Spontaneous migraine attack causes alterations in default mode network connectivity

BACKGROUND: Although migraine is one of the most investigated neurologic disorders, we do not have a perfect neuroimaging biomarker for its pathophysiology. One option to improve our knowledge is to study resting-state functional connectivity in and out of headache pain. However, our understanding of the functional connectivity changes during spontaneous migraine attack is partial and incomplete. CASE PRESENTATION: Using resting-state functional magnetic resonance imaging we assessed a 24-year old woman affected by migraine without aura at two different times: during a spontaneous migraine attack and in interictal phase. Seed-to-voxel whole brain analysis was carried out using the posterior cingulate cortex as a seed, representing the default mode network (DMN). Our results showed decreased intrinsic connectivity within core regions of the DMN with an exception of a subsystem including the dorsal medial and superior frontal gyri, and the mid-temporal gyrus which is responsible for pain interpretation and control. In addition, increased connectivity between the DMN and pain and specific migraine-related areas, such as the pons and hypothalamus, developed during the spontaneous migraine attack. CONCLUSION: Our preliminary results provide further support for the hypothesis that alterations of the DMN functional connectivity during migraine headache may lead to maladaptive top-down modulation of migraine pain-related areas which might be a specific biomarker for migraine

Rumination in Migraine: Mediating Effects of Brooding and Reflection between Migraine and Psychological Distress

OBJECTIVE: The relationship between migraine and psychological distress has been consistently reported in cross-sectional and longitudinal studies. We hypothesized that a stable tendency to perseverative thoughts such as rumination would mediate the relationship between migraine and psychological distress. Design and Main Outcomes Measures: Self-report questionnaires measuring depressive rumination, current psychological distress and migraine symptoms in two independent European population cohorts, recruited from Budapest (N=1139) and Manchester (N=2004), were used. Structural regression analysis within structural equation modelling was applied to test the mediational role of brooding and reflection, the components of rumination, between migraine and psychological distress. Sex, age and lifetime depression were controlled for in the analysis. RESULTS: Migraine predicted higher brooding and reflection scores, and brooding proved to be a mediator between migraine and psychological distress in both samples, while reflection mediated the relationship significantly only in the Budapest sample. CONCLUSIONS: Elevated psychological distress in migraine is partially attributed to ruminative response style. Further studies are needed to expand our findings to clinical samples and to examine how rumination links to the adjustment to migraine

Preoptic leptin signaling modulates energy balance independent of body temperature regulation

© Yu et al. The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight

Analysis of responses to the TRPV4 agonist GSK1016790A in the pulmonary vascular bed of the intact-chest rat

The transient receptor potential vanilloid 4 (TRPV4) channel is a nonselective cation channel expressed on many cell types, including the vascular endothelium and smooth muscle cells. TRPV4 channels play a role in regulating vasomotor tone and capillary permeability. The present study was undertaken to investigate responses to the TRPV4 agonist GSK101790A on the pulmonary and systemic vascular beds in the rat. Intravenous injection of GSK1016790A at doses of 2–10 μg/kg produced dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and small increases in cardiac output, and responses were not altered by the cyclooxygenase inhibitor meclofenamate or the cytochrome P-450 inhibitor miconazole. Injection of GSK1016790A at a dose of 12 μg/kg iv produced cardiovascular collapse that was reversible in some animals. GSK1016790A produced dose-related decreases in pulmonary and systemic arterial pressure when baseline tone in the pulmonary vascular bed was increased with U-46619. After treatment with the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester, GSK1016790A produced larger decreases in systemic arterial pressure and dose-dependent increases in pulmonary arterial pressure followed by a small decrease. These results demonstrate that GSK1016790A has vasodilator activity in pulmonary and systemic vascular beds and that when NOS is inhibited, GSK1016790A produced pulmonary vasoconstrictor responses that were attenuated by the L-type Ca2+ channel antagonist isradipine. The presence of TRPV4 immunoreactivity was observed in small pulmonary arteries and airways. The present data indicate that responses to TRPV4 are modulated differently by NOS in pulmonary and systemic vascular beds and are attenuated by the TRPV4 antagonist GSK2193874. </jats:p

ASSOCIATION ANALYSIS OF 5-HTTLPR VARIANTS, 5-HT2A RECEPTOR GENE 102T/C POLYMORPHISM AND MIGRAINE

It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. There is evidence to suggest that serotonin-related genes participate in the pathogenesis of migraine. Previous studies have shown that gender differences influence the serotonergic neurotransmission and, in addition, the migraine prevalence is higher in females than males. Therefore, we investigated the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the 102T/C polymorphism of the 5-HT2A receptor gene in the Hungarian female population. These genes were analysed in 126 migraine sufferers (with or without aura)and 101 unrelated healthy controls using case control design. A borderline association (chi2 = 3.84, df = 1, p = 0.049; OR = 1.45, 95% CI = 1.00-2.12) between 5-HTTLPR short (S) allele and migraine was found. No significant difference between migraine sufferers and controls was observed for the 102T/C polymorphism of 5-HT2A receptor gene. Furthermore, there was no significant interaction between5-HTTLPR and 102T/C polymorphisms in our study population. In conclusion, our results support that the genetic susceptibility of migraine may be associated with a locus at or near the 5-HT transporter gene

Activation of ADAM17 (A Disintegrin and Metalloprotease 17) on Glutamatergic Neurons Selectively Promotes Sympathoexcitation

Chronic activation of the brain renin-angiotensin system contributes to the development of hypertension by altering autonomic balance. Beyond the essential role of Ang II (angiotensin II) type 1 receptors, ADAM17 (A disintegrin and metalloprotease 17) is also found to promote brain renin-angiotensin system overactivation. ADAM17 is robustly expressed in various cell types within the central nervous system. The aim of this study was to determine whether ADAM17 modulates presympathetic neuronal activity to promote autonomic dysregulation in salt-sensitive hypertension. To test our hypothesis, ADAM17 was selectively knocked down in glutamatergic neurons using Cre-loxP technology. In mice lacking ADAM17 in glutamatergic neurons, the blood pressure increase induced by deoxycorticosterone acetate-salt treatment was blunted. Deoxycorticosterone acetate-salt significantly elevated cardiac and vascular sympathetic drive in control mice, while such effects were reduced in mice with ADAM17 knockdown. This blunted sympathoexcitation was extended to the spleen, with a lesser activation of the peripheral immune system, translating into a sequestration of circulating T cells within this organ, compared with controls. Within the paraventricular nucleus, Ang II–induced activation of kidney-related presympathetic glutamatergic neurons was reduced in ADAM17 knockdown mice, with the majority of cells no longer responding to Ang II stimulation, confirming the supportive role of ADAM17 in increasing presympathetic neuronal activity. Overall, our data highlight the pivotal role of neuronal ADAM17 in regulating sympathetic activity and demonstrate that activation of ADAM17 in glutamatergic neurons leads to a selective increase of sympathetic output, but not vagal tone, to specific organs, ultimately contributing to dysautonomia and salt-sensitive hypertension.</jats:p