Spontaneous Migraine Attacks Research Articles

Decrement of choroid vascularization during spontaneous migraine attacks: An optical coherence tomography angiography study.

This study aimed to analyze the microcirculation of the macula, the optic nerve, and the choroid in patients with migraine by optical coherence tomography angiography (OCTA) during spontaneous migraine attacks, comparing the findings with scans performed in the interictal period in the same subjects and healthy controls (HCs). In this case-crossover design study, patients diagnosed with migraine who underwent an OCTA during a migraine attack were enrolled. A cohort of HCs was recruited for comparison. Data from ocular and orthotic examinations and clinical and demographical information were collected. All subjects were imaged with Solix full range OCT, recording the following parameters: macular vessel density (VD), inside disc VD, peripapillary VD, disc whole image VD, fovea choriocapillaris VD, fovea VD, parafovea VD, peripapillary thickness, fovea thickness, parafovea thickness, macular full retinal thickness, and foveal avascular zone (FAZ). Thirteen patients (26 eyes individually assessed) with a diagnosis of migraine were included (9 without aura [69.2%] and 4 with aura [30.7%], with a mean age of 25.2 ± 3.4 years) and scanned during the ictal and interictal phase. Fifteen age-matched HCs (30 eyes individually assessed) were included. The foveal choriocapillaris VD was significantly lower in the ictal phase (63.3 ± 2.47%) compared to the interictal phase in the same patients (64.9 ± 2.79%) (p = 0.0019). Comparing the ictal scans from migraine patients and HCs, the FAZ area was significantly larger, and the inside disc, fovea, and fovea choriocapillaris VDs were significantly lower. The study demonstrated a dynamic decrement in choroidal vascularization in migraine patients during spontaneous migraine attacks.

Cycling sensitivity across migraine phases: A longitudinal case-control study.

Functional neuroimaging studies indicate that central transmission of trigeminal pain may commence up to 48 h prior to the onset of headache. Whether these cyclic changes are associated with somatosensory alteration remains incompletely understood. The present study aimed to investigate the temporal progression of somatosensory alterations preceding the onset of a migraine attack. Patients with menstrually related migraine (n = 10) and matched healthy controls (n = 13) underwent consecutive daily quantitative sensory tests, commencing 6 days prior to the expected onset of the migraine attack and menstruation. Each subject was investigated for 7-11 consecutive days, resulting in 85 and 91 days of experimentation for the respective cohorts. Electrical/heat/cold pain thresholds showed a phase-dependent decline towards the spontaneous migraine attack, which had commenced 48 h prior to the onset of the headache. The pain thresholds further declined towards the ictal phase, with only the electrical pain threshold reaching statistical significance (ictal vs. preictal). In healthy controls, the pain thresholds remained stable and unaltered during the consecutive daily measurements. In an exploratory analysis, the pain thresholds at baseline (interictal phase) were comparable between both cohorts. The data suggest the existence of a trigeminal somatosensory alteration in the preictal phase of migraine, occurring up to 48 h prior to the onset of the headache. This change occurred in a chronologically synchronous manner with the brain activation in the preictal phase in functional neuroimaging studies. It will be important to combine pain threshold measurement and functional neuroimaging in future studies. Our data suggest the existence of a somatosensory behavioural correlate of the functional neuroimaging changes starting 48 h before the onset of headache. Despite the concurrence of the behavioural and functional neuroimaging changes in a chronological sequence, the next step in elucidating the cause of migraine is to combine the behavioural and functional neuroimaging changes in a temporal sequence, i.e. to identify the generator behind the cyclic sensory fluctuation.

Preserved working memory performance along with subcortical modulation during peri-ictal phases in spontaneous migraine attacks.

To analyze cognitive performance and brain activation during a working memory task in patients with migraine during various phases of the migraine cycle and compare to healthy participants. Cognitive difficulties reported during migraine attacks remain poorly understood, despite evidence that the lateral frontoparietal network undergoes reversible disturbances and decreased activation during attacks. Recent findings in resting state functional magnetic resonance imaging suggest that brain areas involved in this network interact with subcortical regions during spontaneous migraine attacks. In this prospective, within-subject study, 10 patients with diagnosed menstrual-related episodic migraine without aura underwent 3T functional magnetic resonance imaging assessments while performing a working memory task across four phases of the natural migraine cycle: peri-ictal (preictal, ictal, postictal) phases and interictally (between attacks). Migraine prophylaxis was an exclusion criterion. Fourteen healthy controls were assessed during the corresponding phases of their menstrual cycles. The protocol was completed by 24 female participants aged 21 to 47 years: 10 with migraine (four sessions each) and 14 healthy controls (two sessions each) yielding a total of 68 analyzed datasets. Patients and controls showed similar performance on the working memory task and displayed increased brain activity in regions linked to this function, namely the middle frontal gyrus, inferior parietal lobe, and anterior cingulate cortex, during all phases of the migraine/menstrual cycle. Patients with migraine (N = 10) exhibited a significant decrease in hypothalamic activity (p = 0.007) as measured by the percent signal change (PSC) during the postictal phase compared to perimenstrual controls (N = 14), with -2 (16) and 31 (35) PSC, respectively. Comparing across the migraine cycle, the change in hypothalamic activity relative to controls in the postictal phase -0.33 (0.2) ΔPSC was significantly different from the ones in the interictal (0.006 [0.5] ΔPSC; p = 0.002) and preictal (-0.08 [0.4] ΔPSC; p = 0.034) phases. During a working memory task, cognition-related brain activation was present across all phases of the migraine cycle similarly to healthy control participants. Patients with migraine, however, displayed lower neural activity at the subcortical level in the postictal phase. Nonetheless, the sample size is a limitation for the generalization of our results. More research is needed to fully understand how the brain copes with cognitive demands during spontaneous migraine attacks.

Mechanisms of GTN-induced migraine: Role of NOS isoforms, sGC and peroxynitrite in a migraine relevant mouse model.

Migraine research has highlighted the pivotal role of nitric oxide (NO) in migraine pathophysiology. Nitric oxide donors such as glyceryl trinitrate (GTN) induce migraine attacks in humans, whereas spontaneous migraine attacks can be aborted by inhibiting NO production. The present study aimed to investigate how GTN triggers migraine through its three nitric oxide synthase (NOS) isoforms (neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)) via a suspected feed-forward phenomenon. Migraine-relevant hypersensitivity was induced by repeated injection of GTN in an in vivo mouse model. Cutaneous tactile sensitivity was assessed using von Frey filaments. Signaling pathways involved in this model were dissected using non-selective and selective NOS inhibitors, knockout mice lacking eNOS or nNOS and their wild-type control mice. Also, we tested a soluble guanylate cyclase inhibitor and a peroxynitrite decomposition catalyst (Ntotal = 312). Non-selective NOS inhibition blocked GTN-induced hypersensitivity. This response was partially associated with iNOS, and potentially nNOS and eNOS conjointly. Furthermore, we found that the GTN response was largely dependent on the generation of peroxynitrite and partly soluble guanylate cyclase. Migraine-relevant hypersensitivity induced by GTN is mediated by a possible feed-forward phenomenon of NO driven mainly by iNOS but with contributions from other isoforms. The involvement of peroxynitrite adds to the notion that oxidative stress reactions are also involved.

Working memory during spontaneous migraine attacks: an fMRI study

ObjectiveTo investigate the neural correlates of working memory during a spontaneous migraine attack compared to the interictal phase, using functional magnetic resonance imaging (fMRI).BackgroundCognitive disturbances are commonly observed during migraine attacks, particularly in the headache phase. However, the neural basis of these changes remains unknown.MethodsIn a fMRI within-subject test-retest design study, eleven women (32 years of age, average) with episodic migraine were evaluated twice, first during a spontaneous migraine attack, and again in a pain-free period. Each session consisted in a cognitive assessment and fMRI while performing a working memory task (N-back).ResultsCognitive test scores were lower during the ictal session than in the pain-free session. Regions typically associated with working memory were activated during the N-back task in both sessions. A voxel wise between session comparison showed significantly greater activation in the left frontal pole and orbitofrontal cortex during the attack relative to the interictal phase.ConclusionMigraine patients exhibited greater activation of the left frontal pole and orbitofrontal cortex while executing a verbal working memory task during a spontaneous migraine attack when compared to the interictal state. Given the association of these regions with pain processing and inhibitory control, these findings suggest that patients recruit inhibitory areas to accomplish the cognitive task during migraine attacks, a neural signature of their cognitive difficulties.

Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms

Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e. serotonin receptor agonists. However, triptans are effective in ~ 60% of the population, and the mechanisms of triptans are debated. Here, we aim to expose the mechanisms of triptan using metabolomics and transcriptomics in spontaneous migraine attacks. We collected temporal multi-omics profiles on 24 migraine patients, using samples collected at a migraine attack, 2 h after treatment with a triptan, when headache-free, and after a cold-pressor test. Differential metabolomic analysis was performed to find metabolites associated with treatment. Their effect was further investigated using correlation analysis and a machine learning approach. We found three differential metabolites: cortisol, sumatriptan and glutamine. The change in sumatriptan levels correlated with a change in GNAI1 and VIPR2 gene expression, both known to regulate cAMP levels. Furthermore, we found fatty acid oxidation to be affected, a mechanism known to be involved in migraine but not previously found in relation to triptans. In conclusion, using an integrative approach we find evidence for a role of glutamine, cAMP regulation, and fatty acid oxidation in the molecular mechanisms of migraine and/or the effect of triptans.

Altered functional connectivity in a sensorimotor-insular network during spontaneous migraine attacks: A resting-state FMRI study

BackgroundPrevious functional magnetic resonance imaging studies have identified brain-connectivity alterations across multiple regions in people with migraine when compared to healthy controls. Few studies have focused on such changes throughout the different phases of the migraine cycle. We aimed to investigate functional connectivity during spontaneous occurring episodic migraine attacks, in comparison to interictal periods. MethodsEleven women with episodic migraine without aura underwent two sessions of resting-state fMRI, during and outside of a spontaneous migraine attack. Functional connectivity changes were assessed across canonical resting-state networks, identified by independent component analysis. Significantly altered connectivity was correlated with migraine attack symptoms. ResultsDecreased functional connectivity between subregions of the sensorimotor network (specifically, the primary somatosensory and motor cortices) and the posterior insula, bilaterally, was found during attacks. In both sessions, the functional connectivity between these regions was lower in patients who usually suffered longer attacks. DiscussionThe sensorimotor and insular regions are involved in nociceptive, autonomic, and somatosensory processing so the finding of reduced connectivity between these structures within a migraine attack is likely associated to the perception of pain and the heighten sensitivity to stimuli experienced in this disorder.

A Hypothalamic Mechanism Regulates the Duration of a Migraine Attack: Insights from Microstructural and Temporal Complexity of Cortical Functional Networks Analysis.

The role of the hypothalamus and the limbic system at the onset of a migraine attack has recently received significant interest. We analyzed diffusion tensor imaging (DTI) parameters of the entire hypothalamus and its subregions in 15 patients during a spontaneous migraine attack and in 20 control subjects. We also estimated the non-linear measure resting-state functional MRI BOLD signal's complexity using Higuchi fractal dimension (FD) and correlated DTI/fMRI findings with patients' clinical characteristics. In comparison with healthy controls, patients had significantly altered diffusivity metrics within the hypothalamus, mainly in posterior ROIs, and higher FD values in the salience network (SN). We observed a positive correlation of the hypothalamic axial diffusivity with migraine severity and FD of SN. DTI metrics of bilateral anterior hypothalamus positively correlated with the mean attack duration. Our results show plastic structural changes in the hypothalamus related to the attacks severity and the functional connectivity of the SN involved in the multidimensional neurocognitive processing of pain. Plastic changes to the hypothalamus may play a role in modulating the duration of the attack.

Investigation of cortical thickness and volume during spontaneous attacks of migraine without aura: a 3-Tesla MRI study

BackgroundStructural imaging has revealed changes in cortical thickness in migraine patients compared to healthy controls is reported, but presence of dynamic cortical and subcortical changes during migraine attack versus inter-ictal phase is unknown. The aim of the present study was to investigate possible changes in cortical thickness during spontaneous migraine attacks. We hypothesized that pain-related cortical area would be affected during the attack compared to an inter-ictal phase.MethodsTwenty-five patients with migraine without aura underwent three-dimensional T1-weighted imaging on a 3-Tesla MRI scanner during spontaneous and untreated migraine attacks. Subsequently, 20 patients were scanned in the inter-ictal phase, while 5 patients did not show up for the inter-ictal scan. Four patients were excluded from the analysis because of bilateral migraine pain and another one patient was excluded due to technical error in the imaging. Longitudinal image processing was done using FreeSurfer. Repeated measures ANOVA was used for statistical analysis and to control for multiple comparison the level of significance was set at p = 0.025.ResultsIn a total of 15 patients, we found reduced cortical thickness of the precentral (p = 0.023), pericalcarine (p = 0.024), and temporal pole (p = 0.017) cortices during the attack compared to the inter-ictal phase. Cortical volume was reduced in prefrontal (p = 0.018) and pericalcarine (p = 0.017) cortices. Hippocampus volume was increased during attack (p = 0.007). We found no correlations between the pain side or any other clinical parameters and the reduced cortical size.ConclusionSpontaneous migraine attacks are accompanied by transient reduced cortical thickness and volume in pain-related areas. The findings constitute a fingerprint of acute pain in migraine patients, which can be used as a possible biomarker to predict antimigraine treatment effect in future studies.Trial registrationThe study was registered at ClinicalTrials.gov (NCT02202486).

Hypothalamic functional MRI activity in the initiation phase of spontaneous and glyceryl trinitrate-induced migraine attacks.

The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl‐trinitrate (GTN)‐induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level‐dependent (BOLD) response to oral glucose ingestion with 3T‐functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN‐triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between‐ and within‐group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose‐induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD‐response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN‐provoked and spontaneous migraine attacks.

Protein kinase Cδ as a neuronal mechanism for headache in a chronic intermittent nitroglycerin model of migraine in mice.

Migraine is one of the most common neurological disorders characterized by recurrent attacks of typically throbbing and unilateral headaches, affecting up to 20% of the population worldwide. Despite the high prevalence and severity of this primary headache disorder, it remains to be a challenge to fully understand and treat migraine headaches. By characterizing and validating a mouse migraine model, this study aimed to investigate the functional contribution of protein kinase C (PKC) isoforms in migraine. In this study, we identified the presence of migraine-like ongoing pain in mice after chronic intermittent treatment with nitroglycerin (NTG). The peptide antagonist of calcitonin gene-related peptide α-CGRP (8-37), but not topiramate nor sumatriptan, effectively blocked ongoing pain and elicited pain relief-induced conditioned place preference in NTG-treated mice. Prominent activation of PKCδ was observed in chronic NTG-treated mice. Functional inhibition of PKCδ significantly attenuated ongoing spontaneous pain in chronic NTG-treated mice. Furthermore, we recapitulated the NTG-triggered migraine behavior in wild-type mice, but not in PKCδ-null mice. In response to repeated administration of NTG, ongoing spontaneous pain was not developed in mice lacking the specific PKC isoform. This study identified the presence of ongoing pain in mice treated with NTG, a known human migraine trigger that closely resembles the common manifestation of spontaneous migraine attacks in humans. These findings demonstrated a critical regulatory role of PKCδ in migraine pathophysiology, which may offer new pharmacological targets for antimigraine treatment.

Changes in the gene expression profile during spontaneous migraine attacks

Migraine attacks are delimited, allowing investigation of changes during and outside attack. Gene expression fluctuates according to environmental and endogenous events and therefore, we hypothesized that changes in RNA expression during and outside a spontaneous migraine attack exist which are specific to migraine. Twenty-seven migraine patients were assessed during a spontaneous migraine attack, including headache characteristics and treatment effect. Blood samples were taken during attack, two hours after treatment, on a headache-free day and after a cold pressor test. RNA-Sequencing, genotyping, and steroid profiling were performed. RNA-Sequences were analyzed at gene level (differential expression analysis) and at network level, and genomic and transcriptomic data were integrated. We found 29 differentially expressed genes between ‘attack’ and ‘after treatment’, after subtracting non-migraine specific genes, that were functioning in fatty acid oxidation, signaling pathways and immune-related pathways. Network analysis revealed mechanisms affected by changes in gene interactions, e.g. ‘ion transmembrane transport’. Integration of genomic and transcriptomic data revealed pathways related to sumatriptan treatment, i.e. ‘5HT1 type receptor mediated signaling pathway’. In conclusion, we uniquely investigated intra-individual changes in gene expression during a migraine attack. We revealed both genes and pathways potentially involved in the pathophysiology of migraine and/or migraine treatment.

Headache and non-headache symptoms provoked by nitroglycerin in migraineurs: A human pharmacological triggering study.

BackgroundStudying a spontaneous migraine attack is challenging, particularly the earliest components. Nitroglycerin is a potent, reliable and reproducible migraine trigger of the entirety of the migraine attack, making its use experimentally attractive.MethodsFifty-three subjects with migraine with a history of spontaneous premonitory symptoms were exposed to a 0.5 mcg/kg/min nitroglycerin infusion. Eighty-three percent (n = 44) developed typical premonitory and headache symptomatology. Fifty-seven percent (n = 25) were invited back to further study visits, during which they were re-exposed to nitroglycerin or placebo infusion in a double-blind randomised design. The phenotype of premonitory symptoms and headache was captured and compared to spontaneous attacks and between triggered attacks using agreement analysis.ResultsMore premonitory symptoms were triggered with nitroglycerin than placebo (mean symptom difference = 4, t20 = 7.06, p < 0.001). The agreement in triggering for the most commonly reported premonitory symptoms (concentration difficulty and tiredness) was >66%. The retriggering agreement for all but one premonitory symptom was >60%. The agreement in timing to onset of premonitory symptoms was reliable across two triggered attacks. The agreement with spontaneous attacks and between attacks for headache and its associated symptoms, including laterality, was less reliable.ConclusionsNitroglycerin can reliably and reproducibly provoke premonitory symptomatology associated with migraine. This forms an ideal model to study the earliest manifestations of migraine attacks.

PAC1 receptor blockade reduces central nociceptive activity: new approach for primary headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.

Longitudinal Neuroimaging over 30 Days: Temporal Characteristics of Migraine.

Although migraine is defined by the headache and headache-associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well-described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well-established paradigm for functional MRI of trigeminal nociception. Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646-651.

Plasma Glucose Levels Increase During Spontaneous Attacks of Migraine With and Without Aura.

To investigate plasma glucose changes during the ictal state of migraine compared to the interictal state. Previous studies suggest abnormal glucose metabolism in migraine patients during and outside of attacks. It is not known if plasma glucose levels change during spontaneous migraine attacks. Plasma glucose levels were measured during and outside of spontaneous migraine attacks with and without aura. Plasma glucose values were corrected for diurnal variation of plasma glucose by subtracting the difference between the moving average (intervals of 2 hours) and overall mean from the plasma glucose values. This was a sub-study of a larger study conducted at Rigshospitalet Glostrup in the Capital Region of Denmark. Thirty-one patients (24 F, 7 M, 13 with aura, 18 without aura) were included in the study. Mean time from attack onset to blood sampling was 7.6hours. Mean pain at the time of investigation was 6 on a 0-10 verbal rating scale. Plasma glucose was higher ictally compared to the interictal phase (interictal mean: 88.63mg/dL, SD 11.70mg/dL; ictal mean: 98.83mg/dL, SD 13.16mg/dL, difference 10.20mg/dL, 95% CI=[4.30; 16.10]), P=.0014). The ictal increase was highest in patients investigated early during attacks and decreased linearly with time from onset of migraine (-1.57mg/dL/hour from onset of attack, P=.020). The attack-related increase in blood glucose was not affected by pain intensity or presence of aura symptoms. We demonstrated higher plasma glucose values during spontaneous migraine attacks, independent of the presence of aura symptoms and not related to pain intensity, peaking in the early phase of attacks. Additional studies are necessary to confirm our findings and explore the possible underlying mechanisms.

Impaired functional connectivity of limbic system in migraine without aura.

Aberrant functional connectivity of brain networks has been demonstrated in migraine sufferers. Functional magnetic resonance imaging (fMRI) may illustrate altered connectivity in patients suffering from migraine without aura (MwoA). Here, we applied a seed-based approach based on limbic regions to investigate disrupted functional connectivity between spontaneous migraine attacks. Resting-state fMRI data were obtained from 28 migraine patients without aura and 23 well-matched healthy controls (HC). The functional connectivity of the limbic system was characterized using a seed-based whole-brain correlation method. The resulting functional connectivity measurements were assessed for correlations with other clinical features. Neuropsychological data revealed significantly increased connectivity between the limbic system (bilateral amygdala and right hippocampus) and left middle occipital gyrus (MOG), and a positive correlation was revealed between disease duration and connective intensity of the left amygdala and the ipsilateral MOG. There was decreased functional connectivity between the right amygdala and contralateral orbitofrontal cortex (OFC). In addition, resting-state fMRI showed that, compared to HC, patients without aura had significant functional connectivity consolidation between the bilateral hippocampus and cerebellum, and a negative correlation was detected between scores on the headache impact test (HIT) and connectivity intensity of the right hippocampus and bilateral cerebellum. There was decreased functional connectivity between the left hippocampus and three brain areas, encompassing the bilateral inferior parietal gyri (IPG) and contralateral supplementary motor area (SMA). There were no structural differences between the two groups. Our data suggest that migraine patients have disrupted limbic functional connectivity to pain-related regions of the modulatory and encoding cortices, which are associated with specific clinical characteristics. Disturbances of resting-state functional connectivity may play a key role in neuropathological features, perception and affection of migraine. The current study provides further insights into the complex scenario of migraine mechanisms. .

Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity.

Cranial allodynia associated with spontaneous migraine is reported as either responsive to triptan treatment or to be predictive of lack of triptan efficacy. These conflicting results suggest that a single mechanism mediating the underlying neurophysiology of migraine symptoms is unlikely. The lack of a translational approach to study cranial allodynia reported in migraine patients is a limitation in dissecting potential mechanisms. Our objective was to study triptan-responsive cranial allodynia in migraine patients, and to develop an approach to studying its neural basis in the laboratory. Using nitroglycerine to trigger migraine attacks, we investigated whether cranial allodynia could be triggered experimentally, observing its response to treatment. Preclinically, we examined the cephalic response properties of central trigeminocervical neurons using extracellular recording techniques, determining changes to ongoing firing and somatosensory cranial-evoked sensitivity, in response to nitroglycerine followed by triptan treatment. Cranial allodynia was triggered alongside migraine-like headache in nearly half of subjects. Those who reported cranial allodynia accompanying their spontaneous migraine attacks were significantly more likely to have symptoms triggered than those that did not. Patients responded to treatment with aspirin or sumatriptan. Preclinically, nitroglycerine caused an increase in ongoing firing and hypersensitivity to intracranial-dural and extracranial-cutaneous (noxious and innocuous) somatosensory stimulation, reflecting signatures of central sensitization potentially mediating throbbing headache and cranial allodynia. These responses were aborted by a triptan. These data suggest that nitroglycerine can be used as an effective and reliable method to trigger cranial allodynia in subjects during evoked migraine, and the symptom is responsive to abortive triptan treatments. Preclinically, nitroglycerine activates the underlying neural mechanism of cephalic migraine symptoms, central sensitization, also predicting the clinical outcome to triptans. This supports a biological rationale that several mechanisms can mediate the underlying neurophysiology of migraine symptoms, with nitrergic-induced changes reflecting one that is relevant to spontaneous migraine in many migraineurs, whose symptoms of cranial allodynia are responsive to triptan treatment. This approach translates directly to responses in animals and is therefore a relevant platform to study migraine pathophysiology, and for use in migraine drug discovery.

Altered thalamic connectivity during spontaneous attacks of migraine without aura: A resting-state fMRI study.

Background Functional connectivity of brain networks may be altered in migraine without aura patients. Functional magnetic resonance imaging (fMRI) studies have demonstrated changed activity in the thalamus, pons and cerebellum in migraineurs. Here, we investigated the thalamic, pontine and cerebellar network connectivity during spontaneous migraine attacks. Methods Seventeen patients with episodic migraine without aura underwent resting-state fMRI scan during and outside of a spontaneous migraine attack. Primary endpoint was a difference in functional connectivity between the attack and the headache-free days. Functional connectivity was assessed in four different networks using seed-based analysis. The chosen seeds were in the thalamus (MNI coordinates x,y,z: right, 22,-24,0 and left, -22,-28,6), pons (right, 8,-24,-32 and left, -8,-24,-32), cerebellum crus I (right, 46,-58,-30 and left, -46,-58,-30) and cerebellum lobule VI (right, 34,-42,-36 and left, -32,-42,-36). Results We found increased functional connectivity between the right thalamus and several contralateral brain regions (superior parietal lobule, insular cortex, primary motor cortex, supplementary motor area and orbitofrontal cortex). There was decreased functional connectivity between the right thalamus and three ipsilateral brain areas (primary somatosensory cortex and premotor cortex). We found no change in functional connectivity in the pontine or the cerebellar networks. Conclusions The study indicates that network connectivity between thalamus and pain modulating as well as pain encoding cortical areas are affected during spontaneous migraine attacks.

Intact blood−brain barrier during spontaneous attacks of migraine without aura: a 3T DCE‐MRI study

The integrity of the blood-brain barrier (BBB) has been questioned in migraine, but BBB permeability has never been investigated during spontaneous migraine attacks. In the present study, BBB permeability during spontaneous attacks of migraine without aura was investigated compared to an interictal state. Seventy-four patients suffering from migraine without aura were recruited to participate in this cross-sectional dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) study. The patients were instructed to report at the hospital for DCE-MRI scan during and outside of a spontaneous migraine attack. The primary end-point was a difference in the BBB permeability (ml/100 g/min) between the attack and the headache-free days. The permeability was assessed in five different regions of interest (ROIs) located in the anterior, middle and posterior cerebral area, brain stem, posterior pons and whole brain. The paired samples t test was used to compare Ki (permeability) values between the attack and headache-free days. Nineteen patients completed the study. Median time from onset of migraine attack to scan was 6.5 h (range 4.0-15.5 h). No change in the mean BBB permeability (ml/100 g/min) was found between the attack and the headache-free days in any of the measured ROIs. No relationship between the pain side or intensity and BBB permeability was found in 15 patients with unilateral pain during the examined attack. It was demonstrated that the BBB permeability during spontaneous migraine attacks without aura was unchanged.