Nouchine Hadjikhani, Margarita Sanchez del Rio, Ona Wu, Denis Schwartz, Dick Bakker, Bruce Fischl, Kenneth K. Kwong, F. Michael Cutrer, Bruce R. Rosen, Roger B. H. Tootell, A. Gregory Sorensen, and Michael A. Moskowitz
Mechanisms of migraine aura revealed by functional MRI in human visual cortex
PNAS 98: 4687-4692; published online before print as 10.1073/pnas.071582498
"Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 +/- 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex." [Full Text]

Cao Y, Welch KM, Aurora S, Vikingstad EM.
Functional MRI-BOLD of visually triggered headache in patients with migraine.
Arch Neurol. 1999 May;56(5):548-54.
"BACKGROUND: Spreading depression of Leao has been hypothesized as the basis for the visual aura of the migraine attack, supported by cerebral blood flow measurements of spreading hypoperfusion. The early depolarizing or activation phase of experimental spreading depression, however, is associated with a transient but pronounced cerebral blood flow increase that precedes spreading hypoperfusion. OBJECTIVE: To study this early phase of the migraine attack, we investigated visually triggered attacks of headache and visual symptoms using a red-green checkerboard stimulus in patients with migraine. INTERVENTIONS: We studied occipital cortex activation during visual stimulation by measuring occipital cortex perfusion with functional magnetic resonance imaging-blood oxygenation level-dependent contrast in 10 patients with migraine with aura and 2 patients with migraine without aura and 6 healthy subjects. RESULTS: In 6 patients with migraine with aura and 2 patients with migraine without aura, their typical headache with (n = 2) or without visual change was visually triggered at 7.3 minutes (mean time) after visual stimulation began. In 5 of these patients, the onset of headache or visual change, or both, was preceded by suppression of initial activation (mean onset time, 4.3 minutes; P<.001) The suppression slowly propagated into contiguous occipital cortex at a rate ranging from 3 to 6 mm/ min. This neuronal suppression was accompanied by baseline contrast intensity increases that indicated vasodilatation and tissue hyperoxygenation. CONCLUSIONS: We conclude that visually triggered headache and visual change in patients with migraine is accompanied by spreading suppression of initial neuronal activation and increased occipital cortex oxygenation. We postulate that this spreading suppression may be associated with initial activation of a migraine attack, independent of whether there are associated aura symptoms. We further postulate that there may be an association between vasodilation accompanying the initial stage of suppression and the induction of headache." [Abstract]

Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA.
Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model.
Nat Med. 2002 Feb;8(2):136-42.
"Although the trigeminal nerve innervates the meninges and participates in the genesis of migraine headaches, triggering mechanisms remain controversial and poorly understood. Here we establish a link between migraine aura and headache by demonstrating that cortical spreading depression, implicated in migraine visual aura, activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache. Cortical spreading depression caused long-lasting blood-flow enhancement selectively within the middle meningeal artery dependent upon trigeminal and parasympathetic activation, and plasma protein leakage within the dura mater in part by a neurokinin-1-receptor mechanism. Our findings provide a neural mechanism by which extracerebral cephalic blood flow couples to brain events; this mechanism explains vasodilation during headache and links intense neurometabolic brain activity with the transmission of headache pain by the trigeminal nerve." [Abstract]

Sanchez-Del-Rio M, Reuter U.
Migraine aura: new information on underlying mechanisms.
Curr Opin Neurol. 2004 Jun;17(3):289-293.
"PURPOSE OF REVIEW: Since the initial description of cortical spreading depression by Leao, evidence that cortical spreading depression is the underlying pathomechanism of migraine aura has increased. The purpose of this review is to describe the ultimate genetic and molecular mechanisms of migraine aura. RECENT FINDINGS: It has been debated how a primarily cortical phenomenon (aura phase) may activate trigeminal fibres (headache phase). Recent data have demonstrated a link between cortical events and activation of the pain-sensitive structures of the dura mater. The initial cortical hyperperfusion in cortical spreading depression is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibres, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. With regard to molecular mechanisms, cortical spreading depression upregulates a variety of genes coding for COX-2, TNF-alpha and IL-1beta, galanin or metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine and other products released by cortical spreading depression to reach and sensitize the dural perivascular trigeminal afferents. In familial hemiplegic migraine, new mutations have been described in chromosome 1q23, leading to a haploinsufficiency of the sodium/potassium pump, producing an increase in intracellular calcium, similar to the CACNA1A mutation. SUMMARY: Recent studies have helped unravel the basic mechanisms involved in migraine aura. Far from being a simple phenomenon, a sequence of events leads from the cortex to the activation of pain-sensitive structures. The role of the brainstem is still poorly described. The identification of target molecules may provide new therapies." [Abstract]

Gursoy-Ozdemir, Yasemin, Qiu, Jianhua, Matsuoka, Norihiro, Bolay, Hayrunnisa, Bermpohl, Daniela, Jin, Hongwei, Wang, Xiaoying, Rosenberg, Gary A., Lo, Eng H., Moskowitz, Michael A.
Cortical spreading depression activates and upregulates MMP-9
J. Clin. Invest. 2004 113: 1447-1455
"Cortical spreading depression (CSD) is a propagating wave of neuronal and glial depolarization and has been implicated in disorders of neurovascular regulation such as stroke, head trauma, and migraine. In this study, we found that CSD alters blood-brain barrier (BBB) permeability by activating brain MMPs. Beginning at 3-6 hours, MMP-9 levels increased within cortex ipsilateral to the CSD, reaching a maximum at 24 hours and persisting for at least 48 hours. Gelatinolytic activity was detected earliest within the matrix of cortical blood vessels and later within neurons and pia arachnoid (> or =3 hours), particularly within piriform cortex; this activity was suppressed by injection of the metalloprotease inhibitor GM6001 or in vitro by the addition of a zinc chelator (1,10-phenanthroline). At 3-24 hours, immunoreactive laminin, endothelial barrier antigen, and zona occludens-1 diminished in the ipsilateral cortex, suggesting that CSD altered proteins critical to the integrity of the BBB. At 3 hours after CSD, plasma protein leakage and brain edema developed contemporaneously. Albumin leakage was suppressed by the administration of GM6001. Protein leakage was not detected in MMP-9-null mice, implicating the MMP-9 isoform in barrier disruption. We conclude that intense neuronal and glial depolarization initiates a cascade that disrupts the BBB via an MMP-9-dependent mechanism." [Full Text]

van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD.
A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.
Neuron. 2004 Mar 4;41(5):701-10.
"Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments." [Abstract]

Diener HC.
Positron emission tomography studies in headache.
Headache. 1997 Nov-Dec;37(10):622-5.
"Positron emission tomography (PET) allows the quantitative measurement of regional cerebral flow (rCBF) in humans in quantitative terms. Gross changes in rCBF are due to variation in vessel diameter. Changes of rCBF also reflect synaptic activity (inhibition and excitation). Therefore, PET was used to monitor changes in blood flow during the aura and headache phase of a migraine attack and to investigate focal areas of increased or decreased blood flow, e.g., in the brain stem and midbrain. Hemispheric rCBF was unchanged in spontaneous migraine attacks without aura. This was true for the headache side as well as for the nonheadache side. Sumatriptan had no effects on cerebral blood flow. Regional cerebral blood flow was increased in midline brain stem structures during the headache phase, but also when the headache had been treated with sumatriptan. This persisting increased activity might reflect activity of a presumed migraine center in the brain stem. These changes are specific for migraine attacks and are not seen during attacks of cluster headache. Positron emission tomography measurements in the early phase of a migraine attack in a single subject showed flow reductions in the occipital cortex spreading forwards; an observation which would be compatible with the existence of spreading depression in humans. Our attempts to study the aura phase with PET have, to date, been unsuccessful." [Abstract]

Lauritzen M, Skyhoj Olsen T, Lassen NA, Paulson OB.
Changes in regional cerebral blood flow during the course of classic migraine attacks.
Ann Neurol. 1983 Jun;13(6):633-41.
"Regional cerebral blood flow (rCBF) following carotid arteriography was studied in thirteen patients with classic migraine. Using the 133xenon intraarterial injection method, rCBF was measured in 254 areas in one hemisphere. Nine patients developed a characteristic attack following arteriography and were examined by a series of rCBF studies, spaced by intervals of 5 to 10 minutes. A wave of reduced blood flow originating in the posterior part of the brain and progressing anteriorly was observed in eight of the nine patients. The oligemia advanced at a speed of 2 mm per minute over the hemisphere, progressing anteriorly but not crossing the rolandic or sylvian sulcus. Typically, the spreading oligemia reached the primary sensorimotor area after symptoms from that area had begun and persisted there long after the focal symptoms had disappeared. The observed time course suggests that the focal symptoms are not secondary to the oligemia. We suggest that focal symptoms and blood flow changes may be secondary to spreading depression of Leao." [Abstract]

Russell MB, Olesen J.
A nosographic analysis of the migraine aura in a general population.
Brain. 1996 Apr;119 ( Pt 2):355-61.
"The study presented here is the first detailed nosographic analysis of migraine aura, diagnosed using the criteria of the International Headache Society, in a sufficiently large sample for statistical analysis. Of 4,000 people, 163 had migraine with aura. Sixty-two had attacks of migraine aura with headache as well as migraine aura without headache, and seven had exclusively migraine aura without headache. Visual symptoms were most frequent (99%), followed by sensory (31%), aphasic (18%) and motor (6%) symptoms. Those with several types of aura symptoms had visual aura in virtually every attack, while sensory, motor and aphasic aura were present only in a small number of their attacks. The typical visual aura starts as a flickering, uncoloured, zig-zag line in the centre of the visual field and affect the central vision. It gradually progresses towards the periphery of one hemifield and often leaves a scotoma. The typical sensory aura is unilateral, starts in the hand, progresses towards the arm and then affects the face and tongue. The typical motor aura is half-sided and affects the hand and arm. The visual, sensory and aphasic auras rarely lasted > 1 h, while the motor aura did in 67% (six out of nine). Four people had exclusively acute onset visual aura. The duration of the aura and the characteristics of the ensuing headache were typical for migraine with aura, suggesting that acute onset aura is a real phenomenon. Headache followed the aura in 93%, headache and aura occurred simultaneously in 4% and aura followed headache in 3%. The characteristic spread of each symptom and the sequence of different symptoms suggest that cortical spreading depression is the mechanism underlying the migraine aura. Our results do not suggest that alterations of the diagnostic criteria of the International Headache Society are needed. The intra-individual variation of aura symptoms shown in this study indicates that a simplification of the International Classification of Diseases, Neurological Adaptation is appropriate." [Abstract]

Shibata K, Osawa M, Iwata M.
Pattern reversal visual evoked potentials in classic and common migraine.
J Neurol Sci. 1997 Feb 12;145(2):177-81.
"Pattern reversal visual evoked potentials (PVEPs) to transient checkerboard were recorded in 19 patients with migraine with visual aura (i.e., classic migraine), 14 patients with migraine without aura (i.e., common migraine) in the interictal period and 43 normal subjects. Latencies and amplitudes of PVEPs in each group were analyzed. In classic migraine patients, P100 amplitude was significantly higher than in normal subjects (p < 0.01), whereas latencies of PVEPs did not significantly differ. There were no significant differences between the common migraine and normal subjects, nor within the classic and common migraine groups in latencies and amplitudes of PVEP. Four patients with classic migraine underwent PVEPs during or 1-2 h immediately after their migraine attacks. Two of these patients who underwent PVEPs 1.5-2 h after their attacks showed abnormally increased PVEP amplitudes. These results suggest that there are different pathophysiologies in the visual pathway between classic and common migraine and furthermore, classic migraine patients in interictal periods may have hyperexcitability in the visual pathway and that the increased amplitude of PVEPs after attacks may be due to cortical spreading depression." [Abstract]

Shibata K, Osawa M, Iwata M.
Pattern reversal visual evoked potentials in migraine with aura and migraine aura without headache.
Cephalalgia. 1998 Jul-Aug;18(6):319-23.
"Pattern reversal visual evoked potentials (PVEPs) were recorded in 20 patients with migraine with aura (MA), 19 patients with migraine without headache (migraine equivalent; ME) during interictal periods, and 34 normal subjects. All migraine patients had hemianopsia or fortification spectra during attacks. In both MA and ME patients of less than 49 years of age, there were significant (p<0.01) differences in amplitude of PVEPs at the mid-occipital and contralateral to visual aura electrode sites compared to normal subjects. Amplitude of PVEPs in MA and ME showed significant (p<0.001) increases when recorded soon after attacks, especially within 10 days. There was a significant (p<0.01) correlation between percentage asymmetries and the duration of illness in both MA and ME. We conclude from our PVEP findings that cortical spreading depression remains the most likely explanation for the migraine visual aura." [Abstract]

de Tommaso M, Sciruicchio V, Guido M, Sasanelli G, Specchio LM, Puca FM.
EEG spectral analysis in migraine without aura attacks.
Cephalalgia. 1998 Jul-Aug;18(6):324-8.
"In 16 patients suffering from migraine without aura, we examined quantitative EEG and steady-state visual evoked potentials (SSVEPs) at 27 Hz stimulation during the critical phase of migraine and in attack-free periods. The main spontaneous EEG abnormalities found during the critical phase were the slowing and asymmetry of the dominant frequency in the alpha range. The amplitude of the SSVEP F1 component was significantly reduced during the attack phase compared with the intercritical phase; in the latter condition the visual reactivity to 27 Hz stimulus was increased over almost the entire scalp compared with normal subjects. The EEG abnormalities confirm a fluctuating modification of alpha activity during the migraine attack, probably related to a functional disorder. The suppression of visual reactivity during the migraine attack could be related to a phenomenon of neuronal depolarization such as spreading depression, occurring in a situation of central neuronal increased excitability predisposing to migraine attacks." [Abstract]

Aurora SK, Ahmad BK, Welch KM, Bhardhwaj P, Ramadan NM.
Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine.
Neurology. 1998 Apr;50(4):1111-4.
"OBJECTIVES: We hypothesized that the hyperexcitability of occipital cortex neurons may predispose migraine subjects to develop spreading depression, the putative basis of migraine with aura (MwA). To date there is no direct physiologic correlate confirming this in patients. Accordingly, we evaluated the differences in the threshold of occipital cortex excitation between MwA patients and normal controls (C) using transcranial magnetic stimulation (TMS). METHODS: TMS was performed using the Cadwell MES 10 stimulator. A circular coil 9.5 cm in diameter was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulation intensity was then fine-tuned to determine the threshold at which phosphenes were just visualized. RESULTS: Eleven MwA patients, mean age 37 +/- 7 years, were compared with 11 C, mean age 37.7 +/- 7 years. The difference in the proportion of subjects with phosphene generation between MwA patients and C was significant (MwA patients 100% versus C 27.3%, p = 0.001). The mean threshold level for MwA patients was 44.2 +/- 8.6 versus 68.7 +/- 3.1 for C (p = 0.0001). All threshold levels for MwA patients were lower than the lowest threshold for C; the MwA patient with the lowest threshold had an aura after stimulation. CONCLUSIONS: The threshold for excitability of occipital cortex is lower in MwA patients compared with C. This is a direct neurophysiologic correlate for clinical observations that have indicated hyperexcitability of the occipital cortex in migraineurs." [Abstract]

Spierings EL.
Pathogenesis of the migraine attack.
Clin J Pain. 2003 Jul-Aug;19(4):255-62.
"BACKGROUND: There is clinical experimental evidence that extracranial arterial vasodilation, extracranial neurogenic inflammation, and decreased inhibition of central pain transmission are involved in the pathogenesis of the migraine headache. The migraine aura is likely caused by a neurophysiologic phenomenon akin to Leao's cortical spreading depression, a wave of short-lasting neuronal excitation that travels over the cerebral cortex, followed by prolonged depression of cortical neuronal activity. METHOD: A concept of the pathogenesis of the migraine attack is presented, in which the relation of the mechanism of the migraine aura and that of the migraine headache is considered parallel rather than sequential in nature. CONCLUSIONS: The process driving the pathogenesis of the migraine attack and susceptible to the migraine trigger factors may be located in the brain stem." [Abstract]

Baron JC.
[The pathophysiology of migraine: insights from functional neuroimaging]
Rev Neurol (Paris). 2000;156 Suppl 4:4S15-23.
"Over the last 20 years, functional neuroimaging has led to major advances in the understanding of the pathophysiology of migraine. The migraine aura is characterized by the occurrence of an hypoperfusion of moderate intensity which is peculiar by its initial appearance in the posterior cortex and its anterior spread at a speed of about 2 to 3mm per minute, congruent with the migrainous march of neurologic deficit and reminiscent of the phenomenon of cortical spreading depression described in the laboratory animal after various neuronal aggressions. The hypoperfusion is followed by a phase of long-lasting hyperperfusion temporally dissociated from the headache, which seems rather to result from vasodilatation and inflammation of the extra-cerebral large vessels. Although this sequence of hypoperfusion followed by hyperperfusion would be consistent with an ischemic process, there is presently no formal argument in favour of such a process being operational in migraine aura. It is however possible that migrainous subjects are genetically susceptible to the development of some unknown process at the borderline between spreading depression and classic ischemia. In migraine without aura, the data indicate only rare and mild changes in brain perfusion, although there also exist isolated observations of pauci-symptomatic spreading bilateral hypoperfusion. Physiologic imaging has also documented the occurrence during migraine without aura of a dorsal mesencephalic activation in the vicinity of the raphe and the locus coeruleus, independent of the pain itself and which might represent the long sought-after "migraine generator". It remains unknown if this phenomenon is also present in migraine with aura. The main prevalent hypotheses attempting a synthesis of all the available data are briefly presented in the conclusion." [Abstract]

Kaube H, Knight YE, Storer RJ, Hoskin KL, May A, Goadsby PJ.
Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat.
Cephalalgia. 1999 Jul;19(6):592-7.
"It remains an open question as to whether cortical spreading depression (CSD) is the pathophysiological correlate of the neurological symptoms in migraine with aura. In the experimental animal, CSD is an electrophysiological phenomenon mainly mediated via NMDA receptors. However, according to case reports in humans, visual aura in migraine can be alleviated by vasodilator substances, such as amyl nitrite and isoprenaline. There is also circumstantial evidence that brainstem nuclei (dorsal raphe nucleus and locus coeruleus) may play a pivotal role in the initiation of aura. In this study, CSD was elicited in alpha-chloralose anesthetized cats by cortical needle stab injury and monitored by means of laser Doppler flowmetry. Topical application of isoprenaline (0.1-1%) and amyl nitrite (0.05%) onto the exposed cortex had no effect on the elicitation or propagation of CSD. Also, after supracollicular transection, subsequent CSDs showed no differences in the speed of propagation and associated flow changes. We conclude from these data that--given CSD probably exists in humans during migraine--spreading neurological deficits during migraine aura are independent of brainstem influence and have a primarily neuronal rather than vascular mechanism of generation." [Abstract]

Ingvardsen BK, Laursen H, Olsen UB, Hansen AJ.
Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression.
Pain. 1997 Sep;72(3):407-15.
"Cortical spreading depression (CSD) is characterized by a transient, reversible depression of EEG activity which advances across the cortical surface at a velocity of 2-5 mm/min. CSD was originally linked to the aura phase of migraine, but recently also to migraine headache. The theory is that CSD activates meningeal trigeminal C-fibers causing neurogenic inflammation and pain (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177). The present study is an examination of the proposed link between CSD elicited in rats and activation of trigeminal nerve fibers. Multiple CSDs were elicited unilaterally for 1 h by KCl injections (1 M, 5 microliters) into the right hemisphere, while NaCl (1 M, 5 microliters) was injected into the left as control. After an additional 1 h the animals were sacrificed and trigeminal activation assessed by the expression of c-fos in trigeminal nucleus caudalis (TNC) using immunohistochemistry. The correlation between the number of CSDs and the extent of c-fos expression was determined. In addition the effect of sumatriptan (0.3 mg/kg) and morphine (3 mg/kg) given i.v. 30 min before elicitation of CSD was evaluated. CSD caused increased c-fos expression in lamina I and II of TNC where C-fibers, end, the response being greater ipsilaterally. Morphine, but not sumatriptan, reduced c-fos expression in both the ipsilateral and contralateral TNC by 71% (P < 0.05 and P = 0.19, respectively), confirming that nociceptors have been activated. No positive correlation was seen between the number of CSDs and the extent of c-fos expression in TNC. Instead we observed a positive, linear correlation between the number of KCl injections and the extent of c-fos expression in TNC (correlation coefficient r = 0.709, P < 0.05). We suggest that the C-fiber activation observed is caused by hyperosmolar KCl/NaCl and not CSD. Hence, our results do not support the hypothesis of Moskowitz et al. (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177) which links CSD with migraine headache." [Abstract]

Moskowitz MA, Nozaki K, Kraig RP.
Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms.
J Neurosci. 1993 Mar;13(3):1167-77.
"The effects of neocortical spreading depression (SD) on the expression of immunoreactive c-fos protein were examined within the superficial laminae of trigeminal nucleus caudalis (TNC), a brainstem region processing nociceptive information. KCl was microinjected into the left parietal cortex at 9 min intervals over 1 hr, and SD was detected by a shift in interstitial DC potential within adjacent frontal cortex. The stained cells in lower brainstem and upper cervical spinal cord were counted on both sides after tissues were sectioned (50 microns) and processed for c-fos protein-like immunoreactivity (LI) using a rabbit polyclonal antiserum. C-fos protein-LI was visualized in the ventrolateral TNC, chiefly in laminae I and Ilo and predominantly within spinal segment C1-2 (e.g., -1.5 to -4.5 mm from obex) ipsilaterally. SD significantly increased cell staining within ipsilateral TNC. The ratio of cells in laminae I and Ilo on the left: right sides was 1.32 +/- 0.13 after 1 M KCl, as compared to 1.06 +/- 0.05 in control animals receiving 1 M NaCl instead of KCl microinjections (p < 0.01). The ratio was reduced to an insignificant difference after chronic surgical transection of meningeal afferents and recurrent SD (1.09 +/- 0.11). Pretreatment with intravenous sumatriptan, a 5-HT1-like receptor agonist that selectively blocks meningeal C-fibers and attenuates c-fos protein-LI within TNC after noxious meningeal stimulation, also reduced the ratio to an insignificant difference (1.10 +/- 0.09). Sumatriptan or chronic surgical transection of meningeal afferents, however, did not reduce the ability of KCl microinjections to induce SD. On the other hand, combined hyperoxia and hypercapnia not only reduced the number of evoked SDs from 6.3 +/- 1.0 to 2.5 +/- 1.2 after 0.15 M KCl microinjection, but also significantly (p < 0.01) reduced associated c-fos protein-LI in TNC. These data indicate that multiple neocortical SDs activate cells within TNC. The increase in c-fos protein-LI, observed predominantly ipsilaterally, was probably mediated by SD-induced stimulation of ipsilaterally projecting unmyelinated C-fibers innervating the meninges. If true, this is the first report demonstrating that neurophysiological events within cerebral cortex can activate brainstem regions involved in the processing of nociceptive information via trigeminovascular mechanisms." [Abstract]

Gorji A.
Spreading depression: a review of the clinical relevance.
Brain Res Brain Res Rev. 2001 Dec;38(1-2):33-60. [Abstract]

Lauritzen M.
Cortical spreading depression in migraine.
Cephalalgia. 2001 Sep;21(7):757-60. [Abstract]

Wiedemann M, de Lima VM, Hanke W.
Effects of antimigraine drugs on retinal spreading depression.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Apr;353(5):552-6.
"It has been suggested that spreading depression may play a role in triggering classical migraine. In this study the retinal spreading depression was used as a pharmacological tool to test the neuronal effects of several common antimigraine drugs. As the chicken retina is void of any blood vessels the observed effects must be of pure neuronal origin. It is shown that propranolol, sumatriptan, methysergide, paracetamol and acetylsalicyclic acid decrease the propagation velocity of retinal spreading depression waves, accelerate the recovery of the optical and electrical signal and reduce the amplitude of the negative potential shift, concomitant with the spreading depression. Barbiturate increases the spreading velocity, and the amplitude of the potential shift. Ergotamine, clonidine, lisuride and iprazochrome have no significant influence on retinal spreading depression." [Abstract]

Brand S, Fernandes de Lima VM, Hanke W.
Pharmacological modulation of the refractory period of retinal spreading depression.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Apr;357(4):419-25. [Abstract]

Read SJ, Parsons AA.
Sumatriptan modifies cortical free radical release during cortical spreading depression. A novel antimigraine action for sumatriptan?
Brain Res. 2000 Jul 7;870(1-2):44-53.
"Increases in concentration of brain NO are proposed to initiate and mediate migraine headache. Triggered by focal depolarisation, spreading depression (SD) represents a suitable mechanism for eliciting widespread release of nitric oxide. The current study examines the effect of sumatriptan, a 5-HT(1B/1D) agonist and effective antimigraine therapy, on free radical release (nitric oxide and superoxide) in SD in the simple and complex cortices of the rat and cat. Following initiation of SD, sumatriptan pretreatment (300 microg kg(-1) i.v., 15 min prior to SD) modulated all phases of nitric oxide release associated with each SD in both cats and rats. As a result, superoxide levels were observed to significantly (ANOVA, post hoc LSD) increase versus vehicle treated animals (saline 1 ml kg(-1) i.v. 15 min prior to SD) during specific phases of each SD depolarisation. Averaged over all SD depolarisations, mean peak SD nitric oxide levels per depolarisation were 0.73+/-0.23 microM (n=29) in cats, and 0.42+/-0.09 microM (n=34) in rats. Sumatriptan significantly (Students t-test, P<0.05, two tailed hypothesis, P<0.05) modulated this increase in cortical nitric oxide concentrations to 0.32+/-0.06 microM (n=25) and 0. 22+/-0.07 microM (n=37) in cats and rats. Sumatriptan appears to decrease the amplitude of nitric oxide release but enhances extracellular superoxide concentrations in both lissencephalic and gyrencephalic cortices during SD." [Abstract]

Bradley DP, Smith MI, Netsiri C, Smith JM, Bockhorst KH, Hall LD, Huang CL, Leslie RA, Parsons AA, James MF.
Diffusion-weighted MRI used to detect in vivo modulation of cortical spreading depression: comparison of sumatriptan and tonabersat.
Exp Neurol. 2001 Dec;172(2):342-53.
"Spreading cortical depolarization and depression of electroencephalographic activity (SD) may underlie the aura and spreading neurovascular events of migraine. Cortical depolarization may also precipitate the progressive development of cerebral pathology following ischemia. However, data on SD in the human brain are sparse, most likely reflecting the technical difficulties involved in performing such clinical studies. We have previously shown that the transient cerebral water disturbances during SD can be quantitatively investigated in the gyrencephalic brain using repetitive diffusion-weighted magnetic resonance imaging (DWI). To investigate whether DWI could detect modulation of the spatiotemporal properties of SD in vivo, the effects of the antimigraine drug sumatriptan (0.3 mg/kg iv) and the novel anticonvulsant tonabersat (10 mg/kg ip) were evaluated in the cat brain. Supporting previous findings, sumatriptan did not affect the numbers of events (range, 4-8), the duration of SD activity (39.8 +/- 4.4 min, mean +/- SEM), and event velocity (2.2 +/- 0.4 mm min(-1)); tonabersat significantly reduced SD event initiation (range, 0-3) and duration (13.2 +/- 5.0 min) and increased primary event velocity (5.4 +/- 0.7 mm min(-1)). However, both drugs significantly decreased, by >50%, the spatial extent of the first KCl-evoked SD event, and sumatriptan significantly increased event propagation across the suprasylvian sulcus (5.5 +/- 0.6 vs 2.4 +/- 0.4 events in controls). These results demonstrate (1) the feasibility of using DWI to evaluate therapeutic effects on SD, and (2) that sumatriptan may directly modulate the spatial distribution of SD activity in the gyrencephalic brain." [Abstract]

Read SJ, Hirst WD, Upton N, Parsons AA.
Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan.
Brain Res. 2001 Feb 9;891(1-2):69-77.
"Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineurs have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have focused on CSD-associated NO release at highly acute time points (min-hours) and have not employed markers of NO metabolism with direct clinical application e.g. cGMP. The current study evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 microg kg(-1) i.v, n=3) or tonabersat (SB-220453 10 mg kg(-1) i.p., n=3), CSD was evoked in anaesthetised rats by a 6-min KCl application to the parietal cortex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, whereas tonabersat significantly reduced the number of events (median=2). No depolarisation events were observed throughout the recording period in the sham group. Following KCl application plasma cGMP concentrations were reduced up to 24 h post-CSD, but not significantly different from sham animals at 3 days. CSD in vehicle-treated animals produced a highly significant elevation in cGMP concentration in the brain stem 3 days after application of KCl. cGMP concentration increased 2.3-fold from 68+/-8 fmol/mg in sham animals (n=3) to 158+/-28 fmol/mg in the vehicle group. This increase in brain stem cGMP was abolished by tonabersat pre-treatment but not by sumatriptan." [Abstract]

Wang M, Urenjak J, Fedele E, Obrenovitch TP.
Effects of phosphodiesterase inhibition on cortical spreading depression and associated changes in extracellular cyclic GMP.
Biochem Pharmacol. 2004 Apr 15;67(8):1619-27.
"Cortical spreading depression (CSD) is a temporary disruption of local ionic homeostasis that propagates slowly across the cerebral cortex, and may contribute to the pathophysiology of stroke and migraine. Previous studies demonstrated that nitric oxide (NO) formation promotes the repolarisation phase of CSD, and this effect may be cyclic GMP (cGMP)-mediated. Here, we have examined how phosphodiesterase (PDE) inhibition, either alone or superimposed on NO synthase (NOS) inhibition, alters CSD and the associated changes in extracellular cGMP. Microdialysis probes incorporating an electrode were implanted into the frontoparietal cortex of anaesthetised rats for quantitative recording of CSD, pharmacological manipulations, and dialysate sampling for cGMP measurements. CSD was induced by cathodal electrical stimulation in the region under study by microdialysis. Extracellular cGMP increased, but only slightly, during CSD. Perfusion of either zaprinast or sildenafil through the microdialysis probe, at concentrations that inhibited both PDE5 and PDE9 (and possibly other PDE), increased significantly extracellular cGMP. Unexpectedly, these levels remained high when NOS was subsequently inhibited with N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME, 1mM). The most interesting pharmacological effect on CSD was obtained with sildenafil. This drug altered neither CSD nor the subsequent characteristic effect of NOS inhibition, i.e. a marked widening of CSD. The fact that NOS inhibition still widened CSD in the presence of the high extracellular levels of cGMP associated with PDE inhibition, suggests that NO may promote CSD recovery, independently of cGMP formation." [Abstract]

Smith MI, Read SJ, Chan WN, Thompson M, Hunter AJ, Upton N, Parsons AA.
Repetitive cortical spreading depression in a gyrencephalic feline brain: inhibition by the novel benzoylamino-benzopyran SB-220453.
Cephalalgia. 2000 Jul;20(6):546-53.
"Transient cortical depolarization is implicated in the pathology of migraine. SB-220453 is a potent anti-convulsant which inhibits neurogenic inflammation and cortical spreading depression (SD)-evoked nitric oxide release via a novel but unknown mechanism. This study further investigates the effects of SB-220453 on generation and propagation of repetitive SD in the anaesthetized cat. Vehicle or SB-220453 1, 3 or 10 mg/kg was administered intraperitoneally 90 min prior to induction of SD in the suprasylvian gyrus (SG). Changes in d.c. potential were recorded in the SG and the adjacent marginal gyrus (MG). In vehicle-treated animals (n = 7), a brief exposure (6 min) to KCl induced a median (25-75% range) number of five (four to six) and three (two to four) depolarizations over a duration of 55 min (32-59 min) and 51 min (34-58 min) in the SG and MG, respectively. SB-220453 produced dose-related inhibition of the number of events and period of repetitive SD activity. SB-220453 also reduced SD-induced repetitive pial vasodilatation but had no effect on resting haemodynamics. However, when SD events were observed in the presence of SB-220453, it had no effect on metabolic coupling. These results show that SB-220453 produces marked inhibition of repetitive SD in the anaesthetized cat. SB-220453 may therefore have therapeutic potential in treatment of SD-like activity in migraine." [Abstract]

Read SJ, Smith MI, Hunter AJ, Upton N, Parsons AA.
SB-220453, a potential novel antimigraine agent, inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat.
Cephalalgia. 2000 Mar;20(2):92-9.
"Profound nitric oxide release associated with cortical spreading depression (SD), has been implicated in stroke, traumatic brain injury and migraine pathophysiology. SB-220453 represents a mechanistically novel, well-tolerated class of compounds which may have therapeutic potential in the treatment of conditions associated with neuronal hyperexcitability and inflammation. The aim of the present study was to investigate the effects of SB-220453 on the nitric oxide (NO) release associated with SD in the anaesthetized cat. In vehicle treated animals, KCl application for 6 min to the cortical suface produced repeated changes in extracellular direct current field potential with associated NO release. This activity was sustained for a median duration of 55 min (25-75% range, 32-59 min) and 59 min (25-75% range, 34-59 min), respectively. SB-220453 (1, 3 and 10 mg/kg i.p.) produced a dose-related inhibition of this activity and at the highest dose tested, the median duration of changes in extracellular field potential and NO release were reduced to 4 min (25-75% range, 4-5 min) and 5 min (25-75% range, 5-5 min), respectively. No effect was observed on basal systemic haemodynamic parameters or resting cerebral laser Doppler blood flux at any of the doses of SB-220453 tested. SB-220453 therefore represents a novel compound to assess the potential benefit of inhibiting SD associated nitric oxide release in neurological disease." [Abstract]

MaassenVanDenBrink A, van den Broek RW, de Vries R, Upton N, Parsons AA, Saxena PR.
The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan.
Cephalalgia. 2000 Jul;20(6):538-45. [Abstract]

Hara H, Shimazawa M, Hashimoto M, Sukamoto T.
[Anti-migraine effects of lomerizine]
Nippon Yakurigaku Zasshi. 1998 Oct;112 Suppl 1:138P-142P.
"Lomerizine, a novel Ca2+ channel blocker, is under development as an anti-migraine drug. We examined the effects on spreading depression (SD) induced by a brief period of hypoxia (40 to 60 sec) in rat hippocampal slices, the cortical hypoperfusion and cortical c-Fos-like immunoreactivity that follow KCl-induced SD in anesthetized rats as compared with those of flunarizine. Extracellular recording was made from the CA1 subfield. The latency of initiated SD was examined. Lomerizine (1 and 10 nM) and flunarizine (1 microM) significantly prolonged the latency in a concentration-dependent manner. After KCl application to the cortex, cerebral blood flow monitored by the laser Doppler flowmetry was approximately 20 to 30% below baseline for at least 60 min. Lomerizine (0.3 and 1 mg/kg, i.v.) and flunarizine (1 and 3 mg/kg, i.v.) administered 5 min before KCl application inhibited the cortical hypoperfusion that followed KCl application. c-Fos-like immunoreactivity, an indicator of neuronal activation, was detected in the ipsilateral, but not in the contralateral frontoparietal cortex 2 hr after KCl application. Lomerizine (3-30 mg/kg, p.o.) and flunarizine (30 mg/kg, p.o.) significantly attenuated the expression of c-Fos-like immunoreactivity in the ipsilateral frontoparietal cortex. Lomerizine was 3 to 1000 times more potent than flunarizine in the above SD models. These findings suggest that the inhibitory effects of lomerizine and flunarizine on the interval between the initiated and subsequent spontaneous SDs, the cortical hypoperfusion and expression of c-Fos-like immunoreactivity induced by SD are mediated via the effects of Ca2+ entry blockade, which may include an increase in cerebral blood flow and the prevention of excessive Ca2+ influx into brain cells." [Abstract]

Kaube H, Goadsby PJ.
Anti-migraine compounds fail to modulate the propagation of cortical spreading depression in the cat.
Eur Neurol. 1994;34(1):30-5.
"Leao's cortical spreading depression (SD) is often cited as the pathophysiological substrate for the neurological symptoms of migraine with aura. If this is the case it might be expected that drugs useful as anti-migraine agents, particularly those useful in prophylaxis, may alter or prevent SD. Indeep it has been suggested that the anti-migraine compound dihydroergotamine (DHE) blocks or reduces the speed of propagation of SD in the rabbit. In this study we attempted to further investigate the effects of DHE and other anti-migraine drugs on SD by measuring cortical blood flow with laser Doppler flowmetry (CBFLDF) and cortical single unit activity in the alpha-chloralose-anaesthetised cat. The following substances were tested: DHE, acetylsalicylic acid, lignocaine, metoprolol, clonazepam and valproate. The NMDA-receptor blocker MK-801 and halothane (1.5%) were used as reference substances that reliably block SD. The outcome measures were speed of propagation of the wave of SD across the cortex and the CBFLDF increase during the hyperaemic phase of SD. Data were taken from three control episodes (60 min apart) and after drug administration. The rate of propagation was significantly reduced from the first control period (3.0 +/- 0.3 mm/min) to the subsequent 2 control observations (2.3 +/- 0.1 mm/min) even without any drug treatment. Following the control observations the test drug was administered and a further SD elicited. This fourth SD was reliably blocked by MK-801 and halothane. None of the other test drugs inhibited SD, reduced the rate of propagation or changed the amplitude of the CBFLDF increase." [Abstract]

Fuentes B, Diez Tejedor E, Pascual J, Coya J, Quirce R.
Cerebral blood flow changes in pseudomigraine with pleocytosis analyzed by single photon emission computed tomography. A spreading depression mechanism?
Cephalalgia. 1998 Oct;18(8):570-3; discussion 531.
"Pseudomigraine with pleocytosis is a benign and autolimited syndrome. The etiology has been related to viral infection, but its pathophysiology is not yet well identified. To investigate this point, and to see if there were changes in cerebral blood flow (as in migraine), we performed single photon emission computed tomography (SPECT) studies in four patients who fulfilled the diagnostic criteria for this syndrome. This was done during the acute phase and we repeated SPECT after resolution of the syndrome in two of them. We found a reduction in brain blood flow on the side of origin of the neurological deficits during the acute phase. This normalized after recovery of the syndrome. The finding suggests that the neurological deficits in this syndrome could be produced by a spreading depression-like mechanism similar to that proposed for migraine with aura." [Abstract]

Leniger T, Von Den Driesch S, Isbruch K, Diener HC, Hufnagel A.
Clinical characteristics of patients with comorbidity of migraine and epilepsy.
Headache. 2003 Jun;43(6):672-7.
"Objective.-Neuronal hyperexcitability might explain the comorbidity of migraine and epilepsy. Spreading depression, a postulated pathophysiological mechanism of epileptic seizures and migraine with aura, may hypothetically be the link between the disorders in these comorbid conditions. The aim of the present study was to determine whether certain clinical characteristics associated with spreading depression are overrepresented in patients with comorbidity. Methods.-In an outpatient clinic-based series, clinical characteristics of 61 patients with a comorbidity of migraine and epilepsy were compared to those of 280 patients with epilepsy alone and 248 patients with migraine alone. Patients were interviewed with a standardized questionnaire. Results.-The proportion of females was significantly higher in patients with comorbidity and patients with migraine as compared to patients with epilepsy (P <.001). Comparing patients with epilepsy and comorbidity, the frequency of epilepsy syndromes and seizure types was not significantly different. Comparing patients with migraine and comorbidity, migraine with aura was significantly more frequent in patients with comorbidity (P =.019). Other migraine features such as moderate to severe pain intensity, worsening of pain on activity, phonophobia, and photophobia were significantly more frequent in patients with comorbidity as compared to patients with migraine (P </=.001). Conclusion.-No specific epileptic characteristics could be found in patients with comorbidity. Altered cerebral excitability resulting in an increased occurrence of spreading depression may explain the differences in migraine attacks in patients with comorbidity as compared to patients with migraine alone." [Abstract]

Kaube H, Limmroth V.
[Animal models and their results in relation to the therapy of migraine]
Schmerz. 1996 Jun 17;10(3):114-20.
"Until now, our understanding of migraine pathophysiology has been fairly incomplete. So far no animal model has allowed an explanation of all facets of the clinically heterogenous condition migraine. However, it is now generally accepted that the migraine headache is due to activation of the trigeminal system. The model of neurogenic inflammation after stimulation of the trigeminal ganglion or systemic administration of capsaicin allows study of the inhibitory interactions between antimigraine compounds and peripheral trigeminal fibre terminals that sustain a sterile meningeal inflammation through release of alogenic and vasoactive neuropeptides, such as substance P and calcitonin gene-related peptide. Studies with the model of superior sagittal sinus stimulation have revealed central actions of antimigraine agents such as ergotamine and sumatriptan, but also acetylsalicylic acid on neurotransmission of trigeminal nociceptive input in the brainstem. A likely explanation for the slowly progressing neurological deficits is cortical spreading depression (CSD), which can easily be elicited in many species. However, CSD has not been observed in vivo in humans. The described models strongly influenced the development of new medications for migraine treatment and have improved our understanding of migraine pathophysiology." [Abstract]

Piper RD, Lambert GA.
Inhalational anesthetics inhibit spreading depression: relevance to migraine.
Cephalalgia. 1996 Apr;16(2):87-92.
"Cortical spreading depression (SD) has not been shown in the human neocortex by direct cortical recordings. However, animal studies suggest that cortical injury, such as that occurring during neurosurgical procedures, should result in the initiation of SD. It is possible that inhibition of SD by volatile anesthetic agents may partially explain the failure to observe SD in the human neocortex during surgery. This study examines the effect of the anesthetic agents alpha-chloralose, halothane, nitrous oxide and isoflurane on the initiation of cortical SD in the cat neocortex. SD was seen in 100% of cats anesthetized with alpha-chloralose (n = 15), in 3 of 7 (42%) animals anesthetized with isoflurane (p < 0.05, chi 2 with Yates correction) and none of the animals (n = 4, 6 hemispheric preparations) anesthetized with halothane (p < 0.005, chi 2 with Yates correction, halothane vs alpha-chloralose group). In all cases this inhibitory effect was reversible. In four animals the administration of nitrous oxide (66%) reduced the inspired concentration of isoflurane required to inhibit SD by 0.75%. This study suggests that halothane, and to a lesser extent isoflurane and nitrous oxide, protect against the initiation of cortical SD. This observation may partially explain why SD has not been demonstrated in human neocortex during surgery. Further studies are needed to determine if SD may occur under pathological conditions, such as during migraine with aura, where the cortex may be predisposed to SD." [Abstract]

Kunkler PE, Kraig RP.
Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents.
Hippocampus. 2003;13(7):835-44. [Abstract]

Koroleva VI, Bures J.
Rats do not experience cortical or hippocampal spreading depression as aversive.
Neurosci Lett. 1993 Jan 12;149(2):153-6.
"Cortical spreading depression (SD) may produce some symptoms of the aura of classical migraine but it is less probable that it can account for the headache. The aversiveness of SD was examined in unanesthetized rats. In Exp. 1, rats with implanted cortical cannulae were confined in the dark compartment of the step-through apparatus and repeated waves of SD were elicited in one hemisphere. After two such training sessions the rats did not evince passive avoidance of the compartment associated with cortical SD. In Exp. 2, thirsty rats with implanted hippocampal electrodes were trained to drink from two different spouts A and B. Hippocampal SD was elicited when the animal was drinking from spout A but not from spout B. Drinking was interrupted shortly after appearance of the SD wave and gradually recovered over the subsequent 10 min, but up to ten spout A-SD pairings did not change the animal's preference for spout A. It is concluded that cortical or hippocampal SD has no immediate or delayed aversive consequences." [Abstract]

George G. Somjen
Mechanisms of Spreading Depression and Hypoxic Spreading Depression-Like Depolarization
Physiol. Rev. 81: 1065-1096, 2001.
Spreading depression (SD) and the related hypoxic SD-like depolarization (HSD) are characterized by rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution of ions between intracellular and extracellular compartments, that evolves as a regenerative, "all-or-none" type process, and propagates slowly as a wave in brain tissue. This article reviews the characteristics of SD and HSD and the main hypotheses that have been proposed to explain them. Both SD and HSD are composites of concurrent processes. Antagonists of N-methyl-D-aspartate (NMDA) channels or voltage-gated Na(+) or certain types of Ca(2+) channels can postpone or mitigate SD or HSD, but it takes a combination of drugs blocking all known major inward currents to effectively prevent HSD. Recent computer simulation confirmed that SD can be produced by positive feedback achieved by increase of extracellular K(+) concentration that activates persistent inward currents which then activate K(+) channels and release more K(+). Any slowly inactivating voltage and/or K(+)-dependent inward current could generate SD-like depolarization, but ordinarily, it is brought about by the cooperative action of the persistent Na(+) current I(Na,P) plus NMDA receptor-controlled current. SD is ignited when the sum of persistent inward currents exceeds persistent outward currents so that total membrane current turns inward. The degree of depolarization is not determined by the number of channels available, but by the feedback that governs the SD process. Short bouts of SD and HSD are well tolerated, but prolonged depolarization results in lasting loss of neuron function. Irreversible damage can, however, be avoided if Ca(2+) influx into neurons is prevented. [Full Text]

Read SJ, Smith MI, Hunter AJ, Parsons AA.
Enhanced nitric oxide release during cortical spreading depression following infusion of glyceryl trinitrate in the anaesthetized cat.
Cephalalgia. 1997 May;17(3):159-65.
"Intravenous infusion of glyceryl trinitrate (GTN) into migraineurs induces an immediate headache followed by migraine. We studied the effect of GTN (0.25 microgram kg-1 min-1) on local cerebrovascular laser Doppler flux (rCBFLDF), artery diameter and NO concentration (selective NO microelectrode) in the pial middle cerebral artery perfusion territory of the anaesthetized cat, at rest and during cortical spreading depression (SD). GTN infusion induced a significant increase in pial artery diameter, rCBFLDF, and NO concentration. Following termination of infusion, NO concentrations remained significantly elevated above controls for 60 min, other parameters returned to baseline within 10 min (p < 0.05, ANOVA, post hoc Dunnett's multiple comparison procedure). Two hours after termination of infusion KCl-evoked SD was initiated. GTN-treated animals exhibited significantly (p < 0.05, Kruskal-Wallis) elevated SD-induced NO release compared to controls. All other parameters remained unaffected. Our results demonstrate that GTN induces a prolonged increase in local NO concentrations and enhances SD-induced NO release." [Abstract]

Christiansen I, Thomsen LL, Daugaard D, Ulrich V, Olesen J.
Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura.
Cephalalgia. 1999 Sep;19(7):660-7; discussion 626.
"Migraine with aura and migraine without aura have the same pain phase, thus indicating that migraine with aura and migraine without aura share a common pathway of nociception. In recent years, increasing evidence has suggested that the messenger molecule nitric oxide (NO) is involved in pain mechanisms of migraine without aura. In order to clarify whether the same is true for migraine with aura, in the present study we examined the headache response to intravenous infusion of glyceryl trinitrate (GTN) (0.5 microg/kg/min for 20 min) in 12 sufferers of migraine with aura. The specific aim was to elucidate whether an aura and/or an attack of migraine without aura could be induced. Fourteen healthy subjects served as controls. Aura symptoms were not elicited in any subject. Headache was more severe in migraineurs than in the controls during and immediately after GTN infusion (p=0.037) as well as during the following 11 h (p = 0.008). In the controls, the GTN-induced headache gradually disappeared, whereas in migraineurs peak headache intensity occurred at a mean time of 240 min post-infusion. At this time the induced headache in 6 of 12 migraineurs fulfilled the diagnostic criteria for migraine without aura of the International Headache Society. The results therefore suggest that NO is involved in the pain mechanisms of migraine with aura. Since cortical spreading depression has been shown to liberate NO in animals, this finding may help our understanding of the coupling between cortical spreading depression and headache in migraine with aura." [Abstract]

Wahl M, Schilling L, Parsons AA, Kaumann A.
Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression.
Brain Res. 1994 Feb 21;637(1-2):204-10.
"The aim of the present study was to examine whether the initial transient arterial dilatation during cortical spreading depression (CSD) was mediated by the release of calcitonin gene-related peptide (CGRP) and/or nitric oxide (NO). This question is of interest as the initial phase of CSD appears to be a model of events occurring during functional hyperemia and during the first period of classic migraine. Using an open cranial window technique, pial arterial diameter in the parietal cortex of cats was recorded with an image splitting method. Employing micropuncture technique, perivascularly applied CGRP8-37 did not alter the resting diameter of pial arteries but antagonized concentration dependently (5 x 10(-9)-10(-6) M) the dilatation (35%) due to 5 x 10(-8) M CGRP. NG-Nitro-L-Arginine (NOLAG, 10(-4) M) also had no effect on resting diameter of pial arteries, indicating that their resting tone is neither mediated by a continuous release of CGRP nor of NO. CSD was triggered by a remote intracortical injection of KCl (150 mM) and recorded by a microelectrode placed adjacent to the artery under investigation. CSD elicited a transient negative DC shift which was accompanied by a peak dilatation of 44 +/- 5.2% (S.E.M.). This dilatation was reduced by approximately 50% during topical application of 10(-7) M CGRP8-37 and 10(-4) M NOLAG each. A 75% inhibition of the CSD-induced dilatation was found during simultaneous application of both compounds. These data indicate that the initial dilatation during CSD is mediated, at least in part, by a release of CGRP and NO." [Abstract]

Piper RD, Edvinsson L, Ekman R, Lambert GA.
Cortical spreading depression does not result in the release of calcitonin gene-related peptide into the external jugular vein of the cat: relevance to human migraine.
Cephalalgia. 1993 Jun;13(3):180-3; discussion 149.
"There is circumstantial evidence that cortical spreading depression (SD) may account for the scotoma and the "spreading cortical oligemia" seen during migraine with aura. It has been shown that calcitonin gene-related peptide (CGRP) is increased in blood taken from the external jugular vein (EJV) in humans during migraine and after stimulation of the trigeminal ganglion. To test the hypothesis that cortical SD may elevate the concentration of this vasoactive peptide in the EJV during migraine, we have measured its concentration in the external jugular vein of cats during cortical SD. This study demonstrates that SD has no effect on the concentration of CGRP either during the passage of a wave of spreading depression across the cortex or, 60 min later, during the period of post-SD cortical oligemia." [Abstract]

Wang M, Obrenovitch TP, Urenjak J.
Effects of the nitric oxide donor, DEA/NO on cortical spreading depression.
Neuropharmacology. 2003 Jun;44(7):949-57.
"Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD." [Abstract]

Fabricius M, Akgoren N, Lauritzen M.
Arginine-nitric oxide pathway and cerebrovascular regulation in cortical spreading depression.
Am J Physiol. 1995 Jul;269(1 Pt 2):H23-9.
"Nerve cells release nitric oxide (NO) in response to activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. We explored the hypothesis that NO influences the changes of cerebral blood flow (CBF) during cortical spreading depression (CSD), which is known to be associated with NMDA receptor activation. CBF was monitored in parietal cortex by laser-Doppler flowmetry in halothane-anesthetized rats. Under control conditions, CSD induced regular changes of CBF, which consisted of four phases: a brief hypoperfusion before the direct current (DC) shift; a marked CBF rise during the DC shift; followed by a smaller, but protracted increase of CBF; and a prolonged CBF reduction (the oligemia). NO synthase inhibition by intravenous and/or topical application of NG-nitro-L-arginine enhanced the brief initial hypoperfusion, but the CBF increases and the oligemia were unchanged. L-Arginine prevented the development of the prolonged oligemia after CSD but had no influence on the marked rise of CBF during CSD. Animals treated with L-arginine recovered the reduced vascular reactivity to hypercapnia after CSD much faster than control rats. Functional denervation of cortical and pial arterioles by tetrodotoxin accentuated the pre-CSD hypoperfusion and the oligemia but did not affect the CBF increases. The results suggest that NO is important for the changes of cerebrovascular regulation following CSD. The observations may have clinical importance, since CBF changes during migraine may be triggered by CSD." [Abstract]

Wolf T, Lindauer U, Obrig H, Dreier J, Back T, Villringer A, Dirnagl U.
Systemic nitric oxide synthase inhibition does not affect brain oxygenation during cortical spreading depression in rats: a noninvasive