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Mechanisms underlying chronic neuropathic pain associated with HIV-associated distal sensory polyneuropathy are poorly understood, yet 40% of those with distal neuropathy (or 20% of all people with HIV) suffer from this debilitating condition. Central pain processing mechanisms are thought to contribute to the development of HIV neuropathic pain, yet studies investigating central mechanisms for HIV neuropathic pain are few. Considering the motivational nature of pain, we aimed to examine the degree to which expectation of pain onset and expectation of pain offset are altered in sixty-one male patients with HIV-related distal sensory polyneuropathy with ( = 30) and without ( = 31) chronic neuropathic pain. By contrasting painful (foot) and non-painful (hand) sites between those with and without neuropathic pain, we could identify unique neural structures that showed altered activation during expectation of pain offset or relief. Our results showed no evidence for peripheral mechanisms evidenced by lack of significant between group differences in thermo-sensation, subjective pain response or epidermal nerve fibre density. Likewise, we found no significant differences between groups in subjective or brain mechanisms underlying the expectation of pain onset. Conversely, we found significant interaction within right anterior insula during expectation of pain offset in our study in that individuals in the pain group compared to the no-pain group exhibited increased anterior insula activation on the painful compared to the non-painful site. Our findings are consistent with abnormal processing of expectation of pain offset or abnormal pain relief-related mechanisms potentially due to increased emotional distress regarding the experience of chronic endogenous pain.
Learn More >Cluster headache is a primary headache form occurring in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in periods lasting 1-2months, the cluster periods. A genetic component is suggested by the familial occurrence of the disease but a genetic linkage is yet to be identified. Contemporary activation of trigeminal and cranial parasympathetic systems-the so-called trigemino-parasympathetic reflex-during the headache attacks seem to cause the pain and accompanying oculo-facial autonomic phenomena respectively. At peripheral level, the increased calcitonin gene related peptide (CGRP) plasma levels suggests trigeminal system activation during cluster headache attacks. The temporal pattern of the disease both in terms of circadian rhythmicity and seasonal recurrence has suggested involvement of the hypothalamic biological clock in the pathophysiology of cluster headache. The posterior hypothalamus was investigate as the cluster generator leading to activation of the trigemino-parasympathetic reflex, but the accumulated experience after 20 years of hypothalamic electrical stimulation to treat the condition indicate that this brain region rather acts as pain modulator. Efficacy of monoclonal antibodies to treat episodic cluster headache points to a key role of CGRP in the pathophysiology of the condition.
Learn More >HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP. In the present study, we measured indices of peripheral neuropathy in the doxycycline (DOX)-inducible HIV-TAT (iTAT) transgenic mouse and investigated the therapeutic efficacy of a selective muscarinic subtype-1 receptor (MR) antagonist, pirenzepine (PZ). PZ was selected as we have previously shown that it prevents and/or reverses indices of peripheral neuropathy in multiple disease models. DOX alone induced weight loss, tactile allodynia and paw thermal hypoalgesia in normal C57Bl/6J mice. Conduction velocity of large motor fibers, density of small sensory nerve fibers in the cornea and expression of mitochondria-associated proteins in sciatic nerve were unaffected by DOX in normal mice, whereas these parameters were disrupted when DOX was given to iTAT mice to induce TAT expression. Daily injection of PZ (10 mg/kg s.c.) prevented all of the disorders associated with TAT expression. These studies demonstrate that TAT expression disrupts mitochondria and induces indices of sensory and motor peripheral neuropathy and that MR antagonism may be a viable treatment for HIV-DSP. However, some indices of neuropathy in the DOX-inducible TAT transgenic mouse model can be ascribed to DOX treatment rather than TAT expression and data obtained from animal models in which gene expression is modified by DOX should be accompanied by appropriate controls and treated with due caution.
Learn More >Despite considerable evidence of chronic pain in adolescents, and its adverse consequences for their health and well-being, less is known about pain-related stigma that these youth face, such as pain disbelief by others. Adolescents with chronic pain may conceal their symptoms as a coping strategy to avoid pain-related stigma, contributing to further social isolation and disruptions in medical treatment. In the current study, we used focus group methodology to examine adolescent motivations for using concealment and the possible benefits and harmful consequences of this form of coping.
Learn More >Migraine is a chronic neurological disorder characterized by attacks of moderate or severe headache and various neurological symptoms. Migraine is typically treated by pharmacological or non-pharmacological therapies to relieve pain or prevent migraine attacks. Pharmacological therapies show limited efficacy in relieving headache and are often accompanied by adverse effects, while the benefits of acupuncture, a non-pharmacological therapy, have been well-documented in both the treatment and prevention of acute migraine attacks. However, the underlying mechanism of the effect of acupuncture on relieving migraine remains unclear. Recent advances in neuroimaging technology have offered new opportunities to explore the underlying neural mechanism of acupuncture in treating migraine. To pave the way for future research, this review provides an overview neuroimaging studies on the use of acupuncture for migraine in the last 10 years. Using search terms about acupuncture, neuroimaging and migraine, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure from January 2009 to June 2020 for neuroimaging studies that examined the effect of acupuncture in migraine. All published randomized and non-randomized controlled neuroimaging studies were included. We summarized the proposed neural mechanism underlying acupuncture analgesia in acute migraine, and the proposed neural mechanism underlying the sustained effect of acupuncture in migraine prophylaxis. A total of 619 articles were retrieved. After removing reviews, meta-analyses, animal studies and etc., 15 articles were eligible and included in this review. The methods used were positron emission computed tomography (PET-CT; = 2 studies), magnetic resonance spectroscopy ( = 1), and functional magnetic resonance imaging (fMRI; = 12). The analyses used included the regional homogeneity (ReHo) method (n = 3), amplitude of low frequency (ALFF) method ( = 2), independent component analysis (ICA; = 3), seed-based analysis (SBA; = 1), both ICA and SBA ( = 1), Pearson's correlation to calculate functional connectivity (FC) between brain regions ( = 1), and a machine learning method ( = 1). Five studies focused on the instant effect of acupuncture, and the research objects were those with acute migraine ( = 2) and migraine in the interictal phase ( = 3). Ten studies focused on the lasting effect of acupuncture, and all the studies selected migraine patients in the interictal phase. This review included five task-based studies and 10 resting-state studies. None of the studies conducted a correlation analysis between functional brain changes and instant clinical efficacy. For studies that performed a correlation analysis between functional brain changes and sustained clinical efficacy, the prophylactic effect of acupuncture on migraine might be through regulation of the visual network, default mode network (DMN), sensory motor network, frontoparietal network (FPN), limbic system, and/or descending pain modulatory system (DPMS). The neural mechanism underlying the immediate effect of acupuncture analgesia remains unclear, and the neural mechanism of sustained acupuncture treatment for migraine might be related to the regulation of pain-related brain networks. The experimental design of neuroimaging studies that examined the effect of acupuncture in migraine also have some shortcomings, and it is necessary to standardize and optimize the experimental design. Multi-center neuroimaging studies are needed to provide a better insight into the neural mechanism underlying the effect of acupuncture on migraine. Multi-modality neuroimaging studies that integrate multiple data analysis methods are required for cross-validation of the neuroimaging results. In addition, applying machine learning methods in neuroimaging studies can help to predict acupuncture efficacy and screen for migraineurs for whom acupuncture treatment would be suitable.
Learn More >Atopic dermatitis (AD) is among the most frequent inflammatory skin diseases in humans, affecting up to 20% of children and 10% of adults in higher income countries. Chronic pruritus is a disease-defining symptom of AD, representing the most burdensome symptom for patients. Severe chronic pruritus causes significant sleep disturbances and impaired quality of life, as well as increased anxiety, depression and suicidal behavior. Until recently, skin care, topical corticosteroids, and calcineurin-inhibitors were primarily used to treat mild to moderate AD, while phototherapy and immunosuppressive agents such as corticosteroids, cyclosporine, and methotrexate were used to treat patients with moderate to severe AD. The potential short- and long-term adverse events associated with these treatments or their insufficient therapeutic efficacy limited their use in controlling pruritus and eczema in AD patients over longer periods of time. As our understanding of AD pathophysiology has improved and new systemic and topical treatments have appeared on the market, targeting specific cytokines, receptors, or their intracellular signaling, a new era in atopic dermatitis and pruritus therapy has begun. This review highlights new developments in AD treatment, placing a specific focus on their anti-pruritic effects.
Learn More >The growing awareness of the critical role played by the innate and adaptive immune systems in the mechanisms underlying chronic pain has prompted further research examining the modalities by which immune cells communicate with neurones, the aim being to identify new players involved in inflammatory and neuropathic pain signalling. This collection of research includes 9 articles on neuroimmune interactions as the underlying mechanisms for neuropathic pain including peripheral neuropathies, pain in rheumatoid arthritis and osteoarthritis, and bone cancer pain. The immune cells under scrutiny include macrophages, microglia, osteoclasts, and B cells, and their interactions with neurones in locations such as the dorsal root ganglia, blood-spinal cord barrier, spinal cord, and brain. Our hope is that this body of work may serve to furnish existing interest while also constituting a springboard of sorts for indispensable further investigation on neuroimmune interactions in chronic pain.
Learn More >There is very limited data on women with migraine disease as they age and transition to menopause. Despite evidence for the increased burden of the disease during this transition, there is no data on the association between migraine and allostatic load as a marker of cumulative biological risk. We aimed to determine whether women with migraine suffer from higher levels of allostatic load during perimenopausal transition. A total of 2,105 perimenopausal women from the first wave of the Study of Women's Health Across the Nation (SWAN) were included in this study. Allostatic Load (AL) score was estimated for each participant from the measurements of: systolic and diastolic blood pressure, C-reactive protein level, high-density lipoprotein cholesterol level, total cholesterol level, waist-to-hip ratio, fasting serum glucose, triglycerides, and dehydroepiandrosterone levels. Of the 2,105 participants included in the study, there were 369 migraineurs and 1,730 controls. Migraineurs had 63% higher odds of increased load score (odds ratio 1.63; 95% confidence interval, 1.17-2.29). Compared to controls, migraineurs were more likely to experience sleep problems in the univariate analysis, however despite the high burden of sleep problems, there were no significant associations between allostatic load and sleep disturbances in perimenopausal women with migraine after controlling for other factors. This is the first study to systematically and quantitatively examine allostatic load in migraine patients. The findings establish that migraineurs are more likely to experience higher allostatic load than their non-migraine counterparts during perimenopausal transition. The findings encourage new lines of investigation for lowering the burden of the disease through interventions that modify the levels of allostatic load biomarkers examined in this study.
Learn More >Migraine is a common neurological disorder which affects 15-20% of the population; it has a high socioeconomic impact through treatment and loss of productivity. Current forms of diagnosis are primarily clinical and can be difficult owing to comorbidity and symptom overlap with other neurological disorders. As such, there is a need for better diagnostic tools in the form of genetic testing. Migraine is a complex disorder, encompassing various subtypes, and has a large genetic component. Genetic studies conducted on rare monogenic subtypes, including familial hemiplegic migraine, have led to insights into its pathogenesis via identification of causal mutations in three genes (, and ) that are involved in transport of ions at synapses and glutamatergic transmission. Study of familial migraine with aura pedigrees has also revealed other causal genes for monogenic forms of migraine. With respect to the more common polygenic form of migraine, large genome-wide association studies have increased our understanding of the genes, pathways and mechanisms involved in susceptibility, which are largely involved in neuronal and vascular functions. Given the preponderance of female migraineurs (3:1), there is evidence to suggest that hormonal or X-linked components can also contribute to migraine, and the role of genetic variants in mitochondrial DNA in migraine has been another avenue of exploration. Epigenetic studies of migraine have shown links between hormonal variation and alterations in DNA methylation and gene expression. While there is an abundance of preliminary studies identifying many potentially causative migraine genes and pathways, more comprehensive genomic and functional analysis to better understand mechanisms may aid in better diagnostic and treatment outcomes.
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