Margarita Sanchez del Rio

Mechanisms of migraine aura revealed by functional MRI in human visual cortex

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.

The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis

&NA; The effect of the N‐methyl‐d‐aspartate (NMDA) receptor antagonist (5R,10S)‐(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine hydrogen maleate (MK‐801) was examined on c‐fos‐like immunoreactivity (c‐fos‐LI) in urethane‐anesthetized Sprague‐Dawley rats using a polyclonal antibody. C‐fos, an indicator of neuronal activation, was assessed within the trigeminal nucleus caudalis (TNC), area postrema, lateral reticular and solitary tract nuclei 2 h after intracisternal injection of capsaicin. C‐fos‐positive cells were counted at three representative levels corresponding to obex, −2.05 mm and −6.45 mm in 18 tissue sections (50 &mgr;m). A weighted average was obtained reflecting total brainstem expression within lamina I, II of TNC using a recently validated method. Capsaicin (0.1, 1, 5, 10 and 15 nmol) caused a dose‐dependent labeling of cells in lamina I, II at obex similar to that previously reported after intracisternal blood or carrageenin administration in rats and guinea pigs. MK‐801 (0.3, 1 and 3 mg/kg) administered i.p. 30 min before capsaicin (5 nmol in 100 &mgr;l artificial CSF) reduced significantly and dose‐dependently (12%, 36% and 47%, respectively) the c‐fos‐LI cells in TNC at each level from rostral to caudal but not in solitary tract, area postrema and lateral reticular nuclei, and for unexplained reasons, increased c‐fos‐LI within the inferior olive. These results suggest that NMDA receptors provide a potential therapeutic target for cephalic pain (e.g. migraine) due to trigeminovascular activation from meningeal afferents.

Functional neuroimaging of headaches

Summary Functional neuroimaging, mainly PET and functional MRI, is the main tool that allows the capturing of neurovascular events during a headache attack. In migraine, functional imaging has clarified the underlying pathophysiology of the visual aura, whereas in migraine without aura, brainstem findings suggest a dysfunctional pain system. In cluster headache, the activation and morphological changes seen in a region posterior and inferior to the hypothalamus has provided a useful therapeutic target using deep-brain stimulation. We will discuss the main neuroimaging findings pertaining to the pathophysiology of these two common headache disorders, migraine and cluster headache.

Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine

In intracranial structures unmyelinated C- and Adelta-fibers of the trigeminal nerve transmit pain stimuli from meninges to the trigeminal nucleus caudalis (Sp5C). Peripheral nerve endings surround meningeal vessels (the so-called trigeminovascular system) and contain vasoactive neuropeptides (calcitonin gene-related peptide, substance P and neurokinin A). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response through the release of neuropeptides by peripheral endings. Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos gene within post-synaptic Sp5C neurons, as a marker of neuronal activity within central nociceptive pathways. In laboratory animals the system is activated by either electrical stimulation of the TG, chemical stimulation of the meninges, electrical or mechanical stimulation of the superior sagittal sinus or by induction of cortical spreading depression. All these techniques induce c-fos within Sp5C and are used as a rodent/feline model of vascular headache in humans. Up-to-date there is evidence that at least ten receptors (5-HT(1B), 5-HT(1D), 5-HT(lF), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors, and opioids mu receptors) modulate c-fos expression within Sp5C. These receptors represent potential targets for anti-migraine drugs as shown by triptans (5-HT(1B/1D/1F)) and ergot alkaloids (5-HT(1A1B/1D/1F)). This review discusses the importance of c-fos expression within Sp5C as a marker of cephalic nociception, the different cephalic pain models that induce c-fos within Sp5C, the receptors involved and their potential role as targets for anti-migraine drugs.

Cessation versus continuation of 6-month migraine preventive therapy with topiramate (PROMPT): a randomised, double-blind, placebo-controlled trial

BACKGROUND Use of preventive therapy for migraine is often recommended for only 6-9 months, but no randomised, placebo-controlled trials have investigated migraine frequency after the end of prophylaxis. We assessed the effects of discontinuation of topiramate after a treatment period of 6 months. METHODS 818 patients who have migraines were enrolled from 88 clinics in 21 countries. After a 4-8-week lead-in period, patients received topiramate in a 26-week open-label phase. Daily dose was increased from 25 mg to 100 mg in steps of 25 mg every week; the dose could be adjusted further in the range 50-200 mg/day, but was stable for the final 4 weeks. Patients were randomly assigned to continue this dose or switch to placebo for a 26-week double-blind phase. The primary endpoint was the difference in number of days with migraine during the last 4 weeks of the double-blind phase compared with the last 4 weeks of the open-label phase. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-000321-29. FINDINGS 559 patients (68.3%) completed the open-label phase; 514 entered the double-blind phase and were assigned to topiramate (n=255) or placebo (n=259). The mean increase in number of migraine days was greater in the placebo group (1.19 days in 4 weeks, 95% CI 0.71 to 1.66; p<0.0001) than in the topiramate group (0.10, -0.36 to 0.56; p=0.5756; mean difference between groups -1.09, -1.75 to -0.43; p=0.0011) [corrected] Patients in the placebo group had a greater number of days on acute medication than did those in the topiramate group (mean difference between groups -0.95, -1.49 to -0.41; p=0.0007). Quality of life, as assessed by the MIDAS questionnaire, fell in the placebo group but remained stable in the topiramate group. Patients were more satisfied with the efficacy of topiramate than with that of placebo, whereas satisfaction with tolerability was similar in both treatment groups. INTERPRETATION Sustained benefit was reported after discontinuation of topiramate, although number of migraine days did increase. These findings suggest that patients should be treated for 6 months, with the option to continue to 12 months in some patients.

Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis.

We examined the effects of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate receptor antagonists 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) and 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzol[f]quinoxaline‐7‐sulphonamide (NBQX), the kainate receptor antagonists γ‐(R‐)‐glutamylaminomethanesulphonic acid (GAMS) and 6,7,8,9‐tetrahydro‐5‐nitro‐1H‐benz[g]indole‐2,3‐dione‐3‐oxime (NS‐102), and the group III metabotropic glutamate receptor (mGluR) agonist 2‐amino‐4‐phosphono‐S‐butanoic acid (L‐AP4) on c‐fos‐like immunoreactivity (c‐fos LI) in trigeminal caudalis (Sp5C), lateral reticular (LRt), medullary reticular (Md) and solitary tract (Sol) nuclei, after intracisternal injection of capsaicin in urethane anaesthetized Sprague‐Dawley rats. Few c‐fos labelled cells were observed within Sp5C in capsaicin‐vehicle treated animals. The number of positive c‐fos cells increased by 17 fold after intracisternal capsaicin (5 nmol) administration. Pretreatment with CNQX (0.02, 0.1, 0.6, 3 and 15 mg kg−1) or NBQX (0.01, 0.1 and 1 mg kg−1), administered intraperitoneally 15 min before capsaicin, significantly reduced labelled cells within Sp5C by a maximum of 45 and 34%, respectively. The number of c‐fos LI cells within LRt, Md and Sol was not affected. Pretreatment with  L‐AP4 (1, 3 and 10 mg kg−1) decreased the number of Sp5C c‐fos LI cells by a maximum of 30%, whereas GAMS (1 and 10 mg kg−1) and NS‐102 (1 and 5 mg kg−1) did not show any significant effect. These results suggest that blockade of AMPA receptors, but not kainate receptors, or the activation of group III mGluRs, decrease the response of Sp5C neurons to trigeminovascular activation. Thus, in addition to NMDA receptors, mGluRs and AMPA receptors may modulate cephalic pain and may provide a potential therapeutic target for antimigraine drugs.

Both 5-HT1B and 5-HT1F receptors modulate c-fos expression within rat trigeminal nucleus caudalis

A possible mechanism of action of antimigraine drugs such as sumatriptan is inhibition of the trigeminovascular pathway. Sumatriptans effects might be mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors. To establish the relative importance of these subtypes, we compared the effects of sumatriptan with those of a selective 5-HT1F receptor agonist (LY 344864) on c-fos protein expression in the trigeminal nucleus caudalis. c-fos expression was induced in urethane-anaesthetized rats by intracisternal capsaicin administration. Sumatriptan and LY 344864 decreased the number of capsaicin-induced c-fos-like immunoreactive cells within trigeminal nucleus caudalis (ID50 = 0.04 and 0.6 mg kg(-1)). The effect of sumatriptan, but not of LY 344864, was prevented by pretreatment with the antagonist SDZ 21-009, which displays high affinity for rat 5-HT1B receptors. LY 344864 appears to attenuate c-fos-like immunoreactivity via 5-HT1F receptors, while sumatriptan acts via 5-HT1B receptors. The fact that activation of 5-HT1F receptors is sufficient to modulate the activity of the trigeminal system suggests that this receptor may be a target for antimigraine drugs with improved safety profile.

High Altitude Headache

There is little known about high altitude headache, except that it is an important and serious problem that often heralds the onset of acute mountain sickness. We do know that the brain itself is an insensate organ except for its meninges which contain sensory axons projecting from the trigeminal nerve. These nerve fibers travel in proximity to meningeal blood vessels and constitute an important component of the trigeminovascular system. Signals generated at high altitude which may activate the trigeminovascular system can arise from brain, blood or the blood vessel wall, include protons, neurotransmitters and other potential noxious agents which can discharge or sensitize small unmyelinated fibers. Brain edema and raised intracranial pressure may cause headache by compressing brain structures leading to displacement and stretching of the pain-sensitive intracranial structures. Small hemorrhage may irritate and discharge these fibers chemically. Furthermore, high altitude seems capable of decreasing the threshold of response to sensory stimulation. Therefore, headache can be attributed to activation of a common pathway, the trigeminovascular system by both chemical or mechanical stimulation.

Photoreactivity of the Occipital Cortex Measured by Functional Magnetic Resonance Imaging–Blood Oxygenation Level Dependent in Migraine Patients and Healthy Volunteers: Pathophysiological Implications

Background.— The brain of migraineurs is hyperexcitable, particularly the occipital cortex, which is probably hypersensitive to light. Photophobia or hypersensitivity to light may be accounted for by an increased excitability of trigeminal, the visual pathways, and the occipital cortex.

Attenuation by butalbital of capsaicin-induced C-fos-like immunoreactivity in trigeminal nucleus caudalis

We examined the effects of butalbital (30, 100, and 1000 μg/kg) on the number of cells expressing c‐fos—like immunoreactivity (c‐fos—LI), a marker of neuronal activation, within lamina I, II0 of the trigeminal nucleus caudalis and the nucleus of the solitary tract 2 hours after the intracisternal injection of capsaicin (0.1 mL; 15.25 mg/mL) or vehicle in urethane‐anesthetized guinea pigs (N=45). Robust c‐fos—LI was observed within nuclei of cells in the trigeminal nucleus caudalis after capsaicin (329 ± 35). Butalbital dose‐dependently reduced the number of labeled cells to a maximum of 66% (1000 μg/kg intraperitoneally [IP], P<.01) in lamina I, II0 but not within area postrema, medial reticular nucleus, or the nucleus of the solitary tract. Pretreatment with bicuculline (30 μg/kg IP) blocked the effect of butalbital, thereby suggesting the importance of the GABAA receptor to activation involved in the transmission of nociceptive information. Our studies suggest the possibility that GABAA, receptors might provide an important therapeutic target in migraine and related headache disorders.