Emerging Mechanisms in Migraine and Headache Disorders

Headache disorders are a leading cause of pain and disability worldwide. This panel will highlight novel mechanisms underlying migraine pathophysiology and new approaches to identify and validate drug targets. The panelists include international experts in the field of headache and include female representation. This session will feature preclinical, translational, and clinical research that addresses fundamental mechanisms of broad relevance to headache and pain. Panelists are as follows:
1) Role of Perineuronal Nets in Migraine Chronicity – Professor Amynah Pradhan PhD (Washington University, USA). The extracellular matrix (ECM) surrounds all cells in the central nervous system and can regulate diffusion of neurotransmitters and guidance and growth of neuronal processes. Perineuronal nets (PNNs) are a specialized ECM structure that envelops a subset of parvalbumin positive interneurons in the brain. PNNs are dynamically regulated and subtle changes in PNN integrity can affect neuroplasticity and behavior. Our lab has recently identified a novel population of PNN+ cells enveloping parvalbumin+ neurons in the mesencephalic/midbrain reticular formation, which innervates several pain processing regions. We show that the integrity of these midbrain PNNs decreases in a model of chronic migraine, and that effective migraine treatments correspondingly result in reformation of these PNNs. We also find that degradation of these PNNs in naïve mice results in increased pain-like behaviors.
2) Evaluation of migraine targets using human sensory neurons – Professor Gregory Dussor PhD (UT Dallas, USA). Preclinical migraine studies in rodents have identified protease-activated receptor 2 (PAR2) and acid-sensing ion channels (ASICs) as potential therapeutic targets. Rodent sensory neurons express PAR2 in less than 5% of dorsal root (DRG) and trigeminal ganglia (TG) neurons. However, human DRG and TG show RNA and protein expression in 20% to 35% of neurons. Functional analysis, including among the first known patch-clamp electrophysiology recordings of cultured human TG, shows activity in similarly larger percentages of neurons. ASIC1 and ASIC3 are found in under 50% of rodent DRG and TG neurons but nearly 100% of human DRG neurons. Electrophysiology shows ASIC currents in nearly all cultured human DRG and TG. These substantial species differences suggest a broader role in human migraine and pain than previously recognized and demonstrate the importance of cross-species validation in target evaluation.
3) Glymphatics and meningeal lymphatics in headache disorders - Professor Shih-Pin Chen MD, PhD (National Yang Ming Chiao Tung University, Taiwan) The discovery of the glymphatic and meningeal lymphatic systems has reshaped how we think about headache disorders. These pathways, responsible for waste clearance and immune surveillance in the brain, open new perspectives on migraine, cluster headache, and other secondary headache disorders. Dysregulation of glymphatic flow and meningeal lymphatic drainage may contribute to neuroinflammation, altered intracranial homeostasis or neurovascular coupling, and potentially the development and persistence of headache symptoms. This talk will highlight insights from recent clinical and preclinical research, positioning headaches within the context of intracranial fluid dynamics and neural-immune interactions. The impact on the field is profound: linking sleep, neurovascular function, and immune activity to headache pathophysiology, and pointing toward novel diagnostic markers and therapeutic strategies.