Table 1.
Clinical studies providing information about the temporal relation between aura and headache symptoms in patients with migraine with aura.
Fig 1.
Initiation and propagation of spreading depolarization.
(A) A visual migraine aura in the form of a gradually developing scintillating scotoma (adopted from Airy, Phil. Trans. R. Soc. 1870) [41], reflecting a spreading depolarization (SD) wave propagating in the visual cortex. (B) Occipital cortex (c) and its anatomical relation to the subarachnoid space (sas) with pial blood vessels, the meninges, and the skull. (C) Close-up view of the cerebral cortex, containing neurons and glial cells (only astrocytes and microglia depicted here). The initiation of SD in migraine is still poorly understood but it is likely that a combination of strong excitatory activity, reduced inhibitory activity, and/or reduced clearance of excitatory substances, perhaps in combination with metabolic compromise, is required to simultaneously depolarize a minimum critical volume of gray matter (lightning bolt), raising the extracellular [K+] to above approximately 12 mM. Recent work shows that along with K+ release, there are large glutamate (Glu) release events that likely interact with [K+] elevation to form a nidus of SD initiation. Mechanisms that help buffer extracellular [K+] and excitatory neurotransmitters, such as astrocytic uptake of K+ and glutamate, limit SD initiation and propagation. When a critical threshold is reached, neuronal membrane resistance is rapidly lost due to a large cation conductance, resulting in a massive K+ efflux raising the extracellular K+ concentration to 20–60 mM. Meanwhile, influx of Na+, Ca2+, and water leads to marked cell swelling and release of neurotransmitters, including Glu, to the extracellular space. The resulting increased extracellular [K+] and concentration of excitatory neurotransmitter triggers the same reaction in neighboring neurons and glial cells. In this way, SD spreads as a wave of tissue depolarization traveling at a slow rate of 2–5 mm/min through contiguous gray matter. (D) The depolarizing wave and associated K+ efflux is accompanied by a dramatic change of the local electrical potential (Ve). In otherwise normal brains, the disturbance is self-limiting and apparently harmless, and after a few minutes, normal cellular ion homeostasis is re-established, though other parameters such as neurovascular coupling can take over an hour to return to normal. Note the logarithmic scale. Adapted from Hansen and Zeuthen (Acta Physiol Scand, 1981) [35]. Created with Biorender.
Fig 2.
A simplified overview of proposed mechanisms underlying different phases of a migraine attack.
Premonitory symptoms (green) – symptoms occurring up to 48 h before headache onset in a subset of patients – have been suggested to arise from the hypothalamus or other diencephalic structures, although their origin is largely unknown. The migraine aura (red), which usually precedes the onset of migraine headache, represents spreading depolarization propagating in eloquent cerebral cortex. Migraine headache (blue) may, in a minority of patients, start before the aura symptoms. The head pain of migraine is believed to depend on sensory input from activated meningeal nociceptors, involving the release of vasoactive peptides and vasodilation. Nociceptive signals project to central pain pathways via the trigeminal ganglion and upper cervical sensory ganglia (the latter not depicted). Note that structures believed to be involved in the premonitory and aura symptoms are protected by the blood–brain barrier, while structures involved in the nociceptive pathway are located inside as well as outside of the blood–brain barrier. Created with Biorender.
Table 2.
Experimental migraine provocation studies including migraine patients with aura.