Insular cortex involvement in migraine patients with chronic pain: A volumetric radiological and clinical study.

BACKGROUND: This study aimed to assess abnormalities in the insular cortex of individuals suffering from migraines and examine their associations with pain duration, medication usage, and clinical symptoms. METHODS: We analyzed radiological data from 38 migraine patients who had undergone 3D iso T1-weighted brain MRI at our university hospital between 2019 and 2023. Structured questionnaires were used to collect information on participants' age, migraine type, disease duration, clinical symptoms, and medication use. Volumetric analysis was performed on the insular regions using Volbrain and 3DSlicer. The results were statistically analyzed. RESULTS: Comparing groups with chronic pain to normal groups revealed significant differences in several insular regions, including the posterior insula (p = 0.034), parietal operculum (p = 0.04), and the entire insular cortex (p = 0.023). Further group comparisons (Group 1, 2, and 3) showed significant differences in specific insular regions. For instance, the anterior insula (p = 0.032) was associated with taste changes, the posterior insula (p = 0.010) with smell-related changes, and the central operculum (p = 0.046) with sensations of nausea. Additionally, significant changes were observed in the parietal operculum concerning nausea, photophobia, phonophobia, and changes in smell. CONCLUSION: To the best of our knowledge, there have been no studies investigating the relationship between clinical manifestations and volumetric correlation. This study provides insights into abnormalities in the insular cortex among migraine patients and their potential relevance to pain duration, severity, and migraine type. The results suggest that understanding alterations in insular regions possibly linked to pain could contribute to the development of innovative approaches to managing chronic pain.

Decreased Cerebral Perfusion in Chronic Migraine: A Voxel-based Cerebral Blood Flow Analysis Using 3D Pseudo-continuous Arterial Spin Labeling.

BACKGROUND: A contrast agent-free approach would be preferable to the frequently used invasive approaches for evaluating cerebral perfusion in chronic migraineurs (CM). In this work, non-invasive quantitative volumetric perfusion imaging was used to evaluate alterations in cerebral perfusion in CM. METHODS: We used conventional brain structural imaging sequences and 3D pseudo-continuous arterial spin labeling (3D PCASL) to examine thirteen CM patients and fifteen normal controls (NCs). The entire brain gray matter underwent voxel-based analysis, and the cerebral blood flow (CBF) values of the altered positive areas were retrieved to look into the clinical variables' significant correlation. RESULTS: Brain regions with the decreased perfusion were located in the left postcentral gyrus, bilateral middle frontal gyrus, left middle occipital gyrus, left superior parietal lobule, left medial segment of superior frontal gyrus, and right orbital part of the inferior frontal gyrus. White matter fibers with decreased perfusion were located in bilateral superior longitudinal tracts, superior corona radiata, external capsules, anterior and posterior limbs of the internal capsule, anterior corona radiata, inferior longitudinal fasciculus, and right corticospinal tract. However, the correlation analysis showed no significant correlation between the CBF value of the above positive brain regions with clinical variables (p > 0.05). CONCLUSION: The current study provided more useful information to comprehend the pathophysiology of CM and revealed a new insight into the neural mechanism of CM from the pattern of cerebral hypoperfusion.

The glymphatic system in migraine and other headaches.

Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer's disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy.

Specific cognitive and psychological alterations are more strongly linked to increased migraine disability than chronic migraine diagnosis.

INTRODUCTION: The efficiency of The International Classification of Headache Disorders (ICHD-3) in reflecting patients' disability has recently been questioned. This prompts consideration that clinical features beyond pain may more accurately indicate the extent of underlying brain impairment than the mere frequency of headache days. Important cognitive dysfunctions and psychological impairment have been reported in burdensome cases of migraine, and the presence of these alterations has been associated with biological changes in the nervous system. This study aimed to compare migraine-related disability within a specific patient group, classified using ICHD-3 criteria or classified based on findings from a neuropsychological evaluation using machine learning. Additionally, a complementary voxel-based morphometry (VBM) comparison was conducted to explore potential neuroanatomical differences between the resulting groups. PATIENTS AND METHODS: The study included episodic and chronic migraine patients seeking consultation at a specialized headache department. A neuropsychological evaluation protocol, encompassing validated standardized tests for cognition, anxiety, depression, perceived stress, and headache-related impact (HIT-6) and disability (MIDAS), was administered. Results from this evaluation were input into an automated K-means clustering algorithm, with a predefined K=2 for comparative purposes. A supplementary Voxel-based Morphometry (VBM) evaluation was conducted to investigate neuroanatomical contrasts between the two distinct grouping configurations. RESULTS: The study involved 111 participants, with 49 having chronic migraine and 62 having episodic migraine. Seventy-four patients were assigned to cluster one, and 37 patients were assigned to cluster two. Cluster two exhibited significantly higher levels of depression, anxiety, and perceived stress, and performed worse in alternating and focalized attention tests. Differences in HIT-6 and MIDAS scores between episodic and chronic migraine patients did not reach statistical significance (HIT-6: 64.39 (±7,31) vs 62.92 (±11,61); p= 0. 42 / MIDAS: 73.63 (±68,61) vs 84.33 (±63,62); p=0.40). In contrast, patients in cluster two exhibited significantly higher HIT-6 (62.32 (±10,11) vs 66.57 (±7,21); p=0.03) and MIDAS (68.69 (±62,58) vs 97.68 (±70,31); p=0.03) scores than patients in cluster one. Furthermore, significant differences in grey matter volume between the two clusters were noted, particularly involving the precuneus, while differences between chronic and episodic migraine patients did not withstand correction for multiple comparisons. CONCLUSIONS: The classification of migraine patients based on neuropsychological characteristics demonstrates a more effective separation of groups in terms of disability compared to categorizing them based on the chronic or episodic diagnosis of ICHD-3. These findings could reveal biological changes that might explain differences in treatment responses among apparently similar patients.

Alterations of amygdala volume and functional connectivity in migraine patients comorbid with and without depression.

OBJECTIVE: The comorbid relationship between migraine and depression has been well recognized, but its underlying pathophysiology is unclear. Here, we aimed to explore the structural changes of the amygdala and the abnormal functional connectivity of the centromedial amygdala (CMA) in migraineurs with depression. METHODS: High-resolution T1-weighted and functional magnetic resonance images were acquired from 22 episodic migraineurs with comorbid depression (EMwD), 21 episodic migraineurs without depression (EM), and 17 healthy controls (HC). Voxel-based morphometry and resting-state functional connectivity (rsFC) were applied to examine the intergroup differences in amygdala volume. RESULTS: The bilateral amygdala volume was increased in the EMwD and EM groups compared with the HC group, but there were no differences between the EMwD and EM groups. The right CMA exhibited decreased rsFC in the left dorsolateral prefrontal cortex (DLPFC) in the EMwD group compared with the EM group, while rsFC increased between the CMA and the contralateral DLPFC in the EM group compared with the HC group. In addition, the EM group showed decreased rsFC between the left CMA and the left pallidum compared with the HC group. CONCLUSIONS: Enlarged amygdala is an imaging feature of EM and EMwD. The inconsistency of rsFC between CMA and DLPFC between migraineurs with and without depression might indicate that decreased rsFC between CMA and DLPFC is a neuropathologic marker for the comorbidity of migraine and depression. The core regions might be a potential intervention target for the treatment of EMwD in the future.

Development of an innovative turn-on fluorescent probe for targeted in-vivo detection of nitric oxide in rat brain extracts as a biomarker for migraine disease.

Nitric oxide (NO) is one of the reactive nitrogen species (RNS) that has been proposed to be a key signaling molecule in migraine. Migraine is a neurological disorder that is linked to irregular NO levels, which necessitates precise NO quantification for effective diagnosis and treatment. This work introduces a novel fluorescent probe, 2,3-diaminonaphthelene-1,4-dione (DAND), which was designed and synthesized to selectively detect NO in-vitro and in-vivo as a migraine biomarker. DAND boasts high aqueous solubility, biocompatibility, and facile synthesis, which enable highly selective and sensitive detection of NO under physiological conditions. NO reacts with diamine moieties (recognition sites) of DAND, results in the formation of a highly fluorescent product (DAND-NO) known as 1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione at λem 450 nm. The fluorescence turn-on sensing mechanism operates through an intramolecular charge transfer (ICT) mechanism. To maximize fluorescence signal intensity, parameters including DAND concentration, reaction temperature, reaction time and pH were systematically optimized for sensitive and precise NO determination. The enhanced detection capability (LOD = 0.08 µmol L-1) and high selectivity of the probe make it a promising tool for NO detection in brain tissue homogenates. This demonstrates the potential diagnostic value of the probe for individuals suffering from migraine. Furthermore, this study sheds light on the potential role of zolmitriptan (ZOLM), an antimigraine medication, in modulating NO levels in the brain of rats with nitroglycerin-induced migraine, emphasizing its significant impact on reducing NO levels. The obtained results could have significant implications for understanding how ZOLM affects NO levels and may aid in the development of more targeted and effective migraine treatment strategies.

Treatment patterns and characteristics of patients with migraine: results from a retrospective database study in Japan.

BACKGROUND: Clinical characteristics and treatment practice of patients with migraine in Japan in real-world setting have not been fully investigated. We conducted a retrospective cohort study using claims database to understand the clinical practice of migraine in recent years and to characterize patients potentially not managed well by current treatment options. METHODS: Our study used data from the large claims database maintained by JMDC Inc. Patients with diagnosis of headache or migraine between January 1, 2018, and July 31, 2022, were defined as the headache cohort, and those with migraine diagnosis and prescription of migraine treatments among the headache cohort were included in the migraine cohort. In the headache cohort, characteristics of medical facilities and status of imaging tests to distinguish secondary headache were examined. Treatment patterns and characteristics of patients potentially not managed well by acute/preventive treatment were described in migraine cohort. RESULTS: In the headache cohort, 989,514 patients were included with 57.0% females and mean age of 40.3 years; 77.0% patients visited clinics (with ≤ 19 bed capacities) for their primary diagnosis, and 30.3% patients underwent imaging tests (computed tomography and/or magnetic resonance imaging). In the migraine cohort, 165,339 patients were included with 65.0% females and mean age of 38.8 years. In the migraine cohort, 95.6% received acute treatment while 20.8% received preventive treatment. Acetaminophen/non-steroidal anti-inflammatory drugs were most common (54.8%) as the initial prescription for migraine treatment followed by triptan (51.4%). First treatment prescription included preventive treatment in 15.6%, while the proportion increased to 82.2% in the fourth treatment prescription. Among patients with more than 12 months of follow-up, 3.7% had prescription patterns suggestive of risk of medication-overuse headache, and these patients were characterized by a higher percentage of females and a higher prevalence of comorbidities. CONCLUSIONS: This study revealed that approximately one-fifth of the patients with migraine visiting medical facilities use preventive drugs. The presence of potential patients at risk of medication-overuse headache and the role of clinics in migraine treatment were also described.

Comparison of echocardiographic and clinical characteristics in embolic stroke and migraine patients with patent foramen ovale.

BACKGROUND: This single-center observational study aimed to compare the echocardiographic and clinical features in patients diagnosed with migraine and embolic stroke of undetermined source (ESUS) who presented with a known patent foramen ovale (PFO). METHODS: Two-dimensional and color Doppler images were obtained using various transthoracic echocardiography views for both migraine and ESUS patients. Suspected PFO cases underwent further assessment through contrast echocardiography and transesophageal echocardiography (TEE). High-risk PFO characteristics were evaluated using TEE, and the Risk of Paradoxical Embolism (RoPe) score was calculated. RESULTS: The study included 310 participants (age range: 18-60, 73.2% female), with 43.5% diagnosed with migraine and 56.5% with ESUS. Common comorbidities included diabetes (26.1%). High-velocity shunting through the interatrial septum was observed in 35.5% of patients. ESUS patients were older, with higher rates of diabetes and hypertension, while active smoking was more prevalent among migraine patients. Basic echocardiographic parameters were mostly similar, except for elevated pulmonary artery systolic pressure in ESUS. ESUS patients exhibited a greater occurrence of large microbubble passage through the interatrial septum and longer PFO lengths compared to migraine patients. However, the RoPe and High-risk PFO scores were similar between the groups. CONCLUSIONS: ESUS patients, characterized by older age and higher rates of diabetes and hypertension, demonstrated increased pulmonary artery pressure, more significant microbubble crossings, and longer PFO lengths. Conversely, migraine patients had a higher prevalence of active smoking. Despite differing clinical profiles, the risk scores for PFO-related embolic events were comparable between the groups. These findings underscore potential distinctions between ESUS and migraine patients with PFO and their implications for management strategies.

Double-blind, randomized, placebo-controlled study to evaluate erenumab-specific central effects: an fMRI study.

OBJECTIVE: Given the findings of central effects of erenumab in the literature, we aimed to conduct a rigorous placebo-controlled, double-blind, randomized study to elucidate whether the observed changes are directly attributable to the drug. METHODS: We recruited 44 patients with migraine, randomly assigning them to either the erenumab 70 mg or the placebo group. 40 patients underwent fMRI scanning using a trigeminal nociceptive paradigm both, pre- and four weeks post-treatment. Participants kept a headache diary throughout the whole study period of two months in total. A clinical response was defined as a ≥30% reduction in headache frequency at follow-up. Details of this study have been preregistered in the open science framework: https://osf.io/ygf3t . RESULTS: Seven participants of the verum group (n=33.33%) and 4 of the placebo group (21.05%) experienced improvements in migraine activity, characterized by a minimum of 30% reduction in monthly headache frequency compared to baseline. The imaging data show an interaction between the verum medication and the response. Whilst numbers were too small for individual analyses (Verum vs. Placebo and Responder vs. Non-Responder), the variance-weighted analysis (Verum vs Placebo, scan before vs after weighted for response) revealed specific decrease in thalamic, opercular and putamen activity. INTERPRETATION: The central effects of erenumab could be reproduced in a placebo randomized design, further confirming its central role in migraine modulation. The mechanism, whether direct or secondary to peripheral mode of action, needs further exploration. It is important to note that the response rate to erenumab 70mg in this study was not as substantial as anticipated in 2019, when this study was planned. This resulted in a too small sample size for a subgroup analysis based on the responder status was associated with both the verum drug and the relative reduction in headache days.

Dynamics and concordance alterations of regional brain function indices in vestibular migraine: a resting-state fMRI study.

BACKGROUND: Prior MRI studies on vestibular migraine (VM) have revealed abnormalities in static regional intrinsic brain activity (iBA) and dynamic functional connectivity between brain regions or networks. However, the temporal variation and concordance of regional iBA measures remain to be explored. METHODS: 57 VM patients during the interictal period were compared to 88 healthy controls (HC) in this resting-state functional magnetic resonance imaging (fMRI) study. The dynamics and concordance of regional iBA indices, including amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo), were examined by utilizing sliding time-window analysis. Partial correlation analyses were performed between clinical parameters and resting-state fMRI indices in brain areas showing significant group differences. RESULTS: The VM group showed increased ALFF and ReHo dynamics, as well as increased temporal concordance between ALFF and ReHo in the bilateral paracentral lobule and supplementary motor area relative to the HC group. We also found decreased ReHo dynamics in the right temporal pole, and decreased ALFF dynamics in the right cerebellum posterior lobe, bilateral angular gyrus and middle occipital gyrus (MOG) in the VM group compared with the HC group. Moreover, a positive correlation was observed between ALFF dynamics in the left MOG and vertigo disease duration across all VM patients. CONCLUSION: Temporal dynamics and concordance of regional iBA indices were altered in the motor cortex, cerebellum, occipital and temporoparietal cortex, which may contribute to disrupted multisensory processing and vestibular control in patients with VM. ALFF dynamics in the left MOG may be useful biomarker for evaluating vertigo burden in this disorder.

Impaired Glymphatic and Meningeal Lymphatic Functions in Patients with Chronic Migraine.

OBJECTIVE: This study was undertaken to investigate migraine glymphatic and meningeal lymphatic vessel (mLV) functions. METHODS: Migraine patients and healthy controls (HCs) were prospectively recruited between 2020 and 2023. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index for glymphatics and dynamic contrast-enhanced magnetic resonance imaging parameters (time to peak [TTP]/enhancement integral [EI]/mean time to enhance [MTE]) for para-superior sagittal (paraSSS)-mLV or paratransverse sinus (paraTS)-mLV in episodic migraine (EM), chronic migraine (CM), and CM with and without medication-overuse headache (MOH) were analyzed. DTI-ALPS correlations with clinical parameters (migraine severity [numeric rating scale]/disability [Migraine Disability Assessment (MIDAS)]/bodily pain [Widespread Pain Index]/sleep quality [Pittsburgh Sleep Quality Index (PSQI)]) were examined. RESULTS: In total, 175 subjects (112 migraine + 63 HCs) were investigated. DTI-ALPS values were lower in CM (median [interquartile range] = 0.64 [0.12]) than in EM (0.71 [0.13], p = 0.005) and HCs (0.71 [0.09], p = 0.004). CM with MOH (0.63 [0.07]) had lower DTI-ALPS values than CM without MOH (0.73 [0.12], p < 0.001). Furthermore, CM had longer TTP (paraSSS-mLV: 55.8 [12.9] vs 40.0 [7.6], p < 0.001; paraTS-mLV: 51.2 [8.1] vs 44.0 [3.3], p = 0.002), EI (paraSSS-mLV: 45.5 [42.0] vs 16.1 [9.2], p < 0.001), and MTE (paraSSS-mLV: 253.7 [6.7] vs 248.4 [13.8], p < 0.001; paraTS-mLV: 252.0 [6.2] vs 249.7 [1.2], p < 0.001) than EM patients. The MIDAS (p = 0.002) and PSQI (p = 0.002) were negatively correlated with DTI-ALPS index after Bonferroni corrections (p < q = 0.01). INTERPRETATION: CM patients, particularly those with MOH, have glymphatic and meningeal lymphatic dysfunctions, which are highly clinically relevant and may implicate pathogenesis for migraine chronification. ANN NEUROL 2024;95:583-595.

Working memory during spontaneous migraine attacks: an fMRI study.

OBJECTIVE: To investigate the neural correlates of working memory during a spontaneous migraine attack compared to the interictal phase, using functional magnetic resonance imaging (fMRI). BACKGROUND: Cognitive disturbances are commonly observed during migraine attacks, particularly in the headache phase. However, the neural basis of these changes remains unknown. METHODS: In 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). RESULTS: Cognitive 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. CONCLUSION: Migraine 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.

Evaluation of forward head posture and thoracic kyphosis in migraine.

BACKGROUND: The purpose of the current study was to investigate the forward head posture (FHP), thoracic kyphosis and their relationships between individuals with migraine and healthy controls using the DIERS Formetric 4D motion imaging system. METHODS: In this observational case-control study, a total of 39 migraine patients and 44 healthy subjects were enrolled. FHP and thoracic kyphosis were assessed by using the 4D Formetric DIERS system. The visual analogue scale (VAS) and Neck Disability Index (NDI) was used to evaluate neck pain and neck disability. Headache status were evaluated through Migraine Disability Assessment (MIDAS) and Numeric Pain Rating Scale (NPRS) questionnaires. RESULTS: The fleche cervicale (57.72 ± 13.72 mm vs. 40.00 ± 4.75 mm; p < 0.001) and kyphotic angle (57.39 ± 8.76° vs. 38.21 ± 5.67°; p < 0.001) were significantly higher in patients with migraine compared to control group. When NDI categories were compared, the migraine group showed significantly increase in the number of patients with moderate or severe disability (p < 0.001). A positive correlation was found between fleche cervicale and thoracic kyphosis (r = 0.71, p < 0.001). CONCLUSIONS: This study revealed that patients with migraine exhibited a greater FHP and thoracic kyphosis compared to the control group. A 3-dimensional objective measurement may be a reliable diagnostic tool to evaluate posture analysis in clinical practice in the future.

What imaging has revealed about migraine and chronic migraine.

Although migraine pathophysiology is not yet entirely understood, it is now established that migraine should be viewed as a complex neurological disease, which involves the interplay of different brain networks and the release of signaling molecules, instead of a pure vascular disorder. The field of migraine research has also progressed significantly due to the advancement of brain imaging techniques. Numerous studies have investigated the relation between migraine pathophysiology and cerebral hemodynamic changes, showing that vascular changes are neither necessary nor sufficient to cause the migraine pain. Abnormal function and structure of key cortical, subcortical, and brainstem regions involved in multisensory, including pain, processing have been shown to occur in migraine patients during both an acute attack and the interictal phase. Whether brain imaging alterations represent a predisposing trait or are the consequence of the recurrence of headache attacks is still a matter of debate. It is highly likely that brain functional and structural alterations observed in migraine patients derive from the interaction between predisposing brain traits and experience-dependent responses. Neuroimaging studies have also enriched our knowledge of the mechanisms responsible for migraine chronification and have shed light on the mechanisms of actions of acute and preventive migraine treatments.

Changes in the hippocampal volume in chronic migraine, episodic migraine, and medication overuse headache patients.

Background and purpose:

Hippocampi are the structures located in the medial depths of both temporal lobes, mainly responsible for memory, navigation and regulation of emotions, and activated during the processing of pain and the modification of nociceptive stimuli. Chronic pain is thought to have stress-like detrimental modulatory effects on the hippocampal neurogenesis, and adults with chronic pain have been showed to have lower hippocampal volumes. The present study aims to show the relationship between headaches and hippocampal volume by comparing the right, left and total hippocampal volumes of patients with Episodic Migraine (EM), Chronic Migraine (CM) and Medication Overuse Headache (MOH) to those of the healthy control group using the Magnetic Resonance Imaging (MRI) technique, also by looking into the correlation between the number of painful days and attacks and the current hippocampal volumes.

A total of 30 patients (10 EM, 10 CM, 10 MOH) from 18 to 45 years of age diagnosed with migraine and also followed up by the neurology outpatient clinic from February to May 2022 and 30 healthy volunteers of similar ages and sexes to the patient group were included in the study. In addition to the routine cranial MRI protocols of all the participants, further cranial images were taken with the addition of the T1W 3D FSPGR sequence adjusted to the hippocampal body in the coronal plane and covering the whole brain. Hippocampal volumes were measured manually.

There were 27 females and 3 males in the patient group versus 28 females and 2 males in the control group, and no statistically significant differences in age and sex were found between the groups. The control group had higher average right, left and total hippocampal volumes than the whole patient group, but only the total hippocampal volume was significantly different between the groups. There was a negative correlation between the number of painful days and the measured right hippocampal and total hippocampal volumes; however, the measured values were not statistically significant. 

It was concluded that the changes in the hippocampal volume in migraine might be associated with the pain characteristics of the disorder. 

Microstructural differences in migraine: A diffusion-tensor imaging study.

BACKGROUND: Diffusion-tensor imaging can be applied to describe the microstructural integrity of the whole brain. As findings about microstructural alterations in migraine are inconsistent, we aimed to replicate the most frequent results and assess a relationship between migraine parameters and changes in microstructure. METHODS: Diffusion-weighted MRI data of 37 migraine patients and 40 controls were collected. Two indices of diffusion of water molecules, fractional anisotropy and mean diffusivity were used in a voxel-wise analysis. Group comparisons were carried out in SPM12 using age and sex as covariates. Statistically significant results survived family-wise error correction (pFWE < 0.05). Migraine intensity, frequency, and duration were self-reported and correlated with mean fractional anisotropy and mean diffusivity values across clusters. RESULTS: Migraine patients showed significantly lower fractional anisotropy in occipital regions, and significantly higher fractional anisotropy in thirteen clusters across the brain. Mean diffusivity of migraine patients was significantly decreased in the cerebellum and pons, but it was not increased in any area. Correlation between migraine duration and fractional anisotropy was significantly positive in the frontal cortex and significantly negative in the superior parietal lobule. CONCLUSION: We suggest that microstructural integrity of the migraine brain is impaired in visual areas and shows duration-related alterations in regions of the default mode network.

Multilayer network changes in patients with migraine.

INTRODUCTION: To investigate changes in the multilayer network in patients with migraine compared to healthy controls. METHODS: This study enrolled 82 patients with newly diagnosed migraine without aura and 53 healthy controls. Brain magnetic resonance imaging (MRI) was conducted using a 3-tesla MRI scanner, including three-dimensional T1-weighted and diffusion tensor imaging (DTI). A gray matter layer matrix was created with a morphometric similarity network using T1-weighted imaging and the FreeSurfer program. A white matter layer matrix was also created with structural connectivity using the DTI studio (DSI) program. A multilayer network analysis was then performed by applying graph theory using the BRAPH program. RESULTS: Significant changes were observed in the multilayer network at the global level in patients with migraines compared to the healthy controls. The multilayer modularity (0.177 vs. 0.160, p = .0005) and average multiplex participation (0.934 vs. 0.924, p = .002) were higher in patients with migraines than in the healthy controls. In contrast, the average multilayer clustering coefficient (0.406 vs. 0.461, p = .0005), average overlapping strength (56.061 vs. 61.676, p = .0005), and average weighted multiplex participation (0.847 vs. 0.878, p = .0005) were lower in patients with migraine than in the healthy controls. In addition, several regions showed significant changes in the multilayer network at the nodal level, including multiplex participation, multilayer clustering coefficients, overlapping strengths, and weighted multiplex participation. CONCLUSION: This study demonstrated significant changes in the multilayer network in patients with migraines compared to healthy controls. This could aid an understanding of the complex brain network in patients with migraine and may be associated with the pathophysiology of migraines. Patients with migraine show multilayer network changes in widespreading brain regions compared to healthy controls, and specific brain areas seem to play a hub role for pathophysiology of the migraine.

Functional connectivity of the visual cortex in chronic migraine before and after medication withdrawal therapy.

Acute withdrawal of headache medication in chronic migraine patients with medication overuse may lead to a dramatic reduction in headache frequency and severity. However, the brain networks underlying chronic migraine and a favorable response to acute withdrawal are still poorly understood. The goal of the present study was to characterize the pattern of intrinsic magnetic resonance imaging (MRI) functional connectivity (FC) specific to chronic migraine and to identify changes in FC that characterize subjects with CM reverting to less frequent headaches. Subjects with chronic migraine (N = 99) underwent a resting-state functional MRI scan before and after three months of medication withdrawal therapy. In addition, we included four control groups who were scanned once: healthy participants (N = 27), patients with episodic migraine (N = 25), patients with chronic back pain (N = 22), and patients with clinical depression (N = 17). Using dual regression analysis, we compared whole-brain voxel-level functional connectivity with ten well-known resting-state networks between chronic migraine and control groups, and between responders to treatment (≥50 % reduction in monthly headache days) and non-responders (<50 % reduction), before and after treatment. Subjects with chronic migraine showed differences in FC with a number of RS-networks, most of which involved the visual cortex, compared with healthy controls. A comparison with patients with episodic migraine, chronic pain and depression showed differences in the same direction, suggesting that altered patterns of functional connectivity in chronic migraine patients could to some extent be explained by shared symptomatology with other pain, depression, or migraine conditions. A comparison between responders and non-responders indicated that effective withdrawal reduced FC with the visual cortex for responders. Interestingly, responders already differed in functional connectivity of the visual cortex at baseline compared with non-responders. Altogether, we show that chronic migraine and successful medication withdrawal therapy are linked to changes in the functional connectivity of the visual cortex. These neuroimaging findings provide new insights into the pathways underlying migraine chronification and its reversibility.

Increased glymphatic system activity in migraine chronification by diffusion tensor image analysis along the perivascular space.

BACKGROUND: Preliminary evidence suggests that several headache disorders may be associated with glymphatic dysfunction. However, no studies have been conducted to examine the glymphatic activity in migraine chronification. PURPOSES: To investigate the glymphatic activity of migraine chronification in patients with episodic migraine (EM) and chronic migraine (CM) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. METHODS: In this cross-sectional study, patients with EM, CM, and healthy controls (HCs) were included. All participants underwent a standard brain magnetic resonance imaging (MRI) examination. Bilateral DTI-ALPS indexes were calculated for all participants and compared among EM, CM, and HC groups. Correlations between the DTI-ALPS index and clinical characteristics were analyzed. RESULTS: A total of 32 patients with EM, 24 patients with CM, and 41 age- and sex-matched HCs were included in the analysis. Significant differences were found in the right DTI-ALPS index among the three groups (p = 0.011), with CM showing significantly higher values than EM (p = 0.033) and HCs (p = 0.015). The right DTI-ALPS index of CM group was significantly higher than the left DTI-ALPS index (p = 0.005). And the headache intensity was correlated to DTI-ALPS index both in the left hemisphere (r = 0.371, p = 0.011) and in the right hemisphere (r = 0.307, p = 0.038), but there were no correlations after Bonferroni correction. CONCLUSIONS: Glymphatic system activity is shown to be increased instead of impaired during migraine chronification. The mechanism behind this observation suggests that increased glymphatic activity is more likely to be a concomitant phenomenon of altered vascular reactivity associated with migraine pathophysiology rather than a risk factor of migraine chronification.

Hyperperfusion of bilateral amygdala in patients with chronic migraine: an arterial spin-labeled magnetic resonance imaging study.

BACKGROUND: Amygdala, an essential element of the limbic system, has served as an important structure in pain modulation. There is still a lack of clarity about altered cerebral perfusion of amygdala in migraine. This study aimed to investigate the perfusion variances of bilateral amygdala in episodic migraine (EM) and chronic migraine (CM) using multi-delay pseudo-continuous arterial spin-labeled magnetic resonance imaging (pCASL-MRI). METHODS: Twenty-six patients with EM, 55 patients with CM (33 CM with medication overuse headache (MOH)), and 26 age- and sex-matched healthy controls (HCs) were included. All participants underwent 3D multi-delay pCASL MR imaging to obtain cerebral perfusion data, including arrival-time-corrected cerebral blood flow (CBF) and arterial cerebral blood volume (aCBV). The CBF and aCBV values in the bilateral amygdala were compared among the three groups. Correlation analyses between cerebral perfusion parameters and clinical variables were performed. RESULTS: Compared with HC participants, patients with CM were found to have increased CBF and aCBV values in the left amygdala, as well as increased CBF values in the right amygdala (all P < 0.05). There were no significant differences of CBF and aCBV values in the bilateral amygdala between the HC and EM groups, the EM and CM groups, as well as the CM without and with MOH groups (all P > 0.05). In patients with CM, the increased perfusion parameters of bilateral amygdala were positively correlated with MIDAS score after adjustments for age, sex, and body mass index (BMI). CONCLUSION: Hyperperfusion of bilateral amygdala might provide potential hemodynamics evidence in the neurolimbic pain network of CM.