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1.  Studies on the Pathophysiology and Genetic Basis of Migraine 
Current Genomics  2013;14(5):300-315.
Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people’s daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies.
PMCID: PMC3763681  PMID: 24403849
Migraine; Migraine with aura; Migraine without aura; Familial hemiplegic migraine; Molecular genetics; Genes
2.  Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification 
The Journal of Headache and Pain  2009;10(4):227-233.
There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease.
PMCID: PMC3451739  PMID: 19506799
Disease modification; Child; Adolescent; Migraine
3.  Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine 
Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal–glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.
PMCID: PMC3142555  PMID: 19723120
Connexins; cortical spreading depression; gap junctions; tonabersat; trigeminovascular
4.  Electrophysiological response patterns of primary sensory cortices in migraine 
The Journal of Headache and Pain  2006;7(6):377-388.
Migraine is an ictal disorder characterised by a particular vulnerability of patients to sensory overload, both during and outside of the attack. Central nervous system dysfunctions are supposed to play a pivotal role in migraine. Electroneurophysiological methods, which aim to investigate sensory processing, seem thus particularly appropriate to study the pathophysiology of migraine. We have thus reviewed evoked potential studies performed in migraine patients. Although results are in part contradictory, these studies nonetheless demonstrate an interictal dysfunction of sensory cortices, and possibly of subcortical structures, in migraine with and without aura. The predominant abnormality is a deficient habituation of evoked responses to repeated stimuli, probably due to cortical, and possibly widespread neural, "dysexcitability".
PMCID: PMC3452223  PMID: 17164990
Migraine; Pathophysiology; Evoked potentials; Sensory cortices; Cortical excitability
5.  New directions in migraine 
BMC Medicine  2011;9:116.
Migraine is a highly prevalent neurological disorder imparting a major burden on health care around the world. The primary pathology may be a state of hyperresponsiveness of the nervous system, but the molecular mechanisms are yet to be fully elucidated. We could now be at a watershed moment in this respect, as the genetic loci associated with typical forms of migraine are being revealed. The genetic discoveries are the latest step in the evolution of our understanding of migraine, which was initially considered a cerebrovascular condition, then a neuroinflammatory process and now primarily a neurogenic disorder. Indeed, the genetic findings, which have revealed ion channels and transporter mutations as causative of migraine, are a powerful argument for the neurogenic basis of migraine. Modulations of ion channels leading to amelioration of the migraine 'hyperresponsive' brain represent attractive targets for drug discovery. There lies ahead an exciting and rapidly progressing phase of migraine translational research, and in this review we highlight recent genetic findings and consider how these may affect the future of migraine neurobiology and therapy.
PMCID: PMC3217871  PMID: 22027350
6.  Migraine pathogenesis and state of pharmacological treatment options 
BMC Medicine  2009;7:71.
Migraine is a largely inherited disorder of the brain characterized by a complex, but stereotypical, dysfunction of sensory processing. Often the most obvious clinical symptom is head pain, but non-headache symptoms such as photophobia, phonophobia and nausea are clearly part of the typical presentation. This review discusses the current pathophysiological concepts of migraine and migraine aura, such as a possible brainstem dysfunction and cortical spreading depression. Acute and preventive migraine treatment approaches are briefly covered with a focus on shortcomings of the currently available treatment options. A number of different receptors, such as calcitonin gene-related peptide (CGRP), TRPV1 and glutamate receptors, are currently being targeted by potential novel migraine therapeutics. The prospects of this research are exciting and are likely to improve patient care.
PMCID: PMC2784479  PMID: 19917094
7.  Possible sites of action of the new calcitonin gene-related peptide receptor antagonists 
Migraine is considered a neurovascular disease affecting more than 10% of the general population. Currently available drugs for the acute treatment of migraine are vasoconstrictors, which have limitations in their therapeutic use. The calcitonin gene-related peptide (CGRP) has a key role in migraine, where levels of CGRP are increased during acute migraine attacks. CGRP is expressed throughout the central and peripheral nervous system, consistent with control of vasodilatation and transmission of nociceptive information. In migraine, CGRP is released from the trigeminal system. At peripheral synapses CGRP results in vasodilatation via receptors on the smooth muscle cells. At central synapses, CGRP acts postjunctionally on second-order neurons to transmit pain centrally via the brainstem and midbrain to higher cortical pain regions. The recently developed CGRP-receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine attacks. A remaining question is their site of action. The CGRP-receptor components (calcitonin receptor-like receptor, receptor activity modifying protein 1 and receptor component protein) are found to colocalize in the smooth muscle cells of intracranial arteries and in large-sized neurons in the trigeminal ganglion. The CGRP receptor has also been localized within parts of the brain and the brainstem. The aim of this paper is to review recent localization studies of CGRP and its receptor components within the nervous system and to discuss whether these sites could be possible targets for the CGRP-receptor antagonists.
PMCID: PMC3002638  PMID: 21179597
brainstem; calcitonin gene-related peptide; calcitonin gene-related peptide antagonists; migraine; trigeminal ganglion
8.  Involvement of gap junction channels in the pathophysiology of migraine with aura 
Migraine is a common, recurrent, and disabling primary headache disorder with a genetic component which affects up to 20% of the population. One third of all patients with migraine experiences aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms preceding the headache. In the pathophysiology of migraine with aura, activation of the trigeminovascular system from the meningeal vessels mediates migraine pain via the brainstem and projections ascend to the thalamus and cortex. Cortical spreading depression (CSD) was proposed to trigger migraine aura and to activate perivascular trigeminal nerves in the cortex. Quinine, quinidine and the derivative mefloquine are able to inhibit CSD suggesting an involvement of neuronal connexin36 channels in CSD propagation. More recently, CSD was shown to induce headache by activating the trigeminovascular system through the opening of stressed neuronal Pannexin1 channels. A novel benzopyran compound, tonabersat, was selected for clinical trial on the basis of its inhibitory activity on CSD and neurogenic inflammation in animal models of migraine. Interestingly, in the time course of animal model trials, tonabersat was shown to inhibit trigeminal ganglion (TGG) neuronal-glial cell gap junctions, suggesting that this compound could prevent peripheral sensitization within the ganglion. Three clinical trials aimed at investigating the effectiveness of tonabersat as a preventive drug were negative, and conflicting results were obtained in other trials concerning its ability to relieve attacks. In contrast, in another clinical trial, tonabersat showed a preventive effect on attacks of migraine with aura but had no efficacy on non-aura attacks. Gap junction channels seem to be involved in several ways in the pathophysiology of migraine with aura and emerge as a new promising putative target in treatment of this disorder.
PMCID: PMC3933780  PMID: 24611055
aura; connexin; cortical spreading depression; gap junction; pannexin; tonabersat; trigeminovascular
9.  Migraine Features, Associated Symptoms, and Triggers: A Principal Component Analysis in the Women's Health Study 
Migraine has a wide clinical spectrum. Our aim was to group information on migraine characteristics into meaningful components and to identify key components of the migraine phenotype.
We performed two principal component analyses, one among participants in the Women's Health Study enrolment cohort and one in a sub-cohort with additional migraine-specific information.
Among the 9,427 women with migraine attack-related information at enrolment, the three most important components pertained to central nervous system (CNS) sensitization, attack frequency/pain location, and aura/visual phenomena. In the sub-group of 1,675 women with more detailed information, food triggers and unspecific symptoms constituted two principal components that explain more of the variance of the migraine phenotype than the three attack-related components.
Our results indicate that information on migraine-associated features, symptoms, and triggers is highly correlated allowing the extraction of principal components. Migraine attack-related symptoms are best summarized by symptoms related to CNS sensitization, attack frequency/pain location, and aura/visual phenomena. Taking a more general view, unspecific symptoms and food triggers appear to carry stronger importance in characterizing the migraine phenotype. These components are useful for future research on the pathophysiology and genetics of migraine and may have implications for diagnosing and treating patients.
PMCID: PMC3100409  PMID: 21398421
migraine; features; triggers; sensitization; principal component analysis
10.  Anatomical Alterations of the Visual Motion Processing Network in Migraine with and without Aura 
PLoS Medicine  2006;3(10):e402.
Patients suffering from migraine with aura (MWA) and migraine without aura (MWoA) show abnormalities in visual motion perception during and between attacks. Whether this represents the consequences of structural changes in motion-processing networks in migraineurs is unknown. Moreover, the diagnosis of migraine relies on patient's history, and finding differences in the brain of migraineurs might help to contribute to basic research aimed at better understanding the pathophysiology of migraine.
Methods and Findings
To investigate a common potential anatomical basis for these disturbances, we used high-resolution cortical thickness measurement and diffusion tensor imaging (DTI) to examine the motion-processing network in 24 migraine patients (12 with MWA and 12 MWoA) and 15 age-matched healthy controls (HCs). We found increased cortical thickness of motion-processing visual areas MT+ and V3A in migraineurs compared to HCs. Cortical thickness increases were accompanied by abnormalities of the subjacent white matter. In addition, DTI revealed that migraineurs have alterations in superior colliculus and the lateral geniculate nucleus, which are also involved in visual processing.
A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability observed in migraineurs. The finding in patients with both MWA and MWoA of thickness abnormalities in area V3A, previously described as a source in spreading changes involved in visual aura, raises the question as to whether a “silent” cortical spreading depression develops as well in MWoA. In addition, these experimental data may provide clinicians and researchers with a noninvasively acquirable migraine biomarker.
A structural abnormality in the network of motion-processing areas could account for, or be the result of, the cortical hyperexcitability seen in people who have migraine.
Editors' Summary
Migraine is a disabling brain disorder that affects more than one in ten people during their lifetimes. It is characterized by severe, recurrent headaches, often accompanied by nausea, vomiting, and light sensitivity. In some migraineurs (people who have migraines), the headaches are preceded by neurological disturbances known as “aura.” These usually affect vision, causing illusions of flashing lights, zig-zag lines, or blind spots. There are many triggers for migraine attacks—including some foods, stress, and bright lights—and every migraineur has to learn what triggers his or her attacks. There is no cure for migraine, although over-the-counter painkillers can ease the symptoms and doctors can prescribe stronger remedies or drugs to reduce the frequency of attacks. Exactly what causes migraine is unclear but scientists think that, for some reason, the brains of migraineurs are hyperexcitable. That is, some nerve cells in their brains overreact when they receive electrical messages from the body. This triggers a local disturbance of brain function called “cortical spreading depression,” which, in turn, causes aura, headache, and the other symptoms of migraine.
Why Was This Study Done?
Researchers need to know more about what causes migraine to find better treatments. One clue comes from the observation that motion perception is abnormal in migraineurs, even between attacks—they can be very sensitive to visually induced motion sickness, for example. Another clue is that aura are usually visual. So could brain regions that process visual information be abnormal in people who have migraines? In this study, the researchers investigated the structure of the motion processing parts of the brain in people who have migraine with aura, in people who have migraine without aura, and in unaffected individuals to see whether there were any differences that might help them understand migraine.
What Did the Researchers Do and Find?
The researchers used two forms of magnetic resonance imaging—a noninvasive way to produce pictures of internal organs—to examine the brains of migraineurs (when they weren't having a migraine) and healthy controls. They concentrated on two brain regions involved in motion processing known as the MT+ and V3A areas and first measured the cortical thickness of these areas—the cortex is the wrinkled layer of gray matter on the outside of the brain that processes information sent from the body. They found that the cortical thickness was increased in both of these areas in migraineurs when compared to healthy controls. There was no difference in cortical thickness between migraineurs who had aura and those who did not, but the area of cortical thickening in V3A corresponded to the source of cortical spreading depression previously identified in a person who had migraine with aura. The researchers also found differences between the white matter (the part of the brain that transfers information between different regions of the gray matter) immediately below the V3A and MT+ areas in the migraineurs and the controls but again not between the two groups of migraineurs.
What Do These Findings Mean?
This study provides new information about migraine. First, it identifies structural changes in the brains of people who have migraines. Until now, it has been thought that abnormal brain function causes migraine but that migraineurs have a normal brain structure. The observed structural differences might either account for or be caused by the hyperexcitability that triggers migraines. Because migraine runs in families, examining the brains of children of migraineurs as they grow up might indicate which of these options is correct, although it is possible that abnormalities in brain areas not examined here actually trigger migraines. Second, the study addresses a controversial question about migraine: Is migraine with aura the same as migraine without aura? The similar brain changes in both types of migraine suggest that they are one disorder. Third, the abnormalities in areas MT+ and V3A could help to explain why migraineurs have problems with visual processing even in between attacks. Finally, this study suggests that it might be possible to develop a noninvasive test to help doctors diagnose migraine.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has several pages on migraine
The US National Institute of Neurological Disorders and Stroke offers patient information on migraine and other headaches
The NHS Direct Online contains patient information on migraine from the UK National Health Service
MAGNUM provides information from The US National Migraine Association
The Migraine Trust is a UK charity that supports research and provides support for patients
The Migraine Aura Foundation is a site about aura that includes a section on art and aura
PMCID: PMC1609120  PMID: 17048979
11.  Brain-derived neurotrophic factor in primary headaches 
The Journal of Headache and Pain  2012;13(6):469-475.
Brain derived neurotrophic factor (BDNF) is associated with pain modulation and central sensitization. Recently, a role of BDNF in migraine and cluster headache pathophysiology has been suspected due to its known interaction with calcitonin gene-related peptide. Bi-center prospective study was done enrolling four diagnostic groups: episodic migraine with and without aura, episodic cluster headache, frequent episodic tension-type headache, and healthy individuals. In migraineurs, venous blood samples were collected twice: outside and during migraine attacks prior to pain medication. In cluster headache patients serum samples were collected in and outside cluster bout. Analysis of BDNF was performed using enzyme-linked immunosorbent assay technique. Migraine patients revealed significantly higher BDNF serum levels during migraine attacks (n = 25) compared with headache-free intervals (n = 53, P < 0.01), patients with tension-type headache (n = 6, P < 0.05), and healthy controls (n = 22, P < 0.001). There was no significant difference between patients with migraine with aura compared with those without aura, neither during migraine attacks nor during headache-free periods. Cluster headache patients showed significantly higher BDNF concentrations inside (n = 42) and outside cluster bouts (n = 24) compared with healthy controls (P < 0.01, P < 0.05). BDNF is increased during migraine attacks, and in cluster headache, further supporting the involvement of BDNF in the pathophysiology of these primary headaches.
PMCID: PMC3464472  PMID: 22584531
Migraine; Cluster headache; Tension-type headache; Brain-derived neurotrophic factor
12.  Comorbidities of Migraine 
Migraine is a common neurological disorder and can be severely disabling during attacks. The highest prevalence occurs between the ages of 25 and 55 years, potentially the most productive period of life. Migraine leads to a burden not only for the individual, but also for the family and society in general. Prior studies have found that migraine occurs together with other illnesses at a greater coincidental rate than is seen in the general population. These occurrences are called “comorbidities,” which means that these disorders are interrelated with migraine. To delineate the comorbidities of migraine is important, because it can help improve treatment strategies and the understanding of the possible pathophysiology of migraine. The comorbid illnesses in patients with migraine include stroke, sub-clinical vascular brain lesions, coronary heart disease, hypertension, patent foramen ovale, psychiatric diseases (depression, anxiety, bipolar disorder, panic disorder, and suicide), restless legs syndrome, epilepsy and asthma. In this paper, we review the existing epidemiological and hospital-based studies, and illustrate the connections between these illnesses and migraine.
PMCID: PMC3008936  PMID: 21188255
migraine; cerebrovascular disorder; depression; anxiety; comorbidity
13.  Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system 
Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers.
PMCID: PMC2245994  PMID: 18217201
Trigemino-cerebrovascular system; CGRP; Triptan; Olcegepant; MK-0974
14.  Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system 
Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers.
PMCID: PMC2245994  PMID: 18217201
Trigemino-cerebrovascular system; CGRP; Triptan; Olcegepant; MK-0974
15.  microRNAs in nociceptive circuits as predictors of future clinical applications 
Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.
PMCID: PMC3798051  PMID: 24151455
chronic pain; biomarker; polymorphism; miRNA-based diagnostics; miRNA expression patterns; miRNA polymorphisms; antagomir; miRNA-based analgesic
16.  Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome 
Fibromyalgia (FM) pain is frequent in the general population but its pathogenesis is only poorly understood. Many recent studies have emphasized the role of central nervous system pain processing abnormalities in FM, including central sensitization and inadequate pain inhibition. However, increasing evidence points towards peripheral tissues as relevant contributors of painful impulse input that might either initiate or maintain central sensitization, or both. It is well known that persistent or intense nociception can lead to neuroplastic changes in the spinal cord and brain, resulting in central sensitization and pain. This mechanism represents a hallmark of FM and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established only minimal nociceptive input is required for the maintenance of the chronic pain state. Additional factors, including pain related negative affect and poor sleep have been shown to significantly contribute to clinical FM pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of FM and other chronic pain syndromes.
PMCID: PMC1526632  PMID: 16684376
17.  Optimizing prophylactic treatment of migraine: Subtypes and patient matching 
Advances in our understanding of the pathophysiology of migraine have resulted in important breakthroughs in treatment. For example, understanding of the role of serotonin in the cerebrovascular circulation has led to the development of triptans for the acute relief of migraine headaches, and the identification of cortical spreading depression as an early central event associated wih migraine has brought renewed interest in antiepileptic drugs for migraine prophylaxis. However, migraine still remains inadequately treated. Indeed, it is apparent that migraine is not a single disease but rather a syndrome that can manifest itself in a variety of pathological conditions. The consequences of this may be that treatment needs to be matched to particular patients. Clinical research needs to be devoted to identifying which sort of patients benefit best from which treatments, particularly in the field of prophylaxis. We propose four patterns of precipitating factors (adrenergic, serotoninergic, menstrual, and muscular) which may be used to structure migraine prophylaxis. Finally, little is known about long-term outcome in treated migraine. It is possible that appropriate early prophylaxis may modify the long-term course of the disease and avoid late complications.
PMCID: PMC2621398  PMID: 19209286
migraine; diagnosis; treatment; prophylaxis; subtypes
18.  Modeling Neural Immune Signaling of Episodic and Chronic Migraine Using Spreading Depression In Vitro 
Migraine and its transformation to chronic migraine are healthcare burdens in need of improved treatment options. We seek to define how neural immune signaling modulates the susceptibility to migraine, modeled in vitro using spreading depression (SD), as a means to develop novel therapeutic targets for episodic and chronic migraine. SD is the likely cause of migraine aura and migraine pain. It is a paroxysmal loss of neuronal function triggered by initially increased neuronal activity, which slowly propagates within susceptible brain regions. Normal brain function is exquisitely sensitive to, and relies on, coincident low-level immune signaling. Thus, neural immune signaling likely affects electrical activity of SD, and therefore migraine. Pain perception studies of SD in whole animals are fraught with difficulties, but whole animals are well suited to examine systems biology aspects of migraine since SD activates trigeminal nociceptive pathways. However, whole animal studies alone cannot be used to decipher the cellular and neural circuit mechanisms of SD. Instead, in vitro preparations where environmental conditions can be controlled are necessary. Here, it is important to recognize limitations of acute slices and distinct advantages of hippocampal slice cultures. Acute brain slices cannot reveal subtle changes in immune signaling since preparing the slices alone triggers: pro-inflammatory changes that last days, epileptiform behavior due to high levels of oxygen tension needed to vitalize the slices, and irreversible cell injury at anoxic slice centers.
In contrast, we examine immune signaling in mature hippocampal slice cultures since the cultures closely parallel their in vivo counterpart with mature trisynaptic function; show quiescent astrocytes, microglia, and cytokine levels; and SD is easily induced in an unanesthetized preparation. Furthermore, the slices are long-lived and SD can be induced on consecutive days without injury, making this preparation the sole means to-date capable of modeling the neuroimmune consequences of chronic SD, and thus perhaps chronic migraine. We use electrophysiological techniques and non-invasive imaging to measure neuronal cell and circuit functions coincident with SD. Neural immune gene expression variables are measured with qPCR screening, qPCR arrays, and, importantly, use of cDNA preamplification for detection of ultra-low level targets such as interferon-gamma using whole, regional, or specific cell enhanced (via laser dissection microscopy) sampling. Cytokine cascade signaling is further assessed with multiplexed phosphoprotein related targets with gene expression and phosphoprotein changes confirmed via cell-specific immunostaining. Pharmacological and siRNA strategies are used to mimic and modulate SD immune signaling.
PMCID: PMC3125108  PMID: 21694695
19.  GABA and glutamate in migraine 
The Journal of Headache and Pain  2001;2(Suppl 1):s57-s60.
GABA and glutamic acid are the main inhibitory and excitatory neurotransmitters of central nervous system. Among other functions they modulate the pain threshold in the CNS. For this reason it has been hypothesized that anomalies of GABA and glutamate turn–over may play a role in migraine pathogenesis. In this review are discussed the evidences in favour of this hypothesis. A derangement of GABA may be an important factor in the occurrence of migraine attacks and their recurrence, whereas high level of glutamic acid may represent a biochemical marker of the neuronal hyperexcitability that may be the underlying cause of the aura. The pharmacological modulation of metabolism of both neurotransmitters is a promising approach to improve migraine therapy. In particular the studies presented here suggest that gabaergic drugs may be useful in migraine without aura, antiglutamatergic drugs are indicated to treat migraine with aura.
PMCID: PMC3451832
GABA; Glutamic acid; Migraine with and without aura; Migraine pathogenesis
20.  Migraine: An Overview 
The pathophysiology of migraine is not completely understood and continues to be investigated. The complexity of interactions taking place in the sensory neuronal network with the mediation of all different neurotransmitters involved gives the measure of the extreme difficulty connected with the knowledge of migraine pathogenesis and in particular of its cardinal sign. Neuronal components are relevant in migraine pathophysiology: there could be a generalized interictal abnormal excitability of the cerebral cortex in migraine, possibly favoring the occurrence of spreading depression with consequent activation of the trigeminal system. Many theories have been formulated in these last sixty years about the pathogenesis of migraine and other forms of primary headache, but the problem is still far to be fully clarified. The present review is focused on the description of different theories on the migraine pathogenesis.
      This review is dedicated to the memory of Prof. Alfredo Bianchi.
PMCID: PMC2771268  PMID: 19888434
21.  Limb pain in migraine and cluster headache. 
Upper limb pain occurred in close temporal association with attacks of migraine, cluster headache and cluster-migraine in 22 cases. Seven had also lower limb pain. Limb pain was usually ipsilateral to the headache but could alternate sides and behaved like other accepted migraine accompaniments. It was always ipsilateral to the associated paraesthesiae/numbness (9 cases) and weakness (6 cases). The distribution and restricted localisations of limb pain were similar to those of the sensory symptoms and could not be accounted for by primary dysfunction of the peripheral or autonomic nervous systems. A central origin for limb pain is postulated. A temporary dysfunction in the somatosensory cortex, and/or its thalamic connections, during migraine or cluster headache attacks, might mediate such pain in a number of patients.
PMCID: PMC1033109  PMID: 3216204
22.  Migraine Changes the Brain – Neuroimaging Imaging Makes its Mark 
Current Opinion in Neurology  2012;25(3):252-262.
Purpose of review
To summarize key findings of the current literature on functional neuroimaging in migraine and to describe how these studies have changed our view of the disorder. Recent findings: Recent studies have started to investigate not only the global cerebral activation pattern during migraine attacks, but to address specific aspects of migraine attacks such as photophobia, osmophobia as well as pain perception with the aim of disentangling the underlying mechanisms. There is also more and more evidence that the migraine brain is abnormal even outside of attacks and that repeated attacks are leading to functional and structural alterations in the brain, which may in turn drive the transformation of migraine to its chronic form. Some new results are pinpointing towards a potential role of interesting new brain areas in migraine pathophysiology such as the temporal cortex or the basal ganglia.
Neuroimaging studies are beginning to shed light on the mechanisms underlying the development and evolution of migraine and its specific symptoms. Future studies have the potential to also improve our understanding of established and upcoming treatment approaches and to monitor treatment effects in an objective and non-invasive way.
PMCID: PMC3380341  PMID: 22487570
fMRI; MRS; voxel based morphometry; PET; migraine
23.  Molecular mechanisms of antimigraine drugs: past, present, and future 
The Journal of Headache and Pain  2004;5(Suppl 2):s99-s102.
Pharmacotherapeutic treatments for migraine have been documented for more than a century. Drugs that are effective in aborting an ongoing migraine attack exhibit a diversity of molecular mechanisms of action, but usually produce constriction of cranial arterial blood vessels, reversal of neurogenic inflammatory processes, and/or inhibition of sensory neuronal firing. This general understanding of drug action has led to the development of a unitary hypothesis for migraine pathophysiology, in which the onset of migraine is associated with activation of the trigemino-vascular system. Drugs which inhibit or reverse the activation of this system are effective acute treatments for migraine. Drugs useful in migraine prophylaxis have been discovered largely serendipitously, and display a fundamentally different pharmacology to the acutely effective agents. These drugs act at membrane receptors and ion channels, or by targeting intracellular biochemical pathways, and tend to reduce neuronal excitability in higher centers of the CNS. However, other than to suggest that this inhibits various migraine trigger events, it is not yet possible to delineate precisely how these drugs act to decrease the frequency and severity of migraine attacks. More recently, it has been observed that migraine is accompanied by sensory neuronal central sensitization that manifests as cutaneous allodynia in territory innervated by the trigeminal nerve. Although little is presently known about the ability of prophylactic drugs to modulate this process, it was recently shown that acute relief of migraine with triptan drugs is only reliably achieved when the drugs are given prior to the development of central sensitization. This important observation suggests that inhibition of migraine-related central sensitization could be an important new focus for future drug discovery, and may, for the first time, provide a rational target for the development of preventative medicines.
PMCID: PMC3451579
Trigemino-vascular system; Migraine; Acute treatment; Prophylaxis; Pathophysiology
24.  Migraine attacks the Basal Ganglia 
Molecular Pain  2011;7:71.
With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF).
In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain.
Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.
PMCID: PMC3192678  PMID: 21936901
Headache; Pain; Migraine; fMRI; Functional Connectivity; Morphometry; Gray Matter Volume; Basal Ganglia
25.  Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan 
Pain  2008;139(3):533-540.
Sumatriptan and the other triptan drugs target the serotonin receptor subtypes1B, 1D, and 1F (5-HT1B/D/F), and are prescribed widely in the treatment of migraine. An anti-migraine action of triptans has been postulated at multiple targets, within the brain and at both the central and peripheral terminals of trigeminal “pain-sensory” fibers. However, as triptan receptors are also located on “pain-sensory” afferents throughout the body, it is surprising that triptans only reduce migraine pain in humans, and experimental cranial pain in animals. Here we tested the hypothesis that sumatriptan can indeed reduce non-cranial, somatic and visceral pain in behavioral models in mice. Because sumatriptan must cross the blood brain barrier to reach somatic afferent terminals in the spinal cord, we compared systemic to direct spinal (intrathecal) sumatriptan. Acute nociceptive thresholds were not altered by sumatriptan pre-treatment, regardless of route. However, in behavioral models of persistent inflammatory pain, we found a profound anti-hyperalgesic action of intrathecal, but not systemic, sumatriptan. By contrast, sumatriptan was completely ineffective in an experimental model of neuropathic pain. The pronounced activity of intrathecal sumatriptan against inflammatory pain in mice raises the possibility that there is a wider spectrum of therapeutic indications for triptans beyond headache.
PMCID: PMC2869302  PMID: 18723285
Migraine; Headache; Inflammation; Serotonin; Sumatriptan; Intrathecal; Blood brain barrier

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