Epigenetic Landscapes of Pain: DNA Methylation Dynamics in Chronic Pain.

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management.

Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial.

BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.

Towards a Real-Life Understanding of the Altered Functional Behaviour of the Default Mode and Salience Network in Chronic Pain: Are People with Chronic Pain Overthinking the Meaning of Their Pain?

Chronic pain is a source of substantial physical and psychological suffering, yet a clear understanding of the pathogenesis of chronic pain is lacking. Repeated studies have reported an altered behaviour of the salience network (SN) and default mode network (DMN) in people with chronic pain, and a majority of these studies report an altered behaviour of the dorsal ventromedial prefrontal cortex (vmPFC) within the anterior DMN. In this topical review, we therefore focus specifically on the role of the dorsal vmPFC in chronic pain to provide an updated perspective on the cortical mechanisms of chronic pain. We suggest that increased activity in the dorsal vmPFC may reflect maladaptive overthinking about the meaning of pain for oneself and one's actions. We also suggest that such overthinking, if negative, may increase the personal "threat" of a given context, as possibly reflected by increased activity in, and functional connectivity to, the anterior insular cortex within the SN.

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation.

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF's pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

Personalized Multimodal Lifestyle Intervention as the Best-Evidenced Treatment for Chronic Pain: State-of-the-Art Clinical Perspective.

Chronic pain is the most prevalent disease worldwide, leading to substantial disability and socioeconomic burden. Therefore, it can be regarded as a public health disease and major challenge to scientists, clinicians and affected individuals. Behavioral lifestyle factors, such as, physical (in)activity, stress, poor sleep and an unhealthy diet are increasingly recognized as perpetuating factors for chronic pain. Yet, current management options for patients with chronic pain often do not address lifestyle factors in a personalized multimodal fashion. This state-of-the-art clinical perspective aims to address this gap by discussing how clinicians can simultaneously incorporate various lifestyle factors into a personalized multimodal lifestyle intervention for individuals with chronic pain. To do so the available evidence on (multimodal) lifestyle interventions targeting physical (in)activity, stress, sleep and nutritional factors, specifically, was reviewed and synthetized from a clinical point of view. First, advise is provided on how to design a personalized multimodal lifestyle approach for a specific patient. Subsequently, best-evidence recommendations on how to integrate physical (in)activity, stress, sleep and nutritional factors as treatment targets into a personalized multimodal lifestyle approach are outlined. Evidence supporting such a personalized multimodal lifestyle approach is growing, but further studies are needed.

Non-invasive Brain Stimulation for Chronic Pain: State of the Art and Future Directions.

As a technique that can guide brain plasticity, non-invasive brain stimulation (NIBS) has the potential to improve the treatment of chronic pain (CP) because it can interfere with ongoing brain neural activity to regulate specific neural networks related to pain management. Treatments of CP with various forms of NIBS, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), using new parameters of stimulation have achieved encouraging results. Evidence of moderate quality indicates that high-frequency rTMS of the primary motor cortex has a clear effect on neuropathic pain (NP) and fibromyalgia. However, evidence on its effectiveness regarding pain relief in other CP conditions is conflicting. Concerning tDCS, evidence of low quality supports its benefit for CP treatment. However, evidence suggesting that it exerts a small treatment effect on NP and headaches is also conflicting. In this paper, we describe the underlying principles behind these commonly used stimulation techniques; and summarize the results of randomized controlled trials, systematic reviews, and meta-analyses. Future research should focus on a better evaluation of the short-term and long-term effectiveness of all NIBS techniques and whether they decrease healthcare use, as well as on the refinement of selection criteria.

Dance movement therapy for neurodegenerative diseases: A systematic review.

Background: The proportion of the world's elderly population continues to rise, and the treatment and improvement of neurodegenerative diseases have become issue of public health importance as people live longer and many countries have aging populations. This systematic review aims to discuss the effects of dance movement therapy (DMT) on motor function, cognitive deficit, mood, and quality of life in people with neurodegenerative diseases, such as Parkinson's disease (PD), mild cognitive impairment (MCI), Alzheimer's disease (AD). Methods: Two reviewers independently conducted systematic search on the Cochrane library, PubMed database, Web of Science Core Collection database, and Physiotherapy Evidence database until February 1, 2022. Only systematic analyses and randomized controlled trials were included and further analyzed. Results: Thirty-three studies on PD, 16 studies on MCI, 4 studies on AD were obtained. This systematic review found that DMT substantially improved the global cognitive function, memory, and executive function on the population with MCI. Compared with the non-dance group, DMT remarkably improved general disease condition, balance, and gait for individuals with PD. The evidence of the efficacy of DMT on AD is insufficient, and further research is needed. Conclusion: DMT can effectively improve the motor function and cognitive deficits in neurodegenerative diseases. Positive effects of DMT on the mood and quality of life in ND patients are controversial and require further evidence. Future research on the effects of DMT on AD requires scientific design, large sample size, long-term comprehensive intervention, and clear reporting standards. Systematic review registration: www.osf.io/wktez, identifier: 10.17605/OSF.IO/UYBKT.

The effect and mechanism of traditional Chinese exercise for chronic low back pain in middle-aged and elderly patients: A systematic review.

Background: Increasing lines of evidence indicate that traditional Chinese exercise (TCE) has potential benefits in improving chronic low back pain (CLBP) symptoms. To assess the clinical efficacy of TCE in the treatment of CLBP, we performed a systematic review of existing randomized controlled trials (RCTs) of CLBP and summarized the neural mechanisms underlying TCE in the treatment of CLBP. Methods: A systematic search was conducted in four electronic databases: PubMed, Embase, the Cochrane Library, and EBSCO from January 1991 to March 2022. The quality of all included RCTs was evaluated by the Physiotherapy Evidence Database Scale (PEDro). The primary outcomes included pain severity and pain-related disability. Results: A total of 11 RCTs with 1,256 middle-aged and elderly patients with CLBP were included. The quality of all 11 included RCTs ranged from moderate to high according to PEDro. Results suggested that TCE could considerably reduce pain intensity in patients with CLBP. Overall, most studies did not find any difference in secondary outcomes (quality of life, depression, and sleep quality). Conclusion: The neurophysiological mechanism of TCE for treating CLBP could be linked to meditation and breathing, posture control, strength and flexibility training, and regulation of pain-related brain networks. Our systematic review showed that TCE appears to be effective in alleviating pain in patients with CLBP.

Top 100 Most-Cited Papers in Neuropathic Pain From 2000 to 2020: A Bibliometric Study.

Background: Neuropathic pain research has grown impressively in the past two decades, as evidenced by improvements in research quality and increments in the number of research papers. In views of this situation, the use of quantitative measurements to analyze and characterize existing research has become imperative. The aim of this research is to identify and analyze the 100 most-cited papers in neuropathic pain research. Methods: Neuropathic pain-related articles published between 2000 and 2020 were screened from Web of Science (WOS) by using the following subject terms: TI = (Neuralgia$ OR Neurodynia$ OR "Neuropathic pain" OR sciatica OR "Nerve pain$"). The publications were ranked in a descending order on the basis of citation counts, and the top 100 most-cited neuropathic pain papers were determined. Subsequently, we conducted a bibliometric study to determine the authors, journals, countries, and institutions that contributed the most to the top 100 neuropathic pain lists; describe the keywords and hotspots of the top 100 most-cited papers; and explore the factors associated with successful citations. Results: The top 100 most-cited papers were published from 2000 to 2017, and 2003 had the largest number of published papers (n = 16). The mean number of citations per paper was 480.72, with a range of 262-1,569. Forty-four kinds of journals contributed to the top 100 most-cited papers, which were predominantly published in "Pain" (n = 23). The USA was determined to be the leader of neuropathic pain research in terms of quality and quantity. Conclusion: This study provides a comprehensive list of the most influential papers on neuropathic pain and demonstrates the important advances in this field to help understand academic concerns and the directions of technological innovations in neuropathic pain worldwide.

Bibliometric Analysis of Research on the Comorbidity of Pain and Inflammation.

Objectives: To provide a comprehensive review on the global scientific research status of comorbid pain and inflammation from 1981 to 2019 and capture its subsequent development trends. Data Sources. The primary database chosen to collect publications on comorbid pain and inflammation research from 1981 to 2019 was the Web of Science (WOS). Core of the search strategy was the key word "pain" and the key word "inflammation" in the medical subject headings' major field. Study Selection. All articles retrieved were included in the bibliometric analysis. Data Extraction. We used CiteSpace to analyze publication outputs, subject categories, distribution by country/institution/journal, and other types of information. Then, knowledge base, hot issues, and future development directions were explained. Data Synthesis. A total of 2887 papers met the inclusion criteria in our research. Linear regression analysis results showed that the publications of studies of comorbid pain and inflammation significantly increased (P < 0.001) and have grown about 192 times in 40 years. The countries with the most outputs were the USA (886 publications), China (375 publications), and England (236 publications). Besides, Harvard University was the most prolific institution with 730 publications and 6646 citations. In accordance with the subject categories of WOS, neurosciences (31.832%), pharmacology/pharmacy (18.427%), and clinical neurology (15.206%) were the main research areas of these 2887 papers. Conclusions: The current study reveals that research on comorbid pain and inflammation has gradually become more extensive worldwide since 1981, and neuropathic pain was the most popular study type. Most of our research output in this field came from countries in Europe and North America, although some Asian countries showed promising performance.