A. Historical Aspects

Headache has been known for probably 6,000 years, although it is not clear what type of headache (232). Migraine, indeed the more modern construct of chronic migraine, can be readily recognized in the work of Willis in the 17th Century (855). The debate over the pathophysiology of migraine has largely centered on neural or vascular mechanisms that may be involved in triggering and driving attacks. The arguments have existed for several centuries and have cycled somewhat. Historically, nearly 150 years ago both seemed to be prevalent, migraine was thought of as a disorder of the brain by Edward Liveing. In his famous text“On Megrim, Sick Headache, and Some Allied Disorders: A Contribution to the Pathology of Nerve-Storms”, he describes migraine as the result of “nerve-storm, an inherited tendency for the discharge of nerve force, a “neurosal seizure” (544). At the same time Peter Wallwork Latham lectured (509,510) and published“On Nervous or Sick-Headache” (511), describing the likely origin of migraine through vasodilation, triggered, interestingly, by aura; both theories have been reviewed in historical context (840). Latham used experimental observations in his laboratory, and migraine triggers, to demonstrate his theory, and he could be considered a trailblazer in some ways.

The studies of Wolff and colleagues in the 1940s on cranial blood vessels in conscious patients revisited the idea of migraine perhaps most likely being a vascular disorder (358,679,861). The concept persisted for nearly five decades until the development of sumatriptan both supported it (266), and yet led to its further questioning (435). As it emerged sumatriptan had both vascular and neural effects, so the role of the cranial vasculature was questioned. The theory of migraine pain being due to a sterile inflammation of the dural meninges caused by antidromic activation of the trigeminal nerve evolved (566). However, the spectacular failure of as many as 10 compounds that were active in the preclinical dural neurogenic inflammation model has cast considerable doubt on the concept (660). The description of purely neural effects of sumatriptan, such as those on nociceptive durovascular neurons in the trigeminocervical complex (419,462), began a renaissance of thinking of migraine and its treatment as primarily a neural construct.

B. Where Do We Stand Now?

Migraine certainly involves the brain. In some respects the controversy remains rather similar and pivots around two issues: initiation and the origin of the pain. While the initiation of a migraine attack is frequently associated with reported internal and external triggers, even this concept is being revisited by a more central interpretation that arises when considering the premonitory phase. The origin of the neuronal mechanisms that underlie the primary condition in susceptible people is still not known, and that must be a primary goal of research in this area. It is certainly widely accepted that migraine involves activation and sensitization of trigeminovascular pathways, as well as brain stem and diencephalic nuclei (21,91). Furthermore, a primary dysregulation of sensory processing is likely to result in the constellation of neurological symptoms that affect our senses. It has been suggested that migraine may be considered as a brain state of altered excitability (158,182,183,206,750). Certainly migrainous premonitory symptoms can occur many days before the headache (300,466,712); they are neurological symptoms that are non-nociceptive in their nature, which points to an origin in the brain. Furthermore, the identification of multiple genes responsible for familial hemiplegic migraine (FHM) (268), which increases the likelihood of severe aura symptoms, and the identification of a genetic predisposition in family studies (795), provides strong support for the view that migraineurs may be genetically susceptible or predisposed. While the termexcitability is often used to characterize these responses, a state of hypersynchrony (49,627) would explain the clinical symptoms of migraine very well.

C. Objectives of the Review

The objective of this review is to describe the clinical manifestations of migraine in a context of the clinical and preclinical data that illustrate the anatomy, physiology, and pharmacology relevant to these symptoms. The reviewed data will support the theory that migraine, at its core, is a disorder of the brain, caused by a dysfunction in areas of the brain stem and diencephalon that alter the perception of sensory inputs, and cause other neurological deficits. We will show how brain function is broadly affected when these system changes take place in migraine.

A. International Classification of Headache Disorders

The International Classification of Headache Disorders (ICHD), a valuable tool for the standardized diagnosis of primary and secondary headache disorders, which is now available in its third edition (ICHD-3, summarized inTable 1) (386). From its first (384) through second (385) editions, it led to a significant improvement in diagnostic accuracy, and to improved and focused preclinical and clinical research, in particular clinical trials, in an unprecedented way. However, given its aim to define the clinical picture for the use in a clinical setting, it focuses on the headache and aura phases as they are characterized by disabling symptoms that commonly require medical intervention. Its weakness is the over-reliance on a polythetic approach where there are a broad set of criteria without one or the other being necessary or sufficient. This contrasts to a monothetic approach where some or all parts are necessary and sufficient. The conflict comes with face validity for clinicians; it remains an unresolved issue. The impact on physiology is where migraine symptoms, such as osmophobia (464,714,878), are not mentioned because they are not usually “needed” by a polythetic approach, which may leave them less studied. In the review, we aim to capture as much of the pathophysiology as possible, and will be inclusive where possible, symptom-wise, and use the concept of phases, as limited as they be in a disorder that often is marked by a continuum.

B. Premonitory Symptoms

The majority of migraineurs experience a range of premonitory symptoms well before the typical migraine headache initiates. Despite being described in the literature for decades (228), their pathophysiological relevance and their clinical implications have been largely neglected. Premonitory symptoms of a migraine attack, which may precede the headache phase by up to 72 h (300), include changes in mood and activity, irritability, fatigue, food cravings, repetitive yawning, stiff neck, and phonophobia. These symptoms may endure well into the aura, headache (373), and even postdrome phases (105,299,465). The current ICHD-3beta precludes the existence of premonitory symptoms within 2 h of headache onset (386); this clearly has no logical basis and needs attention. We adopted above the definition of the symptoms starting anytime prior to headache. The consistency of these symptoms allows some migraineurs to reliably predict their migraine attacks (300). The fact that these symptoms are to a large extent of hypothalamic origin and imaging studies using H₂O PET show an increase in hypothalamic blood flow during the presence of premonitory symptoms (559) suggests a prominent role of the hypothalamus in the early stages of the attack.

Interestingly many of the trigger factors described by migraineurs, such as for example sleep deprivation, hunger, or bright light, may in fact represent premonitory symptoms of an already ongoing attack. This relationship explains why observations in clinical studies that aimed at prospectively identifying and validating trigger factors of migraine commonly differ from findings obtained from questionnaire-based studies in which patients merely describe their own perception of factors triggering their migraine attacks (401).

Understanding the pathophysiological mechanisms underlying the premonitory symptoms may offer insights in the structures of the central nervous system involved in the early phases of a migraine attack and ultimately contribute to identifying a novel therapeutic approach that would exert its action before the headache begins.

C. Aura Phase

About one-third of migraineurs experience transient neurological deficits, the migraine aura, in the context of their migraine attacks (678). The ICHD-3 defines the migraine aura as one or more transient, fully reversible neurological deficits, of which at least one has to have a unilateral localization, that develop over 5 min or more and of which each deficit lasts between 5 and 60 min. Detailed prospective diary study work has shown that 26% of patients have at least one of three auras that lasts longer than an hour (825). This draws attention to the polythetic problem, since investigation of aura lasting over an hour would be a large waste of resources. Five percent of auras are over 4 h (825), so perhaps that is a useful cut-off. While a visual aura, which may show positive (fortification spectra), negative (scotoma), or both phenomena, is found in over 90% of the cases, and the most common deficit, sensory, motor, speech, brain stem and retinal aura symptoms may also occur. Aura symptoms may precede the headache phase but may last well into the headache phase or even initiate during the headache phase. In contrast to the common belief that the aura and headache phases follow a sequential order, recent studies have demonstrated that the overlap of these phases is very common rather than being the exception (373). In migraineurs suffering from motor aura symptoms such as in hemiplegic migraine, aura symptoms usually show a longer duration and may last up to 72 h. In these severe cases of migraine aura, the deficits usually coexist with migraine headache. Remarkably, positive phenomena in hemiplegic aura are very unusual; one would predict jerks prior to weakness if there was invariably an initial depolarization. Since that is not the rule, the clinical phenomenology insists that one keeps an open mind about migraine aura pathophysiology going forward.

A transient wave of neuronal depolarization of the cortex, the cortical spreading depression (CSD), is believed to be the pathophysiological brain mechanism underlying the clinical phenomenon of migraine aura. While in humans the electrophysiological correlate of a CSD has not been demonstrated during a migraine aura, the correlation between the neurophysiological characteristics of a CSD, its retinotopic propagation on the visual cortex, and the characteristics and dynamics of the visual deficits suggest CSD as its pathophysiological correlate (158,513). Indirect observations derived from imaging studies further support this concept (192,366,640). Whether CSD is causally linked to the initiation of headache is still extensively debated and discussed in greater detail below; nevertheless, on the basis of the current understanding of migraine, it is unlikely that CSD is involved in the initiation of the complete syndrome of migraine (307).

D. Headache Phase

In the latest edition of the ICHD-3, migraine is defined as headache attacks lasting 4–72 h that are accompanied by nausea, photophobia and phonophobia, or both. The headache is characterized as unilateral, pulsating, of moderate or severe intensity and aggravated by physical activity; two of these characteristics suffice to fulfill the diagnostic criteria. Compared with previous editions, ICHD-3 distinguishes chronic migraine, which occurs on 15 or more days per month, from episodic migraine in a more practical fashion, building on the appendix definition (637). Whether the distinction has utility as it stands, i.e., whether the 15-day cut-off is appropriate, remains unclear. As yet, the distinction has not offered ground-breaking physiological insights.

E. Postdrome

The postdrome phase has been largely neglected and is not even defined in the glossary of terms in ICHD-3beta (386). The findings from the few studies that have focused on this last phase of a migraine attack indicate that its characteristic symptoms reflect those observed during the premonitory phase (105,299,465). A prospective, systematic electronic diary study, typical postdrome symptoms include tiredness, difficulties in concentrating, and neck stiffness. It remains unclear whether these symptoms initiate in the premonitory phase and persist throughout the headache phase into the postdrome phase, if they may also initiate during the headache phase, or even appear after the headache phase has ended. Migraineurs commonly relate symptoms of the postdrome phase to the medication that successfully abolished their headache, indicating that these symptoms appear or reappear after the headache phase has ended while they seem to play a negligible role during the headache phase. However, a meta-analysis of a clinical trial program revealed that postdrome symptoms are seen in the placebo arm most prominently when pain is relieved (318).

A. Neurophysiology of Migraine as a Backdrop to Imaging

The application of neurophysiological methods in migraine patients has offered important insights into the condition. These approaches offer temporal over spatial discrimination and prior to MRI, and still to some extent, better opportunities for repetition. What has emerged very clearly from studies in visual, somatosensory, auditory, and nociceptive domains is activation that differs from controls reliably. A prevailing synthesis of the data is to consider thalamocortical dysrhythmia (185,819) to be key to migraine pathophysiology (206). It has been observed for some time that migraine patients fail to habituate normally between attacks, for example, the intensity dependence auditory evoked potentials is augmented between attacks in migraine patients (37,834). Remarkably this normalizes in the days before an attack (452). Interestingly, this measure has a serotonin dependence that can be altered by triptans, serotonin 5-HT_1B/1D receptor agonists (see sect. IX) (671). Potentiation of the passive “oddball” auditory event-related potential similarly suggests migraineur's brains do not habituate as non-migraineurs do (833), as does an interical habituation deficit as measured by the nociceptive blink reflex in migraineurs (213). This has led to the concept that the migraine brain over-responds, as distinct from being hyperexcitable (38,181,182,709).

B. Inter-attack Imaging Studies

C. Premonitory Phase

From a clinical perspective, the premonitory phase that connects the asymptomatic interictal phase with the headache attack has to be crucial for understanding the mechanism of migraine ignition. One of the most important fMRI studies in this respect assessed the (de-)activation pattern elicited by trigemino-nociceptive stimulation of the nasal mucosa as the headache day approached (749). Compared with control subjects, interictal migraineurs have reduced activation of the spinal trigeminal nuclei. This deactivation had a cyclic behavior over the course of a migraine interval: there was normalization prior to the next attack and a significant reduction of deactivation during the attack (Figure 1). This cyclic behavior might thus reflect the increased susceptibility of the brain to generate the next attack, and the identification of its pacemaker would be crucial for our understanding of the start of a migraine attack.

The earliest clinical signs of a migraine attack are so-called premonitory symptoms, which occur prior to head pain but already tell the patient that a headache is on its way. Based on their manifestation, they are likely related to the hypothalamus (56,482) and include concentration problems, tiredness, irritability, or depression. Compared with the headache phase, they typically resemble some of the non-headache symptoms of a migraine attack and thus might persist during the headache phase. Recently, Maniyar et al. (559) triggered migraine attacks in eight patients with migraine without aura who could predict the occurrence of headache by a pronounced premonitory phase. During the premonitory phase, i.e., still in the absence of head pain, H₂¹⁵O-PET demonstrated activation of the hypothalamus, the midbrain ventral tegmental area, and the PAG (Figure 2). This functional correlate of premonitory symptoms suggests a possible role of the hypothalamus in generating migraine attacks. Of great interest in this regard are data from a single patient whose responses to trigeminal nociceptive stimuli were tracked with BOLD-fMRI over a 30-day period. Hypothalamic responses were increased as the attack neared, and there was coupling of the effects with the dorsolateral pons (715). In addition, the hypothalamus might be important for the non-headache symptoms during the pain phase since when studied in seven spontaneous migraine attacks with H₂¹⁵O-PET activation of the hypothalamus was seen (209), although the locations of both activations were distinct. It is noteworthy that activations seen in the trigeminal-autonomic cephalalgias (575,576,581,582,748) are more posterior than reported in migraine.

D. Aura Phase

The typical visual aura usually begins prior to the headache phase, but can also occur at the same time or even independently from any headaches (373,825). It often starts with a blind or scintillating spot in the center of the visual field (15). Lashley (506) reported some observations of his own visual aura: in his case, the scotoma increased in size over ∼1 h drifting in a C-shape toward the temporal field of one side. The velocity of the corresponding spread over the visual cortex was calculated to ∼3 mm/min. A hypothetical underlying mechanism was established only a few years later by Leão (517–519), who stimulated rabbit cortex electrically and found an EEG depression spreading at a similar rate of 3 mm/min centrifugally from the site of stimulation, and suggested it might be the basis for migraine aura (520). Over decades it was suggested that typical visual aura could be attributed to such a “cortical spreading depression” (CSD, see below) (513). The occurrence of CSD in humans remained hypothetical until Olesen et al. (640) injected¹³³Xe into the carotid artery during human migraine aura and demonstrated a spreading alteration of rCBF. Two decades later, patients who could trigger their visual aura or who were able to get access to the study center in the early phase of a visual aura were scanned with fMRI using checkerboard stimulation (366). The change of blood oxygenation level-dependent (BOLD) signal in the visual cortex in response to this checkerboard stimulation during the course of a visual aura behaved in various aspects similarly to the CSD from the animal model (518,519). This included a signal spread with a velocity of ∼3.5 mm/min, which corresponded to the clinical prediction (506) and the CSD elicited in rabbit cortex (518,519). This suggests that visual aura in migraine might indeed be a consequence of a CSD-like event. Hadjikhani et al. (366) further identified the origin of this peculiar response to checkerboard stimulation being in the visual association cortex V3A.

E. Headache Phase

As described earlier, perhaps the most striking symptom of a migraine attack for most patients is headache, although additional symptoms have to be present to make the diagnosis, such as nausea, photophobia, phonophobia, and movement sensitivity (386). Accordingly, the imaging pattern obtained during migraine attacks always represents a combination of these symptoms with some possibly reflecting individual symptoms, such as head pain, photophobia or allodynia, and others giving evidence of the underlying mechanisms.

F. Postdromal Phase

The postdromal phase follows the end of head pain for hours or days when the patient is pain-free but still does not feel back to normal. In contrast to the headache phase and the premonitory phase, the postdrome has not been studied specifically with brain imaging. This remains a substantial opportunity and a real challenge.

A. Peripheral Afferent Projections

The pain associated with the head in a migraine attack, including the frontal, temporal, parietal, occipital and high cervical region, is thought to be the consequence of activation of the trigeminovascular system (Figure 4). The anatomy of the trigeminovascular system has been well described over the last 70 years, and this has helped to understand the pathophysiology of migraine and the distribution of its pain. The brain is known to be largely insensate, but a rich plexus of nociceptive nerve fibers that originate in the trigeminal ganglion innervate the pial, arachnoid, and dural blood vessels, including the superior sagittal sinus and middle meningeal artery, as well as large cerebral arteries (594,658,679). Activation of these structures, particularly the dura mater, with mechanical, chemical, or electrical stimulation results in headache pain very similar to the pain in migraine, as well as other symptoms associated with migraine, including nausea and photophobia (594,658,679). Interestingly, stimulation of sites away from these blood vessels is much less nociceptive, with correspondingly lower symptoms of headache. The nociceptive innervation of the intracranial vasculature and meninges includes nonmyelinated (C-fibers) and thinly myelinated (Aδ-fibers) axonal projections, mainly through the ophthalmic (V1) division of the trigeminal nerve, but also to a lesser extent, through the maxillary (V2) and mandibular divisions (V3). There is also neuronal innervation of the dura mater from the cervical dorsal root ganglia (563). The axon terminals of nociceptive nerve fibers that innervate the dura mater contain vasoactive neuropeptides CGRP, substance P, neurokinin A, and pituitary adenylate cyclase-activating peptide (PACAP) (237,804–806) (Table 1), which are thought to be released upon stimulation causing vasodilation of dural and pial vessels (234,662,852).

B. Central Afferent Projection

There is also a central afferent projection from the trigeminal ganglion that enters the caudal medulla of the brain stem, via the trigeminal tract, which terminates in the spinal trigeminal nucleus caudalis (Sp5C; TNC), as well as the upper cervical spinal cord (C1–C2). Nociceptive Aδ- and C-fibers predominantly terminate in the superficial laminae, I and IIo, as well as deeper laminae V–VI (22,135,408,541,542,601) of the TNC and cervical extension. Stimulation of the dural vasculature in animal models, including the superior sagittal and transverse sinuses, and middle meningeal artery, results in activation of neurons in the TNC, C₁ and C₂ regions of the cervical spinal cord, together known as the trigeminocervical complex (TCC) (135,329,334,461). Furthermore, stimulation of the greater occipital nerve also causes neuronal activation in the same regions and enhances convergent inputs from the dural vasculature (75,76). These data suggest that the trigeminal nucleus extends beyond its caudalis boundary to the dorsal horn of the higher cervical region in a functional continuum that includes the cervical extension. This convergence of neuronal inputs into the TCC (330,422,463) and the convergence of inputs from intracranial and extracranial structures probably accounts for the distribution of pain perception in migraine over the frontal and temporal regions, plus the involvement of parietal, occipital, and higher cervical regions (74). Therefore, the severe and throbbing nature of pain in migraine is thought to result from activation, or the perception of activation, of these nociceptive inputs from intracranial and extracranial structures, that converge and are relayed through the TCC. Activation of these neural pathways in animal models of migraine has become a reliable way to further understand migraine pathophysiology, as well as being used to screen for potential therapeutic targets.

C. Ascending Projections From the TCC

All nociceptive information from craniovascular structures is relayed through the TCC, and via ascending connections to other areas of the brain stem and diencephalon, involved in the processing of pain and other sensory information. Functional physiological and tracing studies have allowed mapping of these ascending connections. Activation of these structures is thought to contribute to the perception of pain during migraine, and also to autonomic, endocrine, cognitive and affective symptoms that last throughout the entire migrainous episode.

There is a reflex connection from the trigeminal nucleus to the parasympathetic outflow to the cranial vasculature via the superior salivatory nucleus (SuS) (584). The SuS is activated by dural electrical stimulation (473), or directly from the brain stem (336), and this traverses back to the TCC via the parasympathetic outflow to the craniovasculature (25,312). There are also direct ascending connections with other medullary pontine nuclei including the rostral ventromedial medulla (RVM), nucleus raphe magnus (NRM), parabrachial nucleus and locus coeruleus (543,688), and midbrain nuclei, the ventrolateral periaqueductal gray (vlPAG) and cuneiform nucleus (543), with demonstrated functional nociceptive inputs from the dura mater (133,135,236,330,418,422). Somatosensory and visceral nociceptive information from the head and orofacial structures, via the TCC, is also conveyed directly to hypothalamic nuclei, along the trigeminohypothalamic tract, including the anterior, lateral, posterior, ventromedial, perifornical, and supraoptic hypothalamic nuclei (126,129,556–558), and activated by dural nociceptive stimulation (85,556). Likewise, functional dural inputs are relayed through the caudal medullary TCC, via the quintothalamic (trigeminothalamic) tract, to the thalamus (543,579,731,820,851). Specifically dural nociceptive inputs are processed in the ventroposteromedial (VPM) thalamus and its ventral periphery, the medial nucleus of the posterior complex, including posterior thalamic nucleus and the intralaminar thalamus (132,135,346,347).

D. Brain Stem and Thalamic Projections to Subcortical and Cortical Structures

The processing of pain is complex and mediated by a network of neuronal structures which include the cingulate cortex, insulae, and thalamus (211,799). The thalamus is believed to be at the heart of the central processing and integration of nociceptive information and is regarded as a relay center for handling the incoming sensory information, and even modulating it. A so-called “pain matrix,” which includes the thalamus, as well as primary (S1) and secondary (S2) somatosensory areas, anterior cingulate cortex (ACC), and prefrontal cortex, is believed to be involved in integrating all sensory, affective, and cognitive responses to pain, and becomes active during nociceptive processing (211,799). The extent to which parts of this matrix are attentional as much as a pain-related is debated (615). Other subcortical structures, which have anatomical connections to brain stem and thalamic nuclei, are known to be involved in this fluid network depending on the context of the pain, and likely contribute to the complexity of neurological symptoms experienced by migraineurs, additional to their headache. The amygdala and hippocampus are structures likely to be crucial in processing affective and cognitive responses to pain, respectively. Retrograde tracing from the amygdala reveals projections from the parabrachial nucleus and specifically lamina I and II of the TNC (445), which may contribute to an altered emotional state during migraine, and its comorbidity with anxiety disorders and depression (130). Furthermore, indirect projections from the trigeminal nucleus, through the amygdala to the hippocampus (484), confirmed in rodents, may contribute to altered cognition. It is likely that in time, continued research will reveal the importance of these and other subcortical structures to the pathophysiology of associated neurological symptoms in migraine.

Craniovascular projections, via trigeminovascular neurons, to VPM thalamic nuclei (876,877), have been identified and are believed to be the principal thalamic relay conveying nociceptive information to higher cortical pain processing regions (659). Other thalamic nuclei, which may also be involved in processing nociceptive craniovascular inputs includes the posterior (Po) and lateral posterior/dorsal (LP/LD) thalamic nuclei (132,202,632). Two recent studies have been able to trace the connections of these nuclei to the regions of the cortex that ultimately process this information (illustrated inFigure 4). In rat (631) and cat (501), dural nociceptive VPM neurons projected to mainly primary (S1) and secondary (S2) somatosensory cortices, as well as the insula. These data suggest that the processing of craniovascular sensory and discriminatory information, particularly in the ophthalmic (V1) trigeminal division, is somatotopically organized to cortical regions, which may account for the ability of migraineurs to localize their intracranial pain to specific head regions, as well as the intensity and quality of their pain. On the other hand, dural nociceptive Po, LP, and LD thalamic neurons project to many functionally distinct and anatomically remote cortical regions, including S1 and S2, but also to motor, parietal association, retrosplenial, auditory, visual and olfactory cortices (631). These data suggest that the processing of craniovascular nociceptive information in Po, LP, and LD thalamic neurons relay directly to cortical areas, suggesting a role in cognitive and motor deficits during migraine, as well as allodynia, photophobia, phonophobia, and osmophobia.

E. Interpretation of Human Imaging in Context

In the section on imaging studies the specific regions of the brain activated during spontaneous and experimentally induced migraine, and their contribution to other symptoms is explored. The anatomical and physiological preclinical studies described in this section plot the pathway of nociceptive craniovascular inputs through the trigeminovascular system that project and are processed in higher pain processing centers, and parallel the findings from the imaging studies in migraineurs. Thus there is clear translation between preclinical studies and clinical findings, with evidence of dorsal pontine and midbrain activation occurring during a migraine attack (9,842), even during premonitory symptoms, triggered by an experimental mediator (559). Also PET imaging studies demonstrate evidence of activation of hypothalamic nuclei (209), and activation in the ACC, frontal cortex, visual and auditory cortices, as well as the thalamic nuclei contralateral to the side in which the pain is experienced (9,66,842). Therefore, similar processing centers to those utilized after nociceptive activation are involved, with recent work using functional connectivity approaches that describe statistical dependencies between spatially segregated neurons (748,755,801). The anatomy and physiology of the pain pathways involved in migraine are well described and help us to understand their role in the pathophysiology of the generation of pain in migraine and the associated neurological symptoms.

A. Brain Stem Modulation

B. Hypothalamic Modulation

Imaging studies in migraine have predominantly located activation in the midbrain, with increased activation in the hypothalamus before (559) and during (209) also demonstrated. Activation in the hypothalamus more posteriorly in trigeminal autonomic cephalalgias (339) is well described (575,576,580,581). The hypothalamus is involved in a number of crucial physiological functions including controlling the sleep-wake cycle, feeding, thirst, arousal, and urination, as well as autonomic and endocrine regulation (650,727). These mechanisms implicate it in the early origins and premonitory symptoms of migraine, where sleep disturbance (348), changes in arousal (197) and mood, food craving, thirst, and urination (300) are known to occur and can increase the likelihood of an attack, as well as early symptoms.

The hypothalamus is also thought to be involved in pain processing. It has reciprocal connections with the TCC, including the trigeminal nucleus caudalis (556,558,688), as well as many structures involved in the processing of nociceptive inputs, including the nucleus tractis solitaris, RVM, PAG, and NRM (727). Nociceptive stimulation of the dura mater activates neurons in the anterior, posterior, ventromedial, and supraoptic hypothalamic nuclei, and potentially paraventricular hypothalamic nuclei (85,557). Hypothalamic nuclei also have descending projections to the SuS (423,424,688,745), where they are thought to be in involved in autonomic regulation, and its activation may contribute to autonomic symptoms in migraine (494), and especially trigeminal autonomic cephalalgias (315), as well as contributing to further activation of trigeminal afferents from the cranial vasculature (25,26,635). Hypothalamic descending projections are known to be involved in the descending modulation of nociceptive inputs at the spinal level (277), and several of these descending projections have been shown to modulate trigeminovascular nociceptive processing.

A. Premonitory Symptoms

Premonitory symptoms are part of the nonheadache symptoms of migraine attacks. Per definition, they occur prior to the onset of headache and are different from migraine aura. In a prospective electronic diary study, Giffin et al. (300) assessed whether migraineurs were able to identify non-headache symptoms that could predict migraine attacks. From the symptoms entered by the patients, 72% were indeed able to do so. The most common premonitory symptoms were feeling tired and weary (72%), concentration problems (51%), and neck stiffness (50%). Less common, but importantly, associated with a higher predictability of migraine attacks were yawning, blurred vision, noise sensitivity, difficulties of higher cortical function (such as reading, writing, speech, thinking), and feeling emotional and irritable. In addition, homeostatic regulation seems to be disturbed during the premonitory phase manifesting with thirst, nausea, hunger, frequent urination, or constipation (300). This complex pattern of symptoms has led to the hypothesis that the symptoms might be hypothalamic in nature and/or diffuse cerebral (106). Due to the difficulties of predicting migraine attacks, only a few basic science studies have addressed the pathomechanism of these symptoms despite the enormous implications for our understanding of migraine.

As mentioned in detail in section III, Stankewitz et al. (749) used fMRI after trigeminal nociceptive stimulation and found interictal reduced activation of the spinal trigeminal nuclei. This normalized prior to the next attack with even increased activation during the attack (Figure 1), although strictly not a study of the premonitory phase since the clinical phenomenology were not documented to make that distinction. Maniyar et al. (559) triggered acute migraine attacks with nitroglycerin and assessed rCBF in eight migraineurs using H₂¹⁵O-PET. Similar to the clinical description (106,300), they found a complex pattern of rCBF increase during the premonitory phase including subcortical (posterior hypothalamus, ventral tegmental area, PAG, dorsal pons, putamen, caudate nucleus, and the pulvinar nucleus of the thalamus) as well as cortical areas (occipital cortex, frontal, prefrontal, temporal, parietal cortex, anterior cingulate, and posterior cingulate) (Figure 2). The premonitory symptoms of the study participants were tiredness, neck stiffness, thirst, frequent urination, photophobia, nausea, yawning, and mood changes. By combining the clinical picture with the functional imaging results, we can map various premonitory symptoms to specific brain areas with putative novel treatment options of migraine. A key structure seems to be the hypothalamus, which could account for yawning, frequent urination, thirst, mood changes, through connections with the limbic system; food intake, craving and changes in sleep-wake cycle. Possible neurotransmitter systems involved in these processes are the dopaminergic system (56), vasopressin (482) and the orexins, which have in part been implicated in migraine therapy (78,284,829,830). Interestingly, the late premonitory phase does not show the hypothalamic activation, whereas, particularly, the cortical activity does persists, and even into the headache phase (559). One speculative interpretation is that the hypothalamic involvement might ignite the migrainous process that finally results in the disinhibition of the top-down modulation of the trigeminal activity resulting in head pain and thus the migraine attack (21).

B. Headache Characteristics

According to the ICHD, the headache in migraine has to have at least two properties that include unilateral, pulsating quality, moderate or severe intensity, and aggravation by or causing avoidance of routine physical activity (Table 1). As discussed in section I, activation of trigeminovascular pain pathways that innervate the dural vasculature is thought to be responsible for this headache quality. Studies in the 1940s on conscious patients undergoing cranial surgery confirm this (658,679). They found that manipulation of the dura mater with mechanical distension or electrical stimulation produced pain referred to the head that was localized to different regions depending on the sites of stimulation. While this stimulation did not trigger migraine in these patients, it did cause pain referred to specific regions of the head as well as some of its common associated symptoms (658,679). Stimulation of the superior sagittal sinus produced pain in the peri-orbital region; stimulation of the middle meningeal artery produced pain in the parietal or temporal region; and stimulation at the floor of the posterior fossa, sigmoid, transverse and occipital sinuses produced pain in the occipital region. Interestingly, stimulation away from the dural vessels was much less pain-producing.

Clearly activation of axons that innervate the dural vasculature and originate in the trigeminal ganglion is painful, and produces head pain. It seems likely that activation, or the perception of activation under normal conditions, of these nociceptive nerve fibers, sometimes termed meningeal nociceptors, which innervate the dural blood vessels is likely responsible for the severe and throbbing nature of pain in migraine. It remains unclear where that percept is processed. In preclinical studies, stimulation of the nociceptive specific dura mater (347,497) causes much greater increases in cerebral blood flow and release of CGRP and VIP, neuropeptides known to be released in severe migraine, than after stimulation of the trigeminal ganglion (324). While no animal model can claim to be inducing migraine, preclinical animal models that use mechanical or electrical stimulation of these dural blood vessels are likely activating the nociceptive pathways involved in generating the severe and pulsatile nature of the pain in migraine, as well as neurotransmitter release coincident in migraine.

In preclinical studies, mechanical or electrical stimulation of the dura mater only produces a short burst of neuronal activity in the TCC, whereas migraine pain and trigeminovascular activation is sustained for many hours. These short bursts of neuronal firing are likely to represent the severe and throbbing/pulsatile quality of head pain experienced during migraine, although experimentally for only a short time. However, it is believed that peripheral and central sensitization of trigeminovascular neurons may contribute to migraine duration. In preclinical studies an inflammatory soup placed upon the dura mater is able to activate and sensitize peripheral and central trigeminovascular neurons for several hours (135,766). This sensitization causes hypersensitivity to mechanical stimulation of the dural vasculature, including the sagittal and transverse sinuses, as well as expansion of the intracranial dural receptive field. More recent studies have shown that chemical migraine triggers, such the nitric oxide donor nityroglycerin, also cause sensitization of central trigeminovascular neurons, which produces hypersensitive responses to dural electrical stimulation (20). These studies demonstrate that peripheral and central sensitization of the trigeminovascular projection to the dural vasculature can exacerbate neuronal responses to innocuous mechanical and noxious intracranial dural inputs. This neural mechanism may provide an explanation for why normally innocuous physical activities such as exercise, or even unavoidable actions such as coughing, bending, and taking the stairs, can exacerbate the headache in migraine, and are frequently avoided where possible. It may also add to the throbbing nature of pain in migraine as well as explaining why migraineurs tend to try to stay still as much as they can, and more often stay in bed during an attack.

C. Photophobia and Phonophobia

How migraineurs commonly deal with their migraine is a clear indication of their hypersensitivity to sensory stimulation. Many patients will certainly report that during an attack they will go to bed, turn off the lights, and avoid any type of sensory stimulation from light, sound, touch, or smells, as if they are shutting themselves away from all possible sensory inputs. Indeed, included in the classification of migraine by the ICHD is that accompanying their migraine must be at least one of photophobia, phonophobia, nausea, and vomiting (386). Photophobia in migraine may take the form of migraine pain being worsened by light, photic allodynia, where the light is itself unpleasant without pain, photic hypersensitivity. In recent years, studies have begun to disseminate the likely neural mechanisms involved in their pathophysiology, specifically related to migraine (631). Findings determined that exacerbation of migraine headache requires an intact optic nerve, irrespective of visual ability. Damage to the optic nerve prevents the exacerbation of migraine headache to light, yet blind migraineurs with an intact optic nerve can experience worsening pain as a consequence of light (632). Studies in rats were also able to demonstrate that light is able to activate specifically dural-nociceptive posterior thalamic neurons, and this activation increases with increasing light intensity (632). A subgroup of these posterior thalamic neurons receives inputs from retinal ganglion cells, and these posterior thalamic neurons project to the somatosensory, visual, and associative cortices (Figure 8A). Similar findings have been made with respect to the TCC, where light can also activate nociceptive trigeminal neurons (635). The neural substrate for the exacerbation of migraine headache by light would seem to be a consequence of convergence of photic signals from the retina, via an intact optic nerve, onto dural nociceptive trigeminothalamic neurons, which subsequently project onto cortical areas (S1 and S2) involved in nociceptive processing.

As described in section III, migraineurs also report a hypersensitivity or abnormal sensitivity to light, something which is likely to be the consequence of cortical hyperresponsiveness. Interictally in migraineurs, luminous stimulation (600–1,800 Cd/m²) activates the visual cortex bilaterally, but there is no such activation in controls. Furthermore, when visual luminescent stimulation was combined with trigeminal pain stimulation, using heat applied to the ophthalmic region of the face, cortical activation was determined in the visual cortex in controls, and it potentiated activation in migraineurs (116) (Figure 8B). During spontaneous migraine, low luminescence (median 240 Cd/m²) that does not provoke visual cortical activation outside of migraine does cause activation during migraine, and also after pain relief with sumatriptan treatment (208) (Figure 8C), although this activation was statistically lower than during migraine. These studies demonstrate that interictally and ictally there is cortical hyperexcitability to light in migraineurs, and convergence of trigeminovascular nociceptive inputs with photic signals, potentially in the posterior thalamic region described above (632), from where axons project to the visual cortex, may explain the neural mechanism for hypersensitivity to light in migraineurs. Given that there is cortical hyperexcitability even after pain relief, it implies that cortical hyperexcitability, and heightened sensitivity to light, is not dependent on nociceptive trigeminovacular activation. Therefore, modulation of cortical excitability may also be under the control of other regions of the brain relevant to migraine pathophysiology, potentially brain stem nuclei.

D. Nausea and Vomiting

Nausea and vomiting are common features of migraine, and disturbance of food intake is frequently reported, whether this is reduced food intake from nausea, or food craving, which is often reported in the premonitory phase.

A. CSD and Brain Injury

For some time, CSD-like events had not been clearly demonstrated in migraine with aura patients, despite the evidence available from cases of brain injury (259,589,768). In a number of patients who had undergone craniotomies for subarachnoid hemorrhage, stroke, and traumatic brain injury, direct cortical electrocorticography recording demonstrated repetitive CSDs, which were negatively associated with outcome. It is clear from the available clinical data that the occurrence of CSDs may have a severe detrimental outcome, and this has recently been supported using experimental stroke models in familial hemiplegic migraine (FHM) mice (249). FHM mice exposed to transient occlusion of the middle cerebral artery experienced increased numbers of CSD, greater brain damage, and poorer outcome than controls. Originally the association between CSD and aura was postulated based on a number of similar features including rate of propagation. More recently, advances in brain imaging have enabled characteristic blood flow changes to be observed in humans, where an initial brief hyperemia (or hyperperfusion) is followed by a more prolonged oligemia (or hypoperfusion) spreading across the cortex, starting at the occipital lobe (192,366,636,702). The hypoperfusion correlates with the scotoma experienced by some patients during aura (369), and it is thought the hyperperfusion correlates with the negative symptoms.

B. CSD and Migraine Genetics

The genetics of migraine are clearly complex and are addressed in section X. It is however clear from a number of studies that alterations in CSD properties are a common phenotype. Initial studies characterizing the transgenic FHM mice which represent rare monogenic forms of migraine with aura highlighted an increased susceptibility to CSD, likely via increased cortical excitability. This increased propensity for cortical spreading depression was initially highlighted in FHM 1 (CACNA1A) mice (813) and later in FHM 2 (ATP1A2) mice (524). Despite early suggestions (586,787), the lack of a clear link with more common forms of migraine (795), the above models of genetic susceptibility for migraine with aura have advanced our understanding of possible links between the two related conditions (795). Recently a mutation in the casein kinase 1δ (CK1δ) enzyme was found to be associated with increased prevalence of migraine with aura; interestingly, a common phenotype of the newly developed transgenic mouse is also an increased susceptibility to CSD (119).

The question of the role CSD has in migraine remains, that is, does CSD predispose individuals to migraine without aura or is it simply an additive phenotype which transforms migraine without aura, to that with aura? Regardless of the ongoing debate which will only be answered by detailed translational research, the impact of CSD on the trigeminovascular system is giving up its secrets.

C. CSD Physiology

CSD was originally described in 1944 by Leao (518,519) as a spreading suppression of spontaneous EEG activity evoked by electrical stimulation of the rabbit cortex, and he later demonstrated that an initial depolarizing wave preceded the prolonged depression. It is now clear through a number of excellent studies that CSD results from the depolarization, followed by a sustained hyperpolarization [or quiescence (512,513)] of neurons and glial cells with almost a complete reversal of membrane potential resulting in breakdown of normal ionic gradients (743). Although the exact role of glial cells is unclear, blockade of astrocytic calcium waves (661) fails to block the spread of CSD indicating two parallel phenomenon. As a result of CSD, the cortical microenvironment is dramatically altered with large increases in extracellular potassium and hydrogen ions along with the release of arachidonic acid, glutamate, serotonin, and nitric oxide and concurrent decreases in intracellular sodium (743). Changes in perfusion that accompany the metabolic/electrocortical changes during CSD result in cortical blood flow changes: hyperemia (increased blood flow) followed by sustained oligemia (reduced blood flow) (120,519). These changes are thought to be a consequence of neurovascular coupling where perfusion increases to meet the demand of depolarization, and decreases following the hyperpolarization or quiescence (732). However, recent data have indicated that this neurovascular coupling is impaired during the oligemic phase (665) or there may even be an uncoupling of the vasomotor and neuronal changes (120,153), especially under conditions of brain injury (259,589,768). Interestingly, from a clinical perspective, brain stem changes may be seen with CSD in rat (616), although many antimigraine drugs do not alter it when used acutely (460). Moreover, the phenomenon is more easily triggered in female mice (121), implicating sex steroids. In addition, it has been shown that female mice with mutations known to produce familial hemiplegic migraine (see sect. X), S218L and R192Q, are more susceptible than CSD than males (248).

It has been demonstrated, using experimental animal models, that CSD induced by mechanical stimulation, pin-prick to the cortical surface, causes blood flow changes (23,407) that travel across the cortex, vasodilation of the middle meningeal artery, and increased neuronal activity of the TCC (110). This arterial vasodilation occurs coincident with the spread of blood flow changes, but also independently, after the initial increase in blood flow. More recently, electrophysiological studies have demonstrated that CSD induced with chemical, mechanical, or electrical stimulation can produce prolonged activation in ∼50% of meningeal nociceptors (879,880), which could last for nearly 2 h in some cases. If one looks at these data set as a whole, it would appear than CSD, approximately half the time, is able to activate neurons of the trigeminovascular system, specifically at the C1–C2 level of the spinal cord, and activation of meningeal nociceptors may contribute to the delayed dural vasculature changes that appear to be independent of CSD wave. However, this activation of trigeminovascular structures is not always observed (235,499,500), which may be explained by experimental and species differences, and has been observed independent of a peripheral input (500).

D. CSD and Trigeminovascular Activation

The exact mechanism leading to increased CSD evoked trigeminovascular throughput is, like so many other aspects, still debated (62,134,157,313). Interestingly, medicines used in migraine prevention can block CSD (19,63), as does vagal nerve stimulation (163). Recent evidence suggests that localized release of molecules activates meningeal nociceptors that can drive peripheral inputs to the TCC. In one study, CSD was shown to activate neuronal Panx1 megachannels, which can result in local sensitization of trigeminovascular afferents (457). However, CSD can also evoke brain stem and trigeminovascular mechanisms without activation of meningeal nociceptors; indeed, painless aura is a well-recognized concept (825). It is known to disrupt normal pain modulatory centers including the NRM (498), altering the processing of nociceptive inputs to the TCC. Direct corticotrigeminal projections have been demonstrated using a combination of electrophysiology and tract tracing. Two distinct functional networks exist (630), the first of which arises in the insula, projects to lamina I and II neurons in the TCC, and facilitates trigeminovascular nociceptive tone. The second originates in the primary sensory cortex, projects to deeper TCC lamina (III and IV), and is inhibitory. The exact impact of CSD on two distinct populations of cells each with opposing effects is difficult to ascertain in the rat due to spatial localization and rapid spread of CSD. However, in gyrencephalic brains where spatial distribution is greater and CSD is thought to be more localized, it is possible that individual CSDs could result in both a clear suppression and facilitation of trigeminal pain, based on their anatomical localization.

Thus it is likely that a combination of CSD peripheral trigeminovascular activation and central pain modulatory dysregulation underlie the association of CSD/aura and migraine. Perhaps the field of migraine research has been too focused on if CSD/aura is a trigger for migraine (discussed in sect. XIII) with or without aura, as many triggers are known to exist and should look at the disease as a whole. As presented above, migraine occurs in three stages with a premonitory phase starting 24–48 h before the attack long before CSD is known to occur. It is thus conceivable that a central disruption predisposes individuals to specific triggers, of which CSD/aura is one of many which may potentiate an already perturbed system.

A. Familial Hemiplegic Migraine

FHM represents a monogenic subtype of migraine with aura that involves at least one limb weakness. It does not, in spite of the name, usually involve plegia, rather weakness; the termhemiplegic is retained for historical consistency rather than neurological accuracy. The three responsible genes currently recognized were identified by classical linkage analysis in which genetic markers are compared with a specific disease trait. All three known FHM mutations encode mechanisms that impact ion transporters: theCACNA1A (FHM1) (645),ATP1A2 (FHM2) (203), andSCN1A (FHM3) (215) genes; their dysfunction ultimately leads to an increase in neuronal excitability (63).

B. Casein Kinase 1δ

In clinical practice migraineurs commonly report that abnormal sleep may trigger migraine attacks and that migraine leads to an abnormal sleep pattern (859,860). Attacks frequently start in the early morning (399), a time in which affected individuals usually are in their rapid-eye-movement (REM) sleep phase or shortly after waking up. In addition, changes in wakefulness may be part of the premonitory symptoms of a migraine attack. These observations and the fact that migraineurs show a higher incidence of narcolepsy (194,195) suggest that migraine may be linked to circadian mechanisms.

A missense mutation in the gene encoding casein kinase 1δ (CK1δ) has been linked to migraine (119,863). TheCK1δ gene is a ubiquitous serine-threonine kinase involved in the regulation of sleep patterns. A missense mutation in the DNA-sequence of theCK1δ gene results in a threonine-to-alanine alteration at amino acid 44 (T44A) of the protein leading to reduced enzyme activity. This genetic alteration and its functional consequences lead in humans, and transgenic mice with the human mutation inserted, to the clinical phenotype of the Familial Advanced Sleep Phase Syndrome (FASPS), which is characterized by an abnormal sleep pattern consisting of early sleep times and early-morning awakening (794,864). In six individuals of one family, the genetic alteration has not only been associated with FASPS but also with migraine with and without aura (119). This observation suggests that beyond being a central element in the regulation of sleep, CK1δ may be functionally relevant in migraine pathophysiology. A second missense mutation with a histidine-to-arginine change at amino acid 46 of theCK1δ gene has been identified to cause reduced enzyme activity and cosegregate with FASPS and migraine highlighting its potential functional relevance in both disorders (119).

To assess their functional relevance in migraine, a series of in vivo studies have been conducted on transgenic in vivo models with mice carrying the T44A mutation (119). These studies revealed that compared with their wild-type littermates, mice carrying the T44A mutation show increased hyperalgesia after intraperitoneal injection of nitroglycerin, a substance known to induce neuronal activation in the dorsal horn in mice and migraine attacks in migraineurs. Mice carrying theCK1δ-T44A gene also show a reduced threshold for the induction of CSD as well as an enhanced vasodilation of meningeal and cortical arteries following CSD. The latter is interesting in the context of CK1δ playing a role in glutamatergic transmission (164). Moreover, mice with the T44A mutation display a similar reduced trigeminocervical complex activation profile (400), as that cited above for FHM1 mice (654), linking in some respects the migraine-related biology of these two very different mutations. These observations suggest a pathophysiological influence on migraine aura and its functional consequences. Taken together, these preclinical and clinical findings suggest that mutations in theCK1δ gene may contribute to the pathogenesis of migraine and migraine aura.

C. TWIK-Related Spinal Cord Potassium Channel

A candidate gene approach led to the identification of the frameshift mutation F139WfsX24, encoded within theKCNK18 gene, which prematurely truncates the TWIK-related spinal cord potassium channel (TRESK) protein to 162 residues inducing a complete loss-of-function, in a large multigenerational family affected by migraine with aura (493). The influence of TRESK on neuronal resting membrane potential, its wide distribution throughout the CNS, its functional implication in pain pathways, and the segregation with migraine with aura led to the conclusion that theKCNK18 gene may be functionally involved in the pathogenesis of migraine, and the TRESK channel even represents a potential therapeutic target. This hypothesis has been supported by the fact that two-pore domain (K2P) potassium channels, such as the TRESK channel, are targeted by several volatile anesthetics leading to its activation. Investigation of mutant TRESK function points towards altered hyperexcitability in trigeminal ganglion neurons (540) and further that TRESK channel openers can reverse this hyperexcitability and may hold potential as therapeutic targets (365). However, further studies have revealed that other genetic mutations that also cause a complete loss-of-function of the TRESK channel and do not specifically segregate with migraine (48) have raised doubt on the functional consequence of mutations within theKCNK18 gene that lead to a dysfunctional TRESK channel, in regard to the pathogenesis of migraine. Nevertheless, the influence of K2P channels on neuronal excitability and on pain pathways may warrant further studies to investigate their potential as a therapeutic target.

D. Genome-Wide Association Studies

In recent years, genome-wide association studies (GWAS) have identified a series of single nucleotide polymorphisms (SNP) that may be relevant for the pathogenesis of migraine (53,54,159,160,283). GWAS are based on the hypothesis-free analysis of a large amount of SNPs in relation to specific disease traits. The advantage of this technique lies in the fact that compared with other genetic approaches a large number of genes can be analyzed with respect to a specific disease. However, due to the large amount of tests, GWAS are associated with several caveats inherent to the technique. Results have to be cautiously corrected for multiple testing, and only associations withP values below 5 × 10⁻⁸ can be considered significant (250). Furthermore, the identified genetic variants are characterized by a very low relative risk questioning their clinical significance. In contrast, if high-risk genetic variants exist which show only marginal allele frequency, a GWAS approach will likely miss this genetic association. Finally, GWAS do not capture interactions between allele variants that may be functionally relevant. As a result of these difficulties, conclusions regarding the relevance of GWAS findings for the pathophysiological mechanisms of migraine and their clinical significance, especially conclusions on an individual genetic risk, have to be interpreted with caution. Therefore, an identified association should always be confirmed in independent case-control studies before any conclusions are drawn.

Regardless of these technical considerations, three GWAS have been published with respect to migraine (53,54,159,160,283). These studies identified a series of potentially migraine-relevant susceptibility genes that are involved in glutamatergic neurotransmission (MTDH,LRP1, andMEF2D) and are functionally involved in pain-sensing pathways (TRPM8), neuronal development (MEF2D,ASTN2,PRDM16,PHACTR1, andTGFBR2), and brain vasculature function (PHACTR1 andTGFBR2). Among these genetic variants, the most consistent results have been observed forLRP1 andTRPM8. WhileLRP1 encodes a lipoprotein involved in nociceptive glutamatergic signaling (147),TRPM8 encodes a cold-sensitive calcium channel that may induce burning pain (84,592,656). The TRPM8-channel is expressed on unmyelinated C-fibers and myelinated Aδ-fibers (477) and may coexpress with TRPV1-channels and CGRP (212). Beyond peripheral sensory neurons (477), the TRPM8 channel has been identified on the trigeminal (2) and dorsal root ganglia (431), indicating a functional relevance in migraine. However, despite these anatomical observations, further in vivo studies are required to elucidate the functional consequences of mutations within theTRPM8 gene.

A challenging and exciting observation for the future is an initial finding of the SNP rs2651899 inPRDM16 has an odds ratio of 2.6 in predicting triptan efficacy in acute migraine treatment (168). Such a result suggests the eventual possibility of personalized medicine for the treatment of migraine.

Taken together, recent data suggest that in contrast to FHM, which appears to be a monogenic disease, common forms of migraine are likely to be the result of several genetic factors which interact with each other and with environmental influences that finally lead to an increase in the susceptibility of migraine.

A. Chemical Triggers and Inflammation

Environmental or experimental chemical triggers of migraine have proven, over the last 25 years, to be the most reliable approach for experimentally triggering migraine in the clinical setting (441). A number of molecules are accepted to trigger migraine (386). These are largely vasoactive and many are present at the nerve endings of perivascular nerve fibers innervating the cranial vasculature from the sensory, parasympathetic, and sympathetic nervous systems (Table 2) and are released as a consequence of activation, although not all appear to be released during migraine.

B. “Skipping Meals”

It is generally accepted that metabolic disturbances, such as fluctuations in water balance, food intake, mood, and sleep, contribute to migraine in some patients (228,300). According to some studies, lifetime migraineurs experience headache attacks preceded by triggering factors such as food deprivation and/or fasting (skipping meals) (196). However, it is debated whether fasting is actually a headache trigger or rather that food craving is a symptom in the premonitory phase of migraine. Blau and Cumings (108) attempted to identify a correlation between blood glucose and migraine, rather than fasting itself, and reported that fasting caused headache in 50% of migraineurs. The authors proposed “some patients have some of their attacks of migraine fired off by missing a meal, and that this is related to a low blood sugar, which must persist in that individual for a certain length of time to cause headache.” Although there are many observations of food cravings during the premonitory phase of migraine, with researchers reporting that some patients would crave for sweet foods (228), and one study, using individual electronic diaries, reported that 18% of the patients reported hunger or food craving as triggers of their headache (300). These studies clearly demonstrate a blurring of the lines between altered feeding as either a cause or a symptom in migraine.

Some authors have tried to reconcile these two migrainous attributes, with Martin and Seneviratne (568) offering an explanation for their finding that food deprivation caused headache in 58% of patients with frequent migraine or tension-type headache. The authors write that “hunger arising from low blood sugar levels, for example, may lead to cravings for particular foods such as chocolate, on the one hand, and lead to headaches, on the other hand, but the headaches may be erroneously attributed to the food consumption rather than the low blood sugar levels.” Perhaps what these studies demonstrate most is the importance of alteration of the feeding schedule, either skipping or delaying meals, in migraineurs, as it clearly has an impact on the phenotype of patient suffering.

What is understood about the neural mechanisms that regulate feeding is that they are controlled within the hypothalamus (742,869), a brain structure that we know to be active and involved in migraine pathophysiology (21,559), and this structure is likely to impact our understanding of the role of altered feeding in migraine. The hypothalamus is a major center of convergence and integration of several nutrient-related signals and, thus, hypothalamic neurons are thought to promote the homeostasis of physiological systems involved in synchronization of circadian rhythms, salt balance, appetite and energy expenditure, thirst and water balance, among other functions (690). A summary of the hypothalamic pathways and neuropeptides involved can be found inFigure 9, and the subject is extensively reviewed elsewhere (220,742,869).

C. “Sleep Disruption”

The relationship between migraine and sleep has been debated for a number of years (625). Sleep is considered an effective means of alleviating pain associated with migraine, migraine can emerge during nocturnal sleep or following a brief period of daytime sleep, and attacks can be preceded by a lack of sleep. Furthermore, sleepiness might also emerge during various phases of a migraine attack (71). Sleep deprivation or consistent interrupted or reduced sleep is also described by many patients as a possible trigger of migraine (107). The regulation of sleep, particularly within the hypothalamus, is strongly linked to the regulation of feeding processes, and the interaction of both of these homeostatic mechanisms is likely involved in the triggering of migraine.

D. “Stress”

Stress and negative emotions are commonly listed as triggers by migraineurs (227,300). Although stress-sensitive patients may perceive more stress in the days before an impending migraine attack, there is very little experimental evidence showing a biological stress response in migraineurs. Migraine patients were reported to have large variations in plasma cortisol levels, a stress response indicator, compared with the control group, and a subgroup of migraine patients exhibited abnormal circadian levels of cortisol (882). A study also showed statistically significant associations between the cortisol response and both headache severity and duration (355). While stress as a trigger may also be related to other potential triggers that are a response to disrupted homeostasis, such as sleep and food deprivation reviewed above, we will describe the mechanisms through which “stress” may contribute to these processes.

The hypothalamo-pituitary-adrenocortical (HPA) axis is recruited by the organism in response to real or perceived threats to homeostasis or “stress.” Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are produced in the parvocellular neurons of the hypothalamic PVN. These neurons secrete peptides into the portal vessel system to activate the synthesis of pro-opiomelanocortin (POMC) in the anterior pituitary, which is processed to corticotropin (ACTH), opioid and melanocortin peptides, among others. Then, ACTH stimulates the adrenal cortex to secrete cortisol (humans) and corticosterone (humans, rats, and mice) as a stress response (reviewed in Ref.205). Signals of homeostatic imbalance in the brain stem also lead to activation of the HPA axis:ascending brain stem and spinal pathways project to the parvocellular divisions of the PVN. For instance, noradrenergic and adrenergic projections to the hypophysiotrophic zone of the PVN originate in the NTS and C1–C3 (189,190) and participate in the HPA axis. Furthermore, in a preclinical animal model of migraine using nociceptive activation of trigeminovascular neurons, a stress protocol in these animal reduced the ability of PVN neurons to provide descending control of trigeminovascular nociceptive neurons (688).

A. Serotonin

The initial involvement of serotonin (5-HT) in migraine was postulated more than 50 years ago with seminal observations of increased 5-hydroxyindoleacetic acid (metabolite of 5-HT) associated with migraine attacks (191,734). Further evidence was gained from two key studies identifying reductions in platelet 5-HT during attack onset (50) and that infusion of 5-HT could abort both reserpine-induced (468) and spontaneous headache (503). In response to these seminal studies, the 5-HT receptor system gained much attention culminating in the discovery of the triptans, serotonin, 5-HT_1B/1Dreceptor agonists (434).

B. CGRP

CGRP is a 37-amino acid neuropeptide with potent vasodilator effects (486,852) that is produced by alternative splicing of the calcitonin gene (35,692). Other members of the gene family are amylin, adrenomedullin, and adrenomedullin 2 (intermedin) (694). With respect to the nervous system, αCGRP is predominantly expressed, while βCGRP is associated with the enteric sensory system (617). CGRP acts at two receptors: one, the so-called canonical CGRP-receptor complex, is made up of a G protein-coupled receptor consisting of a seven transmembrane spanning protein (calcitonin receptor-like receptor; CLR) and a single transmembrane receptor modifying protein (RAMP) 1 (16,593). RAMP 1 is critical for the transport and cell surface expression of the CGRP receptor complex (593), and its overexpression results in migraine like phenotypes including light aversion and CGRP induced allodynia (453,680,681,696). The second CGRP receptor has been called the amylin receptor (AMY₁) and consists of the calcitonin receptor (CTR) and RAMP 1 (382). It has now been clearly shown that CGRP activates this receptor (831). Amylin is a glucoregulatory hormone and has additional bone metabolism effects.

CGRP is widely distributed including in the striatum, amygdala, hypothalamus, thalamus, brain stem, and TCC (404,816,868). Within the primary afferent trigeminovascular pathways, CGRP expression is highest in the sensory trigeminal ganglion and its Aδ and C-fiber projections to cerebral and dural blood vessels as well as centrally to the spinal cord (242,246,780), where it can impact second-order ascending projections. Functional CGRP receptors and binding sites have been identified on dural artery smooth muscle cells and in the trigeminal ganglia, thalamus, hypothalamus, amygdala, cortex, and brain stem (238,246,523,643,769). Interestingly, in the TCC, CGRP receptors are thought to colocalize with CGRP in terminals of primary afferents and not ascending fibers (523).

CGRP is a potent vasodilator which when given to migraine sufferers is known to trigger attacks (508); however, the exact triggering mechanism is not clear since VIP, another potent vasodilator, fails to initiate attacks (674), suggesting a nonvascular mechanism. As discussed earlier, CGRP is released during spontaneous (325) or triggered attacks (289), which can be inhibited by triptan treatment (323). Experimental activation of trigeminal ganglion cells is known to result in the release of CGRP, which is dose dependently inhibited by 5-HT_1B1D agonists (231), highlighting the trigeminal ganglion as a key site that may be a target of CGRP receptor antagonism and triptan response (245,247). In addition to its vascular effects, CGRP has emerged as a key modulator of neuronal function, which has important effects on neurotransmitter systems such as the glutamatergic system (760). Local administration of CGRP facilitates dorsal horn and TCC nociceptive neurons, while CGRP antagonism points towards a tonic facilitatory role as blockade with the truncated CGRP_8–37reduced neuronal responses below baseline levels (760). Similarly targeted administration of CGRP to the ventrolateral PAG facilitates trigeminovascular processing via descending modulatory mechanisms (668), while thalamic modulation identified a clear inhibitory action of CGRP antagonism, both on nociceptive signaling and spontaneous background activity (769).

C. NO Synthase

NO is an abundant gaseous signaling molecule which like the previously mentioned neuropeptides is involved in a variety of functions including endothelial dependent vasodilation (441). NO donors, such as glyceryltrinitrate/nitroglycerin, like CGRP (508) and PACAP (720), are used for the experimental induction of migraines (439,441) and premonitory symptoms (11). Given the clear role of NO donors in triggering attacks, it is not surprising that they have received similar attention in preclinical models where they produce vasodilation (30,767) and trigeminovascular activation (480,495,783). Perhaps the most interesting feature of experimental NO use is the biphasic nature of the TCC activation with an initial acute activation and a delayed general activation (20,480) which appears to mirror the acute throbbing and delayed migraine seen in patients. NO donors clearly facilitate trigeminovascular activation resulting in activation of the TCC with resultant increases in CGRP and neuronal NO synthase (652,653) and NO synthase inhibitors have also proven preclinical efficacy. NO synthases are a family of enzymes which catalyze the production of NO consisting of endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Nonspecific blockade of NOS prevents neurogenic dural vasodilation (31) and TCC neuronal activation (417,634). Interestingly, and in support of the current theme of migraine as a neurovascular disorder, specific nNOS inhibitors mimic the effects of nonspecific blockers (31,93).

The available clinical and preclinical data highlighted NOS inhibitors as a reasonable target for anti-migraine therapy, and while early studies showed beneficial outcomes (507), they were not without issue. Given the unwanted side effects of eNOS actions, current research has focused towards other specific NOS inhibitors, with the initial study of a specific iNOS inhibitor failing to reach its clinical end point in both an acute (649) and preventive study (403). A mixed triptan and nNOS inhibitor NXN-188 was also found to be ineffective in both migraine without aura (595) and specifically in the aura phase (428). The issue of a possible effect of a specific nNOS inhibitor is unresolved.

D. PACAP

PACAP like CGRP is released during migraine (803,874,875) and can trigger attacks (720) in patients leading to its exploration as a possible anti-migraine target. It is a member of the VIP-glucagon growth hormone releasing factor-secretin superfamily which comes in two forms; PACAP-38 accounts for ∼90%, whereas PACAP-27 is relatively poorly expressed (57). Like the majority of neuropeptide targets, PACAP is widespread throughout the CNS and peripheral tissue (574,806,808) where it has potent vasodilator effects. PACAP is known to have a specific uptake mechanism into the brain (70). The pharmacology of PACAP is slightly more complex due to its binding affinities to three G protein-coupled receptors which also bind VIP. It should be highlighted again that VIP does not induce migraine unlike PACAP and CGRP, highlighting the importance of nonvascular targets. VPAC1 and -2 bind VIP, PACAP-38, and PACAP-27 in order of descending affinity while PAC1 is relatively specific for PACAP (492). It is expressed in the TCC, spinal cord, trigeminal ganglia, sphenopalatine ganglia, and CNS structures including the thalamus, hypothalamus, and brain stem (186,450,574,779,808). It is likely the central expression pattern underlies the proposed role in migraine, and like CGRP, PACAP has been linked to sensitization and light aversion (564). This facilitatory role has recently been demonstrated in the hypothalamus where PACAP administration facilitated trigeminovascular nociception via a PAC1 mechanism (688).

Recently, in a rodent model of nociceptive trigeminovascular activation, it has been shown that VIP and PACAP-38 caused short-lived meningeal vasodilation mediated by VPAC2 receptors, without activation of central trigeminovascular neurons (17). PACAP-38 and not VIP caused a delayed activation and sensitization of central trigeminovascular neurons, in this context behaving as it does in triggering migraine (720). Intravenous delivery of a PAC1 receptor antagonist inhibited the peripheral meningeal vasodilatory effects of dural trigeminovascular nociception, whereas only central (intracerebroventricular) administration of the PAC1 receptor antagonist inhibited dural nociceptive trigeminovascular activation (17), suggesting a central PAC1 receptor as an important target. While not as advanced as CGRP targeting, it is clear that PACAP has a role to play in the pathogenesis of migraine and as such will continue to progress as a therapeutic target.

• 1.Abdallah K, Artola A, Monconduit L, Dallel R, Luccarini P. Bilateral descending hypothalamic projections to the spinal trigeminal nucleus caudalis in rats. PLoS One8: e73022, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 2.Abe J, Hosokawa H, Okazawa M, Kandachi M, Sawada Y, Yamanaka K, Matsumura K, Kobayashi S. TRPM8 protein localization in trigeminal ganglion and taste papillae. Brain Res136: 91–98, 2005. [DOI] [PubMed] [Google Scholar]
• 3.Abizaid A.Ghrelin and dopamine: new insights on the peripheral regulation of appetite. J Neuroendocrinol21: 787–793, 2009. [DOI] [PubMed] [Google Scholar]
• 4.Abizaid A, Horvath TL. Ghrelin and the central regulation of feeding and energy balance. Indian J Endocrinol Metab16: S617–626, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 5.Adam JA, Menheere PP, van Dielen FM, Soeters PB, Buurman WA, Greve JW. Decreased plasma orexin-A levels in obese individuals. Int J Obes Relat Metab Disord26: 274–276, 2002. [DOI] [PubMed] [Google Scholar]
• 6.Adamantidis A, Salvert D, Goutagny R, Lakaye B, Gervasoni D, Grisar T, Luppi PH, Fort P. Sleep architecture of the melanin-concentrating hormone receptor 1-knockout mice. Eur J Neurosci27: 1793–1800, 2008. [DOI] [PubMed] [Google Scholar]
• 7.Adrian TE, Allen JM, Bloom SR, Ghatei MA, Rossor MN, Roberts GW, Crow TJ, Tatemoto K, Polak JM. Neuropeptide Y distribution in human brain. Nature306: 584–586, 1983. [DOI] [PubMed] [Google Scholar]
• 8.Afra J.Intensity dependence of auditory evoked cortical potentials in migraine. Changes in the peri-ictal period. Funct Neurol20: 199–200, 2005. [PubMed] [Google Scholar]
• 9.Afridi S, Giffin NJ, Kaube H, Friston KJ, Ward NS, Frackowiak RSJ, Goadsby PJ. A PET study in spontaneous migraine. Arch Neurol62: 1270–1275, 2005. [DOI] [PubMed] [Google Scholar]
• 10.Afridi S, Giffin NJ, Kaube H, Goadsby PJ. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology80: 642–647, 2013. [DOI] [PubMed] [Google Scholar]
• 11.Afridi S, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain110: 675–680, 2004. [DOI] [PubMed] [Google Scholar]
• 12.Afridi S, Kaube H, Goadsby PJ. Occipital activation in glyceryl trinitrate-induced migraine with visual aura. J Neurol Neurosurg Psychiatry76: 1158–1160, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 13.Afridi S, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RSJ, Goadsby PJ. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain128: 932–939, 2005. [DOI] [PubMed] [Google Scholar]
• 14.Ahn AH.On the temporal relationship between throbbing migraine pain and arterial pulse. Headache50: 1507–1510, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 15.Airy H.On a distinct form of transient hemiopsia. Philos Trans R Soc Lond160: 247, 1870. [Google Scholar]
• 16.Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, Li Y. A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J Biol Chem271: 11325–11329, 1996. [DOI] [PubMed] [Google Scholar]
• 17.Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: relevance to migraine. Sci Transl Med7: 1–11, 2015. [DOI] [PubMed] [Google Scholar]
• 18.Akerman S, Goadsby PJ. The role of dopamine in a model of trigeminovascular nociception. J Pharmacol Exp Ther314: 162–169, 2005. [DOI] [PubMed] [Google Scholar]
• 19.Akerman S, Goadsby PJ. Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura. Neuroreport16: 1383–1387, 2005. [DOI] [PubMed] [Google Scholar]
• 20.Akerman S, Hoffmann J, Goadsby PJ. A translational approach to studying triptan-induced reversal of established central sensitization of trigeminovascular neurons. Cephalalgia33: 211, 2013. [Google Scholar]
• 21.Akerman S, Holland P, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nature Rev Neurosci12: 570–584, 2011. [DOI] [PubMed] [Google Scholar]
• 22.Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther320: 64–71, 2007. [DOI] [PubMed] [Google Scholar]
• 23.Akerman S, Holland PR, Goadsby PJ. Mechanically-induced cortical spreading depression associated regional cerebral blood flow changes are blocked by Na⁺ ion channel blockade. Brain Res1229: 27–36, 2008. [DOI] [PubMed] [Google Scholar]
• 24.Akerman S, Holland PR, Lasalandra M, Goadsby PJ. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in migraine. J Neurosci33: 14869–14877, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 25.Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not via direct dural activation of trigeminal afferents. Headache49: 1131–1143, 2009. [DOI] [PubMed] [Google Scholar]
• 26.Akerman S, Holland PR, Summ O, Lasalandra MP, Goadsby PJ. A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization. Brain135: 3664–3675, 2012. [DOI] [PubMed] [Google Scholar]
• 27.Akerman S, Kaube H, Goadsby PJ. Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors. Br J Pharmacol142: 1354–1360, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 28.Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther309: 56–63, 2004. [DOI] [PubMed] [Google Scholar]
• 29.Akerman S, Williamson DJ, Kaube H, Goadsby PJ. The effect of anti-migraine compounds on nitric oxide-induced dilation of dural meningeal vessels. Eur J Pharmacol452: 223–228, 2002. [DOI] [PubMed] [Google Scholar]
• 30.Akerman S, Williamson DJ, Kaube H, Goadsby PJ. Nitric oxide synthase inhibitors can antagonise neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol137: 62–68, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 31.Akerman S, Williamson DJ, Kaube H, Goadsby PJ. Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels. Br J Pharmacol137: 62–68, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 32.Albers HE, Ottenweller JE, Liou SY, Lumpkin MD, Anderson ER. Neuropeptide Y in the hypothalamus: effect on corticosterone and single-unit activity. Am J Physiol Regul Integr Comp Physiol258: R376–R382, 1990. [DOI] [PubMed] [Google Scholar]
• 33.Alstadhaug K, Salvesen R, Bekkelund S. Insomnia and circadian variation of attacks in episodic migraine. Headache47: 1181–1188, 2007. [DOI] [PubMed] [Google Scholar]
• 34.Altier N, Stewart J. Intra-VTA infusions of the substance P analog, DiMe-C7, and intra-accumbens infusions of amphetamine induce analgesia in the formalin test for tonic pain. Brain Res628: 279–285, 1993. [DOI] [PubMed] [Google Scholar]
• 35.Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature298: 240–244, 1982. [DOI] [PubMed] [Google Scholar]
• 36.Amaral DG, Sinnamon HM. The locus coeruleus: neurobiology of a central noradrenergic nucleus. Prog Neurobiol9: 147–196, 1977. [DOI] [PubMed] [Google Scholar]
• 37.Ambrosini A, Rossi P, De Pasqua V, Pierelli F, Schoenen J. Lack of habituation causes high intensity dependence of auditory evoked cortical potentials in migraine. Brain126: 2009–2015, 2003. [DOI] [PubMed] [Google Scholar]
• 38.Ambrosini A, Schoenen J. The electrophysiology of migraine. Curr Opin Neurol16: 327–331, 2003. [DOI] [PubMed] [Google Scholar]
• 39.Amin FM, Asghar MS, Guo S, Hougaard A, Hansen AE, Schytz HW, van der Geest RJ, de Koning PJ, Larsson HB, Olesen J, Ashina M. Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia32: 140–149, 2012. [DOI] [PubMed] [Google Scholar]
• 40.Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJ, Larsson HB, Olesen J, Ashina M. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol12: 454–461, 2013. [DOI] [PubMed] [Google Scholar]
• 41.Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain137: 779–794, 2014. [DOI] [PubMed] [Google Scholar]
• 42.Amrutkar DV, Ploug KB, Hay-Schmidt A, Porreca F, Olesen J, Jansen-Olesen I. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system. Pain153: 830–838, 2012. [DOI] [PubMed] [Google Scholar]
• 43.Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol12: 1–27, 2005. [DOI] [PubMed] [Google Scholar]
• 44.Andreou AP, Goadsby PJ. Topiramate in the treatment of migraine: a kainate (glutamate) receptor antagonist within the trigeminothalamic pathway. Cephalalgia31: 1343–1358, 2011. [DOI] [PubMed] [Google Scholar]
• 45.Andreou AP, Holland PR, Akerman S, Summ O, Fredrick J, Goadsby PJ. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain. In press. [DOI] [PMC free article] [PubMed]
• 46.Andreou AP, Holland PR, Lasalandra M, Goadsby PJ. Modulation of nociceptive dural input to the trigeminocervical complex via GluK1 kainate receptors. Pain156: 439–450, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 47.Andreou AP, Shields KG, Goadsby PJ. GABA and valproate modulate trigeminovascular nociceptive transmission in the thalamus. Neurobiol Dis37: 314–323, 2010. [DOI] [PubMed] [Google Scholar]
• 48.Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafreniere RG, Roy B, Griffiths LR, Rouleau GA, Ebers GC, Cader ZM, Tucker SJ. Functional analysis of missense variants in the TRESK (KCNK18) K channel. Scientific Reports2: 237, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 49.Angelini L, de Tommaso M, Guido M, Hu K, Ivanov P, Marinazzo D, Nardulli G, Nitti L, Pellicoro M, Pierro C, Stramaglia S. Steady-state visual evoked potentials and phase synchronization in migraine patients. Phys Rev Lett93: 038103–038104, 2004. [DOI] [PubMed] [Google Scholar]
• 50.Anthony M, Hinterberger H, Lance JW. Plasma serotonin in migraine and stress. Arch Neurol16: 544–552, 1967. [DOI] [PubMed] [Google Scholar]
• 51.Antonijevic IA, Murck H, Bohlhalter S, Frieboes RM, Holsboer F, Steiger A. Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men. Neuropharmacology39: 1474–1481, 2000. [DOI] [PubMed] [Google Scholar]
• 52.Antonova M, Wienecke T, Olesen J, Ashina M. Prostaglandin E₂ induces immediate migraine-like attack in migraine patients without aura. Cephalalgia32: 822–833, 2012. [DOI] [PubMed] [Google Scholar]
• 53.Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, Nyholt DR, Dimas AS, Freilinger T, Muller-Myhsok B, Artto V, Inouye M, Alakurtti K, Kaunisto MA, Hamalainen E, de Vries B, Stam AH, Weller CM, Heinze A, Heinze-Kuhn K, Goebel I, Borck G, Gobel H, Steinberg S, Wolf C, Bjornsson A, Gudmundsson G, Kirchmann M, Hauge A, Werge T, Schoenen J, Eriksson JG, Hagen K, Stovner L, Wichmann HE, Meitinger T, Alexander M, Moebus S, Schreiber S, Aulchenko YS, Breteler MM, Uitterlinden AG, Hofman A, van Duijn CM, Tikka-Kleemola P, Vepsalainen S, Lucae S, Tozzi F, Muglia P, Barrett J, Kaprio J, Farkkila M, Peltonen L, Stefansson K, Zwart JA, Ferrari MD, Olesen J, Daly M, Wessman M, van den Maagdenberg AM, Dichgans M, Kubisch C, Dermitzakis ET, Frants RR, Palotie A. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet42: 869–873, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 54.Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, Kallela M, Malik R, de Vries B, Terwindt G, Medland SE, Todt U, McArdle WL, Quaye L, Koiranen M, Ikram MA, Lehtimaki T, Stam AH, Ligthart L, Wedenoja J, Dunham I, Neale BM, Palta P, Hamalainen E, Schurks M, Rose LM, Buring JE, Ridker PM, Steinberg S, Stefansson H, Jakobsson F, Lawlor DA, Evans DM, Ring SM, Farkkila M, Artto V, Kaunisto MA, Freilinger T, Schoenen J, Frants RR, Pelzer N, Weller CM, Zielman R, Heath AC, Madden PA, Montgomery GW, Martin NG, Borck G, Gobel H, Heinze A, Heinze-Kuhn K, Williams FM, Hartikainen AL, Pouta A, van den Ende J, Uitterlinden AG, Hofman A, Amin N, Hottenga JJ, Vink JM, Heikkila K, Alexander M, Muller-Myhsok B, Schreiber S, Meitinger T, Wichmann HE, Aromaa A, Eriksson JG, Traynor BJ, Trabzuni D, Rossin E, Lage K, Jacobs SB, Gibbs JR, Birney E, Kaprio J, Penninx BW, Boomsma DI, van Duijn C, Raitakari O, Jarvelin MR, Zwart JA, Cherkas L, Strachan DP, Kubisch C, Ferrari MD, van den Maagdenberg AM, Dichgans M, Wessman M, Smith GD, Stefansson K, Daly MJ, Nyholt DR, Chasman DI, Palotie A, North American Brain Expression Committee, Consortium UKBE, International Headache Genetics Committee. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet45: 912–917, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 55.Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci14: 351–355, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 56.Argiolas A, Melis MR. The neuropharmacology of yawning. Eur J Pharmacol343: 1–16, 1998. [DOI] [PubMed] [Google Scholar]
• 57.Arimura A.Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research. Regul Pept37: 287–303, 1992. [PubMed] [Google Scholar]
• 58.Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning P, Larsson HB, Olesen J, Ashina M. Evidence for a vascular factor in migraine. Ann Neurol69: 635–645, 2011. [DOI] [PubMed] [Google Scholar]
• 59.Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology75: 1520–1526, 2010. [DOI] [PubMed] [Google Scholar]
• 60.Aurora SK, Al-Sayeed F, Welch KMA. The cortical silent period is shortened in migraine with aura. Cephalalgia19: 708–712, 1999. [DOI] [PubMed] [Google Scholar]
• 61.Aurora SK, Cao Y, Bowyer SM, Welch KMA. The occipital cortex is hyperexcitable in migraine: experimental evidence. Headache39: 469–476, 1999. [DOI] [PubMed] [Google Scholar]
• 62.Ayata C.Cortical spreading depression triggers migraine attack: pro. Headache50: 725–730, 2010. [DOI] [PubMed] [Google Scholar]
• 63.Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol59: 652–661, 2006. [DOI] [PubMed] [Google Scholar]
• 64.Azhdari-Zarmehri H, Reisi Z, Vaziri A, Haghparast A, Shaigani P. Involvement of orexin-2 receptors in the ventral tegmental area and nucleus accumbens in the antinociception induced by the lateral hypothalamus stimulation in rats. Peptides47: 94–98, 2013. [DOI] [PubMed] [Google Scholar]
• 65.Baez MA, Brink TS, Mason P. Roles for pain modulatory cells during micturition and continence. J Neurosci25: 384–394, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 66.Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstem activation specific to migraine headache. Lancet357: 1016–1017, 2001. [DOI] [PubMed] [Google Scholar]
• 67.Bai FL, Yamano M, Shiotani Y, Emson PC, Smith AD, Powell JF, Tohyama M. An arcuato-paraventricular and -dorsomedial hypothalamic neuropeptide Y-containing system which lacks noradrenaline in the rat. Brain Res331: 172–175, 1985. [DOI] [PubMed] [Google Scholar]
• 68.Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. Diabetes52: 1195–1203, 2003. [DOI] [PubMed] [Google Scholar]
• 69.Banks WA, Kastin AJ, Komaki G, Arimura A. Passage of pituitary adenylate cyclase activating polypeptide1-27 and pituitary adenylate cyclase activating polypeptide1-38 across the blood-brain barrier. J Pharmacol Exp Ther267: 690–696, 1993. [PubMed] [Google Scholar]
• 70.Banks WA, Kastin AJ, Komaki G, Arimura A. Pituitary adenylate cyclase activating polypeptide (PACAP) can cross the vascular component of the blood-testis barrier in the mouse. J Androl14: 170–173, 1993. [PubMed] [Google Scholar]
• 71.Barbanti P, Fabbrini G, Aurilia C, Vanacore N, Cruccu G. A case-control study on excessive daytime sleepiness in episodic migraine. Cephalalgia27: 1115–1119, 2007. [DOI] [PubMed] [Google Scholar]
• 72.Barriere G, Cazalets JR, Bioulac B, Tison F, Ghorayeb I. The restless legs syndrome. Prog Neurobiol77: 139–165, 2005. [DOI] [PubMed] [Google Scholar]
• 73.Barsh GS, Schwartz MW. Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet3: 589–600, 2002. [DOI] [PubMed] [Google Scholar]
• 74.Bartsch T, Goadsby PJ. Anatomy and physiology of pain referral in primary and cervicogenic headache disorders. Headache Currents2: 42–48, 2005. [Google Scholar]
• 75.Bartsch T, Goadsby PJ. Increased responses in trigeminocervical nociceptive neurones to cervical input after stimulation of the dura mater. Brain126: 1801–1813, 2003. [DOI] [PubMed] [Google Scholar]
• 76.Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain125: 1496–1509, 2002. [DOI] [PubMed] [Google Scholar]
• 77.Bartsch T, Knight YE, Goadsby PJ. Activation of 5-HT_1B/1D receptors in the periaqueductal gray inhibits meningeal nociception. Ann Neurol56: 371–381, 2004. [DOI] [PubMed] [Google Scholar]
• 78.Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypocretin] Orexin A and B receptor activation in the posterior hypothalamic area. Pain109: 367–378, 2004. [DOI] [PubMed] [Google Scholar]
• 79.Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Inhibition of nociceptive dural input in the trigeminal nucleus caudalis by somatostatin receptor blockade in the posterior hypothalamus. Pain117: 30–39, 2005. [DOI] [PubMed] [Google Scholar]
• 80.Basbaum AI, Fields HL. Endogenous pain control mechanisms: review and hypothesis. Ann Neurol4: 451–462, 1978. [DOI] [PubMed] [Google Scholar]
• 81.Baskin DG, Hahn TM, Schwartz MW. Leptin sensitive neurons in the hypothalamus. Horm Metab Res31: 345–350, 1999. [DOI] [PubMed] [Google Scholar]
• 82.Battelli L, Black KR, Wray SH. Transcranial magnetic stimulation of visual area V5 in migraine. Neurology58: 1066–1069, 2002. [DOI] [PubMed] [Google Scholar]
• 83.Baun M, Hay-Schmidt A, Edvinsson L, Olesen J, Jansen-Olesen I. Pharmacological characterization and expression of VIP and PACAP receptors in isolated cranial arteries of the rat. Eur J Pharmacol670: 186–194, 2011. [DOI] [PubMed] [Google Scholar]
• 84.Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature448: 204–208, 2007. [DOI] [PubMed] [Google Scholar]
• 85.Benjamin L, Levy MJ, Lasalandra MP, Knight YE, Akerman S, Classey JD, Goadsby PJ. Hypothalamic activation after stimulation of the superior sagittal sinus in the cat: a Fos study. Neurobiol Dis16: 500–505, 2004. [DOI] [PubMed] [Google Scholar]
• 86.Berde B, Schild HO. Ergot Alkaloids and Related Compounds. Berlin: Springer-Verlag, 1978. [Google Scholar]
• 87.Bergendahl M, Vance ML, Iranmanesh A, Thorner MO, Veldhuis JD. Fasting as a metabolic stress paradigm selectively amplifies cortisol secretory burst mass and delays the time of maximal nyctohemeral cortisol concentrations in healthy men. J Clin Endocrinol Metab81: 692–699, 1996. [DOI] [PubMed] [Google Scholar]
• 88.Bergerot A, Holland PR, Akerman S, Bartsch T, Ahn AH, MaassenVanDenBrink A, Reuter U, Tassorelli C, Schoenen J, Mitsikostas DD, van den Maagdenberg AMJM, Goadsby PJ. Animal models of migraine. Looking at the component parts of a complex disorder. Eur J Neurosci24: 1517–1534, 2006. [DOI] [PubMed] [Google Scholar]
• 89.Bergerot A, Storer RJ, Goadsby PJ. Dopamine inhibits trigeminovascular transmission in the rat. Ann Neurol61: 251–262, 2007. [DOI] [PubMed] [Google Scholar]
• 90.Bernecker C, Pailer S, Kieslinger P, Horejsi R, Möller R, Lechner A, Wallner-Blazek M, Weiss S, Fazekas F, Truschnig-Wilders M, Gruber HJ. GLP-2 and leptin are associated with hyperinsulinemia in nonobese female migraineurs. Cephalalgia30: 1366–1374, 2010. [DOI] [PubMed] [Google Scholar]
• 91.Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol8: 89–99, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 92.Bes A, Dupui P, Guell A, Bessoles G, Geraud G. Pharmacological exploration of dopamine hypersensitivity in migraine patients. Int J Clin Pharmacol Res6: 189–192, 1986. [PubMed] [Google Scholar]
• 93.Bhatt DK, Gupta S, Jansen-Olesen I, Andrews JS, Olesen J. NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models. Cephalalgia33: 87–100, 2013. [DOI] [PubMed] [Google Scholar]
• 94.Bhola R, Kinsella E, Giffin N, Lipscombe S, Ahmed F, Weatherall M, Goadsby PJ. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: Evaluation of outcome data for the UK post market pilot program. J Headache Pain16: 51, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 95.Bigal ME, Ashina S, Burstein R, Reed ML, Buse D, Serrano D, Lipton RB. Prevalence and characteristics of allodynia in headache sufferers: a population study. Neurology70: 1525–1533, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 96.Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, Loupe PS, Burstein R, Newman LC, Lipton RB. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol14: 1081–1090, 2015. [DOI] [PubMed] [Google Scholar]
• 97.Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener HC, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol14: 1091–1100, 2015. [DOI] [PubMed] [Google Scholar]
• 98.Bigal ME, Escandon R, Bronson M, Walter S, Sudworth M, Huggins JP, Garzone P. Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: results of the Phase 1 program. Cephalalgia34: 483–492, 2013. [DOI] [PubMed] [Google Scholar]
• 99.Bigal ME, Liberman JN, Lipton RB. Obesity and migraine: a population study. Neurology66: 545–550, 2006. [DOI] [PubMed] [Google Scholar]
• 100.Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. Neurology71: 848–855, 2008. [DOI] [PubMed] [Google Scholar]
• 101.Bigal ME, Lipton RB, Holland PR, Goadsby PJ. Obesity, migraine and chronic migraine. Possible mechanisms of interaction. Neurology68: 1851–1861, 2007. [DOI] [PubMed] [Google Scholar]
• 102.Bigal ME, Tsang A, Loder E, Serrano D, Reed ML, Lipton RB. Body mass index and episodic headaches: a population-based study. Arch Intern Med167: 1964–1970, 2007. [DOI] [PubMed] [Google Scholar]
• 103.Bigal ME, Walter S, Bronson M, Alibhoy A, Escandon R. Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia34: 968–976, 2014. [DOI] [PubMed] [Google Scholar]
• 104.Bittencourt JC, Elias CF. Diencephalic origins of melanin-concentrating hormone immunoreactive projections to medial septum/diagonal band complex and spinal cord using two retrograde fluorescent tracers. Ann NY Acad Sci680: 462–465, 1993. [DOI] [PubMed] [Google Scholar]
• 105.Blau J.Migraine postdromes: symptoms after attacks. Cephalalgia11: 229–231, 1991. [DOI] [PubMed] [Google Scholar]
• 106.Blau JN.Migraine prodromes separated from the aura: complete migraine. Br Med J21: 658–660, 1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 107.Blau JN.Sleep deprivation headache. Cephalalgia10: 157–160, 1990. [DOI] [PubMed] [Google Scholar]
• 108.Blau JN, Cumings JN. Method of precipitating and preventing migraine attacks. Br Med JII: 1242–1243, 1966. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 109.Blin O, Azulay J, Masson G, Aubrespey G, Serratrice G. Apomorphine-induced yawning in migraine patients: enhanced responsiveness. Clin Neuropharmacol14: 91–95, 1991. [DOI] [PubMed] [Google Scholar]
• 110.Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nature Med8: 136–142, 2002. [DOI] [PubMed] [Google Scholar]
• 111.Boni LJ, Ploug KB, Olesen J, Jansen-Olesen I, Gupta S. The in vivo effect of VIP, PACAP-38 and PACAP-27 and mRNA expression of their receptors in rat middle meningeal artery. Cephalalgia29: 837–847, 2009. [DOI] [PubMed] [Google Scholar]
• 112.Borbély AA.Sleep in the rat during food deprivation and subsequent restitution of food. Brain Res124: 457–471, 1977. [DOI] [PubMed] [Google Scholar]
• 113.Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes46: 1235–1238, 1997. [DOI] [PubMed] [Google Scholar]
• 114.Bouchelet I, Case B, Olivier A, Hamel E. No contractile effect for 5-HT_1D and 5-HT_1F rececptor agonists in human and bovine cerebral arteries: similarity with human coronary artery. Br J Pharmacol129: 501–508, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 115.Bouchelet I, Cohen Z, Case B, Hamel E. Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels. Mol Pharmacol50: 219–223, 1996. [PubMed] [Google Scholar]
• 116.Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Geraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry81: 978–984, 2010. [DOI] [PubMed] [Google Scholar]
• 117.Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci20: 7760–7765, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 118.Brady LS, Smith MA, Gold PW, Herkenham M. Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats. Neuroendocrinology52: 441–447, 1990. [DOI] [PubMed] [Google Scholar]
• 119.Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang YH, Lee HY, Jones CR, Fu YH, Charles AC, Ptacek LJ. Casein kinase Id mutations in familial migraine and advanced sleep phase. Science Transl Med5: 183ra156, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 120.Brennan KC, Beltran-Parrazal L, Lopez Valdes HE, Theriot J, Toga A, Charles AC. Distinct vascular conduction with cortical spreading depression. J Neurophysiol97: 4143–4151, 2007. [DOI] [PubMed] [Google Scholar]
• 121.Brennan KC, Romero-Reyes M, Lopez Valdes HE, Arnold AP, Charles AC. Reduced threshold for cortical spreading depression in female mice. Ann Neurol61: 603–606, 2007. [DOI] [PubMed] [Google Scholar]
• 122.Brighina F, Piazza A, Daniele O, Fierro B. Modulation of visual cortical excitability in migraine with aura: effects of 1 Hz repetitive transcranial magnetic stimulation. Exp Brain Res145: 177–181, 2002. [DOI] [PubMed] [Google Scholar]
• 123.Broberger C, De Lecea L, Sutcliffe JG, Hökfelt T. Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol402: 460–474, 1998. [PubMed] [Google Scholar]
• 124.Bruinvels AT, Landwehrmeyer B, Gustafson EL, Durkin MM, Mengod G, Branchek TA, Hoyer D, Palacios JM. Localization of 5-HT1B, 5-HT1Dalpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology33: 367–386, 1994. [DOI] [PubMed] [Google Scholar]
• 125.Burdakov D, Gerasimenko O, Verkhratsky A. Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J Neurosci25: 2429–2433, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 126.Burstein R, Cliffer KD, Giesler GJ Jr. Direct somatosensory projections from the spinal cord to the hypothalamus and telencephalon. J Neurosci7: 4159–4164, 1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 127.Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol55: 19–26, 2004. [DOI] [PubMed] [Google Scholar]
• 128.Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack. Brain123: 1703–1709, 2000. [DOI] [PubMed] [Google Scholar]
• 129.Burstein R, Dado RJ, Giesler GJ Jr.. The cells of origin of the spinothalamic tract of the rat: a quantitative reexamination. Brain Res511: 329–337, 1990. [DOI] [PubMed] [Google Scholar]
• 130.Burstein R, Jakubowski M. Neural substrate of depression during migraine. Neurol Sci30Suppl 1: S27–31, 2009. [DOI] [PubMed] [Google Scholar]
• 131.Burstein R, Jakubowski M. Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol493: 9–14, 2005. [DOI] [PubMed] [Google Scholar]
• 132.Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, Hargreaves R, Becerra L, Borsook D. Thalamic sensitization transforms localized pain into widespread allodynia. Ann Neurol68: 81–91, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 133.Burstein R, Jakubowski M, Levy D. Anti-migraine action of triptans is preceded by transient aggravation of headache caused by activation of meningeal nociceptors. Pain115: 21–28, 2005. [DOI] [PubMed] [Google Scholar]
• 134.Burstein R, Strassman A, Moskowitz M. Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept. Cephalalgia32: 509–511, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 135.Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol79: 964–982, 1998. [DOI] [PubMed] [Google Scholar]
• 136.Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol47: 614–624, 2000. [PubMed] [Google Scholar]
• 137.Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry81: 428–432, 2010. [DOI] [PubMed] [Google Scholar]
• 138.Buzzi MG, Moskowitz MA. The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol99: 202–206, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 139.Buzzi MG, Sakas DE, Moskowitz MA. Indomethacin and acetylsalicylic acid block neurogenic plasma protein extravasation in rat dura mater. Eur J Pharmacol165: 251–258, 1989. [DOI] [PubMed] [Google Scholar]
• 140.Cahill GF.Starvation in man. N Engl J Med282: 668–675, 1970. [DOI] [PubMed] [Google Scholar]
• 141.Cai XJ, Evans ML, Lister CA, Leslie RA, Arch JR, Wilson S, Williams G. Hypoglycemia activates orexin neurons and selectively increases hypothalamic orexin-B levels: responses inhibited by feeding and possibly mediated by the nucleus of the solitary tract. Diabetes50: 105–112, 2001. [DOI] [PubMed] [Google Scholar]
• 142.Cai XJ, Widdowson PS, Harrold J, Wilson S, Buckingham RE, Arch JR, Tadayyon M, Clapham JC, Wilding J, Williams G. Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes48: 2132–2137, 1999. [DOI] [PubMed] [Google Scholar]
• 143.Cailotto C, La Fleur SE, Van Heijningen C, Wortel J, Kalsbeek A, Feenstra M, Pévet P, Buijs RM. The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes involved?Eur J Neurosci22: 2531–2540, 2005. [DOI] [PubMed] [Google Scholar]
• 144.Calzá L, Giardino L, Battistini N, Zanni M, Galetti S, Protopapa F, Velardo A. Increase of neuropeptide Y-like immunoreactivity in the paraventricular nucleus of fasting rats. Neurosci Lett104: 99–104, 1989. [DOI] [PubMed] [Google Scholar]
• 145.Canteras NS, Simerly RB, Swanson LW. Organization of projections from the ventromedial nucleus of the hypothalamus: aPhaseolus vulgaris-leucoagglutinin study in the rat. J Comp Neurol348: 41–79, 1994. [DOI] [PubMed] [Google Scholar]
• 146.Caproni S, Corbelli I, Pini LA, Cupini ML, Calabresi P, Sarchielli P. Migraine preventive drug-induced weight gain may be mediated by effects on hypothalamic peptides: the results of a pilot study. Cephalalgia31: 543–549, 2011. [DOI] [PubMed] [Google Scholar]
• 147.Casse F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, Alahari A, Galli T, Vivien D, Docagne F. Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals. J Neurosci32: 5186–5199, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 148.Cavestro C, Rosatello A, Micca G, Ravotto M, Marino MP, Asteggiano G, Beghi E. Insulin metabolism is altered in migraineurs: a new pathogenic mechanism for migraine?Headache47: 1436–1442, 2007. [DOI] [PubMed] [Google Scholar]
• 149.Cerbo R, Barbanti P, Buzzi MG, Fabbrini G, Brusa L, Roberti C. Dopamine hypersensitivity in migraine: role of the apomorphine test. Clin Neuropharmacol20: 36–41, 1997. [DOI] [PubMed] [Google Scholar]
• 150.Chabi A, Zhang Y, Jackson S, Cady R, Lines C, Herring WJ, Connor KM, Michelson D. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia35: 379–388, 2015. [DOI] [PubMed] [Google Scholar]
• 151.Chabriat H, Tournier-Lasserve E, Vahedi K, Leys D, Joutel A, Nibbio A, Escaillas JP, Iba-Zizen MT, Bracard S, Tehindrazanarivelo A, Gastaut JL, Bousser MG. Autosomal dominant migraine with MRI white-matter abnormalities mapping to the CADASIL locus. Neurology45: 1086–1091, 1995. [DOI] [PubMed] [Google Scholar]
• 152.Chai NC, Shapiro RE, Rapoport AM. Why does vomiting stop a migraine attack?Curr Pain Headache Rep17: 362, 2013. [DOI] [PubMed] [Google Scholar]
• 153.Chang JC, Shook LL, Biag J, Nguyen EN, Toga AW, Charles AC, Brennan KC. Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression. Brain133: 996–1012, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 154.Chaput JP, Després JP, Bouchard C, Tremblay A. Short sleep duration is associated with reduced leptin levels and increased adiposity: Results from the Quebec family study. Obesity15: 253–261, 2007. [DOI] [PubMed] [Google Scholar]
• 155.Charbit AR, Akerman S, Goadsby PJ. Trigeminocervical complex responses after lesioning dopaminergic A11 nucleus are modified by dopamine and serotonin mechanisms. Pain152: 2365–2376, 2011. [DOI] [PubMed] [Google Scholar]
• 156.Charbit AR, Akerman S, Holland PR, Goadsby PJ. Neurons of the dopaminergic/Calcitonin gene-related peptide A11 cell group modulate neuronal firing in the trigeminocervical complex: an electrophysiological and immunohistochemical study. J Neurosci29: 12532–12541, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 157.Charles A.Does cortical spreading depression initiate a migraine attack? Maybe not. Headache50: 731–733, 2010. [DOI] [PubMed] [Google Scholar]
• 158.Charles A.Migraine: a brain state. Curr Opin Neurol26: 235–239, 2013. [DOI] [PubMed] [Google Scholar]
• 159.Chasman DI, Anttila V, Buring JE, Ridker PM, Schurks M, Kurth T, International Headache Genetics Consortium. Selectivity in genetic association with sub-classified migraine in women. PLoS Genet10: e1004366, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 160.Chasman DI, Schurks M, Anttila V, de Vries B, Schminke U, Launer LJ, Terwindt GM, van den Maagdenberg AM, Fendrich K, Volzke H, Ernst F, Griffiths LR, Buring JE, Kallela M, Freilinger T, Kubisch C, Ridker PM, Palotie A, Ferrari MD, Hoffmann W, Zee RY, Kurth T. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet43: 695–698, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 161.Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong YM, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell98: 437–451, 1999. [DOI] [PubMed] [Google Scholar]
• 162.Chen L, Philippe J, Unger RH. Glucagon responses of isolated alpha cells to glucose, insulin, somatostatin, and leptin. Endocr Pract17: 819–825, 2011. [DOI] [PubMed] [Google Scholar]
• 163.Chen SP, Ay I, Lopes de Morais A, Qin T, Zheng Y, Sadeghian H, Oka F, Simon B, Eikermann-Haerter K, Ayata C. Vagus nerve stimulation inhibits cortical spreading depression. Pain157: 797–805, 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 164.Chergui K, Svenningsson P, Greengard P. Physiological role for casein kinase 1 in glutamatergic synaptic transmission. J Neurosci25: 6601–6609, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 165.Chizh B, Palmer J, Lai R, Guillard F, Bullman J, Baines A, Napolitano A, Appleby J. A randomised, two-period cross-over study to investigate the efficacy of the Trpv1 antagonist SB-705498 in acute migraine. Eur J Pain13: S202a–S202, 2009. [Google Scholar]
• 166.Chong CD, Gaw N, Fu Y, Li J, Wu T, Schwedt TJ. Migraine classification using magnetic resonance imaging resting-state functional connectivity data. Cephalalgia. In press. [DOI] [PubMed]
• 167.Chou TC, Scammell TE, Gooley JJ, Gaus SE, Saper CB, Lu J. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J Neurosci23: 10691–10702, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 168.Christensen AF, Esserlind AL, Werge T, Stefansson H, Stefansson K, Olesen J. The influence of genetic constitution on migraine drug responses. Cephalalgia36: 624–639, 2016. [DOI] [PubMed] [Google Scholar]
• 169.Chronicle EP, Mulleners WM. Visual system dysfunction in migraine: a review of clinical and psychophysical findings. Cephalalgia16: 525–535, 1996. [DOI] [PubMed] [Google Scholar]
• 170.Classey JD, Bartsch T, Goadsby PJ. Distribution of 5-HT_1B, 5-HT_1D and 5-HT_1F receptor expression in rat trigeminal and dorsal root ganglia neurons: relevance to the selective anti-migraine effect of triptans. Brain Res1361: 76–85, 2010. [DOI] [PubMed] [Google Scholar]
• 171.Classey JD, Knight YE, Goadsby PJ. The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res907: 117–124, 2001. [DOI] [PubMed] [Google Scholar]
• 172.Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology67: 125–130, 2006. [DOI] [PubMed] [Google Scholar]
• 173.Coghill RC, Sang CN, Berman KF, Bennett GJ, Iadarola MJ. Global cerebral blood flow decreases during pain. J Cereb Blood Flow Metab18: 141–147, 1998. [DOI] [PubMed] [Google Scholar]
• 174.Cohen ML, Johnson KW, Schenck KW, Phebus LA. Migraine therapy: relationship between serotonergic contractile receptors in canine and rabbit saphenous veins to human cerebral and coronary arteries. Cephalalgia17: 631–638, 1997. [DOI] [PubMed] [Google Scholar]
• 175.Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P, Mombaerts P, Friedman JM. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest108: 1113–1121, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 176.Connor HE, Bertin L, Gillies S, Beattie DT, Ward P, The GR205171 Clinical Study Group. Clinical evaluation of a novel, potent, CNS penetrating NK₁ receptor antagonist in the acute treatment of migraine. Cephalalgia18: 392, 1998. [Google Scholar]
• 177.Connor HE, Feniuk W, Beattie DT, North PC, Oxford AW, Saynor DA, Humphrey PPA. Naratriptan: biological profile in animal models relevant to migraine. Cephalalgia17: 145–152, 1997. [DOI] [PubMed] [Google Scholar]
• 178.Connor KM, Aurora SK, Loeys T, Ashina M, Jones C, Giezek H, Massaad R, Williams-Diaz A, Lines C, Ho TW. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache51: 73–84, 2011. [DOI] [PubMed] [Google Scholar]
• 179.Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, Fei K, Assaid C, Lines C, Ho TW. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology73: 970–977, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 180.Coppola G, Di Renzo A, Tinelli E, Iacovelli E, Lepre C, Di Lorenzo C, Di Lorenzo G, Di Lenola D, Parisi V, Serrao M, Pauri F, Fiermonte G, Bianco F, Pierelli F. Evidence for brain morphometric changes during the migraine cycle: a magnetic resonance-based morphometry study. Cephalalgia35: 783–791, 2015. [DOI] [PubMed] [Google Scholar]
• 181.Coppola G, Pierelli F, Schoenen J. Habituation and migraine. Neurobiol Learn Mem92: 249–259, 2009. [DOI] [PubMed] [Google Scholar]
• 182.Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine?Cephalalgia27: 1427–1439, 2007. [DOI] [PubMed] [Google Scholar]
• 183.Coppola G, Pierelli F, Schoenen J. Reply to the topical review entitled “the phenomenon of changes in cortical excitability in migraine is not migraine-specific–a unifying thesis” by Anne Stankewitz and Arne May published inPain 2009;145:14-7. Pain149: 407–409, 2010. [DOI] [PubMed] [Google Scholar]
• 184.Coppola G, Tinelli E, Lepre C, Iacovelli E, Di Lorenzo C, Di Lorenzo G, Serrao M, Pauri F, Fiermonte G, Bianco F, Pierelli F. Dynamic changes in thalamic microstructure of migraine without aura patients: a diffusion tensor magnetic resonance imaging study. Eur J Neurol21: 287–e213, 2014. [DOI] [PubMed] [Google Scholar]
• 185.Coppola G, Vandenheede M, Di Clemente L, Ambrosini A, Fumal A, De Pasqua V, Schoenen J. Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks. Brain128: 98–103, 2005. [DOI] [PubMed] [Google Scholar]
• 186.Csati A, Tajti J, Kuris A, Tuka B, Edvinsson L, Warfvinge K. Distribution of vasoactive intestinal polypeptide, pituitary adenylate cyclase activating peptide, nitric oxide synthase and their receptors in human and rat sphenopalatine ganglion. Neuroscience202: 158–168, 2012. [DOI] [PubMed] [Google Scholar]
• 187.Cumberbatch MJ, Hill RG, Hargreaves RJ. Differential effects of the 5HT_1B/1D receptor agonist naratriptan on trigeminal versus spinal nociceptive responses. Cephalalgia18: 659–664, 1998. [DOI] [PubMed] [Google Scholar]
• 188.Cumberbatch MJ, Williamson DJ, Mason GS, Hill RG, Hargreaves RJ. Dural vasodilatation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT_1B/1D agonist. Br J Pharmacol126: 1478–1486, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 189.Cunningham ET, Bohn MC, Sawchenko PE. Organization of adrenergic inputs to the paraventricular and supraoptic nuclei of the hypothalamus in the rat. J Comp Neurol292: 651–667, 1990. [DOI] [PubMed] [Google Scholar]
• 190.Cunningham ET, Sawchenko PE. Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus. J Comp Neurol274: 60–76, 1988. [DOI] [PubMed] [Google Scholar]
• 191.Curran DA, Hinterberger H, Lance JW. Total plasma serotonin, 5-hydroxyindoleacetic acid andp-hydroxy-m-methoxymandelic acid excretion in normal and migrainous subjects. Brain88: 997–1010, 1965. [DOI] [PubMed] [Google Scholar]
• 192.Cutrer FM, Sorensen AG, Weisskoff RM, Ostergaard L, Sanchez del Rio M, Lee J, Rosen BR, Moskowitz MA. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol43: 25–31, 1998. [DOI] [PubMed] [Google Scholar]
• 193.Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand62: 1–55, 1964. [PubMed] [Google Scholar]
• 194.Dahmen N, Kasten M, Wieczorek S, Gencik M, Epplen JT, Ullrich B. Increased frequency of migraine in narcoleptic patients: a confirmatory study. Cephalalgia23: 14–19, 2003. [DOI] [PubMed] [Google Scholar]
• 195.Dahmen N, Querings K, Grun B, Bierbrauer J. Increased frequency of migraine in narcoleptic patients. Neurology52: 1291–1293, 1999. [DOI] [PubMed] [Google Scholar]
• 196.Dalkara T, Kiliç K. How does fasting trigger migraine? A hypothesis. Curr Pain Headache Rep17: 368, 2013. [DOI] [PubMed] [Google Scholar]
• 197.Dalkvist J, Ekbom K, Waldenlind E. Headache and mood: a time-series analysis of self-ratings. Cephalalgia4: 45–52, 1984. [DOI] [PubMed] [Google Scholar]
• 198.Danguir J, Nicolaidis S. Dependence of sleep on nutrients' availability. Physiol Behav22: 735–740, 1979. [DOI] [PubMed] [Google Scholar]
• 199.DaSilva AF, Granziera C, Tuch DS, Snyder J, Vincent M, Hadjikhani N. Interictal alterations of the trigeminal somatosensory pathway and periaqueductal gray matter in migraine. Neuroreport18: 301–305, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 200.Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA96: 748–753, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 201.Davidson AJ, Yamazaki S, Arble DM, Menaker M, Block GD. Resetting of central and peripheral circadian oscillators in aged rats. Neurobiol Aging29: 471–477, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 202.Davis KD, Dostrovsky JO. Properties of feline thalamic neurons activated by stimulation of the middle meningeal artery and sagittal sinus. Brain Res454: 89–100, 1988. [DOI] [PubMed] [Google Scholar]
• 203.De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G. Haploinsufficiency of ATP1A2 encoding the Na⁺/K⁺ pump a2 subunit associated with familial hemiplegic migraine type 2. Nature Genet33: 192–196, 2003. [DOI] [PubMed] [Google Scholar]
• 204.De Hoon J, Montieth D, Vermeersch S, Van Hecken A, Abu-Raddad E, Collins E, Schuetz T, Scherer J, Grayzel D. Safety, pharmacokinetics, and pharmacodynamics of LY2951742: a monoclonal antibody targeting CGRP. Cephalalgia33: 247–248, 2013. [Google Scholar]
• 205.De Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci6: 463–475, 2005. [DOI] [PubMed] [Google Scholar]
• 206.De 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 Neurol10: 144–155, 2014. [DOI] [PubMed] [Google Scholar]
• 207.Demarquay G, Royet JP, Mick G, Ryvlin P. Olfactory hypersensitivity in migraineurs: a H(2)(15)O-PET study. Cephalalgia28: 1069–1080, 2008. [DOI] [PubMed] [Google Scholar]
• 208.Denuelle M, Boulloche N, Payoux P, Fabre N, Trotter Y, Geraud G. A PET study of photophobia during spontaneous migraine attacks. Neurology76: 213–218, 2011. [DOI] [PubMed] [Google Scholar]
• 209.Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Hypothalamic activation in spontaneous migraine attacks. Headache47: 1418–1426, 2007. [DOI] [PubMed] [Google Scholar]
• 210.Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Posterior cerebral hypoperfusion in migraine without aura. Cephalalgia28: 856–862, 2008. [DOI] [PubMed] [Google Scholar]
• 211.Derbyshire SWG, Jones AKP, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain73: 431–445, 1997. [DOI] [PubMed] [Google Scholar]
• 212.Dhaka A, Earley TJ, Watson J, Patapoutian A. Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J Neurosci28: 566–575, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 213.Di Clemente L, Coppola G, Magis D, Fumal A, De Pasqua V, Di Piero V, Schoenen J. Interictal habituation deficit of the nociceptive blink reflex: an endophenotypic marker for presymptomatic migraine?Brain130: 765–770, 2007. [DOI] [PubMed] [Google Scholar]
• 214.Diano S, Horvath B, Urbanski HF, Sotonyi P, Horvath TL. Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets. Endocrinology144: 3774–3778, 2003. [DOI] [PubMed] [Google Scholar]
• 215.Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM. Mutation in the neuronal voltage-gated sodium channelSCN1A causes familial hemiplegic migraine. Lancet366: 371–377, 2005. [DOI] [PubMed] [Google Scholar]
• 216.Diener HC, Barbanti P, Dahlof C, Reuter U, Habeck J, Podhorna J. BI 44370 TA, an oral CGRP antagonist for the acute treatment of migraine attacks: results from a phase II study. Cephalalgia31: 573–584, 2011. [DOI] [PubMed] [Google Scholar]
• 217.Diener HC, Dodick DW, Goadsby PJ, Lipton RB, Olesen J, Silberstein SD. Chronic migraine-classification, characteristics and treatment. Nature Rev Neurol14: 162–171, 2012. [DOI] [PubMed] [Google Scholar]
• 218.Diener HC, The RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia23: 183–185, 2003. [DOI] [PubMed] [Google Scholar]
• 219.Diener HC, Gendolla A, Feuersenger A, Evers S, Straube A, Schumacher H, Davidai G. Telmisartan in migraine prophylaxis: a randomized, placebo-controlled trial. Cephalalgia29: 921–927, 2009. [DOI] [PubMed] [Google Scholar]
• 220.Dietrich MO, Horvath TL. Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci36: 65–73, 2013. [DOI] [PubMed] [Google Scholar]
• 221.DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med348: 2556–2668, 2004. [DOI] [PubMed] [Google Scholar]
• 222.Dimitrov EL, DeJoseph MR, Brownfield MS, Urban JH. Involvement of neuropeptide Y Y1 receptors in the regulation of neuroendocrine corticotropin-releasing hormone neuronal activity. Endocrinology148: 3666–3673, 2007. [DOI] [PubMed] [Google Scholar]
• 223.Dodick D, Lipton RB, Martin V, Papademetriou V, Rosamond W, MaassenVanDenBrink A, Loutfi H, Welch KM, Goadsby PJ, Hahn S, Hutchinson S, Matchar D, Silberstein S, Smith TR, Purdy RA, Saiers J. Consensus statement: cardiovascular safety profile of triptans (5-HT_1B/1D Agonists) in the acute treatment of migraine. Headache44: 414–425, 2004. [DOI] [PubMed] [Google Scholar]
• 224.Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J. Randomized, Double-blind, Placebo-controlled, Phase II Trial of ALD403, an anti-CGRP peptide antibody in the prevention of frequent episodic migraine. Lancet Neurol13: 1100–1107, 2014. [DOI] [PubMed] [Google Scholar]
• 225.Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. CGRP monoclonal antibody LY2951742 for the prevention of migraine: a phase 2, randomized, double-blind, placebo-controlled study. Lancet Neurol13: 885–892, 2014. [DOI] [PubMed] [Google Scholar]
• 226.Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol129: 420–423, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 227.Drummond PD.Predisposing, precipitating and relieving factors in different categories of headache. Headache25: 16–22, 1985. [DOI] [PubMed] [Google Scholar]
• 228.Drummond PD, Lance JW. Neurovascular disturbances in headache patients. Clin Exp Neurol20: 93–99, 1984. [PubMed] [Google Scholar]
• 229.Dube MG, Sahu A, Kalra PS, Kalra SP. Neuropeptide Y release is elevated from the microdissected paraventricular nucleus of food-deprived rats: an in vitro study. Endocrinology131: 684–688, 1992. [DOI] [PubMed] [Google Scholar]
• 230.Dunckley P, Wise RG, Fairhurst M, Hobden P, Aziz Q, Chang L, Tracey I. A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging. J Neurosci25: 7333–7341, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 231.Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci19: 3423–3429, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 232.Eadie MJ.A history of migriane. In: The Migraine Brain, edited by Borsook D, May A, Goadsby PJ, and Hargeaves R. New York: Oxford Univ. Press, 2012, p. 3–16. [Google Scholar]
• 233.Earl NL, McDonald SA, Lowy MT, 4991W93 Investigator Group. Efficacy and tolerability of the neurogenic inflammation inhibitor, 4991W93, in the acute treatment of migraine. Cephalalgia19: 357, 1999. [Google Scholar]
• 234.Ebersberger A, Averbeck B, Messlinger K, Reeh PW. Release of substance P, calcitonin gene-related peptide and prostaglandin E₂ from rat dura mater encephali following electrical and chemical stimulation in vitro. Neuroscience89: 901–907, 1999. [DOI] [PubMed] [Google Scholar]
• 235.Ebersberger A, Schaible HG, Averbeck B, Richter F. Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache?Ann Neurol41: 7–13, 2001. [PubMed] [Google Scholar]
• 236.Edelmayer RM, Vanderah TW, Majuta L, Zhang ET, Fioravanti B, De Felice M, Chichorro JG, Ossipov MH, King T, Lai J, Kori SH, Nelsen AC, Cannon KE, Heinricher MM, Porreca F. Medullary pain facilitating neurons mediate allodynia in headache-related pain. Ann Neurol65: 184–193, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 237.Edvinsson L, Brodin E, Jansen I, Uddman R. Neurokinin A in cerebral vessels: characterization, localization and effects in vitro. Regul Pept20: 181–197, 1988. [DOI] [PubMed] [Google Scholar]
• 238.Edvinsson L, Eftekhari S, Salvatore CA, Warfvinge K. Cerebellar distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat. Mol Cell Neurosci46: 333–339, 2011. [DOI] [PubMed] [Google Scholar]
• 239.Edvinsson L, Emson P, McCulloch J, Tatemoto K, Uddman R. Neuropeptide Y: cerebrovascular innervation and vasomotor effects in the cat. Neurosci Lett43: 79–84, 1983. [DOI] [PubMed] [Google Scholar]
• 240.Edvinsson L, Goadsby PJ. Neuropeptides in headache. Eur J Neurol5: 329–341, 1998. [Google Scholar]
• 241.Edvinsson L, Goadsby PJ. Neuropeptides in the cerebral circulation: relevance to headache. Cephalalgia15: 272–278, 1995. [DOI] [PubMed] [Google Scholar]
• 242.Edvinsson L, Mulder H, Goadsby PJ, Uddman R. Calcitonin gene-related peptide and nitric oxide in the trigeminal ganglion: cerebral vasodilatation from trigeminal nerve stimulation involves mainly calcitonin gene-related peptide. J Auton Nerv Syst70: 15–22, 1998. [DOI] [PubMed] [Google Scholar]
• 243.Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia28: 1245–1258, 2008. [DOI] [PubMed] [Google Scholar]
• 244.Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol160: R7–12, 1999. [DOI] [PubMed] [Google Scholar]
• 245.Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disorders3: 369–378, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 246.Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience169: 683–696, 2010. [DOI] [PubMed] [Google Scholar]
• 247.Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res1600: 93–109, 2015. [DOI] [PubMed] [Google Scholar]
• 248.Eikermann-Haerter K, Dilekoz E, Kudo C, Savitz SI, Waeber C, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest119: 99–109, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 249.Eikermann-Haerter K, Lee JH, Yuzawa I, Liu CH, Zhou Z, Shin HK, Zheng Y, Qin T, Kurth T, Waeber C, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C. Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation125: 335–345, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 250.Eising E, de Vries B, Ferrari MD, Terwindt GM, van den Maagdenberg AM. Pearls and pitfalls in genetic studies of migraine. Cephalalgia33: 614–625, 2013. [DOI] [PubMed] [Google Scholar]
• 251.Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB, Elmquist JK. Chemical characterization of leptin-activated neurons in the rat brain. J Comp Neurol423: 261–281, 2000. [PubMed] [Google Scholar]
• 252.Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Ollmann MM, Barsh GS, Sakurai T, Yanagisawa M, Elmquist JK. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol402: 442–459, 1998. [PubMed] [Google Scholar]
• 253.Ellrich J.Brain stem reflexes: probing human trigeminal nociception. News Physiol Sci15: 94–97, 2000. [DOI] [PubMed] [Google Scholar]
• 254.Ellrich J, Messlinger K, Chiang CY, Hu JW. Modulation of neuronal activity in the nucleus raphe magnus by the 5-HT(1)-receptor agonist naratriptan in rat. Pain90: 227–231, 2001. [DOI] [PubMed] [Google Scholar]
• 255.Elmquist JK, Ahima RS, Elias CF, Flier JS, Saper CB. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci USA95: 741–746, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 256.Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology138: 839–842, 1997. [DOI] [PubMed] [Google Scholar]
• 257.Espana RA, Plahn S, Berridge CW. Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin. Brain Res943: 224–236, 2002. [DOI] [PubMed] [Google Scholar]
• 258.Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE. Fos expression in orexin neurons varies with behavioral state. J Neurosci21: 1656–1662, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 259.Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, Lauritzen M. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain129: 778–790, 2006. [DOI] [PubMed] [Google Scholar]
• 260.Farkkila M, Diener HC, Geraud G, Lainez M, Schoenen J, Harner N, Pilgrim A, Reuter U. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol11: 405–413, 2012. [DOI] [PubMed] [Google Scholar]
• 261.Fava A, Pirritano D, Consoli D, Plastino M, Casalinuovo F, Cristofaro S, Colica C, Ermio C, De Bartolo M, Opipari C, Lanzo R, Consoli A, Bosco D. Chronic migraine in women is associated with insulin resistance: a cross-sectional study. Eur J Neurol21: 267–272, 2014. [DOI] [PubMed] [Google Scholar]
• 262.Felgenhauer K.Protein size and cerebrospinal fluid composition. Klinische Wochenschrift52: 1158–1164, 1974. [DOI] [PubMed] [Google Scholar]
• 263.Felig P, Marliss E, Owen OE, Cahill GF. Blood glucose and cluconeogenesis in fasting man. Arch Intern Med123: 293–298, 1969. [PubMed] [Google Scholar]
• 264.Feniuk W, Humphrey PP, Perren MJ. GR43175 does not share the complex pharmacology of the ergots. Cephalalgia9: 35–39, 1989. [DOI] [PubMed] [Google Scholar]
• 265.Feniuk W, Humphrey PPA, Perren MJ. The selective carotid arterial vasoconstrictor action of GR43175 in anaesthetised dogs. Br J Pharmacol96: 83–90, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 266.Feniuk W, Humphrey PPA, Perren MJ, Connor HE, Whalley ET. Rationale for the use of 5-HT1-like agonists in the treatment of migraine. J Neurol238: S57–S61, 1991. [DOI] [PubMed] [Google Scholar]
• 267.Ferrari MD, Farkkila M, Reuter U, Pilgrim A, Davis C, Krauss M, Diener HC. Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmidita: a randomised proof-of-concept trial. Cephalalgia30: 1170–1178, 2010. [DOI] [PubMed] [Google Scholar]
• 268.Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol14: 65–80, 2015. [DOI] [PubMed] [Google Scholar]
• 269.Fields H.State-dependent opioid control of pain. Nat Rev Neurosci5: 565–575, 2004. [DOI] [PubMed] [Google Scholar]
• 270.Fields HL.Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res122: 245–253, 2000. [DOI] [PubMed] [Google Scholar]
• 271.Fields HL, Basbaum AI, Clanton CH, Anderson SD. Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons. Brain Res126: 441–453, 1977. [DOI] [PubMed] [Google Scholar]
• 272.Fields HL, Bry J, Hentall I, Zorman G. The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat. J Neurosci3: 2545–2552, 1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 273.Fields HL, Heinricher MM. Anatomy and physiology of a nociceptive modulatory system. Philos Trans R Soc Lond B Biol Sci308: 361–374, 1985. [DOI] [PubMed] [Google Scholar]
• 274.Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci14: 219–245, 1991. [DOI] [PubMed] [Google Scholar]
• 275.Fields HL, Vanegas H, Hentall ID, Zorman G. Evidence that disinhibition of brain stem neurones contributes to morphine analgesia. Nature306: 684–686, 1983. [DOI] [PubMed] [Google Scholar]
• 276.Fischer MJ, Koulchitsky S, Messlinger K. The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus. J Neurosci25: 5877–5883, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 277.Fleetwood-Walker SM, Hope PJ, Mitchell R. Antinociceptive actions of descending dopaminergic tracts on cat and rat dorsal horn somatosensory neurones. J Physiol399: 335–348, 1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 278.Foo H, Mason P. Brainstem modulation of pain during sleep and waking. Sleep Med Rev7: 145–154, 2003. [DOI] [PubMed] [Google Scholar]
• 279.Foo H, Mason P. Sensory suppression during feeding. Proc Natl Acad Sci USA102: 16865–16869, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 280.Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci8: 700–711, 2007. [DOI] [PubMed] [Google Scholar]
• 281.Fox MD, Snyder AZ, Vincent JL, Raichle ME. Intrinsic fluctuations within cortical systems account for intertrial variability in human behavior. Neuron56: 171–184, 2007. [DOI] [PubMed] [Google Scholar]
• 282.Frederich RC, Löllmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB, Flier JS. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest96: 1658–1663, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 283.Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, van Oosterhout WP, Artto V, Todt U, Hamalainen E, Fernandez-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimaki T, Vila-Pueyo M, Gobel H, Wichmann E, Sintas C, Uitterlinden AG, Hofman A, Rivadeneira F, Heinze A, Tronvik E, van Duijn CM, Kaprio J, Cormand B, Wessman M, Frants RR, Meitinger T, Muller-Myhsok B, Zwart JA, Farkkila M, Macaya A, Ferrari MD, Kubisch C, Palotie A, Dichgans M, van den Maagdenberg AM, International Headache Genetics Consortium. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet44: 777–782, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 284.Friedman BW, Garber L, Yoon A, Solorzano C, Wollowitz A, Esses D, Bijur PE, Gallagher EJ. Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine. Neurology82: 1–8, 2014. [DOI] [PubMed] [Google Scholar]
• 285.Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature395: 763–770, 1998. [DOI] [PubMed] [Google Scholar]
• 286.Fuller PM, Saper CB, Lu J. The pontine REM switch: past and present. J Physiol584: 735–741, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 287.Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN, Maratos-Flier E, Flier JS. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron51: 811–822, 2006. [DOI] [PubMed] [Google Scholar]
• 288.Gais S, Born J, Peters A, Schultes B, Heindl B, Fehm HL, Werner K. Hypoglycemia counterregulation during sleep. Sleep26: 55–59, 2003. [DOI] [PubMed] [Google Scholar]
• 289.Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Trequattrini A, Palumbo R. Vasoactive peptides levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia15: 384–390, 1995. [DOI] [PubMed] [Google Scholar]
• 290.Gangwisch JE, Malaspina D, Boden-Albala B, Heymsfield SB. Inadequate sleep as a risk factor for obesity: analyses of the NHANES I. Sleep28: 1289–1296, 2005. [DOI] [PubMed] [Google Scholar]
• 291.Gao K, Mason P. Physiological and anatomic evidence for functional subclasses of serotonergic raphe magnus cells. J Comp Neurol439: 426–439, 2001. [DOI] [PubMed] [Google Scholar]
• 292.Gao K, Mason P. Serotonergic Raphe magnus cells that respond to noxious tail heat are not ON or OFF cells. J Neurophysiol84: 1719–1725, 2000. [DOI] [PubMed] [Google Scholar]
• 293.Geerling JC, Loewy AD. Aldosterone-sensitive neurons in the nucleus of the solitary tract: efferent projections. J Comp Neurol497: 223–250, 2006. [DOI] [PubMed] [Google Scholar]
• 294.Gelfand AA, Goadsby PJ. A neurologist's guide to acute migraine therapy in the emergency room. The NeuroHospitalist2: 51–59, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 295.Gervil M, Ulrich V, Kaprio J, Olesen J, Russell MB. The relative role of genetic and environmental factors in migraine without aura. Neurology53: 995–999, 1999. [DOI] [PubMed] [Google Scholar]
• 296.Gervil M, Ulrich V, Kaprio J, Russell MB. Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population-based family twin study of migraine without aura. Eur J Neurol8: 231–235, 2001. [DOI] [PubMed] [Google Scholar]
• 297.Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB. Migraine without aura: a population-based twin study. Ann Neurol46: 606–611, 1999. [DOI] [PubMed] [Google Scholar]
• 298.Giffin NJ, Kaube H. The electrophysiology of migraine. Curr Opin Neurol15: 303–309, 2002. [DOI] [PubMed] [Google Scholar]
• 299.Giffin NJ, Lipton RB, Silberstein SD, Olesen J, Goadsby PJ. The migraine postdrome. An electronic diary study. Neurology. In press. [DOI] [PMC free article] [PubMed]
• 300.Giffin NJ, Ruggiero L, Lipton RB, Silberstein S, Tvedskov JF, Olesen J, Altman J, Goadsby PJ, Macrae A. Premonitory symptoms in migraine: an electronic diary study. Neurology60: 935–940, 2003. [DOI] [PubMed] [Google Scholar]
• 301.Glasow A, Bornstein SR. Leptin and the adrenal gland. Eur J Clin Invest30Suppl 3: 39–45, 2000. [DOI] [PubMed] [Google Scholar]
• 302.Glasow A, Haidan A, Hilbers U, Breidert M, Gillespie J, Scherbaum WA, Chrousos GP, Bornstein SR. Expression of Ob receptor in normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin. J Clin Endocrinol Metab83: 4459–4466, 1998. [DOI] [PubMed] [Google Scholar]
• 303.Global Burden of Disease Study. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet386: 743–800, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 304.Goadsby PJ.Characteristics of facial nerve elicited cerebral vasodilatation determined with laser Doppler flowmetry. Am J Physiol Regul Integr Comp Physiol260: R255–R262, 1991. [DOI] [PubMed] [Google Scholar]
• 305.Goadsby PJ.Effect of stimulation of the facial nerve on regional cerebral blood flow and glucose utilization in cats. Am J Physiol Regul Integr Comp Physiol257: R517–R521, 1989. [DOI] [PubMed] [Google Scholar]
• 306.Goadsby PJ.Incredible progress in migraine for an era of better care. Nature Rev Neurol11: 621–622, 2015. [DOI] [PubMed] [Google Scholar]
• 307.Goadsby PJ.Migraine, aura and cortical spreading depression: why are we still talking about it?Ann Neurol49: 4–6, 2001. [DOI] [PubMed] [Google Scholar]
• 308.Goadsby PJ.Parallel concept of migraine pathogensis. Ann Neurol51: 140, 2002. [DOI] [PubMed] [Google Scholar]
• 309.Goadsby PJ.Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol1: 37–43, 2002. [DOI] [PubMed] [Google Scholar]
• 310.Goadsby PJ.The pharmacology of headache. Prog Neurobiol62: 509–525, 2000. [DOI] [PubMed] [Google Scholar]
• 311.Goadsby PJ.Sphenopalatine ganglion stimulation increases regional cerebral blood flow independent of glucose utilization in the cat. Brain Res506: 145–148, 1990. [DOI] [PubMed] [Google Scholar]
• 312.Goadsby PJ.Trigeminal autonomic cephalalgias. Continuum Lifelong Learning Neurol18: 883–895, 2012. [DOI] [PubMed] [Google Scholar]
• 313.Goadsby PJ, Akerman S. The trigeminovascular system does not require a peripheral sensory input to be activated–migraine is a central disorder. Focus on ‘Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system.’Cephalalgia32: 3–5, 2012. [DOI] [PubMed] [Google Scholar]
• 314.Goadsby PJ, Akerman S, Storer RJ. Evidence for postjunctional serotonin (5-HT₁) receptors in the trigeminocervical complex. Ann Neurol50: 804–807, 2001. [DOI] [PubMed] [Google Scholar]
• 315.Goadsby PJ, Cittadini E, Cohen AS. Trigeminal autonomic cephalalgias: paroxysmal hemicrania, SUNCT/SUNA and hemicrania continua. Semin Neurol30: 186–191, 2010. [DOI] [PubMed] [Google Scholar]
• 316.Goadsby PJ, Classey JD. Evidence for 5-HT_1B, 5-HT_1Dand 5-HT_1F receptor inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience122: 491–498, 2003. [DOI] [PubMed] [Google Scholar]
• 317.Goadsby PJ, Classey JD. Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res875: 119–124, 2000. [DOI] [PubMed] [Google Scholar]
• 318.Goadsby PJ, Dodick DW, Almas M, Diener HC, Tfelt-Hansen P, Lipton RB, Parsons B. Treatment-emergent CNS symptoms following triptan therapy are part of the attack. Cephalalgia27: 254–262, 2007. [DOI] [PubMed] [Google Scholar]
• 319.Goadsby PJ, Duckworth JW. Low frequency stimulation of the locus coeruleus reduces regional cerebral blood flow in the spinalized cat. Brain Res476: 71–77, 1989. [DOI] [PubMed] [Google Scholar]
• 320.Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Brain117: 427–434, 1994. [DOI] [PubMed] [Google Scholar]
• 321.Goadsby PJ, Edvinsson L. Neuropeptide changes in a case of chronic paroxysmal hemicrania- evidence for trigemino-parasympathetic activation. Cephalalgia16: 448–450, 1996. [DOI] [PubMed] [Google Scholar]
• 322.Goadsby PJ, Edvinsson L. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache34: 394–399, 1994. [DOI] [PubMed] [Google Scholar]
• 323.Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol33: 48–56, 1993. [DOI] [PubMed] [Google Scholar]
• 324.Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of man and the cat during activation of the trigeminovascular system. Ann Neurol23: 193–196, 1988. [DOI] [PubMed] [Google Scholar]
• 325.Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol28: 183–187, 1990. [DOI] [PubMed] [Google Scholar]
• 326.Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG. Randomized double blind, placebo-controlled proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis. Cephalalgia29: 742–750, 2009. [DOI] [PubMed] [Google Scholar]
• 327.Goadsby PJ, Grosberg BM, Mauskop A, Cady R. Effect of non-invasive vagus nerve stimulation on acute migraine: an open label pilot study. Cephalalgia34: 986–993, 2014. [DOI] [PubMed] [Google Scholar]
• 328.Goadsby PJ, Gundlach AL. Localization of [³H]-dihydroergotamine binding sites in the cat central nervous system: relevance to migraine. Ann Neurol29: 91–94, 1991. [DOI] [PubMed] [Google Scholar]
• 329.Goadsby PJ, Hoskin KL. Differential effects of low dose CP122,288 and eletriptan on fos expression due to stimulation of the superior sagittal sinus in cat. Pain82: 15–22, 1999. [DOI] [PubMed] [Google Scholar]
• 330.Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brainMacaca nemestrina: a c-fos immunocytochemical study. J Anat190: 367–375, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 331.Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)_1B/D receptor agonist zolmitriptan (311C90): are brain stem sites a therapeutic target in migraine?Pain67: 355–359, 1996. [DOI] [PubMed] [Google Scholar]
• 332.Goadsby PJ, Hoskin KL. Serotonin inhibits trigeminal nucleus activity evoked by craniovascular stimulation through a 5-HT_1B/1D receptor: a central action in migraine?Ann Neurol43: 711–718, 1998. [DOI] [PubMed] [Google Scholar]
• 333.Goadsby PJ, Knight YE. Direct evidence for central sites of action of zolmitriptan (311C90): an autoradiographic study in cat. Cephalalgia17: 153–158, 1997. [DOI] [PubMed] [Google Scholar]
• 334.Goadsby PJ, Knight YE. Inhibition of trigeminal neurons after intravenous administration of naratriptan through an action at the serotonin (5HT_1B/1D) receptors. Br J Pharmacol122: 918–922, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 335.Goadsby PJ, Lambert GA, Lance JW. Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation. Brain Res249: 247–254, 1982. [DOI] [PubMed] [Google Scholar]
• 336.Goadsby PJ, Lambert GA, Lance JW. Effects of locus coeruleus stimulation on carotid vascular resistance in the cat. Brain Res278: 175–183, 1983. [DOI] [PubMed] [Google Scholar]
• 337.Goadsby PJ, Lambert GA, Lance JW. The mechanism of cerebrovascular vasoconstriction in response to locus coeruleus stimulation. Brain Res326: 213–217, 1985. [DOI] [PubMed] [Google Scholar]
• 338.Goadsby PJ, Lambert GA, Lance JW. The peripheral pathway for extracranial vasodilatation in the cat. J Auto Nerv Syst10: 145–155, 1984. [DOI] [PubMed] [Google Scholar]
• 339.Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic features, including new cases. Brain120: 193–209, 1997. [DOI] [PubMed] [Google Scholar]
• 340.Goadsby PJ, Lipton RB, Ferrari MD. Migraine–current understanding and treatment. N Engl J Med346: 257–270, 2002. [DOI] [PubMed] [Google Scholar]
• 341.Goadsby PJ, Macdonald GJ. Extracranial vasodilatation mediated by VIP (vasoactive intestinal polypeptide). Brain Res329: 285–288, 1985. [DOI] [PubMed] [Google Scholar]
• 342.Goadsby PJ, Piper RD, Lambert GA, Lance JW. The effect of activation of the nucleus raphe dorsalis (DRN) on carotid blood flow. I. The monkey. Am J Physiol Regul Integr Comp Physiol248: R257–R262, 1985. [DOI] [PubMed] [Google Scholar]
• 343.Goadsby PJ, Piper RD, Lambert GA, Lance JW. The effect of activation of the nucleus raphe dorsalis (DRN) on carotid blood flow. II. The cat. Am J Physiol Regul Integr Comp Physiol248: R263–R269, 1985. [DOI] [PubMed] [Google Scholar]
• 344.Goadsby PJ, Shelley S. High frequency stimulation of the facial nerve results in local cortical release of vasoactive intestinal polypeptide in the anesthetised cat. Neurosci Lett112: 282–289, 1990. [DOI] [PubMed] [Google Scholar]
• 345.Goadsby PJ, Sprenger T. Current practice and future directions in the management of migraine: acute and preventive. Lancet Neurol9: 285–298, 2010. [DOI] [PubMed] [Google Scholar]
• 346.Goadsby PJ, Zagami AS. Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain114: 1001–1011, 1991. [DOI] [PubMed] [Google Scholar]
• 347.Goadsby PJ, Zagami AS. Thalamic processing of craniovascular pain in the cat: a 2-deoxyglucose study. Proc Soc Neurosci16: 1144, 1990. [Google Scholar]
• 348.Goder R, Fritzer G, Kapsokalyvas A, Kropp P, Niederberger U, Strenge H, Gerber WD, Aldenhoff JB. Polysomnographic findings in nights preceding a migraine attack. Cephalalgia21: 31–37, 2001. [DOI] [PubMed] [Google Scholar]
• 349.Goldstein DJ, Offen WW, Klein EG, Phebus LA, Hipskind P, Johnson KW, Ryan RE. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia21: 102–106, 2001. [DOI] [PubMed] [Google Scholar]
• 350.Goldstein DJ, Roon KI, Offen WW, Ramadan NM, Phebus LA, Johnson KW, Schaus JM, Ferrari MD. Selective serotonin 1F [5-HT(1F)] receptor agonist LY334370 for acute migraine: a randomised controlled trial. Lancet358: 1230–1234, 2001. [DOI] [PubMed] [Google Scholar]
• 351.Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia17: 785–790, 1997. [DOI] [PubMed] [Google Scholar]
• 352.Goldstein J, Dahlof CGH, Diener HC, Olesen J, Schellens R, Senard JM, Simard D, Steiner TJ. Alniditan in the acute treatment of migraine attacks: a subcutaneous dose-finding study. Cephalalgia16: 497–502, 1996. [DOI] [PubMed] [Google Scholar]
• 353.Gomez-Mancilla B, Brand R, Jurgens TP, Gobel H, Sommer C, Straube A, Evers S, Sommer M, Campos V, Kalkman HO, Hariry S, Pezous N, Johns D, Diener HC. Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks. Cephalalgia34: 103–113, 2014. [DOI] [PubMed] [Google Scholar]
• 354.Gooley JJ, Schomer A, Saper CB. The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nat Neurosci9: 398–407, 2006. [DOI] [PubMed] [Google Scholar]
• 355.Gordon ML, Lipton RB, Brown SL, Nakraseive C, Russell M, Pollack SZ, Korn ML, Merriam A, Solomon S, van Praag HM. Headache and cortisol responses to m-chlorophenylpiperazine are highly correlated. Cephalalgia13: 400–405, 1993. [DOI] [PubMed] [Google Scholar]
• 356.Gotter AL, Roecker AJ, Hargreaves R, Coleman PJ, Winrow CJ, Renger JJ. Orexin receptors as therapeutic drug targets. Prog Brain Res198: 163–188, 2012. [DOI] [PubMed] [Google Scholar]
• 357.Gowers WR.A Manual of Diseases of the Nervous System. Philadelphia, PA: Blakiston, 1899, p. 1357. [Google Scholar]
• 358.Graham JR, Wolff HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry39: 737–763, 1938. [Google Scholar]
• 359.Granziera C, Daducci A, Romascano D, Roche A, Helms G, Krueger G, Hadjikhani N. Structural abnormalities in the thalamus of migraineurs with aura: a multiparametric study at 3 T. Hum Brain Mapp35: 1461–1468, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 360.Gray H.Anatomy of the Human Body. Philadelphia, PA: Lea & Febiger, 1918. [Google Scholar]
• 361.Greco R, Gasperi V, Maccarrone M, Tassorelli C. The endocannabinoid system and migraine. Exp Neurol224: 85–91, 2010. [DOI] [PubMed] [Google Scholar]
• 362.Grill HJ, Ginsberg AB, Seeley RJ, Kaplan JM. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. J Neurosci18: 10128–10135, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 363.Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology143: 239–246, 2002. [DOI] [PubMed] [Google Scholar]
• 364.Guldiken B, Guldiken S, Demir M, Turgut N, Tugrul A. Low leptin levels in migraine: a case control study. Headache48: 1103–1107, 2008. [DOI] [PubMed] [Google Scholar]
• 365.Guo Z, Cao YQ. Over-Expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors. PLoS One9: e87029, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 366.Hadjikhani N, Sanchez del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Wong KK, Cutrer FM, Rosen BR, Tootell RBH, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA98: 4687–4692, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 367.Hamblin MW, Ariani K, Adriaenssens PI, Ciaranello RD. [³H]Dihydroergotamine as a high-affinity, slowly dissociating radioligand for 5HT_1b binding sites in rat brain membranes: evidence for guanine nucleotide regulation of agonist affinity states. J Pharmacol Exp Ther243: 989–1001, 1987. [PubMed] [Google Scholar]
• 368.Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, Brust PF, Johnson EC, Harpold MM, Stauderman KA, Pietrobon D. Functional consequences of mutations in the human alpha(1A) calcium channel subunit linked to familial hemiplegic migraine. J Neurosci19: 1610–1619, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 369.Hansen JM, Baca SM, VanValkenburgh P, Charles A. Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording. Brain136: 3589–3595, 2013. [DOI] [PubMed] [Google Scholar]
• 370.Hansen JM, Bolla M, Magis D, de Pasqua V, Ashina M, Thomsen LL, Olesen J, Schoenen J. Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine. Eur J Neurol18: 478–485, 2011. [DOI] [PubMed] [Google Scholar]
• 371.Hansen JM, Hauge AW, Ashina M, Olesen J. Trigger factors for familial hemiplegic migraine. Cephalalgia31: 1274–1281, 2011. [DOI] [PubMed] [Google Scholar]
• 372.Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia30: 1179–1186, 2010. [DOI] [PubMed] [Google Scholar]
• 373.Hansen JM, Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Goadsby PJ, Charles A. Migraine headache is present in the aura phase: a prospective study. Neurology79: 2044–2049, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 374.Hansen JM, Thomsen LL, Marconi R, Casari G, Olesen J, Ashina M. Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine. Cephalalgia28: 367–375, 2008. [DOI] [PubMed] [Google Scholar]
• 375.Hansen JM, Thomsen LL, Olesen J, Ashina M. Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine. Headache51: 544–553, 2011. [DOI] [PubMed] [Google Scholar]
• 376.Hansen JM, Thomsen LL, Olesen J, Ashina M. Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide. Cephalalgia28: 496–505, 2008. [DOI] [PubMed] [Google Scholar]
• 377.Hanson ES, Levin N, Dallman MF. Elevated corticosterone is not required for the rapid induction of neuropeptide Y gene expression by an overnight fast. Endocrinology138: 1041–1047, 1997. [DOI] [PubMed] [Google Scholar]
• 378.Harper AM, MacKenzie ET, McCulloch J, Pickard JD. Migraine and the blood-brain barrier. Lancet1: 1034–1036, 1977. [DOI] [PubMed] [Google Scholar]
• 379.Harrison SD, Balawi SA, Feinmann C, Harris M. Atypical facial pain: a double-blind placebo-controlled crossover pilot study of subcutaneous sumatriptan. Eur Neuropsychopharmacol7: 83–88, 1997. [DOI] [PubMed] [Google Scholar]
• 380.Hasler G, Buysse DJ, Klaghofer R, Gamma A, Ajdacic V, Eich D, Rössler W, Angst J. The association between short sleep duration and obesity in young adults: a 13-year prospective study. Sleep27: 661–666, 2004. [DOI] [PubMed] [Google Scholar]
• 381.Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J. Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol8: 718–723, 2009. [DOI] [PubMed] [Google Scholar]
• 382.Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev67: 564–600, 2015. [DOI] [PubMed] [Google Scholar]
• 383.Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M, Arch JR. Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides20: 1099–1105, 1999. [DOI] [PubMed] [Google Scholar]
• 384.Headache Classification Committee of The International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia8: 1–96, 1988. [PubMed] [Google Scholar]
• 385.Headache Classification Committee of The International Headache Society. The international classification of headache disorders, 2nd edition. Cephalalgia24: 1–160, 2004. [Google Scholar]
• 386.Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition. Cephalalgia33: 629–808, 2013. [DOI] [PubMed] [Google Scholar]
• 387.Heilig M.The NPY system in stress, anxiety and depression. Neuropeptides38: 213–224, 2004. [DOI] [PubMed] [Google Scholar]
• 388.Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology138: 3859–3863, 1997. [DOI] [PubMed] [Google Scholar]
• 389.Heinrichs SC, Menzaghi F, Pich EM, Hauger RL, Koob GF. Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y. Brain Res611: 18–24, 1993. [DOI] [PubMed] [Google Scholar]
• 390.Held K, Antonijevic I, Murck H, Kuenzel H, Steiger A. Neuropeptide Y (NPY) shortens sleep latency but does not suppress ACTH and cortisol in depressed patients and normal controls. Psychoneuroendocrinology31: 100–107, 2006. [DOI] [PubMed] [Google Scholar]
• 391.Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge J, Bachman R, Taraborelli D, Fan X, Assaid C, Lines C, Ho TW. Randomized controlled trial of the CGRP receptor antagonist, MK-3207, in the acute treatment of migraine. Cephalalgia31: 712–722, 2011. [DOI] [PubMed] [Google Scholar]
• 392.Hisano S, Kagotani Y, Tsuruo Y, Daikoku S, Chihara K, Whitnall MH. Localization of glucocorticoid receptor in neuropeptide Y-containing neurons in the arcuate nucleus of the rat hypothalamus. Neurosci Lett95: 13–18, 1988. [DOI] [PubMed] [Google Scholar]
• 393.Ho T, Mannix L, Fan X, Assaid C, Furtek C, Jones C, Lines CR, Rapoport A, MK0974 Protocol 004 Study Group. Randomized controlled trial of an oral CGRP antagonist, MK-0974, in acute treatment of migraine. Neurology70: 1004–1012, 2008. [DOI] [PubMed] [Google Scholar]
• 394.Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, Lines C, Edvinsson L, Goadsby PJ, Michelson D. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology83: 958–966, 2014. [DOI] [PubMed] [Google Scholar]
• 395.Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nature Rev Neurol6: 573–582, 2010. [DOI] [PubMed] [Google Scholar]
• 396.Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner PK. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet372: 2115–2123, 2008. [DOI] [PubMed] [Google Scholar]
• 397.Ho TW, Ho AP, Chaitman BR, Johnson C, Mathew NT, Kost J, Fan X, Aurora SK, Brandes JL, Fei K, Beebe L, Lines C, Krucoff MW. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache52: 224–235, 2012. [DOI] [PubMed] [Google Scholar]
• 398.Ho YC, Lee HJ, Tung LW, Liao YY, Fu SY, Teng SF, Liao HT, Mackie K, Chiou LC. Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci31: 14600–14610, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 399.Hoffmann J, Lo H, Neeb L, Martus P, Reuter U. Weather sensitivity in migraineurs. J Neurol258: 596–602, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 400.Hoffmann J, Martins-Oliveira M, Supronsinchai W, Akerman S, Lasalandra M, Zhao Y, Matsson L, Economou-Olsson E, Lee HY, Ptacek LJ, Goadsby PJ. The functional consequence of the ck1d t44a mutation on nociceptive activation of the trigeminocervical complex. Cepahalalgia35: 8, 2015. [Google Scholar]
• 401.Hoffmann J, Recober A. Migraine and triggers: post hoc ergo propter hoc?Curr Pain Headache Rep17: 370, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 402.Hoffmann J, Supronsinchai W, Akerman S, Andreou AP, Winrow CJ, Renger J, Hargreaves R, Goadsby PJ. Evidence for orexinergic mechanisms in migraine. Neurobiol Dis74: 137–143, 2015. [DOI] [PubMed] [Google Scholar]
• 403.Hoivik HO, Laurijssens BE, Harnisch LO, Twomey CK, Dixon RM, Kirkham AJ, Williams PM, Wentz AL, Lunnon MW. Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. Cephalalgia30: 1458–1467, 2010. [DOI] [PubMed] [Google Scholar]
• 404.Hokfelt T, Arvidsson U, Ceccatelli S, Cortes R, Cullheim S, Dagerlind A. Calcitonin gene-related peptide in the brain, spinal cord, and some peripheral systems. Ann NY Acad Sci657: 119–134, 1992. [DOI] [PubMed] [Google Scholar]
• 405.Holland P, Goadsby PJ. The hypothalamic orexinergic system: pain and primary headaches. Headache47: 951–962, 2007. [DOI] [PubMed] [Google Scholar]
• 406.Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ. Acid-sensing ion channel-1: a novel therapeutic target for migraine with aura. Ann Neurol72: 559–563, 2012. [DOI] [PubMed] [Google Scholar]
• 407.Holland PR, Akerman S, Goadsby PJ. Cortical spreading depression associated cerebral blood flow changes induced by mechanical stimulation are modulated by AMPA and GABA receptors. Cephalalgia30: 519–527, 2010. [DOI] [PubMed] [Google Scholar]
• 408.Holland PR, Akerman S, Goadsby PJ. Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat. Eur J Neurosci24: 2825–2833, 2006. [DOI] [PubMed] [Google Scholar]
• 409.Holland PR, Akerman S, Goadsby PJ. Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception. J Pharmacol Exp Ther315: 1380–1385, 2005. [DOI] [PubMed] [Google Scholar]
• 410.Holland PR, Akerman S, Lasalandra MP, Goadsby PJ. Antinociceptive effects of Orexin A in the ventrolateral periaqueductal gray are blocked by 5HT 1B/D receptor antagonism. Headache48: S6, 2008. [Google Scholar]
• 411.Holland PR, Goadsby PJ. The hypothalamic orexinergic system: pain and primary headaches. Headache47: 951–962, 2007. [DOI] [PubMed] [Google Scholar]
• 412.Holstege G, Kuypers HGJM, Martin GF. The anatomy of brain stem pathways to the spinal cord in cat.A labelled amino acid tracing study. In: Descending Spinal Pathways to the Spinal Cord Progress in Brain Research, edited by Kuypers HGJM.New York: Elsevier Biomedical Press, 1982, p. 145–175. [DOI] [PubMed] [Google Scholar]
• 413.Holstege JC, Van Dijken H, Buijs RM, Goedknegt H, Gosens T, Bongers CM. Distribution of dopamine immunoreactivity in the rat, cat and monkey spinal cord. J Comp Neurol376: 631–652, 1996. [DOI] [PubMed] [Google Scholar]
• 414.Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron51: 801–810, 2006. [DOI] [PubMed] [Google Scholar]
• 415.Horvath TL, Gao XB. Input organization and plasticity of hypocretin neurons: possible clues to obesity's association with insomnia. Cell Metab1: 279–286, 2005. [DOI] [PubMed] [Google Scholar]
• 416.Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol415: 145–159, 1999. [PubMed] [Google Scholar]
• 417.Hoskin KL, Bulmer DCE, Goadsby PJ. Fos expression in the trigeminocervical complex of the cat after stimulation of the superior sagittal sinus is reduced by l-NAME. Neurosci Lett266: 173–176, 1999. [DOI] [PubMed] [Google Scholar]
• 418.Hoskin KL, Bulmer DCE, Lasalandra M, Jonkman A, Goadsby PJ. Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation. J Anat198: 29–35, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 419.Hoskin KL, Kaube H, Goadsby PJ. Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain119: 1419–1428, 1996. [DOI] [PubMed] [Google Scholar]
• 420.Hoskin KL, Knight YE, Goadsby PJ. Zolmitriptan inhibits c-Fos expression in the dorsal horn of the medulla and upper cervical horn evoked by sagittal sinus stimulation in the cat. Cephalalgia16: 355, 1996.9026407 [Google Scholar]
• 421.Hoskin KL, Lambert GA, Donaldson C, Zagami AS. The 5-hydroxytryptamine1B/1D/1F receptor agonists eletriptan and naratriptan inhibit trigeminovascular input to the nucleus tractus solitarius in the cat. Brain Res998: 91–99, 2004. [DOI] [PubMed] [Google Scholar]
• 422.Hoskin KL, Zagami A, Goadsby PJ. Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat. J Anat194: 579–588, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 423.Hosoya Y, Matsushita M, Sugiura Y. A direct hypothalamic projection to the superior salivatory nucleus neurons in the rat. A study using anterograde autoradiographic and retrograde HRP methods. Brain Res266: 329–333, 1983. [DOI] [PubMed] [Google Scholar]
• 424.Hosoya Y, Sugiura Y, Ito R, Kohno K. Descending projections from the hypothalamic paraventricular nucleus to the A5 area, including the superior salivatory nucleus, in the rat. Exp Brain Res82: 513–518, 1990. [DOI] [PubMed] [Google Scholar]
• 425.Hostetler ED, Joshi AD, Sanabria-Bohorquez S, Fan H, Zeng Z, Purcell M, Gantert L, Riffel K, Williams M, O'Malley S, Miller P, Selnick HG, Gallicchio SN, Bell IM, Salvatore CA, Kane SA, Li CC, Hargreaves RJ, de Groot T, Bormans G, Van Hecken A, Derdelinckx I, de Hoon J, Reynders T, Declercq R, De Lepeleire I, Kennedy WP, Blanchard R, Marcantonio EE, Sur C, Cook JJ, Van Laere K, Evelhoch JL. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [¹¹C]MK-4232. J Pharmacol Exp Ther347: 478–486, 2013. [DOI] [PubMed] [Google Scholar]
• 426.Hou M, Kanje M, Longmore J, Tajti J, Uddman R, Edvinsson L. 5-HT_1B and 5-HT_1D receptors in the human trigeminal ganglion: co-localization with calitonin gene-related peptide, substance P and nitric oxide synthase. Brain Res909: 112–120, 2001. [DOI] [PubMed] [Google Scholar]
• 427.Hougaard A, Amin F, Hauge AW, Ashina M, Olesen J. Provocation of migraine with aura using natural trigger factors. Neurology80: 428–431, 2013. [DOI] [PubMed] [Google Scholar]
• 428.Hougaard A, Hauge AW, Guo S, Tfelft-Hansen P. The nitric oxide synthase inhibitor and serotonin-receptor agonist NXN-188 during the aura phase of migraine with aura: a randomized, double-blind, placebo-controlled cross-over study. Scand J Pain4: 48–52, 2013. [DOI] [PubMed] [Google Scholar]
• 429.Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey PP, O'Carroll AM, Patel YC, Schonbrunn A, Taylor JE, Reisine T. Classification and nomenclature of somatostatin receptors. Trends Pharmacol Sci16: 86–88, 1995. [DOI] [PubMed] [Google Scholar]
• 430.Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav71: 533–554, 2002. [DOI] [PubMed] [Google Scholar]
• 431.Huang D, Li S, Dhaka A, Story GM, Cao YQ. Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura. Mol Pain8: 66, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 432.Huhman KL, Albers HE. Neuropeptide Y microinjected into the suprachiasmatic region phase shifts circadian rhythms in constant darkness. Peptides15: 1475–1478, 1994. [DOI] [PubMed] [Google Scholar]
• 433.Humphrey PPA, Feniuk W, Marriott AS, Tanner RJN, Jackson MR, Tucker ML. Preclinical studies on the anti-migraine drug, sumatriptan. Eur Neurol31: 282–290, 1991. [DOI] [PubMed] [Google Scholar]
• 434.Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET. Serotonin and migraine. Ann NY Acad Sci600: 587–598, 1990. [DOI] [PubMed] [Google Scholar]
• 435.Humphrey PPA, Goadsby PJ. Controversies in headache. The mode of action of sumatriptan is vascular? A debate. Cephalalgia14: 401–410, 1994. [DOI] [PubMed] [Google Scholar]
• 436.Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N. Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun270: 318–323, 2000. [DOI] [PubMed] [Google Scholar]
• 437.Inoue T, Inui A, Okita M, Sakatani N, Oya M, Morioka H, Mizuno N, Oimomi M, Baba S. Effect of neuropeptide Y on the hypothalamic-pituitary-adrenal axis in the dog. Life Sci44: 1043–1051, 1989. [DOI] [PubMed] [Google Scholar]
• 438.Ivanusic JJ, Kwok MM, Ahn AH, Jennings EA. 5-HT(1D) receptor immunoreactivity in the sphenopalatine ganglion: implications for the efficacy of triptans in the treatment of autonomic signs associated with cluster headache. Headache51: 392–402, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 439.Iversen H.Human migraine models. Cephalalgia21: 781–785, 2001. [DOI] [PubMed] [Google Scholar]
• 440.Iversen HK, Olesen J. Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan–a human model for development of migraine drugs. Cephalalgia16: 412–418, 1996. [DOI] [PubMed] [Google Scholar]
• 441.Iversen HK, Olesen J, Tfelt-Hansen P. Intravenous nitroglycerin as an experimental headache model Basic characteristics. Pain38: 17–24, 1989. [DOI] [PubMed] [Google Scholar]
• 442.Jacobowitz DM, O'Donohue TL. alpha-Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc Natl Acad Sci USA75: 6300–6304, 1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 443.Jacobs BL, McGinty DJ. Effects of food deprivation on sleep and wakefulness in the rat. Exp Neurol30: 212–222, 1971. [DOI] [PubMed] [Google Scholar]
• 444.Jankord R, Herman JP. Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann NY Acad Sci1148: 64–73, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 445.Jasmin L, Burkey AR, Card JP, Basbaum AI. Transneuronal labeling of a nociceptive pathway, the spino-(trigemino-)parabrachio-amygdaloid, in the rat. J Neurosci17: 3751–3765, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 446.Jászberényi M, Bujdosó E, Pataki I, Telegdy G. Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol12: 1174–1178, 2000. [DOI] [PubMed] [Google Scholar]
• 447.Johnson K, Johnson MP, Ellis B, Maren DL, Morin S, Wroblewski VJ. Peripheral and central distribution of the CGRP neutralizing antibody [¹²⁵I]-LY2951742 in male rats. Headache56: 67, 2016. [DOI] [PubMed] [Google Scholar]
• 448.Johnson KW, Nisenbaum ES, Johnson MP, Dieckman DK, Clemens-Smith A, Siuda ER, Dell CP, Dehlinger V, Hudziak KJ, Filla SA, Ornstein PL, Ramadan NM, Bleakman D. Innovative drug development for headache disorders: glutamate. In: Innovative Drug Development for Headache Disorders, edited by Olesen J, Ramadan N. Oxford, UK: Oxford Univ. Press, 2008, p. 185–194. [Google Scholar]
• 449.Johnson KW, Schaus JM, Durkin MM, Audia JE, Kaldor SW, Flaugh ME, Adham N, Zgombick JM, Cohen ML, Branchek TA, Phebus LA. 5-HT_1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. Neuroreport8: 2237–2240, 1997. [DOI] [PubMed] [Google Scholar]
• 450.Joo KM, Chung YH, Kim MK, Nam RH, Lee BL, Lee KH, Cha CI. Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain. J Comp Neurol476: 388–413, 2004. [DOI] [PubMed] [Google Scholar]
• 451.Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marecha E, Maciazek J, Vayssiere C, Craud C, Cabanis EA, Ruchoux MM, Wissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature383: 707–710, 1996. [DOI] [PubMed] [Google Scholar]
• 452.Judit A, Sandor PS, Schoenen J. Habituation of visual and intensity dependence of cortical auditory evoked potentials tend to normalise just before and during migraine attacks. Cephalalgia20: 714–719, 2000. [DOI] [PubMed] [Google Scholar]
• 453.Kaiser EA, Kuburas A, Recober A, Russo AF. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist. J Neurosci32: 15439–15449, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 454.Kakui N, Kitamura K. Direct evidence that stimulation of neuropeptide Y Y5 receptor activates hypothalamo-pituitary-adrenal axis in conscious rats via both corticotropin-releasing factor- and arginine vasopressin-dependent pathway. Endocrinology148: 2854–2862, 2007. [DOI] [PubMed] [Google Scholar]
• 455.Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci USA88: 10931–10935, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 456.Kalsbeek A, Fliers E, Romijn JA, La Fleur SE, Wortel J, Bakker O, Endert E, Buijs RM. The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels. Endocrinology142: 2677–2685, 2001. [DOI] [PubMed] [Google Scholar]
• 457.Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Kocak E, Sen ZD, Dalkara T. Spreading depression triggers headache by activating neuronal Panx1 channels. Science339: 1092–1095, 2013. [DOI] [PubMed] [Google Scholar]
• 458.Karteris E, Machado RJ, Chen J, Zervou S, Hillhouse EW, Randeva HS. Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex. Am J Physiol Endocrinol Metab288: E1089–E1100, 2005. [DOI] [PubMed] [Google Scholar]
• 459.Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med14: 923–930, 2008. [DOI] [PubMed] [Google Scholar]
• 460.Kaube H, Goadsby PJ. Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat. Eur Neurol34: 30–35, 1994. [DOI] [PubMed] [Google Scholar]
• 461.Kaube H, Hoskin KL, Goadsby PJ. An intact blood-brain barrier prevents central inhibition of trigeminovascular neurons by sumatriptan. J Cereb Blood Flow Metab13: S119, 1993. [Google Scholar]
• 462.Kaube H, Hoskin KL, Goadsby PJ. Sumatriptan inhibits central trigeminal neurons only after blood-brain barrier disruption. Cephalalgia13: 41, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 463.Kaube H, Keay KA, Hoskin KL, Bandler R, Goadsby PJ. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat. Brain Res629: 95–102, 1993. [DOI] [PubMed] [Google Scholar]
• 464.Kelman L.The place of osmophobia and taste abnormalities in migraine classification: a tertiary care study of 1237 patients. Cephalalgia24: 940–946, 2004. [DOI] [PubMed] [Google Scholar]
• 465.Kelman L.The postdrome of the acute migraine attack. Cephalalgia26: 214–220, 2006. [DOI] [PubMed] [Google Scholar]
• 466.Kelman L.The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs. Headache44: 865–872, 2004. [DOI] [PubMed] [Google Scholar]
• 467.Kim JH, Kim S, Suh SI, Koh SB, Park KW, Oh K. Interictal metabolic changes in episodic migraine: a voxel-based FDG-PET study. Cephalalgia30: 53–61, 2010. [DOI] [PubMed] [Google Scholar]
• 468.Kimball RW, Friedman AP, Vallejo E. Effect of serotonin in migraine patients. Neurology10: 107–111, 1960. [DOI] [PubMed] [Google Scholar]
• 469.Kiyashchenko LI, Mileykovskiy BY, Maidment N, Lam HA, Wu MF, John J, Peever J, Siegel JM. Release of hypocretin (orexin) during waking and sleep states. J Neurosci22: 5282–5286, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 470.Klopstock T, May A, Seibel P, Papagiannuli E, Diener HC, Reichmann H. Mitochondrial DNA in migraine with aura. Neurology46: 1735–1738, 1996. [DOI] [PubMed] [Google Scholar]
• 471.Knight YE, Bartsch T, Goadsby PJ. Trigeminal antinociception induced by bicuculline in the periaqueductal grey (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci Lett336: 113–116, 2003. [DOI] [PubMed] [Google Scholar]
• 472.Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q-type calcium channel blockade in the PAG facilitates trigeminal nociception: a functional genetic link for migraine?J Neurosci22: 1–6, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 473.Knight YE, Classey JD, Lasalandra MP, Akerman S, Kowacs F, Hoskin KL, Goadsby PJ. Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat. Brain Res1045: 1–11, 2005. [DOI] [PubMed] [Google Scholar]
• 474.Knight YE, Goadsby PJ. The periaqueductal gray matter modulates trigeminovascular input: a role in migraine?Neuroscience106: 793–800, 2001. [DOI] [PubMed] [Google Scholar]
• 475.Knutson KL, Spiegel K, Penev P, Van Cauter E. The metabolic consequences of sleep deprivation. Sleep Med Rev11: 163–178, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 476.Koban M, Le WW, Hoffman GE. Changes in hypothalamic corticotropin-releasing hormone, neuropeptide Y, and proopiomelanocortin gene expression during chronic rapid eye movement sleep deprivation of rats. Endocrinology147: 421–431, 2006. [DOI] [PubMed] [Google Scholar]
• 477.Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A, Noguchi K. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol493: 596–606, 2005. [DOI] [PubMed] [Google Scholar]
• 478.Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF. Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes45: 1511–1515, 1996. [DOI] [PubMed] [Google Scholar]
• 479.Koob GF.Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci13: 177–184, 1992. [DOI] [PubMed] [Google Scholar]
• 480.Koulchitsky S, Fischer MJ, De Col R, Schlechtweg PM, Messlinger K. Biphasic response to nitric oxide of spinal trigeminal neurons with meningeal input in rat–possible implications for the pathophysiology of headaches. J Neurophysiol92: 1320–1328, 2004. [DOI] [PubMed] [Google Scholar]
• 481.Koulchitsky S, Fischer MJ, Messlinger K. Calcitonin gene-related peptide receptor inhibition reduces neuronal activity induced by prolonged increase in nitric oxide in the rat spinal trigeminal nucleus. Cephalalgia29: 408–417, 2009. [DOI] [PubMed] [Google Scholar]
• 482.Krowicki ZK, Kapusta DR. Microinjection of glycine into the hypothalamic paraventricular nucleus produces diuresis, natriuresis, and inhibition of central sympathetic outflow. J Pharmacol Exp Ther337: 247–255, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 483.Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, Launer LJ. Migraine as a risk factor for subclinical brain lesions. J Am Med Assoc291: 427–434, 2004. [DOI] [PubMed] [Google Scholar]
• 484.Kunkler PE, Kraig RP. Cortical spreading depression bilaterally activates the caudal trigeminal nucleus in rodents. Hippocampus13: 835–844, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 485.Kuphal KE, Solway B, Pedrazzini T, Taylor BK. Y1 receptor knockout increases nociception and prevents the anti-allodynic actions of NPY. Nutrition24: 885–891, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 486.Kurosawa M, Messlinger K, Pawlak M, Schmidt RF. Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene-related peptide. Br J Pharmacol114: 1397–1402, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 487.Kurth T, Chabriat H, Bousser MG. Migraine and stroke: a complex association with clinical implications. Lancet Neurol11: 92–100, 2012. [DOI] [PubMed] [Google Scholar]
• 488.Kuru M, Ueta Y, Serino R, Nakazato M, Yamamoto Y, Shibuya I, Yamashita H. Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport11: 1977–1980, 2000. [DOI] [PubMed] [Google Scholar]
• 489.Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M, Nakamura M. Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. Proc Natl Acad Sci USA95: 15659–15664, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 490.Kuypers HG.Corticobular connexions to the pons and lower brain-stem in man: an anatomical study. Brain81: 364–388, 1958. [DOI] [PubMed] [Google Scholar]
• 491.La Fleur SE, Kalsbeek A, Wortel J, Buijs RM. A suprachiasmatic nucleus generated rhythm in basal glucose concentrations. J Neuroendocrinol11: 643–652, 1999. [DOI] [PubMed] [Google Scholar]
• 492.Laburthe M, Couvineau A. Molecular pharmacology and structure of VPAC receptors for VIP and PACAP. Regul Pept108: 165–173, 2002. [DOI] [PubMed] [Google Scholar]
• 493.Lafreniere RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafreniere F, McLaughlan S, Dube MP, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G, Rouleau GA. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med16: 1157–1160, 2010. [DOI] [PubMed] [Google Scholar]
• 494.Lai TH, Fuh JL, Wang SJ. Cranial autonomic symptoms in migraine: characteristics and comparison with cluster headache. J Neurol Neurosurg Psychiatry80: 1116–1119, 2009. [DOI] [PubMed] [Google Scholar]
• 495.Lambert GA, Donaldson C, Boers PM, Zagami AS. Activation of trigeminovascular neurons by glycerol trinitrate. Brain Res887: 253–259, 2000. [DOI] [PubMed] [Google Scholar]
• 496.Lambert GA, Donaldson C, Hoskin KL, Boers PM, Zagami AS. Dilatation induced by 5-HT in the middle meningeal artery of the anaesthetised cat. Naunyn-Schmiedebergs Arch Pharmacol369: 591–601, 2004. [DOI] [PubMed] [Google Scholar]
• 497.Lambert GA, Goadsby PJ, Zagami AS, Duckworth JW. Comparative effects of stimulation of the trigeminal ganglion and the superior sagittal sinus on cerebral blood flow and evoked potentials in the cat. Brain Res453: 143–149, 1988. [DOI] [PubMed] [Google Scholar]
• 498.Lambert GA, Hoskin KL, Zagami AS. Cortico-NRM influences on trigeminal neuronal sensation. Cephalalgia28: 640–652, 2008. [DOI] [PubMed] [Google Scholar]
• 499.Lambert GA, Michalicek J, Storer RJ, Zagami AS. Effect of cortical spreading depression on activity of trigeminovascular sensory neurons. Cephalalgia19: 631–638, 1999. [DOI] [PubMed] [Google Scholar]
• 500.Lambert GA, Truong L, Zagami AS. Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system. Cephalalgia31: 1439–1451, 2011. [DOI] [PubMed] [Google Scholar]
• 501.Lambert GA, Zagami AS. Trigeminovascular sensory signals CAN be modulated by central mechanisms. A response to a Cephalalgia Viewpoint. Cephalalgia33: 347–350, 2013. [DOI] [PubMed] [Google Scholar]
• 502.Lance JW.Mechanism and Management of Migraine. Sydney: Butterworths, 1982. [Google Scholar]
• 503.Lance JW, Anthony M, Hinterberger H. The control of cranial arteries by humoral mechanisms and its relation to the migraine syndrome. Headache7: 93–102, 1967. [DOI] [PubMed] [Google Scholar]
• 504.Lance JW, Goadsby PJ. Mechanism and Management of Headache. New York: Elsevier, 2005. [Google Scholar]
• 505.Lang E, Kaltenhauser M, Neundorfer B, Seidler S. Hyperexcitability of the primary somatosensory cortex in migraine–a magnetoencephalographic study. Brain127: 2459–2469, 2004. [DOI] [PubMed] [Google Scholar]
• 506.Lashley KS.Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatry46: 331–339, 1941. [Google Scholar]
• 507.Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J. Nitric oxide synthesis inhibition in migraine. Lancet349: 401–402, 1997. [DOI] [PubMed] [Google Scholar]
• 508.Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia22: 54–61, 2002. [DOI] [PubMed] [Google Scholar]
• 509.Latham PW.Clinical lecture on nervous or sick-headaches. Br Med J1: 336–337, 1872. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 510.Latham PW.Clinical lecture on nervous or sick-headaches. Br Med J1: 305–306, 1872. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 511.Latham PW.On Nervous or Sick-Headache. Cambridge, UK: Deighton, Bell and Co, 1873. [Google Scholar]
• 512.Lauritzen M.Pathophysiology of the migraine aura. The spreading depression theory. Brain117: 199–210, 1994. [DOI] [PubMed] [Google Scholar]
• 513.Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab31: 17–35, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 514.Laursen JC, Cairns BE, Kumar U, Somvanshi RK, Dong XD, Arendt-Nielsen L, Gazerani P. Nitric oxide release from trigeminal satellite glial cells is attenuated by glial modulators and glutamate. Int J Physiol Pathophysiol Pharmacol5: 228–238, 2013. [PMC free article] [PubMed] [Google Scholar]
• 515.Laws GL.The effects of nitrogylcerin upon those who manufacture it. J Am Med Assoc31: 793–794, 1898. [Google Scholar]
• 516.Le Doare K, Akerman S, Holland PR, Lasalandra MP, Classey JD, Knight YE, Goadsby PJ. Occipital afferent activation of second order neurons in the trigeminocervical complex in rat. Neurosci Lett403: 73–77, 2006. [DOI] [PubMed] [Google Scholar]
• 517.Leao AAP.Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol10: 409–414, 1947. [DOI] [PubMed] [Google Scholar]
• 518.Leao AAP.Pial circulation and spreading activity in the cerebral cortex. J Neurophysiol7: 391–396, 1944. [Google Scholar]
• 519.Leao AAP.Spreading depression of activity in cerebral cortex. J Neurophysiol7: 359–390, 1944. [DOI] [PubMed] [Google Scholar]
• 520.Leao AP, Morison RS. Propagation of spreading cortical depression. J Neurophysiol8: 33–45, 1945. [Google Scholar]
• 521.Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci25: 6716–6720, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 522.Leibowitz SF.Brain neuropeptide Y: an integrator of endocrine, metabolic and behavioral processes. Brain Res Bull27: 333–337, 1991. [DOI] [PubMed] [Google Scholar]
• 523.Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, Messlinger K. Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol507: 1277–1299, 2008. [DOI] [PubMed] [Google Scholar]
• 524.Leo L, Gherardini L, Barone V, De Fusco M, Pietrobon D, Pizzorusso T, Casari G. Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet7: e1002129, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 525.Leung CG, Mason P. Physiological properties of raphe magnus neurons during sleep and waking. J Neurophysiol81: 584–595, 1999. [DOI] [PubMed] [Google Scholar]
• 526.Levy D, Burstein R, Strassman AM. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol58: 698–705, 2005. [DOI] [PubMed] [Google Scholar]
• 527.Levy MJ, Matharu MS, Bhola R, Meeran K, Goadsby PJ. Octreotide is not effective in the acute treatment of migraine. Cephalalgia25: 48–55, 2005. [DOI] [PubMed] [Google Scholar]
• 528.Leysen JE, Gommeren W, Heylen L, Luyten WHML, Weyer IVD, Vanhoenacker P, Haegeman G, Schotte A, Gompel Pv Wouters R, Lasage AS. Alniditan, a new 5-hydroxytryptamine_1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine_1Da, human 5-hydroxytryptamine_1Db, and calf 5-hydroxytryptamine_1D receptors investigated with [³H]-5-hydroxytryptamine and [³H]alniditan. Mol Pharmacol50: 1567–1580, 1996. [PubMed] [Google Scholar]
• 529.Li C, Chen P, Smith MS. Corticotropin releasing hormone neurons in the paraventricular nucleus are direct targets for neuropeptide Y neurons in the arcuate nucleus: an anterograde tracing study. Brain Res854: 122–129, 2000. [DOI] [PubMed] [Google Scholar]
• 530.Li JJ, Zhou X, Yu LC. Involvement of neuropeptide Y and Y1 receptor in antinociception in the arcuate nucleus of hypothalamus, an immunohistochemical and pharmacological study in intact rats and rats with inflammation. Pain118: 232–242, 2005. [DOI] [PubMed] [Google Scholar]
• 531.Limmroth V, May A, Auerbach P, Wosnitza G, Eppe T, Diener HC. Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine. J Neurol Sci138: 60–65, 1996. [DOI] [PubMed] [Google Scholar]
• 532.Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell98: 365–376, 1999. [DOI] [PubMed] [Google Scholar]
• 533.Lindell SG, Schwandt ML, Sun H, Sparenborg JD, Björk K, Kasckow JW, Sommer WH, Goldman D, Higley JD, Suomi SJ, Heilig M, Barr CS. Functional NPY variation as a factor in stress resilience and alcohol consumption in rhesus macaques. Arch Gen Psychiatry67: 423–431, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 534.Liposits Z, Sievers L, Paull WK. Neuropeptide-Y and ACTH-immunoreactive innervation of corticotropin releasing factor (CRF)-synthesizing neurons in the hypothalamus of the rat. An immunocytochemical analysis at the light and electron microscopic levels. Histochemistry88: 227–234, 1988. [DOI] [PubMed] [Google Scholar]
• 535.Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, Serrano D, Stewart WF. Cutaneous allodynia in the migraine population. Ann Neurol63: 148–158, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 536.Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, Advisory Group AMPP. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology68: 343–349, 2007. [DOI] [PubMed] [Google Scholar]
• 537.Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, Fischell RE, Ruppel PL, Goadsby PJ. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol9: 373–380, 2010. [DOI] [PubMed] [Google Scholar]
• 538.Lipton RB, Goadsby PJ, Cady RK, Aurora SK, Grosberg BM, Freitag FG, Silberstein SD, Whiten DM, Jaax KN. PRISM study: occipital nerve stimulation for treatment-refractory migraine. Cephalalgia29: 30, 2009. [Google Scholar]
• 539.Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache41: 646–657, 2001. [DOI] [PubMed] [Google Scholar]
• 540.Liu P, Xiao Z, Ren F, Guo Z, Chen Z, Zhao H, Cao YQ. Functional analysis of a migraine-associated TRESK K⁺ channel mutation. J Neurosci33: 12810–12824, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 541.Liu Y, Broman J, Edvinsson L. Central projections of sensory innervation of the rat superior sagittal sinus. Neuroscience129: 431–437, 2004. [DOI] [PubMed] [Google Scholar]
• 542.Liu Y, Broman J, Edvinsson L. Central projections of the sensory innervation of the rat middle meningeal artery. Brain Res1208: 103–110, 2008. [DOI] [PubMed] [Google Scholar]
• 543.Liu Y, Broman J, Zhang M, Edvinsson L. Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia29: 935–948, 2009. [DOI] [PubMed] [Google Scholar]
• 544.Liveing E.On Megrim, Sick-Headache, and Some Allied Disorders. A Contribution to the Pathology of Nerve-Storms. London: Arts & Boeve Nijmegen, 1873. [Google Scholar]
• 545.Lodi R, Montagna P, Soriani S, Iotti S, Arnaldi C, Cortelli P, Pierangeli G, Patuelli A, Zaniol P, Barbiroli B. Deficit of brain and skeletal muscle bioenergetics and low brain magnesium in juvenile migraine: an in vivo³¹P magnetic resonance spectroscopy interictal study. Pediatr Res42: 866–871, 1997. [DOI] [PubMed] [Google Scholar]
• 546.Lovick TA, Robinson JP. Bulbar raphe neurones with projections to the trigeminal nucleus caudalis and the lumbar cord in the rat: a fluorescence double-labelling study. Exp Brain Res50: 299–308, 1983. [DOI] [PubMed] [Google Scholar]
• 547.Lovick TA, Wolstencroft JH. Projections from brain-stem nuclei to the spinal trigeminal nucleus in the cat. Neuroscience9: 411–418, 1983. [DOI] [PubMed] [Google Scholar]
• 548.Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB. Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep. J Neurosci22: 4568–4576, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 549.Lu J, Jhou TC, Saper CB. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J Neurosci26: 193–202, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 550.Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for control of REM sleep. Nature441: 589–594, 2006. [DOI] [PubMed] [Google Scholar]
• 551.Lu XY, Bagnol D, Burke S, Akil H, Watson SJ. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav37: 335–344, 2000. [DOI] [PubMed] [Google Scholar]
• 552.Ma QP, Hill R, Sirinathsinghji D. Colocalization of CGRP with 5-HT_1B/1D receptors and substance P in trigeminal ganglion neurons in rats. Eur J Neurosci13: 2099–2104, 2001. [DOI] [PubMed] [Google Scholar]
• 553.Magon S, May A, Stankewitz A, Goadsby PJ, Tso A, Ashina M, Amin FM, Seifert C, Chakravarty M, Muller J, Sprenger T. Morphological abnormalities of thalamic subnuclei in migraine: a multi-center MRI study at 3T. J Neurosci35: 13800–13806, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 554.Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol70: 838–845, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 555.Maleki N, Becerra L, Nutile L, Pendse G, Brawn J, Bigal M, Burstein R, Borsook D. Migraine attacks the Basal Ganglia. Mol Pain7: 71, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 556.Malick A, Burstein R. Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol400: 125–144, 1998. [DOI] [PubMed] [Google Scholar]
• 557.Malick A, Burstein R. A neurohistochemical blueprint for pain-induced loss of appetite. Proc Natl Acad Sci USA98: 9930–9935, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 558.Malick A, Strassman AM, Burstein R. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat. J Neurophysiol84: 2078–2112, 2000. [DOI] [PubMed] [Google Scholar]
• 559.Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin triggered migraine attacks. Brain137: 232–242, 2014. [DOI] [PubMed] [Google Scholar]
• 560.Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. The origin of nausea in migraine: a PET study. J Headache Pain15: 84, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 561.Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer T. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo-controlled, dose-ranging trial. Cephalalgia33: 94, 2013. [DOI] [PubMed] [Google Scholar]
• 562.Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia34: 114–125, 2014. [DOI] [PubMed] [Google Scholar]
• 563.Marfurt CF.The central projections of trigeminal primary afferent neurons in the cat as determined by the tranganglionic transport of horseradish peroxidase. J Comp Neurol203: 785–798, 1981. [DOI] [PubMed] [Google Scholar]
• 564.Markovics A, Kormos V, Gaszner B, Lashgarara A, Szoke E, Sandor K, Szabadfi K, Tuka B, Tajti J, Szolcsanyi J, Pinter E, Hashimoto H, Kun J, Reglodi D, Helyes Z. Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice. Neurobiol Dis45: 633–644, 2012. [DOI] [PubMed] [Google Scholar]
• 565.Markowitz S, Saito K, Buzzi MG, Moskowitz MA. The development of neurogenic plasma extravasation in the rat dura mater does not depend upon the degranulation of mast cells. Brain Res477: 157–165, 1989. [DOI] [PubMed] [Google Scholar]
• 566.Markowitz S, Saito K, Moskowitz MA. Neurogenically mediated leakage of plasma proteins occurs from blood vessels in dura mater but not brain. J Neurosci7: 4129–4136, 1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 567.Markowitz S, Saito K, Moskowitz MA. Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache. Cephalalgia8: 83–91, 1988. [DOI] [PubMed] [Google Scholar]
• 568.Martin PR, Seneviratne HM. Effects of food deprivation and a stressor on head pain. Health Psychol16: 310–318, 1997. [DOI] [PubMed] [Google Scholar]
• 569.Martins-Oliveira M, Hoffmann J, Akerman S, Goadsby PJ. Modulation of trigeminovascular activity by leptin: a novel antinociceptive mechanism?Cephalalgia33: 209, 2013. [Google Scholar]
• 570.Martins-Oliveira M, Akerman S, Tavares I, Goadsby PJ.. Neuropeptide Y inhibits the trigeminovascular pathway through NPY Y1 receptor: implications for migraine. Pain. In press. [DOI] [PMC free article] [PubMed]
• 571.Mason P.Deconstructing endogenous pain modulations. J Neurophysiol94: 1659–1663, 2005. [DOI] [PubMed] [Google Scholar]
• 572.Mason P.Physiological identification of pontomedullary serotonergic neurons in the rat. J Neurophysiol77: 1087–1098, 1997. [DOI] [PubMed] [Google Scholar]
• 573.Mason P.Ventromedial medulla: pain modulation and beyond. J Comp Neurol493: 2–8, 2005. [DOI] [PubMed] [Google Scholar]
• 574.Masuo Y, Ohtaki T, Masuda Y, Tsuda M, Fujino M. Binding sites for pituitary adenylate cyclase activating polypeptide (PACAP): comparison with vasoactive intestinal polypeptide (VIP) binding site localization in rat brain sections. Brain Res575: 113–123, 1992. [DOI] [PubMed] [Google Scholar]
• 575.Matharu MS, Cohen AS, Frackowiak RSJ, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol59: 535–545, 2006. [DOI] [PubMed] [Google Scholar]
• 576.Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RSJ, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache44: 747–761, 2004. [DOI] [PubMed] [Google Scholar]
• 577.Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache-randomized placebo-controlled double-blind cross-over study. Ann Neurol56: 488–494, 2004. [DOI] [PubMed] [Google Scholar]
• 578.Mathew R, Chami L, Bergerot A, van den Maagdenberg AMJM, Ferrari MD, Goadsby PJ. Immunohistochemical characterization of calcitonin gene-related peptide in the trigeminal system of the familial hemiplegic migraine 1 knock-in mouse. Cephalalgia31: 1368–1380, 2011. [DOI] [PubMed] [Google Scholar]
• 579.Matsushita M, Ikeda M, Okado N. The cells of origin of the trigeminothalamic, trigeminospinal and trigeminocerebellar projections in the cat. Neuroscience7: 1439–1454, 1982. [DOI] [PubMed] [Google Scholar]
• 580.May A, Ashburner J, Buchel C, McGonigle DJ, Friston KJ, Frackowiak RSJ, Goadsby PJ. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nature Med5: 836–838, 1999. [DOI] [PubMed] [Google Scholar]
• 581.May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet352: 275–278, 1998. [DOI] [PubMed] [Google Scholar]
• 582.May A, Bahra A, Buchel C, Turner R, Goadsby PJ. Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol46: 791–793, 1999. [DOI] [PubMed] [Google Scholar]
• 583.May A, Goadsby PJ. Substance P receptor antagonists in the therapy of migraine. Expert Opin Invest Drugs10: 1–6, 2001. [DOI] [PubMed] [Google Scholar]
• 584.May A, Goadsby PJ. The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab19: 115–127, 1999. [DOI] [PubMed] [Google Scholar]
• 585.May A, Kaube H, Buechel C, Eichten C, Rijntjes M, Jueptner M, Weiller C, Diener HC. Experimental cranial pain elicited by capsaicin: a PET-study. Pain74: 61–66, 1998. [DOI] [PubMed] [Google Scholar]
• 586.May A, Ophoff RA, Terwindt GM, Urban C, VanEijk R, Haan J, Diener HC, Lindhout D, Frants RR, Sandkuijl A, Ferrari MD. Familial hemiplegic migraine locus on chromosome 19p13 is involved in common forms of migraine with and without aura. Hum Genet96: 604–608, 1995. [DOI] [PubMed] [Google Scholar]
• 587.May A, Shepheard S, Wessing A, Hargreaves RJ, Goadsby PJ, Diener HC. Retinal plasma extravasation can be evoked by trigeminal stimulation in rat but does not occur during migraine attacks. Brain121: 1231–1237, 1998. [DOI] [PubMed] [Google Scholar]
• 588.Mayer DJ.Analgesia produced by electrical stimulation of the brain. Prog Neuropsychopharmacol Biol Psychiatry8: 557–564, 1984. [DOI] [PubMed] [Google Scholar]
• 589.Mayevsky A, Doron A, Manor T, Meilin S, Zarchin N, Ouaknine GE. Cortical spreading depression recorded from the human brain using a multiparametric monitoring system. Brain Res740: 268–274, 1996. [DOI] [PubMed] [Google Scholar]
• 590.McCarthy LC, Hosford DA, Riley JH, Bird MI, White NJ, Hewett DR, Peroutka SJ, Griffiths LR, Boyd PR, Lea RA, Bhatti SM, Hosking LK, Hood CM, Jones KW, Handley AR, Rallan R, Lewis KF, Yeo AJ, Williams PM, Priest RC, Khan P, Donnelly C, Lumsden SM, O'Sullivan J, See CG, Smart DH, Shaw-Hawkins S, Patel J, Langrish TC, Feniuk W, Knowles RG, Thomas M, Libri V, Montgomery DS, Manasco PK, Xu CF, Dykes C, Humphrey PP, Roses AD, Purvis IJ. Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine. Genomics78: 135–149, 2001. [DOI] [PubMed] [Google Scholar]
• 591.McCrone P, Seed PT, Dowson AJ, Clark LV, Goldstein LH, Morgan M, Ridsdale L. Service use and costs for people with headache: a UK primary care study. J Headache Pain12: 617–623, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 592.McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature416: 52–58, 2002. [DOI] [PubMed] [Google Scholar]
• 593.McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature393: 333–339, 1998. [DOI] [PubMed] [Google Scholar]
• 594.McNaughton FL, Feindel WH. Innervation of intracranial structures: a reappraisal. In: Physiological Aspects of Clinical Neurology, edited by Rose FC.Oxford: Blackwell Scientific, 1977, p. 279–293. [Google Scholar]
• 595.Medve RA, Andrews JS. Effects of fixed dose combination of nNOS inhibition and 5HT agonism on progression of migraine with and without aura. Cephalalgia29: 126, 2009. [Google Scholar]
• 596.Meguid MM, Yang ZJ, Laviano A. Meal size and number: relationship to dopamine levels in the ventromedial hypothalamic nucleus. Am J Physiol Regul Integr Comp Physiol272: R1925–R1930, 1997. [DOI] [PubMed] [Google Scholar]
• 597.Meng ID, Johansen JP. Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience124: 685–693, 2004. [DOI] [PubMed] [Google Scholar]
• 598.Meng W, Ayata C, Waeber C, Huang PL, Moskowitz MA. Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice. Am J Physiol Heart Circ Physiol274: H411–H415, 1998. [DOI] [PubMed] [Google Scholar]
• 599.Mercer JG, Moar KM, Hoggard N. Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. Endocrinology139: 29–34, 1998. [DOI] [PubMed] [Google Scholar]
• 600.Meye FJ, Adan RA. Feelings about food: the ventral tegmental area in food reward and emotional eating. Trends Pharmacol Sci35: 31–40, 2014. [DOI] [PubMed] [Google Scholar]
• 601.Millan MJ.Descending control of pain. Prog Neurobiol66: 355–474, 2002. [DOI] [PubMed] [Google Scholar]
• 602.Miller AD, Ruggiero DA. Emetic reflex arc revealed by expression of the immediate-early gene c-fos in the cat. J Neurosci14: 871–888, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 603.Mirza AF, Mo J, Holt JL, Kairalla JA, Heft MW, Ding M, Ahn AH. Is there a relationship between throbbing pain and arterial pulsations?J Neurosci32: 7572–7576, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 604.Mitsikostas DD, Sanchez del Rio M, Moskowitz MA, Waeber C. Both 5-HT_1B and 5-HT_1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis. Eur J Pharmacol369: 271–277, 1999. [DOI] [PubMed] [Google Scholar]
• 605.Mitsikostas DD, Sanchez del Rio M, Waeber C. 5-Hydroxytryptamine(1B/1D) and 5-hydroxytryptamine1F receptors inhibit capsaicin-induced c-fos immunoreactivity within mouse trigeminal nucleus caudalis. Cephalalgia22: 384–394, 2002. [DOI] [PubMed] [Google Scholar]
• 606.Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, pharmacology. Pharmacol Rev43: 109–142, 1991. [PubMed] [Google Scholar]
• 607.Montagna P, Cortelli P, Monari L, Pierangeli G, Parchi P, Lodi R, Iotti S, Frassineti C, Zaniol P, Lugaresi E..³¹P-magnetic resonance spectroscopy in migraine without aura. Neurology44: 666–669, 1994. [DOI] [PubMed] [Google Scholar]
• 608.Monteleone P, Bortolotti F, Fabrazzo M, La Rocca A, Fuschino A, Maj M. Plamsa leptin response to acute fasting and refeeding in untreated women with bulimia nervosa. J Clin Endocrinol Metab85: 2499–2503, 2000. [DOI] [PubMed] [Google Scholar]
• 609.Moreau JL, Fields HL. Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission. Brain Res397: 37–46, 1986. [DOI] [PubMed] [Google Scholar]
• 610.Moreno MJ, Abounader R, Hebert E, Doods H, Hamel E. Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment. Neuropharmacology42: 568–576, 2002. [DOI] [PubMed] [Google Scholar]
• 611.Moriguchi T, Sakurai T, Takahashi S, Goto K, Yamamoto M. The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus. J Biol Chem277: 16985–16992, 2002. [DOI] [PubMed] [Google Scholar]
• 612.Moskowitz MA.The neurobiology of vascular head pain. Ann Neurol16: 157–168, 1984. [DOI] [PubMed] [Google Scholar]
• 613.Moulton EA, Becerra L, Maleki N, Pendse G, Tully S, Hargreaves R, Burstein R, Borsook D. Painful heat reveals hyperexcitability of the temporal pole in interictal and ictal migraine states. Cereb Cortex21: 435–448, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 614.Moulton EA, Burstein R, Tully S, Hargreaves R, Becerra L, Borsook D. Interictal dysfunction of a brainstem descending modulatory center in migraine patients. PLoS One3: e3799, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 615.Mouraux A, Diukova A, Lee MC, Wise RG, Iannetti GD. A multisensory investigation of the functional significance of the “pain matrix.”Neuroimage54: 2237–2249, 2011. [DOI] [PubMed] [Google Scholar]
• 616.Mraovitch S, Calando Y, Goadsby PJ, Seylaz J. Subcortical cerebral blood flow and metabolic changes elicited by cortical spreading depression in rat. Cephalalgia12: 137–141, 1992. [DOI] [PubMed] [Google Scholar]
• 617.Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, Kanse S, Amara SG, Burrin JM, Legon S. Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience25: 195–205, 1988. [DOI] [PubMed] [Google Scholar]
• 618.Mullington JM, Chan JL, Van Dongen HP, Szuba MP, Samaras J, Price NJ, Meier-Ewert HK, Dinges DF, Mantzoros CS. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol15: 851–854, 2003. [DOI] [PubMed] [Google Scholar]
• 619.Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, Shibahara M, Kuramochi M, Takigawa M, Yanagisawa M, Sakurai T, Shioda S, Yada T. Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca²⁺ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci19: 1524–1534, 2004. [DOI] [PubMed] [Google Scholar]
• 620.Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basanez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabe E, Bhalla K, Bhandari B, Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fevre EM, Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FG, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gonzalez-Medina D, Gosselin R, Grainger R, Grant B, Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Laden F, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh J, Levinson D, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M, Ohno SL, Lyons R, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGill N, McGrath J, Medina-Mora ME, Meltzer M, Mensah GA, Merriman TR, Meyer AC, Miglioli V, Miller M, Miller TR, Mitchell PB, Mock C, Mocumbi AO, Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM, Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R, O'Donnell M, O'Hanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope CA 3rd Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Leon FR, Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S, Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM, Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL, Stapelberg NJ, Steer A, Steiner T, Stolk WA, Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K, Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM, White RA, Whiteford H, Wiebe N, Wiersma ST, Wilkinson JD, Williams HC, Williams SR, Witt E, Wolfe F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies D, Lopez AD, AlMazroa MA, Memish ZA. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet380: 2197–2223, 2012. [DOI] [PubMed] [Google Scholar]
• 621.Myers MG, Münzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab9: 117–123, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 622.Myren M, Baun M, Ploug KB, Jansen-Olesen I, Olesen J, Gupta S. Functional and molecular characterization of prostaglandin E2 dilatory receptors in the rat craniovascular system in relevance to migraine. Cephalalgia30: 1110–1122, 2012. [DOI] [PubMed] [Google Scholar]
• 623.Myren M, Olesen J, Gupta S. Pharmacological and expression profile of the prostaglandin I(2) receptor in the rat craniovascular system. Vasc Pharmacol55: 50–58, 2011. [DOI] [PubMed] [Google Scholar]
• 624.Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, Xu YC. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia30: 1159–1169, 2010. [DOI] [PubMed] [Google Scholar]
• 625.Nesbitt AD, Leschziner GD, Peatfield RC. Headache, drugs and sleep. Cephalalgia34: 756–766, 2014. [DOI] [PubMed] [Google Scholar]
• 626.Nicolodi M, Moneti G, Pieraccini G, Conti P, Del Bianco PL, Sicuteri F. Sumatriptan pharmacokinetics in the spinal fluid following oral administration of the drug. Cephalalgia20: 272, 2000. [Google Scholar]
• 627.Niebur E, Hsiao SS, Johnson KO. Synchrony: a neural mechanism for attentional selection?Curr Opin Neurobiol12: 190–194, 2002. [DOI] [PubMed] [Google Scholar]
• 628.Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet355: 39–40, 2000. [DOI] [PubMed] [Google Scholar]
• 629.Norman B, Panebianco D, Block GA. A placebo-controlled, in-clinic study to explore the preliminary safety and efficacy of intravenous L-758,298 (a prodrug of the NK1 receptor antagonist L-754,030) in the acute treatment of migraine. Cephalalgia18: 407, 1998. [Google Scholar]
• 630.Noseda 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 Neurosci30: 14420–14429, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 631.Noseda R, Jakubowski M, Kainz V, Borsook D, Burstein R. Cortical projections of functionally identified thalamic trigeminovascular neurons: implications for migraine headache and its associated symptoms. J Neurosci31: 14204–14217, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 632.Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light. Nat Neurosci13: 239–245, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 633.Nowak KW, Maćkowiak P, Switońska MM, Fabiś M, Malendowicz LK. Acute orexin effects on insulin secretion in the rat: in vivo and in vitro studies. Life Sci66: 449–454, 2000. [DOI] [PubMed] [Google Scholar]
• 634.Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh-Hofer S, Rohde W, Arnold G, Dirnagl U, Jansen-Olesen I, Reuter U. CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia25: 225–236, 2005. [DOI] [PubMed] [Google Scholar]
• 635.Okamoto K, Tashiro A, Chang Z, Bereiter DA. Bright light activates a trigeminal nociceptive pathway. Pain149: 235–242, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 636.Olesen J.Cerebral and extracranial circulatory disturbances in migraine: pathophysiological implications. Cerebrovasc Brain Metab Rev3: 1–28, 1991. [PubMed] [Google Scholar]
• 637.Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby P, Gobel H, Lainez M, Lance J, Lipton R, Nappi G, Sakai F, Schoenen J, Silberstein SD, Steiner TJ. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia26: 742–746, 2006. [DOI] [PubMed] [Google Scholar]
• 638.Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med350: 1104–1110, 2004. [DOI] [PubMed] [Google Scholar]
• 639.Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport4: 1027–1030, 1993. [DOI] [PubMed] [Google Scholar]
• 640.Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol9: 344–352, 1981. [DOI] [PubMed] [Google Scholar]
• 641.Olesen J, Thomsen LL, Iversen HK. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci15: 149–153, 1994. [DOI] [PubMed] [Google Scholar]
• 642.Olesen J, Thomsen LL, Lassen LH, Olesen IJ. The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia15: 94–100, 1995. [DOI] [PubMed] [Google Scholar]
• 643.Oliver KR, Wainright A, Edvinsson L, Pickard JD, Hill RG. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature. J Cereb Blood Flow Metab22: 620–629, 2002. [DOI] [PubMed] [Google Scholar]
• 644.Ondo WG, He Y, Rajasekaran S, Le WD. Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord15: 154–158, 2000. [DOI] [PubMed] [Google Scholar]
• 645.Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJB, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca²⁺ channel gene CACNL1A4. Cell87: 543–552, 1996. [DOI] [PubMed] [Google Scholar]
• 646.Otsuka R, Yatsuya H, Tamakoshi K, Matsushita K, Wada K, Toyoshima H. Perceived psychological stress and serum leptin concentrations in Japanese men. Obesity14: 1832–1838, 2006. [DOI] [PubMed] [Google Scholar]
• 647.Pages N, Orosco M, Rouch C, Yao O, Jacquot C, Bohuon C. Refeeding after 72 hour fasting alters neuropeptide Y and monoamines in various cerebral areas in the rat. Comp Biochem Physiol Comp Physiol106: 845–849, 1993. [DOI] [PubMed] [Google Scholar]
• 648.Palm-Meinders IH, Koppen H, Terwindt GM, Launer LJ, Konishi J, Moonen JME, Bakkers JTN, Hofman PAM, van Lew B, Middelkoop HAM, van Buchem MA, Ferrari MD, Kruit MC. Structural brain changes in migraine. JAMA308: 1889–1897, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 649.Palmer JE, Guillard FL, Laurijssens BE, Wentz AL, Dixon RM, Williams PM. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine. Cephalalgia29: 124, 2009. [Google Scholar]
• 650.Panda S, Hogenesch JB. It's all in the timing: many clocks, many outputs. J Biol Rhythms19: 374–387, 2004. [DOI] [PubMed] [Google Scholar]
• 651.Paranjape SA, Vavaiya KK, Kale AY, Briski KP. Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure. Regul Pept135: 1–6, 2006. [DOI] [PubMed] [Google Scholar]
• 652.Pardutz A, Krizbai I, Multon S, Vecsei L, Schoenen J. Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis. Neuroreport11: 3071–3075, 2000. [DOI] [PubMed] [Google Scholar]
• 653.Pardutz A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J. Effect of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal nucleus and its modulation by estrogen. Eur J Neurosci15: 1803–1809, 2002. [DOI] [PubMed] [Google Scholar]
• 654.Park JW, Moon HS, Akerman S, Holland PR, Lasalandra M, Andreou AP, van den Maagdenberg AM, Goadsby PJ. Differential trigeminovascular nociceptive responses in the thalamus in the familial hemiplegic migraine 1 knock-in mouse: a Fos protein study. Neurobiol Dis64: 1–7, 2014. [DOI] [PubMed] [Google Scholar]
• 655.Parker RM, Herzog H. Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci11: 1431–1448, 1999. [DOI] [PubMed] [Google Scholar]
• 656.Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell108: 705–715, 2002. [DOI] [PubMed] [Google Scholar]
• 657.Pelzer N, Stam AH, Haan J, Ferrari MD, Terwindt GM. Familial and sporadic hemiplegic migraine: diagnosis and treatment. Curr Treat Options Neurol15: 13–27, 2013. [DOI] [PubMed] [Google Scholar]
• 658.Penfield W, McNaughton FL. Dural headache and the innervation of the dura mater. Arch Neurol Psychiatry44: 43–75, 1940. [Google Scholar]
• 659.Percheron G.Thalamus. In: The Human Nervous System, edited by Paxinos G, May J. Amsterdam: Elsevier, 2003. [Google Scholar]
• 660.Peroutka SJ.Neurogenic inflammation and migraine: implications for therapeutics. Mol Interventions5: 306–313, 2005. [DOI] [PubMed] [Google Scholar]
• 661.Peters O, Schipke CG, Hashimoto Y, Kettenmann H. Different mechanisms promote astrocyte Ca²⁺ waves and spreading depression in the mouse neocortex. J Neurosci23: 9888–9896, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 662.Petersen KA, Birk S, Doods H, Edvinsson L, Olesen J. Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat. Br J Pharmacol143: 697–704, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 663.Phebus LA, Johnson KW, Zgombick JM, Gilbert PJ, Van Belle K, Mancuso V, Nelson DL, Calligaro DO, Kiefer AD Jr, Branchek TA, Flaugh ME. Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine. Life Sci61: 2117–2126, 1997. [DOI] [PubMed] [Google Scholar]
• 664.Pietrobon D.Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. J Physiol588: 1871–1878, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 665.Piilgaard H, Lauritzen M. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex. J Cereb Blood Flow Metab29: 1517–1527, 2009. [DOI] [PubMed] [Google Scholar]
• 666.Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci25: 319–325, 2002. [DOI] [PubMed] [Google Scholar]
• 667.Powell KJ, Ma W, Sutak M, Doods H, Quirion R, Jhamandas K. Blockade and reversal of spinal morphine tolerance by peptide and non-peptide calcitonin gene-related peptide receptor antagonists. Br J Pharmacol131: 875–884, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 668.Pozo-Rosich P, Storer RJ, Charbit AR, Goadsby PJ. Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia35: 1298–1307, 2015. [DOI] [PubMed] [Google Scholar]
• 669.Pralong FP, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, Gaillard RC. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology139: 4264–4268, 1998. [DOI] [PubMed] [Google Scholar]
• 670.Price GW, Burton MJ, Collins LJ, Duckworth M, Gaster L, Gothert M, Jones BJ, Roberts C, Watson JM, Middlesmiss DN. SB 216641 and BRL-15572- compounds to pharmacologically discriminate h5-HT_1B and h5-HT_1D receptors. Naunyn-Schmiedebergs Arch Pharmacol356: 312–320, 1997. [DOI] [PubMed] [Google Scholar]
• 671.Proletti-Cecchini P, Afra J, Schoenen J. Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT_1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia17: 849–854, 1997. [DOI] [PubMed] [Google Scholar]
• 672.Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature380: 243–247, 1996. [DOI] [PubMed] [Google Scholar]
• 673.Rabinowitch IM.Acute nitroglycerine poisoning. Can Med Assoc J50: 199–202, 1944. [PMC free article] [PubMed] [Google Scholar]
• 674.Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilatation but does not induce migraine. Cephalalgia28: 226–236, 2008. [DOI] [PubMed] [Google Scholar]
• 675.Rainero I, Ferrero M, Rubino E, Valfrè W, Pellegrino M, Arvat E, Giordano R, Ghigo E, Limone P, Pinessi L. Endocrine function is altered in chronic migraine patients with medication-overuse. Headache46: 597–603, 2006. [DOI] [PubMed] [Google Scholar]
• 676.Rainero I, Limone P, Ferrero M, Valfrè W, Pelissetto C, Rubino E, Gentile S, Lo Giudice R, Pinessi L. Insulin sensitivity is impaired in patients with migraine. Cephalalgia25: 593–597, 2005. [DOI] [PubMed] [Google Scholar]
• 677.Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache27: 416–420, 1987. [DOI] [PubMed] [Google Scholar]
• 678.Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia12: 221–228, 1992. [DOI] [PubMed] [Google Scholar]
• 679.Ray BS, Wolff HG. Experimental studies on headache. Pain sensitive structures of the head and their significance in headache. Arch Surg41: 813–856, 1940. [Google Scholar]
• 680.Recober A, Goadsby PJ. Calcitonin gene-related peptide (CGRP): a molecular link between obesity and migraine?Drug News Perspect23: 112–117, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 681.Recober A, Kuburas A, Zhang Z, Wemmie JA, Anderson MG, Russo AF. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J Neurosci29: 8798–8804, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 682.Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain124: 2490–2502, 2001. [DOI] [PubMed] [Google Scholar]
• 683.Reyngoudt H, Paemeleire K, Descamps B, De Deene Y, Achten E..³¹P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients. Cephalalgia31: 1243–1253, 2011. [DOI] [PubMed] [Google Scholar]
• 684.Reynolds AC, Dorrian J, Liu PY, Van Dongen HP, Wittert GA, Harmer LJ, Banks S. Impact of five nights of sleep restriction on glucose metabolism, leptin and testosterone in young adult men. PLoS One7: e41218, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 685.Reynolds DV.Surgery in the rat during electrical analgesia induced by focal brian stimulation. Science164: 444–445, 1969. [DOI] [PubMed] [Google Scholar]
• 686.Rhode AM, Hosking VG, Happe S, Biehl K, Young P, Evers S. Comorbidity of migraine and restless legs syndrome–a case-control study. Cephalalgia27: 1255–1260, 2007. [DOI] [PubMed] [Google Scholar]
• 687.Rinaman L.Visceral sensory inputs to the endocrine hypothalamus. Front Neuroendocrinol28: 50–60, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 688.Robert C, Bourgeais L, Arreto CD, Condes-Lara M, Noseda R, Jay T, Villanueva L. Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches. J Neurosci33: 8827–8840, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 689.Rocca MA, Ceccarelli A, Falini A, Colombo B, Tortorella P, Bernasconi L, Comi G, Scotti G, Filippi M. Brain gray matter changes in migraine patients with T2-visible lesions: a 3-T MRI study. Stroke37: 1765–1770, 2006. [DOI] [PubMed] [Google Scholar]
• 690.Rolls A, Schaich Borg J, de Lecea L. Sleep and metabolism: role of hypothalamic neuronal circuitry. Best Pract Res Clin Endocrinol Metab24: 817–828, 2010. [DOI] [PubMed] [Google Scholar]
• 691.Roon KI, Olesen J, Diener HC, Ellis P, Hettiarachchi J, Poole PH, Christianssen I, Kleinermans D, Kok JG, Ferrari MD. No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized double-blind placebo-controlled clinical trials. Ann Neurol47: 238–241, 2000. [PubMed] [Google Scholar]
• 692.Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM. Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing. Nature304: 129–135, 1983. [DOI] [PubMed] [Google Scholar]
• 693.Ruiter M, La Fleur SE, van Heijningen C, van der Vliet J, Kalsbeek A, Buijs RM. The daily rhythm in plasma glucagon concentrations in the rat is modulated by the biological clock and by feeding behavior. Diabetes52: 1709–1715, 2003. [DOI] [PubMed] [Google Scholar]
• 694.Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev94: 1099–1142, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 695.Russell MB, Iselius L, Olesen J. Investigation of the inheritance of migraine by complex segregation analysis. Human Genet96: 726–730, 1995. [DOI] [PubMed] [Google Scholar]
• 696.Russo AF, Kuburas A, Kaiser EA, Raddant AC, Recober A. A potential preclinical migraine model: CGRP-sensitized mice. Mol Cell Pharmacol1: 264–270, 2009. [PMC free article] [PubMed] [Google Scholar]
• 697.Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci14: 609–625, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 698.Sadeghi S, Reisi Z, Azhdari-Zarmehri H, Haghparast A. Involvement of orexin-1 receptors in the ventral tegmental area and the nucleus accumbens in antinociception induced by lateral hypothalamus stimulation in rats. Pharmacol Biochem Behav105: 193–198, 2013. [DOI] [PubMed] [Google Scholar]
• 699.Sahu A, Kalra PS, Kalra SP. Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus. Peptides9: 83–86, 1988. [DOI] [PubMed] [Google Scholar]
• 700.Sakurai T.The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci8: 171–181, 2007. [DOI] [PubMed] [Google Scholar]
• 701.Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell92: 696–697, 1998. [DOI] [PubMed] [Google Scholar]
• 702.Sanchez del Rio M, Bakker D, Wu O, Agosti R, Mitsikostas DD, Ostergaard L, Wells WA, Rosen DR, Sorensen G, Moskowitz MA, Cutrer FM. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia19: 701–707, 1999. [DOI] [PubMed] [Google Scholar]
• 703.Sandkuhler J, Gebhart GF. Relative contributions of the nucleus raphe magnus and adjacent medullary reticular formation to the inhibition by stimulation in the periaqueductal gray of a spinal nociceptive reflex in the pentobarbital-anesthetized rat. Brain Res305: 77–87, 1984. [DOI] [PubMed] [Google Scholar]
• 704.Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia24: 596–602, 2004. [DOI] [PubMed] [Google Scholar]
• 705.Saper J, Dodick DW, Silberstein S, McCarville S, Sun M, Goadsby PJ. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia41: 271–285, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 706.Sarchielli P, Rainero I, Coppola F, Rossi C, Mancini M, Pinessi L, Calabresi P. Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication-overuse headache: findings from cerebrospinal fluid. Cephalalgia28: 714–722, 2008. [DOI] [PubMed] [Google Scholar]
• 707.Saudek CD, Felig P. The metabolic events of starvation. Am J Med60: 117–126, 1976. [DOI] [PubMed] [Google Scholar]
• 708.Schankin CJ, Maniyar FH, Seo Y, Kori S, Eller M, Chou DE, Blecha J, Murphy ST, Hawkins RA, Sprenger T, van Brocklin HF, Goadsby PJ.. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for [¹¹C]-dihydroergotamine during glyceryl trinitrate-induced migraine. Brain. In press. [DOI] [PMC free article] [PubMed]
• 709.Schoenen J, Ambrosini A, Sandor PS, Maertens de Noordhout A. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin Neurophysiol114: 955–972, 2003. [DOI] [PubMed] [Google Scholar]
• 710.Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis: a randomized controlled trial. Neurology50: 466–470, 1998. [DOI] [PubMed] [Google Scholar]
• 711.Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gerard P, Magis D. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology80: 697–704, 2013. [DOI] [PubMed] [Google Scholar]
• 712.Schoonman GG, Evers DJ, Terwindt GM, van Dijk JG, Ferrari MD. The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients. Cephalalgia26: 1209–1213, 2006. [DOI] [PubMed] [Google Scholar]
• 713.Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation–a 3T magnetic resonance angiography study. Brain131: 2192–2200, 2008. [DOI] [PubMed] [Google Scholar]
• 714.Schulte LH, Jurgens TP, May A. Photo-, osmo- and phonophobia in the premonitory phase of migraine: mistaking symptoms for triggers?J Headache Pain16: 14, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 715.Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain139: 1987–1993, 2016. [DOI] [PubMed] [Google Scholar]
• 716.Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and meta-analysis. Br Med J339: b3914, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 717.Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest98: 1101–1106, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 718.Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes46: 2119–2123, 1997. [DOI] [PubMed] [Google Scholar]
• 719.Schwedt TJ, Berisha V, Chong CD. Temporal lobe cortical thickness correlations differentiate the migraine brain from the healthy brain. PLoS One10: e0116687, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 720.Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain132: 16–25, 2009. [DOI] [PubMed] [Google Scholar]
• 721.Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM, Elmquist JK. Leptin targets in the mouse brain. J Comp Neurol514: 518–532, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 722.Segal-Lieberman G, Bradley RL, Kokkotou E, Carlson M, Trombly DJ, Wang X, Bates S, Myers MG, Flier JS, Maratos-Flier E. Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. Proc Natl Acad Sci USA100: 10085–10090, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 723.Selby G, Lance JW. Observations on 500 cases of migraine and allied vascular headache. J Neurol Neurosurg Psychiatry23: 23–32, 1960. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 724.Selkirk JV, Scott C, Ho M, Burton MJ, Watson J, Gaster LM, Collin L, Jones BJ, Middlemiss DN, Price GW. SB-224289: a novel selective (human) 5-HT1B receptor antagonist with negative intrinsic activity. Br J Pharmacol125: 202–208, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 725.Serra G, Collu M, Gessa GL. Dopamine receptors mediating yawning: are they autoreceptors?Eur J Pharmacol120: 187–192, 1986. [DOI] [PubMed] [Google Scholar]
• 726.Serra G, Collu M, Gessa GL. Yawning is elicited by D2 dopamine agonists but is blocked by the D1 antagonist, SCH23390. Psychopharmacology91: 330–333, 1987. [DOI] [PubMed] [Google Scholar]
• 727.Settle M.The hypothalamus. Neonatal Netw19: 9–14, 2000. [DOI] [PubMed] [Google Scholar]
• 728.Shepheard S, Edvinsson L, Cumberbatch M, Williamson D, Mason G, Webb J, Boyce S, Hill R, Hargreaves R. Possible antimigraine mechanisms of action of the 5HT_1F receptor agonist LY334370. Cephalalgia19: 851–858, 1999. [DOI] [PubMed] [Google Scholar]
• 729.Shields KG, Goadsby PJ. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine?Brain128: 86–97, 2005. [DOI] [PubMed] [Google Scholar]
• 730.Shields KG, Goadsby PJ. Serotonin receptors modulate trigeminovascular responses in ventroposteromedial nucleus of thalamus: a migraine target?Neurobiol Dise23: 491–501, 2006. [DOI] [PubMed] [Google Scholar]
• 731.Shigenaga Y, Nakatani Z, Nishimori T, Suemune S, Kuroda R, Matano S. The cells of origin of cat trigeminothalamic projections: especially in the caudal medulla. Brain Res277: 201–222, 1983. [DOI] [PubMed] [Google Scholar]
• 732.Shinohara M, Dollinger B, Brown G, Rapoport S, Sokoloff L. Cerebral glucose utilization: local changes during and after recovery from spreading cortical depression. Science203: 188–190, 1979. [DOI] [PubMed] [Google Scholar]
• 733.Shiraishi T, Oomura Y, Sasaki K, Wayner MJ. Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons. Physiol Behav71: 251–261, 2000. [DOI] [PubMed] [Google Scholar]
• 734.Sicuteri F, Testi A, Anselmi B. Biochemical investigations in headache: increase in hydroxyindoleacetic acid excretion during migraine attacks. Int Arch Allergy19: 55–58, 1961. [Google Scholar]
• 735.Silberstein S, Dodick D, Saper J, Huh B, Slavin K, Sharan A, Reed K, Narouze S, Mogilner A, Goldstein J, Trentman T, Vaisma J, Ordia J, Weber P, Deer T, Levy R, Diaz RL, Washburn SN, Mekhail N. The safety and efficacy of occipital nerve stimulation for the management of chronic migraine. Cephalalgia32: 1165–1179, 2012. [DOI] [PubMed] [Google Scholar]
• 736.Silberstein SD, Da Silva AN, Calhoun AH, Grosberg BM, Lipton RB, Cady RK, Goadsby PJ, Simmons K, Mullin C, Saper JR, Liebler EJ. Non-invasive Vagus Nerve Stimulation for Chronic Migraine Prevention in a Prospective, Randomized, Sham-Controlled Pilot Study (the EVENT Study): report from the double-blind phase. Headache54: 1426, 2014. [Google Scholar]
• 737.Sim LJ, Joseph SA. Arcuate nucleus projections to brainstem regions which modulate nociception. J Chem Neuroanat4: 97–109, 1991. [DOI] [PubMed] [Google Scholar]
• 738.Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest97: 1344–1347, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 739.Sinton CM, Fitch TE, Gershenfeld HK. The effects of leptin on REM sleep and slow wave delta in rats are reversed by food deprivation. J Sleep Res8: 197–203, 1999. [DOI] [PubMed] [Google Scholar]
• 740.Skagerberg G, Bjorklund A, Lindvall O, Schmidt RH. Origin and termination of the diencephalo-spinal dopamine system in the rat. Brain Res Bull9: 237–244, 1982. [DOI] [PubMed] [Google Scholar]
• 741.Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC. SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol132: 1179–1182, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 742.Sohn JW, Elmquist JK, Williams KW. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci36: 504–512, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 743.Somjen GG.Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev81: 1065–1096, 2001. [DOI] [PubMed] [Google Scholar]
• 744.Sommer WH, Lidström J, Sun H, Passer D, Eskay R, Parker SC, Witt SH, Zimmermann US, Nieratschker V, Rietschel M, Margulies EH, Palkovits M, Laucht M, Heilig M. Human NPY promoter variation rs16147:T>C as a moderator of prefrontal NPY gene expression and negative affect. Hum Mutat31: E1594-1608, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 745.Spencer SE, Sawyer WB, Wada H, Platt KB, Loewy AD. CNS projections to the pterygopalatine parasympathetic preganglionic neurons in the rat: a retrograde transneuronal viral cell body labeling study. Brain Res534: 149–169, 1990. [DOI] [PubMed] [Google Scholar]
• 746.Spiegel K, Leproult R, L'hermite-Balériaux M, Copinschi G, Penev PD, Van Cauter E. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab89: 5762–5771, 2004. [DOI] [PubMed] [Google Scholar]
• 747.Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet354: 1435–1439, 1999. [DOI] [PubMed] [Google Scholar]
• 748.Sprenger T, Goadsby PJ. What has functional neuroimaging done for primary headache…and for the clinical neurologist?J Clin Neurosci17: 547–553, 2010. [DOI] [PubMed] [Google Scholar]
• 749.Stankewitz A, Aderjan D, Eippert F, May A. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J Neurosci31: 1937–1943, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 750.Stankewitz A, May A. The phenomenon of changes in cortical excitability in migraine is not migraine-specific–a unifying thesis. Pain145: 14–17, 2009. [DOI] [PubMed] [Google Scholar]
• 751.Stanley BG, Leibowitz SF. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA82: 3940–3943, 1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 752.Stanley BG, Leibowitz SF. Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci35: 2635–2642, 1984. [DOI] [PubMed] [Google Scholar]
• 753.Stanley BG, Magdalin W, Seirafi A, Thomas WJ, Leibowitz SF. The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res604: 304–317, 1993. [DOI] [PubMed] [Google Scholar]
• 754.Stengel A, Karasawa H, Tache Y. The role of brain somatostatin receptor 2 in the regulation of feeding and drinking behavior. Horm Behav73: 15–22, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 755.Stephan KE, Friston KJ. Analyzing effective connectivity with fMRI. Wiley Interdiscip Rev Cogn Sci1: 446–459, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 756.Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature377: 530–532, 1995. [DOI] [PubMed] [Google Scholar]
• 757.Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA290: 2443–2454, 2003. [DOI] [PubMed] [Google Scholar]
• 758.Stewart WF, Staffa J, Lipton RB, Ottman R. Familial risk of migraine: a population-based study. Ann Neurol41: 166–172, 1997. [DOI] [PubMed] [Google Scholar]
• 759.Stewart WF, Wood C, Reed ML, Roy J, Lipton RB. Cumulative lifetime migraine incidence in women and men. Cephalalgia28: 1170–1178, 2008. [DOI] [PubMed] [Google Scholar]
• 760.Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol142: 1171–1181, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 761.Storer RJ, Akerman S, Goadsby PJ. Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex. Br J Pharmacol138: 317–324, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 762.Storer RJ, Goadsby PJ. 5-HT1F agonists inhibit nociceptive transmission at the trigeminocervical complex. Cephalalgia31: 9, 2011. [Google Scholar]
• 763.Storer RJ, Goadsby PJ. Microiontophoretic application of serotonin (5HT)_1B/1D agonists inhibits trigeminal cell firing in the cat. Brain120: 2171–2177, 1997. [DOI] [PubMed] [Google Scholar]
• 764.Storer RJ, Goadsby PJ. Trigeminovascular nociceptive transmission involvesN-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. Neuroscience90: 1371–1376, 1999. [DOI] [PubMed] [Google Scholar]
• 765.Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, Hagen K. A comparative study of candesartan versus propranolol for migraine prophylaxis: a randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia34: 523–532, 2014. [DOI] [PubMed] [Google Scholar]
• 766.Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature384: 560–563, 1996. [DOI] [PubMed] [Google Scholar]
• 767.Strecker T, Dux M, Messlinger K. Increase in meningeal blood flow by nitric oxide interaction with calcitonin gene-related peptide receptor and prostaglandin synthesis inhibition. Cephalalgia22: 233–241, 2002. [DOI] [PubMed] [Google Scholar]
• 768.Strong AJ, Fabricius M, Boutelle MG, Hibbins SJ, Hopwood SE, Jones R, Parkin MC, Lauritzen M. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke33: 2738–2743, 2002. [DOI] [PubMed] [Google Scholar]
• 769.Summ O, Charbit AR, Andreou AP, Goadsby PJ. Modulation of nocioceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain133: 2540–2548, 2010. [DOI] [PubMed] [Google Scholar]
• 770.Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R. A randomised, double-blind, placebo-controlled, phase 2 study to evaluate the efficacy and safety of AMG 334 for the prevention of episodic migraine. Lancet Neurol15: 382–390, 2016. [DOI] [PubMed] [Google Scholar]
• 771.Supronsinchai W, Hoffmann J, Akerman S, Goadsby PJ. KCl-induced repetitive cortical spreading depression inhibits trigeminal neuronal firing mediated by 5-HT1B/1D and opioid receptor. J Headache Pain14: P69, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 772.Supronsinchai W, Hoffmann J, Akerman S, Goadsby PJ. The role of the orexin-2 receptor in the nucleus raphe magnus on trigeminovascular nociceptive transmission. Cephalalgia33: 223, 2013.23223494 [Google Scholar]
• 773.Supronsinchai W, Storer RJ, Hoffmann J, Andreou AP, Akerman S, Goadsby PJ. GABA_A receptors in the nucleus raphe magnus modulate trigeminal cell firing responsive to activation of craniovascular dural afferents. Headache52: 903–904, 2012. [Google Scholar]
• 774.Sutcliffe JG, de Lecea L. The hypocretins: setting the arousal threshold. Nat Rev Neurosci3: 339–349, 2002. [DOI] [PubMed] [Google Scholar]
• 775.Swanson LW, Sawchenko PE. Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology31: 410–417, 1980. [DOI] [PubMed] [Google Scholar]
• 776.Szentirmai E, Krueger JM. Central administration of neuropeptide Y induces wakefulness in rats. Am J Physiol Regul Integr Comp Physiol291: R473–R480, 2006. [DOI] [PubMed] [Google Scholar]
• 777.Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med1: e62, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 778.Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci25: 283–313, 2002. [DOI] [PubMed] [Google Scholar]
• 779.Tajti J, Uddman R, Edvinsson L. Neuropeptide localization in the “migraine generator” region of the human brainstem. Cephalalgia21: 96–101, 2001. [DOI] [PubMed] [Google Scholar]
• 780.Tajti J, Uddman R, Moller S, Sundler F, Edvinsson L. Messenger molecules and receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst76: 176–183, 1999. [DOI] [PubMed] [Google Scholar]
• 781.Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell83: 1263–1271, 1995. [DOI] [PubMed] [Google Scholar]
• 782.Tassorelli C, Costa A, Blandini F, Joseph SA, Nappi G. Effect of nitric oxide donors on the central nervous system: nitroglycerin studies in the rat. Funct Neurol15: 19–27, 2000. [PubMed] [Google Scholar]
• 783.Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brain-stem and forebrain structures of the rat. Brain Res682: 167–181, 1995. [DOI] [PubMed] [Google Scholar]
• 784.Tavraz NN, Friedrich T, Durr KL, Koenderink JB, Bamberg E, Freilinger T, Dichgans M. Diverse functional consequences of mutations in the Na⁺/K⁺-ATPase alpha2-subunit causing familial hemiplegic migraine type 2. J Biol Chem283: 31097–31106, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 785.Tedeschi G, Russo A, Conte F, Corbo D, Caiazzo G, Giordano A, Conforti R, Esposito F, Tessitore A. Increased interictal visual network connectivity in patients with migraine with aura. Cephalalgia36: 139–147, 2016. [DOI] [PubMed] [Google Scholar]
• 786.Terwindt G, Kors E, Haan J, Vermeulen F, Van den Maagdenberg A, Frants R, Ferrari M. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Arch Neurol59: 1016–1018, 2002. [DOI] [PubMed] [Google Scholar]
• 787.Terwindt GM, Ophoff RA, van Eijk R, Vergouwe MN, Haan J, Frants RR, Sandkuijl LA, Ferrari MD. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology56: 1028–1032, 2001. [DOI] [PubMed] [Google Scholar]
• 788.Tessitore A, Russo A, Giordano A, Conte F, Corbo D, De Stefano M, Cirillo S, Cirillo M, Esposito F, Tedeschi G. Disrupted default mode network connectivity in migraine without aura. J Headache Pain14: 89, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 789.Thompson RH, Canteras NS, Swanson LW. Organization of projections from the dorsomedial nucleus of the hypothalamus: a PHA-L study in the rat. J Comp Neurol376: 143–173, 1996. [DOI] [PubMed] [Google Scholar]
• 790.Thompson RH, Swanson LW. Organization of inputs to the dorsomedial nucleus of the hypothalamus: a reexamination with Fluorogold and PHAL in the rat. Brain Res27: 89–118, 1998. [DOI] [PubMed] [Google Scholar]
• 791.Thomsen LL, Ostergaard E, Romer SF, Andersen I, Eriksen MK, Olesen J, Russell MB. Sporadic hemiplegic migraine is an aetiologically heterogeneous disorder. Cephalalgia23: 921–928, 2003. [DOI] [PubMed] [Google Scholar]
• 792.Thorsell A.Central neuropeptide Y in anxiety- and stress-related behavior and in ethanol intake. Ann NY Acad Sci1148: 136–140, 2008. [DOI] [PubMed] [Google Scholar]
• 793.Tkacs NC, Pan Y, Sawhney G, Mann GL, Morrison AR. Hypoglycemia activates arousal-related neurons and increases wake time in adult rats. Physiol Behav91: 240–249, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 794.Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science291: 1040–1043, 2001. [DOI] [PubMed] [Google Scholar]
• 795.Tolner EA, Houben T, Terwindt GM, de Vries B, Ferrari MD, van den Maagdenberg AM. From migraine genes to mechanisms. Pain156Suppl 1: S64-74, 2015. [DOI] [PubMed] [Google Scholar]
• 796.Tóth A, Hajnik T, Záborszky L, Détári L. Effect of basal forebrain neuropeptide Y administration on sleep and spontaneous behavior in freely moving rats. Brain Res Bull72: 293–301, 2007. [DOI] [PubMed] [Google Scholar]
• 797.Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg AM, Pietrobon D. Specific kinetic alterations of human CaV2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma. J Biol Chem280: 17678–17686, 2005. [DOI] [PubMed] [Google Scholar]
• 798.Tottene A, Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D. Familial hemiplegic migraine mutations increase Ca²⁺ influx through single human CaV2.1 channels and decrease maximal Ca_V21 current density in neurons. Proc Natl Acad Sci USA99: 13284–13289, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 799.Tracey I.Imaging pain. Br J Anaesth101: 32–39, 2008. [DOI] [PubMed] [Google Scholar]
• 800.Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA289: 65–69, 2003. [DOI] [PubMed] [Google Scholar]
• 801.Tso AR, Trujillo A, Guo C, C , Goadsby PJ, Seeley WW. The anterior insula shows heightened interictal intrinsic connectivity in migraine without aura. Neurolgy84: 1043–1050, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 802.Tsuneki H, Wada T, Sasaoka T. Role of orexin in the central regulation of glucose and energy homeostasis. Endocr J59: 365–374, 2012. [DOI] [PubMed] [Google Scholar]
• 803.Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsanyi J, Szabo N, Toth E, Kincses ZT, Vecsei L, Tajti J. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia33: 1085–1095, 2013. [DOI] [PubMed] [Google Scholar]
• 804.Uddman R, Edvinsson L. Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev1: 230–252, 1989. [PubMed] [Google Scholar]
• 805.Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett62: 131–136, 1985. [DOI] [PubMed] [Google Scholar]
• 806.Uddman R, Goadsby PJ, Jansen I, Edvinsson L. PACAP, a VIP-like peptide, immunohistochemical localization and effect upon cat pial arteries and cerebral blood flow. J Cereb Blood Flow Metab13: 291–297, 1993. [DOI] [PubMed] [Google Scholar]
• 807.Uddman R, Moller S, Nilsson T, Nystrom S, Ekstrand J, Edvinsson L. Neuropeptide Y Y1 and neuropeptide Y Y2 receptors in human cardiovascular tissues. Peptides23: 927–934, 2002. [DOI] [PubMed] [Google Scholar]
• 808.Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L. Neuropeptide expression in the human trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia22: 112–116, 2002. [DOI] [PubMed] [Google Scholar]
• 809.Ullmer C, Schmuck K, Kalkman HO, Lubbert H. Expression of serotonin receptor mRNAs in blood vessels. FEBS Lett370: 215–221, 1995. [DOI] [PubMed] [Google Scholar]
• 810.Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB. Evidence of a genetic factor in migraine with aura: a population based Danish twin study. Ann Neurol45: 242–246, 1999. [DOI] [PubMed] [Google Scholar]
• 811.Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB. The inheritance of migraine with aura estimated by means of structural equation modelling. J Med Genet36: 225–227, 1999. [PMC free article] [PubMed] [Google Scholar]
• 812.Valfre W, Rainero I, Bergui M, Pinessi L. Voxel-based morphometry reveals gray matter abnormalities in migraine. Headache48: 109–117, 2008. [DOI] [PubMed] [Google Scholar]
• 813.Van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, van de Ven RCG, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD. A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron41: 701–710, 2004. [DOI] [PubMed] [Google Scholar]
• 814.Van den Pol AN.Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci19: 3171–3182, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 815.Van Dijk G, Thiele TE, Donahey JC, Campfield LA, Smith FJ, Burn P, Bernstein IL, Woods SC, Seeley RJ. Central infusions of leptin and GLP-1-(7–36) amide differentially stimulate c-FLI in the rat brain. Am J Physiol Regul Integr Comp Physiol271: R1096–R1100, 1996. [DOI] [PubMed] [Google Scholar]
• 816.Van Rossum D, Hanisch UK, Quirion R. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev21: 649–678, 1997. [DOI] [PubMed] [Google Scholar]
• 817.Vanagaite J, Pareja JA, Storen O, White LR, Sand T, Stovner LJ. Light-induced discomfort and pain in migraine. Cephalalgia17: 733–741, 1997. [DOI] [PubMed] [Google Scholar]
• 818.Vance ML, Thorner MO. Fasting alters pulsatile and rhythmic cortisol release in normal man. J Clin Endocrinol Metab68: 1013–1018, 1989. [DOI] [PubMed] [Google Scholar]
• 819.Vandenheede M, Copploa G, Di Clemente L, De Pasqua V, Schoenen J. High frequency oscillations (600Hz) of somatosensory evoked potentials in migraine between attacks: a measure of thalamocortical activation. Cephalalgia23: 574, 2003. [Google Scholar]
• 820.Veinante P, Jacquin MF, Deschenes M. Thalamic projections from the whisker-sensitive regions of the spinal trigeminal complex in the rat. J Comp Neurol420: 233–243, 2000. [DOI] [PubMed] [Google Scholar]
• 821.Velati D, Viana M, Cresta S, Mantegazza P, Testa L, Bettucci D, Rinaldi M, Sances G, Tassorelli C, Nappi G, Canonico PL, Martignoni E, Genazzani AA. 5-Hydroxytryptamine(1B) receptor and triptan response in migraine, lack of association with common polymorphisms. Eur J Pharmacol580: 43–47, 2007. [DOI] [PubMed] [Google Scholar]
• 822.Veloso F, Kumar K, Toth C. Headache secondary to deep brain implantation. Headache38: 507–515, 1998. [DOI] [PubMed] [Google Scholar]
• 823.Vera-Portocarrero LP, Ossipov MH, King T, Porreca F. Reversal of inflammatory and noninflammatory visceral pain by central or peripheral actions of sumatriptan. Gastroenterology135: 1369–1378, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 824.Verret L, Goutagny R, Fort P, Cagnon L, Salvert D, Léger L, Boissard R, Salin P, Peyron C, Luppi PH. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci4: 19, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 825.Viana M, Linde M, Sances G, Ghiotto N, Guaschino E, Allena M, Terrazzino S, Nappi G, Goadsby PJ, Tassorelli C. Migraine aura symptoms: duration, succession and temporal relationship to headache. Cephalalgia36: 413–421, 2016. [DOI] [PubMed] [Google Scholar]
• 826.Vorona RD, Winn MP, Babineau TW, Eng BP, Feldman HR, Ware JC. Overweight and obese patients in a primary care population report less sleep than patients with a normal body mass index. Arch Intern Med165: 25–30, 2005. [DOI] [PubMed] [Google Scholar]
• 827.Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basanez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabe E, Bhalla K, Bhandari B, Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fevre EM, Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gosselin R, Grainger R, Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh J, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M, Ohno SL, Lyons R, Ma J, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGill N, McGrath J, Medina-Mora ME, Meltzer M, Mensah GA, Merriman TR, Meyer AC, Miglioli V, Miller M, Miller TR, Mitchell PB, Mocumbi AO, Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM, Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R, O'Donnell M, O'Hanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope CA 3rd Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Leon FR, Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S, Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM, Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL, Stapelberg NJ, Steer A, Steiner T, Stolk WA, Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K, Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams SR, Witt E, Wolfe F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies D, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet380: 2163–2196, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 828.Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, Assaid C, Aurora SK, Michelson D. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia36: 887–898, 2016. [DOI] [PubMed] [Google Scholar]
• 829.Waelkens J.Domperidone in the prevention of complete classical migraine. Br Med J284: 944, 1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 830.Waelkens J.Dopamine blockade with domperidone: bridge between prophylactic and abortive treatment of migraine? A dose-finding study. Cephalalgia4: 85–90, 1984. [DOI] [PubMed] [Google Scholar]
• 831.Walker CS, Eftekhari S, Bower RL, Wilderman A, Insel PA, Edvinsson L, Waldvogel HJ, Jamaluddin MA, Russo AF, Hay DL. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol2: 595–608, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 832.Wang JH, Wang F, Yang MJ, Yu DF, Wu WN, Liu J, Ma LQ, Cai F, Chen JG. Leptin regulated calcium channels of neuropeptide Y and proopiomelanocortin neurons by activation of different signal pathways. Neuroscience156: 89–98, 2008. [DOI] [PubMed] [Google Scholar]
• 833.Wang W, Schoenen J. Interictal potentiation of passive “oddball” auditory event-related potentials in migraine. Cephalalgia18: 261–265, 1998. [DOI] [PubMed] [Google Scholar]
• 834.Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of the auditory cortical evoked potentials is pronounced in migraine: an indication of cortical potentiation and low serotonergic transmission?Neurology46: 1404–1409, 1996. [DOI] [PubMed] [Google Scholar]
• 835.Waschek JA.VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair. Br J Pharmacol169: 512–523, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 836.Waters AJ, Lumb BM. Descending control of spinal nociception from the periaqueductal grey distinguishes between neurons with and without C-fibre inputs. Pain134: 32–40, 2008. [DOI] [PubMed] [Google Scholar]
• 837.Waters AJ, Lumb BM. Inhibitory effects evoked from both the lateral and ventrolateral periaqueductal grey are selective for the nociceptive responses of rat dorsal horn neurones. Brain Res752: 239–249, 1997. [DOI] [PubMed] [Google Scholar]
• 838.Watts AG, Swanson LW, Sanchez-Watts G. Efferent projections of the suprachiasmatic nucleus: I Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J Comp Neurol258: 204–229, 1987. [DOI] [PubMed] [Google Scholar]
• 839.Waung MW, Akerman S, Wakefield M, Keywood C, Goadsby PJ.. Metabotropic glutamate receptor 5: A target for migraine therapy. Ann Clin Transl Neurol.In press. [DOI] [PMC free article] [PubMed]
• 840.Weatherall MW.The migraine theories of Liveing and Latham: a reappraisal. Brain135: 2560–2568, 2012. [DOI] [PubMed] [Google Scholar]
• 841.Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL. Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab82: 561–565, 1997. [DOI] [PubMed] [Google Scholar]
• 842.Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, Coenen HH, Diener HC. Brain stem activation in spontaneous human migraine attacks. Nature Med1: 658–660, 1995. [DOI] [PubMed] [Google Scholar]
• 843.Welch KM, Levine SR, D'Andrea G, Schultz LR, Helpern JA. Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy. Neurology39: 538–541, 1989. [DOI] [PubMed] [Google Scholar]
• 844.Welch KM, Nagesh V, Aurora S, Gelman N. Periaqueductal grey matter dysfunction in migraine: cause or the burden of illness?Headache41: 629–637, 2001. [DOI] [PubMed] [Google Scholar]
• 845.Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TVB, Snutch TP, Catterall WA. Immunochemical identification and subcellular distribution of the alpha(1a) subunits of brain calcium channels. J Neurosci15: 6403–6418, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 846.White JD, Kershaw M. Increased hypothalamic neuropeptide Y expression following food deprivation. Mol Cell Neurosci1: 41–48, 1990. [DOI] [PubMed] [Google Scholar]
• 847.Wiater MF, Mukherjee S, Li AJ, Dinh TT, Rooney EM, Simasko SM, Ritter S. Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus. Am J Physiol Regul Integr Comp Physiol301: R1569–R1583, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 848.Wienecke T, Olesen J, Ashina M. Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D(2) [PGD(2)]. Cephalalgia31: 65–76, 2011. [DOI] [PubMed] [Google Scholar]
• 849.Wienecke T, Olesen J, Ashina M. Prostaglandin I2 (epoprostenol) triggers migraine-like attacks in migraineurs. Cephalalgia30: 179–190, 2010. [DOI] [PubMed] [Google Scholar]
• 850.Williams DL, Kaplan JM, Grill HJ. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology141: 1332–1337, 2000. [DOI] [PubMed] [Google Scholar]
• 851.Williams MN, Zahm DS, Jacquin MF. Differential foci and synaptic organization of the principal and spinal trigeminal projections to the thalamus in the rat. Eur J Neurosci6: 429–453, 1994. [DOI] [PubMed] [Google Scholar]
• 852.Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural blood vessel diameter in the anaesthetized rat. Cephalalgia17: 518–524, 1997. [DOI] [PubMed] [Google Scholar]
• 853.Williamson DJ, Hargreaves RJ, Hill RG, Shepheard SL. Sumatriptan inhibits neurogenic vasodilation of dural blood vessels in the anaesthetized rat- intravital microscope studies. Cephalalgia17: 525–531, 1997. [DOI] [PubMed] [Google Scholar]
• 854.Williamson DJ, Shepheard SL, Hill RG, Hargreaves RJ. The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. Eur J Pharmacol328: 61–64, 1997. [DOI] [PubMed] [Google Scholar]
• 855.Willis T, Pordage S. Two Discourses Concerning the Soul of Brutes, which Is that of the Vital and Sensitive of Man: The First Is Physiological, Shewing the Nature, Parts, Powers, And Affections Of The Same; And The Other Is Pathological, Which Unfolds the Diseases Which Affect It and Its Primary Seat, to Wit, the Brain and Nervous Stock, and Treats of Their Cures: With Copper Cuts. London: Dring, Harper and Leigh, 1683. [Google Scholar]
• 856.Winsky-Sommerer R, Boutrel B, de Lecea L. Stress and arousal: the corticotrophin-releasing factor/hypocretin circuitry. Mol Neurobiol32: 285–294, 2005. [DOI] [PubMed] [Google Scholar]
• 857.Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T, Kilduff TS, Horvath TL, de Lecea L. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci24: 11439–11448, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 858.Winter AC, Berger K, Buring JE, Kurth T. Body mass index, migraine, migraine frequency and migraine features in women. Cephalalgia29: 269–278, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 859.Wober C, Brannath W, Schmidt K, Kapitan M, Rudel E, Wessely P, Wober-Bingol C, Group PS. Prospective analysis of factors related to migraine attacks: the PAMINA study. Cephalalgia27: 304–314, 2007. [DOI] [PubMed] [Google Scholar]
• 860.Wober C, Holzhammer J, Zeitlhofer J, Wessely P, Wober-Bingol C. Trigger factors of migraine and tension-type headache: experience and knowledge of the patients. J Headache Pain7: 188–195, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 861.Wolff HG.Headache and Other Head Pain. New York: Oxford Univ. Press, 1963. [Google Scholar]
• 862.Xu B, Kalra PS, Moldawer LL, Kalra SP. Increased appetite augments hypothalamic NPY Y1 receptor gene expression: effects of anorexigenic ciliary neurotropic factor. Regul Pept75–76: 391–395, 1998. [DOI] [PubMed] [Google Scholar]
• 863.Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptacek LJ, Fu YH. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature434: 640–644, 2005. [DOI] [PubMed] [Google Scholar]
• 864.Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptacek LJ. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell128: 59–70, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 865.Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron38: 701–713, 2003. [DOI] [PubMed] [Google Scholar]
• 866.Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res859: 404–409, 2000. [DOI] [PubMed] [Google Scholar]
• 867.Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, Block GD, Sakaki Y, Menaker M, Tei H. Resetting central and peripheral circadian oscillators in transgenic rats. Science288: 682–685, 2000. [DOI] [PubMed] [Google Scholar]
• 868.Yasui Y, Saper CB, Cechetto DF. Calcitonin gene-related peptide (CGRP) immunoreactive projections from the thalamus to the striatum and amygdala in the rat. J Comp Neurol308: 293–310, 1991. [DOI] [PubMed] [Google Scholar]
• 869.Yeo GS, Heisler LK. Unraveling the brain regulation of appetite: lessons from genetics. Nat Neurosci15: 1343–1349, 2012. [DOI] [PubMed] [Google Scholar]
• 870.Yettefti K, Orsini JC, Perrin J. Characteristics of glycemia-sensitive neurons in the nucleus tractus solitarii: possible involvement in nutritional regulation. Physiol Behav61: 93–100, 1997. [DOI] [PubMed] [Google Scholar]
• 871.Yi CX, Serlie MJ, Ackermans MT, Foppen E, Buijs RM, Sauerwein HP, Fliers E, Kalsbeek A. A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes58: 1998–2005, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 872.Young RF, Brechner T. Electrical stimulation of the brain for relief of intractable pain due to cancer. Cancer57: 1266–1272, 1986. [DOI] [PubMed] [Google Scholar]
• 873.Yuan PQ, Yang H. Neuronal activation of brain vagal-regulatory pathways and upper gut enteric plexuses by insulin hypoglycemia. Am J Physiol Endocrinol Metab283: E436–E448, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 874.Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and Migraine. Ann Clin Transl Neurol1: 1036–1040, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 875.Zagami AS, Edvinsson L, Hoskin KL, Goadsby PJ. Stimulation of the superior sagittal sinus causes extracranial release of PACAP. Cephalalgia15: 109, 1995.7641244 [Google Scholar]
• 876.Zagami AS, Lambert GA. Craniovascular application of capsaicin activates nociceptive thalamic neurons in the cat. Neurosci Lett121: 187–190, 1991. [DOI] [PubMed] [Google Scholar]
• 877.Zagami AS, Lambert GA. Stimulation of cranial vessels excites nociceptive neurones in several thalamic nuclei of the cat. Exp Brain Res81: 552–566, 1990. [DOI] [PubMed] [Google Scholar]
• 878.Zanchin G, Dainese F, Trucco M, Mainardi F, Mampreso E, Maggioni F. Osmophobia in migraine and tension-type headache and its clinical features in patients with migraine. Cephalalgia27: 1061–1068, 2007. [DOI] [PubMed] [Google Scholar]
• 879.Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol69: 855–865, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 880.Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci30: 8807–8814, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 881.Zhang XC, Strassman AM, Burstein R, Levy D. Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. J Pharmacol Exp Ther322: 806–812, 2007. [DOI] [PubMed] [Google Scholar]
• 882.Ziegler DK, Hassanein RS, Kodanaz A, Meek JC. Circadian rhythms of plasma cortisol in migraine. J Neurol Neurosurg Psychiatry42: 741–748, 1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
• 883.Zurak N.Role of the suprachiasmatic nucleus in the pathogenesis of migraine attacks. Cephalalgia17: 723–728, 1997. [DOI] [PubMed] [Google Scholar]