ABSTRACT
Figure 4.3 Propagation of cortical spreading depression (CSD) across the surface of the cat brain in vivo. Top left, control, horizontal, gradient-echo anatomic image depicting the suprasylvian and marginal gyri. Remaining images (b - x): coloured overlays, shown at 10 s intervals starting about 50 s after KCI application, represent elliptical regions of reduced diffusion travelling away from the KCI application site with a velocity of 3.2 – 0.1 mm/min (mean – SEM of 5 measurements). Over the first eleven frames (b - 1) the wave travels both rostrally and caudally along the suprasylvian gyrus; when it reaches the caudal junction of the two gyri (m - s), it appears to pass into the marginal gyrus (t-x); likewise, rostrally, the wave passes first (r - x) into the ectosylvian gyrus where it dissipates (v-x) and then into the marginal gyrus (t-x). Waves were never detected in the contralateral hemisphere. A, anterior; P, posterior; R, right; L, left; overlays were obtained by subtracting a baseline image from the high-b images obtained in the DWEP sequence and transforming the signal difference into a percentage change (blue 5%, red 30%). Scale bar, 15 mm.This image represents the first reported detection of CSD with magnetic resonance imaging (MRI) in a species which shares with man a complex, gyrencephalic brain structure. Reproduced with permission from James MF, Smith MI, Bockhorst KH, et al. Cortical spreading depression in the gyrencephalic feline brain studied by magnetic resonance imaging. J Physiol 1999;519:415-25
Figure 4.4 Spreading depression: A model of migraine. Colored overlays of changes in blood oxygenation in an experimental model of cortical spreading depression. Overlays a-d represent the points 0.5, 1.0, 1.4 and 5.1 min post-induction. Reproduced with permission from James MF, Smith MI, Bockhorst KH, et al. Cortical spreading depression in the gyrencephalic feline brain studied by magnetic resonance imaging. J Physiol 1999;519:415-25
a b c d
Figure 4.5 Blood oxygenation level-dependent (BOLD) changes during an exercisetriggered migraine visual aura. Time-dependent BOLD activity changes from a single region of interest in the primary visual cortex (Vl), aquired before and during episodes of induced visual aura.The upper panel shows a series of anatomic images, including BOLD activity on ‘inflated’ cortical hemispheres showing the medial bank (similar to a conventional mid-sagittal view). Images were sampled at 32 s intervals, showing the same region of interest (circle) in VI.The lower panel shows the MR signal perturbation over time from the circled region of interest. Variations in time are color-coded (deep red to magenta) and the four-colored circles match corresponding times within the VI region of interest. Prior to the onset of the aura, the BOLD response to visual stimulation shows a normal, oscillating activation pattern. Following the onset of aura (red arrow), the BOLD response shows a marked increase in mean level and a marked suppression to light modulation followed by a partial recovery of the response to light modulation at a decreased mean level. Reproduced with kind permission of Margarita Sanchez del Rio
Figure 4.6 Spreading suppression of cortical activation during migraine visual aura. Data from the same patient as in Figure 4.5. The posterior medial aspect of the occipital lobe is shown in an ‘inflated cortex’ format. The cortical sulci and gyri appear in darker and lighter gray respectively,on a computationally inflated surface. MR signal changes over time are shown on the right. Each time course was recorded from one in a sequence of voxels which were sampled along the calcarine sulcus in V1, from the posterior pole to the more anterior location, as indicated by the arrow. A similar BOLD response was found within all the extrastriate areas, differing only in the time of onset of the MR perturbation. The MR perturbations developed earlier in the foveal representation, compared to the more eccentric representation of the retinotropic visual cortex. This was consistent with the progression of the aura from central to peripheral eccentricities in the corresponding visual field. Reproduced with kind permission of Margarita Sanchez del Rio
Figure 4.7 BOLD changes during spontaneous migraine visual aura. Data from a spontaneous attack captured approximately 18 min after the onset of the visual symptoms affecting the right hemifield.The data represent the time course in the left visual area V1, at an eccentricity of approximately 20º of visual angle. BOLD signal changes resemble the changes observed at a similar time point in Figure 4.5. Reproduced with kind permission of Margarita Sanchez del Rio
Figure 4.8 Perfusion weighted imaging (PWI) during migraine with aura attacks. PWI maps obtained at different time points during migraine with aura attacks during the presence of the stereotypical visual aura (patient I, approximately 20 min after onset of visual symptoms) and after resolution of the aura and into the headache phase (patients 2 and 3). In all cases a perfusion defect (decreased rCBF and rCBV, the latter not shown, and increased MTT) was observed in the occipital cortex contralateral to the visual field defect. rCBF, reduced cerebral blood flow; rCBV, regional cerebral blood volume; MTT, mean transit time. Reproduced with kind permission of Margarita Sanchez del Rio
Figure 4.9 Schematic representation of the primary sequence of the 5-HT2 receptor. Reproduced from Hartig PR. Molecular biology of 5-HT receptor. Trends Pharmacol Sci 1989;10:64-9, with permission from Elsevier Science
Figure 4.10 Trigeminal stimulation in the rat produces plasma protein extravasation. 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block this effect. (a) control; (b) stimulated. Reproduced from Buzzi MG, Dimitriadou V, Theoharides TC, Moskowitz MA. 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Res 1992;583:137-49, with permission from Elsevier Science
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Figure 4.11 Brainstem nuclei thought to be involved in migraine generation include the periaqueductal gray matter and dorsal raphe nucleus
Capsaicin
No brain stem/hypothalamic activation
Sinus z = - 32mm z = - 30mm
R
z = - 28mm
Z V
al ue
Figure 4.12 An experimental pain study was conducted in healthy volunteers to further test whether brain stem neuronal activation during migraine is specific to the generation of migraine symptoms. In this study, capsaicin was injected subcutaneously into the right forehead to evoke a painful burning sensation in the first division of the trigeminal nerve.The monoaminergic brain stem regions (raphe nucleus and the locus coeruleus) and the periaqueductal gray were not activated in the acute pain state compared to the painfree state.Thus, brain stem activation during a migraine attack is probably not a generalized response to head pain but instead represents sites in the nervous system that may give rise to migraine symptomatology. Adapted with permission from May A, Kaube H, Buchel C, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain 1998;74:61-6
*Areas of red indicate cerebral blood flow increases (p < 0.001)
Figure 4.13 The development of migraine, e.g. episodes in patients undergoing surgery to implant electrodes in the periaqueductal gray and raphe nuclei for the treatment of chronic pain, generated the hypothesis that CNS dysfunction early in the migraine attack could provoke changes in these brain stem nuclei.Weiller et al. used positron emission tomography (PET) to examine the changes in regional cerebral blood flow, an index of neuronal activity, during spontaneous migraine attacks. The left panel above is a PET scan from an individual during a migraine attack treated acutely with sumatriptan. The scan depicts neuronal activity in a section through the brain stem.The authors of this study reported that monoaminergic brain stem regions (raphe nucleus comprising serotonergic neurons and the locus coeruleus comprising noradrenergic neurons) and the periaqueductal gray are selectively activated during a migraine attack. When this patient used subcutaneous sumatriptan to acutely relieve his headache pain, the brain stem centers continued to appear active on the follow-up PET scans. By contrast, the anterior cingulate cortex, a region thought to be involved in processing affective components of pain, was also activated during spontaneous migraine attacks, and this activation was reduced concomitantly with headache pain relief after administration of sumatriptan. Taken together, these observations suggest that the raphe nucleus, locus coeruleus and the periaqueductal gray are regions that may be involved in the generation of headache pain and associated symptoms during a migraine attack. Adapted with permission from Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995;1:658-60
Figure 5.2 Migraine visual auras are very similar to epileptic visual hallucinations seen here. Reproduced from Panayiotopoulos CP. Elementary visual hallucinations in migraine and epilepsy. J Neurol Neurosurg Psychiatr 1994;57: 1371-4, with permission from the BMJ Publishing Group
Figure 5.1 Fortification spectra seen in migraine visual auras have been compared to the aerial view of the fortified, walled city of Palmanova, Italy. Reproduced with permission from Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. Oxford, UK: Isis Medical Media, 1998:64
Figure 4.14 Brainstem nuclei and their transmitters. Ach, acetylcholine; C2, second cervical segment of the spinal cord; CGRP, calcitonin gene-related peptide; CL, centrolateral nucleus of thalamus; CM, centromedial nucleus of thalamus; NA, noradrenaline; NKA, neurokinin A; NPY, neuropeptide Y; Otic, otic ganglion; PHI, peptide histidine isoleucine (methionine in man); POm, medial nucleus of the posterior complex; PYY, peptide YY; SCG, superior cervical ganglion; SP, substance P; SPG, sphenopalatine ganglion; SSN, superior salivatory nucleus; STN, spinal trigeminal nucleus; T2-3, second and third thoracic segments of the spinal cord; TNC, trigeminal nucleus caudalis;VII, seventh cranial nerve (parasympathetic outflow); VIP, vasoactive intestinal polypeptide; VPL, ventroposterolateral nucleus of thalamus; VPM, ventroposteromedial nucleus of thalamus; Vg, trigeminal ganglion; VI-3, first, second and third divisions of the trigeminal nerve.Reproduced with permission from Goadsby PJ, Zagami AS, Lambert GA.Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 1991;31:365-71
Figure 5.4 Paresthesias are the second most common migraine aura.Adapted from Spierings ELH. Symptomatology and pathogenesis. In: Management of Migraine. Boston, MA: Butterworth-Heinemann, 1996:7-19
Figure 5.3 (a) An artist’s representation of his visual disturbance during a migraine attack. In this the fortification spectrum is part of a formal design but still maintains a crescentic shape. There is also an associated partial visual loss. (b) An artist’s representation similar to one of the images in Sir William Gowers’ 1904 paper showing a progressive central scotoma with a jagged edge. The scotoma gradually increases to fill most of the central field. Reproduced with permission from Wilkinson M, Robinson D. Migraine art. Cephalalgia 1985;5:151-7
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Figure 5.5 Fortification spectra as depicted by Lashley. An arch of scintillating lights, usually but not always beginning near the point of fixation, may form into a herring bone-like pattern that expands to encompass an increasing portion of the visual hemifield. It migrates across the visual field with a scintillating edge of often zigzag, flashing or occasionally colored phenomena. Reproduced with permission from Lashley K. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatr 1941;46:331-9
Figure 5.6 Migraine aura. 1-4, Early stages of sinistral teichopsia beginning close to the sight point, as seen in the dark.The letter O marks the sight point in every figure; 5-8, a similar series of the early stages of sinistral teichopsia beginning a few degrees below and to the left of the sight point; 9, sinistral teichopsia fully developed. Beginning of a secondary attack, which never attains full development, until it arises on the opposite side
Left visual field Right visual field
beginning
Left visual field Right visual field
Figure 5.7 (a) and (b) Adapted from drawings by Professor Leao depicting an expanding hemianopsia as seen by a patient experiencing migraine visual aura, with kind permission of Luiz Paulo de Queiroz
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b
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Figure 5.8 (a) to (f) Adapted from drawings by Professor Leao depicting a variety of visual auras described by patients, with kind permission of Luiz Paulo de Queiroz
Figure 5.9 Motorist’s right-sided hemianopic loss of vision, the scotomatous area being surrounded by a crescentic area of brighter lights. Reproduced with permission from Wilkinson M, Robinson D. Migraine art. Cephalalgia 1985;5:151-7
Figure 5.10 Pathophysiologic mechanism and postulated anti-nociceptive site for sumatriptan and ergot alkaloids in vascular headaches.The triggers for headache activate perivascular trigeminal axons, which release vasoactive neuropeptides to promote neurogenic inflammation (vasodilation, plasma extravasation, mast cell degranulation). Ortho-and antidromic conduction along trigeminovascular fibers spreads the inflammatory response to adjacent tissues and transmits nociceptive information towards the trigeminal nucleus caudalis and higher brain centers for the registration of pain. TNC, trigeminal nucleus caudalis. Adapted from Moskowitz MA.Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 1992;13:307-11, with permission from Elsevier Science
5 HT1B receptors
1 Vasodilation
Cortex
Trigeminal ganglion
5-HT1D receptors4 Central pain transmission
2 Neuropeptide release - vasodilation - neurogenic inflammation
3 Pain signal transmission
Pain
Neurokinin A Substance P CGRP
Neuropeptides
Figure 5.11 A primary dysfunction of brain stem pain and vascular control centers elicits a cascade of secondary changes in vascular regulation within pain-producing intracranial structures that ultimately manifests in headache pain and associated symptoms. A synthesis of these views and observations forms the neurovascular hypothesis of migraine. It is critical to understand the anatomy of the trigeminal vascular system and the pathophysiologic events that arise during a migraine attack before considering the proposed mechanisms of action of acute therapies. Current theories suggest that there are several key steps in the generation of migraine pain: (1) Intracranial meningeal blood vessel dilation which activates perivascular sensory trigeminal nerves. (2) Vasoactive neuropeptide release from activated trigeminal sensory nerves.These peptides can worsen and perpetuate any existing vasodilation, setting up a vicious cycle that increases sensory nerve activation and intensifies headache pain.The peptides include substance P (increased vascular permeability), neurokinin A (dilation and permeability changes) and calcitonin gene-related peptide (CGRP; long-lasting vasodilation). (3) Pain impulses from activated peripheral sensory nerves are relayed to second-order sensory neurons within the trigeminal nucleus caudalis in the brain stem and upper cervical spinal cord (C1 and C2, trigeminocervical complex). (4) Headache pain signals ascend to the thalamus, via the quintothalamic tract which decussates in the brain stem, and on to higher cortical centers where migraine pain is registered and perceived.Adapted with permission from Hargreaves RJ, Shepheard SL. Pathophysiology of migraine – new insights. Can J Neurol Sci 1999;26(Suppl 3):S12-19
1 Activation of 5 HT1B
receptors
Cortex
Trigeminal ganglion
5-HT1D receptors trigeminal inhibition4 Inhibition of
central pain transmission
4 Neuropeptide release
3 Decreased pain transmission
2 Presynaptic 5-HT1D activation
Neurokinin A Substance P CGRP
Neuropeptides
Direct vasoconstriction
Inhibits neuropeptide release - blocks vasodilation - inhibits neurogenic
inflammation
Pain
Figure 5.12 Increased knowledge of 5-HT receptor distribution within the trigeminovascular system has led to the introduction of highly effective serotonergic anti-migraine drug therapies. Detailed molecular biology mapping of mRNA (RT-PCR and in situ hybridization) and immunohistochemical studies of recepter proteins have revealed populations of vasoconstrictor 5-HT1B receptors on the smooth muscle of human meningeal blood vessels.Thus, agonists of 5-HT1B receptors, which cause vasoconstriction, are ideally placed to reverse the dilation of meningeal vessels that is thought to occur during a migraine attack (see 1). 5-HT1B receptors have also been found on human coronary arteries making it important to establish the relative contribution of this subtype to the contractile response in coronary arteries compared with the target meningeal blood vessels. While 5-HT1F mRNA has also been demonstrated in human blood vessels, there appears to be no expression of functional receptors since 5-HT1F agonists appear devoid of vasoconstrictor effects. Immunohistochemical mapping studies on the localization of 5-HT1D and 5-HT1F receptor proteins in human trigeminal nerves have shown that 5-HT1D and 5-HT1F receptors are present on trigeminal nerves projecting peripherally to the dural vasculature and centrally to the brain stem trigeminal nuclei. Activation of such prejunctional receptors on nerve terminals can modulate neurotransmitter release. In this context, agonists of 5-HT1D and 5-HT1F receptors are ideally placed, peripherally (see 2) to inhibit activated trigeminal nerves and promote normalization of blood vessel caliber (by preventing the release of vasoactive neuropeptides) and centrally (see 3) to intercept pain signal transmission from the meningeal blood vessels to second-order sensory neurons in the trigeminal nucleus caudalis of the brain stem (see 4). Adapted with permission from Hargreaves RJ, Shepheard SL. Pathophysiology of migraine – new insights. Can J Neurol Sci 1999;26(Suppl 3):S12-19
Figure 5.13 5-HT1B/1D receptor immunoreactivity in human cranial and coronary arteries. The left column reveals positive immunofluorescence consistent with the presence of 5-HT1B receptors on the blood vessels, while the right column shows negative staining for 5-HT1D receptors. Therefore, it is the agonist effect at 5-HT1B receptors that results in vasoconstriction. Reproduced with permission from Longmore J, Razzaque Z, Shaw D, et al. Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistochemical demonstration of the involvement of 5-HTIB receptors. Br J Clin Pharmacol 1998;46:577-82
Figure 5.14 Results from a preclinical intravital microscope dural plasma protein extravasation (DPPE) assay that was used to investigate the anti-migraine action of rizatriptan.These videoframes show a branch of the middle meningeal artery embedded within the dura mater (running bottom left to top right of each section).The sequence shows the artery at baseline (left panel), in a dilated state after electrically evoked vasoactive neuropeptide release from the perivascular nerves (middle panel) and when normalized by drug treatment.
