M. Denuelle, MD N. Boulloche, MD P. Payoux, MD, PhD N. Fabre, MD Y. Trotter, PhD G. Géraud, MD

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1 ARTICLES A PET study of photophobia during spontaneous migraine attacks M. Denuelle, MD N. Boulloche, MD P. Payoux, MD, PhD N. Fabre, MD Y. Trotter, PhD G. Géraud, MD Address correspondence and reprint requests to Dr. Marie Denuelle, Service de Neurologie, Hôpital de Rangueil, 1, Avenue Jean Poulhès, TSA 50032, Toulouse Cedex 9, France denuelle.m@chu-toulouse.fr ABSTRACT Background: Photophobia is an abnormal sensitivity to light experienced by migraineurs during attacks. The pathophysiology of photophobia is poorly understood. Nevertheless, 2 facts appear to have a link with photophobia: visual cortex hyperexcitability on the one hand and interactions between visual pathway and trigeminal nociception on the other. Methods: We used H 15 2 O PET to study photophobia induced by continuous luminous stimulation covering the whole visual field in 8 migraineurs during spontaneous migraine attacks, after headache relief by sumatriptan and during attack-free interval. The intensity of the luminous stimulation provoking photophobia with subsequent headache enhancement was specifically determined for each patient. Results: We found that low luminous stimulation (median of 240 Cd/m 2 ) activated the visual cortex during migraine attacks and after headache relief but not during the attack-free interval. The visual cortex activation was statistically stronger during migraine headache than after pain relief. Conclusion: These findings suggest that ictal photophobia is linked with a visual cortex hyperexcitability. The mechanism of this cortical hyperexcitability could not be explained only by trigeminal nociception because it persisted after headache relief. We hypothesize that modulation of cortical excitability during migraine attack could be under brainstem nuclei control. Neurology 2011;76: GLOSSARY ANOVA analysis of variance; IHCD International Classification of Headache Disorders, second edition; IHS International Headache Society; rcbf regional cerebral blood flow. Migraine is a complex disorder of the brain that manifests itself as attacks of throbbing head pain with sensory sensitivity to light, sound, odor, and head movement. Photophobia and phonophobia are included as criteria for migraine diagnosis in the International Headache Society classification. Osmophobia seems also to be specific to migraine. 1,2 The sensory sensitivity developed by migraineurs persists at a lower level between attacks. 3 6 Therefore migraine would be a form of sensory dysmodulation as a result of a system failure of normal sensory processing. 7 The concept of central neuronal hyperexcitability is proposed as a pivotal physiologic disturbance in migraine. 8,9 We chose to study photophobia as a marker of sensory hypersensitivity in migraine using functional imaging by H 2 15 O PET. Photophobia is defined by The International Classification of Headache Disorders, second edition (IHCD) as an hypersensitivity to light, usually causing avoidance. 10 In migraine, this hypersensitivity to light can take 2 forms: an uncomfortable sense of glare between attacks, and an increase of pain on exposure to light during migraine attacks. 3 The aim of this study was to explore photophobia during spontaneous migraine attacks. To do this we applied an increasing luminous stimulation until reaching photophobia Editorial, page 206 e-pub ahead of print on December 9, 2010, at From the Service de Neurologie et Explorations Fonctionnelles du Système Nerveux (M.D., N.B., N.F., G.G.), CHU Rangueil; INSERM U825 (P.P.), Université Paul Sabatier, CHU Purpan; and Centre de Recherche Cerveau et Cognition (Y.T.), UMR 5549-CNRS, Faculté demédecine de Rangueil, Université Paul Sabatier, Toulouse, France. Study funding: Supported by a grant from the Délégation Régionale à la Recherche Clinique des Hôpitaux de Toulouse Disclosure: Author disclosures are provided at the end of the article. Copyright 2011 by AAN Enterprises, Inc. 213

2 and causing headache worsening during migraine attacks. We reproduced the same luminous stimulation during attack-free intervals and after pain relief by sumatriptan. We hypothesize that photophobia during migraine attack is linked with visual cortex hyperexcitability and trigeminal nociception. METHODS Patients. For patient characteristics, see table 1. From 2002 to 2005, we selected 8 patients from the neurology department of the Toulouse Hospital (7 female, 1 male, mean age 36.5 years) with episodic migraine without aura (ICHD-II code 1.1) as defined by International Headache Society (IHS) criteria and systematically complaining of photophobia during the attacks. None of the patients was receiving prophylactic treatment. Other medications included oral contraceptive pills in 5 of the subjects and thyroxin therapy in 1 subject. All patients were studied during a spontaneous, acute migraine attack. They were instructed not to take any triptan or analgesic. A pregnancy test was performed in female subjects of childbearing age before each scan. All patients gave written informed consent for this study, which was approved by the local ethics committee. PET study. Conditions. Patients were scanned during spontaneous migraine headache (within 7 hours after the onset of migraine symptoms), after headache relief following 6 mg sumatriptan SC injection, and during an attack-free interval (15 to 82 days later). To provoke photophobia, we used a luminous stimulation through white semiopaque polyphane goggles covering the whole visual field to avoid any stimulus like movement, shape, color, or contrast, so patients could only see a white diffuse light. A transformer fitted with an ammeter allowed precise tuning of luminance intensity. Calibration of the system was verified using a lux meter (Minolta PS100). Stimulation was continuous and started 20 seconds before the beginning of PET scan acquisition to promote the habituation mechanism. Using a luminous stimulation without spatial or temporal contrast, we expected no activation of the visual cortex. 11,12 During the attack, patients were studied in darkness. Then we gradually increased the luminance intensity until reaching the threshold which provoked a headache increase of 2 points on a scale of 0 to 10 (0 no pain and 10 the most severe pain possible): 6.6 before and 8.6 after luminous stimulation in average. For each patient, we noted this threshold luminance intensity in order to reproduce it after headache relief by sumatriptan and during the headachefree period. Then patients were scanned in 6 conditions with 2 scans for each condition: 1) migraine headache in darkness, 2) migraine headache with luminous stimulation provoking painful photophobia, 3) headache relief in darkness, 4) headache relief with luminous stimulation, 5) attack-free interval in darkness, and 6) attack-free interval with luminous stimulation. The 6 conditions could not be randomized because the luminous intensity provoking painful photophobia needed to be determined during migraine attack. Before each scan, patients were strongly asked to keep their eyes open until the end of acquisition. At the end of each scan, the subjects were asked to rate their headache on a scale of 0 to 10. After sumatriptan injection, pain rate was evaluated every 10 minutes until complete relief (0 at the pain scale). Then scan in condition 3 was realized 10 minutes after pain relief. The time interval between conditions 2 and 3 (the latency of complete headache relief) varied from 20 to 120 minutes. Two patients needed a complementary treatment to obtain total headache relief by 1 g aspirin IV injection for one and 100 mg of ketoprofen IV injection for the other. Patients did not have migraine attacks at least 48 hours before and after the attack-free scans. Image acquisition. Patients had their head immobilized, and head position was aligned transaxially to the orbitomeatal line with a laser beam and controlled before each acquisition. PET measurements were performed with a PET EXACT-HR (CTI-Siemens, Knoxville, TN) that allowed 3-dimensional acquisition of 63 transaxial slices. Spatial resolution was 4.5 mm and 4.1 mm in the transaxial and axial directions, respectively. A venous cannula was inserted to administer tracer, 350 mbq of H 2 15 O, in the left arm. The tracer was infused over 30 seconds. Integrated radioactivity counts were acquired in 3 30-second frames beginning 5 to 15 seconds before the peak of the head curve. The interval between 2 scans for a same condition was 8 Table 1 Patient characteristics (demographics, migraine, and stimuli) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Sex F F F F F M F F Age, y Disease duration, y Attack frequency per month Delay between onset of headache and the beginning of PET h30 2h45 3h50 2h15 3h30 3h50 3h20 2h45 Nausea No No Yes Yes Yes Yes Yes No Photophobia Yes Yes Yes Yes Yes Yes Yes Yes Phonophobia Yes No Yes No Yes Yes Yes Yes Pain intensity in obscurity (scale 0 10) Luminous intensity which provokes pain increase, Cd/m² Pain intensity with luminous stimulation (scale 0 10) Neurology 76 January 18, 2011

3 Table 2 Clinical conditions Activations induced by continuous luminous stimulation during migraine headache, after headache relief, and during attack-free interval a Brain regions Brodmann area MNI coordinates (xyz) Z score Migraine headache Left cuneus Headache relief Attack-free interval Right lingual gyrus Left cuneus No significant activation 18 Abbreviation: MNI Montreal National Institute template. a p false discovery rate corrected 0.05, volume k 50 voxels. Table 3 Migraine headache vs headache relief b Migraine headache vs attack-free interval b Headache relief vs attack-free interval b minutes in order to accommodate the radioactivity decrease. A transmission scan was obtained prior to the collection of emission data for each study to correct for attenuation by tissues. Data analysis. Image analysis was performed using statistical parametric mapping SPM2 (Wellcome Department of Cognitive Neurology, London, UK, implemented on a MATLAB platform (Mathworks, Inc.). Images of each subject were initially realigned according to the reference to the first image in order to correct for motion artifact and then spatially normalized into the stereotaxic Montreal National Institute template. The normalized images were smoothed with a gaussian kernel of 8 mm full width at half maximum to account for intersubject differences in anatomy and allow valid statistical inference as per the Gaussian random field theory. Statistical parametric maps were generated using a repeatedmeasures analysis of variance (ANOVA) model analysis after proportional scaling normalization for global cerebral blood flow changes. We used a threshold with false discovery rate correction of p 0.05 and a cluster extent of k 50 voxels for statistical analysis. To determine the effect of luminous stimulation during migraine headache, after headache relief and during attack-free interval, we compared the luminous stimulation vs darkness for each clinical situation. To compare the effect of luminous stimulation among the 3 clinical situations, second-order analyses were performed for individual subjects using ANOVA (comparison by SPM2 of the first-order individual comparisons). Individual repeatedmeasures ANOVA models were performed for each subject. This allowed the extraction of images of the contrast of activation by luminous stimulation for each subject and in each clinical situation. These images of activation by light in each clinical situation were then compared in a global second-order repeated-measures Comparison of the effect of luminous stimulation in the 3 clinical situations a Brain regions Left lingual gyrus Right cuneus Left lingual gyrus left cuneus Right lingual gyrus right cuneus Right cuneus Right lingual gyrus Left cuneus Brodmann area MNI coordinates (xyz) Z score Abbreviation: MNI Montreal National Institute template. a Second-order analysis within the assumption mask, p uncorrected 0.05, volume k 100 voxels. b Reverse contrast did not induce any significant activation. ANOVA model. Second-order analyses were performed within the mask of the cerebral volume activated by luminous stimulation in the global analysis (8 patients, p uncorrected 0.05, k 10,000 voxels). Significance level for the second-order analysis was p uncorrected 0.05 and volume of activation k 100 voxels. RESULTS The luminous intensity that induces a pain increase during migraine attacks was extremely variable between migraineurs (see table 1): from 50 to 565 Cd/m 2 with median of 240 Cd/m 2. The pain rate did not change between the 2 scans of a same condition in every patient. Using H 2 O 15 TEP, we measured regional cerebral blood flow (rcbf) variation, which is thought to be highly correlated to synaptic activity. 13 Our results are presented in terms of activation when there is an increase of rcbf between 2 conditions. During migraine attacks, luminous stimulation induced activation of the primary visual cortex. After headache relief, the same luminous stimulation also induced activation of the visual cortex although patients did not report any pain or photophobia. With exactly the same luminous stimulation, no cortical activation was found during the attack-free periods as expected by the characteristics of luminous stimulation (table 2). The second-order analysis enabled us to compare the effect of the same continuous luminous stimulation among the 3 clinical situations. Activation induced by light is statistically stronger bilaterally in the visual cortex during migraine headache than after headache relief or during attack-free interval. Activation is also statistically stronger bilaterally in the visual cortex after headache relief than during attackfree interval (table 3 and figure). It appears that the luminous stimulation used in this experiment activates the visual cortex during migraine attacks and not during attack-free intervals. The visual cortex activation observed during migraine attacks was stronger during the headache phase than after headache relief. The reverse comparisons (Are cortical activations by luminous stimulation stronger during attack-free interval than during migraine headache or headache relief, and are they stronger after headache relief than during migraine headache?) are negative. DISCUSSION With a same luminous stimulation, the visual cortex is activated during migraine headaches and after headache relief by sumatriptan but not during attack-free intervals. Thus visual cortex excitability or responsiveness appears to be different during migraine attacks and attack-free intervals. The absence of cortical activation during the attack-free interval is explained by the characteristics of the luminous stimulation (see Methods 11,12 ). Also, cortical response to uniform luminance stimulus has Neurology 76 January 18,

4 Figure Comparison of the effect of luminous stimulation in the 3 clinical situations Second-order analysis within the assumption mask, p uncorrected 0.05, volume k 100 voxels, Z 4. Reverse contrast did not induce any significant activation. been carefully studied in different conditions using fmri. Only peripheral part of area V1 has been reported to be activated due to intraocular scattering of light in luminance flicker situation, but not with constant uniform luminance stimulus. 14 In a previous PET study, the same luminous stimulations with higher intensities (600 and 1,800 Cd/m 2 ) did not induce cortical activation in controls, which is in accordance with the habituation phenomenon, but activated visual cortex in migraineurs during attackfree intervals. 15 The absence of cortical activation during the attack-free interval in our study could be explained by the luminous intensity effect. 15 Low luminous intensity stimulation, less than 300 Cd/m 2 on average, failed to induce visual cortex activation in migraineurs during attack-free periods, probably because this intensity was below the activation threshold. During migraine headache, the luminous stimulation induced visual cortex activation and a clinically painful photophobia with headache worsening. This result could be explained by the interaction between visual and trigeminal nerve pathways, the latter being involved in the migraine headache. Clinical experiments in migraineurs have shown that there is a reciprocal relationship between pain in the ophthalmic territory of the trigeminal nerve and photophobia. 16, This relationship was demonstrated in a previous PET study. 15 In this study, the sequence of scans started with the migraine attack session without randomization between the different phases (migraine attack and attack-free interval). Nevertheless, our results are in agreement with the other PET study in which conditions were randomized. 15 It has been suggested that signals from trigeminal nucleus interact with visual traffic in the thalamus. 18 Recently, it has been demonstrated that neurons in the rat lateral posterior thalamus could be excited by dural stimulation (dependant on trigeminal pathway) and these neurons activity was increased by bright light. Axons from these thalamic neurons project to somatosensory and visual cortices. 19 This circuitry could explain why headache and sensitivity to light increase in a vicious circle during migraine attack. Using electrophysiologic techniques, the most consistent abnormality found in migraineurs between attacks is a deficit of habituation. 20 But within the 12 to 24 hours preceding the attack, the pattern of evoked potentials normalizes The normalization of electrocortical patterns starts in the preictal period, is most pronounced during the attack itself, and takes 1 or 2 days after the attack before evoked potentials become abnormal. 21 Clinically, migraineurs have a lower visual and auditory discomfort threshold compared with healthy subjects and this discomfort threshold decreases even more during attacks. 4,5,24,25 It has been hypothesized that decreased preactivation levels of sensory cortices could be the underlying mechanism of the deficit of habituation between attacks which increases during attack. 26 This could explain why low luminous stimulation did not induce cortical activation between attacks. Then during migraine attack, photophobia would be promoted by increased cortical activity. After pain relief by sumatriptan, patients did not complain of headache or photophobia any more. Nevertheless the luminous stimulation induced in this painfree phase visual cortex activation. This activation was lesser than during the headache phase of the migraine attack but the visual cortex was still hyperresponsive to light after headache relief compared with the attack-free intervals. Even when patients did not report any photophobia after sumatriptan, they could have been more sensitive to light than during attack-free intervals if 216 Neurology 76 January 18, 2011

5 tested with a higher light intensity. According to the literature, photophobia can appear during the premonitory phase of migraine attacks and persist in the postdromal phase. 27 If photophobia is linked to a cortical hyperexcitability, the change in hyperexcitability during migraine attack could be controlled by brainstem nuclei modulation. Indeed, brainstem activation has been demonstrated during migraine attacks but also after headache relief by sumatriptan. 28,29 Moreover, some experiments in animals have demonstrated the influence of brainstem nuclei such as locus coeruleus and raphe dorsal nuclei on the neuronal excitability of sensory cortex via the thalamus Regarding the modulation of visual cortex responsiveness during interictal, ictal, and postictal periods in our study, it appears that 2 systems are candidates for influencing cortical responsiveness: one in relation to the migraine attack including the preictal and postictal periods possibly dependent on brainstem nuclei and the other dependent on trigeminal nociception. This hypothesis may explain why visual cortex hyperresponsiveness is maximal during the migraine headache phase and persists after headache relief by sumatriptan although to a lesser degree. ACKNOWLEDGMENT The authors thank the TEP Centre of Toulouse for participation and motivation and the Clinical Investigation Centre for management of the patients. DISCLOSURE Dr. Denuelle and Dr. Boulloche report no disclosures. Dr. Payoux serves on a scientific advisory board for GE Healthcare. Dr. Fabre and Dr. Trotter report no disclosures. Prof. Géraud serves on a scientific advisory board for MSD France; has received funding for travel and speaker honoraria from MSD France, the Menarini Group, and Astra Zeneca; and serves as a consultant for Allergan, Inc., the Menarini Group, and MSD France. Received March 9, Accepted in final form July 1, REFERENCES 1. Kelman L. Osmophobia and taste abnormality in migraineurs: a tertiary care study. Headache 2004;44: Vingen JV, Sand T, Stovner LJ. Sensitivity to various stimuli in primary headaches: a questionnaire study. Headache 1999;39: Vanagaite J, Pareja JA, Storen O, White LR, Sand T, Stovner LJ. 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6 28. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995;1: Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Hypothalamic activation in spontaneous migraine attacks. Headache 2007;47: Filippov IV, Williams WC, Krebs AA, Pugachev KS. Dynamics of infraslow potentials in the primary auditory cortex: component analysis and contribution of specific thalamic-cortical and non-specific brainstem-cortical influences. Brain Res 2008;1219: Filippov IV, Williams WC, Frolov VA. Very slow potential oscillations in locus coeruleus and dorsal raphe nucleus under different illumination in freely moving rats. Neurosci Lett 2004;363: Devilbiss DM, Page ME, Waterhouse BD. Locus ceruleus regulates sensory encoding by neurons and networks in waking animals. J Neurosci 2006;26: The AAN Provides a New Resource for Your Patients Written by Ronald DeVere, MD, Director of the Taste and Smell Disorders Clinic in Austin, Texas and Marjorie Calvert, Food Consultant at the clinic, Navigating Smell and Taste Disorders includes causes, treatment options, and 36 recipes and additional tips that will make food appealing again. More than 200,000 people visit doctors each year for smell and taste problems, which often are the first sign of neurologic disorders, such as Alzheimer s disease, Parkinson s disease, head injury, or multiple sclerosis, said DeVere. An enlightening guide... this patient-oriented approach should be hailed as a groundbreaking book. It is highly recommended for any patients suffering from these often undiagnosed and untreated disorders and the relatives who help care for them. Alan R. Hirsch, MD, neurological director at the Smell and Taste Treatment and Research Foundation in Chicago Invite your patients to visit for more information about this invaluable resource. Available from all major booksellers. 218 Neurology 76 January 18, 2011