- Email: [email protected]
Migraine, Pathophysiology of
Migraine, Pathophysiology of S Akerman, University of California San Francisco, San Francisco, CA, USA PJ Goadsby, Wellcome-NIHR Clinical Research Facility, King’s College Hospital, London, UK; and University of California San Francisco, San Francisco, CA, USA r 2014 Elsevier Inc. All rights reserved.
Introduction Migraine is a complex and disabling disorder of the brain. It is the most common disabling form of primary headache. It has a varied symptomatology that includes pain referred to the head, but it is the associated (nonpain) neurological features that make this disorder so complex and draws us to its likely pathophysiology. The clinical aspects of migraine, and other headache disorders, are defined according to the International Classification of Headache Disorders (2004). Additional clinical features can include premonitory symptoms such as fatigue, altered feeding, yawning, and sleep, to migraine aura, and those that occur usually with the head pain, such as nausea, vomiting, photo- and phonophobia, and cutaneous allodynia. This article will integrate these symptoms with the authors’ current understanding of the pathophysiology of migraine, including the physiology and pharmacology of peripheral and central aspects of the trigeminovascular system, the brainstem and diencephalic modulatory systems that influence processing of nociceptive information in the trigeminovascular system, and cortical sensory processing.
Trigeminovascular Anatomical Mechanisms Peripheral Connections Migraine clearly involves nociceptive pathways from the trigeminovascular system. The anatomy of the trigeminovascular system has been well described over the past 50 years. It includes the trigeminal (Gasserian) ganglion (TG) that has afferent projections to the trigeminal nucleus caudalis in the medullary spinal cord and an efferent projection, largely from the ophthalmic division of the TG, to the cranial blood vessels, including those of the pain-producing dura mater. This dural innervation is enriched for calcitonin gene-related peptide (CGRP), which may explain the lack of effect of substance P (SP), neurokinin-1 receptor antagonists in migraine. There is a reflex connection from the trigeminal nucleus to the parasympathetic outflow to the cranial vasculature (Figure 1). Although the brain is largely insensate, stimulation of dural structures, such as the superior sagittal sinus, is painful in humans and produces pain referred to the head, similar to headache. Stimulation of the TG in humans and cats results in the release of SP and CGRP, and in the cat increases cerebral blood flow, whereas in rodents this results in dural plasma extravasation. Stimulation of the more pain-producing dural sites in these animals causes greater increase in cerebral blood flow and release of only CGRP, but not substance P. Evidence from patients with severe migraine and those with nitric oxide (NO)-triggered migraine also show increase in only CGRP levels; moreover, both migraine and CGRP
Encyclopedia of the Neurological Sciences, Volume 3
levels are normalized with sumatriptan. Interestingly, molecules that failed to inhibit CGRP release in animal models, the extravasation inhibitors CP122,288 and 4991w93, also failed in the clinic, whereas the development of specific CGRP receptor antagonists has proven to be an effective treatment for migraine. Thus, an emerging therapy and reliable pathophysiological mechanism for migraine were established.
Central Activation In animal models, electrical or mechanical stimulation of the dural vasculature results in neuronal activation not only in the trigeminal nucleus caudalis but also in the C1 and C2 region of the cervical spinal cord. This region also receives direct inputs from the greater occipital nerve. It is thought that the trigeminal nucleus extends beyond its caudalis boundary to the dorsal horn of the higher cervical region in a functional continuum commonly described as the trigeminocervical complex (TCC). It is more likely that the common distribution of pain in migraine over the frontal and temporal regions, plus the involvement of parietal, occipital, and high cervical regions, may be explained by this functional convergence of neurons in the TCC. Experimental pharmacological studies show that abortive antimigraine drugs such as ergot derivatives, triptans, and CGRP receptor antagonists can all reduce neuronal activity on second-order trigeminal neurons, suggesting a possible locus of therapeutic action. Although it is acknowledged that stimulation and activation of meningeal nociceptors innervating the pain-producing intracranial structures is painful, and will cause vasodilation of intracranial vessel, it is hard to reconcile that this contributes solely to the pain in migraine. It is perhaps more likely that a reduction/dysfunction in the normal gating of the endogenous pain control pathway, within the brain that modulates trigeminovascular nociceptive processing, is responsible for the pain in migraine. Through this process, other areas of the brain may become sensitized and migraineurs’ response to external and centrally mediated triggers may be heightened.
Higher Central Pain Processing of the Trigeminovascular System The TCC is a key relay center for the transmission of nociceptive information from the cranial vasculature to the brainstem and higher pain-processing structures. Anatomically, the TCC makes ascending and receives descending connections with many higher brain structures. Animal studies that use dural stimulation demonstrate neuronal activation in areas of the brainstem including the ventrolateral periaqueductal gray (vlPAG), nuclei in the rostral ventromedial medulla (RVM), such as the nucleus raphe magnus, and pontine nuclei. Additionally, somatosensory and visceral nociceptive information from the
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Parasympathetic Trigeminal ACh, VIP, PACAP, NPY and NO
CGRP, SP NKA and PACAP
5-HT1D receptors Cortex 5-HT1B receptors
Thalamus A11
Hypothalamus
Cervical inputs
PAG
LC TG Pons SuS
5-HT1B/1D/1F receptors
RVM TCC
PG CG
Figure 1 The physiology and pharmacology of migraine (provided by Dr Philip R. Holland). The key pathways involved in the anatomy of migraine are the trigeminovascular inputs from the meningeal vessels, which pass through the trigeminal ganglion and synapse on the secondorder neurons in the trigeminocervical complex (TCC – purple neuron), as well as afferents from the cervical nerve via the cervical ganglion (CG – light blue). These neurons, in turn, ascend through the quintothalamic tract (dark blue neuron), and after decussating in the brainstem, they form synapses with neurons in the thalamus. There is a reflex connection with the parasympathetic outflow to the cranial vasculature via the superior salivatory nucleus (SuS), mediated through the pterygopalatine ganglion (PG – green neuron). These pathways are activated via the release of various neurotransmitters but predominantly via calcitonin gene-related peptide (CGRP). It is thought that the therapeutic action of triptans, 5HT1B/1D receptor agonists, is mainly through receptors located on pre- and postsynaptic sites in the central TCC, and peripherally on prejunctional nerve endings innervating dural arterial blood vessels, preventing the release of CGRP (via 5-HT1D receptors), and on the vessels themselves causing vasoconstriction (5-HT1B receptors). Brain imaging and experimental animal studies suggest that the importance of descending modulation (red neurons) of trigeminovascular nociceptive inputs comes from the rostral ventromedial medulla (RVM), periaqueductal gray (PAG), hypothalamus, and A11 nucleus. There are further ascending connections (blue neurons) from the TCC to the locus coeruleus (LC), PAG and hypothalamus, and indirectly to the cortex. The migraine pain system involves descending and ascending modulatory systems that help to define the pain and the associated triggers and symptoms that may explain the timeline of the clinical syndrome. ACh, acetylcholine; NKA, neurokinin A; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating peptide; SP, substance P; VIP, vasoactive intestinal peptide.
head and orofacial structures project directly to specific hypothalamic nuclei, via the trigeminohypothalamic tract, and are also activated by dural stimulation. Nociceptive signaling from the dural vasculature, processed via the TCC is relayed to the third-order neurons in the thalamus via the ‘quintothalamic tract.’ These trigeminovascular dural nociceptive inputs are predominantly processed in the ventroposteromedial (VPM)
nucleus in the thalamus, ventral periphery of the VPM, posterior thalamic nucleus, medial nucleus of the posterior complex, and intralaminar thalamus. It is an important translational validation that areas of neuronal activation in dural stimulation animal models are paralleled by central activation in patients during migraine. Positron emission tomography (PET) imaging of patients during both spontaneous and experimentally
Migraine, Pathophysiology of
triggered migraine demonstrates activation in the brainstem, including the pons and midbrain, the hypothalamus, thalamus, and cortex.
Cortical Processing of Trigeminovascular Information The processing of pain is complex and mediated by a network of neuronal structures called the ‘pain matrix,’ which includes the thalamus, primary and secondary somatosensory areas, the anterior cingulate cortex (ACC), and prefrontal cortex. They are active during nociceptive processing and involved in integrating this information. During migraine, PET imaging reveals that the ACC, frontal cortex, visual and auditory cortices, and thalamic nuclei contralateral to the side of pain are activated. It is thought that the VPM thalamus is the principal nucleus involved in relaying nociceptive information to the cortex. The data suggest that neurons of the cortex and thalamus are crucial to the higher level processing of the pain coming from the head.
Central Control of Trigeminovascular Nociceptive Traffic and Migraine Symptoms If migraine is a disorder of the brain and a consequence of reduction/dysfunction of the normal gating of the endogenous pain control pathway, is it then possible that changes in the brain can alter the processing of trigeminovascular nociceptive traffic and other migrainous symptoms? Weiller and colleagues’ observation in the 1990s that areas of the brainstem are active during migraine, specifically the dorsal midbrain and dorsal pons, might imply this. Interestingly, these areas that are active during pain remain active even after successful treatment. This may indicate that brainstem activity is not simply a response to pain but an underlying cause of this brain disorder. Many brainstem nuclei have bidirectional descending connections with the trigeminovascular system and ascending connections with ‘diencephalic’ structures involved in pain processing. These nuclei are ideally placed to affect both the trigeminovascular system and diencephalic nuclei thought to be responsible for nonpain symptoms of migraine.
Brainstem Nuclei The superior salivatory nucleus (SuS) in the pons receives a reflex connection with the trigeminal nucleus and contains the cell bodies of neurons that make up the parasympathetic autonomic vasodilator pathway. These neurons project through the greater petrosal branch of the facial (VIIth) nerve via the pterygopalatine ganglion (sphenopalatine in rodents) to the cranial vasculature. Activation of this pathway may cause autonomic symptoms during migraine and other primary headaches. In animal models, neurons within the SuS are activated after dural electrical stimulation. Stimulation of the SuS causes neuronal activation in the TCC as well as enhances light-responsive TCC activity. Also, stimulation of the SuS, the sphenopalatine ganglion, and the facial (VIIth) nerve all cause increases in cerebral blood flow, dilating blood vessels, and
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potentially activating trigeminal nerve endings. The SuS also has connections to the hypothalamus, as well as limbic and cortical areas, regions crucial in the regulation of sleep, stress, and food intake, and may trigger migraine and affect its symptomatology. The RVM is a cluster of neurons in the medulla thought to be involved in the descending control of the endogenous ‘opioid’ pain-processing pathway in the spinal dorsal horn. It is hypothesized that ‘on,’ ‘off,’ and ‘neutral cells’ in the RVM provide descending control of spinal nociceptive neurons.‘On’ cells facilitate firing of neurons that receive nociceptive inputs and are inhibited by opioids, whereas ‘off’ cells are tonically active and inhibit nociceptive inputs and are activated by opioids. The RVM may be involved in the modulation of trigeminovascular nociceptive traffic in migraine. Activation and central sensitization of trigeminovascular neurons, using an inflammatory soup applied to the dura mater of the rat, causes cutaneous facial hypersensitivity and allodynia in the ophthalmic dermatome. These responses are inhibited by the direct application of bupivacaine into the RVM. Electrophysiological recording in the RVM identified that ‘on’ cells were activated by the inflammatory soup applied to the dura mater, whereas ‘off’ cells were inhibited. Therefore, trigeminovascular nociceptive traffic may be under the control of the neurons descending from the RVM. The RVM makes direct bidirectional connections with the vlPAG. The dorsal midbrain region highlighted as active in many studies during migraine includes the vlPAG and therefore may be indicated in its pathophysiology. In animal experimental assays, dural evoked nociceptive activation in the TCC is inhibited by electrical stimulation of the vlPAG and local application of g-aminobutyric acid (GABAA) receptor antagonists as well as triptans, whereas blockade of the P/Q-type voltagegated Ca2þ channels facilitates these trigeminovascular nociceptive responses, independent of the local GABAergic system. A mutation of the CACNA1A gene that encodes the a1a subunit of the P/Q-type voltage-gated calcium channel is present in approximately 55% of patients with familial hemiplegic migraine. This inherited channelopathy mutation may contribute to the hemiplegic aura and may additionally implicate a dysfunction of the brainstem in migraine. The PAG is thought to modulate spinal and trigeminal nociceptive processing directly through the RVM. Until recently, it was believed that this pathway was involved exclusively in endogenous pain modulation through opioidmediated responses. However, this pathway responds to the activation of innocuous stimuli, motor activity, and homeostatic processes including sleep, feeding, and micturition. The RVM and PAG have connections with forebrain structures, including the hypothalamus, and through these connections they are hypothesized to be involved in the control of sensory, autonomic, and motor processes in the spinal cord across normal conditions and primed to prioritize responses to nociceptive inputs. Migraine triggers, such as sleep and food deprivation, are homeostatic processes that are, in some way, regulated by the PAG and RVM, whereas accompanying symptoms of migraine including altered feeding, the need for sleep, excessive urination, and the tendency to avoid activity could also be described as a consequence of changes in the processing of these brainstem structures. Taken as a whole,
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altered functioning in areas of the brainstem including the SuS, RVM, and PAG may gate nociceptive and nonnociceptive cranial and spinal sensory, autonomic and motor processing, and affect homeostatic balance contributing migraine symptoms and act as a migraine trigger.
Diencephalic Nuclei Imaging studies in migraineurs and other primary headaches have demonstrated activation of hypothalamic nuclei, particularly in the posterior region. Many of the clinical features associated with migraine triggers and premonitory symptoms, including sleep disturbance, changes in arousal, mood, food craving, thirst, and urination, would seem to be regulated by the hypothalamus and its controls of circadian rhythm and sleep–wake cycle. The hypothalamus is also involved in the descending control of spinal and trigeminal nociceptive responses through its bidirectional connections with many brainstem structures involved in pain processing and autonomic responses. In animal studies, posterior and ventromedial hypothalamic nuclei are activated after dural evoked trigeminovascular activation and sensitization. Interestingly, in awake animals, after trigeminovascular sensitization, their feeding is altered for many hours when levels of the anorective peptide cholecystokinin B receptor are increased. Orexin A and B are hypothalamic neuropeptides involved in feeding, sleep–wake cycle, and hormone regulation. Orexin A inhibits peripheral and central dural evoked trigeminovascular nociceptive traffic, whereas descending orexinergic neurons in the posterior hypothalamus have both pro- and antinociceptive effects on nociceptive trigeminovascular responses. Many of the premonitory symptoms also suggest involvement of dopaminergic neurons. Dopamine (D2)-mediated responses can inhibit trigeminovascular nociceptive transmission. The hypothalamic A11 nucleus is believed to be the sole source of dopamine to the spinal cord and provides direct inhibitory projections. Electrical stimulation of this nucleus inhibits nociceptive trigeminal afferent responses through the D2 receptor, whereas lesioning this structure facilitates both nociceptive and nonnociceptive trigeminovascular traffic. These data provide further insights into regions whose dysfunction may alter the perception of head pain and other sensory responses, such as feeding and sleep.
Thalamus Processing of trigeminovascular nociceptive signals occurs in the VPM thalamus and its ventral periphery. A common symptom of migraine is cutaneous allodynia and hyperalgesia, the perception of pain in response to normally innocuous stimuli and hypersensitivity to noxious stimuli, respectively. Ipsilateral extracranial cutaneous allodynia and facial hypersensitivity are thought to result from central sensitization of the second-order neurons of the TCC. Using dural inflammatory soup assay in rats, to induce central sensitization, thalamic neurons were hyperresponsive to innocuous and noxious contralateral extracranial and extracephalic inputs. In patients suffering from allodynia during migraine, brushing or innocuous heat applied to the hand produced larger blood oxygen
level dependent (BOLD) signals in the thalamus, compared with interictally. Spreading of pain to the contralateral side, as well as referral of cutaneous allodynia to extracephalic areas, may be a result of sensitization of the third-order trigeminovascular neurons in the thalamus. Activation of trigeminothalamic neurons also offers an opportunity to explain photophobia in migraine. Photophobia is a kind of pain that is worsened by light, photic allodynia, or light itself seeming unusually unpleasant (pure photophobia). In rats, neurons of the dorsal portion of the posterior thalamic nuclear group receiving nociceptive inputs from dural trigeminovascular afferents are photosensitive to increasing light stimulation in the contralateral eye. The same neurons receive inputs from retinal ganglion cells, which themselves project to somatosensory, visual, and associative cortices. The data imply that changes in light intensity may exacerbate the processing of dural nociceptive inputs to the TCC and thalamus. The VPM neurons in the thalamus may also be the target of migraine therapeutics. The migraine preventives sodium valproate, through GABAA receptors, and propranolol, through b1-adrenoceptors, modulate dural nociceptive inputs in the VPM. Remarkably, the acute treatments for migraine, the triptans, through 5-hydroxytryptamine (5-HT)1B/1D receptors, and the CGRP receptor antagonist, olcegepant, also locally inhibited dural nociceptive trigeminothalmic neurons, suggesting a locus of action of these targets in this important pain-processing structure.
Cortical Modulation of Nociceptive Pathways The connection of cortical neurons to subcortical structures is integral to the processing of pain information in the ‘pain matrix,’ but the cortex may also be involved in modulating nociceptive responses in migraine. Migraine aura is described as a focal neurological disturbance manifest as visual, sensory, or motor symptoms that can precede the headache and is driven by cortical changes. It is essentially neurally driven and is thought to be the human equivalent of the experimental phenomenon, cortical spreading depression (CSD). CSD is a wave of neuronal depolarization that crosses the cortex, followed by a prolonged hyperpolarization. Many studies demonstrate increases in activity of trigeminovascular neurons as a consequence of CSD induction in rodents. It has been proposed that CSD and aura is pain producing, exciting dural meningeal nociceptive afferents to activate the trigeminovascular system serving as a trigger to migraine, to some or even all patients. Trigeminovascular activation is also apparent when the peripheral nociceptive input is removed, by locally anesthetizing the TG, implying that peripheral input may not be necessary to activate trigeminal neurons and cortical changes may provide descending modulation of the trigeminovascular system. This mechanism is further supported as CSD is able to inhibit neuronal responses in the nucleus raphe magnus, antagonizing descending inhibitory control of dural nociceptive trigeminal neurons in the nucleus caudalis. The role of the cortex and aura in migraine presents several unanswered clinical questions. Aura is not present in most patients, it may be silent, but if CSD underlies the mechanisms of triggering migraine, it has proven virtually
Migraine, Pathophysiology of
impossible to demonstrate in patients, with only blood perfusion changes presenting any correlate. Aura does not always precede pain, it can even be present without pain or indeed can be treated without prevention of the headache. The role of aura in migraine seems far from resolved.
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challenge for researchers; however, the benefit it can bring to patients is a driving motivation for the future.
See also: Migraine; Clinical Aspects. Migraine; Genetics. Migraine, Medical Treatment of
The Migrainous Brain It is now acknowledged that migraine is a disorder of the brain; patients have a predisposition for migraine and the many symptoms cannot be simply explained. It is clear that the trigeminovascular system is crucial to facilitating the acute pain attack, perhaps as a result of a lowered threshold for activation, but its triggering, premonitory, and accompanying symptoms can only be explained by changes in other areas of the brain. What is still unclear and hotly debated is what the primary event is that causes activation of the trigeminovascular system. It has been proposed that the primary event is firing of the first-order peripheral trigeminal meningeal nociceptors producing pain referred to the head. Continued activation of these nociceptors results in the sequential sensitization of the first-, second-, and the third-order trigeminovascular neurons, which, in turn, activate brainstem and forebrain regions, resulting in all migrainous symptoms. However, this theory does not seem to readily explain how meningeal nociceptors are initially triggered or the likely central triggers of migraine and the premonitory phase that precedes any pain. Rather than a sequential activation of trigeminovascular neurons, migraine is more likely a ‘brain state,’ as a result of dysfunction in brainstem and diencephalic nuclei that modulate sensory inputs of craniovascular afferents. This region acts as a ‘migraine mediator’ and dysfunction leads to the perception of activation in the TCC, resulting in the first-, second-, and the third-order sensitization of trigeminovascular neurons and pathways that activate central structures responsible for other migraine symptoms. Although the general understanding of the pathophysiology behind migraine has improved greatly in the past 30 years, it is still a major
Further Reading Akerman S, Holland PR, and Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nature Reviews Neuroscience 12: 570–584. Ayata C (2010) Cortical spreading depression triggers migraine attack: Pro. Headache 50: 725–730. Bernstein C and Burstein R (2012) Sensitization of the trigeminovascular pathway: Perspective and implications to migraine pathophysiology. Journal of Clinical Neurology 8: 89–99. Burstein R, Jakubowski M, Garcia-Nicas E, et al. (2010) Thalamic sensitization transforms localized pain into widespread allodynia. Annals of Neurology 68: 81–91. Eikermann-Haerter K and Ayata C (2010) Cortical spreading depression and migraine. Current Neurology and Neuroscience Reports 10: 167–173. Fields HL and Heinricher MM (1985) Anatomy and physiology of a nociceptive modulatory system. Philosophical Transactions of the Royal Society London B Biological Sciences 308: 361–374. Goadsby PJ, Edvinsson L, and Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Annals of Neurology 28: 183–187. Mason P (2005) Deconstructing endogenous pain modulations. Journal of Neurophysiology 94: 1659–1663. Olesen J, Diener HC, Husstedt IW, et al. (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. New England Journal of Medicine 350: 1104–1110. Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, and Welch KMA (eds.) (2005) The Headaches. Philadelphia: Lippincott Williams and Wilkins. Peroutka SJ (2005) Neurogenic inflammation and migraine: Implications for the therapeutics. Molecular Interventions 5: 304–311. Sprenger T and Goadsby PJ (2010) What has functional neuroimaging done for primary headache ... and for the clinical neurologist? Journal of Clinical Neuroscience 17: 547–553. Summ O, Charbit AR, Andreou AP, and Goadsby PJ (2010) Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 133: 2540–2548.
Introduction Migraine is a complex and disabling disorder of the brain. It is the most common disabling form of primary headache. It has a varied symptomatology that includes pain referred to the head, but it is the associated (nonpain) neurological features that make this disorder so complex and draws us to its likely pathophysiology. The clinical aspects of migraine, and other headache disorders, are defined according to the International Classification of Headache Disorders (2004). Additional clinical features can include premonitory symptoms such as fatigue, altered feeding, yawning, and sleep, to migraine aura, and those that occur usually with the head pain, such as nausea, vomiting, photo- and phonophobia, and cutaneous allodynia. This article will integrate these symptoms with the authors’ current understanding of the pathophysiology of migraine, including the physiology and pharmacology of peripheral and central aspects of the trigeminovascular system, the brainstem and diencephalic modulatory systems that influence processing of nociceptive information in the trigeminovascular system, and cortical sensory processing.
Trigeminovascular Anatomical Mechanisms Peripheral Connections Migraine clearly involves nociceptive pathways from the trigeminovascular system. The anatomy of the trigeminovascular system has been well described over the past 50 years. It includes the trigeminal (Gasserian) ganglion (TG) that has afferent projections to the trigeminal nucleus caudalis in the medullary spinal cord and an efferent projection, largely from the ophthalmic division of the TG, to the cranial blood vessels, including those of the pain-producing dura mater. This dural innervation is enriched for calcitonin gene-related peptide (CGRP), which may explain the lack of effect of substance P (SP), neurokinin-1 receptor antagonists in migraine. There is a reflex connection from the trigeminal nucleus to the parasympathetic outflow to the cranial vasculature (Figure 1). Although the brain is largely insensate, stimulation of dural structures, such as the superior sagittal sinus, is painful in humans and produces pain referred to the head, similar to headache. Stimulation of the TG in humans and cats results in the release of SP and CGRP, and in the cat increases cerebral blood flow, whereas in rodents this results in dural plasma extravasation. Stimulation of the more pain-producing dural sites in these animals causes greater increase in cerebral blood flow and release of only CGRP, but not substance P. Evidence from patients with severe migraine and those with nitric oxide (NO)-triggered migraine also show increase in only CGRP levels; moreover, both migraine and CGRP
Encyclopedia of the Neurological Sciences, Volume 3
levels are normalized with sumatriptan. Interestingly, molecules that failed to inhibit CGRP release in animal models, the extravasation inhibitors CP122,288 and 4991w93, also failed in the clinic, whereas the development of specific CGRP receptor antagonists has proven to be an effective treatment for migraine. Thus, an emerging therapy and reliable pathophysiological mechanism for migraine were established.
Central Activation In animal models, electrical or mechanical stimulation of the dural vasculature results in neuronal activation not only in the trigeminal nucleus caudalis but also in the C1 and C2 region of the cervical spinal cord. This region also receives direct inputs from the greater occipital nerve. It is thought that the trigeminal nucleus extends beyond its caudalis boundary to the dorsal horn of the higher cervical region in a functional continuum commonly described as the trigeminocervical complex (TCC). It is more likely that the common distribution of pain in migraine over the frontal and temporal regions, plus the involvement of parietal, occipital, and high cervical regions, may be explained by this functional convergence of neurons in the TCC. Experimental pharmacological studies show that abortive antimigraine drugs such as ergot derivatives, triptans, and CGRP receptor antagonists can all reduce neuronal activity on second-order trigeminal neurons, suggesting a possible locus of therapeutic action. Although it is acknowledged that stimulation and activation of meningeal nociceptors innervating the pain-producing intracranial structures is painful, and will cause vasodilation of intracranial vessel, it is hard to reconcile that this contributes solely to the pain in migraine. It is perhaps more likely that a reduction/dysfunction in the normal gating of the endogenous pain control pathway, within the brain that modulates trigeminovascular nociceptive processing, is responsible for the pain in migraine. Through this process, other areas of the brain may become sensitized and migraineurs’ response to external and centrally mediated triggers may be heightened.
Higher Central Pain Processing of the Trigeminovascular System The TCC is a key relay center for the transmission of nociceptive information from the cranial vasculature to the brainstem and higher pain-processing structures. Anatomically, the TCC makes ascending and receives descending connections with many higher brain structures. Animal studies that use dural stimulation demonstrate neuronal activation in areas of the brainstem including the ventrolateral periaqueductal gray (vlPAG), nuclei in the rostral ventromedial medulla (RVM), such as the nucleus raphe magnus, and pontine nuclei. Additionally, somatosensory and visceral nociceptive information from the
doi:10.1016/B978-0-12-385157-4.01087-3
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Parasympathetic Trigeminal ACh, VIP, PACAP, NPY and NO
CGRP, SP NKA and PACAP
5-HT1D receptors Cortex 5-HT1B receptors
Thalamus A11
Hypothalamus
Cervical inputs
PAG
LC TG Pons SuS
5-HT1B/1D/1F receptors
RVM TCC
PG CG
Figure 1 The physiology and pharmacology of migraine (provided by Dr Philip R. Holland). The key pathways involved in the anatomy of migraine are the trigeminovascular inputs from the meningeal vessels, which pass through the trigeminal ganglion and synapse on the secondorder neurons in the trigeminocervical complex (TCC – purple neuron), as well as afferents from the cervical nerve via the cervical ganglion (CG – light blue). These neurons, in turn, ascend through the quintothalamic tract (dark blue neuron), and after decussating in the brainstem, they form synapses with neurons in the thalamus. There is a reflex connection with the parasympathetic outflow to the cranial vasculature via the superior salivatory nucleus (SuS), mediated through the pterygopalatine ganglion (PG – green neuron). These pathways are activated via the release of various neurotransmitters but predominantly via calcitonin gene-related peptide (CGRP). It is thought that the therapeutic action of triptans, 5HT1B/1D receptor agonists, is mainly through receptors located on pre- and postsynaptic sites in the central TCC, and peripherally on prejunctional nerve endings innervating dural arterial blood vessels, preventing the release of CGRP (via 5-HT1D receptors), and on the vessels themselves causing vasoconstriction (5-HT1B receptors). Brain imaging and experimental animal studies suggest that the importance of descending modulation (red neurons) of trigeminovascular nociceptive inputs comes from the rostral ventromedial medulla (RVM), periaqueductal gray (PAG), hypothalamus, and A11 nucleus. There are further ascending connections (blue neurons) from the TCC to the locus coeruleus (LC), PAG and hypothalamus, and indirectly to the cortex. The migraine pain system involves descending and ascending modulatory systems that help to define the pain and the associated triggers and symptoms that may explain the timeline of the clinical syndrome. ACh, acetylcholine; NKA, neurokinin A; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating peptide; SP, substance P; VIP, vasoactive intestinal peptide.
head and orofacial structures project directly to specific hypothalamic nuclei, via the trigeminohypothalamic tract, and are also activated by dural stimulation. Nociceptive signaling from the dural vasculature, processed via the TCC is relayed to the third-order neurons in the thalamus via the ‘quintothalamic tract.’ These trigeminovascular dural nociceptive inputs are predominantly processed in the ventroposteromedial (VPM)
nucleus in the thalamus, ventral periphery of the VPM, posterior thalamic nucleus, medial nucleus of the posterior complex, and intralaminar thalamus. It is an important translational validation that areas of neuronal activation in dural stimulation animal models are paralleled by central activation in patients during migraine. Positron emission tomography (PET) imaging of patients during both spontaneous and experimentally
Migraine, Pathophysiology of
triggered migraine demonstrates activation in the brainstem, including the pons and midbrain, the hypothalamus, thalamus, and cortex.
Cortical Processing of Trigeminovascular Information The processing of pain is complex and mediated by a network of neuronal structures called the ‘pain matrix,’ which includes the thalamus, primary and secondary somatosensory areas, the anterior cingulate cortex (ACC), and prefrontal cortex. They are active during nociceptive processing and involved in integrating this information. During migraine, PET imaging reveals that the ACC, frontal cortex, visual and auditory cortices, and thalamic nuclei contralateral to the side of pain are activated. It is thought that the VPM thalamus is the principal nucleus involved in relaying nociceptive information to the cortex. The data suggest that neurons of the cortex and thalamus are crucial to the higher level processing of the pain coming from the head.
Central Control of Trigeminovascular Nociceptive Traffic and Migraine Symptoms If migraine is a disorder of the brain and a consequence of reduction/dysfunction of the normal gating of the endogenous pain control pathway, is it then possible that changes in the brain can alter the processing of trigeminovascular nociceptive traffic and other migrainous symptoms? Weiller and colleagues’ observation in the 1990s that areas of the brainstem are active during migraine, specifically the dorsal midbrain and dorsal pons, might imply this. Interestingly, these areas that are active during pain remain active even after successful treatment. This may indicate that brainstem activity is not simply a response to pain but an underlying cause of this brain disorder. Many brainstem nuclei have bidirectional descending connections with the trigeminovascular system and ascending connections with ‘diencephalic’ structures involved in pain processing. These nuclei are ideally placed to affect both the trigeminovascular system and diencephalic nuclei thought to be responsible for nonpain symptoms of migraine.
Brainstem Nuclei The superior salivatory nucleus (SuS) in the pons receives a reflex connection with the trigeminal nucleus and contains the cell bodies of neurons that make up the parasympathetic autonomic vasodilator pathway. These neurons project through the greater petrosal branch of the facial (VIIth) nerve via the pterygopalatine ganglion (sphenopalatine in rodents) to the cranial vasculature. Activation of this pathway may cause autonomic symptoms during migraine and other primary headaches. In animal models, neurons within the SuS are activated after dural electrical stimulation. Stimulation of the SuS causes neuronal activation in the TCC as well as enhances light-responsive TCC activity. Also, stimulation of the SuS, the sphenopalatine ganglion, and the facial (VIIth) nerve all cause increases in cerebral blood flow, dilating blood vessels, and
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potentially activating trigeminal nerve endings. The SuS also has connections to the hypothalamus, as well as limbic and cortical areas, regions crucial in the regulation of sleep, stress, and food intake, and may trigger migraine and affect its symptomatology. The RVM is a cluster of neurons in the medulla thought to be involved in the descending control of the endogenous ‘opioid’ pain-processing pathway in the spinal dorsal horn. It is hypothesized that ‘on,’ ‘off,’ and ‘neutral cells’ in the RVM provide descending control of spinal nociceptive neurons.‘On’ cells facilitate firing of neurons that receive nociceptive inputs and are inhibited by opioids, whereas ‘off’ cells are tonically active and inhibit nociceptive inputs and are activated by opioids. The RVM may be involved in the modulation of trigeminovascular nociceptive traffic in migraine. Activation and central sensitization of trigeminovascular neurons, using an inflammatory soup applied to the dura mater of the rat, causes cutaneous facial hypersensitivity and allodynia in the ophthalmic dermatome. These responses are inhibited by the direct application of bupivacaine into the RVM. Electrophysiological recording in the RVM identified that ‘on’ cells were activated by the inflammatory soup applied to the dura mater, whereas ‘off’ cells were inhibited. Therefore, trigeminovascular nociceptive traffic may be under the control of the neurons descending from the RVM. The RVM makes direct bidirectional connections with the vlPAG. The dorsal midbrain region highlighted as active in many studies during migraine includes the vlPAG and therefore may be indicated in its pathophysiology. In animal experimental assays, dural evoked nociceptive activation in the TCC is inhibited by electrical stimulation of the vlPAG and local application of g-aminobutyric acid (GABAA) receptor antagonists as well as triptans, whereas blockade of the P/Q-type voltagegated Ca2þ channels facilitates these trigeminovascular nociceptive responses, independent of the local GABAergic system. A mutation of the CACNA1A gene that encodes the a1a subunit of the P/Q-type voltage-gated calcium channel is present in approximately 55% of patients with familial hemiplegic migraine. This inherited channelopathy mutation may contribute to the hemiplegic aura and may additionally implicate a dysfunction of the brainstem in migraine. The PAG is thought to modulate spinal and trigeminal nociceptive processing directly through the RVM. Until recently, it was believed that this pathway was involved exclusively in endogenous pain modulation through opioidmediated responses. However, this pathway responds to the activation of innocuous stimuli, motor activity, and homeostatic processes including sleep, feeding, and micturition. The RVM and PAG have connections with forebrain structures, including the hypothalamus, and through these connections they are hypothesized to be involved in the control of sensory, autonomic, and motor processes in the spinal cord across normal conditions and primed to prioritize responses to nociceptive inputs. Migraine triggers, such as sleep and food deprivation, are homeostatic processes that are, in some way, regulated by the PAG and RVM, whereas accompanying symptoms of migraine including altered feeding, the need for sleep, excessive urination, and the tendency to avoid activity could also be described as a consequence of changes in the processing of these brainstem structures. Taken as a whole,
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Migraine, Pathophysiology of
altered functioning in areas of the brainstem including the SuS, RVM, and PAG may gate nociceptive and nonnociceptive cranial and spinal sensory, autonomic and motor processing, and affect homeostatic balance contributing migraine symptoms and act as a migraine trigger.
Diencephalic Nuclei Imaging studies in migraineurs and other primary headaches have demonstrated activation of hypothalamic nuclei, particularly in the posterior region. Many of the clinical features associated with migraine triggers and premonitory symptoms, including sleep disturbance, changes in arousal, mood, food craving, thirst, and urination, would seem to be regulated by the hypothalamus and its controls of circadian rhythm and sleep–wake cycle. The hypothalamus is also involved in the descending control of spinal and trigeminal nociceptive responses through its bidirectional connections with many brainstem structures involved in pain processing and autonomic responses. In animal studies, posterior and ventromedial hypothalamic nuclei are activated after dural evoked trigeminovascular activation and sensitization. Interestingly, in awake animals, after trigeminovascular sensitization, their feeding is altered for many hours when levels of the anorective peptide cholecystokinin B receptor are increased. Orexin A and B are hypothalamic neuropeptides involved in feeding, sleep–wake cycle, and hormone regulation. Orexin A inhibits peripheral and central dural evoked trigeminovascular nociceptive traffic, whereas descending orexinergic neurons in the posterior hypothalamus have both pro- and antinociceptive effects on nociceptive trigeminovascular responses. Many of the premonitory symptoms also suggest involvement of dopaminergic neurons. Dopamine (D2)-mediated responses can inhibit trigeminovascular nociceptive transmission. The hypothalamic A11 nucleus is believed to be the sole source of dopamine to the spinal cord and provides direct inhibitory projections. Electrical stimulation of this nucleus inhibits nociceptive trigeminal afferent responses through the D2 receptor, whereas lesioning this structure facilitates both nociceptive and nonnociceptive trigeminovascular traffic. These data provide further insights into regions whose dysfunction may alter the perception of head pain and other sensory responses, such as feeding and sleep.
Thalamus Processing of trigeminovascular nociceptive signals occurs in the VPM thalamus and its ventral periphery. A common symptom of migraine is cutaneous allodynia and hyperalgesia, the perception of pain in response to normally innocuous stimuli and hypersensitivity to noxious stimuli, respectively. Ipsilateral extracranial cutaneous allodynia and facial hypersensitivity are thought to result from central sensitization of the second-order neurons of the TCC. Using dural inflammatory soup assay in rats, to induce central sensitization, thalamic neurons were hyperresponsive to innocuous and noxious contralateral extracranial and extracephalic inputs. In patients suffering from allodynia during migraine, brushing or innocuous heat applied to the hand produced larger blood oxygen
level dependent (BOLD) signals in the thalamus, compared with interictally. Spreading of pain to the contralateral side, as well as referral of cutaneous allodynia to extracephalic areas, may be a result of sensitization of the third-order trigeminovascular neurons in the thalamus. Activation of trigeminothalamic neurons also offers an opportunity to explain photophobia in migraine. Photophobia is a kind of pain that is worsened by light, photic allodynia, or light itself seeming unusually unpleasant (pure photophobia). In rats, neurons of the dorsal portion of the posterior thalamic nuclear group receiving nociceptive inputs from dural trigeminovascular afferents are photosensitive to increasing light stimulation in the contralateral eye. The same neurons receive inputs from retinal ganglion cells, which themselves project to somatosensory, visual, and associative cortices. The data imply that changes in light intensity may exacerbate the processing of dural nociceptive inputs to the TCC and thalamus. The VPM neurons in the thalamus may also be the target of migraine therapeutics. The migraine preventives sodium valproate, through GABAA receptors, and propranolol, through b1-adrenoceptors, modulate dural nociceptive inputs in the VPM. Remarkably, the acute treatments for migraine, the triptans, through 5-hydroxytryptamine (5-HT)1B/1D receptors, and the CGRP receptor antagonist, olcegepant, also locally inhibited dural nociceptive trigeminothalmic neurons, suggesting a locus of action of these targets in this important pain-processing structure.
Cortical Modulation of Nociceptive Pathways The connection of cortical neurons to subcortical structures is integral to the processing of pain information in the ‘pain matrix,’ but the cortex may also be involved in modulating nociceptive responses in migraine. Migraine aura is described as a focal neurological disturbance manifest as visual, sensory, or motor symptoms that can precede the headache and is driven by cortical changes. It is essentially neurally driven and is thought to be the human equivalent of the experimental phenomenon, cortical spreading depression (CSD). CSD is a wave of neuronal depolarization that crosses the cortex, followed by a prolonged hyperpolarization. Many studies demonstrate increases in activity of trigeminovascular neurons as a consequence of CSD induction in rodents. It has been proposed that CSD and aura is pain producing, exciting dural meningeal nociceptive afferents to activate the trigeminovascular system serving as a trigger to migraine, to some or even all patients. Trigeminovascular activation is also apparent when the peripheral nociceptive input is removed, by locally anesthetizing the TG, implying that peripheral input may not be necessary to activate trigeminal neurons and cortical changes may provide descending modulation of the trigeminovascular system. This mechanism is further supported as CSD is able to inhibit neuronal responses in the nucleus raphe magnus, antagonizing descending inhibitory control of dural nociceptive trigeminal neurons in the nucleus caudalis. The role of the cortex and aura in migraine presents several unanswered clinical questions. Aura is not present in most patients, it may be silent, but if CSD underlies the mechanisms of triggering migraine, it has proven virtually
Migraine, Pathophysiology of
impossible to demonstrate in patients, with only blood perfusion changes presenting any correlate. Aura does not always precede pain, it can even be present without pain or indeed can be treated without prevention of the headache. The role of aura in migraine seems far from resolved.
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challenge for researchers; however, the benefit it can bring to patients is a driving motivation for the future.
See also: Migraine; Clinical Aspects. Migraine; Genetics. Migraine, Medical Treatment of
The Migrainous Brain It is now acknowledged that migraine is a disorder of the brain; patients have a predisposition for migraine and the many symptoms cannot be simply explained. It is clear that the trigeminovascular system is crucial to facilitating the acute pain attack, perhaps as a result of a lowered threshold for activation, but its triggering, premonitory, and accompanying symptoms can only be explained by changes in other areas of the brain. What is still unclear and hotly debated is what the primary event is that causes activation of the trigeminovascular system. It has been proposed that the primary event is firing of the first-order peripheral trigeminal meningeal nociceptors producing pain referred to the head. Continued activation of these nociceptors results in the sequential sensitization of the first-, second-, and the third-order trigeminovascular neurons, which, in turn, activate brainstem and forebrain regions, resulting in all migrainous symptoms. However, this theory does not seem to readily explain how meningeal nociceptors are initially triggered or the likely central triggers of migraine and the premonitory phase that precedes any pain. Rather than a sequential activation of trigeminovascular neurons, migraine is more likely a ‘brain state,’ as a result of dysfunction in brainstem and diencephalic nuclei that modulate sensory inputs of craniovascular afferents. This region acts as a ‘migraine mediator’ and dysfunction leads to the perception of activation in the TCC, resulting in the first-, second-, and the third-order sensitization of trigeminovascular neurons and pathways that activate central structures responsible for other migraine symptoms. Although the general understanding of the pathophysiology behind migraine has improved greatly in the past 30 years, it is still a major
Further Reading Akerman S, Holland PR, and Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nature Reviews Neuroscience 12: 570–584. Ayata C (2010) Cortical spreading depression triggers migraine attack: Pro. Headache 50: 725–730. Bernstein C and Burstein R (2012) Sensitization of the trigeminovascular pathway: Perspective and implications to migraine pathophysiology. Journal of Clinical Neurology 8: 89–99. Burstein R, Jakubowski M, Garcia-Nicas E, et al. (2010) Thalamic sensitization transforms localized pain into widespread allodynia. Annals of Neurology 68: 81–91. Eikermann-Haerter K and Ayata C (2010) Cortical spreading depression and migraine. Current Neurology and Neuroscience Reports 10: 167–173. Fields HL and Heinricher MM (1985) Anatomy and physiology of a nociceptive modulatory system. Philosophical Transactions of the Royal Society London B Biological Sciences 308: 361–374. Goadsby PJ, Edvinsson L, and Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Annals of Neurology 28: 183–187. Mason P (2005) Deconstructing endogenous pain modulations. Journal of Neurophysiology 94: 1659–1663. Olesen J, Diener HC, Husstedt IW, et al. (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. New England Journal of Medicine 350: 1104–1110. Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, and Welch KMA (eds.) (2005) The Headaches. Philadelphia: Lippincott Williams and Wilkins. Peroutka SJ (2005) Neurogenic inflammation and migraine: Implications for the therapeutics. Molecular Interventions 5: 304–311. Sprenger T and Goadsby PJ (2010) What has functional neuroimaging done for primary headache ... and for the clinical neurologist? Journal of Clinical Neuroscience 17: 547–553. Summ O, Charbit AR, Andreou AP, and Goadsby PJ (2010) Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 133: 2540–2548.