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Pathophysiology

 

 

The pathophysiology of migraine is not fully understood (25). Recent studies have shed light on the neuronal events mediating the aura and headache phases of migraine. Spreading Cortical depression (SCD) appears to underlie the aura phase in patients with migraine with aura (26, 27), and it may also precede headache in patients with migraine without aura. Recent evidence suggests that the pain of the headache phase is mediated by the trigeminal vascular system and its central projections. (28)

Mechanism of the aura

One fifth of migraineurs experience aura, predominantly visual in nature, before headache onset. (29) The mechanism mediating aura is considered a human analogue to the cortical phenomenon of spreading depression first observed by Leao in 1944(30,31) and Lashley (32)  who calculated  the growth of his own migrainous fortification spectrum corresponding to an event moving across the cortex at a rate of 2 to 3mm/minute.(30,31,32)

Cortical stimulation initiates excitation followed by depression of normal neuronal activity that spreads slowly from the focal site of stimulation at rates between 2 and 6 mm per minute. the phase of oligemia  begins in one occipital pole and spreads forward over the ipsilat­eral hemisphere .Spreading depression does not follow vascular boundaries but crosses the areas perfused by the middle and posterior cerebral arteries while advancing with a distinct wave front until some major change in cortical cellular architecture is reached (e.g.; at the central sulcus) (33)

Olesen and Lauritzen (34,35,36), using Xe single photon emission computed  tomography (SPECT) found 17% to 35% reductions in CBF in posterior regions of the brain, which spreads anteriorly across contiguous areas of cortex at a rate of about 2 to 3mm per minute. It crossed isolated vascular territories and is thus not due to segmental vasoconstriction. Reduced CBF persisted from 30 minutes to 6 hours, then slowly returned to baseline or even increased. Focal hyperemia at times preceded the hypoperfusion. The rate of progression of spreading oligemia are similar to those of migrainous scotoma and CSD, suggesting that these phenomena are related (37).

 

Additional studies using single photon emission tomography (38, 39, 40), positron emission tomography (41) and MRI (42) support the hypothesis that CSD is the basis for the migraine aura. (43)

 

 

 

 

 

 

 

 

 

 

 

 

Figure (1) showing illustrative diagram of the cortical spreading depression(245)

 

Although the cerebral cortex is insensitive to pain, it initiates a painful phenomenon. This stimulated many research to study this point. Bolay et al (44) demonstrated increase in flow of the middle meningeal artery (MMA) after SCD, which was produced by trauma. To clarify the mechanisms underlying these events the trigeminal nerve was transected and demonstrated lack of the delayed phase of increased blood flow in MMA. Furthermore the expression of c-fos - a surrogate marker of pain - was increased in lamina I and II in trigeminal nucleus caudalis. There was also plasma protein extravasation noted in the experiment which was noted to be mediated by neurokinin I. This Important study clearly demonstrated the link between head pain of migraine and SCD( the putative mechanism of aura).

 

 

 

Genesis of the headache syndrome

 

Stimulation of the large cranial vessels and dura mater has long been known to cause headache pain in humans (43). Afferent fibers from these intracranial sites project through the ophthalmic tract of the trigeminal nerve, with cell bodies in the trigeminal ganglion. The trigeminal ganglion neurons also project to the trigeminal nucleus caudalis of the brainstem, C1 and C2 regions of the spinal cord. Together, these trigeminal neurons and the innervated intracranial structures comprise the trigeminovascular system(45,46,47).The vasodilator peptides calcitonin gene-related peptide (CGRP), substance P, and neurokinin A are found in the cell bodies of trigeminal neurons. (48)

 Stimulation of the trigeminal ganglion in cats and humans treated for trigeminal neuralgia leads to an increase in release of these neuropeptides. (49) Venous concentrations of CGRP but not substance P increase during the headache phase of migraine. (50)

CGRP infusion triggers headaches, some migraine-like, in humans, (51) and stimulation of the pain-producing superior sagittal sinus results in release of CGRP, but not substance P. Furthermore, CGRP levels in humans decrease as headache subsides after administration of the antimigraine agent sumatriptan. (52) These observations indicate that venous levels of CGRP may be used as a marker for migraine. Further studies are needed to elucidate the CGRP-mediated mechanisms responsible for migraine headache (53).

      Stimulation of trigeminal sensory neurons induces inflammation and plasma protein extravasation (PPE). (54)The vasoactive peptides substance P and neurokinin A, released by the trigeminovascular system, cause PPE from the vessels, mast cell degranulation, platelet adherence and aggregation, endothelial activation, and formation of endothelial vesicles, microvilli, and vacuoles.(55) The result is meningeal inflammation that persists for minutes to hours. The antimigraine agents sumatriptan, ergotamine, dihydroergotamine, and methysergide have been shown to block this PPE, thereby reducing neurogenic inflammation. (54)

Although trigeminal ganglion stimulation elicits PPE in animals. it is not clear whether PPE and meningeal inflammation occur in humans during migraine. Because it is not possible to measure changes in PPE in humans directly. Studies of the pharmacology of sumatriptan and related 5-HT1B/1D receptor agonists question the role of PPE in migraine. (56)

The anatomy of the projections to the trigeminocervical complex can explain several clinical aspects of migraine. Patients with primary headache complain of pain that does not respect the cutaneous boundaries of either the trigeminal or the cervical nerves. The diffuse pattern of nerve activation in the trigeminocervical complex in response to superior sagittal sinus stimulation shows great anatomic overlap with innervation from other intracranial vessels (57)

      Brainstem activation occurs in attacks of spontaneous migraine without aura. Using PET, in patients with only right sided migraine headache, regional cerebral blood flow (rCBF) was increased bilaterally in the cingulate, auditory association, and visual association cortices, and on the left side only in the inferior anterocaudal cingulate cortex. There was increased rCBF in the left brainstem, anterior to the aqueduct, and posterior to the corticospinal tract. Sumatriptan relieved the headache and its associated symptoms and reversed the cerebral but not the brainstem increase in rCBF. Since the rCBF increase in the brainstem persisted despite resolution of the headache, it seems likely that the activation is due to factors other than, or in addition to, increased activity of the endogenous antinociceptive system in the periaqueductal grey and locus caeruleus. Activation of the brainstem may be inherent in the migraine process itself. (58)

Welch et al. (59) have proposed a theory of central neuronal hyperexcitability. Although the pathways mediating headache pain may be the same in all individuals, these pathways are thought to be more easily triggered in patients with episodic migraines. Several findings support this view. Interictal differences in brain activity between healthy individuals and migraineurs appears in  studies showing that the level of transcranial magnetic stimulation to the occipital cortex required to produce phosphene generation is substantially lower in patients with migraines with aura between their headaches than it is in healthy controls. (60, 61, 62)

Serotonin (5-HT) Receptors and Migraine

Serotonin (5-HT) receptors consist of at least three distinct types of molecular

Structures:

Ř      Guanine nucleotide G protein-coupled receptors,

Ř      Ligand-gated ion channels,

Ř      Transporters.

 

There are seven classes of 5-HT receptors: 5-HT1, 5-HT2, 5-HT3, 5-HT4,

5-HT5, 5-HT6, and 5-HT7. In humans, there are five 5-HT1 receptor subtypes:

5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. (6)

 

The 5-HT1B receptor is located on intracranial blood vessels and CNS neurons. The 5-HT1D receptor is located on CNS neurons and trigeminal nerve endings. 5-HT1F receptors are located on trigeminal nerve endings.(64)The ergots and triptans act at the 5-HT1B, 5-HT1D, and in part at the 5-HT1F receptors. They can constrict extracerebral intracranial vessels, inhibit activity in peripheral trigeminal neurons, and block transmission in the trigeminal nucleus.

 

Triptans minimally constrict the human coronary artery. Triptans and ergots block neurogenic PPE, (65) presumably by activating prejunctional trigeminal 5-HT1D and 5-HT1F heteroreceptors, blocking neuropeptide release. Neurogenic PPE can be also be blocked by NSAIDs, GABA agonists (valproate). They also reduce activity of second order trigeminal neurons through 5-HT1D and/or 5-HT1B receptors. Dihydroergotamine (DHE) and the centrally penetrating triptans pass through the blood-brain barrier and label nuclei in the brainstem and spinal cord that are intimately involved in pain transmission and modulation. The caudal trigeminal nucleus is activated by stimulation of the sagittal sinus, and this activity is transmitted to the thalamus. Ergots and triptans suppress this activation. (66)