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Background: Previous studies have shown that migraines are associated with brain structural changes. However, the causal relationships between these changes and migraine, as well as its subtypes, migraine with aura (MA) and migraine without aura (MO), remain largely unclear., Methods: We utilized genome-wide association study (GWAS) summary statistics from European cohorts for 2,347 cortical structural magnetic resonance imaging (MRI) phenotypes, derived from both T1-weighted and diffusion tensor imaging scans (n = 36,663), with migraine and its subtypes (n = 147,970-375,752). Cortical phenotypes included both macrostructural (e.g., cortical thickness, surface area) and microstructural (e.g., fractional anisotropy, mean diffusivity) features. Genetic correlations were first assessed to identify significant associations, followed by bidirectional Mendelian randomization (MR) analyses to determine causal relationships between these brain phenotypes and migraine, as well as its subtypes (MA and MO). Sensitivity analyses were applied to ensure the robustness of the results., Results: Genetic correlation analysis identified 510 significant associations between cortical structural phenotypes and migraine across 401 distinct traits. Forward MR analysis revealed nine significant causal effects of cortical structural changes on migraine risk. Specifically, increased cortical thickness and local gyrification index in specific cortical regions were associated with a decreased risk of overall migraine, MA, and MO, while intracellular volume fraction and orientation diffusion index in specific regions increased the risk of MA and MO. Reverse MR analysis demonstrated that MA causally increased mean diffusivity in the insular and frontal opercular cortex. Sensitivity analyses confirmed the robustness of these findings, with no evidence of horizontal pleiotropy or heterogeneity., Conclusion: This study identifies causal relationships between cortical neuroimaging phenotypes and migraine, highlighting potential biomarkers for migraine diagnosis, treatment, and prevention., (© 2024. The Author(s).)

Nociceptive signals are processed within a pain-related network of the brain. Migraine is a rather specific model to gain insight into this system. Brain networks may be described by white matter tracts interconnecting functionally defined gray matter regions. Here, we present an overview of the migraine-related pain network revealed by this strategy. Based on diffusion tensor imaging data from subjects in the Human Connectome Project (HCP) database, we used a global tractography approach to reconstruct white matter tracts connecting brain regions that are known to be involved in migraine-related pain signaling. This network includes an ascending nociceptive pathway, a descending modulatory pathway, a cortical processing system, and a connection between pain-processing and modulatory areas. The insular cortex emerged as the central interface of this network. Direct connections to visual and auditory cortical association fields suggest a potential neural basis of phono- or photophobia and aura phenomena. The intra-axonal volume (V intra ) as a measure of fiber integrity based on diffusion microstructure was extracted using an innovative supervised machine learning approach in form of a Bayesian estimator. Self-reported pain levels of HCP subjects were positively correlated with tract integrity in subcortical tracts. No correlation with pain was found for the cortical processing systems., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: Migraine is an exclusively human chronic disorder with ictal manifestations characterized by a multifaceted clinical complexity pointing to a cerebral cortical involvement. The present review is aimed to cover the clinical, neuroimaging, and neurophysiological literature on the role of the cerebral cortex in migraine pathophysiology., Overview: Converging clinical scenarios, advanced neuroimaging data, and experimental neurophysiological findings, indicate that fluctuating excitability, plasticity, and metabolism of cortical neurons represent the pathophysiological substrate of the migraine cycle. Abnormal cortical responsivity and sensory processing coupled to a mismatch between the brain's energy reserve and workload may ignite the trigeminovascular system, leading to the migraine attack through the activation of subcortical brain trigeminal and extra-trigeminal structures, and driving its propagation and maintenance., Discussion: The brain cortex emerges as the crucial player in migraine, a disorder lying at the intersection between neuroscience and daily life. Migraine disorder stems from an imbalance in inhibitory/excitatory cortical circuits, responsible for functional changes in the activity of different cortical brain regions encompassing the neurolimbic-pain network, and secondarily allowing a demodulation of subcortical areas, such as hypothalamus, amygdala, and brainstem nuclei, in a continuous mutual crosstalk., (© 2020 American Headache Society.)

Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in temporal summation of pain and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with 1) stronger rsFCs of the posterior cingulate cortex, with the ventromedial prefrontal cortex and with the pregenual anterior cingulate cortex; 2) weaker rsFC of the anterior insula with the angular gyrus. Conversely, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine. PERSPECTIVE: This article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in health and in the presence of chronic pain., (Copyright © 2020 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Previous voxel- or surface-based morphometric analysis studies have revealed alterations in cortical structure in patients with chronic migraine, yet with inconsistent results. The discrepancies may be derived partly from the sample heterogeneity. Employing both methods in a clinically homogenous group may provide a clearer view., Methods: Structural MRI data from 30 prevention-naïve patients with chronic migraine without medication overuse headache or a history of major depression and 30 healthy controls were analyzed. Vertex-wise (surface-based) or voxel-wise (voxel-based) linear models were applied, after controlling for age and gender, to investigate between-group differences. Averaged cortical thicknesses and volumes from regions showing group differences were correlated with parameters related to clinical profiles., Results: Surface-based morphometry showed significantly thinner cortices in the bilateral insular cortex, caudal middle frontal gyrus, precentral gyrus, and parietal lobes in patients with chronic migraine relative to healthy controls. Additionally, the number of migraine days in the month preceding MRI examination was correlated negatively with right insular cortical thickness. Voxel-based morphometry (VBM) did not show any group differences or clinical correlations., Conclusion: Patients with chronic migraine without medication overuse headache, major depression, or prior preventive treatment had reduced cortical thickness in regions within the pain-processing network. Compared to voxel-based morphometry, surface-based morphometry analysis may be more sensitive to subtle structural differences between healthy controls and patients with chronic migraine.

Among painful disorders, migraine is distinguishable by its chronic pathology and episodic clinical manifestation. Only a small percentage of patients with migraine progress to a chronic form of migraine. Both peripheral and central portions of the trigeminal system are involved in the pathophysiology of migraine pain, as they are involved in the processes of peripheral and central sensitization, alongside various subcortical and cortical brain structures. This review focuses on clinical, neurophysiological, and neuroimaging data underscoring cortical pain processing in migraine. Data obtained from quantitative sensory testings are inconclusive and support the involvement of the peripheral portion of the trigeminovascular system as indirect evidence of peripheral sensitization, solely during the headache phase. The assessment of subjective pain intensity in response to several painful modalities has not been conclusive for the clear state of central sensitization in between migraine attacks but for the subclinical allodynia state that defines the boundary between behavioural responses and an irritable nervous state. Modulation of the brainstem and midbrain pain pathways, in conjunction with the thalamic and thalamocortical pathways, may be critical for the initiation and maintenance of migraine attacks. Several studies using different neuroimaging techniques have demonstrated that brains experiencing migraine undergo plastic changes in both microstructure and macrostructure and in the functioning of cortical networks, which may manifest early in the life of a patient with migraine. Further studies are required to understand how specific these results are to migraine relative to other painful disorders.

Introduction: Previous voxel-based morphometry (VBM) studies have revealed changes in brain structure in patients with vestibular migraine (VM); these findings have improved the present understanding of pathophysiology. Few other studies have assessed the association between structural changes and the severity of dizziness in VM. This study aimed to examine the structural changes and cortical morphometric features associated with migraine and vertigo attacks in patients with VM., Methods: Twenty patients with VM and 20 healthy normal volunteers were scanned on a 3-tesla MRI scanner. The gray matter volume (GMV) was estimated using the automated Computational Anatomy Toolbox (CAT12). The relationship between clinical parameters and morphometric abnormalities was also analyzed in VM., Results: Compared with controls, VM patients have decreased GMV in the prefrontal cortex (PFC), posterior insula-operculum regions, inferior parietal gyrus, and supramarginal gyrus. Moreover, patient scores on the Dizziness Handicap Inventory (DHI) score showed a negative correlation with GMV in the posterior insula-operculum regions., Conclusion: These findings demonstrated abnormality in the central vestibular cortex and correlations between dizziness severity and GMV in core regions of the vestibular cortex of VM patients, suggesting a pathophysiological role of these core vestibular regions in VM patients., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Objectives: The hypothalamus plays a key role in both migraine and cluster headache (CH). As brain region-to-region structural correlations are believed to reflect structural and functional brain connectivity patterns, we assessed the structural covariance patterns between the volume of the hypothalamic region and vertex-by-vertex measurements of cortical thickness in patients with migraine and in those with CH relative to healthy controls (HC)., Methods: T1-weighted images were acquired on a 3T MRI scanner for a total of 59 subjects including 18 patients with CH (age: mean = 43.8, SD = 12.4), 19 with migraine (age: mean = 40.1, SD = 12.2), and 22 HCs (age: mean = 39.1, SD = 8.2). Imaging was collected between attacks (migraineurs) and during out-of-bout phases (CH). Data were post-processed using FreeSurfer version 6.0 and within-group correlations between hypothalamic region volume with cortical thickness were explored using a whole-brain vertex-wise linear model approach. Between-group differences in correlation slopes between hypothalamic region volume and vertex-by-vertex measurements of cortical thickness were interrogated using post-hoc comparisons., Results: There were no significant between-group differences (migraine vs CH; migraine vs HC; or CH vs HC) for age, sex, total brain volume or volume of the left or right hypothalamic region. For each group, there were significant positive correlations (P < .01) between right and left hypothalamic region volumes with cortical thickness measurements. HC had significant positive correlations between hypothalamic region volume and cortical thickness over large portions of the superior and rostral medial frontal, orbitofrontal cortex and rostral anterior cingulate, and smaller clusters in the superior and middle temporal, posterior cingulate, fusiform, and precentral cortex. Post-hoc analysis showed significant differences in covariance patterns in those with migraine and CH relative to HC, with both migraine patients and CH having weaker structural covariance of hypothalamic region volume with frontal and temporal cortical thickness., Conclusion: Recent evidence suggests hypothalamic region connectivity to frontal and temporal areas to be relevant for regulating pain perception. Thus, the diminished structural covariance in migraineurs and CH might suggest abnormal functioning of the pain control circuitry and contribute to mechanisms underlying central sensitization and chronification of pain., (© 2020 American Headache Society.)

Objective: The findings of resting-state functional MRI studies have suggested that abnormal functional integration between interconnected cortical networks characterises the brain of patients with migraine. The aim of this study was to investigate the functional connectivity between the hypothalamus, brainstem, considered as the migraine generator, and the following areas/networks that are reportedly involved in the pathophysiology of migraine: default mode network (DMN), executive control network, dorsal attention system, and primary and dorsoventral visual networks., Methods: Twenty patients with chronic migraine (CM) without medication overuse and 20 healthy controls (HCs) were prospectively recruited. All study participants underwent 3-T MRI scans using a 7.5-min resting-state protocol. Using a seed-based approach, we performed a ROI-to-ROI analysis selecting the hypothalamus as the seed., Results: Compared to HCs, patients with CM showed significantly increased neural connectivity between the hypothalamus and brain areas belonging to the DMN and dorsal visual network. We did not detect any connectivity abnormalities between the hypothalamus and the brainstem. The correlation analysis showed that the severity of the migraine headache was positively correlated with the connectivity strength of the hypothalamus and negatively with the connectivity strength of the medial prefrontal cortex, which belongs to the DMN., Conclusion: These data provide evidence for hypothalamic involvement in large-scale reorganisation at the functional-network level in CM and in proportion with the perceived severity of the migraine pain.

Objective: To review and discuss the literature on the role of cortical structure and function in migraine., Discussion: Structural and functional findings suggest that changes in cortical morphology and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks., Conclusion: Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications.

Based on previous clinic-based magnetic resonance imaging studies showing regional differences in the cerebral cortex between those with and without headache, we hypothesized that headache sufferers have a decrease in volume, thickness, or surface area in the anterior cingulate cortex, prefrontal cortex, and insula. In addition, exploratory analyses on volume, thickness, and surface area across the cerebral cortical mantle were performed. A total of 1006 participants (aged 50-66 years) from the general population were selected to an imaging study of the head at 1.5 T (HUNT-MRI). Two hundred eighty-three individuals suffered from headache, 80 with migraine, and 87 with tension-type headache, whereas 309 individuals did not suffer from headache and were used as controls. T1-weighted 3D scans of the brain were analysed with voxel-based morphometry and FreeSurfer. The association between cortical volume, thickness, and surface area and questionnaire-based headache diagnoses was evaluated, taking into consideration evolution of headache and frequency of attacks. There were no significant differences in cortical volume, thickness, or surface area between headache sufferers and nonsufferers in the anterior cingulate cortex, prefrontal cortex, or insula. Similarly, the exploratory analyses across the cortical mantle demonstrated no significant differences in volume, thickness, or surface area between any of the headache groups and the nonsufferers. Maps of effect sizes showed small differences in the cortical measures between headache sufferers and nonsufferers. Hence, there are probably no or only very small differences in volume, thickness, or surface area of the cerebral cortex between those with and without headache in the general population.

Background: Several previous studies have investigated cortical abnormalities, specifically cortical thickness, in patients with migraine, with variable results. The relatively small sample sizes of most previous studies may partially explain these inconsistencies., Objective: To investigate differences of cortical thickness between control subjects and migraineurs in a large cohort., Methods: Three Tesla MRI data of 131 patients (38 with and 93 without aura) and 115 control subjects were analysed. A vertex-wise linear model was applied controlling for age, gender and MRI scanner to investigate differences between groups and determine the impact of clinical factors on cortical thickness measures., Results: Migraineurs showed areas of thinned cortex compared with controls bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices and the right occipito-temporal gyrus. Frequency of migraine attacks and the duration of the disorder had a significant impact on cortical thickness in the sensorimotor cortex and middle-frontal gyrus. Patients without aura showed thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus and in the right cuneus. Patients with aura showed clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus and in the right anterior cingulate., Conclusion: These results indicate cortical abnormalities in specific brain regions in migraineurs. Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks.

Objectives: The objectives of this cross-sectional pilot study were threefold: to identify regions of cortical thickness that differentiate chronic migraine (CM) from controls, to assess group differences in interregional cortical thickness covariance, and to determine group differences in associations between clinical variables and cortical thickness., Background: Cortical thickness alterations in relation to clinical features have not been adequately explored in CM. Assessment of this relationship can be useful to describe cortical substrates for disease progression in migraine and to identify clinical variables that warrant management emphasis., Methods: Thirty CM cases (mean age 40 years; male-to-female 1:4) and 30 sex-matched healthy controls (mean age 40 years) were enrolled. Participants completed self-administered and standardized questionnaires assessing headache-related clinical features and common psychological comorbidities. T1-weighted brain images were acquired on a 3T MRI. A whole-brain cortical thickness analysis was performed. Additionally, correlations between all brain regions were assessed to examine interregional cortical thickness covariance. Interactions were analyzed to identify clinical variables that were significantly associated with cortical thickness., Results: The whole brain cortical thickness analysis revealed no significant differences between CM patients and controls. However, significant associations between clinical features and cortical thickness were observed for the patients only. These associations included the right superior temporal sulcus (R 2  = 0.72, P = .001) and the right insula (R 2  = 0.71, P = .002) with distinct clinical variables ie, longer history of CM, posttraumatic stress disorder (PTSD), sleep quality, pain self-efficacy, and somatic symptoms. Higher interregional cortical covariance was found in CM compared to controls (OR = 3.1, CI 2.10-4.56, P < .0001), such that cortical thickness between regions tended to be more correlated in patients, particularly in the temporal and frontal lobes., Conclusion: CM patients have significantly greater cortical covariance compared to controls. Cortical thickness in CM patients was predominantly accounted for by CM duration, PTSD, and poor sleep quality, while improved pain self-efficacy buffered cortical thickness. While it is important to address all CM features and comorbidities, it may be useful to emphasize optimizing the management of certain clinical features that contribute to cortical abnormalities including managing PTSD, early management to shorten duration of CM, and improving pain self-efficacy and sleep quality., (© 2018 American Headache Society.)

Background/aim: Migraine-related intracerebral white matter lesions (WMLs) are likely to be microvascular in nature and can be found in all hemispheric lobes. The aim of this study was to investigate migraine patients with or without WMLs to see the effects of these tissue damages on cortical thickness and volume. The role of migraine characteristics (duration of headache, attack frequency, estimated lifetime attack number, aura) was also tested., Methods: As study participants, 161 female migraine patients (63 with aura; 52 with WMLs) and 40 age-matched healthy female subjects were enrolled in the study. None of the included migraine patients' headache or aura (where present) was unilaterally side-locked. Patients and controls were all right handed. Except for migraine, patients were free of any medical comorbidity. Cortical reconstruction and segmentation were performed on the 3D T1-weighted images using Freesurfer 5.3 image analysis suite. The automatic cortical parcellation was based on Freesurfer's Desikan-Killiany-Tourville atlas, which has 31 cortical regions per hemisphere. The segmented regions were divided into five lobes (frontal, parietal, temporal, occipital, insula). Since the left and right differences in lobar and insular volumes/thicknesses were not different among our groups, volume and cortical thickness were calculated for corresponding bilateral lobes., Results: There was no significant difference in age between the whole migraine and the control groups. Migraineurs with WMLs (L+ patients) were significantly older than lesion-free (L-) patients (P = 0.0003) and controls (P = 0.018). Disease duration (P = 0.003), the total number of migraine attacks (P = 0.022) and the rate of aura (P = 0.0003) were significantly higher in L+ patients than in L- patients. Cortical thickness and volume measurements of lobes were not statistically different between the three groups (L+, L-, control). Age showed a significant negative association with both thickness and volume in each examined lobe (P < 0.001). Intracranial volume (ICV) showed a significant positive association with all regional volumes (P < 0.001). There were no significant group*age, group*ICV, or age*ICV interactions. None of the migraine characteristics were selected by stepwise linear regression as significant predictors of cortical thickness or volume. Only age (for both thickness and volume) and ICV (for volume) were identified as significant predictors (P < 0.001). When the L + group was divided into two subgroups by median split of total and lobar lesion number and volume, the cortical measures did not show any significant difference between the groups with low vs. high lesion number/volume by stepwise linear regression., Conclusions: In a female migraine group, we found that the WMLs and clinical migraine characteristics have no effect on cortical thickness and volume of bilateral lobes. Lobar cortical thicknesses were equivalent within the range of ±0.1 mm. Only age and ICV proved to be significant predictors; the former for both cortical thickness and volume, while the latter for cortical volume.

Objective To investigate the intranetwork resting state fMRI connectivity within the Salience Network of chronic migraine with and without medication overuse headache. Methods We compared 351 pairs of intranetwork connectivity in chronic migraine (n = 13) and chronic migraine with medication overuse headache (n = 16) compared to matched controls, and between each chronic migraine subgroup. Results Compared to controls, 17 pairs of intranetwork connections in chronic migraine and 27 pairs in chronic migraine with medication overuse headache were decreased. When comparing chronic migraine with medication overuse headache versus chronic migraine, connectivity between bilateral extended amygdala, and between paracingulate to right ventral tegmental area/substantia nigra were decreased in chronic migraine (chronic migraine < chronic migraine with medication overuse headache). Connectivity between left dorsolateral prefrontal cortex to bilateral ventral striatum/pallidum, to bilateral dorsal anterior cingulate cortex; left anterior prefrontal cortex to contralateral orbitofrontal insula; and left ventral striatum/pallidum to ipsilateral supplementary motor area (SMA)/preSMA were decreased in chronic migraine with medication overuse headache (chronic migraine with medication overuse headache < chronic migraine). Conclusion Both chronic migraine subgroups had shared intranetwork connectivity abnormality, however, each subgroup had unique pattern of disruption within the salience network. The results suggest that the aberrant assignment of salience to external and internal stimuli plays an important role in chronic migraine and chronic migraine with medication overuse headache interictally, mostly involving mesolimbic pathways (especially bilateral extended amygdala) in chronic migraine, and prefrontal-subcortical limbic pathways in chronic migraine with medication overuse headache.

Objective: In this pilot study, the purpose is to investigate if a series of sphenopalatine ganglion (SPG) blockade treatments modulate the functional connectivity within the salience and central executive network (CEN) in chronic migraine with medication overuse headaches (CM w/MOH )., Background: Using intranasal local anesthesia to block the SPG for the treatment of various headache disorders has been employed in clinical practice since the early 1900s. However, the exact mechanism of how SPG modulate resting state intrinsic functional brain networks connectivity remains to be elucidated. This pilot study seeks to understand the resting state connectivity changes in salience and CENs, with emphasis on the mesocorticolimbic systems, before and after a series of SPG block treatments., Methods: Using fMRI, resting state connectivity was derived from predefined networks of nodes (regions of interests) for the salience (27 nodes, 351 connections) and CENs (17 nodes, 136 connections). After treatments, a paired samples t-test (with 10,000 permutations to correct for multiple comparison) was used to evaluate changes in the intranetwork resting state functional connectivity within the salience and executive networks, as well as the overall network connectivity strength., Results: When comparing connectivity strength at baseline to that at the end of treatment in our cohort of 10 CM w/MOH participants, there were several connections within the salience (n = 9) and executive (n = 8) networks that were significantly improved. Within the salience network, improved connectivity was observed between the prefrontal cortex and various regions of the insula, basal ganglia, motor, and frontal cortex. Additionally, changes in connectivity were observed between regions of the temporal cortex with the basal ganglia and supramarginal gyrus. Within the CEN, improved connectivity was observed between the prefrontal cortex and regions of the anterior thalamus, caudate, and frontal cortex. After treatment, the overall CEN connectivity was significantly improved (Baseline 0.00 ± 0.08; 6 weeks 0.03 ± 0.09, P = .01); however, the overall salience network connectivity was not significantly improved (Baseline -0.01 ± 0.10; 6 weeks 0.01 ± 0.12, P = .26). Additionally, after treatment, there was a significant reduction in the number of moderate/severe headache days per month (Baseline 21.1 ± 6.6; 6 weeks 11.2 ± 6.5, P < .001), HIT-6 (Baseline 66.1 ± 2.6; 6 weeks 60.2 ± 3.6, P < .001), and PHQ-9 (Baseline 12.4 ± 5.7; 6 weeks 6.1 ± 3.6, P = .008) scores., Conclusion: In this longitudinal fMRI study, we observed improved functional connectivity within both networks, primarily involving connectivity between regions of the prefrontal cortex and limbic (cortical-limbic) structures, and between different cortical (cortical-cortical) regions after a series of repetitive SPG blockades. The overall CEN strength was also improved. Our results suggest that recurrent parasympathetic inhibition via SPG is associated with improved functional connectivity in brain regions critical to pain processing in CM w/MOH ., (© 2018 American Headache Society.)

Background Previous functional MRI studies have revealed that ongoing clinical pain in different chronic pain syndromes is directly correlated to the connectivity strength of the resting default mode network (DMN) with the insula. Here, we investigated seed-based resting state DMN-insula connectivity during acute migraine headaches. Methods Thirteen migraine without aura patients (MI) underwent 3 T MRI scans during the initial six hours of a spontaneous migraine attack, and were compared to a group of 19 healthy volunteers (HV). We evaluated headache intensity with a visual analogue scale and collected seed-based MRI resting state data in the four core regions of the DMN: Medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and left and right inferior parietal lobules (IPLs), as well as in bilateral insula. Results Compared to HV, MI patients showed stronger functional connectivity between MPFC and PCC, and between MPFC and bilateral insula. During migraine attacks, the strength of MPFC-to-insula connectivity was negatively correlated with pain intensity. Conclusion We show that greater subjective intensity of pain during a migraine attack is associated with proportionally weaker DMN-insula connectivity. This is at variance with other chronic extra-cephalic pain disorders where the opposite was found, and may thus be a hallmark of acute migraine head pain.

Background: To date, few MRI studies have been performed in patients affected by chronic migraine (CM), especially in those without medication overuse. Here, we performed magnetic resonance imaging (MRI) voxel-based morphometry (VBM) analyses to investigate the gray matter (GM) volume of the whole brain in patients affected by CM. Our aim was to investigate whether fluctuations in the GM volumes were related to the clinical features of CM., Methods: Twenty untreated patients with CM without a past medical history of medication overuse underwent 3-Tesla MRI scans and were compared to a group of 20 healthy controls (HCs). We used SPM12 and the CAT12 toolbox to process the MRI data and to perform VBM analyses of the structural T1-weighted MRI scans. The GM volume of patients was compared to that of HCs with various corrected and uncorrected thresholds. To check for possible correlations, patients' clinical features and GM maps were regressed., Results: Initially, we did not find significant differences in the GM volume between patients with CM and HCs (p < 0.05 corrected for multiple comparisons). However, using more-liberal uncorrected statistical thresholds, we noted that compared to HCs, patients with CM exhibited clusters of regions with lower GM volumes including the cerebellum, left middle temporal gyrus, left temporal pole/amygdala/hippocampus/pallidum/orbitofrontal cortex, and left occipital areas (Brodmann areas 17/18). The GM volume of the cerebellar hemispheres was negatively correlated with the disease duration and positively correlated with the number of tablets taken per month., Conclusion: No gross morphometric changes were observed in patients with CM when compared with HCs. However, using more-liberal uncorrected statistical thresholds, we observed that CM is associated with subtle GM volume changes in several brain areas known to be involved in nociception/antinociception, multisensory integration, and analgesic dependence. We speculate that these slight morphometric impairments could lead, at least in a subgroup of patients, to the development and continuation of maladaptive acute medication usage.

Background Blocking the pro-nociceptive action of CGRP is one of the most promising approaches for migraine prophylaxis. The aim of this study was to explore a role for CGRP as a neuroprotective agent for central and peripheral neurons. Methods The viability of isolated rat trigeminal, cortical and cerebellar neurons was tested by fluorescence vital assay. Engagement of Nrf2 target genes was analyzed by qPCR. The neuroprotective efficacy of CGRP in vivo was tested in mice using a permanent cerebral ischemia model. Results CGRP prevented apoptosis induced by the amino acid homocysteine in all three distinct neuronal populations. Using a set of specific kinase inhibitors, we show the role of multi-kinase signaling pathways involving PKA and CaMKII in neuronal survival. Forskolin triggered a very similar signaling cascade, suggesting that cAMP is the main upstream trigger for multi-kinase neuroprotection. The specific CGRP antagonist BIBN4096 reduced cellular viability, lending further support to the proposed neuroprotective function of CGRP. Importantly, CGRP was neuroprotective against permanent ischemia in mice. Conclusion Our data show an unexpected 'positive' role for the endogenous pro-nociceptive migraine mediator CGRP, suggesting more careful examination of migraine prophylaxis strategy based on CGRP antagonism although it should be noted that homocysteine induced apoptosis in primary neuronal cell culture might not necessarily reproduce all the features of cell loss in the living organism.

Objectives: To assess the usefulness of the visual assessment and to determine diagnostic value of the lesion-to-cerebral cortex signal ratio (LCSR) measurement in the differentiation of demyelinating plaques and non-specific T2 hyperintensities on double inversion recovery (DIR) sequence., Material and Methods: DIR and fluid-attenuated inversion recovery (FLAIR) sequences of 25 clinically diagnosed multiple sclerosis (MS) patients and 25 non-MS patients with non-specific T2-hyperintense lesions were evaluated visually and LCSRs were measured by two observers independently., Results: On DIR sequence, the calculated mean LCSR ± SD for demyelinating plaques and non-specific T2-hyperintense lesions were 1.60 ± 0.26 and 0.75 ± 0.19 for observer1, and 1.61 ± 0.27 and 0.74 ± 0.19 for observer2. LCSRs of demyelinating plaques were significantly higher than other non-specific T2-hyperintense lesions on DIR sequence. By using the visual assessment demyelinating plaques were differentiated from non-specific T2-hyperintensities with 92.8 % sensitivity, 97.5 % specificity and 95.1 % accuracy for observer1 and 92.8 % sensitivity, 95 % specificity and 93.9 % accuracy for observer2., Conclusion: Visual assessment and LCSR measurement on DIR sequence seems to be useful for differentiating demyelinating MS plaques from supratentorial non-specific T2 hyperintensities. This feature can be used for diagnosis of MS particularly in patients with only supratentorial T2-hyperintense lesions who are categorized as radiologically possible MS., Key Points: • Demyelinating plaques and non-specific T2-hyperintensities have different SI on DIR images. • These differences can be assessed by LCSR measurement or visual assessment. • There is an excellent inter-observer agreement for both methods. • This feature can be used in radiologically possible MS cases.

Migraine is a recurring, episodic neurological disorder characterized by headache, nausea, vomiting, and sensory disturbances. These events are thought to arise from the activation and sensitization of neurons along the trigemino-vascular pathway. From animal studies, it is known that thalamocortical projections play an important role in the transmission of nociceptive signals from the meninges to the cortex. However, little is currently known about the potential involvement of cortico-cortical feedback projections from higher-order multisensory areas and/or feedforward projections from principle primary sensory areas or subcortical structures. In a large cohort of human migraine patients ( N = 40) and matched healthy control subjects ( N = 40), we used resting-state intrinsic functional connectivity to examine the cortical networks associated with the three main sensory perceptual modalities of vision, audition, and somatosensation. Specifically, we sought to explore the complexity of the sensory networks as they converge and become functionally coupled in multimodal systems. We also compared self-reported retrospective migraine symptoms in the same patients, examining the prevalence of sensory symptoms across the different phases of the migraine cycle. Our results show widespread and persistent disturbances in the perceptions of multiple sensory modalities. Consistent with this observation, we discovered that primary sensory areas maintain local functional connectivity but express impaired long-range connections to higher-order association areas (including regions of the default mode and salience network). We speculate that cortico-cortical interactions are necessary for the integration of information within and across the sensory modalities and, thus, could play an important role in the initiation of migraine and/or the development of its associated symptoms.

The pathophysiology of vestibular migraine (VM) is at present poorly understood. Functional magnetic resonance imaging (fMRI), a technique that measures brain activity by detecting changes associated with blood flow oxygenation, has been used to study neural pathways involved in VM pathophysiology. In this study, we summarize results of previous fMRI studies in VM patients, both during and between vertigo attacks. Moreover, we report our experience in two patients with definite VM, who underwent fMRI during a visual stimulation in a vertigo-free period. Compared with 15 matched healthy controls, fMRI demonstrated activation of brain areas related to integration of visual and vestibular cues (increased activation of the paracentral lobule and bilateral inferior parietal lobule and decreased activation of the left superior frontal gyrus, head of the caudate nucleus, left superior temporal gyrus, left parahippocampal gyrus, and right lingual gyrus). Our results partially confirm those of other authors, reporting increased activation of multimodal association brain areas (BA 40, BA 31/5) and decreased activation of occipital regions In addition, we also found a decreased activation of fronto-temporal areas, such as the parahippocampal region, functionally involved in space memory and navigation.

Unlabelled: To investigate the spatial heterogeneity of cortical excitability in adolescents with migraine, magnetoencephalography (MEG) recordings at a sampling rate of 6,000 Hz were obtained from 35 adolescents with an acute migraine and 35 age- and sex-matched healthy control participants during an auditory-motor task. Neuromagnetic activation from low- to high-frequency ranges (5-1,000 Hz) was measured at sensor and source levels. The heterogeneity of cortical excitability was quantified within each functional modality (auditory vs motor) and hemispherical lateralization. MEG data showed that high-frequency, not low-frequency neuromagnetic signals, showed heterogeneous cortical activation in migraine subjects compared with control participants (P < .001). The alteration of the heterogeneity of cortical excitability in migraine subjects was independent of age and sex. The degree of the neuromagnetic heterogeneity of cortical activation was significantly correlated with headache frequency (r = .71, P < .005). The alteration of cortical excitability in migraine subjects was spatially heterogeneous and frequency dependent, which previously has not been reported. The finding may be critical for developing spatially targeted therapeutic strategies for normalizing cortical excitability with the purpose of reducing headache attacks., Perspective: This article presents a new approach to quantitatively measure the spatial heterogeneity of cortical excitability in adolescents with migraine using MEG signals in a frequency range of 5 to 1,000 Hz. The characteristics of the location and degree of cortical excitability may be critical for spatially targeted treatment for migraine., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Whereas there are many H(2)(15)O-positron emission tomography (PET) studies demonstrating neuronal activation during acute migraine attacks, little information is available on the interictal (headache-free period) glucose metabolic changes in migraine. We therefore conducted voxel-based statistical parametric mapping analysis of (18)F-fluorodeoxyglucose-PET to evaluate interictal metabolic differences between 20 episodic migraine patients (four with aura; three men; mean age 34.0 +/- 6.4 years) and 20 control subjects. Separate correlation analyses were performed to delineate a possible relationship between regional glucose metabolism and disease duration or lifetime headache frequency in migraine patients. Group comparison showed that migraine patients had significant hypometabolism in several regions known to be involved in central pain processing, such as bilateral insula, bilateral anterior and posterior cingulate cortex, left premotor and prefrontal cortex, and left primary somatosensory cortex (uncorrected P < 0.001, corrected P < 0.05 with small volume corrections). Correlation analyses showed that regional metabolism of the insula and anterior cingulate cortex had significant negative correlations with disease duration and lifetime headache frequency (uncorrected P < 0.001, corrected P < 0.05 with small volume corrections). Our findings of progressive glucose hypometabolism in relation to increasing disease duration and increasing headache frequency suggest that repeated migraine attacks over time lead to metabolic abnormalities of selective brain regions belonging to the central pain matrix.

Pain perception involves several cortical areas. Our purpose was to examine cortical activity in patients describing their cephalic pain with the MacGill Pain Questionnaire (MPQ). Two SPECT analyses were performed in pain-free periods in 10 patients with migraine (n=8) or myogenous facial pain (n=2). The MPQ was administered in the first session, while no task was to be performed during the second session. Differences were calculated using statistical parametric mapping (SPM99), also taking the MPQ pain rating index (PRI) as covariance. During the MPQ session, clusters of activation were observed in the orbitofrontal cortex, the insula and the anterior cingulate cortex (ACC) of the left brain, but not significantly so. Using the MPQ PRI as covariate, significant areas of activation were found in the left frontal lobe, the Brodmann area 32 and in the ACC. The description of pain seems to activate cortical areas similar to those involved in actual pain perception.

The reactivity of posterior cerebral artery (PCA) to light stimulation was studied with transcranial Doppler in 9 migraine patients (5 with aura, 4 without aura) within six hours of the onset of headache (mean 115 +/- 78 minutes). The PCA mean flow velocity was recorded while the patient was in the dark and with the eyes closed and, subsequently, while the light was on and with the eyes open. Both symptomatic and asymptomatic sides were recorded. The same test was repeated thirty minutes after injection of sumatriptan 6 mg subcutaneously and again on the third day after cessation of the attack. Photoreactivity was calculated, for each side and for each situation, as percent relative increase of the corresponding averaged mean flow velocity recorded in darkness. The results showed that, although absolute flow velocities were not statistically different between sides and situations, photoreactivity was significantly increased on the symptomatic side during attacks (+28% vs 15% respectively). After sumatriptan, photoreactivity became symmetrical and (nonsignificantly) inferior to the values recorded in the interictal period. These findings suggest that, during headache, peripheral resistance branches of PCA on the symptomatic side are hypersensitive to vasodilatory stimuli. This could represent the counterpart of the clinical scotomata and photophobia commonly experienced by migraine patients during attacks.

High-resolution, color-coded images of local cerebral blood flow (LCBF) were made utilizing stable xenon-enhanced computed tomography among patients with common migraine (n = 18), classic migraine (n = 12) and cluster headache (n = 5). During spontaneously occurring headache in common and classic migraine patients, LCBF values for cerebral cortex and subcortical gray and white matter were diffusely increased by 20-40% with the exception of the occipital lobes. LCBF increases involved both hemispheres whether the head pain was unilateral or bilateral. No significant differences were noted in the degree or pattern of LCBF increases during headaches of common and classic migraineurs. Similar cerebral hyperperfusion of greater magnitude was observed during cluster headaches but was more prominent on the side of the head pain. Present observations do not support the hypothesis of spreading cortical depression as a cause of classic migraine. From a hemodynamic viewpoint, LCBF increases during headaches of common or classic migraine or cluster appear similar. Evidence is adduced that sympathetic hypofunction with denervation hypersensitivity of cerebral vessels plays a role in the cerebral hyperperfusion of migraine headaches. More pronounced unilateral autonomic derangements appear to account for the symptoms and cerebral hyperperfusion associated with cluster headaches.

Color-coded, cross-sectional imaging of local cerebral blood flow (LCBF) was made in a prospective manner among 22 patients with well-established common or classic migraine utilizing the stable xenon-enhanced computed tomographic (Xe CT-CBF) method. LCBF in patients during spontaneously occurring headaches (N = 12) were significantly higher compared to patients without headache (N = 10) by 25-35%. The hyperperfusion involved not only cerebral cortex but also subcortical structures including thalamus, basal ganglia, and subcortical white matter. LCBF increases were not bilateral and sometimes asymmetrical, but LCBF increases were not consistently related to the preponderant side of headache. No significant differences were observed in the degree or pattern of cerebral hyperperfusion during headaches compared among common (N = 6) and classic (N = 6) migraineurs. Results suggest a common etiology for both common and classic migraine. Results are not consistent with spreading oligemia or spreading cortical depression as a cause of migraine. The cerebral hyperperfusion appears to be mediated by various neurogenic and chemical changes accompanying migraine. The unilateral nature of migraine head pain is more likely due to dilation of extracranial vessels.