzyme activity in brain are also warranted. These studies may shed light on the physiological and pathological significance of these ancient enzymes, of evolutionary importance, in humans. Oct and synephrine, in fact, are the main noradrenergic neurotransmitters found in the lowest species of the evolutionary scale, such as worms and insects.^[14] It is possible that in conditions of neuronal energy failure, as has been demonstrated in migraine, the metabolism regresses, under the push of an excitatory status of the cortex,^[3] into an archaic modality of neurotransmission, leading to modifications in the biochemical milieu of synaptic clefts of the pain matrix, the end result of which produces the migraine attacks.

Findings include the following:

• In five studies of chronic migraine (1508 patients; mean, 19.5 headaches monthly), botulinum toxin A significantly reduced the average number of headaches by 2.3 per month compared to placebo; the average monthly reduction in headaches was roughly 8 with botulinum and 6 with placebo.
• In seven studies of chronic tension headache (675 patients, mean, 25.2 headaches monthly), botulinum toxin A did not significantly reduce the average number of headaches compared to placebo.
• In nine studies of episodic migraine (1838 patients; mean, <15 headaches monthly), botulinum toxin A did not significantly reduce the average number of headaches compared to placebo.
• In the few studies that examined the proportion of patients experiencing 50% improvement in headache, botulinum was superior to placebo for chronic migraine; however, these trials included fewer than 100 patients.
• Adverse effects — especially ptosis, muscle weakness, and neck pain — were significantly more common with botulinum than with placebo.

Comment

For prophylaxis against chronic migraine, the average benefit for botulinum toxin A compared to placebo is statistically significant but clinically modest; the placebo effect is impressive in this study. Moreover, treatment is costly (up to several thousand dollars yearly), and side effects are frequent; hence, this intervention will not be worthwhile for most people.