Neuronal activation began within 0. In 27 trigeminovascular neurons not activated by CSD, mean firing rate was 2. We propose that CSD constitutes a nociceptive stimulus capable of activating peripheral and central trigeminovascular neurons that underlie the headache of migraine with aura.
Symptoms of aura typically develop some 30—60 minutes ahead of the onset of migraine headache. Aura has long been suggested to be caused by a biphasic electrophysiological phenomenon dubbed cortical spreading depression CSD.
Animal studies have documented the propagation of spreading depression through the cortex especially the visual cortex as a wave of cellular hyperexcitability depolarization followed by a prolonged phase of quiescence.
It has been proposed that CSD can precipitate headache during migraine with aura by activating a trigeminovascular pathway that originates in meningeal nociceptors. Such activation was manifested as a twofold increase in mean neuronal firing rate which began either immediately, or some 14 min after CSD, and persisted for 45 min or longer. Pursuant to the activation of meningeal nociceptors by CSD, we sought to examine the effects of CSD on the activity of second-order trigeminovascular neurons in spinal trigeminal nucleus.
Such activation has been deduced from evidence that CSD can induce neuronal c-fos immunoreactivity in the superficial laminae of the trigeminal nucleus caudalis at the level of spinal segments C Male Sprague-Dawley rats — g were anesthetized with urethane 1.
Rats were paralyzed with gallamine triethiodide 0. End-tidal CO 2 was continuously monitored and kept within a physiological range of 3.
For single-unit recording in the spinal trigeminal nucleus, a segment of the spinal cord between the obex and C2 was uncovered from overlying tissues, stripped of the dura mater, and kept moist with mineral oil as described before. A tungsten microelectrode impedance 0. A neuron was selected for the study if it exhibited discrete firing bouts in response to ipsilateral electrical and mechanical stimulation of the exposed cranial dura and to mechanical stimulation of the facial skin.
Stimulation of the dura with electric pulses 0. Stimulation of the facial skin consisted of brush, pressure and pinch, delivered sequentially 10 sec each, sec inter-stimulus interval using an artist paint brush, loose arterial clip, and forceps, respectively. Three classes of neurons were thus identified: wide-dynamic-range WDR neurons incrementally responsive to brush, pressure and pinch , low-threshold LT neurons equally responsive to all stimuli and high-threshold HT neurons unresponsive to brush.
Real-time waveform discriminator was used to create and store a template for the action potential evoked in the neuron under study by electrical pulses on the dura; spikes of activity matching the template waveform were acquired and analyzed online and offline using Spike 2 software CED, Cambridge, UK. Single waves of CSD were induced using mechanical and chemical stimulation of the visual cortex, about 6 mm away from the dural receptive field of the neuron under study.
Chemical stimulation was delivered by placing a granule of crystalline KCl on the surface of the cortex; the granule was washed away with SIF at the end of the CSD wave.
Dural receptive field of the nociceptor under study was mapped using calibrated von-Frey monofilaments. Small incisions were made in the dura overlaying the visual cortex at the site designated for cortical stimulation and CSD recording.
Ongoing activity of the nociceptor was recorded over 30 min before dural incision, and for another 30—60 min afterwards.
Once neuronal activity reached a stable rate of firing, the cortex was stimulated to induce a wave of CSD, and ongoing activity was monitored for a period of 30— min after CSD.
At the end of the experiment, a small lesion was produced at the recording site and its localization in the dorsal horn was determined postmortem using histological analysis as described before Latency to onset of neuronal activation and the duration of neuronal activation were compared across WDR, LH and HT neurons using Kruskal-Wallis one-way analysis of variance. Mean firing rates before and after the induction of CSD were compared using Wilcoxon matched-pairs signed-ranks test.
These units were functionally classified as HT, WDR, or LT according to the relative magnitude of their responses to ipsilateral stimulation of the facial skin with brush, pressure and pinch Fig 1D—F. Identification and characterization of central trigeminovascular neurons. Neurons receiving input from the dura were identified based on their responses to electrical A , mechanical B and chemical C stimulation of the dura overlying the visual cortex.
Neurons thus identified were further classified as HT D , WDR E or LT F based on their responses to innocuous and noxious stimulation of their cutaneous receptive field on the ipsilateral face. Br, brush; Pr, pressure; Pi, pinch. Localization of lesions marking the recording sites in the dorsal horn 1 neuron per rat.
A Photomicrographs showing lesion pointed by arrowheads in laminae I left and V right of the first cervical segment C1. B Mapping of 25 lesions marking the locations of activated neurons. C Mapping of 27 lesions marking the locations of non-activated neurons. Neuronal type is indicated by the key at bottom of figure.
Localization of dural red and cutaneous blue receptive fields. A Activated neurons in the superficial dorsal horn. B Non-activated neurons in the superficial dorsal horn. C Activated neurons in the deep dorsal horn. D Non-activated neurons in the deep dorsal horn.
E, Detailed view of drawing illustrating dural receptive field. Arrow points forward. Waves of CSD lasting Twenty seven of those units, however, did not pass the criteria for neuronal activation Fig 4A ; their ongoing firing rate was 2. The fold increase in firing rate was most pronounced in units with mean baseline activity below 0.
Five units all located in the superficial laminae became activated during CSD or immediately after 0. The remaining 20 units equally divided between superficial and deep laminae became activated as late as Neuronal activity returned back to baseline level after Individual examples of neuronal firing before and after CSD. Waves of CSD induced by a single stimulation of the cortex are shown in green cortical activity was monitored continuously throughout the experiment, and no other CSD waves were registered.
Black-line curves shown across the histograms describe the pattern of neuronal activity after applying a moving-average smoothing function. A Example of a neuron that was not activated by CSD. B Example of a neuron that became activated immediately after CSD and remained activated for 78 min, through the end of the recording session. On megrim, sick headache. Long-term effects of migraine on cognitive function: a population-based study of Danish twins. Migraine and cardiovascular disease: systematic review and meta-analysis.
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Distinct vascular conduction with cortical spreading depression. Innocuous, not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers.
Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma. Science New York, NY ; — Tietjen GE. Migraine as a systemic vasculopathy. Endothelial dysfunction in migraine. Microemboli may link spreading depression, migraine aura, and patent foramen ovale. Such nociceptive information is transmitted to second order trigeminovascular neurons in the SpVC. In addition, the ventrolateral area of the upper cervical and medullary dorsal horn — an area containing the majority of second-order trigeminovascular neurons [ 22 ; ; ] — projects to the ventrolateral periaqueductal gray matter vlPAG , rostral trigeminal spinal nuclei, nucleus of the solitary tract, brainstem reticular areas, superior salivatory SSN and cuneiform nuclei [ 22 ; 39 ; 92 ].
Schematic representation of ascending neuronal pathways of the trigeminovascular system that are involved in the different aspects of migraine. A recent neuroanatomical study showed that the axonal trajectories and cortical projections of such neurons are defined by their thalamic nucleus of origin. On the contrary, dura-sensitive neurons in Po, LP and LD project to multiple cortical areas such as motor, parietal association, retrosplenial, somatosensory, auditory, visual and olfactory cortices, suggesting a role in motor clumsiness, difficulty focusing, transient amnesia, allodynia, phonophobia, photophobia and osmophobia [ 90 ; 91 ].
Electrophysiological recordings showing delayed activation of meningeal nociceptors top panel and SpVC trigeminovascular neurons bottom panel by cortical spreading depression. Adapted from Zhang et al. About one third of migraines are preceded by visual, motor or somatosensory symptoms known as aura. The most frequent type of aura is characterized by a visual perception of light flashes moving across the visual field, and has been associated with a reversible, transient cortical event termed cortical spreading depression CSD [ 65 ; 66 ].
At the cellular and molecular level, CSD has been shown to involve the local release of ATP, glutamate, potassium and hydrogen ions by neurons, glia or vascular cells, and CGRP and nitric oxide by activated perivascular nerves [ 23 ; ; ; ]. These molecules are thought to diffuse towards the surface of the cortex where they come in contact and activate pial nociceptors, triggering a consequential neurogenic inflammation vasodilatation, plasma protein extravasation and mast cell degranulation and persistent activation of dural nociceptors [ 7 ; 85 ].
Until recently, the notion that CSD activates the trigeminovascular system was only supported by indirect evidence showing that CSD induces an increase of c-fos expression in SpVC [ 16 ; 86 ]. In support of this notion, direct electrophysiological confirmation of meningeal nociceptors activation by CSD, as well as the subsequent activation of central trigeminovascular neurons in SpVC has emerged [ ; ].
In addition, a potential mechanistic explanation on how meningeal nociceptors activation begins after CSD has been recently proposed [ 51 ]. In this study, various experimental approaches were performed in mice to demonstrate that CSD causes the opening of neuronal Panx1 megachannels, resulting in downstream cascade of events that leads to release of proinflammatory molecules in the meninges.
Novel anatomical evidence of dural nociceptors that issue collateral branches that cross the arachnoid and terminate in the pia provide a neural substrate for this possibility [ 59 ].
Although it is not clear how CSD begins in the human brain, genetic factors are likely to play a role in individual CSD susceptibility [ 7 ; ]. Current understanding of the genetic factors underlying migraine and CSD comes from studies of rare monogenic mutations in patients diagnosed with the common form of familial hemiplegic migraine FHM [ 26 ; 27 ; 31 ; 98 ].
In agreement with the human data, mice carrying FHM mutations show increased susceptibility to CSD and altered synaptic transmission [ 36 ; 68 ; ; ]. That cortical excitability is also altered in common migraine is evident in psychophysical and neurophysiological studies that show abnormal processing of sensory information even between attacks [ 6 ; 24 ; 64 ; ; ]. Such altered excitability may also contribute to typical migraine with aura, as suggested by a genetic mutation in TRESK potassium channels that regulate neuronal resting potential and excitability [ 61 ].
Altogether, these findings support the notion that neuronal excitability plays a pivotal role in the predisposition to develop the different forms of migraine.
A large number of endogenous inflammatory mediators believed to be released during migraine are capable of activating and sensitizing peripheral and central trigeminovascular neurons. Peripheral sensitization mediates the throbbing perception of the headache [ ] Figure 3 , whereas sensitization of second-order neurons in the SpVC mediates cephalic allodynia as well as muscle tenderness [ 19 ; 21 ] Figure 4.
Until recently, no neural substrate had been proposed for the extracephalic allodynia during migraine. Collectively, these data suggest that the whole-body allodynia is mediated, at least in part, by the rostral subdivision of the pulvinar in the posterior thalamus of humans and by the most dorsal and posterior part of the thalamus in animals i.
Sensitization of meningeal nociceptors believed to mediate the throbbing nature of migraine pain. Left panel: Schematic representation of peripheral sensitization and periorbital throbbing pain in the human; fMRI evidence showing activation of the trigeminal ganglion during migraine. Right panel: Electrophysiological recording of a neuron in the rat TG showing increased responsiveness to mechanical stimulation of the dura after topical application of inflammatory mediators IS.
Sensitization of central trigeminovascular neurons in the trigeminal nucleus caudalis believed to mediate cephalic cutaneous allodynia during migraine. Left panel: Schematic representation of central sensitization of SpVC trigeminovascular neurons and cephalic cutaneous allodynia in the human; fMRI evidence showing activation of the spinal trigeminal nucleus during migraine.
Right panel: Electrophysiological recording of a neuron in the rat SpVC showing increased responsiveness to innocuous and noxious stimulation of the skin and the corresponding receptive field after induction of central sensitization. Sensitization of central trigeminovascular neurons in the thalamus believed to mediate the extracephalic whole-body cutaneous allodynia during migraine. Left panel: Schematic representation of central sensitization of thalamic trigeminovascular neurons and extracephalic cutaneous allodynia in the human; fMRI evidence showing activation of the thalamus during migraine.
Right panel: Electrophysiological recording of a neuron in the rat posterior thalamus showing increased responsiveness to mechanical and thermal stimulation of the skin and the corresponding dural and cutaneous receptive fields after induction of central sensitization by inflammatory mediators IS on the dura. In the last few years, new insights into the neurobiological mechanisms of light-induced neurological symptoms have emerged.
Mechanisms of Photophobia. Top panel: Proposed mechanism for exacerbation of headache by light, hypersensitivity to light in migraine patients and ocular pain induced by light Adapted from Noseda and Burstein, Curr Opin Neurol The perception of migraine headache is uniquely intensified during exposure to ambient light [ 52 ; 73 ]. Clinical observations in blind migraineurs suggest that the exacerbation of headache by light depends on photic signals from the eye that converge on trigeminovascular neurons somewhere along its path.
The critical contribution of the optic nerve to migraine-type photophobia is best illustrated in migraine patients lacking any kind of visual perception due to complete damage of the optic nerve.
Such patients testify that light does not hurt them during migraine, that their sleep cycle is irregular, and that light does not induce pupillary response.
Conversely, exacerbation of headache by light is preserved in blind migraineurs with intact optic nerve, partial light perception but no sight due to severe degeneration of rod and cone photoreceptors [ 91 ]. Retinal projections to the brain constitute two functionally different pathways. The first allows the formation of images by photoactivation of rods and cones, and the second allows regulation of biological functions such as circadian photoentrainment, pupillary reflex and melatonin release by activation of intrinsically photosensitive retinal ganglion cells ipRGCs containing melanopsin photoreceptors [ 38 ; 56 ; 75 ].
Activation of ipRGCs is achieved not only by virtue of their unique photopigment melanopsin [ 15 ; ], but also extrinsically by rods and cones [ 42 ]. It is thus likely, that all retinal photoreceptors contribute to migraine-type photophobia in migraineurs with normal eyesight. Such convergence of photic signals from the retina onto the trigeminovascular thalamo-cortical pathway has been proposed as a neural mechanism for the exacerbation of migraine headache by light [ 91 ].
Some migraineurs describe photophobia as abnormal intolerance to light. Such description of photo-hypersensitivity suggests that the flow of nociceptive signals along the trigeminovascular pathway converges on the visual cortex and alters its responsiveness to visual stimuli. Indeed, the visual cortex appears to be hyperexcitable in migraineurs and may be the neural substrate of abnormal processing of light sensitivity [ 28 ]. Additionally, a transgenic mice model of migraine to study light-aversion or increased sensitivity to light has been recently developed.
This genetically engineered model presents increased sensitivity to CGRP due to overexpression of the human receptor activity-modifying protein 1 hRAMP1 and provides strong behavioral evidence of aversion to light following intracerebroventricular administration of CGRP [ ; ].
Another clinical entity falling into the definition of photophobia is ocular discomfort or pain induced in the eye by exposure to bright light [ 88 ]. More appropriately termed photo-oculodynia, this type of photophobia is thought to originate from indirect activation of intraocular trigeminal nociceptors. As proposed by Okamoto et al. Lack of evidence for induction of vasodilatation by light in the human retina question this scenario. Schematic representation of descending neuronal pathways that modulate trigeminovascular nociceptive transmission in the SpVC.
Endogenous modulation of trigeminal nociception certainly originates from the cortex since most nociceptive relays within the central nervous system are under corticofugal control. A large and growing body of clinical and preclinical evidence point to an alteration in cortical excitability dysexcitability as a determinant factor for the susceptibility to migraine [ 6 ; 8 ; 24 ; 64 ; ; ; ].
The mechanisms by which cortical dysexcitability contributes to migraine pathophysiology are largely unknown, however, it is possible that different cortical areas and their degree of excitability might be involved in the modulation of migraine pain through cortico-trigeminal pathways.
In this respect, several anatomical studies have described direct, descending projections from the cerebral cortex to the SpVC in the rat [ 30 ; 48 ; 89 ] and human [ 60 ]. Such cortico-trigeminal projections originate mainly from the contralateral primary somatosensory and insular cortices, and innervate both deep and superficial layers of the SpVC, respectively. These precisely organized cortico-trigeminal networks are anatomically positioned to influence meningeal nociception as shown by S1-mediated inhibition and insula-mediated facilitation of the excitability of SpVC dura-sensitive neurons [ 89 ; ].
Although most of the functional imaging studies showing increased hypothalamic activity have been obtained from trigeminal autonomic cephalalgias TACs [ 82 ; 83 ], there is one implicating the hypothalamus in migraine [ 29 ]. The hypothalamus plays a critical role in autonomic and endocrine regulation [ ], and has been implicated in the premonitory symptoms frequently experienced by migraineurs such as sleep-wake cycle disturbances, changes in mood, appetite, thirst and urination [ 40 ].
The reciprocal anatomical connections between the hypothalamus and SpVC [ 39 ; 44 ; 77 ; 79 ; ] [ ] and the presence of neurons expressing c-fos in several hypothalamic nuclei after dural stimulation [ 14 ; 78 ] support the role of the hypothalamus in different aspects of migraine [ 20 ].
For example, noxious stimulation of the dura activates parabrachial and ventromedial hypothalamic nucleus VMH neurons that expresses the receptor of the anorectic peptide cholecystokinin — creating a trigemino-parabrachial-hypothalamic circuit that can potentially mediates the loss of appetite during migraine [ 78 ]. Evidence showing that hypothalamic regions become activated during migraine [ 29 ] is also consistent with a role in pain modulation and therefore may contribute to the development of central sensitization of trigeminovascular neurons.
In this regard, a recent study has provided experimental support for this scenario by showing in rodents that paraventricular hypothalamic nucleus PVN directly control both spontaneous and evoked activities of SpVC [ ]. Such hypothalamic modulation of pain could be exerted through direct and indirect projections to the spinal and medullary dorsal horn by release of several neuropeptides such as orexin, somatostatin, dopamine and oxytocin [ 45 ; 50 ; 74 ; ; ].
Furthermore, the hypothalamus also sends dense projections to the SSN in the brainstem [ 47 ; ], suggesting that this circuit is contributing to the parasympathetic autonomic symptoms observed in migraine and cluster headache [ 41 ; 62 ]. But evidence supporting the role of PAG as a headache generator are lacking see refs in [ 17 ].
In theory, dysfunctional brainstem areas including the PAG could either enhance activity of neurons that facilitate trigeminovascular pain transmission or suppress activity of neurons that inhibit trigeminovascular pain transmission in the spinal and medullary dorsal horn [ ] in order to generate migraine-like pain. Functionally, activation of lateral and ventrolateral PAG neurons by direct ascending lamina I projections, produce non-selective, non-specific pain relief, cardiovascular decrease in blood pressure , homeostatic temperature changes and defensive reactions immobility, arousal, avoidance behavior and vocalization , as well as a more general emotional state of fear and anxiety [ 10 ; 97 ].
Since the PAG projects minimally to the spinal and medullary dorsal horn but densely to the rostral ventromedial medulla RVM , RVM neurons constitute a direct link for descending modulation through bilateral projections to all levels of spinal and medullary dorsal horns [ 12 ; 37 ; 46 ; 81 ].
These functional and anatomical studies are consistent with a broader modulatory role of the PAG-RVM circuit and suggest an absence of specificity for headache. In this regard, facilitatory influences mediated by RVM neurons have been recently reported in an animal model of migraine pain through the assessment of cutaneous allodynia as a manifestation of central sensitization [ 35 ].
These studies support the role of descendent modulation and the inability of PAG-RVM to induce de novo activity in previously quiescent nociceptive neurons. Conversely, several neuroimaging studies reporting brainstem activation in migraine patients do not include the PAG as an activated region during spontaneous or induced attacks. They do show however, activation in nearby nuclei in the dorsolateral pons DLP that includes the mesencephalic trigeminal nucleus, principal sensory trigeminal nucleus, PB, vestibular nucleus, inferior colliculus, LC and cuneiform nucleus [ 1 ; 9 ; 87 ; ; ].
This complex pattern of activation appears as not specific to migraine [ 13 ; 34 ; 55 ; 71 ; ] and reflects a potential role in facial and muscle tenderness, abnormal tactile sensation, motion sickness, nausea, altered auditory perception and more importantly, modulation of pain. The last 30 years of basic and clinical research in the field of headaches have greatly improved our understanding of migraine pathophysiology and therapy.
Most likely, migraine headache depends on a activation of the trigeminovascular pathway by pain signals that originate in peripheral intracranial nociceptors, and b dysfunction of CNS structures involved in the modulation of neuronal excitability and pain. Because to date there is no evidence on paroxysmal conditions causing pain without peripheral afferent input, efforts to study this complex disorder must continue in order to incorporate additional elements and open the framework in which we conceptualize migraine pathophysiology.
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Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci. Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol. Goadsby PJ. Migraine, aura, and cortical spreading depression: why are we still talking about it? Activation of central trigeminovascular neurons by cortical spreading depression.
Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci. Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system.
Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest.
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