Disease Basis

Understanding migraine can be facilitated by grasping the basic neurobiology of head pain, its processing in the brain, and modulation by centers that facilitate or inhibit sensory transmission. In experimental animals the detailed anatomy of the connections of the pain-producing intracranial extracerebral vessels and the dura mater has built on the classical human observations of Wolff9 and others. It is crucial to remember that, while head pain can be an important manifestation of these disorders, for migraine in particular it is more accurate to think of it as a pansensory abnormality of processing, not simply a disorder generating pain signals.

The key structures whose input must be modulated when considering intracranial nociceptive processing are4:

* the large intracranial vessels and dura mater

* the peripheral terminals of the trigeminal nerve that innervate these structures

* the central terminals and second-order neurons of the caudal trigeminal nucleus and dorsal horns of C and C2, trigeminocervical complex.

6.16.2.1 Trigeminovascular System

The innervation of the large intracranial vessels and dura mater by the trigeminal nerve is known as the trigeminovascular system.10 The cranial parasympathetic autonomic innervation provides the basis for symptoms, such as lacrimation and nasal stuffiness, which are prominent in cluster headache and paroxysmal hemicrania, although they may also be seen in migraine. It is clear from human functional imaging studies that vascular changes in migraine and cluster headache are driven by these neural vasodilator systems, so that these headaches should be regarded as neurovascular.10 The concept of a primary vascular headache should be consigned to the dustbin of history since it neither explains the pathogenesis of what are complex central nervous system disorders, nor does it necessarily predict treatment outcomes. The term 'vascular headache' has no place in modern practice when referring to primary headache.5

6.16.2.2 Migraine Genetics

Migraine is an episodic syndrome of headache with sensory sensitivity, such as to light, sound, and head movement, probably due to dysfunction of aminergic brainstem/diencephalic sensory control systems.11 The first of the migraine genes identified was for familial hemiplegic migraine,12 in which about 50% of families13 have mutations in the gene for the CaV2.1 (a1A) subunit of the neuronal P/Q voltage-gated calcium channel. This finding and the clinical features of migraine suggest it might be part of the spectrum of diseases known as channelopathies,14 disorders involving dysfunction of voltage-gated channels. Subsequently identified migraine genes ATP1A2 (FHM2; chromosome 1q23), encoding a transmembrane transporter (a2-subunit of the Na+, K+-ATPase),15 and SCN1A, encoding the neuronal voltage-gated sodium channel NaV1.1 (FHM3; 2q24-),16 suggest that migraine aura at least may be better described as an ionopathy.

6.16.2.3 Migraine Aura

Migraine aura is defined as a focal neurological disturbance manifest as visual, sensory, or motor symptoms.3 It is seen in about 30% of patients,6 and it is neurally driven.17 The case for the aura being the human equivalent of the cortical spreading depression of Leao18 has been made.19 In humans visual aura has been described as affecting the visual field, suggesting the visual cortex, and it starts at the center of the visual field and propagates to the periphery at a speed of 3 mm min _ 1.20

6.16.2.4 Migraine Disorder Modulation of Afferent Traffic

Stimulation of nociceptive afferents in the superior sagittal sinus of the cat activates neurons in the ventrolateral periaqueductal gray (PAG) matter.21 PAG activation in turn feeds back to the trigeminocervical complex with an inhibitory influence. The PAG is clearly included in the area of activation seen in positron emission tomography (PET) studies in migraineurs,22 although the activation may be more generically antinociceptive.23 This typical negativefeedback system will be further considered below as a possible mechanism for the symptomatic manifestations of migraine.

Another potentially modulatory region activated by stimulation of nociceptive trigeminovascular input is the posterior hypothalamic gray.24 This area is crucially involved in several primary headaches, notably cluster headache,25 short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT),26 paroxysmal hemicrania,27 and hemicrania continua.28 Moreover, the clinical features of the premonitory phase,29 and other features of the disorder, suggest dopamine neuron involvement. Orexinergic neurons in the posterior hypothalamus can be both pro- and antinociceptive,30 offering a further possible region whose dysfunction might involve the perception of head pain.

6.16.2.4.1 Brain imaging in humans

Functional brain imaging with PET has demonstrated activation of the dorsal midbrain, including the PAG, and in the dorsal pons, that would include the nucleus locus coeruleus, in studies during migraine without aura.22 Dorsolateral pontine activation is seen with PET in spontaneous episodic31 and chronic migraine,32 and with nitrogylcerin-triggered attacks.33 These areas are active immediately after successful treatment of the headache but are not active interictally. The activation corresponds to the brain region causing migraine-like headache when stimulated in patients with electrodes implanted for pain control.34 Similarly, it had been noted35 that excess iron in the PAG of patients with episodic and chronic migraine, and chronic migraine, can develop after a bleed into a cavernoma in the region of the PAG35 or with a lesion of the pons.36

6.16.2.4.2 Animal experimental studies of sensory modulation

It has been shown in the experimental animal that stimulation of nucleus locus coeruleus, the main central noradrenergic nucleus, reduces cerebral blood flow in a frequency-dependent manner through an a2-adrenoceptor-linked mechanism.37 This reduction is maximal in the occipital cortex.38 In addition the main serotonin-containing nucleus in the brainstem, the midbrain dorsal raphe nucleus, can increase cerebral blood flow when activated.11 Furthermore, stimulation of PAG will inhibit sagittal sinus-evoked trigeminal neuronal activity in cat while blockade of P/Q-type voltage-gated Ca2 + channels in the PAG facilitates trigeminovascular nociceptive processing39 with the local GABAergic system in the PAG still intact.21

The Prevention and Treatment of Headaches

The Prevention and Treatment of Headaches

Are Constant Headaches Making Your Life Stressful? Discover Proven Methods For Eliminating Even The Most Powerful Of Headaches, It’s Easier Than You Think… Stop Chronic Migraine Pain and Tension Headaches From Destroying Your Life… Proven steps anyone can take to overcome even the worst chronic head pain…

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