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Brandon Aylward, PhD and Scott Powers, PhD, Cincinnati Children's Hospital, Cincinnati, OH
The Multidimensional Impact of Migraine in Adolescents Presenting to Specialty Care
The functional consequences of adolescent migraine can be widespread and have a negative effect on many aspects of normal daily life. To examine this, a longitudinal, multi-method and multifaceted assessment of migraine was conducted in a sample of adolescents presenting to a pediatric headache center. The purpose was to identify and compare the baseline impact of migraine on functioning (physical, emotional, social, and school functioning) with changes at six months after initiating biobehavioral treatment involving preventive medication and lifestyle education. One-hundred and fifteen adolescents participated in the six-month study. Overall, physical functioning at baseline suggested moderate disability. However, there was significant improvement in functioning at the six-month visit.
In addition, a mobile application (iMigraine) was developed by a team of researchers, clinicians, and technology experts to enable adolescents to electronically enter and wirelessly transmit data about headache events and associated symptoms. Participants were prompted to assess their condition daily using the iMigraine app. They reported having a headache on 49% of days they completed at least one prompt. On average, each participant reported having 23 headaches during the 45 day period.
Hypothesis vs. Findings
The working hypothesis of the study was that the experience of migraine in adolescence would be associated with measurable negative impact on physical (including sleep quality), school, emotional, social, and family functioning. Overall, decreased physical and psychosocial functioning was evident in a number of participants in the study. They showed significant improvements in migraine-associated disability at the six-month follow-up visit. This improvement was also associated with changes in other areas, such as emotional functioning and sleep.
Unanswered Questions
Although there were significant improvements in functioning at the six-month follow-up, some participants continued to experience decreased physical and psychosocial functioning and may represent a distinct subset of adolescents with migraine who were not responsive to clinical care. Understanding risk factors and potential mediators of treatment response can help identify targets for future interventions with these individuals. 2010 Heftler Award: Investigating the Cortical Modulation of Trigeminocervical and Thalamic Function during Cortical Spreading Depression About 15-20% of migraine patients have aura. The pathophysiology of aura is generally considered to be due to a wave of cortical spreading depression (CSD) spreading out from the occipital lobe across the cortex. Whether and through what mechanisms CSD and the resultant aura may be responsible for the initiation of head pain in migraine is still under discussion. Migraine pathophysiology is believed to involve activation, or the perception of activation, of primary trigeminal fibers innervating the meninges. These fibers project centrally on second order neurons within the trigeminocervical complex (TCC), before the signal is transmitted to the thalamus, and from there to the cortex where the pain matrix is processed. Both the TCC and the thalamus have been shown to have extensive fiber connections with the cortex. Thus, we hypothesize that a substantial cortical event such as CSD would be expected to influence the sensory responses of TCC and thalamic neurons. In this study we investigated the potential effects of CSD in the transmission of nociceptive information within the TCC and sensory thalamus in animal models of migraine. Our experiments confirmed that our initial hypothesis. The data demonstrate that CSD markedly alters neuronal firing of ipsilateral third order thalamic neurons and of contralateral trigeminocervical neurons, potentially though corticofugal projections. The biggest challenge is to identify these mechanisms in migraine patients and how to best prevent them. Identifying the neurotransmitter pathways involved in these mechanisms may provide further insights on how to best treat migraine patients. The Migraine Research Foundation, through the Heftler award, helped us demonstrate for the first time a new mechanism by which CSD may indeed induce central head pain via cortico-thalamic circuits and may shed more light on the relationship between aura and headache. Neurosteroid Regulation of Cortical Spreading Depression Summary Migraine in women has long been known to be affected by changes in hormone levels that accompany puberty, the menstrual cycle, pregnancy and menopause. To date, most studies have focused on hormones that are produced outside of the brain in the periphery. However, recently it has been shown that individual neurons in the brain can produce similar hormones known as neurosteroids. Neurosteroids act on a unique part of the inhibitory system in the brain that may be important to the development of migraine. Hypothesis vs. Findings The aim of this project was to determine whether neurosteroids acting in the brain alter the susceptibility and severity of spreading depression. That goal was met. We showed that neurosteroids primarily act on select neurons in the brain and as a result increase the susceptibility to spreading depression. Unanswered Questions The funding by the Migraine Research Foundation has been instrumental in establishing a role of neurosteroids in the development of migraine with aura. Additional studies will be needed to answer important questions including: What controls the release of neurosteroids? What impact do neurosteroids and enhanced cortical spreading depression have on the activation of migraine pain pathways? Do migraine patients exhibit altered neurosteroid production? Most importantly, how might we therapeutically target neurosteroids to treat migraine? What This Research Means To You Our research suggests that neurosteroids may play an important role in predisposing the brain to develop migraine aura. Neurosteroids may represent a new target for the development of novel migraine treatments. N-Methyl-D-Aspartate Receptor Glycine Coagonist Site Modulation as a Potential Treatment for Migraine Summary In previous work, we developed a novel pharmacological agent, GLYX-13, with unprecedented modulatory effects on the activation of the key neuronal glutamate receptor known as the N-methyl-D-aspartate receptor (NMDAR). This agent normalizes activation of this critical In our work supported by MRF’s grant, we have shown that GLYX-13 is, indeed, able to suppress the induction of SD in brain tissue. Furthermore, GLYX-13 also improved the return of These experiments confirm the potential for GLYX-13 as a therapeutic worth further evaluation as a possible treatment that could help millions of migraine sufferers not helped by any existing drug treatments. Hypothesis vs. Findings Our original working hypotheses were: 1. GLYX-13 would raise the threshold and/or prevent SD in hippocampal brain slices. We have confirmed this, in that GLYX-13 significantly slowed the propagation of SD, and sometimes prevented it entirely. 2. GLYX-13 could also prevent the retraction and/or improve the recovery of dendritic spines in response to SD. In reference to this hypothesis, we discovered that, while GLYX-13 does not alter the effects of SD in causing dendritic spines to retract, it does improve their recovery to their original sizes. Unanswered Questions There are a number of unanswered questions: 1. We conducted our study only on brain slices from male animals. It is crucial to know whether GLYX-13 has similar regulatory actions on SD in the female brain, and whether these actions vary in the presence and absence of estrogen. This is because women are three times as likely to experience migraines as men, and migraine attacks can be most severe in the days leading up to menstruation, suggesting that the drop in estrogen during normal female hormonal cycles may be an important contributor to migraine attacks. 2. Does slowing SD propagation translate to fewer or less severe migraine attacks? 3. Do repeated SDs, as a model for repeated migraine attacks, have lasting effects on synaptic plasticity and/or dendritic spine architecture? Do they cause neuronal damage/death, or do they trigger neuroprotective changes? 4. Can GLYX-13 protect neurons from long-term toxicity produced by repeated SDs, as a model for repeated migraine attacks? What This Research Means To You For migraine sufferers for whom none of the available treatments is effective, our discovery that the novel therapeutic GLYX-13 can also slow and even suppress the propagation of Spreading Depression in the brain offers hope for an entirely new mechanistic treatment for migraine. GLYX-13 may be useful both prophylactically and acutely to ameliorate the severity, or even abort, migraine attacks. Mechanisms of Blood Brain Barrier Dysfunction Induced Medication OveruseHeadache Summary Triptan medication is often used in chronic migraine therapy. However, it appears that prolonged frequent triptan use may induce headache, a condition termed “medication overuse headache” (MOH). The mechanisms that underlie MOH are not fully understood, but may be induced by periods of absence of medication. In this study we hypothesized that prolonged triptan medication induces changes in the blood brain barrier (BBB). This change in BBB integrity provides the stimuli that activate pain-signaling pathways and provoke migraine attack selectively in migraineurs. An intact BBB is critical in maintaining brain homeostasis. To test our hypothesis, we infused rats with either saline or sumatriptan for 7 days. We then administered an intraperitoneal injection of either saline or sumatriptan antagonist to pharmacologically induce triptan medication withdrawal. Changes in BBB integrity were assessed in the trigeminal nucleus caudalis brain region, an area involved in the transmission of headache pain. Results show that animals dosed with saline for 7 days and injected with either saline or the Hypothesis vs. Findings The results confirmed and validated the original hypothesis. Unanswered Questions We show that triptan based medication modulates BBB integrity. However, the mechanism of What This Research Means to You Results from this study suggest that triptan based medication modulates the integrity of the A Pilot Study of Family-Based Cognitive Behavioral Therapy for Treating Chronic Pediatric Headache/Migraine and Comorbid Anxiety Summary The purpose of this pilot study was to refine a family-based cognitive-behavioral therapy (CBT) intervention for youth with chronic tension headaches and/or migraines and excessive anxiety and to evaluate the feasibility, acceptability, and preliminary impact of the intervention. A total of 15 families were randomized to the Children’s Headache and Anxiety Management Program (CHAMP; n = 9) or Relaxation Training (RELAX; n = 6). A total of 9 families completed all evaluations (4 in CHAMP, 5 in RELAX). Of these families, preliminary data indicate that both treatments were associated with symptom reduction and satisfaction. At post-treatment, all 4 CHAMP participants reported an average reduction in headache frequency of 42%. RELAX participants reported an average reduction in headache frequency of 22%. Children in both groups reported little to no headache-related disability at post-treatment according to the PedMIDAS. Average reduction in anxiety severity from pre- to post-treatment was 44% for CHAMP and 37% for RELAX. From pre- to post-treatment, parental reinforcement of illness behavior reduced by an average of 43% for CHAMP and 7% for RELAX parents. Children in both groups reported increased perceived control over anxiety. Consumer satisfaction was rated on a scale from 1 (not at all helpful) to 7 (very much helpful). Average satisfaction ratings were similar in both groups (6.13 for CHAMP and 5.45 for RELAX). These findings suggest that both interventions were perceived as helpful by all participants. While the sample size of this pilot study is small and does not permit tests of efficacy, the preliminary findings are promising. We achieved our goal of refining the interventions and methods in preparation for a large clinical trial to fully evaluate the comparative efficacy of RELAX versus CHAMP. Hypothesis vs. Findings The primary aim of this study was to refine the interventions and evaluate the feasibility and acceptability of the intervention and methods (e.g., recruitment, assessments) and this aim was completed and validated. Manuals and handouts have been finalized. Moreover, of those families that completed the interventions, parents and children in both groups reported a high degree of satisfaction. However, recruitment goals for the study were not met. The reason for this is likely due to an underestimate of the funds needed for advertising. The secondary aim was to compare the relative efficacy of CHAMP and RELAX for reducing anxiety and chronic headaches in youth. We hypothesized that CHAMP would result in greater reductions in both anxiety and headache frequency and severity compared to RELAX. As is the case with small pilot studies, this study was not powered to conduct a definitive test of the intervention’s efficacy. However, CHAMP did lead to greater reductions on measures of headache frequency (PedMIDAS) and parental reinforcement of illness behavior (ARCS). No differences were found between groups in terms of headache-related disability (PedMIDAS), IE-rated anxiety (PARS) or headache (CGI-S) severity, or child or parent reports of anxiety symptoms (SCARED). Unanswered Questions There are several unanswered questions including: Answering these questions would move the field forward by elucidating the mechanisms by which symptom reduction occurs and by providing information that could inform researchers and practitioners about what treatments are most effective and how treatments can be tailored – or personalized – based on child and family characteristics to optimize outcomes. What This Research Means to You Findings from this small pilot study suggest that brief behavioral interventions, including CBT and relaxation, may reduce headache frequency, disability, and comorbid symptoms of anxiety in children. Furthermore, there may be an added benefit of the CHAMP treatment in terms of reducing parental accommodation of headache-related behaviors. 2011 Heftler Award Final Report: Finding the Molecular Mechanism of Casein Kinase 1δ Mediated Migraine Summary Migraine can include aura, head pain, dilation of blood vessels, and hypersensitivity to heat, touch, light, and sound. Migraines can be inherited. We found that mutations in a gene called casein kinase 1 delta (CK1δ) are associated with migraines. We showed that in mice, this mutation causes sensitivity to a chemical migraine trigger, increased blood vessel dilation in the brain. A mutant form of CKIδ also makes the mice more susceptible to aura. One of the targets of CK1δ is an estrogen receptor (ER). Decreased CKIδ function causes less estrogen receptor to be made in cells. Converging evidence led us to think that estrogen may be part of the mechanism of migraine. Migraines affect three times more post-pubescent women than men. For women, migraine increases in frequency and severity during puberty and pregnancy, and often subsides after menopause. For some female patients, migraine is triggered monthly at the same point of the menstrual cycle. Estrogen regulates inflammation and pain and can sensitize pain-sensing neurons. In addition, estrogen can regulate neuronal activity. Estrogen signals through estrogen receptors dilate veins/arteries in response to a common chemical migraine trigger. Thus, it could be that in response to a migraine trigger, the mutant CKIδ could modify estrogen receptors to increase pain responses. Similarly, estrogen could be causing abnormal dilation of cranial blood vessels. These correlations led us to test the hypothesis that estrogen signaling is important for susceptibility to migraine. We hypothesized that an estrogen receptor is downstream of CK1δ in the molecular mechanism of migraine. To this end, we generated mice that lack either estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) and carry the mutant CKIδ. We are testing whether either ERα or ERβ changes migraine pain behavior. What this research means to you: This research may have implications about the use of estrogen-based birth control or hormone replacement therapy for women with migraines. It also may teach us if one estrogen receptor is more important for the induction of migraine than another. This could be a precursor to finding a therapeutic target to prevent or alleviate migraine. Preclinical Development of Nasal Insulin as a Therapy for Chronic Migraine Published in Journal of Neurochemistry, Volume 122, Issue 1, July 2012 Summary The overall goal of this grant was to develop nasal insulin as a preclinical therapy to reduce susceptibility to chronic migraine. We studied how insulin alters neural circuit electrical susceptibility to spreading depression, a most likely cause of episodic and, we hypothesize, chronic migraine. The idea for this work stemmed from data showing that environmental enrichment (increased physical, social, and intellectual activity), which increases memory and learning, can reduce spreading depression in animals, and by extension, migraine in humans. Recently, nasal insulin has been used as an environmental enrichment and shown to be effective at reducing cognitive decline from Alzheimer’s disease. Accordingly, we reasoned that insulin might be similarly protective against spreading depression. We found that chronic insulin improved electrical function in hippocampal slice cultures grown over weeks, and used this pilot data to propose this grant. Our recent work involved extensive dose-response and time studies. We were able to show that insulin can acutely, and for days afterward, reduce susceptibility to spreading depression. This ‘proof of principle’ work has now been published, and is the first to show that an enrichment-based environment may provide novel therapeutics for migraine. Hypothesis vs. Findings Our original hypothesis that insulin might be protective against spreading depression was validated by the current work. Unanswered Questions While we demonstrated the 'proof of principle' notion that insulin can reduce susceptibility to spreading depression, we need to extend this result to the in vivo condition. To-date our work with whole animals has been in designing and confirming the utility of a protocol for the effective nasal delivery of potential migraine therapeutics to the brain. With this accomplished, we next turned to improving models of whole animal spreading depression (involving both neocortex and hippocampus) that would allow us to detect subtle differences in therapeutic efficacy. This too has been accomplished, and we are now poised to study the use of insulin both in vivo and in vitro, using whole animals and hippocampal slice cultures. We expect this combination of models to provide detailed information about the potential clinical use and mechanisms of action of targeted therapeutics for chronic migraine. What This Research Means to You This Migraine Research Foundation grant helped us demonstrate for the first time that enrichment-based environments like insulin may be a novel source of effective therapeutics against high-frequency and chronic migraine. Julie Wieseler, PhD & Linda Watkins, PhD, University of Colorado at Boulder, Boulder, CO Why Opioids Enhance Migraine Pain: Summary The behavioral data collected in this experiment led to the development of a clinically relevant headache model for medication overuse headache (MOH), a common phenomenon with little understanding of the underlying mechanisms. MOH is a headache induced in patients by the over-use of medications such as opioids to treat migraine. It is noteworthy that MOH does not develop de novo with treatment of pain conditions other than headache. Our behavioral data were collected when morphine was administered shortly after surgery. Because MOH does not develop except during headache treatment, we tested if the enhancement we initially observed was due to the administration of morphine just a few days post-surgery. Indeed, when we tested 10 days post-surgery, the morphine did not create the enhanced responsiveness to low dose inflammatory mediators. Next we tested if, at 10 days post-surgery, supradural inflammatory mediators, at a dose known to induce facial allodynia, followed by morphine created the vulnerability previously observed when morphine was given just a few days after surgery. The low dose of supradural inflammatory mediators reliably induced facial allodynia. Taken together, these data suggest that morphine increases the effectiveness of the biochemical environment that creates enhanced pain states. Hypothesis v. Findings Our hypothesis that prior exposure to morphine creates a vulnerability to allodynia induction by subsequent supradural immune challenge was validated, as was the hypothesis that this vulnerability is dependent on glial activity as supported by a blockade of this morphine-induced vulnerability by the co-administration of a glial activation inhibitor. Unanswered Questions What This Research Means To You We have identified a potential mechanism underlying opioid-induced medication overuse headaches, providing a novel target for the development of pharmacotherapies to be administered with headache treatment. Towards a Migraine Genetics Population Laboratory: Building on the American Migraine Prevalence and Prevention (AMPP) Study Summary Migraine is a major public health concern that has an impact on individual sufferers, their families, the healthcare system, employers and society. It is a complex disorder influenced by numerous genetic and environmental risk factors. Although a number of genes have been identified to be involved in migraine and pain progression, there are likely many unknown genetic factors at play. Our ultimate goal is to establish a Migraine Genetics Population Laboratory (MGPL) at the Albert Einstein College of Medicine to study the genetics of migraine. The goal of the current study was to examine the feasibility of collecting usable genetic data from a large population sample through the mail. We sent genetic sample collection kits to participants from the American Migraine Prevalence and Prevention (AMPP) study, the largest and longest population study of persons with migraine in the world to date. DNA collection kits and consent form packets were mailed to 240 AMPP questionnaire respondents: 80 individuals in each of three headache status groups: No headache (control group), episodic migraine, and chronic migraine. Each subgroup was equally divided into two groups by the presence of clinical depression. A total of 152 samples were returned (63%), yielding 147 samples with usable DNA (61%). Return rates were higher among persons with episodic migraine (68%) and chronic migraine (69%) compared to those in the no headache control group (54%), indicating, as would be expected, that response rates were higher among those with migraine. These data will be used as pilot feasibility data in support of an NIH grant to study the genetics of migraine on a large-scale basis. In addition, this sample may be used to pilot test the viability of these samples in genotyping using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing over 350 genes known to be involved in biological pathways relevant to nociception, inflammation, and mood. Based on the results of this study, we demonstrated that it is possible to collect DNA samples from both subjects with migraine and without headache through the mail using a genetic testing saliva kit. Furthermore, the returned samples produced good quality, usable DNA that could be used in various genetic studies that will help us better understand the underlying causes and potential treatments of migraine. Hypothesis v. Findings Hypothesis 1: Among selected AMPP participants we can achieve 90% participation in saliva. We will explore the role of recruiting and reminder phone calls and repeated mailings to optimize participation rates and minimize cost. Result: We received a 63% return response rate. We reviewed many possible combinations of incentive amounts and numbers of follow-ups (phone calls, postcards) as well as the sequencing and timing of the mailing (e.g. to mail the consent form and kit together vs. mailing the consent form first, waiting for consent to participate then mailing the genetic data collection kit). Hypothesis 2: Among those who provide saliva, we will achieve a 90% yield of usable DNA. If DNA is un-usable, at least 80% of subjects will send a second usable sample when they are recontacted. Result: Of those who provided DNA, 96.7% was usable. We did not have the funds to recontact, send new kits, and reanalyze data from the 5 subjects who provided data that was not usable. These results show that collecting genetic data through saliva through the mail is a viable collection method. The kits were effective and the samples are stable at room temperature for 18 months. Hypothesis 3: Participation rates and yields will be similar across the 3 groups and will not differ by headache or demographic characteristics, minimizing the prospects for selection bias. Result: We had an overall return rate of 63%. Return rates were higher among persons with episodic migraine (68%) and chronic migraine (69%) compared to those in the no headache control group (54%), indicating as would be expected that response rates were higher among those with migraine. Also, we can hypothesize that we have a strong relationship with the persons in the migraine group as we have followed them every year between 2004-2009, while we have been in contact with the non-headache control group in the years 2004, 2008 and 2009. We also found differences in the rate of return within groups by depression status and found that for the control group 48% of those without depression and 60 % of those with depression responded, and within the chronic migraine condition, 73% of those without depression and 65% of those with depression responded. These results do not predict a particular hypothesis as they are in the opposite direction in the two groups. The rates of response within the episodic migraine sample were exactly the same by depression status. Unanswered Questions The primary question arising out of this research is how to achieve higher response rates. Possible approaches may lie in selection of participants, providing participants with clear rationale and answering questions about concerns they may have about giving genetic data, increasing compensation for participation, increasing follow-up via phone, mail, or in person, and the costs associated with each of these strategies. An in person data collection paradigm may yield the highest participation rates, but the costs associated with this strategy may make it prohibitive. What This Research Means To You Our research demonstrates that collection by mail of usable genetic data from migraine sufferers is feasible and may yield answers to a myriad of questions regarding migraine heritability, expression, development, and progression. Published in Molecular Pain, Volume 8, Issue 66, September 2012 Summary Hypotheses v. Findings We validated our hypothesis. Our results indicate that the mutation preferentially causes the hyper-excitation of neurons mediating migraine headache but not those mediating facial pain. This points to a possible mechanism through which abnormal calcium channel activity contributes to the generation of migraine headache but not other types of pain. Unanswered Questions Additional experiments will be necessary to address many unanswered questions from this study. For example, why does the mutant P/Q-type calcium channel cause hyper-excitation of primary sensory neurons mediating migraine headache but not those transmitting facial or somatic pain? Is the activity of other ion channels altered in neurons expressing mutant P/Q-type channels? And if so, how does that contribute to the onset of headache? Understanding these questions will not only advance our knowledge of migraine pathophysiology, but also will help us identify potential new targets for migraine treatment. What this Research Means to You Understanding the role of mutant PQ-type channels will not only advance our knowledge of migraine pathophysiology, but also will help us identify potential new targets for migraine treatment. To investigate this, we compared 35 glutamate receptor gene variants between migraineurs and controls and found three variants strongly associated with migraine with aura, and another variant which was associated with migraine without aura. This study represents the first genetic evidence of a link between glutamate receptors and migraine. Hypothesis vs. Findings The goal of the project was to determine whether glutamate receptors are responsible for a susceptibility to migraine. That goal was met. We showed that variants in glutamate receptor genes are associated with migraine. Moreover, we demonstrated that at risk variants may affect the expression of glutamate receptor genes, which consequently modulate the individual’s susceptibility to migraine. Unfortunately, the cellular model that we developed for electrophysiological study did not enable us to observe differences in calcium levels. Unanswered Questions What this Research Means to You Summary Hypothesis vs. Findings Unanswered Questions What this Research Means to You Central Mechanisms of Opioids in the Transformation of Migraine Summary Hypothesis vs. Findings The hypotheses of the original proposal were partially validated - morphine has complex effects on brain excitability underlying migraine. Further investigation of these hypotheses is ongoing. We diverged from our original hypothesis to investigate the effects of different types of opioids that target different opioid receptors. These drugs have been studied in clinical trials for other types of pain, but have not been studied for migraine. We found two medications that inhibited basic mechanisms of migraine in the laboratory. These findings are exciting, because these drugs do not have many of the same side effects of morphine. Based on their tolerability and mechanisms of action, we believe that they may be candidates for new migraine therapies. We are now planning further basic as well as clinical studies to investigate the possibility that these medications may be a novel treatment for migraine. Unanswered Questions The most interesting question generated by our research: Do medications that target different types of opioid receptors represent a novel treatment for migraine? Answering this question with further basic and clinical studies will have substantial implications for the field of migraine and for migraine patients. Identification of Genetic Determinants of the Association between Migraine and Cardiovascular Events: A Genome-Wide Association Study Hypothesis vs. Findings The approach of our study, a genome-wide association study, is essentially hypothesis free, since it does not favor any gene or genetic marker over others. It was based on two kinds of previous findings: First, studies indicate a strong genetic component for both migraine and CVD. Second, migraine, in particular migraine with aura, increases the risk for CVD, especially ischemic stroke, which appears to be largely independent of classical risk factors for CVD. While we did not find gene variants that were strongly associated with CVD events among migraineurs, five variants were suggestive of an association. These appear to increase the risk for CVD by 3- to 12-fold. The findings that four of the gene variants showed and association among women with migraine with aura and two of those with ischemic stroke are in line with studies linking migraine with aura with ischemic stroke. Second, despite the large number of women with migraine (5,122) in our study the absolute number of CVD events among migraineurs is moderate. Hence, even larger numbers of migraineurs and CVD events among them would be needed to achieve a stronger level of significance. Unanswered Questions We were successful in identifying gene variants with potential roles in increasing the risk for CVD among women with migraine. Two important questions remain unanswered. First, can the associations seen in our study also be found in other studies? The limitation with regard to this question is that no other population-based study with validated information on migraine and CVD events, detailed information about CVD risk factors, and genome-wide genetic information is available at present. Second, what are the biological mechanisms of these variants with respect to the migraine-CVD association? Microglia and Cytokines Modulate Chronic Migraine Summary Chronic migraine is a prevalent healthcare burden whose cause is only partly known, a void that hampers development of new treatments. Considerable research shows that chronic pain, including that from migraine, may alter pain pathways so that they are more sensitive. This effect involves cytokines, small molecules first recognized for their role in signaling between immune cells. We hypothesized that pro-inflammatory cytokines produced after migraine could make it easier to trigger subsequent migraines as modeled by spreading depression, a most likely cause of migraine pain and aura. We confirmed this hypothesis by triggering spreading depression in hippocampal slice cultures, thin sections of brain that can be kept in a dish for months. We found that spreading depression triggered cytokine changes in the brain that both increased and decreased susceptibility to spreading depression on subsequent days. Importantly, we also identified cytokine changes from neurons that prevented this increased susceptibility to spreading depression. Our work is the first to show that the interplay of cytokine changes between microglia and neurons may be ideal targets for the development of novel therapeutics to prevent migraine and its transformation to chronic migraine. Hypothesis vs. Findings We validated our original hypothesis, as explained above. First, we showed that spreading depression made it easier to elicit subsequent spreading depression days later. Second, we found this increased susceptibility was due to tumor necrosis factor alpha (TNF-α) signaling from microglia. Third, we extended our initial plans to include delineation of the cytokine signaling involved in cold-preconditioning neuroprotection. Finally, we entered into a collaborative effort with Marilyn Cipolla from the University of Vermont to examine how brain function is altered during pregnancy to resist seizure, and by extension, migraine, from peripheral pro-inflammatory changes. The rationale again is that pregnancy also raises TNF-α levels in the blood, as well as brain, yet susceptibility to seizures (and migraine) are reduced. Our work will define how the blood, blood brain barrier, and brain adapt to reduce brain excitability. We decided not to pursue the relation of TNF-α to reduced GABAergic function mediated by BDNF. The rationale for this move was based on work suggesting that paired pulse inhibition was too complex to be solely due to alterations in GABAergic function. We are now developing plans to resolve this impediment to experimental design. Glial Activation and the Chronification of Migraine Summary The brain is composed of neurons and glia. In fact, glia are three quarters of the cells in the brain. To date, most of the studies of the pathophysiology of headache have focused on the neurons. We studied the activation of glia in the area of the brain that processes sensory information in a rat model of chronic daily headache (CDH). We compared activation following chronic stimulation to the effect of a single painful stimulus. Repeated, episodic activation models the progression of episodic headache to chronic daily headache. This chronic state is stable long after the last stimulation (more than 8 weeks). Hypothesis vs. findings The overall aim of the study was to test the hypothesis that activation of neuroglia in the trigeminal nucleus caudalis contributes to the development of chronic facial allodynia in a rat model of CDH. We discovered that a consequence of this persistent neuroglia activation is an increase in permeability of the Blood Brain Barrier (BBB). We demonstrated that blocking glia activation blocks increases in trigeminal allodynia and increases in BBB permeability. Unanswered Questions There are many unanswered questions from this study. Pursuing the answers will significantly contribute to our understanding of the pathophysiology of chronic daily headache and its treatment. The questions are: Investigation of the Genetic Basis of Migraine: Building a DNA Library in Migraine Sufferers Summary In the application we proposed to establish a DNA library with samples from well characterized migraine sufferers and unrelated age/gender matched controls whose detailed clinical and diagnostic phenotype is carefully gathered and recorded in a searchable electronic database. The first use of the library will be to carry out the first whole genome association study of migraine in a well characterized American population. Our proposal was not a specific study but rather the development of a DNA library that will serve as a resource for migraine research in the coming decades. We have accomplished our proposed goal in no small part due to the generosity of the Migraine Research Foundation. We have established what is probably the largest migraine specific DNA repository in the world. In the 12 months that we have received MRF support, we have sampled over 1400 migraine case and non-migraine controls subjects, bringing to the total samples to 2316. Of those we have sampled 737 Migraine without aura subjects (MWO), 716 Migraine with aura (MWA) subjects and 863 non-Migraine controls (NMC) subjects. Later this year, we will begin the application process for funding of the first migraine specific genome-wide association study of Migraine in the US. Because of the increasingly competitive environment especially as it pertains to NIH funding, we are increasing the number of sampled subjects that we will include in our proposal as we go forward. Our goal is to have sampled 4500 subjects for the GWAS (1500 MWO, 1500 MWA, 1500 NMC). We have acquired funding which will hopefully carry us to the completion of this goal. Our work is on-going and progressing well. Hypothesis vs. Findings Our hypotheses that establishment of such a repository was feasible and that we would have the capability to sample the large number of subjects required to carry out this research have been validated. Unanswered Questions It is our hope and expectation that the library will form the basis of the first Genome Wide Association Study (GWAS) in the United States. We will also use this repository to carry out migraine genetics research projects with a more limited scope as we continue to recruit and sample subjects for the GWAS. Two genetics projects are underway: In addition, we have begun to glean clinical data from the computerized repository of clinical phenotypic information to which the DNA genotypic data will be correlated. Behavioral Model of Medication Overuse Headache Published in Cephalalgia, Volume 29, Issue 12, December 2009 Summary Medication overuse headache (MOH) is a disorder that develops from the frequent use of medications taken for the treatment of migraine headache pain. MOH affects an estimated 3-5% of the general population. The mechanisms underlying the development of MOH remain unknown. Among the medications associated with the development of MOH are opiates and triptans. While the effects of repeated opiate or triptan use for headache are unknown, it is possible that these medications may elicit neural adaptations in peripheral nociceptive fibers that innervate the dura that contribute to the increased frequency and occurrence of such headaches. Our preclinical studies were designed to explore possible neuroadaptive changes elicited by sustained exposure to morphine in order to give insight into possible causes of MOH. We found that morphine treatments elicited acute cutaneous allodynia of the facial regions that resolves after discontinuation. Additionally, morphine increased the expression of calcitonin gene related peptide (CGRP) and nNOS in trigeminal primary afferent neurons identified with Flurogold to innervate the dura. Critically, these neuroadaptive changes persist for long periods of time and can result in different effects that occur even long after the discontinuation of the medication. Stimuli known to elicit migraine headache, such as NO donor or stress, produce facial allodynia, in morphine pre-treated rats while having no effects in vehicle treated animals. Such persistent neuroadaptive changes may be relevant to the processes that promote MOH. Acute and chronic blockade of nNOS did not prevent morphine-induced cutanoeus allodynia. More importantly, the blockade of CGRP fully reversed morphine-induced facial allodynia both during morphine infusion or after exposure to a stimulus known to elicit migraine headache, i.e. stress. Hypothesis vs. Findings We began by investigating the peripheral sensory fibers within the trigeminal ganglia following sustained exposure to morphine, and we found a remarkable and persistent upregulation of CGRP and nNOS. This discovery was relevant to the known efficacy of CGRP antagonists in migraine pain. Additionally, we found that assay of NGF in the skin was negative suggesting that our research would benefit from focus on of the role of CGRP and nNOS as potential mediators of medication overuse headache. For this reason, we believe that our hypothesis of NGF-dependency was not supported and we modified the experiments to fit the data observed. Unanswered Questions Additional studies will be necessary to better understand the mechanisms of medication overuse headache specifically related to opiates and to other medications such as triptans. In particular, we are now poised to understand if initiating factors of headache (i.e., stress, NO donors or induction of CSD) are capable of producing activation of dural afferents in animals pre-exposed to morphine (but with normal sensory thresholds) and whether activation of afferents is dependent upon nNOS and results in release of CGRP. Migraine in Middle Age and Late Life: A Longitudinal Analysis of Factors Related to Migraine Prognosis in a Large Population-Based Cohort Published in the Journal of the American Medical Association, Volume 301, Issue 24, June 2009 Summary About one third of migraine sufferers experience transient neurological disturbances during or just before attacks (migraine with aura). There has been considerable interest in recent years regarding the evident increased risk of clinical and sub-clinical cardiovascular disease in migraine sufferers with aura. In this study, we were interested in whether adults with migraine in middle age were at increased risk of stroke-like lesions or white-matter lesions on MRI in later life. We were also interested in whether migraineurs with a certain genetic make-up were particularly at risk for these cardiovascular outcomes. Our study population is a unique population-based cohort of adults in Reykjavik, Iceland who have been followed for more than 25 years. Hypotheses vs. Findings Some of our findings were consistent with our hypotheses and some were not. For example, the only other study that considered this question (Kruit et al, JAMA 2005) also found that the relationship between migraine and these lesions was only evident for individuals with migraine with aura and was strongest for lesions located in the cerebellum. In addition to confirming these earlier results, we also found that the risk appeared to be evident only for women – which was interesting and needs to be confirmed in other studies. In secondary analyses, we also found a suggestion that migraine may be related to cortical lesions in men. Unanswered Questions While the epidemiologic relationship between migraine with aura and clinical and sub-clinical cerebrovascular disease appears increasingly solid, the degree to which these infarct-like lesions have clinical consequences is uncertain. It is possible that people who experience migraine with aura over their lifetimes may have associated subtle problems with, for example, balance in their later years. It is also possible that these lesions are not at all associated with functional consequences. In either event, what these lesions – and even the migraine aura itself – represent is a question of scientific and public health interest. What this Research Means to You We found that migraine sufferers who experienced auras were more likely than others to have small stroke-like lesions in the cerebellum part of their brain. Future research will help to establish whether these lesions mean something and, if so, whether reducing attack frequency might help to prevent them.
What this Research Means to You
Increased attention and research into understanding the broad impact migraine can have can aid in the development and implementation of effective and sustainable interventions for adolescents presenting to specialty care. Technology has the potential to transform treatments provided to youth and their families by giving them a familiar way to actively participate in their own healthcare by recording health symptoms remotely. This can result in personalized and effective clinical care.
Anna P. Andreou, PhD, University of CA at San Francisco and Imperial College London
Summary
Hypothesis vs. Findings
Unanswered Questions
What This Research Means To You
Trent Anderson, PhD, University of Arizona, Phoenix, AZ
For 20-30% of patients their migraine is preceded by an aura that is most often perceived as flashing lights or blind spots in their visual field. This migraine aura is a neurological phenomenon thought to be an underlying cause of migraine and develops from a process known as spreading depression. Initiation of spreading depression can activate the pathways leading to migraine pain and its prevention is a common target of migraine therapies. Previous studies have shown that during periods of high neurosteroid levels, such as prior to menstruation or in pregnancy, women are at an increased risk for migraine with aura. We therefore hypothesized that neurosteroids may act to alter cortical excitability and exacerbate migraine by promoting spreading depression.
To investigate this, we utilized an advanced imaging approach combined with electrophysiological recordings in a rat model of spreading depression. We determined that neurosteroids selectively and rapidly alter inhibitory GABAergic neurotransmission in the cerebral cortex. In doing, neurosteroids alter network excitability and increase the amplitude and propagation speed of cortical spreading depression. Taken together, these data suggest that the actions of neurosteroids may play an important role in the pathophysiology of hormonal related migraine.
Patrick K Stanton, PhD, New York Medical College, Valhalla, NY
receptor, increasing it when it is too low, and suppressing it when it is too high. Studies have shown that the activation of NMDARs also promotes, and can even be necessary for, the phenomenon of Spreading Depression (SD) that is thought to underlie the migraine aura. Therefore, compounds that prevent over-activation of this receptor could be important new therapies for lessening, and even preventing, the onset of migraine attacks.
dendritic spines to their original sizes following an SD, suggesting that the drug could protect synaptic connections in the brain from possible damage from repeated migraine attacks. 
Colin Willis, PhD, University of New England, Biddeford, ME
sumatriptan antagonist for 6 hours had no effect on BBB integrity. However, animals dosed with sumatriptan for 7 days and with either saline or the sumatriptan antagonist for 6 hours showed a loss of vascular integrity typically associated with loss of BBB integrity.
this modulation remains unclear. Triptans may act directly on the vascular endothelial
cells or on other components of the neurovascular unit. To address this question we have started using endothelial and astrocytic cultures. Preliminary studies show that both these cell types express 5HT1B/D receptors. Thus, sumatriptan potentially acts on both cell types at the neurovascular unit. Our ongoing in vitro research may provide insight into the intracellular signaling mechanisms that induce changes in tight junction protein expression. A further potentially very important observation is that in in vivo following sumatriptan administration, there appeared to be a change in astrocyte morphology. In other studies, we have
previously shown that astrocytes play a critical role in maintaining BBB integrity. Therefore this
line of research will be continued. If these further studies support the initial observation, this will represent a major advance in understanding the mechanisms leading to MOH.
BBB. A greater understanding of how alterations in BBB integrity may increase the probability
of MOH will give insight into the underlying pathology of migraine. This study provides novel
therapeutic avenues for migraine suffers aimed at maintaining BBB integrity.
Golda Ginsburg, PhD, Johns Hopkins School of Medicine, Baltimore, MD
Emily Bates, PhD, Brigham Young University, Provo, UT
Richard Kraig, MD, PhD, University of Chicago Medical Center, Chicago, IL
The Puzzle Points to Glia
Opioid pharmacotherapies are often used to treat migraine pain, and while these therapies may be effective in the short term, they become less so with repeated administration. We have previously shown that morphine activates spinal cord glia (non-neuronal cells), and the experiments here were designed to test if morphine- activated-glia in the nucleus caudalis of the trigeminal complex creates a vulnerability. Using our animal model of migraine, we tested this hypothesis and determined vulnerability by degree of facial allodynia (when a previously non-painful touch is now painful). Facial allodynia was the focus here as it represents a critical point in migraine development. When the migraine is treated prior to facial allodynia, standard migraine medications are often successful; when the treatment is administered after the development of facial allodynia, migraine therapies generally fail. Prior treatment with morphine did indeed increase migraine vulnerability. To test if this morphine-induced vulnerability to rat migraine was dependent on glial activity, morphine was co-administered with a glial inhibitor. This injection paradigm suppressed the morphine-induced vulnerability thereby preventing the later development of facial allodynia. The behavioral data support that morphine activates glia, priming the microenvironment to be more responsive to a future challenge. We are currently performing studies to further characterize these effects.
A key question left unanswered centers around the fact that the mechanisms underlying morphine-induced vulnerability remain unknown. Further, it remains unknown how the glial activation inhibitor was able to prevent morphine-induced vulnerability. Given the wide use of morphine and other opioids in the treatment of migraine, and the general issues surrounding medication overuse headache, undertaking studies to understand these questions would be very important.
Richard Lipton, MD, Albert Einstein College of Medicine, Bronx, NY
Our aim was to demonstrate the feasibility of and to optimize procedures for the collection of DNA by saliva in the AMPP, in individuals with episodic migraine, chronic migraine, and non-migraine control subjects.
Yu-Qing Cao, PhD, Washington University Pain Center, St. Louis, MO
The Effects of Calcium Channel Mutations on Trigeminal Ganglion Neurons Innervating the Dura
Multiple mutations of human P/Q-type calcium channels are associated with familial hemiplegic migraine type 1, a rare hereditary form of migraine. Understanding how these channels contribute to the onset of headache will shed light on the mechanisms of migraine in general. In this project, we used leaner, a strain of mouse that has the mutant P/Q-type channels, as a model to investigate the effects of these channels on primary sensory neurons mediating migraine headache and facial pain.
The activation and sensitization of trigeminal ganglion (TG) neurons innervating the meninges and cerebral vessels in the brain is the first step in the onset of headache. We conducted electrophysiological recordings to compare the electrical properties of certain neurons from wild-type and leaner mice. We found that it is easier to excite a leaner neuron than a wild-type neuron. We conclude that mutant P/Q-type calcium channels may cause hyper-excitation of primary sensory neurons innervating the meninges and, in turn, lead to a higher susceptibility of migraine headache. As control experiments, we looked at TG neurons innervating the facial skin and studied their electric properties. Interestingly, the leaner mutation did not cause hyper-excitation of this population of TG neurons. Taken together, our results indicate that mutant P/Q-type channels selectively increase the excitability of TG neurons mediating migraine headache while sparing neurons transmitting other facial pain.
Teresa Esposito, PhD, Institute of Genetics and Biophysics, Naples, Italy
The Role of Ionotropic Glutamate Receptor Genes in Migraine
Summary
Glutamate is the principal excitatory neurotransmitter in the central nervous system and is widely accepted as playing a major role in the pathophysiology of migraine. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could, therefore, be considered potential candidates for causing/predisposing migraine when mutated.
The most important question generated by our research is whether medications that target different types of glutamate receptors could represent a novel treatment for migraine. Answering this question with further basic and clinical studies will have substantial implications for the field of migraine and for migraine patients.
Targeting different types of glutamate receptors might represent a new treatment approach for migraine medications.
David Borsook, MD, PhD, McLean Hospital, Belmont, MA
Mapping Functional Brain Circuits in a Rodent Migraine Model of Central Sensitization
Summary
Based on our studies of imaging the trigeminal nerve (that provides sensation to the head and face) we have developed an animal model to study migraine with techniques that allow us to measure brain function (functional neuroimaging).
Hypothesis vs. Findings
The research findings supported the original hypotheses. Specifically, we could demonstrate that functional (brain) activation in brain regions shown by our group of migraine patients, are similar in this model. Furthermore, these results also replicate data obtained in neurophysiological results.
Unanswered questions
The research did not allow us to gain insights into chronic brain changes in the rat model.
Nancy Berman, PhD, University of Kansas Medical Center, Kansas City, KS
A Behavioral Model of Menstrual Migraine
In this project, we developed a behavioral model of migraine in rats and examined sex differences in migraine-like behaviors. We based the behavioral assays on the diagnostic criteria for migraine established by the International Headache Society, allowing us to diagnose migraine in our rat model using the same criteria used in patients. Behavioral assays of activity allowed us to assess whether the rats reduced their activity during experimental migraine, and measurements of responses to touching their faces allowed us to assess facial allodynia (pain after light touch that normally isn’t painful) that is common during migraine. Additional behavioral measurements of preference for light or dark and tendency to avoid loud noise are being developed to assess photophobia and phonophobia. We found that both male and female rats showed reduced activity and facial allodynia in our migraine model, but that the females showed behavioral changes after lower doses of the agent used to induce migraine than the males. The second goal was to examine the biological basis for sex differences. Here, we found that there are large sex differences in expression of genes that regulate pain, both before the rats have migraine and after repeated migraines, and that these differences are present in both the central and peripheral nervous system.
The goal of the project was to develop a rodent behavioral model and to use that model to understand the biological basis for sex differences in migraine. That goal was met, with the exception that the photophobia and phonophobia tasks were not validated before the first study was complete. Those tasks are still under development. Because we used a method to examine RNA, we were able to explore sex differences in several genes. We found that the sex differences were unexpectedly large. The main finding was that genes related to pain, those that make pain worse by increasing excitability of neurons that signal pain, were regulated at much higher gain in females than in males, some of them increased over 100 fold in the female rats with migraine and not increased at all in males. We also found that the reverse is true; some genes are upregulated in males and not females. These results suggest that the mechanism causing migraine pain may be sex dependent, and that optimal migraine treatments may be different for men and women.
Unanswered questions include
Our research suggests that the mechanism causing migraine pain may be sex dependent, and that optimal migraine treatments may be different for men and women.
Andrew Charles, MD, David Geffen School of Medicine UCLA, Los Angeles, CA
This project investigated the effects of opioids (narcotic pain relievers) on basic mechanisms of migraine, with the goal of understanding how certain types of opioids may in fact worsen migraine. We found that morphine had complex effects on brain excitability underlying migraine. Initial studies indicated that morphine reduced the threshold for activation of cortical spreading depression (CSD), the spreading wave of activity that is believed to be the basis for the migraine aura. These results suggested that medications like morphine could have effects that predispose patients to more frequent migraine. However, subsequent studies indicated that morphine had complex effects on repetitive CSD evoked by continuous stimulation. These effects included a reduced frequency of spreading depression events, but an increase in their amplitude and a slower recovery from CSD. We are currently doing further experiments to try to better understand these effects.
Markus Schürks, MD, MSc, and Tobias Kurth, MD, ScD, Brigham and Women's Hospital, Boston, MA
Published in PLoS One, Volume 6, Issue 7, July 2011
Summary
Migraine increases the risk for cardiovascular disease (CVD), in particular stroke. Genetic factors contribute importantly to both migraine and CVD, however, it is unclear which genetic factors are responsible for the increased CVD risk among migraineurs. To investigate this, we compared >330,000 gene variants between migraineurs, who developed a cardiovascular event, and those who did not. Among the 5,122 women with migraine, there were 164 who developed a CVD event (heart attack, stroke, death due to CVD). No gene variant was strongly associated with any of the CVD events. However, five of the variants were suggestive to increase the risk for CVD by 3- to 12-fold. Of note, four associations appeared among migraineurs with aura and two of those with ischemic stroke. This agrees with findings that migraineurs with aura appear to have an increased risk for CVD, and this is particularly strong for ischemic stroke. But it is less clear for other CVD events like heart attack and death due to CVD. Additional studies are necessary to confirm these associations and to decipher the potential underlying biological mechanisms.
Regarding this question, little is known about the function of the implicated genes and their mechanisms of contributing to CVD among migraineurs. Answering this will involve laboratory work including experiments with cell cultures and animal models.
What this Research Means to You
The results of our work suggest that five genes are involved in the link between migraine and cardiovascular disease, particularly stroke. Our results will generate new hypotheses about the underlying biology as well as promote further targeted research in this area.
Richard Kraig, MD, PhD, University of Chicago Medical Center, Chicago, IL
This extension was based on our hypothesis that cold-preconditioning neuroprotection was also due to TNF-α from microglia. We confirmed this suspicion. Importantly, the gene screening involved with the work led to completely unexpected findings. We showed that interleukin-11 (IL-11), an anti-inflammatory cytokine, was produced by neurons and served to inhibit TNF-α signaling. Thus, when we blocked IL-11, cold-preconditioning was enhanced. This led us to speculate that IL-11 might prevent TNF-α-dependent increased susceptibility to spreading depression. It did!
Unanswered Questions
Michael L. Oshinsky, PhD, Thomas Jefferson University, Philadelphia, PA
We measured the activation of two types of neuroglia (astrocyte and microglia) in the area of the brain that is the first level of sensory information processing, the trigeminal nucleus caudalis (TNC). The results of this study demonstrate that repeated activation leads to persistent activation of both astrocytes and microglia, and that treating the rats with a drug known to prevent the activation of the neuroglia blocks the progression to chronicity.
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What are the consequences of glial activation on trigeminal pain sensitivity in humans?
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What cytokines or chemokines are released by these activated neuroglia that lead to increases in trigeminal excitation?
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Is the increased BBB permeability induced by glial activation functionally relevant in humans with CDH, and does it have implications for treatment?
What this Research Means to You
Our study of the effects of glial activation in the brain following painful stimulation of the dura demonstrates that treatments designed to reverse this activation could be beneficial to migraine sufferers.
F. Michael Cutrer, MD, Mayo Clinic, Rochester, MN
What this Research Means to You
For the first time, we showed that the association with migraine of several genes involved in the hormones underlying the menstrual cycle relate to the variant form of the gene in women whose migraine attacks are worse or more frequent around the time of their menstrual flow. This is the first time that a gene variant has been shown to correlate with a specific clinical characteristic of patients with one of the common forms of migraine. It is an exciting result that may point to a future in which treatment of a patient with migraine is based on the actual genetically-based biological cause of their migraine.
Frank Porreca, PhD, University of Arizona, Tucson
Ann Scher, PhD, Uniformed Services University, Bethesda, MD
We have completed and published our first analysis related to the migraine and sub-clinical stroke-like lesions. We found that the migraineurs who reported aura symptoms in middleage were more likely than others to have stroke-like lesions in the cerebellum.
