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Cluster headache (CH) is among the most common and debilitating autonomic cephalalgias. We characterize clinical outcomes of deep brain stimulation (DBS) to the posterior hypothalamic region through a novel analysis of the electrophysiological topography and tractography-based structural connectivity. The left posterior hypothalamus was targeted ipsilateral to the refractory CH symptoms. Intraoperatively, field potentials were captured in 1 mm depth increments. Whole-brain probabilistic tractography was conducted to assess the structural connectivity of the estimated volume of activated tissue (VAT) associated with therapeutic response. Stimulation of the posterior hypothalamic region led to the resolution of CH symptoms, and this benefit has persisted for 1.5-years post-surgically. Active contacts were within the posterior hypothalamus and dorsoposterior border of the ventral anterior thalamus (VAp). Delta- (3 Hz) and alpha-band (8 Hz) powers increased and peaked with proximity to the posterior hypothalamus. In the posterior hypothalamus, the delta-band phase was coupled to beta-band amplitude, the latter of which has been shown to increase during CH attacks. Finally, we identified that the VAT encompassing these regions had a high proportion of streamlines of pain processing regions, including the insula, anterior cingulate gyrus, inferior parietal lobe, precentral gyrus, and the brainstem. Our unique case study of posterior hypothalamic region DBS supports durable efficacy and provides a platform using electrophysiological topography and structural connectivity, to improve mechanistic understanding of CH and this promising therapy.
Learn More >Acute pain can transition to chronic pain, presenting a major clinical challenge. Electroacupuncture (EA) can partly prevent the transition from acute to chronic pain. However, little is known about the mechanisms underlying the effect of EA. This study investigated the effect of EA on pain transition and the activation of metabotropic glutamate receptor 5 (mGluR5)-protein kinase C epsilon (PKCε) signaling pathway in the dorsal root ganglia (DRG).
Learn More >Although the Eph receptor plays an important role in the development of neuropathic pain following nerve injury, there has been no evidence of the participation of the ephrin A4 receptor (EphA4) in the development of trigeminal neuropathic pain. The present study investigated the role of EphA4 in central nociceptive processing in rats with inferior alveolar nerve injury.
Learn More >Localized neuropathic pain can be relieved following the topical application of high-concentration capsaicin. This clinical effect is thought to be related to the temporary desensitization of capsaicin- and heat-sensitive epidermal nociceptors. The objective of the present study was to examine whether the changes in thermal sensitivity induced by high-concentration topical capsaicin can be explained entirely by desensitization of capsaicin-sensitive afferents. For this purpose, we characterized, in 20 healthy human volunteers, the time course and spatial extent of the changes in sensitivity to thermal stimuli preferentially activating heat-sensitive A-fiber nociceptors, heat-sensitive C-fiber afferents, and cool-sensitive A-fiber afferents. The volar forearm was treated with a high-concentration capsaicin patch for 1 h. Transient heat, warm and cold stimuli designed to activate Aδ- and C-fiber thermonociceptors, C-fiber warm receptors, and Aδ-fiber cold receptors were applied to the skin before and after treatment at days 1, 3, and 7. Reaction times, intensity ratings, and quality descriptors were collected. The stimuli were applied both within the capsaicin-treated skin and around the capsaicin-treated skin to map the changes in thermal sensitivity. We found that topical capsaicin selectively impairs heat sensitivity without any concomitant changes in cold sensitivity. Most interestingly, we observed a differential effect on the sensitivity to thermal inputs conveyed by Aδ- and C-fibers. Reduced sensitivity to Aδ-fiber-mediated heat was restricted to the capsaicin-treated skin, whereas reduced sensitivity to C-fiber-mediated heat extended well beyond the treated skin. Moreover, the time course of the reduced sensitivity to C-fiber-mediated input was more prolonged than the reduced sensitivity to Aδ-fiber-mediated input.
Learn More >Neuropathic pain (NP) is caused by primary or secondary impairment of the peripheral or central nervous systems. Its etiology is complex and involves abnormal patterns of gene expression and pathway activation. Using bioinformatics analysis, we aimed to identify NP-associated changes in genes and pathways in L4 and L5 dorsal root ganglia (DRG) in a rat model of NP induced by chronic compression of the DRG (CCD). Genome-wide transcriptional analyses were used to elucidate the molecular mechanisms underlying NP. We screened differentially expressed genes (DEGs) 7 days after CCD in comparison with sham-operated controls. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were used to confirm the presence of key DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG)-pathway analysis of DEGs and global signal transduction network analysis of DEGs were also conducted. The CCD group developed clear mechanical and thermal allodynia in the ipsilateral hind paw compared with the sham group. This comparison identified 1,887 DEGs, with 1156 upregulated and 731 downregulated DEGs, and 123 DEG-enriched pathways. We identified the key candidate genes that might play a role in the development of NP, namely (), , (), (), (), and () by analyzing the global signal transduction network. RT-qPCR and western blot analysis confirmed the microarray results. The DEGs , , , , and , and the cytokine signaling pathway, the neuroactive ligand-receptor interaction, the toll-like receptor signaling pathway, and the PI3K-Akt signaling pathway may have decisive modulatory roles in both nerve regeneration and NP. These results provide deeper insight into the mechanism underlying NP and promising therapeutic targets for its treatment.
Learn More >Complex Regional Pain Syndrome (CRPS) is a poorly understood chronic pain condition of multifactorial origin. CRPS involves sensory, motor, and autonomic symptoms primarily affecting one extremity. Patients can also present with neuropsychological changes such as reduced attention to the CRPS-affected extremity, reminiscent of hemispatial neglect, yet in the absence of any brain lesions. However, this "neglect-like" framework is not sufficient to characterise the range of higher cognitive functions that can be altered in CRPS. This comprehensive literature review synthesises evidence of neuropsychological changes in CRPS in the context of potential central mechanisms of the disorder. The affected neuropsychological functions constitute three distinct but not independent groups: distorted body representation, deficits in lateralised spatial cognition, and impairment of non-spatially-lateralised higher cognitive functions. We suggest that many of these symptoms appear to be consistent with a broader disruption to parietal function beyond merely what could be considered "neglect-like." Moreover, the extent of neuropsychological symptoms might be related to the clinical signs of CRPS, and rehabilitation methods that target the neuropsychological changes can improve clinical outcomes in CRPS and other chronic pain conditions. Based on the limitations and gaps in the reviewed literature, we provide several suggestions to improve further research on neuropsychological changes in chronic pain.
Learn More >In this chapter, we describe the impact and etiology of chronic pain, the associated changes in the nervous system, and the mechanisms by which exercise may be able to affect and reverse these changes. Evidence for efficacy of exercise in different conditions associated with chronic pain is presented, with focus on chronic low back pain, fibromyalgia, osteoarthritis, rheumatoid arthritis, and migraines. While the efficacy of exercise and level of evidence supporting it vary in different diseases, exercise has direct and indirect benefits for most patients suffering from chronic pain. Effective exercise regimens include education and cognitive restructuring to promote behavioral activation and reconceptualization of what pain means, with the goal of gradually reversing the vicious cycle of pain, inertia, sedentary behavior, and worsening disability. Long-term, consistent, individualized exercise-based treatment approaches are most likely to result in improvements in pain and function.
Learn More >To report the theoretical basis and design of a novel digital Acceptance and Commitment Therapy (ACT) intervention for people with chronic pain, the Pain Tracker Self Manager (PTSM), which had promising efficacy in a recent pilot trial.
Learn More >Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for neuropathic pain (NP). This study aims to investigate whether botulinum toxin type A (BTX-A) regulates microglial M1/M2 polarization by inhibiting P2X7 expression in a rat model of NP.
Learn More >Recent task-based fMRI studies have shown that Persistent Somatoform Pain Disorder (PSPD) patients demonstrated aberrant activity in a wide range of brain regions associated with sensation, cognition and emotion. However, these specific task-based studies could not clearly uncover the alterations in the spontaneous brain networks that were associated with the general pain-related symptoms in PSPD.
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