Structural and functional brain changes in migraine

Migraine is a prevalent primary headache disorder and is usually considered as benign. However, structural and functional changes in the brain of individuals with migraine have been reported. High frequency of white matter abnormalities, silent infarct-like lesions, and volumetric changes in both gray and white matter in individuals with migraine compared to controls have been demonstrated. Functional magnetic resonance imaging (MRI) studies found altered connectivity in both the interictal and ictal phase of migraine. MR spectroscopy and positron emission tomography studies suggest abnormal energy metabolism and mitochondrial dysfunction, as well as other metabolic changes in individuals with migraine. In this review, we provide a brief overview of neuroimaging studies that have helped us to characterize some of these changes and discuss their limitations, including small sample sizes and poorly defined control groups. A better understanding of alterations in the brains of patients with migraine could help not only in the diagnosis but may potentially lead to the optimization of a targeted anti-migraine therapy

Corticosterone enhances CSD susceptibility via glucocorticoid receptor activation in familial hemiplegic migraine 1 Cacna1a knock-in mice

Paroxysmal Cerebral Disorder

Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties

Functional analysis of missense variants in the TRESK (KCNK18) K+ channel

A loss of function mutation in the TRESK K2P potassium channel (KCNK18), has recently been linked with typical familial migraine with aura. We now report the functional characterisation of additional TRESK channel missense variants identified in unrelated patients. Several variants either had no apparent functional effect, or they caused a reduction in channel activity. However, the C110R variant was found to cause a complete loss of TRESK function, yet is present in both sporadic migraine and control cohorts, and no variation in KCNK18 copy number was found. Thus despite the previously identified association between loss of TRESK channel activity and migraine in a large multigenerational pedigree, this finding indicates that a single non-functional TRESK variant is not alone sufficient to cause typical migraine and highlights the genetic complexity of this disorder

Potential Role of Aromatase over Estrogen Receptor Gene Polymorphisms in Migraine Susceptibility: A Case Control Study from North India

BACKGROUND: The present study was undertaken to find out the role of estrogen pathway related gene polymorphisms in susceptibility to migraine in Northern Indian population. Aromatase, CYP19A1 (rs10046 and rs4646); estrogen receptors, ESR1 (rs2234693, rs1801132, rs2228480 and rs9340799) and ESR2 (rs1271572 and rs1256049) polymorphisms were selected for the present study. METHODOLOGY/PRINCIPAL FINDINGS: The patients were recruited in two cohorts - primary (207) and replicative (127) along with 200 healthy controls and genotyped for various polymorphisms. Logistic regression analysis was applied for statistical analyses. The results were validated in the replicative cohort and pooled by meta analysis using Fisher's and Mantel-Haenszel test. Furthermore, Benjamini - Hochberg false discovery rate test was used to correct for multiple comparisons. CYP19A1 rs10046 and CYP19A1 rs4646 polymorphisms were found to confer risk and protective effect, respectively. Out of four ESR1 polymorphisms, only rs2234693 variant allele was significantly associated in migraine with aura. No significant associations were observed for ESR2 polymorphisms. Significant haplotypes were identified for CYP19A1 and ESR1 polymorphisms. Gene- gene interactions of genotypes as well as haplotypes were observed for CYP19A1- ESR1 showing both risk and protective combinations. CONCLUSION: We strongly suggest CYP19A1 polymorphisms to be the major contributing factors in migraine susceptibility instead of genetic variants of estrogen receptors

Migraine headaches in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>Headaches are more frequent in Chronic Fatigue Syndrome (CFS) than healthy control (HC) subjects. The 2004 International Headache Society (IHS) criteria were used to define CFS headache phenotypes.</p> <p>Methods</p> <p>Subjects in Cohort 1 (HC = 368; CFS = 203) completed questionnaires about many diverse symptoms by giving nominal (yes/no) answers. Cohort 2 (HC = 21; CFS = 67) had more focused evaluations. They scored symptom severities on 0 to 4 anchored ordinal scales, and had structured headache evaluations. All subjects had history and physical examinations; assessments for exclusion criteria; questionnaires about CFS related symptoms (0 to 4 scale), Multidimensional Fatigue Inventory (MFI) and Medical Outcome Survey Short Form 36 (MOS SF-36).</p> <p>Results</p> <p>Demographics, trends for the number of diffuse "functional" symptoms present, and severity of CFS case designation criteria symptoms were equivalent between CFS subjects in Cohorts 1 and 2. HC had significantly fewer symptoms, lower MFI and higher SF-36 domain scores than CFS in both cohorts. Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC. The CFS group had migraine without aura (60%; MO; CFS+MO), with aura (24%; CFS+MA), tension headaches only (12%), or no headaches (4%). Co-morbid tension and migraine headaches were found in 67% of CFS. CFS+MA had higher severity scores than CFS+MO for the sum of scores for poor memory, dizziness, balance, and numbness ("Neuro-construct", p = 0.002) and perceived heart rhythm disturbances, palpitations and noncardiac chest pain ("Cardio-construct"; p = 0.045, t-tests after Bonferroni corrections). CFS+MO subjects had lower pressure-induced pain thresholds (2.36 kg [1.95-2.78; 95% C.I.] n = 40) and a higher prevalence of fibromyalgia (47%; 1990 criteria) compared to HC (5.23 kg [3.95-6.52] n = 20; and 0%, respectively). Sumatriptan was beneficial for 13 out of 14 newly diagnosed CFS migraine subjects.</p> <p>Conclusions</p> <p>CFS subjects had higher prevalences of MO and MA than HC, suggesting that mechanisms of migraine pathogenesis such as central sensitization may contribute to CFS pathophysiology.</p> <p>Clinical Trial Registration</p> <p>Georgetown University IRB # 2006-481</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00810329">NCT00810329</a></p

Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization

Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection