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Previous studies suggested that both maladaptive stress response and circadian dysregulation might have a role in the background of migraine. However, effects of circadian genes on migraine have not been tested yet. In the present study, we investigated the main effect of rs10462028 of the circadian locomotor output cycles kaput () gene and its interaction with different stress factors on migraine. In our cross-sectional study 2,157 subjects recruited from Manchester and Budapest completed the ID-Migraine questionnaire to detect migraine type headaches (migraineID). Additional stress factors were assessed by a shortened version of the Childhood Trauma Questionnaire, the List of Threatening Experiences questionnaire, and a validated questionnaire to identify financial difficulties. Rs10462028 showed no main genetic effect on migraineID. However, chronic stress indexed by financial difficulties showed a significant interaction effect with rs10462028 ( = 0.006 in recessive model) on migraineID. This result remained significant after correction for lifetime bipolar and unipolar depression and was replicated in both subsamples, although only a trend effect was reached after Bonferroni-correction, which is the strictest correction not considering interdependences. Childhood adversity (CHA) and Recent negative life events (RLE) showed no significant gene × stress interaction with rs10462028. In addition, analysis demonstrated that the genetic region tagged by rs10462028 alters the binding of several miRNAs. Our exploratory study suggests that variations in the gene, with moderating effect on gene function through miRNA binding, in interaction with financial difficulties might influence the risk of migraine-type headaches. Thus, financial hardship as a chronic stress factor may affect migraine through altering circadian rhythms.
Learn More >Few studies have been conducted on the prodromal and postdromal phases of the migraine attack in children and adolescents. Using a questionnaire, we found that 67% of 103 children and adolescents with migraine reported at least one prodromal symptom, with a mean number per subject of 1.8 (median 2.2). The most frequently reported prodromal symptoms were face changes, fatigue and irritability. In pediatric patients selected as having prodrome, fatigue, mood change and neck stiffness were the most frequently reported prodromal symptoms. Using a different design, Laurell et al. found that 71% of 137 pediatric patients reported at least one prodromal symptom with a mean number per subject of 1.9 ± 2.0. Studying postdrome was fraught with unexpected difficulties as our preliminary research showed. Patients reported 2 groups of symptoms occurring during the resolution phase of the headache: symptoms whose onset was headache cessation and were persisting it, and symptoms whose onset was headache cessation. We referred to the former as persistent symptoms and to the latter as true postdromes. Ninety-one per cent of patients reported persistent symptoms, with a mean of 6.0 and a median of 2, asthenia, pallor, cognitive difficulties, anorexia, somnolence, and nausea being the more frequently reported. True postdromes were reported by 82% of patients, with a mean of 2.6 and a median of 2, thirst, somnolence, visual disturbances, food craving, paraesthesias, and ocular pain being the most frequent reported. Interestingly, several prodromal and postdromal symptoms are also encountered during the aura classic and/or accompany the headache phase. Functional imaging in migraine has showed that the activations in areas such as hypothalamus or brainstem may begin before headache onset and/or persist after headache relief. Thus, one may wonder whether prodromal and postdromal symptoms may indicate the involvement of the limbic system, dopaminergic pathways, the hypothalamus and the brainstem. Differences between children, adolescents and adults might contribute to the understanding of migraine neurobiology.
Learn More >Previous studies of prognosis for women with Fibromyalgia (FM) or chronic widespread pain (CWP) show contradictory results. However, some women appear to improve in pain and other core symptoms over time. There is limited knowledge about predictors of substantial improvement in pain intensity over a longer period of time. The primary objective of this study was to investigate the natural course of pain intensity and distribution of pain over 10 to 12 years in a cohort of 166 women with FM or CWP. Secondarily we wanted to investigate predictors of substantial improvement (50%) in pain intensity after 10 to 12 years.
Learn More >Neuroimmune interactions are important in the pathophysiology of many chronic inflammatory diseases, particularly those associated with alterations in sensory processing and pain. Mast cells and sensory neuron nerve endings are found in areas of the body exposed to the external environment, both are specialized to sense potential damage by injury or pathogens and signal to the immune system and nervous system, respectively, to elicit protective responses. Cell adhesion molecule 1 (CADM1), also known as SynCAM1, has previously been identified as an adhesion molecule which may couple mast cells to sensory neurons however, whether this molecule exerts a functional as well as structural role in neuroimmune cross-talk is unknown. Here we show, using a newly developed co-culture system consisting of murine bone marrow derived mast cells (BMMC) and adult sensory neurons isolated from dorsal root ganglions (DRG), that CADM1 is expressed in mast cells and adult sensory neurons and mediates strong adhesion between the two cell types. Non-neuronal cells in the DRG cultures did not express CADM1, and mast cells did not adhere to them. The interaction of BMMCs with sensory neurons was found to induce mast cell degranulation and IL-6 secretion and to enhance responses to antigen stimulation and activation of FcεRI receptors. Secretion of TNFα in contrast was not affected, nor was secretion evoked by compound 48/80. Co-cultures of BMMCs with HEK 293 cells, which also express CADM1, while also leading to adhesion did not replicate the effects of sensory neurons on mast cells, indicative of a neuron-specific interaction. Application of a CADM1 blocking peptide or knockdown of CADM1 in BMMCs significantly decreased BMMC attachment to sensory neurites and abolished the enhanced secretory responses of mast cells. In conclusion, CADM1 is necessary and sufficient to drive mast cell-sensory neuron adhesion and promote the development of a microenvironment in which neurons enhance mast cell responsiveness to antigen, this interaction could explain why the incidence of painful neuroinflammatory disorders such as irritable bowel syndrome (IBS) are increased in atopic patients.
Learn More >Patient education constitutes a relevant strategy to improve pain management. In the field of therapeutic patient education (TPE), we aimed 1) to assess pain impact in cancer patients, 2) to identify patients' educative needs in pain management, and 3) to refine research criteria for its future evaluation. Pain intensity, relief and interference were assessed in 75 cancer patients with unbalanced background pain. Self-assessment questionnaire evaluated i) patients' pain management and ii) their knowledge and needs in TPE. Most patients experienced pain for more than 6 months and 41.6% reported adequate pain relief. Understanding pain and pain management were major patients' preferences (>58%). Most patients declared they knew their pain treatments, but fewer than half of them were able to name them. However, education concerning pain treatment was considered as essential in <30% of patients. Almost all patients (97.1%) stated pain education as beneficial, with a preference for individualized sessions (41.2%). In addition, the assessment criteria for its future evaluation were refined. Targeted population mainly concerned patients with persistent pain. Only half of patients reported pain relief despite antalgics. Patient education was declared as beneficial for almost all participants. Tailoring a pain TPE on patients' needs has the potential to help them to optimally manage their pain daily.
Learn More >The aims of the present study were to investigate whether the association between the Central Sensitization Inventory (CSI) score, pain-related symptoms, pain-related disability, and health-related quality of life differed by disease (chronic low back pain [CLBP] vs knee osteoarthritis [KOA]), and to determine optimal cutoff scores for the CSI reflecting disease-specific characteristics. A total of 104 patients with CLBP and 50 patients with KOA were recruited. Central sensitization-related symptoms (CSI), EuroQol 5-dimension (EQ-5D), Brief Pain Inventory, widespread pain (Widespread Pain Index [WPI]), pressure pain threshold (PPT), and temporal summation (TS) were assessed and compared between the CLBP and KOA groups. Univariate correlation analysis was performed in each group. The receiver operating characteristic (ROC) curve analysis was performed to identify 1) presence/absence of central sensitization (CS), 2) presence/absence of central sensitivity syndromes (CSSs), and 3) pain intensity and pain interference in each group. The CSI and WPI scores were significantly higher in the CLBP group than in the KOA group. EQ-5D and pain interference scores significantly correlated with the CSI score in both the CLBP and KOA groups. The WPI score, PPT, and TS did not correlate with the CSI score in either the CLBP or KOA group. The suggested cutoff scores were 28 in the CLBP group and 17 in the KOA group to identify presence or absence of CSSs, and 34 in the CLBP group and 18-19 in the KOA group to identify pain severity. The impact of CS on pain could differ between CLBP and KOA and that cutoff scores differ by each parameter we attempted to identify. Therefore, we should use the appropriate cutoff scores for the purposes and consider the difference in the impact of CS on pain by the patient group.
Learn More >There is strong evidence that neuronal hyper-excitability underlies migraine, and may or may not be preceded by cortical spreading depression. However, the mechanisms for cortical spreading depression and/or migraine are not established. Previous studies reported that cerebrospinal fluid (CSF) [Na+] is higher during migraine, and that higher extracellular [Na+] leads to hyper-excitability. We raise the hypothesis that altered choroid plexus Na+, K+-ATPase activity can cause both migraine phenomena: inhibition raises CSF [K+] and initiates cortical spreading depression, while activation raises CSF [Na+] and causes migraine. In this study, we examined levels of specific Na+, K+-ATPase inhibitors, endogenous ouabain-like compounds (EOLC), in CSF from migraineurs and controls. CSF EOLC levels were significantly lower during ictal migraine (0.4 nM +/- 0.09) than from either controls (1.8 nM +/- 0.4) or interictal migraineurs (3.1 nM +/- 1.9). Blood plasma EOLC levels were higher in migraineurs than controls, but did not differ between ictal and interictal states. In a Sprague-Dawley rat model of nitroglycerin-triggered central sensitization, we changed the concentrations of EOLC and CSF sodium, and measured aversive mechanical threshold (von Frey hairs), trigeminal nucleus caudalis activation (cFos), and CSF [Na+] (ultra-high field 23Na MRI). Animals were sensitized by three independent treatments: intraperitoneal nitroglycerin, immunodepleting EOLC from cerebral ventricles, or cerebroventricular infusion of higher CSF [Na+]. Conversely, nitroglycerin-triggered sensitization was prevented by either vascular or cerebroventricular delivery of the specific Na+, K+-ATPase inhibitor, ouabain. These results affirm our hypothesis that higher CSF [Na+] is linked to human migraine and to a rodent migraine model, and demonstrate that EOLC regulates them both. Our data suggest that altered choroid plexus Na+, K+-ATPase activity is a common source of these changes, and may be the initiating mechanism in migraine.
Learn More >Migraine is a neurological disorder characterized by paroxysms of head pain accompanied by trigeminovascular system activation and autonomic dysfunction. Diagnosis is currently based on clinical diagnostic criteria. Though physiological differences exist between migraineurs and non-headache controls, true physiological biomarkers have been elusive, especially for the full clinical spectrum of migraine, inclusive of chronic, episodic, and probable migraine. We used edge-light pupil cycle time (PCT) as a probe of the pupillary light circuit in migraine, paired with clinical assessment of migraine characteristics, and compared these to non-headache controls. We found significantly increased PCT in probable, episodic, and chronic migraine, compared to controls. Additionally, increased PCT correlated with the presence of craniofacial autonomic symptoms, linking pupillary circuit dysfunction to peripheral trigeminal sensitization. The sensitivity of PCT, especially for all severities of disease, distinguishes it from other physiological phenotypes, which may make it useful as a potential biomarker.
Learn More >Motor imagery (M.I.) training has been widely used to enhance motor behavior. To characterize the neural foundations of its rehabilitative effects in a pathological population we studied twenty-two patients with rhizarthrosis, a chronic degenerative articular disease in which thumb-to-fingers opposition becomes difficult due to increasing pain while the brain is typically intact. Before and after surgery, patients underwent behavioral tests to measure pain and motor performance and fMRI measurements of brain motor activity. After surgery, the affected hand was immobilized, and patients were enrolled in a M.I. training. The sample was split in those who had a high compliance with the program of scheduled exercises (T+, average compliance: 84%) and those with low compliance (T-, average compliance: 20%; cut-off point: 55%). We found that more intense M.I. training counteracts the adverse effects of immobilization reducing pain and expediting motor recovery. fMRI data from the post-surgery session showed that T+ patients had decreased brain activation in the premotor cortex and the supplementary motor area (SMA); meanwhile, for the same movements, the T- patients exhibited a reversed pattern. Furthermore, in the post-surgery fMRI session, pain intensity was correlated with activity in the ipsilateral precentral gyrus and, notably, in the insular cortex, a node of the pain matrix. These findings indicate that the motor simulations of M.I. have a facilitative effect on recovery by cortical plasticity mechanisms and optimization of motor control, thereby establishing the rationale for incorporating the systematic use of M.I. into standard rehabilitation for the management of post-immobilization syndromes characteristic of hand surgery.
Learn More >This study aimed to investigate whether changes in psychosocial factors and pain severity were associated with reduction in disability due to pain among patients with chronic pain. We hypothesized that increased self-efficacy would reduce disability.
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