Written accounts of migraine are nearly as old as writing itself. Descriptions of headaches, dating to roughly 3000 BCE, have been found in the ruins of the ancient Sumerian civilization. When people lacked the understanding of the human body that modern medicine grants us, migraine pain was ascribed to the will of evil spirits or malevolent gods — doctors of the time recommended cranial trepanation as a way to release “unholy forces.” In the early seventeenth century, European clinicians first proposed the vascular hypothesis, which long dominated our views of migraine. Patients’ descriptions of the pulsating character of migraine pain led to the concept that the vasculature might play a central role in the severe headache typical of migraine (1
It was the Canadian psychologist Peter Milner who, in 1958, first noted the striking similarities between the progression of migraine aura and cortical spreading depression (CSD). CSD is a self-propagating wave of tissue depolarization that migrates without a loss in depolarization amplitude and is followed by a prolonged period of suppressed neural activity (2
). Milner saw the connection between this and the migraine aura, because it was known that the scintillating scotomata (often manifesting as flashes of light in a geometric pattern that slowly move across the visual field) that precede and accompany migraine pain propagate at a rate of about 3 mm/min through the visual cortex (3
). It is now generally accepted that CSD constitutes the biological basis of most, if not all, types of migraine. Approximately 30% of migraine patients experience this aura (4
). The idea that CSD is the endogenous trigger of migraine was initially met with considerable skepticism; one article of the time called this theory “ingenious, if absurd” (quoted in ref. 5
). One obvious issue noted was that the brain itself is not capable of sensing pain. Thus, how might a transient wave of cortical depolarization give rise to the prolonged state of pain that clearly involves the vasculature? Insight came from Moskowitz and coworkers, who showed that CSD induces long-lasting changes in extracranial blood flow, including dilatation of the middle meningeal artery and extravasation of plasma protein (6
). In short, CSD disrupted the blood-brain barrier, resulting in MMP9-dependent pathway–mediated extravasation of blood-borne factors, which in turn activated the nociceptive nerve afferent fibers around meningeal vessels (6
) (Figure ). Additional pathways, including those involving gap junctions, cytokines, and NO release, may contribute to the activation of trigeminal ganglion nerve afferents and to the prolonged pain associated with migraine headaches (7
). Migraine without aura may result from advancement of CSD waves in regions (such as cerebellum) where the tissue depolarization is not perceived by the patient.
The link between CSD and migraine pain.
The initial skepticism surrounding CSD as an endogenous trigger of migraine pain has vanished in recent years, because functional MRI imaging of changes in blood oxygen level–dependent (BOLD) signal have shown that the visual aura of migraine is temporally linked to a slowly advancing wave of BOLD signal, which propagates across the visual cortex. The pattern of changes of BOLD signals a patient experienced during visual aura proved identical to those that were observed in experimentally elicited CSD (9
). Additional evidence was obtained by magnetoencephalography, which documented that visual scotomata were accompanied by slow changes in the cortical magnetic field, and these were indistinguishable from those recorded during CSD (10
). An important question thereby arose: What is the nature of the trigger for spontaneous waves of CSD, antecedent to or accompanying a migraine episode? Experimentally, strong focal stimulation is needed to evoke CSD. Various approaches have been used, including inserting a needle into the exposed cortex, electrical stimulation, or topical application of high K+
concentrations or glutamate agonists (e.g., NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]) (11
). It is also known that multiple waves of CSD often are spontaneously elicited in the setting of acute neurological injury, including stroke or head trauma (12
). Interestingly, the CSD waves last longer in the ischemic brain, and the frequency with which they are generated correlates with the degree of ischemic damage (13
). However, stroke or head trauma is not responsible for the CSD waves in patients with migraine, making it difficult to explain how and why CSD is initiated in the absence of focal stimulation.