The Cerebellum and Migraine

Maurice Vincent, MD, PhD; Nouchine Hadjikhani, MD


Headache. 2007;47(6):820-833. 

In This Article

Spreading Depression and the Cerebellum

Leão and Martins-Ferreira first published a 24 line note on SD in the cerebellum, quadrigeminal plate, and olfactory bulb[12] and mentioned that the cerebellum is naturally resistant to SD. Fifková et al described SD in the rat cerebellum[13] and Young wrote on the SD in the elasmobranch fish (Raja erinacea, Raja ocellata).[14] As also pointed by Nicholson in 1984, reviewing cerebellar SD in different species,[15] the cerebellum does not easily supports this phenomenon, unless some "conditioning" takes place. This may happen by raising the extracelullar K+, removing most of the NaCl, or replacing the chloride with another anion. During SD, extracellular calcium concentration falls, reflecting Ca2+ influx with consequent intracellular Ca2+ overload, that may, if sufficiently high, promote cell death.[130] Just as in the isolated retina and hippocampus, also in the turtle cerebellum SD occurs in the absence of blood flow, meaning that SD is not dependent on vascular or blood influence.[15] If cerebellar SD is related to EA-2, pH changes alone may be not sufficient for explaining the acetazolamide effect. Alternatively, SD could occur in the cerebellum through facilitating mechanisms not involving pH reduction.

Other cortical self-propagating waves with potential implications in cerebellar diseases and migraine have been demonstrated. Spreading acidification and depression (SAD) has been observed in the rat cerebellar cortex following suprathreshold electrical stimulation.[131] Substantial differences show that SAD and SD are not the same phenomenon. SAD spreads at a greater rate of 50 to 110 m/s, continues for 1 to 2 minutes, is accompanied by a powerful suppression of the pre and postsynaptic responses, with a refractory period of 90 seconds. Differently from SD, SAD induces no extracellular DC shift, do not change blood vessels and has a shorter recovery period. Besides, the conditioning required for SD in the cerebellum is not required to elicit SAD. While SD propagates radially outwards from the initiating point, SAD spreads perpendicularly to an activated beam of parallel fibers, which makes its spreading pattern dependent on the cerebellar cortex neuronal architecture. Pharmacologically, AMPA receptor blocking, which has little effect on SD, affects SAD, the opposite occurring with NMDA receptor blocking. SAD depends on extracellular Ca2+, while SD does not depend that strictly.[132] SAD has been implicated in the pathophysiology of EA-1, where pathology is related to a Kv1.1 voltage-gated potassium channel abnormality,[133] and is not likely to be involved with the cerebellar symptoms in migraine.

Astrocytes respond to glutamate with rapid calcium influx that propagate as waves from one cell to its neighbors.[134] The so-called calcium waves (CW) constitute a signaling system that allows astrocytes to rapidly activate adjacent astrocytes and neurons, through gap junctions, and extracellular messengers,[135,136] modulating synaptic transmission and neuronal activity.[137] CWs are also triggered by neuronal activity[138] and may be involved in blood flow regulation. CWs have been implicated in cortical spreading depression. They were demonstrated in cell cultures and tissue preparations in different cell populations,[139,140] and precede SD waves in hippocampal cultures.[141,142] Although these 2 forms of waves are related, SD does occur in calcium-free incubated hippocampal slices where CWs are abolished, demonstrating that the latter is not an obligatory requirement for the former.[142] Since FHM and the related CACNA1A mutations diseases directly involve calcium fluxing, it is tempting to consider that CWs associated with SD might have a pathophysiological role in this context.[143] The glutamate release induced by abnormal Cav2.1 channels in migraine could theoretically lead to not only SD, but also CW activation and further vasodilatation, contributing particularly to the phenotype of brain edema and coma following head trauma. The astrocytes' role in brain water homeostasis regulation[144] also supports this possibility.


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