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The automatic detection of migraine states using electrophysiological recordings may play a key role in migraine diagnosis and early treatment. Migraineurs are characterized by a deficit of habituation in cortical information processing, causing abnormal changes of somatosensory evoked potentials. Here, we propose a machine learning approach to utilize somatosensory evoked potential-based biomarkers for migraine classification in a noninvasive setting.
Learn More >Animal experiment: a rat model of lumbar disc herniation (LDH) induced painful radiculopathies.
Learn More >Spatial integration of parts of the body is impaired in patients with complex regional pain syndrome (CRPS). Since the training of mental rotation (MR) has been shown to be among the effective therapy strategies for CRPS, impairment of MR is also important for the pathophysiological understanding of CRPS. The aim of this study was to evaluate whether differences in neural representation of MR occur between CRPS patients and healthy controls. Therefore we included 15 chronic CRPS patients and 15 age-/gender matched healthy controls. We assessed behavioral (accuracy and reaction time for MR of both hands), clinical (DASH) and MRI (T1, fMRI during MR) data. Reaction times in the patient group were delayed compared to healthy controls without a lateralization effect for affected hand side. Although both groups showed an activation pattern typical for MR, only HC showed a highly significant contrast for the rotated versus unrotated hands in the right intraparietal sulcus. CRPS patients showed a reduction of fMRI activation in areas including subthalamic nucleus, nucleus accumbens and putamen. Regression analysis for the CRPS group emphasized the importance of putamen and n. accumbens activation for MR performance. This study highlights the reduced access of CRPS patients for mental resources modulating arousal, emotional response and subcortical sensorimotor integration. PERSPECTIVE: This study localized the underlying neural responses for impaired mental rotation (MR) in patients with complex regional pain syndrome (CRPS) as a decrease in basal ganglia (putamen) and nucleus accumbens activation.
Learn More >Migraine is a prevalent disorder, affecting 15.1% of the world's population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develop chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, we review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. We present evidence from preclinical research that supports this view and discuss the implications for migraine therapy.
Learn More >Obesity is associated with increased sensitivity to pain, including neuropathic pain, but the precise mechanisms are not fully understood. Recent evidence has revealed that AMP‑activated protein kinase (AMPK) in the central nervous system (CNS) regulates the neuropeptide calcitonin gene‑related peptide (CGRP), a principal neurotransmitter of the class C nerve fiber, which serves an important role in initiating and maintaining neuropathic pain. AMPK has been demonstrated to be downregulated in the CNS in obesity. The present study hypothesized that obesity may lead to increased sensitivity to neuropathic pain by downregulating AMPK and upregulating CGRP expression levels in the CNS. Sprague‑Dawley rats consuming a high‑fat diet (HF) for 12 weeks developed obesity; they exhibited significantly decreased levels of phospho (p)‑AMPK and increased CGRP expression levels in the spinal cord (SC) and dorsal root ganglion (DRG), respectively, compared with rats consuming a low‑fat (LF) diet. HF‑fed rats that underwent spared nerve injury (SNI) also exhibited lower p‑AMPK and higher CGRP expression levels in the SC and DRG, compared with the corresponding LF‑diet rats. The 50% paw withdrawal threshold (PWT; as measured by Von Frey testing) was significantly lower in HF‑fed compared with LF‑fed rats, with or without SNI. Through intrathecal treatment, the AMPK activator 5‑aminoimidazole‑4‑carboxamide riboside (AICAR) or the CGRP antagonist CGRP8‑37 decreased CGRP expression levels and increased the 50% PWT; however, the AMPK inhibitor dorsomorphin augmented CGRP expression levels and further reduced the 50% PWT in HF‑fed rats, but not LF‑fed rats, with or without SNI. The results indicated that blocking the AMPK‑CGRP pathway may enhance neuropathic pain in HF‑induced obesity, with or without nerve injury. Targeting AMPK in the CNS may be a novel strategy for the prevention and treatment of obesity‑associated neuropathic pain.
Learn More >Painful diabetic neuropathy (PDN) is a severely debilitating chronic pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of chronic pain induced by peripheral tissue inflammation or nerve injury. In this study we investigated whether CXCL13/CXCR5 mediates PDN and the underlying spinal mechanisms. We used the db/db type 2 diabetes mice, which showed obvious hyperglycemia and obese, long-term mechanical allodynia, and increased expression of CXCL13, CXCR5 as well as pro-inflammatory cytokines TNF-α and IL-6 in the spinal cord. Furthermore, in the spinal cord of db/db mice there is significantly increased gliosis and upregulated phosphorylation of cell signaling kinases, including pERK, pAKT and pSTAT3. Mechanical allodynia and upregulated pERK, pAKT and pSTAT3 as well as production of TNF-α and IL-6 were all attenuated by the noncompetitive NMDA receptor antagonist MK-801. If spinal giving U0126 (a selective MEK inhibitor) or AG490 (a Janus kinase (JAK) -STAT inhibitor) to db/db mice, both of them can decrease the mechanical allodynia, but only inhibit pERK (by U0126) or pSTAT3 (by AG490) respectively. Acute administration of CXCL13 in C57BL/6J mice resulted in exacerbated thermal hyperalgesia and mechanical allodynia, activation of the pERK, pAKT and pSTAT3 pathways and increased production of pro-inflammatory cytokines (IL-1β, TNF-α and IL-6), which were all attenuated by knocking out of Cxcr5. In all, our work showed that chemokine CXCL13 and its receptor CXCR5 in spinal cord contribute to the pathogenesis of PDN and may help develop potential novel therapeutic approaches for patients afflicted with PDN.
Learn More >The neurosteroid dehydroepiandrosterone sulphate (DHEAS) activates the sigma-1 receptor, inhibits gamma-aminobutyric acid A (GABA) and glycine receptors, and induces hyperalgesic effects. Although its effects have been studied in various tissues of the nervous system, its synaptic mechanisms in nociceptive pathways remain to be elucidated.
Learn More >Dopamine-beta-hydroxylase (DBH) enzyme activity is modulated at the genetic level by the presence of several polymorphisms. Among these, the 19-bp insertion/deletion (I/D) polymorphism (rs72393728/rs141116007) was investigated in several genetic association studies for its correlation with the susceptibility to develop episodic migraine, but conflicting results were achieved. In the present study we analyzed this genetic variant in a carefully characterized population of migraineurs encompassing both episodic and chronic migraine (with and without medication overuse) with the aim to perform a replication study and verify any possible correlation with migraine endophenotypes. Genotyping of the DBH 19-bp I/D polymorphism was performed on 400 migraine patients and 204 healthy individuals. The associations between genotypic frequencies and the clinical and sociodemographic features of migraineurs were then investigated. The DBH 19-bp I/D polymorphism did not correlate with migraine susceptibility or most clinical variables, with the exception of a statistically significant correlation within the subgroup of patients affected by chronic migraine were the individuals carrying the deleted (D) allele were significantly more prone to abuse in analgesics. As a result of this finding, the DBH 19-bp I/D polymorphism does not influence migraine susceptibility, but it might contribute to the development of medication overuse in patient with chronic migraine.
Learn More >Children who develop greater negatively-biased recall of pain (ie, recalled pain is higher than the initial pain report) following surgery are at risk for developing chronic pain; therefore, identifying risk factors for the development of biased pain memories is important. Higher anxiety has been implicated in the development of greater negatively-biased recall of pain; however, studies have not examined anxiety at multiple time points before and after a surgery and its relationship to children's postsurgical pain memories after 1 year. This prospective study examined a cohort of 237 children and adolescents undergoing major surgery. Anxiety sensitivity, pain catastrophizing, and pain anxiety were assessed at baseline, 48 to 72 hours after surgery, and at 6- and 12-month follow-ups. Pain intensity at rest, movement-evoked pain intensity, and pain unpleasantness were assessed daily in hospital. Memories for pain were elicited via telephone 1-year post surgery. Findings revealed that children who had higher levels of anxiety at baseline and 48 to 72 hours after surgery developed greater negatively-biased recall of pain intensity 12 months after surgery. Specifically, higher anxiety sensitivity at baseline and greater tendencies to catastrophize about pain at baseline and in the immediate acute recovery phase were most strongly linked to greater negatively-biased recall of pain. Greater negatively-biased recall of pain was related to higher pain intensity at 6 and 12 months post surgery. Findings support conceptual models of anxiety and pain memory biases and can inform intervention efforts to reduce anxiety in the pre- and post-op periods to minimize negative biases in pain memories.
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