Pathophysiology of Migraine.

PURPOSE OF REVIEW: This article summarizes the current understanding of the pathophysiology of migraine, including some controversial aspects of the underlying mechanisms of the disorder. RECENT FINDINGS: Recent functional neuroimaging studies focusing on the nonpainful symptoms of migraine have identified key areas of the central nervous system implicated in the early phases of a migraine attack. Clinical studies of spontaneous and provoked migraine attacks, together with preclinical studies using translational animal models, have led to a better understanding of the disease and the development of disease-specific and targeted therapies. SUMMARY: Our knowledge of the pathophysiology of migraine has advanced significantly in the past decades. Current evidence supports our understanding of migraine as a complex cyclical brain disorder that likely results from dysfunctional sensory processing and dysregulation of homeostatic mechanisms. This article reviews the underlying mechanisms of the clinical manifestations of each phase of the migraine cycle.

Patients With Vestibular Migraine are More Likely to Have Occipital Headaches than those With Migraine Without Vestibular Symptoms.

OBJECTIVE: To determine whether patients with vestibular migraine are more likely to suffer from an occipital headache than patients with migraine without vestibular symptoms. BACKGROUND: Vestibular migraine is an underdiagnosed disorder in which migraine is associated with vestibular symptoms. Anatomical evidence and symptomatology hint at the involvement of brain structures in the posterior fossa (back of the head location). We hypothesized that vestibular migraine patients are more likely than migraineurs without vestibular symptoms to experience headaches located in the back of the head, that is, occipital headaches. METHODS: A retrospective cross-sectional study was conducted at the University of Iowa Hospital and Clinics. Chart analysis of 169 patients was performed. The primary outcome was the location of the headache in vestibular migraine patients and migraineurs without vestibular symptoms. The secondary outcomes included the association of vestibular migraine with gender, age at onset of headache, age at onset of vestibular symptoms (such as vertigo, head motion-induced dizziness), aura, motion sickness, other associated symptoms, family history of headaches, and family history of motion sickness. RESULTS: In vestibular migraine group, 45/103 (44%) had occipital location for their headaches vs 12/66 (18%) in migraine patients without vestibular symptoms, for an odd's ratio of 3.5 (95% CI = 1.7-7.2, P < .001). Additionally, the age at onset of headache was greater in the vestibular migraine group (28 ± 12 vs 18 ± 9 years, P < .001) and motion sickness was more common (41/98 (42%) in the vestibular migraine group, 1/64 (2%) in the migraine without vestibular symptoms group, P < .001). CONCLUSIONS: This study suggests that patients with vestibular migraine are more likely to have occipital headaches than patients with migraine without vestibular symptoms. Our data support the initiation of a prospective study to determine whether a patient presenting with occipital headaches, with late onset of age of headache, and with a history of motion sickness is at an increased risk for the possible development of vestibular migraine.

One-Day Acceptance and Commitment Therapy Compared to Support for Depressed Migraine Patients: a Randomized Clinical Trial.

In patients with migraine, depression is associated with poorer medical prognosis, decreased quality of life, and increased risk of suicidality and disability; yet, behavioral interventions have rarely been investigated. The current study compared the efficacy of two 1-day (5- to 6-h) interventions for co-occurring migraine and depression: (1) acceptance and commitment therapy plus migraine education (ACT-ED), and (2) support plus migraine education (S-ED). One hundred and thirty-six patients with comorbid depression and migraine were randomized to a treatment. One hundred and three (76%) completed the ACT-ED (N = 56) or S-ED (N = 47) workshop. Primary outcomes were depression diagnosis and symptoms. Secondary outcomes were anxiety symptoms, headache-related disability and general functioning, and quality of life. Assessments were completed at baseline and 3 and 6 months following the workshop. At the 6-month follow-up, on categorical outcomes, a significantly greater number of people in the ACT-ED condition no longer met criteria for a major depressive episode and exhibited a > 50% drop in symptoms on the Hamilton Rating Scale of Depression. Similarly, though, weaker results were found when examining depressive symptoms dimensionally. On secondary outcomes, people in the ACT-ED condition exhibited significantly greater improvements in anxiety, headache-related disability, and quality of social relationships, compared to S-ED, No differences between groups were observed in general functioning. A 1-day (5- to 6-h) ACT workshop can deliver substantial and lasting benefits to depressed migraineurs, over and above those provided by group support and education. This approach is an attractive alternative to weekly psychotherapy. Clinicaltrials.gov # NCT02108678.

Trigeminal Pain Responses in Obese ob/ob Mice Are Modality-Specific.

How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.

Sociodemographic Factors Associated With Hospital Care for Pediatric Migraine: A National Study Using the Kids' Inpatient Dataset.

BACKGROUND: Although migraine often starts in childhood or adolescence, hospital care for migraine in children is not well described. We examined patient and hospital characteristics associated with hospital care for migraine among children in the United States. METHODS: We queried the Kids' Inpatient Database (2003 to 2009) for hospitalizations of children aged 3-20. Sociodemographic and hospital characteristics were compared between hospitalizations for migraine and for other common medical conditions. Multivariate logistic regression models estimated the associations between patient, hospital, and socioeconomic characteristics and inpatient migraine care. RESULTS: We identified 11,696 pediatric migraine hospitalizations, the majority (68.7%) occurring at teaching hospitals, involving a female (68.8%) child, ages 13-20 (71%, mean age: 14.6 years). As compared to the overall inpatient sample, migraine hospitalizations were less likely to involve children who were Black (adjusted odds ratio [AOR] 0.54, 95% confidence interval [CI] 0.49 to 0.60), Hispanic (AOR = 0.58, 95% CI 0.50 to 0.68), or Asian (AOR = 0.42, 95% CI 0.32 to 0.55), and more likely to involve females (AOR = 1.49, 95% CI 1.40 to 1.59). Migraine inpatients were more likely to live in higher income postal ZIP code areas (versus lowest ZIP code income quartile: AOR = 1.32, 95% CI 1.18 to 1.48). The average length of stay for migraine was 2.54 (SEM 0.6) days. CONCLUSIONS: Children who are hospitalized for migraines have distinct sociodemographic characteristics and a short length of stay. Understanding the reasons for these variations will inform the design of interventions aimed at reducing the need for pediatric migraine hospitalization.

Benefits of an on-line migraine education video for patients with co-occurring migraine and depression.

OBJECTIVE: To evaluate effects of an online, hour-long migraine education and management education program on health outcomes in people with migraine experiencing significant depressive symptoms. METHODS: Eligible individuals in the community with comorbid migraine and depressive symptoms (n = 95) participated in the 12-week study. Participants completed self-report questionnaires examining general functioning, headache-specific disability, migraine frequency, pain, and depressive symptoms, before, and at 2, 6, and 12 weeks following the migraine education and management program. Primary analyses evaluated change over time in each outcome, using individual linear growth curve models. RESULTS: After watching the migraine education and management video, there were significant effects of time (across all time points) for average pain level in the past 30 days (b = -0.20, p < .001), most intense pain level in the past 30 days (b = -0.33, p < .001) depression (Patient Health Questionnaire-8; b = -0.28, p = .002), and headache-specific disability (Headache Disability Inventory; b = -1.32, p < .001), such that each of these outcomes improved linearly over time. CONCLUSIONS: A brief, online educational video is practical and effective and can lead to enhanced migraine knowledge and self-management skills and lessen the burden of migraine and concurrent depressive symptoms.

Comorbidity of Migraine, Major Depressive Disorder, and Generalized Anxiety Disorder in Adolescents and Young Adults.

PURPOSE: Depression and anxiety are highly comorbid psychiatric conditions and both are common in adult patients with migraine. This study aims to examine the unique associations between major depressive disorder (MDD) and generalized anxiety disorder (GAD) in a well-characterized group of older adolescents and college-age individuals with migraine. METHOD: Participants (N =  227), between 15 and 20 years old, who were unmedicated or within 1 month of beginning antidepressant treatment underwent a comprehensive psychiatric assessment to establish the presence of MDD and GAD, according to the Diagnostic and Statistical Manual, Fourth Edition, Text Revision, and to rate their symptom severity using the Longitudinal Interval Follow-up Evaluation for Adolescents (A-LIFE). They then completed the ID-Migraine. The Student's t test and chi-square test were used to compare continuous and categorical variables, respectively, across participants with vs. without migraine. Logistic regression analysis examined the association between the presence of migraine and psychopathology. RESULTS: A diagnosis of MDD was associated with significantly increased risk of having migraine. Moreover, more severe and persistent ratings of depression were associated with an even higher likelihood of having migraine. A diagnosis of GAD was also significantly associated with the presence of migraine. The prevalence of comorbid MDD and GAD was significantly higher in participants with migraine than those without migraine (55 vs. 22%, p < 0.0001). When examined concurrently, GAD remained significantly associated with migraine, with a statistical trend for MDD to be associated with it. CONCLUSION: The comorbidity of migraine, MDD, and GAD has important clinical and research implications. Patients who suffer from any of these problems should be screened for all three in order to receive comprehensive care. Shared psychological and biological vulnerabilities may be involved in the three conditions. Greater understanding of the shared vulnerabilities can lead to unified treatments.

Anti-CGRP antibodies block CGRP-induced diarrhea in mice.

The multifunctional neuropeptide calcitonin gene-related peptide (CGRP) and its receptor are expressed throughout the gastrointestinal tract. Previous studies have shown that CGRP has roles in intestinal motility, water secretion, and inflammation. Furthermore, animal studies have demonstrated CGRP involvement in diarrhea secondary to C. difficile and food allergies. Diarrhea thus provides a convenient bioassay of CGRP activity in the GI system. In this proof of principle study, we report that prophylactic administration of an anti-CGRP antibody is able to block CGRP-induced diarrhea in mice. As a control, the CGRP-receptor antagonist olcegepant also attenuated the diarrhea response to CGRP. This preclinical study indicates that anti-CGRP antibodies may provide a new preventative therapy for gastrointestinal disorders involving CGRP.

Female sex and obesity increase photophobic behavior in mice.

Migraine affects predominantly women. Furthermore, epidemiological studies suggest that obesity is a risk factor for migraine and this association is influenced by sex. However, the biological basis for this bias is unclear. To address this issue, we assessed light avoidant behavior, a surrogate of photophobia, in female C57BL/6J mice fed regular diet (RD) or high-fat diet (HFD, 60% kcal from fat). We first assessed sex differences in basal photophobia in 20-25-week-old mice and found that both obese and lean females spent significantly less time in light than their male counterparts. Next, we assessed photophobia evoked by trigeminal stimulation with intradermal capsaicin. Females at 20-25weeks of age did not display capsaicin-evoked photophobic behavior unless they had diet-induced obesity. When we tested 8-11-week-old females to determine if the diet alone could be responsible for this effect, we found that both HFD and RD 8-11-week-old females exhibit capsaicin-evoked photophobic behavior. This is in contrast to what we have previously shown in males and indicates a sex difference in the photophobic behavior of mice. Comparison of 20-25-week-old RD mice with 8-11-week-old RD mice suggests that age or age-related weight gain may contribute to capsaicin-evoked photophobic behavior in males, but not in females. These findings suggest that obesity exacerbates photophobia in both sexes, but additional work is needed to understand the sex- and age-specific mechanisms that may contribute to photophobia and trigeminal pain.

Higher augmentation index is associated with tension-type headache and migraine in middle-aged/older humans with obesity.

OBJECTIVE: Obesity is a major risk factor for chronic daily headaches, including migraine and tension-type headache (TTH). Although migraine is associated with increased risk of cardiovascular diseases (CVD), a relation between TTH and CVD risk has not been established. It was hypothesized that higher carotid-femoral pulse wave velocity (CFPWV) and augmentation index (AI), measures of aortic stiffness and pressure wave reflection, respectively, and biomarkers of CVD risk, would be higher among adults with obesity and migraine or TTH compared with those with no headache. METHODS: Adults with obesity (n = 93; body mass index ≥30 kg/m(2) ) who were between 40 and 75 years old with at least one additional CVD risk factor were enrolled. Subjects had CFPWV and AI assessed and a complete neurological exam for diagnosis of headache in the past 12 months. RESULTS: Adults with obesity and TTH (P = 0.018), but not migraine (P = 0.29), had significantly higher AI compared with those with no headache. When both CFPWV and AI were considered in a logistic regression model with migraine or TTH, only AI was associated with TTH (P = 0.008) and migraine (P = 0.032) but could not distinguish between the two headache phenotypes. CONCLUSIONS: Increased aortic AI but not stiffness is associated with TTH and migraine among middle-aged/older adults with obesity and high CVD risk.

Abnormal trigeminal sensory processing in obese mice.

Obesity is associated with several pain disorders including headache. The effects of obesity on the trigeminal nociceptive system, which mediates headache, remain unknown. We used 2 complementary mouse models of obesity (high-fat diet and leptin deficiency) to examine this. We assessed capsaicin-induced nocifensive behavior and photophobia in obese and control mice. Calcium imaging was used to determine the effects of obesity on the activity of primary trigeminal afferents in vitro. We found that obese mice had a normal acute response to a facial injection of capsaicin, but they developed photophobic behavior at doses that had no effect on control mice. We observed higher calcium influx in cultured trigeminal ganglia neurons from obese mice and a higher percentage of medium to large diameter capsaicin-responsive cells. These findings demonstrate that obesity results in functional changes in the trigeminal system that may contribute to abnormal sensory processing. Our findings provide the foundation for in-depth studies to improve the understanding of the effects of obesity on the trigeminal system and may have implications for the pathophysiology of headache disorders.

Photophobia in primary headaches.

BACKGROUND: Photophobia is a debilitating feature of many headache disorders. OVERVIEW: Clinical and preclinical research has identified several potential pathways involved in enhanced light sensitivity. Some of these structures include trigeminal afferents in the eye, second-order neurons in the trigeminal nucleus caudalis, third-order neurons in the posterior thalamus, modulatory neurons in the hypothalamus, and fourth-order neurons in the visual and somatosensory cortices. It is unclear to what degree each site plays a role in establishing the different temporal patterns of photophobia across different disorders. Peptides such as calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide may play a role in photophobia at multiple levels of the visual and trigeminal pathways. CONCLUSION: While our understanding of photophobia has greatly improved in the last decade, there are still unanswered questions. These answers will help us develop new therapies to provide relief to patients with primary headache disorders.

Depression and disability in migraine: the role of pain acceptance and values-based action.

BACKGROUND: Migraine is a complex neurological disorder that substantially impairs a person's functioning and is often comorbid with depression. Currently, little is known about psychological coping strategies that may underlie disability and depression in patients with migraine. PURPOSE: This study examines concurrent relations between depression and disability on the one hand and pain acceptance and values-based action on the other hand in patients with migraine. METHOD: Ninety-three patients with migraine and depressive symptoms-being evaluated for a larger project examining the impact of a behavioral intervention on depression in patients with migraine-completed measures of depression, disability, pain acceptance, and values-based action. Using multiple regression analyses, the contributions of pain acceptance and values-based action to depression and disability were assessed. RESULTS: Low pain acceptance was strongly associated with depression and disability (r s(2) = .15-.37) in these patients. Low pain acceptance also explained unique variance in disability, beyond that of depression. Values-based action related modestly to depression and disability (r s(2) = .02-.07). CONCLUSION: Pain acceptance can contribute to our understanding of psychological health and functioning. An important next step would be to examine whether targeting acceptance in treatment of patients with migraine would lead to improvements in their mental health and functioning.

One-day behavioral intervention in depressed migraine patients: effects on headache.

OBJECTIVE: To determine whether a 1-day behavioral intervention, aimed at enhancing psychological flexibility, improves headache outcomes of migraine patients with comorbid depression. BACKGROUND: Migraine is often comorbid with depression, with each disorder increasing the risk for onset and exacerbation of the other. Managing psychological triggers, such as stress and depression, may result in greater success of headache management. METHOD: Sixty patients with comorbid migraine and depression were assigned to a 1-day Acceptance and Commitment Training plus Migraine Education workshop (ACT-ED; N = 38) or to treatment as usual (TAU; N = 22). Patients completed a daily headache diary prior to, and for 3 months following, the intervention. Clinical variables examined included headache frequency/severity, medication use, disability, and visit to a health care professional. Comparisons were made between baseline findings and findings at the 3-month follow up. RESULTS: Participants assigned to the ACT-ED condition exhibited significant improvements in headache frequency, headache severity, medication use, and headache-related disability. In contrast, the TAU group did not exhibit improvements. The difference in headache outcomes between ACT-ED and TAU was not statistically significant over time (ie, the treatment by time interaction was nonsignificant). These results complement those of a previous report showing effects of ACT-ED vs TAU on depression and disability. CONCLUSION: A 1-day ACT-ED workshop targeting psychological flexibility may convey benefit for patients with comorbid migraine and depression.These pilot study findings merit further investigation using a more rigorously designed large-scale trial.

Headache and obesity in the pediatric population.

Childhood obesity and headache are both significant health concerns that often have a marked impact both personally and socially, that if not addressed can carry over into adulthood. For many individuals, these effects may be magnified when obesity and headache are seen in conjunction. It is this overlap between obesity and headache in children, as well as similarities in the known mechanism of action for feeding and headache, which led to a suspected association between the two. Unfortunately, although recent studies have supported this association, only a limited number have been conducted to directly address this. Furthermore, despite rising rates of childhood obesity and headache, the associated medical comorbidities, and the significant financial cost for these conditions, there is a relative void in studies investigating treatment options that address both underlying conditions of obesity and headache in children.

Migraine and triggers: post hoc ergo propter hoc?

The influence of environmental factors on the clinical manifestation of migraine has been a matter of extensive debate over the past decades. Migraineurs commonly report foods, alcohol, meteorologic or atmospheric changes, exposure to light, sounds, or odors, as factors that trigger or aggravate their migraine attacks. In the same way, physicians frequently follow this belief in their recommendations in how migraineurs may reduce their attack frequency, especially with regard to the consumption of certain food components. Interestingly, despite being such a common belief, most of the clinical studies have shown conflicting results. The aim of the review is to critically analyze clinical and pathophysiological facts that support or refute a correlation between certain environmental stimuli and the occurrence of migraine attacks. Given the substantial discrepancy between patients' reports and objective clinical data, the methodological difficulties of investigating the link between environmental factors and migraine are highlighted.

Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist.

The neuropeptide calcitonin gene-related peptide (CGRP) plays a critical role in the pathophysiology of migraine. We have focused on the role of CGRP in photophobia, which is a common migraine symptom. We previously used an operant-based assay to show that CGRP-sensitized transgenic (nestin/hRAMP1), but not control, mice exhibited light aversion in response to an intracerebroventricular CGRP injection. A key question was whether the transgenic phenotype was due to overexpression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light-aversive behavior, then wild-type mice should also show the phenotype when given a sufficiently strong stimulus. In this study, we report that mice with normal levels of endogenous CGRP receptors demonstrate light avoidance following CGRP administration. This phenotype required the combination of two factors: higher light intensity and habituation to the testing chamber. Control tests confirmed that light aversion was dependent on coincident exposure to CGRP and light and cannot be fully explained by increased anxiety. Furthermore, CGRP reduced locomotion only in the dark, not in the light. Coadministration of rizatriptan, a 5-HT(1B/D) agonist anti-migraine drug, attenuated the effects of exogenous CGRP on light aversion and motility. This suggests that triptans can act by mechanisms that are distinct from inhibition of CGRP release. Thus, we demonstrate that activation of endogenous CGRP receptors is sufficient to elicit light aversion in mice, which can be modulated by a drug commonly used to treat migraine.

One-day behavioral treatment for patients with comorbid depression and migraine: a pilot study.

BACKGROUND: Migraine is a common and disabling disorder that is highly comorbid with depression. The comorbidity of depression and migraine is a major health concern as it results in poorer prognosis and quality of life. Yet, effective treatments have rarely been investigated. METHOD: 45 patients with comorbid migraine and depression were assigned to a 1-day Acceptance and Commitment Training plus Migraine Education workshop (ACT-ED; N = 31) or to Wait List/Treatment as Usual (WL/TAU; N = 14). Assessment of depressive symptoms, general functioning, and migraine related disability were completed at baseline and 2-, 6-, and 12 weeks after the workshop. RESULTS: At the 3-month follow up, participants in the ACT-ED condition exhibited significantly greater improvements in depressive symptoms, general functioning, and migraine-related disability than patients in the WL/TAU group. CONCLUSION: A 1-day ACT-ED workshop is a promising approach to the treatment for depression and disability in migraineurs that merits further investigation.