New findings shed light on the link between the neurological symptoms of aura and subsequent migraines, unveiling potential new proteins that could be key in developing innovative migraine therapies.
Recent research unveils how disruptions and fluid flow in the brain trigger headaches, revealing the connection between aura-related neurological symptoms and migraines. Additionally, new proteins identified in the study may pave the way for novel migraine treatments.
“This study delves into the relationship between the central and peripheral nervous systems, fueled by heightened protein levels released in the brain during spreading depolarization – the process behind migraine auras,” stated lead author Maiken Nedergaard, MD, DMSc, co-director of the University of Rochester Center for Translational Neuromedicine. The study, featured in the journal Science, offers fresh targets to modulate sensory nerve activation for migraine prevention and treatment.
About one in ten individuals experience migraines, with about a quarter of them encountering aura-related symptoms preceding the headache. Aura symptoms like light flashes, blind spots, double vision, and sensory disturbances often precede migraines by five to sixty minutes.
The aura stems from cortical spreading depression, a temporary neuron and cell depolarization triggered by glutamate and potassium diffusion, leading to reduced oxygen levels and blood flow in the brain. Typically, this depolarization event occurs in the brain’s visual processing center, manifesting as visual symptoms signaling an impending headache.
Although migraines originate in the brain, the brain itself cannot sense pain. Instead, pain signals are relayed from the brain via the central nervous system to the peripheral nervous system, responsible for transmitting information between the brain and the body, including sensory nerves for touch and pain sensation.
Insights from Fluid Dynamics Models on Migraine Origin
Nedergaard and collaborators at the University of Rochester and the University of Copenhagen have pioneered the understanding of brain fluid dynamics. In 2012, their lab unveiled the glymphatic system, which employs cerebrospinal fluid (CSF) to clear toxic brain proteins. By partnering with fluid dynamics experts, they’ve created detailed models of CSF movement in the brain and its role in transporting proteins and chemicals.
The prevailing theory implicates nerve endings surrounding brain membranes in post-aura headaches. However, the new study, conducted in mice, identifies a different pathway pinpointing proteins – potential drug targets – responsible for nerve activation and pain.
As the depolarization wave spreads, neurons release various inflammatory and other proteins into the CSF. Through mouse experiments, researchers demonstrated how CSF ferries these proteins to the trigeminal ganglion, a nerve cluster at the skull base supplying sensory inputs to the head and face.
While it was previously believed that the trigeminal ganglion, akin to the peripheral nervous system, lay outside the blood-brain barrier, researchers discovered a gap allowing CSF direct access to the ganglion, exposing sensory nerves to brain-released proteins.
Elevated Migraine-Associated Proteins during Brain Activity
Analysis identified twelve ligand proteins binding to receptors on trigeminal sensory nerves, potentially activating these cells. Post-cortical spreading depression, concentrations of several such proteins in CSF more than doubled. For instance, calcitonin gene-related peptide (CGRP), targeted by a new class of migraine drugs (CGRP inhibitors), was one of these proteins. Other identified proteins play roles in pain conditions like neuropathic pain, likely being crucial in migraines too.
“We’ve uncovered a new signaling pathway and molecules activating peripheral sensory nerves. Some of these molecules are already linked to migraines, but their specific migraine-inducing actions were unknown,” noted study first author Martin Kaag Rasmussen, PhD, a postdoctoral fellow. “Understanding these ligand-receptor pairs could unveil new drug targets, benefiting patients unresponsive to current treatments.”
Researchers noticed that proteins released in one brain hemisphere mostly affect nerves in the corresponding trigeminal ganglion side, elucidating why migraines often manifest on one side of the head.
Additional contributors include researchers from the University of Copenhagen, URMC, and the National Institute of Neurological Disorders and Stroke (NINDS). Funding support came from various foundations and institutions.
