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      Current understanding of cortical structure and function in migraine

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          Abstract

          Objective

          To review and discuss the literature on the role of cortical structure and function in migraine.

          Discussion

          Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks.

          Conclusion

          Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications.

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          Most cited references195

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          Pathophysiology of Migraine: A Disorder of Sensory Processing.

          Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
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            The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.

            The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.
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              Transcranial pulsed ultrasound stimulates intact brain circuits.

              Electromagnetic-based methods of stimulating brain activity require invasive procedures or have other limitations. Deep-brain stimulation requires surgically implanted electrodes. Transcranial magnetic stimulation does not require surgery, but suffers from low spatial resolution. Optogenetic-based approaches have unrivaled spatial precision, but require genetic manipulation. In search of a potential solution to these limitations, we began investigating the influence of transcranial pulsed ultrasound on neuronal activity in the intact mouse brain. In motor cortex, ultrasound-stimulated neuronal activity was sufficient to evoke motor behaviors. Deeper in subcortical circuits, we used targeted transcranial ultrasound to stimulate neuronal activity and synchronous oscillations in the intact hippocampus. We found that ultrasound triggers TTX-sensitive neuronal activity in the absence of a rise in brain temperature (<0.01 degrees C). Here, we also report that transcranial pulsed ultrasound for intact brain circuit stimulation has a lateral spatial resolution of approximately 2 mm and does not require exogenous factors or surgical invasion. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Cephalalgia
                Cephalalgia
                CEP
                spcep
                Cephalalgia
                SAGE Publications (Sage UK: London, England )
                0333-1024
                1468-2982
                28 March 2019
                November 2019
                : 39
                : 13 , Special Issue: Brain Structure and Function related to Headache
                : 1683-1699
                Affiliations
                [1 ]Departments of Neurology and Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
                [2 ]Insitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei
                [3 ]Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei
                [4 ]Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei
                [5 ]Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                Author notes
                [*]Else A Tolner, Departments of Neurology & Human Genetics, Leiden University Medical Center, Postzone S4-P, PO Box 9600, Leiden, The Netherlands. Email: E.A.Tolner@ 123456lumc.nl
                Author information
                https://orcid.org/0000-0003-3492-9902
                Article
                10.1177_0333102419840643
                10.1177/0333102419840643
                6859601
                30922081
                e1265081-6e46-4d4b-a485-97127b058459
                © International Headache Society 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 22 December 2018
                : 28 February 2019
                : 4 March 2019
                Categories
                Reviews

                Neurology
                migraine,cortex,neuroimaging,neurophysiology,cortical spreading depolarization,functional connectivity

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