Welcome to the WCN 2023 Interactive Program

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Correct Title: HOW DO PERIPHERALLY ACTING DRUGS ALTER BRAIN FUNCTIONs AFFECTED BY MIGRAINE?

The unique features of the ‘migraine brain’ are well recognized. What is not well recognized is whether the abnormally hypersensitive, hyperresponsive and hyperexcitable ‘migraine brain’ is hereditarily pre-determined or whether it is the result of being exposed relentlessly to incoming pain signals that invade multiple brain areas that regulate physiological and emotional homeostesis, sensory perception, autonomic functions, and cognition. The effectiveness of migraine prophylactic drugs whose site of action is primarily (if not exclusively) outside the brain allows us to begin tackling these questions. The lecture will feature a series of studies that explain how peripherally acting drugs reverse some of the structural and functional changes seen in the brain of chronic and high-frequency episodic migraine patients. Presented data show that when peripherally-acting drugs reduce the magnitude, duration and intensity of pain signals that reach the brain, gray matter volume of multiple cortical areas begins to decrease within 3 months, and if treatment effectiveness is maintained over 6-9 more months, premonitory symptoms disappear and common migraine triggers no longer trigger the headache. The conclusion of this talk will emphasize the fundamental differences between site of action (defined as the site where the drugs work) and mechanism of action (defined as the process that prevents the brain from initiating a migraine attack).

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Migraine, a prevalent neurological disorder, presents a complex challenge to understanding its underlying mechanisms. Recent progress in neuroimaging has facilitated significant insights into migraine pathophysiology. Multimodal imaging or the combination of different imaging modalities, has emerged as a powerful tool for the comprehensive assessment of structural, functional, and molecular changes in the brain.

By integrating multiple imaging modalities, multimodal imaging offers a comprehensive understanding of migraine's complex neurobiology. It identifies specific brain regions and networks involved in migraine pathophysiology, opening avenues for potential therapeutic targets. Moreover, multimodal imaging holds promise for developing diagnostic and prognostic biomarkers, aiding personalized treatment strategies.

This lecture reviews recent advances in multimodal imaging techniques for the study of migraine. It highlights the contributions of the different imaging modalities, outlines the challenges and discusses future directions in the application of multimodal imaging in migraine research and clinical practice.

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Despite the development of multiple new migraine therapeutics, there is still need for new therapeutics with distinct mechanisms for those who are not adequately treated with any current drug class. Two promising targets are the protease-activated receptor type 2 (PAR-2) and ATP-sensitive potassium (K_ATP) channels. Degranulation of mast cells has been proposed as a sterile inflammatory process in the meninges that may contribute to the headache phase of migraine. Degranulating mast cells release tryptase which cleaves and activates PAR-2, thus initiating signaling in meningeal nociceptors. PAR-2 is also activated by other proteases such as elastase released from neutrophils, and this may similarly activate meningeal nociceptive signaling. Since this receptor is expressed on nociceptors containing CGRP, it may be an upstream mechanism leading to the release of CGRP, and targeting such upstream mechanisms may offer differential or increased efficacy in migraine therapy. Human studies have shown that administration of openers of K_ATP channels such as levcromakalim can trigger migraine attacks in nearly 100% of people with migraine. This strongly suggests a role for these channels in migraine pathology, but the location and mechanism of their action is not clear. This presentation will show data from preclinical rodent models of migraine that demonstrate a mechanistic role for PAR-2 and K_ATP channels in the meninges, leading to behavioral responses consistent with headache. Overall, this lecture will cover the background and rationale for investigation of these targets, new data from animal models, and the need for further investigation of these targets for migraine therapeutics.