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Background: Previous cross-sectional studies reported an increased risk of suicide attempt in persons with migraine headache, which was sustained when psychiatric comorbidity was statistically controlled., Objective: To estimate the risk of suicide attempt in persons with migraine vs controls with no history of severe headache, using prospective data and validated diagnostic assessment. To examine the specificity of the migraine-suicide attempt risk by comparing it to the risk associated with non-migraine headache of comparable severity and disability., Methods: A cohort of persons with migraine (n = 496), non-migraine severe headaches (n = 151), and controls with no history of severe headache (n = 539) was randomly selected from the general community, assessed in 1997 and reassessed 2 years later., Results: Persons with migraine had an increased risk of suicide attempt during the 2-year follow-up period, compared with controls. Odds ratio, adjusted for sex, psychiatric disorder, and previous history of suicide attempt at baseline was 4.43 (95% confidence interval [CI] 1.93, 10.2). Persons with non-migraine headache of comparable intensity and disability also had an increased risk of suicide attempt, compared to controls: odds ratio, adjusted for the same covariates, was 6.20 (95% CI 2.40, 16.0). The difference between the 2 estimates was not significant. In the entire sample, headache severity at baseline predicted suicide attempt: a difference of 1 standard deviation (SD) in pain score increased the risk of suicide attempt by 79%, adjusting for sex and psychiatric disorders., Conclusions: The results suggest the possibility that pain severity might account in part for the increased risk of suicide attempt associated with migraine., (© 2012 American Headache Society.)

A number of pain conditions, acute as well as chronic, are much more prevalent in women, such as temporomandibular disorder (TMD), irritable bowel syndrome, fibromyalgia, and migraine. The association of female sex steroids with these nociceptive conditions is well known, but the mechanisms of their effects on pain signaling are yet to be deciphered. We reviewed the mechanisms through which female sex steroids might influence the trigeminal nociceptive pathways with a focus on migraine. Sex steroid receptors are located in trigeminal circuits, providing the molecular substrate for direct effects. In addition to classical genomic effects, sex steroids exert rapid nongenomic actions to modulate nociceptive signaling. Although there are only a handful of studies that have directly addressed the effect of sex hormones in animal models of migraine, the putative mechanisms can be extrapolated from observations in animal models of other trigeminal pain disorders, like TMD. Sex hormones may regulate sensitization of trigeminal neurons by modulating expression of nociceptive mediator such as calcitonin gene-related peptide. Its expression is mostly positively regulated by estrogen, although a few studies also report an inverse relationship. Serotonin (5-Hydroxytryptamine [5-HT]) is a neurotransmitter implicated in migraine; its synthesis is enhanced in most parts of brain by estrogen, which increases expression of the rate-limiting enzyme tryptophan hydroxylase and decreases expression of the serotonin re-uptake transporter. Downstream signaling, including extracellular signal-regulated kinase activation, calcium-dependent mechanisms, and cAMP response element-binding activation, are thought to be the major signaling events affected by sex hormones. These findings need to be confirmed in migraine-specific animal models that may also provide clues to additional ion channels, neuropeptides, and intracellular signaling cascades that contribute to the increased prevalence of migraine in women., (© 2011 American Headache Society.)

Objectives: Stroke risk is increased in migraine, the basis of which remains to be established. C-reactive protein (CRP) is a marker of cerebrovascular disease, suggesting in part an inflammatory mechanism. Because attacks of migraine may involve repeated sterile vascular inflammation, we measured CRP in migraine patients., Methods: Retrospective review was conducted of 60 randomly sampled charts of patients with the diagnosis of migraine without aura (MwoA, n = 29) and migraine with aura (MwA, n = 31), in which CRP was recorded as part of the differential diagnostic evaluation. CRP was measured by standard commercial laboratory methods; high sensitivity CRP (hs-CRP) values above 3mg/L were considered abnormal., Results: Elevated hs-CRP was found in 43% of all patients (26 of 60). In MwoA, of 29 subjects, abnormal hs-CRP was recorded in 16; in 10 no other conditions were found to explain the abnormality. In MwA, of 31 subjects, abnormal CRP was recorded in 10; in 5 no other condition could explain the abnormality. No associations were found between other demographic or clinical features., Conclusions: CRP may be abnormal in MwoA and MwA patients who present with atypical, severe, or complex clinical features that require extensive differential diagnostic investigation.

Abnormal brain excitability may provide the susceptibility for triggering migraine attacks. Antiepileptic drugs may diminish neuronal excitability and consequently reduce the frequency of migraine. Because migraine aura is predominantly visual, hyperexcitability of the occipital cortex has been the focus of investigations. Functional magnetic resonance imaging of the brain and magnetoencephalography provide the most consistent evidence for the role of brain hyperexcitability in migraine and confirm that triggering an abnormal electric and metabolic event consistent with the cortical spreading depression (CSD) of Leao is anatomically and functionally linked with migraine aura symptoms. Future drug discovery should focus on the interface between the excitable cell and the earliest events of CSD.

Background: Health care providers frequently cite concerns about cardiovascular safety of the triptans as a barrier to their use. In 2002, the American Headache Society convened the Triptan Cardiovascular Safety Expert Panel to evaluate the evidence on triptan-associated cardiovascular risk and to formulate consensus recommendations for making informed decisions for their use in patients with migraine., Objective: To summarize the evidence reviewed by the Triptan Cardiovascular Safety Expert Panel and their recommendations for the use of triptans in clinical practice., Participants: The Triptan Cardiovascular Safety Expert Panel was composed of a multidisciplinary group of experts in neurology, primary care, cardiology, pharmacology, women's health, and epidemiology., Evidence and Consensus Process: An exhaustive search of the relevant published literature was reviewed by each panel member in preparation for an open roundtable meeting. Pertinent issues (eg, cardiovascular pharmacology of triptans, epidemiology of cardiovascular disease, cardiovascular risk assessment, migraine) were presented as a prelude to group discussion and formulation of consensus conclusions and recommendations. Follow-up meetings were held by telephone., Conclusions: (1) Most of the data on triptans are derived from patients without known coronary artery disease. (2) Chest symptoms occurring during use of triptans are generally nonserious and are not explained by ischemia. (3) The incidence of serious cardiovascular events with triptans in both clinical trials and clinical practice appears to be extremely low. (4) The cardiovascular risk-benefit profile of triptans favors their use in the absence of contraindications.

Objective: The periaqueductal gray matter (PAG) is at the center of a powerful descending antinociceptive neuronal network. We studied iron homeostasis in the PAG as an indicator of function in patients with episodic migraine (EM) between attacks and patients with chronic daily headache (CDH) during headache. High-resolution magnetic resonance techniques were used to map the transverse relaxation rates R2, R2*, and R2' in the PAG, red nucleus (RN), and substantia nigra (SN). R2' is a measure of non-heme iron in tissues., Methods: Seventeen patients diagnosed with EM with and without aura, 17 patients diagnosed with CDH and medication overuse, and 17 normal adults (N) were imaged with a 3.0-tesla magnetic resonance imaging system. For each subject, mean values of the relaxation rates, R2 (1/T2), R2* (1/T2*), and R2' (R2* - R2) were obtained for the PAG, RN, and SN. R2, R2*, and R2' values of the EM, CDH, and N groups were compared using analysis of variance, Student t test, and correlation analysis., Results: In the PAG, there was a significant increase in mean R2' and R2* values in both the EM and CDH groups (P<.05) compared with the N group, but no significant difference in these values was demonstrated between the EM and CDH groups, or between those with migraine with or without aura in the EM group. Positive correlations were found for duration of illness with R2' in the EM and CDH groups. A decrease in mean R2' and R2* values also was observed in the RN and SN of the CDH group compared with the N and EM groups (P<.05), explained best by flow activation due to head pain., Conclusions: Iron homeostasis in the PAG was selectively, persistently, and progressively impaired in the EM and CDH groups, possibly caused by repeated migraine attacks. These results support and emphasize the role of the PAG as a possible "generator" of migraine attacks, potentially by dysfunctional control of the trigeminovascular nociceptive system.

Objectives: Threshold for generation of magnetophosphenes has been reported to be lower in migraine. We compared the threshold for eliciting phosphenes by transcranial magnetic stimulation and the ability to visually trigger headache in a select group of individuals with migraine with and without aura to normal controls., Methods: Transcranial magnetic stimulation was performed using the Cadwell MES-10 stimulator. A circular coil, 9.5 cm in diameter, was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulator intensity was then fine-tuned to determine the threshold at which phosphenes were seen. In the same subjects, visual stimulation was given in 3.0 T MRI and if a headache occurred the response was recorded., Results: Fifteen subjects with migraine were compared to 8 controls. A significant proportion of the migraineurs (86.7%) developed phosphenes compared to the controls (25%) (P = .006). The probability of triggering a headache was also higher in the migraineurs (53%); no headache was triggered in the controls (P = .019). A significant correlation was found between the threshold for phosphenes on transcranial magnetic stimulation and visually triggered headache (P = .002). When only migraine was considered, there was again a significant trend (P = .084)., Conclusions: There is a difference in threshold for excitability of occipital cortex in migraineurs and controls. The hyperexcitable visual cortex in migraine is predisposed to visually triggered headache.

Methods for measuring mitochondrial activity from 31P magnetic resonance spectroscopy data collected during and after exercise were compared in controls, weight lifters, and peripheral vascular occlusive disease (PVOD) patients. There were trends toward increasing mitochondrial activity during exercise in order from PVOD patients, moderately active controls, highly active controls, to weight lifters. Results from PVOD patients show divergence of some measures due to 1) the non-exponential nature of phosphocreatine recovery, and 2) potential breakdown of [ADP] control of the mitochondria due to lack of oxygen (for Qmax calculation). These results demonstrate the utility of obtaining and directly analyzing high time resolution data rather than assuming monoexponential behavior of metabolite recovery.

Multislice, two-dimensional phosphorus 31 spectroscopic imaging (SI) of human brain was performed in 15 normal volunteers on a 3-Tesla magnetic resonance system. Images of free magnesium concentrations and pH as well as phosphoesters, inorganic phosphate, phosphocreatine, and adenosine triphosphate (ATP), were calculated from the SI data. By using the equations of Golding and Golding (Magn. Reson. Med. 1995;33: 467-474), average [Mg2+] for all brain regions studied was 0.42+/-0.05 mM, whereas average brain pH was found to be 7.07+/-0.03, with no significant regional variations. Phosphorus metabolite concentrations (relative to ATP, assumed to be 3.0 mM/kg wet weight)were 5.39+/-1.88, 1.30+/-0.39, 5.97+/-3.17, and 4.33+/-1.45 mM/kg wet weight for phosphomonoesters, inorganic phosphate, phosphodiesters, and phosphocreatine (PCr), respectively. These values are in good general agreement with those reported previously. Typical signal-to-noise ratios of 15:1 were obtained for PCr in spectra from nominal 31.5 cc voxel sizes with a 34-min scan time. Limits on spatial resolution and the likely error of the magnesium and pH values are discussed.

Background and Purpose: Headache is the most common neurologic symptom following minor closed head injury. There is often a lack of objective evidence supporting an organic basis of cerebral pathology in these cases. This pilot study considers the possibility of alterations in cerebral blood flow, indicating evidence of an organic disorder in posttraumatic headache., Methods: Regional cerebral blood flow studies of 35 patients with chronic posttraumatic headache (PTH) (International Headache Society criteria), identified retrospectively from our cerebral blood flow data base, were compared with those of 49 nonheadache controls and 92 migraineurs (Ad Hoc Committee criteria). Regional cerebral blood flow (initial slope index method) was measured using the xenon Xe 133 inhalation technique., Results: Compared to migraineurs and controls, and after adjusting for differences (analysis of covariance) in baseline variables such as blood pressure, hematocrit, and PCO2, patients with PTH had: (1) significantly lower mean initial slope indices (P < 0.001, P = 0.002, respectively); (2) regional interhemispheric flow differences (rIFD), with higher distribution of regional asymmetrical probe pairs (rIFD > or = 7%: P[PTH versus control] = 0.006, P[PTH versus migraine] = 0.016: rIFD > or = 10%; P[PTH versus control] = 0.011, P[PTH versus migraine] = 0.003); and (3) more hemispheric asymmetries (P[PTH versus control] = 0.023, P[PTH versus migraine] = 0.57). Lower mean initial slope indices and hemispheric asymmetry (mean interhemispheric flow difference > or = 3.2%) predicted PTH over control (P = 0.023 and 0.002, respectively). Lower mean initial slope indices predicted PTH over migraine (P = 0.002)., Conclusions: Patients with PTH have reduced regional cerebral blood flow, and regional and hemispheric asymmetries. These cerebral hemodynamic alterations support an organic basis to chronic posttraumatic headache.

We investigated the platelet and plasma levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid, in patients suffering from episodic tension-type headache and migraine with and without aura, during a headache-free period. In female subjects, blood samples were drawn during the follicular, ovulatory, and late luteal phases of the menstrual cycle. In tension headache and migraine with aura, the group mean values of serotonin and 5-hydroxyindoleacetic acid in platelets and plasma were significantly increased, but migraine without aura patients' levels were normal. The pattern of menstrual cycle-related fluctuations in platelet serotonin levels were similar in female patients with tension headache and in controls, with a maximum value in the follicular phase. In both migraine groups, in contrast, the peak occurred in the ovulatory phase. The results are discussed in view of whether these aberrations in peripheral markers of the metabolism and menstrual cycle-related rhythmicity of serotonin may reflect similar alterations in the central nervous system.

The transverse relaxation rates R2 and R2* were measured at 3 T in the substantia nigra of the midbrain of adult normal human controls. The relaxation rate arising from magnetic inhomogeneities, R2', was calculated from the relationship R2* = R2 + R2'. No significant differences were found for any parameters between left and right side substantia nigra regions, however, a significant inverse correlation was found between R2 and R2' (r = 0.70, p = 0.035). Water diffusion, in the presence of paramagnetic metal ions, may play a role in determining the relative contributions to reversible and irreversible transverse relaxation and may explain the inverse correlation demonstrated here.

We have noninvasively produced low-resolution, quantitative nuclear magnetic resonance images of cerebral blood flow in 2-ml voxels in eight cats. Typical signal-to-noise of 4 to 1 was obtained in cerebral voxels in 16.5-s epochs. Mean flow during normocapnia (paCO2 = 39 +/- 4 mm Hg) and hypercapnia (paCO2 = 62 +/- 4 mm Hg) was 53 +/- 20 ml/100 g-min and 140 +/- 36 ml/100 g-min, respectively. Fast flows in normocapnia were 94 +/- 13 and 182 +/- 39 ml/100 g-min in hypercapnia. These results suggest that an atraumatic quantitative imaging assessment of cerebral perfusion may be possible in humans using these techniques.

31P NMR spectra obtained in vivo reveal the presence of a few reasonably well defined chemical species, namely, ATP, orthophosphate (Pi), and, in brain, phosphocreatine. The chemical shifts of these resonances respond to changes in concentrations of ions such as H+ and Mg2+ in a manner that depends on both the chemical shifts intrinsic to individual complexes and the formation or binding constants for the several complexes. Values of the appropriate formation constants are well established in the literature. We have derived estimates of the chemical shifts intrinsic to the individual complexes by analyzing high resolution spectra of solutions whose composition brackets the domain of physiological relevance. This provides information sufficient to estimate intracellular concentrations of H+ and Mg2+ from chemical shifts seen with in vivo spectra. The primary finding is an estimate of 0.3 mM for the concentration of free magnesium in human brain. Differing values are obtained from other tissues.

Techniques for the quantitative imaging assessment of cerebral blood flow are presented in a cat using 19F NMR imaging of trifluoromethane. The input function of the indicator was acquired noninvasively, while its uptake and clearance were followed in 2-cc volume voxels from images acquired at 67 s intervals. A single compartment model yielded normal cerebral blood flow estimates.

We report for the first time the detection by magnetoencephalography (MEG) of signals observable in migraine patients during headache, but not in controls. These signals consisted of three features: suppression of spontaneous cortical activity, long duration field changes, and large amplitude waves (LAW) of several seconds duration. LAW were also seen during the interictal period. We discuss the possible relationship of these signals to spreading depression (SD), and why the LAW have not been observed in previous studies of SD.

We used transmission electron microscopy to investigate selected aspects of the platelet response (surface activation as well as aggregation) and quantify cytoplasmic organelles within the cytoplasm of platelets obtained from both healthy control women and women diagnosed as having either common or classic migraine. Comparisons between controls and migraineurs showed no differences for: (1) the number of circulating platelets, (2) degree of surface activation, (3) amount of aggregate formation or (4) percent of hyperactive platelet populations. In contrast, platelets of migraine sufferers uniformly contained a significantly greater number of dense bodies compared to control platelets. Although we did not find functional abnormalities for the platelets obtained from migraineurs, we did demonstrate that they were altered structurally.

Brain magnesium was measured in migraine patients and control subjects using in vivo 31-Phosphorus Nuclear Magnetic Resonance Spectroscopy. pMg and pH were calculated from the chemical shifts between Pi, PCr and ATP signals. Magnesium levels were low during a migraine attack without changes in pH. We hypothesize that low brain magnesium is an important factor in the mechanism of the migraine attack.

An effective shield for the dc fringing fields produced by a large-bore, high field magnet intended for imaging and in vivo spectroscopy is presented. While limiting the extent of fringe fields, the shield has little effect on the homogeneity of the central field of the magnet. The effect of institutional safety policies as well as the exigencies of patient access in a hospital environment are emphasized as influences on the planning of an in vivo NMR installation.

Phosphorus-31 nuclear magnetic resonance spectroscopy (31P NMR) was used to assess the temporal changes of high-energy phosphate metabolites in the region of acute myocardial ischemia of open-chest cats. Eight anesthetized cats were studied following ligation of the left anterior descending coronary artery. Creatine phosphate showed a 79 +/- 16% (mean +/- SD) reduction by 4 min after the onset of ischemia. Prominent qualitative reductions of the spectral peak of creatine phosphate occurred by 40 s after ischemia. Adenosine triphosphate measured under the beta spectral peak (beta-ATP) decreased 37 +/- 9% by 20-25 min after ligation of the left anterior descending coronary artery. These reductions developed more slowly and were of smaller magnitude than those of creatine phosphate. Intracellular pH decreased from 7.39 +/- 0.07 to 7.13 +/- 0.09 units by 40 s after ischemia. By 30 min, pH decreased to 6.07 +/- 0.40 units. The study shows, therefore, the temporal changes of high-energy phosphate metabolites during ischemia in localized regions of the myocardium of open-chest animals.

Dysprosium(III) triethylenetraamine-N,N,N',N",N"',N"'-hexaacetic acid (DyTTHA3-) was used as an aqueous chemical shift reagent in conjunction with high-resolution nuclear magnetic resonance (NMR) spectroscopy to monitor 87-rubidium (87Rb+) transport in human erythrocyte suspensions. NMR spectra demonstrated two resonances which were assigned to the intra- and extracellular compartments of the erythrocyte suspension. Uptake of 87Rb+ was shown to proceed via the [Na,K]-ATPase dependent pump as evidenced by the inhibition of uptake in the presence of ouabain. The steady state intra- to extracellular concentration ratio of 87Rb was 3.00 and 1.13 in the absence and presence of ouabain, respectively. The rate of uptake of 87Rb+ in the absence and presence of ouabain was found to be 1.3 and 0.5 mmol Rb+/L erythrocytes/h at 18 mM Rb+, respectively. Data are also presented which indicate that the intracellular component of 87Rb is less than 100% NMR visible.

31P NMR spectroscopy was used to monitor the metabolic response of the tibialis anterior muscle group to transcutaneous nerve stimulation of the peroneal nerve at a rate of 4 Hz for 5 min in human volunteers (n = 8). It is demonstrated that this technique can be used as a method of investigating effort-free and compensation-independent skeletal muscle exercise.

Fe(III)meso-tetra(4-sulfonatophenyl)porphine (Fe-TPPS4) has been investigated as a potential pH-sensitive nuclear magnetic resonance (NMR) proton image contrast agent. Relaxation rates (1/T1 and 1/T2) of water protons were measured as a function of pH and concentration of Fe-TPPS4 in phosphate-buffered isotonic saline. Transverse relaxation rates (1/T2) did not change appreciably with pH above 6.0. Longitudinal relaxation rates (1/T1) increased significantly between pH 7.75 and 5.75. This effect was more pronounced with the increasing concentration of Fe-TPPS4 from 0.1 to 1.5 mM and is attributed to a pH-dependent equilibrium between the high-spin (S = 5/2) Fe-TPPS4 monomer at low pH and the antiferromagnetically coupled mu-oxodimer O-(FeTPPS4)2 at high pH. The efficacy of this pH-dependent contrast agent is demonstrated in vitro.

Two adults presented with new-onset migrainous-type visual disturbances and had angiographically demonstrated filling defects near the torcular Herophili. Neither patient had a visual field deficit nor cerebral computed tomography evidence of an occipital infarction. The association of migraine-like visual phenomena with cerebral venous thrombosis may provide insight into the pathogenesis of migraine.

Platelet serotonin (5 hydroxytryptamine, 5-HT) and norepinephrine (NE) were measured in common and classic migraine patients and healthy controls. Common migraine sufferers had high NE levels and a low 5-HT/NE ratio. Classic migraine patients had a high 5-HT level and a high 5-HT/NE ratio. The data suggest disparate NE and 5-HT metabolism between common and classic migraine.