Abnormal Thalamo-Cortical Interactions in Overlapping Communities of Migraine: An Edge Functional Connectivity Study.

OBJECTIVE: Migraine has been demonstrated to exhibit abnormal functional connectivity of large-scale brain networks, which is closely associated with its pathophysiology and has not yet been explored by edge functional connectivity. We used an edge-centric approach combined with motif analysis to evaluate higher-order communication patterns of brain networks in migraine. METHODS: We investigated edge-centric metrics in 108 interictal migraine patients and 71 healthy controls. We parcellated the brain into networks using independent component analysis. We applied edge graph construction, k-means clustering, community overlap detection, graph-theory-based evaluations, and clinical correlation analysis. We conducted motif analysis to explore the interactions among regions, and a classification model to test the specificity of edge-centric results. RESULTS: The normalized entropy of lateral thalamus was significantly increased in migraine, which was positively correlated with the baseline headache duration, and negatively correlated with headache duration reduction following preventive medications at 3-month follow-up. Network-wise entropy of the sensorimotor network was significantly elevated in migraine. The community similarity between lateral thalamus and postcentral gyrus was enhanced in migraine. Migraine patients showed overrepresented L-shape and diverse motifs, and underrepresented forked motifs with lateral thalamus serving as the reference node. Furthermore, migraine patients presented with overrepresented L-shape triads, where the postcentral gyrus shared different edges with the lateral thalamus. The classification model showed that entropy of the lateral thalamus had the highest discriminative power, with an area under the curve of 0.86. INTERPRETATION: Our findings indicated an abnormal higher-order thalamo-cortical communication pattern in migraine patients. The thalamo-cortical-somatosensory disturbance of concerted working may potentially lead to aberrant information flow and deficit pain processing of migraine. ANN NEUROL 2023;94:1168-1181.

Altered functional connectivity of the thalamus and salience network in patients with cluster headache: a pilot study.

BACKGROUND AND OBJECTIVE: Previous studies have shown that the salience network (SN) and the thalamus are involved in cluster headache (CH) attacks. However, very little is known regarding the altered thalamus-SN functional connectivity in CH. The aim of this study was to explore alterations of functional connectivity between the thalamus and the SN in patients with CH to further gain insight into the pathophysiology of CH. MATERIALS AND METHODS: The resting-state functional MRI (rs-fMRI) data of 21 patients with CH in the headache attack remission state during in-bout periods and 21 age- and sex-matched normal controls were obtained. The rs-fMRI data were analyzed by the independent component analysis (ICA) method, and the thalamus-SN functional connectivity in patients with right-sided and left-sided CH was compared with that in normal controls. RESULTS: Decreased functional connectivity was found between the thalamus, both ipsilateral and contralateral to the headache side, and the SN during headache remission state in both right-sided CH patients and left-sided CH patients. CONCLUSIONS: The findings suggest that the decreased functional connectivity between the thalamus and SN might be one of the pathologies underpinning the CH. This helps us to understand better the nature of the brain dysfunction in CH and the basic pathologies of CH, which implies that this deserves further investigation.

Cortical mechanisms in migraine.

Migraine is the second most prevalent disorder in the world; yet, its underlying mechanisms are still poorly understood. Cumulative studies have revealed pivotal roles of cerebral cortex in the initiation, propagation, and termination of migraine attacks as well as the interictal phase. Investigation of basic mechanisms of the cortex in migraine not only brings insight into the underlying pathophysiology but also provides the basis for designing novel treatments. We aim to summarize the current research literatures and give a brief overview of the cortex and its role in migraine, including the basic structure and function; structural, functional, and biochemical neuroimaging; migraine-related genes; and theories related to cortex in migraine pathophysiology. We propose that long-term plasticity of synaptic transmission in the cortex encodes migraine.

Enhanced functional connectivity between habenula and salience network in medication-overuse headache complicating chronic migraine positions it within the addiction disorders: an ICA-based resting-state fMRI study.

BACKGROUND: Medication-overuse headache (MOH) is a relatively frequently occurring secondary headache caused by overuse of analgesics and/or acute migraine medications. It is believed that MOH is associated with dependence behaviors and substance addiction, in which the salience network (SN) and the habenula may play an important role. This study aims to investigate the resting-state (RS) functional connectivity between the habenula and the SN in patients with MOH complicating chronic migraine (CM) compared with those with episodic migraine (EM) and healthy controls (HC). METHODS: RS-fMRI and 3-dimensional T1-weighted images of 17 patients with MOH + CM, 18 patients with EM and 30 matched healthy HC were obtained. The RS-fMRI data were analyzed using the independent component analysis (ICA) method to investigate the group differences of functional connectivity between the habenula and the SN in three groups. Correlation analysis was performed thereafter with all clinical variables by Pearson correlation. RESULTS: Increased functional connectivity between bilateral habenula and SN was detected in patients with MOH + CM compared with patients with EM and HC respectively. Correlation analysis showed significant correlation between medication overuse duration and habenula-SN connectivity in MOH + CM patients. CONCLUSIONS: The current study supported MOH to be lying within a spectrum of dependence and addiction disorder. The enhanced functional connectivity of the habenula with SN may correlate to the development or chronification of MOH. Furthermore, the habenula may be an indicator or treatment target for MOH for its integrative role involved in multiple aspects of MOH.

Proposed modified diagnostic criteria for recurrent painful ophthalmoplegic neuropathy: Five case reports and literature review.

BACKGROUND: Recurrent painful ophthalmoplegic neuropathy (RPON) is an uncommon disorder characterized by recurrent unilateral headache attacks associated with ipsilateral ophthalmoplegia. We intend to study the clinical picture in our case series along with the published literature to discuss the pathogenesis and propose modified diagnostic criteria for recurrent painful ophthalmoplegic neuropathy. METHODS: We reported five cases diagnosed as ophthalmoplegic migraine/RPON in our medical centers and reviewed the published literature related to RPON from the Pubmed database between 2000 and 2020. In one of these cases, a multiplanar reformation was performed to look at the aberrant cranial nerve. RESULTS: The mean onset age for RPON was 22.1 years, and the oculomotor nerve was the most commonly involved cranial nerve (53.9%) in 165 reviewed patients. In most patients, ophthalmoplegia started within 1 week of the headache attack (95.7%, 67/70). Additionally, 27.6% (40/145) of patients presented enhancement of the involved nerve(s) from MRI tests. Finally, 78 patients received corticosteroids, out of which 96.2% benefited from them. CONCLUSION: This is the first time multiplanar reformation has been performed to reveal the distortion of the oculomotor nerve. Modified diagnostic criteria are proposed. We hope to expand the current knowledge and increase the detection of recurrent painful ophthalmoplegic neuropathy in the future.

A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2.

BACKGROUND: ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation. METHODS: Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. RESULTS: All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability. CONCLUSION: G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit.

Effects of differences in serum total homocysteine, folate, and vitamin B12 on cognitive impairment in stroke patients.

BACKGROUND: Vascular cognitive impairment-no dementia (VCIND) refers to the early or mild cognitive impairment induced by cerebral vascular injury. Research shows that serum total homocysteine (tHcy) level is an independent risk factor for cerebral vascular disease and may be closely related to cognitive function.Current studies on the tHcy level in VCIND patients are limited, and the relationship of tHcy with cognitive function remains unclear. This study aims to investigate the tHcy levels in patients with VCIND and to determine their correlation with cognitive function, as well as to provide useful clues for preventing and treating VCIND. METHODS: The tHcy, folate, and vitamin B12 levels in 82 patients with VCIND were reviewed retrospectively and compared with those of 80 stroke patients without cognitive impairment and 69 healthy controls by using the Montreal Cognitive Assessment (MoCA) scale and the event-related potential P300 to evaluate cognitive function. RESULTS: The tHcy levels in the VCIND group were higher than those in the other two groups, whereas the folate and Vitamin B12 levels in the VCIND group were lower than those of the other two groups. The tHcy levels in the stroke group were higher than those in the control group, and the folate and vitamin B12 levels in the stroke group were lower than those in the control group. The patients in the VCIND group with high tHcy exhibited lower MoCA scores and prolonged P300 latency than those in with normal tHcy. Correlation analysis showed that tHcy level is positively correlated with P300 latency period and negatively correlated with MoCA score. CONCLUSION: The tHcy levels were significantly higher and the vitamin B12 and folate levels were significantly lower in the patients with VCIND than those in the other groups. The high tHcy levels in the VCIND patients may be correlated with impaired cognitive function.

Protection of flunarizine on cerebral mitochondria injury induced by cortical spreading depression under hypoxic conditions.

A rat cortical spreading depression (CSD) model was established to explore whether cerebral mitochondria injury was induced by CSD under both normoxic and hypoxic conditions and whether flunarizine had a protective effect on cerebral mitochondria. SD rats, which were divided into seven groups, received treatment as follows: no intervention (control Group I); 1 M NaCl injections (Group II); 1 M KCl injections (Group III); intraperitoneal flunarizine (3 mg/kg) 30 min before KCl injections (Group IV); 14% O(2) inhalation before NaCl injections (Group V); 14% O(2) inhalation followed by KCl injections (Group VI); 14% O(2) inhalation and intraperitoneal flunarizine followed by KCl injections (Group VII). Following treatment, brains were removed for the analysis of mitochondria transmembrane potential (MMP) and oxidative respiratory function after recording the number, amplitude and duration of CSD. The duration of CSD was significantly longer in Group VI than that in Group III. The number and duration of CSD in Group VII was significantly lower than that in Group VI. MMP in Group VI was significantly lower than that in Group III, and MMP in Group VII was significantly higher than that in Group VI. State 4 respiration in Group VI was significantly higher than that in Group III, and state 3 respiration in Group VII was significantly higher than that in Group VI. Respiration control of rate in Group VII was also significantly higher than that in Group VI. Thus, we concluded that aggravated cerebral mitochondria injury might be attributed to CSD under hypoxic conditions. Flunarizine can alleviate such cerebral mitochondria injury under both normoxic and hypoxic conditions.

Association between homocysteine and multivascular atherosclerosis in stroke-related vascular beds determined by three-dimensional magnetic resonance vessel wall imaging.

BACKGROUND: Atherosclerosis in stroke-related vascular beds is the major cause of stroke. Studies demonstrated that multivascular atherosclerosis is prevalent in stroke patients and those with multivascular plaques had higher risk of recurrent stroke. OBJECTIVES: This study investigated the relationship between homocysteine and multivascular atherosclerosis in stroke-related vascular beds using magnetic resonance imaging. METHODS: Patients with recent ischemic cerebrovascular symptoms were enrolled and underwent three-dimensional magnetic resonance vessel wall imaging for intracranial arteries, extracranial carotid arteries and aortic arch. Traditional risk factors and homocysteine were measured. Presence of multivascular plaques defined as plaques in at least two stroke-related vascular beds on magnetic resonance imaging was determined. The relationship between homocysteine and characteristics of multivascular plaques was determined. RESULTS: Of 49 enrolled patients (mean age: 56.3 ±â€¯13.8 years; 35 males), 23 had multivascular plaques. Homocysteine (odds ratio, 1.17; 95% confidence interval, 1.02-1.34; p = 0.022) and age (odds ratio, 1.71; 95% confidence interval, 1.22-2.41; p = 0.002) were significantly associated with presence of multivascular plaques. The adjusted associations remained significant (both p < 0.05). In discriminating presence of multivascular plaques, the area-under-the-curve of age, homocysteine and combination of them was 0.79, 0.70 and 0.87 respectively. CONCLUSIONS: Homocysteine is independently associated with stroke-related multivascular plaques and combination of age and homocysteine has stronger predictive value.

[A retrospective study of clinical features of migraine].

OBJECTIVE: To observe the clinical features of migraine based on out-patient clinic data and provide help for the diagnosis and treatment of migraine. METHODS: In a retrospective study of 309 patients with migraine, we investigated the clinical characteristics of migraine of both genders and different types, and the risk factors for MOH transformed from migraine. RESULTS: The female to male ratio was about 3:1, 76.1% of the patients had triggering factors. The most common characteristics of headache were moderate to severe intensity of the pain (97.7%), aggravation by routine physical activity (75.1%), and association with nausea (90.9%) and/or vomiting (70.6%). There were significant differences in some clinical characteristics of migraine in females as compared with those in males and in patients with migraine without aura (MWOA) as compared with those with aura (MWA). The risk factors for MOH transformed from migraine were elder age of onset, high attack frequency and the analgesics frequently used (P < 0.05). CONCLUSION: It is suggested that carefully collecting the characteristics of headache, triggering factors and therapeutic history is the foundation of correct diagnosis and effective treatment for migraine.

Abnormal coactivation of the hypothalamus and salience network in patients with cluster headache.

OBJECTIVE: The purpose of this study was to investigate whether the resting-state coactivation of the hypothalamus, both ipsilateral and contralateral to the headache side, and the salience network (SN) was altered in patients with cluster headache (CH) in the headache attack remission state in the cluster period, and to reveal possible pathogenesis of CH attacks and gain further insight into the pathophysiology of CH. METHODS: Resting-state fMRI scans of 21 patients with CH were obtained (13 with right-sided headache and 8 with left-sided headache) and 21 age- and sex-matched normal controls. The resting-state fMRI data were analyzed using independent component analysis to identify the group differences of hypothalamic-SN coactivation between the patients with CH and healthy controls. RESULTS: Decreased functional coactivation was detected between the hypothalamus, both ipsilateral and contralateral to the headache side, and the SN both in patients with right-sided CH and in those with left-sided CH. CONCLUSION: Our findings suggest that the decreased hypothalamus-SN coactivation may have a role in CH attacks by the defective central pathway of pain control and autonomic nervous system dysregulation. This helps to gain additional insight into the pathophysiologic basis of CH and the nature of the brain dysfunction in CH.

Microarray analysis of gene expression after electrical stimulation of the dura mater surrounding the superior sagittal sinus in conscious adult rats.

BACKGROUND: The molecular and cellular origins of migraine headache are among the most complex problems in contemporary neurology. Up to now the pathogenesis of migraine still remains unclearly defined. The objective of this study was to explore new factors that may be related to the mechanism of migraine. METHODS: The present study performed a comprehensive analysis of gene expression in the trigeminal nucleus caudalis induced by electrical stimulation of dura mater surrounding the superior sagittal sinus in conscious rats using microarray analysis followed by quantitative real-time reverse-transcribed polymerase chain reaction (qRT-PCR) verification. Student's two sample t-test was employed when two groups were compared. A P value <0.05 was considered to be statistically significant. RESULTS: Comparing the placebo and the electrical stimulation groups, 40 genes were determined to be significantly differentially expressed. These significantly differentially expressed genes were involved in many pathways, including transporter activity, tryptophan metabolism, G protein signaling, kinase activity, actin binding, signal transducer activity, anion transport, protein folding, enzyme inhibitor activity, coenzyme metabolism, binding, ion transport, cell adhesion, metal ion transport, oxidoreductase activity, mitochondrion function, and others. Most of the genes were involved in more than 2 pathways. Of particular interest is the up-regulation of Phactr3 and Akap5 and the down-regulation of Kdr. CONCLUSION: These findings may provide important clues for a better understanding of the molecular mechanism of migraine.

Abnormal brain functional connectivity of the hypothalamus in cluster headaches.

The aim of this study was to detect the abnormality of the brain functional connectivity of the hypothalamus during acute spontaneous cluster headache (CH) attacks ('in attack') and headache-free intervals ('out of attack') using resting-state functional magnetic resonance imaging (RS-fMRI) technique. The RS-fMRI data from twelve male CH patients during 'in attack' and 'out of attack' periods and twelve age- and sex-matched normal controls were analyzed by the region-of-interest -based functional connectivity method using SPM5 software. Abnormal brain functional connectivity of the hypothalamus is present in CH, which is located mainly in the pain system during the spontaneous CH attacks. It extends beyond the pain system during CH attack intervals.

Polysomnographic abnormalities in patients with vascular cognitive impairment-no dementia.

OBJECTIVES: We aimed to investigate subjective sleep quality and polysomnographic sleep structure features in patients with vascular cognitive impairment-no dementia (VCIND). METHODS: Fifty-six patients with VCIND, 48 patients with simple stroke (without cognitive impairment), and 48 control subjects were included. The Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG) were used to analyze their sleep characteristics. The Montreal Cognitive Assessment (MoCA) was conducted to assess mental state. RESULTS: Patients with VCIND had higher PSQI scores compared with control subjects and simple stroke patients (P<.01). PSG revealed that patients with VCIND or stroke were more likely to experience prolonged sleep latency (SL), decreased sleep efficiency (SE), increased arousal, and reduced deep sleep and rapid eye movement (REM) sleep than controls. Patients with VCIND had significantly longer SL, increased periodic leg movements in sleep (PLMS), decreased SE, and increased arousal and sleep fragmentation compared to patients with simple stroke (P<.05). In VCIND patients, a significant positive correlation was found between SE and MoCA scores (r=0.632; P<.001), though PSQI, SL, and arousal index were significantly negatively associated with MoCA scores (r=-0.787, -0.740, -0.772, respectively; P<.001 for all). CONCLUSIONS: VCIND patients had different abnormal sleep features, including decreased SE, increased PLMS, and prolonged SL and sleep fragmentation. Abnormal sleep in VCIND may be associated with cognitive impairment.

Gene expression microarray analysis of the spinal trigeminal nucleus in a rat model of migraine with aura.

Cortical spreading depression can trigger migraine with aura and activate the trigeminal vascular system. To examine gene expression profiles in the spinal trigeminal nucleus in rats following cortical spreading depression-induced migraine with aura, a rat model was established by injection of 1 M potassium chloride, which induced cortical spreading depression. DNA microarray analysis revealed that, compared with the control group, the cortical spreading depression group showed seven upregulated genes-myosin heavy chain 1/2, myosin light chain 1, myosin light chain (phosphorylatable, fast skeletal muscle), actin alpha 1, homeobox B8, carbonic anhydrase 3 and an unknown gene. Two genes were downregulated-RGD1563441 and an unknown gene. Real-time quantitative reverse transcription-PCR and bioinformatics analysis indicated that these genes are involved in motility, cell migration, CO2/nitric oxide homeostasis and signal transduction.

Altered regional homogeneity in spontaneous cluster headache attacks: a resting-state functional magnetic resonance imaging study.

BACKGROUND: Functional neuroimaging study has opened an avenue for exploring the pathophysiology of cluster headache (CH). The aim of our study was to assess the changes in brain activity in CH patients by the regional homogeneity method using resting-state functional magnetic resonance imaging technique. METHODS: The functional magnetic resonance imaging scans were obtained for 12 male CH patients with spontaneous right-sided headache attacks during "in attack" and "out of attack" periods and 12 age- and sex-matched normal controls. The data were analyzed to detect the altered brain activity by the regional homogeneity method using statistical parametric mapping software. RESULTS: Altered regional homogeneity was detected in the anterior cingulate cortex, the posterior cingulate cortex, the prefrontal cortex, insular cortex, and other brain regions involved in pain processing and modulation among different groups. CONCLUSION: It is referred that these brain regions with altered regional homogeneity might be related to the pain processing and modulation of CH.

[Effect of electroacupuncture on cortical spreading depression and plasma CGRP and substance P contents in migraine rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on cortical spreading depression (CSD) and contents of plasma calcitonin gene-related peptide (CGRP) and substance P (SP) in migraine rats. METHODS: Thirty male SD rats were equally randomized into control, model and EA groups. Migraine model was established by topical application of KCI (3 mol/L) immersed in a piece of filter paper to the cerebral cortex (parietal lobe, 6 mm posterior to the Bregma and 5 mm to the sagital fissure) after exposure of the skull (in reference to Michael' method). KCI stimulation evoked CSD potentials (3 mm rostral to the Bregma, and 2 mm to the sagital fissure) were recorded by using a glass microelectrode. For rats of control group, filter paper containing 0.9% NaCl was applied to the same parietal cortex area. EA (1 mA, 2 Hz/100 Hz) was applied to bilateral "Yanglingquan" (GB 34) and "Taichong" (LR 3) for 30 min. The contents of plasma CGRP and SP were assayed by radioimmunoassay. RESULTS: CSD was induced 3-5 min after application of KCI to the parietal lobe. The average amplitude of model group was (-25.13 +/- 1.23) mV, and that of EA group was (-19.19 +/- 1.53) mV, displaying a significant reduction of CSD amplitude after EA (P < 0.01). Comparison among 3 groups showed that both plasma CGRP and SP contents in model group were significantly higher than those of control group (P < 0.001, P < 0.01), while compared with model group, plasma CGRP and SP levels in EA group decreased considerably (P < 0.05, P < 0.001), suggesting an inhibitory effect of EA on pain-producing substance. CONCLUSION: EA of GB 34 and LR 3 can effectively suppress KCI provoked cortical spreading depression and plasma CGRP and SP levels in the rat, which may contribute to its effect in relieving migraine in clinic.