A Systems Neuroscience Approach to Migraine
2018; Cell Press; Volume: 97; Issue: 5 Linguagem: Inglês
10.1016/j.neuron.2018.01.029
ISSN1097-4199
AutoresK. C. Brennan, Daniela Pietrobon,
Tópico(s)Neurological Disorders and Treatments
ResumoMigraine is an extremely common but poorly understood nervous system disorder. We conceptualize migraine as a disorder of sensory network gain and plasticity, and we propose that this framing makes it amenable to the tools of current systems neuroscience. Migraine is an extremely common but poorly understood nervous system disorder. We conceptualize migraine as a disorder of sensory network gain and plasticity, and we propose that this framing makes it amenable to the tools of current systems neuroscience. Two characteristics of migraine make it a very interesting systems neuroscience problem. First, the migraine attack is not only an anatomically specific pain state, but also (at least phenotypically) a paroxysmal disorder of pan-sensory gain. Second, the transition from acute to chronic migraine appears to represent a multisite, dysfunctional plasticity of sensory, autonomic, and affective circuits. In order to understand the migraine attack from a systems neuroscience perspective, we need to understand how a sensory and autonomic network can switch, within a few minutes, from a state of relative equilibrium to one in which there is both spontaneous pain and amplification of percepts from multiple senses. We also need to understand how the sensory changes that occur in a migraine attack become a near-constant experience in chronic migraine. Because migraine is a whole nervous system disease, any attempt to summarize it entirely can be daunting. Though we refer to the clinical migraine literature as a reference point, our primary focus is on how the disease (in particular the migraine attack and chronic migraine) can be approached mechanistically in animal model systems. Our overall goal is to increase awareness of this understudied disease in the neuroscientific community by trying to view it through the lens of modern systems neuroscience. Finally, we apologize in advance for citing only selected original research and reviews rather than the more extensive primary literature. Migraine affects 12% of the world’s population (Jensen and Stovner, 2008Jensen R. Stovner L.J. Epidemiology and comorbidity of headache.Lancet Neurol. 2008; 7: 354-361Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar, Lipton et al., 2007Lipton R.B. Bigal M.E. Diamond M. Freitag F. Reed M.L. Stewart W.F. AMPP Advisory GroupMigraine prevalence, disease burden, and the need for preventive therapy.Neurology. 2007; 68: 343-349Crossref PubMed Scopus (1264) Google Scholar). It is commonly thought of as a disorder of episodic, severe headache, but this understates both its pathophysiological complexity and its human impact. Migraine attacks are often incapacitating, and they primarily affect people in their working and child-rearing years. Chronic migraine (migraine more than 15 days of the month) affects 2% of the world’s population (May and Schulte, 2016May A. Schulte L.H. Chronic migraine: risk factors, mechanisms and treatment.Nat. Rev. Neurol. 2016; 12: 455-464Crossref PubMed Scopus (263) Google Scholar). The economic costs of migraine, driven mainly by chronic migraine, range between $20 and $30 billion a year in the United States (Stewart et al., 2003Stewart W.F. Ricci J.A. Chee E. Morganstein D. Lipton R. Lost productive time and cost due to common pain conditions in the US workforce.JAMA. 2003; 290: 2443-2454Crossref PubMed Scopus (1014) Google Scholar). The true societal costs of this stigmatized, poorly understood disease are hard to calculate. Migraine is a disorder primarily affecting the sensory nervous system (Pietrobon and Moskowitz, 2013Pietrobon D. Moskowitz M.A. Pathophysiology of migraine.Annu. Rev. Physiol. 2013; 75: 365-391Crossref PubMed Scopus (300) Google Scholar). It is punctuated by attacks that generally last a few hours and include a throbbing, unilateral head pain that can range from mild to excruciating. However, the headache is only one element of a larger whole. In addition to head pain, there is often pain in the neck and shoulders. Nausea and vomiting, representing interoception and autonomic outflow from the gut, are prominent features. There can also be autonomic phenomena in the face, typically reddening of the eyes, tearing, flushing, or pallor (Goadsby et al., 2002Goadsby P.J. Lipton R.B. Ferrari M.D. Migraine—current understanding and treatment.N. Engl. J. Med. 2002; 346: 257-270Crossref PubMed Scopus (1419) Google Scholar). Finally, the majority of migraine attacks feature sensory amplifications: photophobia, phonophobia, osmophobia, and cutaneous allodynia—the perception of light, sound, smell, and normal touch as amplified or painful (Burstein et al., 2015Burstein R. Noseda R. Borsook D. Migraine: multiple processes, complex pathophysiology.J. Neurosci. 2015; 35: 6619-6629Crossref PubMed Scopus (202) Google Scholar). Thus, the migraine attack is not so much a simple headache as it is a paroxysmal alteration in gain, or input-output modulation (Haider and McCormick, 2009Haider B. McCormick D.A. Rapid neocortical dynamics: cellular and network mechanisms.Neuron. 2009; 62: 171-189Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar), of multiple sensory systems (Figure 1). The migraine attack is the most visible element of a larger disease continuum. In up to a third of patients, the attack is heralded by an aura; this is a typically sensory hallucination, with visual or somatic percepts that do not exist in the environment. It can also affect speech function, indistinguishably from the aphasia seen in stroke, except that it is reversible. Up to 72 hr before an attack, some patients experience premonitory symptoms—cognitive changes, hunger/thirst, euphoria, or irritability. Following the attack, sensory function typically does not immediately return to normal; milder pain and sensory amplifications can persist for hours to days (Goadsby et al., 2002Goadsby P.J. Lipton R.B. Ferrari M.D. Migraine—current understanding and treatment.N. Engl. J. Med. 2002; 346: 257-270Crossref PubMed Scopus (1419) Google Scholar, Olesen et al., 2013Olesen J. Diener H.C. Bousser M.G. Dodick D.W. Goadsby P.J. Lipton R.B. Schoenen J. Silberstein S.D. Nappi G. Sakai F. The international classification of headache disorders, 3rd edition (beta version).Cephalalgia. 2013; 33: 629-808Crossref PubMed Scopus (32) Google Scholar). Between attacks, there are alterations in sensory physiology that appear to vary in time with the attack profile, suggesting an underlying cyclicity in sensory gain that culminates in the attack (de Tommaso et al., 2014de Tommaso M. Ambrosini A. Brighina F. Coppola G. Perrotta A. Pierelli F. Sandrini G. Valeriani M. Marinazzo D. Stramaglia S. Schoenen J. Altered processing of sensory stimuli in patients with migraine.Nat. Rev. Neurol. 2014; 10: 144-155Crossref PubMed Scopus (116) Google Scholar). One of the most important problems in clinical migraine is the progression from an intermittent, self-limited inconvenience to a life-changing disorder of chronic pain, sensory amplification, and autonomic and affective disruption. This progression, sometimes termed chronification in the migraine literature, is common, affecting 3% of migraineurs in a given year, such that 8% of migraineurs have chronic migraine in any given year (May and Schulte, 2016May A. Schulte L.H. Chronic migraine: risk factors, mechanisms and treatment.Nat. Rev. Neurol. 2016; 12: 455-464Crossref PubMed Scopus (263) Google Scholar). The chronification process results in a persistent alteration in the way the sensory network responds to the environment; that is, at least phenomenologically, a dysfunctional plasticity of the sensory network. Craniofacial nociceptive afferents have their cell bodies in the trigeminal ganglion (TG) and the dorsal root ganglia of cervical roots C1–C3. Like nociceptive afferents in the rest of the body, they are thinly myelinated A delta or unmyelinated C fibers, often immunoreactive for calcitonin-gene-related peptide (CGRP) and substance P. Their central processes terminate in the trigeminocervical complex, which includes the trigeminal subnucleus caudalis (TNC) and dorsal horn of the first cervical segments, and is the first CNS relay in the craniofacial nociceptive circuit. For simplicity, we will use the term TNC to refer to all trigeminocervical complex structures. TNC neurons send glutamatergic processes to the ventroposteriomedial (VPM) and posterior (Po) nuclei of the thalamus; VPM neurons project primarily to somatosensory cortex, while Po neurons project more broadly, including sensory cortices, insula, and association cortex. TNC neurons also connect to affective/motivational circuits through the nucleus tractus solitarius (NTS) and parabrachial nucleus (PBN), which send projections diffusely to hypothalamus, thalamic nuclei, amygdala, insular cortex, and frontal cortex. Finally, TNC neurons project directly to output structures effecting pain modulation and autonomic outflow: the hypothalamus, periaqueductal gray, superior salivatory nucleus, and rostral ventromedial medulla (reviewed in Noseda and Burstein, 2013Noseda R. Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain.Pain. 2013; 154: S44-S53Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, Pietrobon and Moskowitz, 2013Pietrobon D. Moskowitz M.A. Pathophysiology of migraine.Annu. Rev. Physiol. 2013; 75: 365-391Crossref PubMed Scopus (300) Google Scholar) (Figure 2A). In summary, craniofacial afferents that synapse in the TNC project, directly or indirectly, to structures involved in the sensory/discriminatory, salience/alerting, and affective/motivational aspects of pain, as well as to structures involved in the response to pain—reflex autonomic and descending facilitatory/inhibitory modulation. For historical reasons, craniofacial pain circuits have acquired a distinct nomenclature: the term trigeminovascular reflex (and the related trigeminoautonomic reflex) arose because it was noted that activation of craniofacial nociceptive afferents resulted in vasodilation and inflammatory mediator release over the dura (Moskowitz, 1984Moskowitz M.A. The neurobiology of vascular head pain.Ann. Neurol. 1984; 16: 157-168Crossref PubMed Google Scholar). This process of nociception-related reflex outflow was important in the development migraine-relevant pain models (Figure 2A). However, in its essence, the trigeminovascular response resembles the neurogenic inflammation (Xanthos and Sandkühler, 2014Xanthos D.N. Sandkühler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity.Nat Rev Neurosci. 2014; 15: 43-53Crossref PubMed Scopus (236) Google Scholar) seen on activation of pain afferents throughout the body. It is unclear how a typical migraine attack is triggered; this is one of the most important unanswered questions in migraine neuroscience. It is likely that the triggers vary between and within subjects (Kelman, 2007Kelman L. The triggers or precipitants of the acute migraine attack.Cephalalgia. 2007; 27: 394-402Crossref PubMed Scopus (387) Google Scholar), depending on preexisting network characteristics that might be quite individual. When designing animal models, it is important to consider that, whatever the trigger, it should result in a sustained, self-perpetuating response, comparable in duration to a migraine attack, and incorporate all of its features, including pain, autonomic outflow, and sensory amplifications. At this point, it is not known whether any migraine model fully meets these criteria. The primary approaches to modeling the craniofacial nociceptive response involve stimulation and recording of trigeminal afferents; these are called trigeminovascular models in the migraine literature (Moskowitz, 1984Moskowitz M.A. The neurobiology of vascular head pain.Ann. Neurol. 1984; 16: 157-168Crossref PubMed Google Scholar, Noseda and Burstein, 2013Noseda R. Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain.Pain. 2013; 154: S44-S53Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar) (Figures 2A–2C). A typical preparation involves applying either electrical stimulation or inflammatory mediators (usually a combination of potassium, bradykinin, serotonin, histamine, ATP, and low pH), to pain-sensitive intracranial structures (e.g., dural sinus or middle meningeal artery; both are densely innervated with trigeminal afferents). After stimulation, the response to innocuous and noxious extra- and intracranial stimulation is measured with electrophysiology or imaging, with the rationale that sensitization of these responses is representative of the migraine headache state (Romero-Reyes and Akerman, 2014Romero-Reyes M. Akerman S. Update on animal models of migraine.Curr. Pain Headache Rep. 2014; 18: 462Crossref PubMed Scopus (3) Google Scholar). More recently, substances known to induce migraine in humans, including nitroglycerin (NTG), CGRP, and others, have been applied in trigeminovascular models to increase translational relevance (Ashina et al., 2017Ashina M. Hansen J.M. Á Dunga B.O. Olesen J. Human models of migraine—short-term pain for long-term gain.Nat. Rev. Neurol. 2017; 13: 713-724Crossref PubMed Scopus (42) Google Scholar, Romero-Reyes and Akerman, 2014Romero-Reyes M. Akerman S. Update on animal models of migraine.Curr. Pain Headache Rep. 2014; 18: 462Crossref PubMed Scopus (3) Google Scholar). Most trigeminovascular models show either persistent increases in TG and TNC firing, c-fos immediate early gene activation, or both after stimulation (Noseda and Burstein, 2013Noseda R. Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain.Pain. 2013; 154: S44-S53Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, Pietrobon and Moskowitz, 2013Pietrobon D. Moskowitz M.A. Pathophysiology of migraine.Annu. Rev. Physiol. 2013; 75: 365-391Crossref PubMed Scopus (300) Google Scholar, Romero-Reyes and Akerman, 2014Romero-Reyes M. Akerman S. Update on animal models of migraine.Curr. Pain Headache Rep. 2014; 18: 462Crossref PubMed Scopus (3) Google Scholar) (Figures 2A–2C). The findings are similar to what is seen in non-headache pain models: an increase in response to both nociceptive and non-nociceptive stimuli that persists beyond the sensitization protocol. In inflammatory and injury-based pain models (e.g., carrageenan paw injection and sciatic nerve ligation) this kind of change in response properties is associated with long-term potentiation (LTP; a persistent strengthening of synaptic activity) in dorsal horn principal cells (Kuner and Flor, 2016Kuner R. Flor H. Structural plasticity and reorganisation in chronic pain.Nat. Rev. Neurosci. 2016; 18: 20-30Crossref PubMed Scopus (114) Google Scholar, Sandkühler and Gruber-Schoffnegger, 2012Sandkühler J. Gruber-Schoffnegger D. Hyperalgesia by synaptic long-term potentiation (LTP): an update.Curr. Opin. Pharmacol. 2012; 12: 18-27Crossref PubMed Scopus (91) Google Scholar). As the TNC is functionally continuous with the dorsal horn of spinal cord, similar plastic changes might be expected, but they remain to be demonstrated. Trigeminovascular models have been used to explore allodynia, one of the sensory amplifications of migraine (Figures 1 and 2). Cutaneous allodynia is seen in approximately two-thirds of migraine attacks in humans (Lipton et al., 2008Lipton R.B. Bigal M.E. Ashina S. Burstein R. Silberstein S. Reed M.L. Serrano D. Stewart W.F. American Migraine Prevalence Prevention Advisory GroupCutaneous allodynia in the migraine population.Ann. Neurol. 2008; 63: 148-158Crossref PubMed Scopus (283) Google Scholar). It is most prominent on the side of the head where pain is most severe; however, spread of allodynia to the contralateral head, ipsilateral and contralateral arms, and even the legs can occur. These sensory findings have been replicated in animal models and are used as evidence for central sensitization. The rationale is that while hyperalgesia in the same territory as the head pain could be caused by peripheral sensitization (an increase in the firing rate of peripheral nociceptors to a given stimulus), allodynia (a pain response generated by light touch) cannot be explained without CNS modulation (Noseda and Burstein, 2013Noseda R. Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain.Pain. 2013; 154: S44-S53Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar). Both peripheral and central sensitization are phenotypes that are associated with synaptic plasticity in non-headache pain models (Costigan et al., 2009Costigan M. Scholz J. Woolf C.J. Neuropathic pain: a maladaptive response of the nervous system to damage.Annu. Rev. Neurosci. 2009; 32: 1-32Crossref PubMed Scopus (977) Google Scholar). However, the underlying mechanisms have not been investigated in migraine models. Another sensory amplification that has been explored in migraine-focused models is photophobia (Figure 2D). Several migraine-relevant interventions, including NTG, CGRP infusion, and mice engineered to overexpress CGRP receptors, generate photophobic behavior in mice during light/dark box testing (Kaiser et al., 2012Kaiser E.A. Kuburas A. Recober A. Russo A.F. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist.J. Neurosci. 2012; 32: 15439-15449Crossref PubMed Scopus (31) Google Scholar, Mason et al., 2017Mason B.N. Kaiser E.A. Kuburas A. Loomis M.M. Latham J.A. Garcia-Martinez L.F. Russo A.F. Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms.J. Neurosci. 2017; 37: 204-216Crossref PubMed Google Scholar, Recober et al., 2009Recober A. Kuburas A. Zhang Z. Wemmie J.A. Anderson M.G. Russo A.F. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine.J. Neurosci. 2009; 29: 8798-8804Crossref PubMed Scopus (75) Google Scholar, Sufka et al., 2016Sufka K.J. Staszko S.M. Johnson A.P. Davis M.E. Davis R.E. Smitherman T.A. Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.J. Headache Pain. 2016; 17: 40Crossref PubMed Scopus (6) Google Scholar). As photophobia is a sustained sensory amplification, it is reasonable to hypothesize that like allodynia, it reflects an underlying gain or plasticity process. While this has not been explicitly tested, the neural circuitry underlying the phenomenon has been examined. Two potentially interacting circuits may both be associated with photophobia (reviewed in Digre and Brennan, 2012Digre K.B. Brennan K.C. Shedding light on photophobia.J. Neuroophthalmol. 2012; 32: 68-81Crossref PubMed Scopus (0) Google Scholar): (1) retinal ganglion cells project to the olivary pretectal nucleus, which in turn projects to the superior salivatory nucleus, mediating parasympathetic outflow and dilation of intra-ocular arterioles that are densely innervated with trigeminal afferents(Okamoto et al., 2010Okamoto K. Tashiro A. Chang Z. Bereiter D.A. Bright light activates a trigeminal nociceptive pathway.Pain. 2010; 149: 235-242Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar), and (2) light-sensitive neurons in the posterolateral thalamus (mostly in the lateral posterior [LP] and Po nuclei) receive monosynaptic, convergent input from retinal ganglion cells and trigeminal afferents in the dura and send projections to several cortical areas, including primary and secondary visual cortex (V1 and V2) (Noseda et al., 2010aNoseda R. Kainz V. Jakubowski M. Gooley J.J. Saper C.B. Digre K. Burstein R. A neural mechanism for exacerbation of headache by light.Nat. Neurosci. 2010; 13: 239-245Crossref PubMed Scopus (284) Google Scholar, Noseda et al., 2016Noseda R. Bernstein C.A. Nir R.-R. Lee A.J. Fulton A.B. Bertisch S.M. Hovaguimian A. Cestari D.M. Saavedra-Walker R. Borsook D. et al.Migraine photophobia originating in cone-driven retinal pathways.Brain. 2016; 139: 1971-1986Crossref PubMed Scopus (44) Google Scholar). The elucidation of specific circuitry allows hypothesis testing on whether the percept of photophobia results from synaptic plasticity and, if so, from what synapse in the circuit. Infusion of CGRP in humans triggers migraine in migraineurs, but not normal subjects (Ashina et al., 2017Ashina M. Hansen J.M. Á Dunga B.O. Olesen J. Human models of migraine—short-term pain for long-term gain.Nat. Rev. Neurol. 2017; 13: 713-724Crossref PubMed Scopus (42) Google Scholar), and CGRP antagonists are a major new class of drugs currently in development for migraine (Russo, 2015Russo A.F. Calcitonin gene-related peptide (CGRP): a new target for migraine.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 533-552Crossref PubMed Scopus (136) Google Scholar). Mice overexpressing the CGRP receptor subunit RAMP1 have significantly increased photophobia compared to littermates (Kaiser et al., 2012Kaiser E.A. Kuburas A. Recober A. Russo A.F. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist.J. Neurosci. 2012; 32: 15439-15449Crossref PubMed Scopus (31) Google Scholar, Recober et al., 2009Recober A. Kuburas A. Zhang Z. Wemmie J.A. Anderson M.G. Russo A.F. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine.J. Neurosci. 2009; 29: 8798-8804Crossref PubMed Scopus (75) Google Scholar). Injection of CGRP, either intraperitoneally or in the cerebral ventricles, generates photophobia in wild-type mice (Mason et al., 2017Mason B.N. Kaiser E.A. Kuburas A. Loomis M.M. Latham J.A. Garcia-Martinez L.F. Russo A.F. Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms.J. Neurosci. 2017; 37: 204-216Crossref PubMed Google Scholar). While the response to peripheral injection might be expected due to expression and response patterns in primary nociceptors (Russo, 2015Russo A.F. Calcitonin gene-related peptide (CGRP): a new target for migraine.Annu. Rev. Pharmacol. Toxicol. 2015; 55: 533-552Crossref PubMed Scopus (136) Google Scholar), the response to cerebroventricular injection is more surprising. Interestingly, the CGRP receptor is also expressed in the CNS; indeed, structures expressing the CGRP receptor are proposed as a “visceral network” in the brain (de Lacalle and Saper, 2000de Lacalle S. Saper C.B. Calcitonin gene-related peptide-like immunoreactivity marks putative visceral sensory pathways in human brain.Neuroscience. 2000; 100: 115-130Crossref PubMed Scopus (56) Google Scholar) (red shading in Figure 2D). This putative network has not been explored in terms of migraine physiology, but it may provide an anatomical framework to test and might help explain photophobic responses to intracerebral injections where no nociceptive fibers are present. Cortical spreading depression (CSD), a massive concentric depolarization of neurons, glia, and vessels (Leao, 1944Leao A.A.P. Spreading depression of activity in cerebral cortex.J. Neurophysiol. 1944; 7: 359-390Crossref Google Scholar), is now recognized as the phenomenon underlying migraine aura (Charles and Brennan, 2009Charles A. Brennan K. Cortical spreading depression-new insights and persistent questions.Cephalalgia. 2009; 29: 1115-1124Crossref PubMed Scopus (92) Google Scholar, Pietrobon and Moskowitz, 2014Pietrobon D. Moskowitz M.A. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations.Nat. Rev. Neurosci. 2014; 15: 379-393Crossref PubMed Google Scholar). CSD passes through the cortex but has network effects that are far-ranging. The massive depolarization of CSD results in a cascade of events at the cortical surface that could trigger trigeminal nociception. Unlike the cortex itself, pial vessels and the dura are innervated with nociceptive afferents. CSD causes neuronal and glial depolarization, initiation of a parenchymal inflammatory cascade triggering release of inflammatory mediators from glia limitans and dural mast cell degranulation, constriction and dilation of surface vessels on which trigeminal afferents are located, and direct depolarization of nociceptive afferents through release of K+ and other mediators into the extracellular space (Charles and Brennan, 2009Charles A. Brennan K. Cortical spreading depression-new insights and persistent questions.Cephalalgia. 2009; 29: 1115-1124Crossref PubMed Scopus (92) Google Scholar, Karatas et al., 2013Karatas H. Erdener S.E. Gursoy-Ozdemir Y. Lule S. Eren-Koçak E. Sen Z.D. Dalkara T. Spreading depression triggers headache by activating neuronal Panx1 channels.Science. 2013; 339: 1092-1095Crossref PubMed Scopus (231) Google Scholar, Pietrobon and Moskowitz, 2014Pietrobon D. Moskowitz M.A. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations.Nat. Rev. Neurosci. 2014; 15: 379-393Crossref PubMed Google Scholar). The net result is a minutes-to-hours increase in the spontaneous firing rate of both TG and TNC neurons (Burstein et al., 2015Burstein R. Noseda R. Borsook D. Migraine: multiple processes, complex pathophysiology.J. Neurosci. 2015; 35: 6619-6629Crossref PubMed Scopus (202) Google Scholar, Noseda and Burstein, 2013Noseda R. Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain.Pain. 2013; 154: S44-S53Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar) (Figure 3A). This minutes-to-hours duration of increased spontaneous activity suggests either a very long-lasting activation of nociceptive fibers, or a potentiation process. Immediate early genes are used as indicators of LTP (Holtmaat and Caroni, 2016Holtmaat A. Caroni P. Functional and structural underpinnings of neuronal assembly formation in learning.Nat. Neurosci. 2016; 19: 1553-1562Crossref PubMed Scopus (60) Google Scholar), and c-fos expression is increased in TNC after CSD (Bolay et al., 2002Bolay H. Reuter U. Dunn A.K. Huang Z. Boas D.A. Moskowitz M.A. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model.Nat. Med. 2002; 8: 136-142Crossref PubMed Scopus (849) Google Scholar, Moskowitz et al., 1993Moskowitz M.A. Nozaki K. Kraig R.P. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms.J. Neurosci. 1993; 13: 1167-1177Crossref PubMed Google Scholar), likely consistent with potentiation of synapses onto TNC neurons by the event. There is also evidence that CSD can modulate evoked TNC activity after the event, which is also potentially consistent with plasticity induction: CSD depolarizes the whole thickness of the cortex, and corticofugal processes from layer 5 of insula and primary somatosensory cortex (S1) connect directly to TNC. Interestingly, CSD can induce opposite effects on evoked TNC firing, depending on whether it was induced in insula (potentiation) or S1 (suppression); this bimodal modulation of trigeminal evoked activity is unlikely to have been effected through trigeminal afferents alone (Noseda et al., 2010bNoseda R. Constandil L. Bourgeais L. Chalus M. Villanueva L. Changes of meningeal excitability mediated by corticotrigeminal networks: a link for the endogenous modulation of migraine pain.J. Neurosci. 2010; 30: 14420-14429Crossref PubMed Scopus (0) Google Scholar) (Figure 3A). In summary, CSD appears sufficient to activate trigeminal nociception, and sustain it for durations consistent with the migraine attack, possibly through plasticity mechanisms within the TNC. Moreover, cortical activity driven by CSD can modulate these TNC effects bidirectionally. However, a direct demonstration of potentiation in the trigeminal dorsal horn (e.g., via generation or occlusion of LTP) has not been performed. The aura, usually lasting tens of minutes, is followed by a much longer period of pain and sensory amplification. Beyond the effects of the depolarizing wave, CSD causes persistent changes in cortical function: there is a significant decrease in spontaneous neuronal activity and a long-lasting depolarization that coincides with cortical hypoperfusion after wave passage (Chang et al., 2010Chang J.C. Shook L.L. Biag J. Nguyen E.N. Toga A.W. Charles A.C. Brennan K.C. Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression.Brain. 2010; 133: 996-1012Crossref PubMed Scopus (72) Google Scholar, Lindquist and Shuttleworth, 2017Lindquist B.E. Shuttleworth C.W. Evidence that adenosine contributes to Leao’s spreading depression in vivo.J. Cereb. Blood Flow Metab. 2017; 37: 1656-1669Crossref PubMed Scopus (2) Google Scholar, Piilgaard and Lauritzen, 2009Piilgaard H. Lauritzen M. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex.J. Cereb. Blood Flow Metab. 2009; 29: 1517-1527Crossref PubMed Scopus (138) Google Scholar, Sawant-Pokam et al., 2017Sawant-Pokam P.M. Suryavanshi P. Mendez J.M. Dudek F.E. Brennan K.C. Mechanisms of neuronal silencing after cortical spreading depression.Cereb. Cortex. 2017; 27: 1311-1325PubMed Google Scholar). The evoked cortical sensory response is also altered during this time period. Both forepaw- and hindpaw-stimulated field potential maps are sharpened after CSD, with receptive field center responses potent
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