Opinion statementMigraine is a very disabling disorder with severe impact on patients’ lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.

Background and purpose CNS complications are often seen after heart surgery, and post-surgical disruption of the blood-brain barrier (BBB) may play an etiologic role. The objective of this study was to determine the prevalence of MRI-detected BBB disruption (Hyperintense Acute Reperfusion Marker: HARM) and DWI lesions after cardiac surgery. Materials & methods All patients had an MRI after cardiac surgery. In half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. In the other half (group 2), we administered gadolinium at the time of the post-operative scan (2-4 days after surgery). Two stroke neurologists evaluated the images. Results We studied 19 patients. None of the patients had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1 and 30% in group 2, p=0.18) and 14 patients (74%) had DWI lesions (70% in group 1 and 78% in group 2, p=1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (p=0.56). Conclusions Almost half the patients undergoing cardiac surgery have evidence of HARM and three quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MRI can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.

Objective: We sought to explore whether patients with migraine show heightened interictal intrinsic connectivity within primary sensory networks, the salience network, and a network anchored by the dorsal pons, a region known to be active during migraine attacks.Methods: Using task-free fMRI and a region-of-interest analysis, we compared intrinsic connectivity patterns in 15 migraineurs without aura to 15 age-and sex-matched healthy controls, focusing on networks anchored by the calcarine cortex, Heschl gyrus, right anterior insula, and dorsal pons, a region active during migraine attacks. We also examined the relationship between network connectivity, migraine frequency, and sensory sensitivity symptoms.Results: Migraineurs showed increased connectivity between primary visual and auditory cortices and the right dorsal anterior insula, between the dorsal pons and the bilateral anterior insulae, and between the right and left ventral anterior insulae. Increased connectivity showed no clinical correlation with migraine frequency or sensory sensitivity. Conclusions:Patients with migraine display interictal changes in the topology of intrinsic connections, with greater connectivity between primary sensory cortices, the pons, and the anterior insula, a region involved in representing and coordinating responses to emotional salience. Migraine is a common, disabling primary headache disorder whose pathophysiology is incompletely understood.1 Migraine attacks often feature an alteration in sensory processing such that normally well-tolerated stimuli become unpleasant, manifesting most frequently as photophobia and phonophobia. These sensory changes may persist between attacks, as migraineurs have lower interictal thresholds for light-and sound-induced discomfort than controls. 2,3Task-free fMRI identifies brain regional ensembles, termed intrinsic connectivity networks (ICNs), 4 that exhibit correlated low-frequency blood oxygen level-dependent signal fluctuations. Previous task-free fMRI studies using independent component analysis revealed altered connectivity of the "executive," "default mode," and "salience" ICNs in migraineurs, although the direction of changes differed between studies. 5,6 Other studies used region-of-interest (ROI) analysis, focusing on pain-related regions such as the periaqueductal gray or amygdala and found increased connectivity in these networks. [7][8][9] Still others have used differences identified with voxel-based morphometry to seed ROI-based connectivity studies. [10][11][12][13] This approach has identified differences between females and males in cortical thickness and connectivity of the posterior insula and precuneus. 12 We studied interictal migraineurs with task-free fMRI to evaluate ICNs relevant to primary sensory processing, nociception, and salience. Given the increased salience of sensory stimuli in migraineurs, we hypothesized that migraineurs would have increased connectivity between the salience network, thought to be involved in identifying homeostatically releva...

The thalamus contains third-order relay neurons of the trigeminal system, and animal models as well as preliminary imaging studies in small cohorts of migraine patients have suggested a role of the thalamus in headache pathophysiology. However, larger studies using advanced imaging techniques in substantial patient populations are lacking. In the present study, we investigated changes of thalamic volume and shape in a large multicenter cohort of patients with migraine. High-resolution T1-weighted MRI data acquired at 3 tesla in 131 patients with migraine (38 with aura; 30.8 Ϯ 9 years old; 109 women; monthly attack frequency: 3.2 Ϯ 2.5; disease duration: 14 Ϯ 8.4 years) and 115 matched healthy subjects (29 Ϯ 7 years old; 81 women) from four international tertiary headache centers were analyzed. The thalamus and thalamic subnuclei, striatum, and globus pallidus were segmented using a fully automated multiatlas approach. Deformation-based shape analysis was performed to localize surface abnormalities. Differences between patients with migraine and healthy subjects were assessed using an ANCOVA model. After correction for multiple comparisons, performed using the false discovery rate approach (p Ͻ 0.05 corrected), significant volume reductions of the following thalamic nuclei were observed in migraineurs: central nuclear complex (F (1,233) ϭ 6.79), anterior nucleus (F (1,237) ϭ 7.38), and lateral dorsal nucleus (F (1,238) ϭ 6.79). Moreover, reduced striatal volume (F (1,238) ϭ 6.9) was observed in patients. This large-scale study indicates structural thalamic abnormalities in patients with migraine. The thalamic nuclei with abnormal volumes are densely connected to the limbic system. The data hence lend support to the view that higher-order integration systems are altered in migraine.

Background and Purpose-Interleukin-6 (IL-6) is associated with atherosclerotic disease and is also a key mediator in the inflammatory response to cerebral ischemia. Although the IL-6 Ϫ174G/C promoter polymorphism has been associated with carotid artery atherosclerosis and coronary heart disease, its relation to ischemic stroke is unclear. This review summarizes the current literature and discusses methodological considerations for future studies. Methods-Electronic searches were conducted in the PubMed MEDLINE, Scopus, and ISI Web of Science databases. Two investigators independently reviewed all abstracts to identify studies examining the association between the IL-6 Ϫ174G/C polymorphism and ischemic cerebrovascular events. Results-Twelve relevant publications were identified. Three reported on a subset of patients from a later publication, leaving 9 independent studies. Two studies found an association between ischemic stroke and the G allele or GG genotype, whereas 4 found an association with the C allele or CC genotype. One study found the CC genotype to be significantly less frequent in retinal artery occlusion patients. Two studies found no association between the Ϫ174G/C polymorphism and stroke. Conclusions-Studies investigating stroke and the Ϫ174G/C polymorphism report conflicting results, which may reflect the complex physiology of IL-6 and true differences between stroke subtypes and populations. However, interpretation of published results is hindered by methodological limitations, and greater rigor and consistency in future studies will help unravel the relationship between the Ϫ174G/C polymorphism and stroke. (Stroke.

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The shift in our understanding of migraine as a vascular disorder to a brain disorder has opened new avenues for the development of novel therapeutics with neural targets. The advent of 5-HT1B/1D receptor agonists, the triptans, in the 1990s was a crucial step in the modern evolution of treatment. The use of triptans, like their predecessors, is limited by their vasoconstrictor effects, and new development has been slowed by poor academic research funding to identify new targets. The development of agents without vascular effects, such as calcitonin gene-related peptide receptor antagonists and selective serotonin 5-HT1F receptor agonists, will bring more effective treatments to a population currently without migraine-specific options. In addition, advances in understanding migraine pathophysiology have identified new potential pharmacologic targets such as acid-sensing ion channels, glutamate and orexin receptors, nitric oxide synthase (NOS), and transient receptor potential (TRP) channels. Although previous attempts to block subtypes of glutamate receptors, NOS, and TRP channels have had mixed outcomes, new molecules for the same targets are currently under investigation. Finally, an entirely new approach to migraine treatment with noninvasive neuromodulation via transcutaneous neurostimulation or transcranial magnetic stimulation is just beginning. Hopefully in the coming years we will see a new era of migraine therapy, with multiple classes of better-tolerated, more effective agents targeting diverse yet specific migraine mechanisms.

IV dihydroergotamine treatment may be associated with an increased risk of catheter-associated venous thrombosis. A low threshold for diagnostic ultrasound investigation is appropriate because anticoagulation therapy was frequently required.