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1.  Anatomical Alterations of the Visual Motion Processing Network in Migraine with and without Aura 
PLoS Medicine  2006;3(10):e402.
Background
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.
Conclusions
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
Background.
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 http://dx.doi.org/10.1371/journal.pmed.0030402.
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
doi:10.1371/journal.pmed.0030402
PMCID: PMC1609120  PMID: 17048979
2.  Migraine and cerebrovascular disease 
The Journal of Headache and Pain  2004;5(Suppl 2):s78-s80.
Migraine and cerebrovascular disease are linked in different ways: migraine may be a potential cause of stroke as in migrainous infarction, headache may be a symptom of cerebrovascular disease and also a risk factor for stroke, the association of migraine and stroke may constitute specific syndromes such as CADASIL and MELAS. The new IHS 2003 criteria, though preserving their main structure, have changed the terminology regarding secondary headaches, now described as “attributed to” another disease rather than “associated with” it. The more detailed knowledge of causal links between the underlying disorder and headache, has allowed to strengthen the terminology. Many cerebrovascular disorders as cerebral haemorrhage, venous sinus thrombosis, carotid or vertebral dissections and ischaemic stroke may present with a headache or be followed by it. In subarachnoid haemorrhage (SAH) headache may constitute an important warning sign before the bleeding. An interesting issue is the hypothesis that migraine may be a potential risk factor for stroke. Recent studies have underlined the increased relative risk of ischemic stroke in female migraineurs. Many potential mechanisms have been hypothesized: (1) alterations of vasoreactivity due to vessel wall dysfunction, (2) release of vasoactive substances during migraine, (3) platelet hyperactivity as expression of serotoninergic dysfunction in migraineurs, (4) intriguing studies have described a high prevalence of migraine with aura in stroke patients with patent foramen ovale (PFO). Differential diagnosis between migraine and stroke remains fundamental: some types of migraine can mimic cerebrovascular disease such as familial hemiplegic migraine, and basilar migraine. Migraine and stroke may be part of syndromic complexes as in CADASIL and MELAS. In conclusion migraine is a risk factor for cerebrovascular disease, it may be the cause of stroke as in migrainous infarctions, stroke may induce headache which may be a relevant symptom of cerebrovascular disease, yet migraine remains an essentially benign condition.
doi:10.1007/s10194-004-0114-5
PMCID: PMC3451598
Migraine; Cerebrovascular disease; IHS criteria
3.  Migraine and Stroke: “Vascular” Comorbidity 
Several comorbidities are associated to migraine. Recent meta-analyses have consistently demonstrated a relationship between migraine and stroke, which is well-defined for ischemic stroke and migraine with aura (MA), even stronger in females on oral contraceptives or smokers. However, there seems to be no clear-cut association between stroke in migraineurs and the common vascular risk factors, at least in the young adult population. Migraineurs also run an increased risk of hemorrhagic stroke, while the association between migraine and cardiovascular disease remains poorly defined. Another aspect is the relationship between migraine and the presence of silent brain lesions. It has been demonstrated that there is an increased frequency of ischemic lesions in the white matter of migraineurs, especially silent infarcts in the posterior circulation territory in patients with at least 10 attacks per month. Although there is a higher prevalence of patent foramen ovale (PFO) in migraineurs, the relationship between migraine and PFO remains controversial and PFO closure is not a recommended procedure to prevent migraine. As an increased frequency of cervical artery dissections has been observed in migrainous patients, it has been hypothesized that migraine may represent a predisposing factor for cervical artery dissection. There still remains the question as to whether migraine should be considered a true “vascular disease” or if the comorbidity between migraine and cerebrovascular disease may have underlying shared risk factors or pathophysiological mechanisms. Although further studies are required to clarify this issue, current evidence supports a clinical management where MA patients should be screened for other concomitant vascular risk factors and treated accordingly.
doi:10.3389/fneur.2014.00193
PMCID: PMC4189436  PMID: 25339937
migraine; stroke; ischemic stroke; hemorrhagic stroke; cerebrovascular disease; vascular risk factors
4.  Pediatric migraine and episodic syndromes that may be associated with migraine 
Importance
Migraine is a common disorder and a frequent cause of medical consultation in children. Many childhood episodic syndromes have been described as common precursors of migraine.
Objective
To review current knowledge on migraine and childhood episodic syndromes, and to discuss future directions for research and clinical practice.
Findings
For most children it is difficult to describe a headache and fully verbalize symptoms such as photophobia and phonophobia that must be inferred from behaviour. Classical migraine features are rare before the age of 6 years, but some migraine-related syndromes have been described. Benign paroxysmal torticollis of infancy, benign paroxysmal vertigo of childhood, cyclic vomiting syndrome and abdominal migraine are currently classified as childhood episodic syndromes, and therefore common precursors of migraine. A strong association between infantile colic and migraine has recently been reported. There are similarities between children with episodic syndromes and children with migraine, regarding social and demographic factors, precipitating and relieving factors, and accompanying gastrointestinal, neurologic, and vasomotor features. The real pathophysiological mechanisms of migraine are not fully understood. Current data obtained through molecular and functional studies provide a complex model in which vascular and neurologic events cooperate in the pathogenesis of migraine attacks. Genetic factors causing disturbances in neuronal ion channels, make a migraineur more sensitive to multiple trigger factors that activate the nociception cascade. The expanding knowledge on migraine genetics and pathophysiology may be applicable to childhood episodic syndromes. Migraine preventive strategies are particularly important in children, and could be beneficial in childhood episodic syndromes. Nonspecific analgesics like ibuprofen and acetaminophen are widely used in pediatrics to control pain and have been found to be effective also in the treatment of acute migraine attacks. Triptans are the specific fist-line drugs for acute migraine treatment.
Conclusions and relevance
Migraine phenotype differs somewhat in the developing brain, and childhood episodic syndromes may arise before typical migraine headache. Diagnosing pediatric migraine may be difficult because of children’s language and cognitive abilities. The risk of underestimating migraine in pediatric age is high. An adequate diagnosis is important to maintain a good quality of life and to avoid inappropriate therapy.
doi:10.1186/s13052-014-0092-4
PMCID: PMC4239406  PMID: 25407042
Infantile colic; Migraine; Cyclic vomiting; Recurrent abdominal pain; Functional abdominal pain; Torticollis
5.  Association between ischemic stroke and migraine in elderly Chinese: a case–control study 
BMC Geriatrics  2013;13:126.
Background
Recent observations suggest that migraine and cerebrovascular disease are comorbid conditions. However, the association of migraine with cerebrovascular disease in the population of elderly Chinese has not been established. This prospective case–control study aimed to investigate the prevalence and lesion characteristics of migraine in elderly Chinese patients with acute cerebral infarction (ACI).
Methods
A total of 968 ACI patients aged 55–70 years and 1024 sex- and age-matched control subjects were recruited between January, 2003 and July, 2009. Migraine was determined based on the International Headache Society’s Classification of Headache Disorders, together with past medical records and admission examination results, following an initial questionnaire screening at the first hospital visit. Prevalence rates of overall migraine, migraine with aura and migraine without aura in both ACI patients and control subjects, the stroke subtypes classified according to the Chinese Ischemic Stroke Subclassification (CISS) system and brain locations of the ischemic lesions in ACI patients were analyzed.
Results
The overall prevalence rate of migraine was 17.15% (166/968) in patients with ACI but only 3.9% (40/1024) in control subjects (P < 0.01). In both subject groups, over 80% of migraine cases were migraine without aura. In the 166 ACI patients with comorbid migraine, large artery atherosclerosis was the most frequent subtype of ischemic lesion (65.06%), followed by cardiogenic stroke (23.50%), and all other lesion subtypes were each less than 10%. Ischemic infarctions were located predominantly in the anterior circulation in the brain in both ACI patients with and without migraine.
Conclusions
The prevalence rate of migraine is significantly higher in ACI patients than non-ACI subjects in the population of elderly Chinese. Migraine without aura is the major form of migraine in both ACI patients and non-ACI subjects. In ACI patients, regardless of migraine, infarction lesions were predominantly located in the anterior cerebral circulation.
doi:10.1186/1471-2318-13-126
PMCID: PMC3835862  PMID: 24245875
Migraine; Acute cerebral infarction; Elderly Chinese; Aura
6.  Comorbid neuropathologies in migraine: an update on cerebrovascular and cardiovascular aspects 
The Journal of Headache and Pain  2008;9(4):237-248.
Several conditions are comorbid with migraine; our review is focused on the relation between migraine, and cerebrovascular and cardiovascular diseases. Despite many studies showed an association between migraine and patent foramen ovale, it is still not known whether its presence might be causal for the migraine pathogenesis and currently its closure cannot be recommended for migraine prevention. On the contrary, conflicting epidemiological data link migraine to arterial hypertension and the use of antihypertensive agents acting on the renin-angiotensin system sounds promising in migraine prevention. A complex bidirectional relation exists between migraine and stroke, and new evidences show a clear association between migraine and coronary heart disease. In both conditions, migraine represents a defined risk factor although the magnitude of the risk varies across the different studies. However, since the risk is low in the general population, it is not possible to identify which migraineurs will develop a cardiovascular or a cerebrovascular event making difficult to apply preventive measures.
doi:10.1007/s10194-008-0048-4
PMCID: PMC3451940  PMID: 18600300
Migraine; Patent forame ovale; Arterial hypertension; Retinal disease; Cardiovascular disease; Cerebrovascular disease; Stroke; Myocardial infarction
7.  Migraine and stroke in young women: case-control study 
BMJ : British Medical Journal  1999;318(7175):13-18.
Objective
To investigate the association between migraine and ischaemic or haemorrhagic stroke in young women.
Design
Hospital based case-control study.
Setting
Five European centres participating in the World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.
Subjects
291 women aged 20-44 years with ischaemic, haemorrhagic, or unclassified arterial stroke compared with 736 age and hospital matched controls.
Intervention
Questionnaire.
Main outcome measure
Self reported history of headaches.
Results
Adjusted odds ratios associated with a personal history of migraine were 1.78 (95% confidence intervals, 1.14 to 2.77), 3.54 (1.30 to 9.61), and 1.10 (0.63 to 1.94) for all stroke, ischaemic stroke, and haemorrhagic stroke respectively. Odds ratios for ischaemic stroke were similar for classical migraine (with aura) (3.81, 1.26 to 11.5) and simple migraine (without aura) (2.97, 0.66 to 13.5). A family history of migraine, irrespective of personal history, was also associated with increased odds ratios, not only for ischaemic stroke but also haemorrhagic stroke. In migrainous women, coexistent use of oral contraceptives or a history of high blood pressure or smoking had greater than multiplicative effects on the odds ratios for ischaemic stroke associated with migraine alone. Change in the frequency or type of migraine on using oral contraceptives did not predict subsequent stroke. Between 20% and 40% of strokes in women with migraine seemed to develop directly from a migraine attack.
Conclusions
Migraine in women of childbearing age significantly increases the risk of ischaemic but not haemorrhagic stroke. The coexistence of oral contraceptive use, high blood pressure, or smoking seems to exert a greater than multiplicative effect on the risk of ischaemic stroke associated with migraine.
Key messagesA personal history of migraine was associated with increased risk of ischaemic but not haemorrhagic strokeCoexistence of risk factors—use of oral contraceptives, high blood pressure, or smoking had more than multiplicative effects on odds ratios for ischaemic stroke associated with migraine aloneA family history of migraine, irrespective of a personal migraine history, was associated with increased risk of ischaemic and haemorrhagic strokeUp to 40% of strokes in migrainous women develop directly out of a migraine attack—so called migrainous strokesA change in type or frequency of migraine with use of oral contraceptives did not predict subsequent stroke
PMCID: PMC27668  PMID: 9872876
8.  Comorbid neuropathologies in migraine 
The Journal of Headache and Pain  2006;7(4):222-230.
The identification of comorbid disorders in migraineurs is important since it may impose therapeutic challenges and limit treatment options. Moreover, the study of comorbidity might lead to improve our knowledge about causes and consequences of migraine. Comorbid neuropathologies in migraine may involve mood disorders (depression, mania, anxiety, panic attacks), epilepsy, essential tremor, stroke, and white matter abnormalities. Particularly, a complex bidirectional relation exists between migraine and stroke, including migraine as a risk factor for cerebral ischemia, migraine caused by cerebral ischemia, migraine as a cause of stroke, migraine mimicking cerebral ischemia, migraine and cerebral ischemia sharing a common cause, and migraine associated with subclinical vascular brain lesions.
doi:10.1007/s10194-006-0300-8
PMCID: PMC3476070  PMID: 16767530
Migraine; Depression; Epilepsy; Tremor; Stroke; White matter lesions; Patent foramen ovale
9.  Selectivity in Genetic Association with Sub-classified Migraine in Women 
PLoS Genetics  2014;10(5):e1004366.
Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.
Author Summary
Migraine is among the most common and debilitating neurological disorders. Diagnostic criteria for migraine recognize a variety of symptoms including a primary dichotomous classification for the presence or absence of aura, typically a visual disturbance phenomenon, as well as others such as sensitivity to light or sound, and nausea, etc. We explored whether any of 12 recently discovered genetic variants associated with common migraine might have selective association for migraine sub-classified by aura status or nine additional migraine features in a population of middle-aged women including 3,003 migraineurs and 18,180 non-migraineurs. Five of the 12 genetic variants met the most stringent significance criterion for association with migraine, among which four had selective association with sub-classified migraine, including one that was selective for migraine without aura. At suggestive significance, all of the remaining genetic variants were selective for sub-classifications of migraine although no two variants showed the same pattern of selectivity. The selectivity patterns suggest very different contributions to migraine pathophysiology among the 12 loci and their implicated genes. Further, the results suggest that future discovery efforts for new migraine susceptibility loci would benefit by considering associations with sub-classified migraine toward the ultimate goals of more specific diagnosis and personalized treatment.
doi:10.1371/journal.pgen.1004366
PMCID: PMC4031047  PMID: 24852292
10.  Migraine and cardiovascular disease 
Neurology  2009;72(21):1864-1871.
Migraine, especially migraine with aura (MA), is an established risk factor for ischemic lesions of the brain. Recent evidence has also linked migraine to a broader range of ischemic vascular disorders including angina, myocardial infarction, coronary revascularization, claudication, and cardiovascular mortality. The mechanisms which link migraine to ischemic vascular disease remain uncertain and are likely to be complex. Cortical spreading depression, the presumed substrate of aura, may directly predispose to brain lesions and that would explain why MA is consistently demonstrated as a risk factor for cerebral ischemia, while for migraine without aura (MO), the evidence is less consistent. Additionally, individuals with migraine have a higher prevalence of risk factors known to be associated with cardiovascular disease (CVD), including hypertension, diabetes, and hyperlipidemia. The increased prevalence of CVD risk factors is also higher for MA than for MO. Since the evidence linking migraine and CVD is getting robust, neurologists should be aware of this association. Individuals with MO seem to be at little increased risk of CVD. MA is associated with an increased risk of ischemic stroke and likely also for other ischemic CVD events. Accordingly, heightened vigilance is recommended for modifiable cardiovascular risk factors in migraineurs, especially with MA. Ultimately, it will be important to determine whether MA is a modifiable risk factor for CVD and if preventive medications for migraine or antiplatelet therapy might reduce the risk of CVD in patients with MA.
GLOSSARY
= body mass index;
= chronic daily headache;
= confidence interval;
= cortical spreading depression;
= cardiovascular disease;
= endothelial progenitor cells;
= hazard ratio;
= migraine with aura;
= matrix metalloproteinase;
= migraine without aura;
= methyltetrahydrofolate reductase;
= relative risk.
doi:10.1212/WNL.0b013e3181a71220
PMCID: PMC2690985  PMID: 19470970
11.  Migraine frequency and risk of cardiovascular disease in women 
Neurology  2009;73(8):581-588.
Background:
Migraine has been associated with risk of cardiovascular disease (CVD). Data on the association between migraine frequency and CVD are sparse.
Methods:
Prospective cohort study of 27,798 US women aged ≥45 years, who were free of CVD, and for whom we had information on lipids and migraine frequency. We categorized migraine frequency as < monthly, monthly, and ≥ weekly. Incident CVD was confirmed after medical record review.
Results:
Of the 3,568 women with active migraine at baseline, 75.3% reported a migraine frequency of < monthly, 19.7% monthly, and 5.0% ≥ weekly. During 11.9 years of follow-up, 706 CVD events occurred. Compared with women without migraine, the multivariable-adjusted hazard ratios (HRs) (95% confidence intervals) among active migraineurs for CVD were 1.55 (1.22–1.97), 0.65 (0.31–1.38), and 1.93 (0.86–4.33) for an attack frequency of < monthly, monthly, and ≥ weekly, respectively. The association between migraine frequency and CVD was only apparent among migraineurs with aura. Among those, the multivariable-adjusted HRs for women with a migraine frequency < monthly ranged from 1.81 (1.30–2.50) for coronary revascularizations to 2.43 (1.58–3.74) for myocardial infarction. For women with active migraine with aura and migraine frequencies of ≥ weekly, we only found significant increased risk of ischemic stroke (HR = 4.25 [1.36–13.29]).
Conclusions:
In our data, the association between migraine and cardiovascular disease varies by migraine frequency. Significant associations were only found among women with migraine with aura. Ischemic stroke was the only outcome associated with a high-attack frequency while a low-attack frequency was associated with any vascular event. Low number of outcome events should caution the interpretation.
GLOSSARY
= confidence interval;
= cardiovascular disease;
= hazard ratio;
= myocardial infarction;
= Women’s Health Study.
doi:10.1212/WNL.0b013e3181ab2c20
PMCID: PMC2731618  PMID: 19553594
12.  Cerebral perfusion changes in migraineurs: a voxelwise comparison of interictal dynamic susceptibility contrast MRI measurements 
Introduction
The increased risk of cerebro- and cardiovascular disease in migraineurs may be the consequence of a systemic condition affecting whole body vasculature. At cerebrovascular level, this may be reflected by interictal global or regional cerebral perfusion abnormalities. Whether focal perfusion changes occur during interictal migraine has not been convincingly demonstrated.
Methods
We measured brain perfusion with dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) in 29 interictal female migraineurs (12 migraine with aura (MA), 17 migraine without aura (MO)) and 16 female controls. Perfusion maps were compared between these groups with a voxelwise (p<0.001, uncorrected, minimum cluster size 20 voxels) and a region-of-interest approach.
Results
In whole brain voxelwise analyses interictal hyperperfusion was observed in the left medial frontal gyrus in migraineurs and in the inferior and middle temporal gyrus in MO patients, in comparison to controls. Hypoperfusion was seen in the postcentral gyrus and in the inferior temporal gyrus in MA patients and in the inferior frontal gyrus in MO patients. Additional focal sites of hyperperfusion were noted in subgroups based on attack frequency and disease history. Region-of-interest analyses of the pons, hypothalamus, occipital lobe and cerebellum did not show interictal perfusion differences between migraineurs and controls.
Conclusion
We conclude that interictal migraine is characterized by discrete areas of hyper- and hypoperfusion unspecific for migraine pathophysiology and not explaining the increased vulnerability of particular brain regions for cerebrovascular damage.
doi:10.1177/0333102411435985
PMCID: PMC3743424  PMID: 22290556
interictal migraine; dynamic susceptibility contrast magnetic resonance imaging; brain perfusion
13.  Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine 
Background
Preventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing.
Objective
To study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention.
Methods
We recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy.
Results
In HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication intake significantly decreased during the treatment period compared to pre-treatment baseline (all p < 0.05), and this benefit persisted on average 4.8 weeks after the end of tDCS.
Conclusions
Anodal tDCS over the visual cortex is thus able to increase habituation to repetitive visual stimuli in healthy volunteers and in episodic migraineurs, who on average lack habituation interictally. Moreover, 2 weekly sessions of anodal tDCS had a significant preventive anti- migraine effect, proofing the concept that the low preactivation level of the visual cortex in migraine patients can be corrected by an activating neurostimulation. The therapeutic results indicate that a larger sham-controlled trial using the same tDCS protocol is worthwhile.
doi:10.1186/1129-2377-14-23
PMCID: PMC3620516  PMID: 23566101
Migraine; Habituation deficit; tDCS; Treatment; Visual cortex
14.  Are Sleep Difficulties Associated With Migraine Attributable to Anxiety and Depression? 
Headache  2008;48(10):1451-1459.
Objective
To examine whether sleep complaints reported by migraineurs can be attributed to comorbid anxiety and/or depression.
Background
A consistent association between migraine and sleep complaints has been reported in community and clinical studies. However, anxiety and depression are often comorbid with migraine. Thus, it may be possible that the increased prevalence of sleep problems in migraineurs is attributable to comorbid anxiety and depression. To our knowledge, no previous studies have demonstrated that the associations are not solely attributed to comorbid anxiety and depression.
Design and Methods
Controlled family study of anxiety disorders and substance use disorders in a community in New Haven County, CT. The sample included 221 probands (41 migraineurs) and their 261 directly interviewed first-degree relatives (39 migrainuers), including parents, siblings, and offspring over age 18. A lifetime history of migraine was obtained using the Diagnostic Interview for Headache Syndromes. A lifetime history of psychiatric disorders was obtained using the semi-structured Schedule for Affective Disorders and Schizophrenia which was modified to incorporate Diagnostic and Statistical Manual diagnostic criteria. Several sleep items on current and lifetime sleep complaints were included as a subset of the interview.
Results
There was a significant association between migraine and the number of sleep problems as well as several specific sleep symptoms among probands and their adult relatives. Adults with migraine reported having significantly more lifetime sleep problems (OR [CI] = 2.3 [1.1-4.6]), and more current sleep difficulties, specifically, inadequate sleep (2.5 [1.2-5.0]), difficulty falling asleep (3.0 [1.5-6.3]), and persistent nightmares of childhood onset (4.3 [1.8-9.9]) than those without migraine. The associations between sleep problems and migraine persisted after controlling for both lifetime and current anxiety and mood disorders.
Conclusions
The association between sleep problems and migraine that is not solely explained by comorbid anxiety disorders or depression suggests that sleep problems should be evaluated among people with migraine.
doi:10.1111/j.1526-4610.2008.01175.x
PMCID: PMC2692650  PMID: 18624714
sleep; migraine; anxiety; depression
15.  New insights into the cardiovascular risk of migraine and the role of white matter hyperintensities: is gold all that glitters? 
The role of migraine as an independent risk factor for cardiovascular events has been debated for several years, while it is more established for ischemic stroke. Recently, new studies have examined the likelihood of migraine to determine cardiovascular events, supporting the hypothesis of a predominant role in patients with migraine with aura, the risk including both sexes. In the literature, multiple pathophysiological mechanisms are described to explain this association, and are here discussed. Furthermore, the emerging evidence that a higher headache frequency and long-term migraine may worsen the cardio-metabolic profile in migraineurs (e.g. with a higher Framingham risk score and risk of developing atherosclerosis, insulin resistance and metabolic syndrome) makes it increasingly necessary to reduce the number and severity of attacks, not only to alleviate the painful symptoms, but also to improve the prognosis in these patients.
doi:10.1186/1129-2377-14-9
PMCID: PMC3620371  PMID: 23565964
Migraine; Cardiovascular events; Risk factors
16.  Migraine and psychiatric comorbidity: a review of clinical findings 
The Journal of Headache and Pain  2011;12(2):115-125.
Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder.
doi:10.1007/s10194-010-0282-4
PMCID: PMC3072482  PMID: 21210177
Migraine; Comorbidity; Psychiatric disorders; Depression; Meta-analysis
17.  Migraine and psychiatric comorbidity: a review of clinical findings 
The Journal of Headache and Pain  2011;12(2):115-125.
Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder.
doi:10.1007/s10194-010-0282-4
PMCID: PMC3072482  PMID: 21210177
Migraine; Comorbidity; Psychiatric disorders; Depression; Meta-analysis
18.  Platelet–leukocyte interaction and platelet activation in migraine: a link to ischemic stroke? 
Objectives: Migraine has been identified as an independent risk factor for ischemic stroke. Both neurogenic inflammation and platelet activation have been linked to the pathophysiology of migraine. Increased platelet activation results in up-regulation of specific binding to leukocytes which promotes pro-inflammatory leukocyte secretion and their tethering to endothelium, a mechanism that has been demonstrated in stroke and which could provide a link to migraine. We aimed to determine whether platelet–leukocyte aggregation is increased in migraine patients outside an acute attack.
Methods: Seventy two patients with migraine according to IHS criteria were compared to a control group (n = 72). Whole blood flow cytometry was used to quantify the activation dependent P selectin on the platelet, and to assess the fraction of platelets bound to the different leukocyte subsets.
Results: Migraine patients showed significantly more platelet–leukocyte aggregates compared to the control subjects (p = 0.003). This effect was driven by an increased polymorphonuclear cell–platelet aggregation (p = 0.003) whereas platelet aggregation with monocytes and lymphocytes was not. Platelet activation was also increased (p = 0.001).
Conclusions: In migraine pro-inflammatory platelet adhesion to leukocytes occurs during the headache free interval similar to that seen in acute coronary and cerebrovascular syndromes. This may suggest a link between migraine and stroke on a cellular level.
doi:10.1136/jnnp.2003.019638
PMCID: PMC1739108  PMID: 15201354
19.  Association between migraine and asthma: matched case-control study. 
BACKGROUND: Earlier studies have suggested a link between asthma and severe headache, and also between migraine and wheezing illness. Recent analysis have also shown an increase of asthma among cases with a prior history of migraine but without a history of hay fever, allergic rhinitis or eczema. AIM: To examine whether there is an association between migraine and asthma in the United Kingdom. DESIGN OF STUDY: Matched case-control study using the General Practice Research Database (GPRD). SETTING: Practices in the United Kingdom providing data on 5,110,619 patients to the GPRD. METHOD: The subjects were the patients with one or more diagnoses of migraine plus treatment for migraine. Each case was matched by general practice, sex, and age, with one control who had never been given a diagnosis of migraine. Case and control groups were compared for prevalence of asthma, chronic obstructive pulmonary disease, respiratory symptoms treated with inhalers or hay fever. Investigations were carried out to determine whether the association between migraine and asthma was stronger among patients with hayfever or those without hayfever, and whether patients with migraine had an increased prescription of other (non-migraine and non-asthma) medications. RESULTS: Among 64 678 case-control pairs, the relative risk of asthma in patients with migraine was 1.59 (95% CI = 1.54 to 1.65) among definite cases, and 0.75 (95% CI = 0.67 to 0.83) among those whose selection as case included beta-blocker prophylaxis. Among definite migraine cases, relative risks of chronic obstructive pulmonary disease, respiratory symptoms, eczema, and hay fever (pollinosis), were all raised (at 1.22, 1.85, 1.55, and 1.67, respectively). The association between migraine and asthma was stronger in patients without a diagnosis of hay fever, than in those with hayfever (relative risk = 1.32 and 1.19, respectively). The relative risk of prescription for a range of non-migraine, non-asthma medications was raised, the exception being anti-diabetic medication. CONCLUSION: This large case-control study provides evidence for an association between migraine and asthma. Frequent attendance at a general practice surgery may confound this association. However, if the association is real, its elucidation may help the understanding of disease mechanisms shared by migraine and asthma.
PMCID: PMC1314412  PMID: 12236275
20.  Migraine Headache in Middle-Age and Late-Life Brain Infarcts: The Age Gene/Environment Susceptibility - Reykjavik Study 
Context
Migraine is considered to be an episodic condition with no long-term consequences. However, recent studies suggest that migraine attacks may be associated with pathologic changes in the brain, particularly in the cerebellum.
Objective
To determine whether, compared to those not reporting symptoms, individuals reporting migraine symptoms in mid-life, particularly aura, are at increased risk of late-life infarct-like lesions (hereafter referred to as infarcts).
Design
A population based cohort of men and women (b 1907-35) followed since 1967, answered questions about migraine symptoms in mid-life (mean age 51, range 33–65), more than 26 years prior to a late-life exam when brain MRI was acquired. Those reporting headaches once or more per month were asked about migraine symptoms, including nausea, unilateral location, photophobia, visual disturbance, and numbness. We classified headache sufferers as having migraine without aura (MO), migraine with aura (MA), or non-migraine headache. A comprehensive cardiovascular risk assessment was performed at both examinations.
Setting
Population-based study in Reykjavik, Iceland
Participants
Men and women (n=4689, 57% women).
Main Outcome Measure
Presence of infarcts – total and specifically located in the cortical, sub-cortical, and cerebellar regions.
Results
After adjusting for age, sex, and follow-up time, compared to those not reporting headaches once or more per month (n=3243), those with mid-life MA (n=361) had an increased risk of late-life infarcts (adjusted OR, 1.4; 95% confidence interval [CI], 1.1–1.8) that specifically reflected an association with cerebellar lesions in women (Women: 23.0% vs. 14.5%, adjusted OR 1.9; 95% CI 1.4–2.6 vs. Men 19.3% vs. 21.3%, adjusted OR, 1.0; 95% CI 0.6–1.8, p<0.04 for interaction by sex). There was no increased risk associated with mid-life MO or non-migraine headache or for other brain regions.
Conclusions
Migraine with aura in mid-life was associated with late-life prevalence of cerebellar infarcts on MRI. This association was statistically significant only for women. This is consistent with the hypothesis that MA in mid-life is associated with late-life vascular disease that appears to be specific for the cerebellum and in women.
doi:10.1001/jama.2009.932
PMCID: PMC3133433  PMID: 19549973
21.  Migraine and cardiovascular disease 
Neurology  2010;74(8):628-635.
Objectives: Although the relationship between migraine and cardiovascular disease (CVD) has been studied, several questions remain unanswered. Herein we contrast the rate of diagnosed CVD as well as of risk factors for CVD in individuals with migraine with and without aura (MA and MO) and in controls.
Methods: In this case-control study, migraineurs (n = 6,102) and controls (n = 5,243) were representative of the adult US population. Headache diagnosis was formally assigned using a validated mailed questionnaire which also obtained details on treatment, comorbidities, and other variables. CVD events were obtained based on self-reported medical diagnosis. Risk factors for CVD and modified Framingham scores were computed.
Results: In unadjusted analyses, migraine overall and MA were associated with myocardial infarction, stroke, and claudication, and MO was associated with myocardial infarction and claudication. Migraineurs were more likely than controls to have a medical diagnosis of diabetes (12.6% vs 9.4%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.2–1.6), hypertension (33.1% vs 27.5%, OR 1.4, 95% CI 1.3–1.6), and high cholesterol (32.7% vs 25.6%, OR 1.4, 95% CI 1.3–1.5). Risk was highest in MA, but remained elevated in MO. Framingham scores were significantly higher in MO and MA than in controls. After adjustments (gender, age, disability, treatment, CVD risk factors), migraine remained significantly associated with myocardial infarction (OR 2.2, 95% CI 1.7–2.8), stroke (OR 1.5, 95% CI 1.2–2.1), and claudication (OR 2.69, 95% CI 1.98–3.23).
Conclusion: Both migraine with and without aura are associated with cardiovascular disease (CVD) and with risk factors for CVD. However, since our sample size is large, the clinical relevance of the differences is yet to be established.
doi:10.1212/WNL.0b013e3181d0cc8b
PMCID: PMC3462501  PMID: 20147658
22.  Migraine may be a risk factor for the development of complex regional pain syndrome 
The aim was to assess the relative frequency of migraine and the headache characteristics of complex regional pain syndrome (CRPS) sufferers. CRPS and migraine are chronic, often disabling pain syndromes. Recent studies suggest that headache is associated with the development of CRPS. Consecutive adults fulfilling International Association for the Study of Pain criteria for CRPS at a pain clinic were included. Demographics, medical history, and pain characteristics were obtained. Headache diagnoses were made using International Classification of Headache Disorders, 2nd edn criteria. Migraine and pain characteristics were compared in those with migraine with those without. ANOVA with Tukey post hoc tests was used to determine the significance of continuous variables and Fisher’s exact or χ2 tests for categorical variables. The expected prevalence of migraine and chronic daily headache (CDH) was calculated based on age- and gender-stratified general population estimates. Standardized morbidity ratios (SMR) were calculated by dividing the observed prevalence of migraine by the expected prevalence from the general population. The sample consisted of 124 CRPS participants. The mean age was 45.5 ± 12.0 years. Age-and gender-adjusted SMRs showed that those with CRPS were 3.6 times more likely to have migraine and nearly twice as likely to have CDH as the general population. Aura was reported in 59.7% (74/124) of participants. Of those CRPS sufferers with migraine, 61.2% (41/67) reported the onset of severe headaches before the onset of CRPS symptoms Mean age of onset of CRPS was earlier in those with migraine (34.9 ± 11.1 years) and CDH (32.5 ± 13.4 years) compared with those with no headaches (46.8 ± 14.9 years) and those with tension-type headache (TTH) (39.9 ± 9.9 years), P < 0.05. More extremities were affected by CRPS in participants with migraine (median of four extremities) compared with the combined group of those CRPS sufferers with no headaches or TTH (median 2.0 extremities), P < 0.05. The presence of static, dynamic and deep joint mechanoallodynia together was reported by more CRPS participants with migraine (72.2%) than those with no headaches or TTH (46.2%), P ≤ 0.05. Migraine may be a risk factor for CRPS and the presence of migraine may be associated with a more severe form of CRPS. Specifically: (i) migraine occurs in a greater percentage of CRPS sufferers than expected in the general population; (ii) the onset of CRPS is reported earlier in those with migraine than in those without; and (iii) CRPS symptoms are present in more extremities in those CRPS sufferers with migraine compared with those without. In addition, as we also found that the presence of aura is reported in a higher percentage of those CRPS sufferers with migraine than reported in migraineurs in the general population, further evaluation of the cardiovascular risk profile of CRPS sufferers is warranted.
doi:10.1111/j.1468-2982.2009.01916.x
PMCID: PMC3979276  PMID: 19614690
Migraine; chronic daily headache; complex regional pain syndrome; allodynia; aura
23.  Evidence of increased restless legs syndrome occurrence in chronic and highly disabling migraine 
Functional Neurology  2012;27(2):91-94.
Summary
The existence of an association between migraine and restless legs syndrome (RLS) has recently been reported, although the possible implications of this for migraine clinical presentation remain poorly understood. The objectives of this study were to determine RLS frequency in a population of migraineurs compared with healthy subjects and to assess RLS occurrence in episodic versus chronic migraine patients; the relationship between migraine-related disability and RLS comorbidity was also evaluated.
Two hundred and seventy-seven consecutive migraineurs (ICHD-II, 2004) were enrolled and compared with 200 controls; migraine was episodic in 175 and chronic in 102 patients. RLS (IRLSSG criteria, 2003) was present in 22.7% of the total sample of migraineurs and in 7.5% of the controls (p<0.0001). RLS occurred significantly more frequently in chronic compared with episodic migraineurs (34.3% vs 16%, respectively, p=0.0006); a significant association between RLS diagnosis and moderate-severe migraine-related disability was also documented (p=0.0003).
In conclusion, the results of the present study not only confirm the higher occurrence of RLS in migraine patients compared with the general population, but also suggest that RLS (the condition itself, or the disruption of sleep patterns often found in patients affected by RLS) might affect migraine clinical presentation, being associated with chronic and highly disabling migraine. These findings could have important therapeutic and prognostic implications in clinical practice.
PMCID: PMC3812772  PMID: 23158580
chronic migraine; migraine; migraine disability; restless legs syndrome; sleep
24.  Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation 
Background
Previous studies suggested that migraine is a risk factor for brain lesions, but methodological issues hampered drawing definite conclusions. Therefore, we initiated the MRI “CAMERA” study.
Procedures
We summarize our previously published results. A total of 295 migraineurs and 140 controls were randomly selected from a previously diagnosed population-based sample (n=6039), who underwent an interview, physical examination, and a brain MRI-scan.
Findings
Migraineurs, notably those with aura, had higher prevalence of subclinical infarcts in the posterior circulation (OR=13.7; 95%CI 1.7–112). Female migraineurs were at independent increased risk of white matter lesions (WML; OR=2.1; 95%CI 1.0–4.1), and migraineurs had a higher prevalence of brainstem hyperintense lesions (4.4% vs. 0.7%, p=0.04). We observed a higher lifetime prevalence of (frequent) syncope and orthostatic insufficiency in migraineurs; future research needs to clarify whether autonomic nervous system dysfunction could explain (part of) the increased risk of WMLs in female migraineurs. Finally, in migraineurs aged <50, compared to controls, we found evidence of increased iron concentration in putamen (p=0.02), globus pallidus (p=0.03) and red nucleus (p=0.03). Higher risks in those with higher attack frequency or longer disease duration were found consistent with a causal relationship between migraine and lesions.
Conclusion
This summary of our population-based data illustrates that migraine is associated with a significantly increased risk of brain lesions. Longitudinal studies are needed to assess whether these lesions are progressive and have relevant (long-term) functional correlates.
doi:10.1111/j.1468-2982.2009.01904.x
PMCID: PMC3241741  PMID: 19515125
25.  Platelets in migraine 
The Journal of Headache and Pain  2001;2(Suppl 1):s61-s66.
Modification in platelet activation and aggregation has been demonstrated in migraine patients both during and between attacks. A different pattern in the secretion of platelet products has also been observed in patients affected by migraine compared with controls. The most important variation concerns a hyposecretion of dense body products. Platelets share structural and functional analogies with monoaminergic neurons, in particular serotoninergic neurons, and have been used as a peripheral model to study monaminergic function in migraine patients. A reduced turnover of serotonin has been shown in migraine patients in the interictal period, whereas a reduced content of this monoamine was detected in patients with chronic daily headache (CDH), particularly in those with analgesic abuse. Nitric oxide metabolism was also studied in platelets of migraine patients between and during attacks. An increased activity of nitric oxide synthase (NOS), which was more accentuated during attacks, was found in these patients compared to healthy individuals. The increase in platelet NOS activity was also confirmed in CDH patients in association with a reduction of serotonin content and increased calcium levels. Variations in aggregation to different agents and secretion may not, at the moment, be indicative of similar changes in cerebral circulation of migraine patients. Its occurrence should be confirmed in samples of jugular venous blood during attacks to establish a definite link with migraine pathogenesis. Moreover changes in serotonin and NO metabolism observed in platelets of migraine patients may only indirectly suggest similar modifications in the neuronal pathways involved in inducing and maintaining head pain in migraineurs.
doi:10.1007/s101940170012
PMCID: PMC3451818
Platelets; Aggregation; Secretion; Serotonin metabolism; NO metabolism; Platelet enzymes; Migraine

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