The Cerebellum and Migraine

Maurice Vincent, MD, PhD; Nouchine Hadjikhani, MD


Headache. 2007;47(6):820-833. 

In This Article

Abstract and Introduction

Clinical and pathophysiological evidences connect migraine and the cerebellum. Literature on documented cerebellar abnormalities in migraine, however, is relatively sparse. Cerebellar involvement may be observed in 4 types of migraines: in the widespread migraine with aura (MWA) and migraine without aura (MWoA) forms; in particular subtypes of migraine such as basilar-type migraine (BTM); and in the genetically driven autosomal dominant familial hemiplegic migraine (FHM) forms. Cerebellar dysfunction in migraineurs varies largely in severity, and may be subclinical. Purkinje cells express calcium channels that are related to the pathophysiology of both inherited forms of migraine and primary ataxias, mostly spinal cerebellar ataxia type 6 (SCA-6) and episodic ataxia type 2 (EA-2). Genetically driven ion channels dysfunction leads to hyperexcitability in the brain and cerebellum, possibly facilitating spreading depression waves in both locations. This review focuses on the cerebellar involvement in migraine, the relevant ataxias and their association with this primary headache, and discusses some of the pathophysiological processes putatively underlying these diseases.

Migraine is a common disease that affects 10 to 12% of the population and is considered by the World Health Organization as one of the most disabling neurological disorders.[1] Migraine attacks typically occur in varying intervals, each lasting 4 to 72 hours by definition. The unilateral, mostly side-shifting throbbing pain, located predominantly to the frontal parts of the cranium, may be intense enough to interrupt daily activity and worsens with physical activity. Nausea, vomiting, photo and phonophobia frequently accompany the annoying moderate to severe pain. A series of different neurological focal abnormalities named aura (from the Greek "breath," gentle breeze), mostly visual in nature, but also sometimes sensory, motor, or dysphasic, may occur in close association with the pain, typically before the headache onset.[2] The International Headache Society (IHS) classifies migraine headaches, among other less frequent subtypes, as migraine with aura (MWA), or migraine without aura (MWoA), according to the presence of aura symptoms.[3]

The mechanisms underlying migraine attacks remain fairly unknown, although accumulating data have demonstrated that this ailment is a primary brain disorder.[4] A dispute whether migraine had either a nervous or a vascular origin, polarizing the 2 so-called "vascular" and "neuronal" theories, has been present for many years,[5] but the central nervous system more probably seems be the ultimate source of migraine. The hitherto suitable vascular theory, which popularized the expression "vascular headache," has been challenged by the information that aura and headache did not parallel changes in the vasculature.[6] The possibility that abnormal brain hyperexcitability primarily originates migraine attacks is now widely accepted,[7] and the disease threshold, at least partially, seems to be determined by genetic predisposition.[8] The hyperexcitability has been confirmed by the relatively higher susceptibility of the migrainous cortex to phosphene induction secondary to transcranial magnetic stimulation.[9] It seems, therefore, that the vascular responses take place because of primarily triggered events in the nervous system intimacy.

Spreading depression (SD) consists of a spreading wave of depolarization associated with a reduction of the cortical activity that lasts for minutes with a propagation speed of around 3 mm/min. The expression "cortical spreading depression" (CSD) is widespread, but since this phenomenon is not exclusively cortical -- it has been recorded in various tissues including the basal ganglia and thalamus,[10,11] cerebellum,[12,13,14,15] tectum and olfactory bulb,[12] retina,[16,17,18,19,20,21,22] and spinal cord[23] -- we believe that "spreading depression" is a better denomination.

In 1945, Leão and Morrison suggested for the first time that SD could be related to the pathophysiology of migraine[24] and Leão postulated that circulatory changes were in close connection with SD waves.[25] SD compatible circulatory changes were subsequently found in migraineurs, making the possibility of SD being an important phenomenon in this disease even more attractive.[6] SD is accompanied by an initial hyperperfusion, followed by prolonged and pronounced spreading hypoperfusion.[26] The genetically hyperexcitable brain in migraine probably facilitates paroxysms of SD-like phenomena initiating each of them the cascade of events ultimately leading to the attacks. Functional imaging studies support the possibility of SD underlying migraine episodes.[27] The trigeminovascular system comprised of the trigeminal fibers innervating meningeal and brain vessels is activated by SD,[28] leading to plasma extravasation and vasodilatation (neurogenic inflammation) in the dura mater.[29] The ability of triptans, a class of 5-HT1 agonists, to block neurogenic inflammation and neuropeptide release centrally, has supported the defense of its use as effective antimigraine agents.[30,31,32]

Although Herophilus (335 to 280 B.C.) is usually cited for firstly recognizing the cerebellum (from Latin, "small brain") as distinct from the brain, Aristotle did so before ("The history of animals" book I, part XVI, 350 B.C.). Galen (131 to 200 A.D.) called the vermis "the worm-like outgrowth," Luigi Rolando (1773 to 1831) concluded the cerebellum was a motor structure, and Marie-Jean-Pierre Flourens (1794 to 1867) finally linked the cerebellum to coordination.[33,34] The relatively simpler structure of the cerebellum is highly specific and uniform, with cells arranged in layers in the cerebellar cortex connected each other by a repetitive microcircuitry.[35] The Purkinje cells are the source of cerebellar output. Therefore, malfunction in Purkinje cells severely impairs motor planning and coordination.


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