Migraine triggers and habituation of visual evoked potentials

Background: Identifying specific subsets of patients within the clinical spectrum of migraine could help in personalizing migraine treatment. Profiling patients by combining clinical characteristics and neurophysiological biomarkers is largely unexplored. We studied the association between migraine attack triggers and habituation of visual evoked potentials. Methods: We personally interviewed 25 patients about their migraine triggers following a structured list, and measured the N1-P1 habituation slope over six blocks of 100 averaged pattern-reversal VEP afterwards. Results: The mean number of triggers per patient was 4.52 1.42. Habituation slopes differed significantly between subjects who reported stress as a migraine trigger (deficient VEP habituation) and subjects who did not (preserved VEP habituation). For the remaining categories, the mean amplitude slope was always positive, indicating deficient habituation, and was not significantly different between subgroups. Conclusions: Migraine patients not reporting perceived stress as a trigger for their attacks might constitute a distinct clinic-physiological subset within the migraine spectrum

Determinants and consequences of abnormal visual cortex responsiveness in migraine without aura

La migraine est une maladie multifactorielle complexe, qui résulte de l'interaction entre une prédisposition génétique et un environnement facilitant. La majeure partie de l' information venant de notre entourage nous atteint via le système visuel, ce qui fait de la vision la modalité sensorielle la plus développée chez l'Homme et celle qui met en jeu les aires cérébrales les plus tendues. Un faisceau de données cliniques et expérimentales a montré que les patients migraineux sont hyper-réactifs à la stimulation visuelle, mais les déterminants de ce phénomène restent méconnus. De plus, bien qu'étroitement associée à la migraine, l‟hyper-réactivité visuelle n'est ni suffisante, ni nécessaire pour développer la, maladie ce qui suggère l'existence de mécanismes physiopathologiques additionnels. Dans cette thèse nous avons analysé des facteurs environnementaux, métaboliques, anatomo-fonctionnels, et neurochimiques liés à la réactivité visuelle chez les migraineux, et la possible implication de leur interaction dans la pathogénie de la maladie. Pour ce faire, nous avons réalisé une série d‟études neurophysiologiques et de neuroimagerie qui explorent des aspects distincts de la physiologie du cerveau. Les résultats montrent que (1) une part de la variabilité interindividuelle de la réactivité visuelle peut être expliquée par des influences environnementales; (2) l‟hyper-réactivité visuelle dans la migraine est le résultat d'un déséquilibre complexe entre les mécanismes qui favorisent une perception renforcée, et ceux qui protègent contre une surcharge sensorielle; (3) la réserve métabolique au niveau cortical est insuffisante face à la demande énergétique accrue due à l'hyper-réactivité visuelle. Ces résultats illustrent la complexité des mécanismes responsables de l'hyperréactivité visuelle dans la migraine, améliorent notre compréhension de la physiopathologie de cette maladie, et ouvrent la voie à des axes de recherche innovants

Métabolisme cérébral distinct en relation avec la sensibilité à la douleur entre sujets sains, migraine épisodique et migraine chronique

Introduction Allodynia, i.e. pain evoked by a non-painful stimulus, is prevalent in chronic pain and in migraine where it augments with disease severity and chronicity [1]. Central sensitization is thought to be the culprit [2]. It is not known, however, which central areas are involved. The aim of the present study was to evaluate whether brain metabolism in subjects that are more sensitive to pain is different between migraine patients and healthy controls. Subjects and methods Quantitative heat sensory testing on the forehead and 18FDG-PET were performed in 55 subjects: 20 healthy volunteers (HV, 21-59 years, 5M), 21 patients with episodic migraine in the interictal phase (MO, age range: 20-63 years, 5M) and 14 patients with chronic migraine (CM, age range: 22-62 years, 1M). The 3 cohorts were subdivided according to the median heat pain threshold into subgroups with low and high pain thresholds. PET results were compared between these subgroups in each cohort. Data analyses were restricted to areas of the pain/salience matrix. Results There was no significant difference in heat pain thresholds between HV (median: 43.7 °C), MO median: 44.2°C) and CM (median: 43.3°C) (p=0.64). In an SPM-ANOVA, a contrast modelling the potential gradual effect of increased differences in pain sensitivity in relation to disease severity showed significant metabolic changes in bilateral thalamus and midbrain (p < 0.001). Additional analyses revealed that hypometabolic areas in subgroups with a low heat pain threshold differed between HV (anterior cingulate and somatosensory cortices), MO (lower pons and somatosensory cortex) and CM (midbrain and thalamus) (Figure 1). Conclusion Overall migraine patients do not have reduced heat pain thresholds. However, hypometabolic areas related to high thermal pain sensitivity are strictly cortical in HV, but comprise the pons in episodic migraine and are restricted to midbrain and thalamus in chronic migraine. The distinct central correlates of heat pain sensitivity in migraine patients might therefore represent a biomarker of migraine and its chronification. Legend to figure Figure 1. Hypometabolic areas in low pain threshold subgroups in HV (green), MO (orange) and CM (red). p < 0.01 for display purpose.Les migraineux ont une sensibilité anormale à la douleur. Les mécanismes cérébraux en sont inconnus. Nous avons comparé le métabolisme cérébral chez des sujets sains et chez des migraineux épisodiques ou chroniques et correlé les résultats avec le seuil douloureux. Les aires cérébrales hypométaboliques liées à un seuil douloureux bas diffèrent entre groupes: régions corticales chez les sujets sains, aires corticales et sous-corticales dans la migraine épisodique, régions sous-corticales dans la migraine chronique .Le contrôle central de la douleur semble modifié distinctement dans les formes de migraine, ce qui pourrait en constituer un biomarqueur et avoir des implications thérapeutiques

Highlights in migraine electrophysiology: are controversies just reflecting disease heterogeneity?

PURPOSE OF REVIEW: In migraine, the brain is 'hyperresponsive', which refers to a deficit of habituation to repeated sensory stimuli between attacks. This deficit normalizes in peri-ictal and ictal phases. A decreased cortical preactivation of thalamo-cortical origin and an impaired intracortical inhibition are probably involved in its pathophysiology. RECENT FINDINGS: The reality of a habituation deficit of visual evoked potentials, a neurophysiological 'hallmark' of interictal migraine, has been questioned. Blinding may be an issue, but some genetic, environmental, or behavioural differences could also exist between populations. A habituation deficit is found interictally in other sensory modalities, and strongly depends on the time of the recordings within the migraine cycle. An impaired thalamocortical drive is demonstrated in interictal phase, and normalizes in ictal phase as well as in chronic migraine, where a strength enhancement of primary cortical activation is observed. An interictal dysexcitability, of subcortical or primary cortical origin, is suggested by magnetic stimulation. These phenomena could occur in varying degrees depending on patients and on the migraine cycle, and account for the heterogeneity of electrophysiological results. SUMMARY: Finding a reliable electrophysiological biomarker for such a multifaceted and cycling disease as migraine is still a challenge. A better standardization of protocols would be worthwhile

METABOLIC CORRELATES OF VISUAL EVOKED POTENTIALS HABITUATION IN MIGRAINEURS AND CONTROLS

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A MACHINE-LEARNING CLASSIFIER FOR EPISODIC MIGRAINE BASED ON VISUAL EVOKED GAMMA BAND ACTIVITY

Introduction: Objective and reliable biomarkers of migraine may be of interest for diagnosis and research purposes. Neuroimaging-based machine-learning classifiers are promising but hampered by availability and cost issues. Conversely, evoked potential are of easy access and affordable. They have provided increasing evidence that sensory information processing is impaired in migraine. We have used gamma band oscillations (GBOs) of visual evoked potentials (VEPs) to compute a machine-learning neural network classifier in episodic migraine. Materials and methods: We analyzed GBOs from VEPs (6x100 responses). Recordings were performed in two matched samples: a training sample composed of 43 migraine patients (EM) and 20 healthy volunteers (HV) and a validating sample of 18 EM and 10 HV. A logistic regression model of the training sample was performed to evaluate the relevance of the predictor variables. Ten neural networks were automatically generated based on late component frequency, n3-p4 and p4-n4 slopes, 1st block n1-p2 amplitude and age. Results: The logistic regression model of the training sample reached a significant classification rate of 79% (EM: 88%; HV: 60%, p¼0.002). The best neural network was able to classify the groups with an accuracy of 73% in the training phase and 89% in the subsequent validation (success rate HV: 90%; EM: 88%). The mean global accuracy within the training and validating samples were 69% (63–78%) and 84% (82–89%). Conclusions: This machine-learning neural network classifier based on visual GBOs provides an accurate and costefficient tool for objective migraine diagnosis. Further training and validation studies with new cohorts are warrante

Brain correlates of single trial visual evoked potentials in migraine: more than meets the eye.

Background: Using conventional visual evoked potentials (VEPs), migraine patients were found to be hyperresponsive to visual stimulus. Considering that a significant portion of neuronal activity is lost for analysis in the averaging process of conventional VEPs, in this study we investigated visual evoked responses of migraine patients and healthy volunteers using a different approach: single trial analysis. This method permits to preserve all stimulus-induced neuronal activations, whether they are synchronized or not. In addition, we used MRI voxel-based morphometry to search for cortical regions where gray matter volume correlated with single trial (st) VEP amplitude. Finally, using resting-state functional MRI, we explored the connectivity between these regions. Results: stVEP amplitude was greater in episodic migraine patients than in healthy volunteers. Moreover, in migraine patients it correlated positively with gray matter volume of several brain areas likely involved in visual processing, mostly belonging to the ventral attention network. Finally, resting state functional connectivity corroborated the existence of functional interactions between these areas and helped delineating their directions. Conclusions: st-VEPs appear to be a reliable measure of cerebral responsiveness to visual stimuli. Mean st-VEP amplitude is higher in episodic migraine patients compared to controls. Visual hyper-responsiveness in migraine involves several functionally-interconnected brain regions, suggesting that it is the result of a complex multi-regional process coupled to stimulus driven attention systems rather than a localized alteration

METABOLIC CHANGES IN THE MIGRAINE BRAIN IN RELATION TO AGEING AND DISEASE LOAD

Introduction: Migraine prevalence tends to decrease with advancing age. Morphological and functional brain changes occuring in migraine could be secondary to repeated attacks and/or to abnormal sensory processing. In normal ageing, brain modifications could traduce a progressive refinement to cope with the environment, associated with a reduction in the complexity of brain connections. We hypothesized that metabolism in various brain regions might be differentially modified by age in migraine patients. Materials and methods: Forty-one subjects underwent a FDG-PET scan: 21 patients with interictal episodic migraine without aura (MO, age range: 20–63 years, 5M) and 20 healthy controls (HV, 21–59 years, 5 M). Results: In MO vs. HV, the overall FDG uptake was reduced in the left visual cortex, left medial frontal gyrus and bilaterally in the insula, somatosensory and motor cortices. Metabolisms of the posterior thalamus, brainstem including the periaqueductal gray (PAG), visual cortex, and (para)hippocampus, strongly increased with age in MO patients but not in HV. Disease duration positively correlated with PAG, (para)hippocampus and rostral anterior cingulate cortex (rACC) metabolisms in MO. Conclusion: Migraine patients, compared to HV, have a decreased resting metabolism in several areas belonging to the ‘‘pain/salience matrix’’, which is in line with previous neuroimaging studies. Metabolism of the rACC is specifically related to disease load whereas metabolism of other sensory processing regions is more affected by age. Whether these functional changes are due to repeated stereotyped attack-related stimulations and to a learning process with complexity reduction of neuronal connections and/or compensatory age-related hyperactivity, remains to be demonstrate