Frequency-Specific Blood Oxygen Level Dependent Oscillations Associated With Pain Relief From Ankle Acupuncture in Patients With Chronic Low Back Pain

Objective: Recent advances in brain imaging have deepened our knowledge of the neural activity in distinct brain areas associated with acupuncture analgesia. However, there has not been conclusive research into the frequency-specific resting-state functional changes associated with acupuncture analgesia in patients with chronic pain. Here, we aimed to characterize changes across multiple frequencies of resting-state cortical activity associated with ankle acupuncture stimulation (AAS) in patients with chronic low back pain (CLBP) and healthy controls.Methods: Twenty seven patients with CLBP and Twenty five age- and gender-matched healthy volunteers were enrolled in the study. Participants received tactile sham acupuncture (TSA) and AAS, respectively. The whole-brain amplitude of low-frequency fluctuation (ALFF) in the range 0.01–0.25 Hz was assessed for changes associated with each intervention. Further, a visual analog scale (VAS) was used to collect subjective measures of pain intensity in patients. Linear mixed-effect modeling (LME) was used to examine the mean ALFF values of AAS and TSA between patients and healthy controls.Results: The ALFF was modulated in the default mode network (an increase in the medial prefrontal cortex, and a decrease in the cerebellum/posterior ingulate/parahippocampus, P < 0.01, corrected) in both patients and controls. Decreased ALFF in the bilateral insular was frequency-dependent. Modulations in the cerebellum and right insular were significantly correlated with VAS pain score after AAS (P < 0.01).Conclusion: Hence, frequency-specific resting-state activity in the cerebellum and insular was correlated to AAS analgesia. Our frequency-specific analysis of ALFF may provide novel insights related to pain relief from acupuncture.

Revealing the Neural Mechanism Underlying the Effects of Acupuncture on Migraine: A Systematic Review

Background: 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.Methods: 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.Results: 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; n = 2 studies), magnetic resonance spectroscopy (n = 1), and functional magnetic resonance imaging (fMRI; n = 12). The analyses used included the regional homogeneity (ReHo) method (n = 3), amplitude of low frequency (ALFF) method (n = 2), independent component analysis (ICA; n = 3), seed-based analysis (SBA; n = 1), both ICA and SBA (n = 1), Pearson's correlation to calculate functional connectivity (FC) between brain regions (n = 1), and a machine learning method (n = 1). Five studies focused on the instant effect of acupuncture, and the research objects were those with acute migraine (n = 2) and migraine in the interictal phase (n = 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).Conclusion: 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.

Neuroimaging in the Understanding of Acupuncture Analgesia: A Review of Acupuncture Neuroimaging Study Based on Experimental Pain Models

With the development of real-time and visualized neuroimaging techniques, the studies on the central mechanism of acupuncture analgesia gain increasing attention. The experimental pain models have been widely used in acupuncture-analgesia neuroimaging studies with quantitative and controlled advantages. This review aimed to analyze the study design and main findings of acupuncture neuroimaging studies to provide reference for future study. The original studies were collected and screened in English databases (PubMed, EMBASE, and Cochrane Library) and Chinese databases (Chinese Nation Knowledge Infrastructure, Chinese Biomedical Literature Database, the Chongqing VIP Database, and Wanfang Database). As a result, a total of 27 articles were included. Heat stimulation and electroacupuncture were the mostly used pain modeling method and acupuncture modality, respectively. The neuroimaging scanning process can be divided into two models and five subtypes. The anterior cingulate cortex and insula were the most commonly reported brain regions involved in acupuncture analgesia with experimental pain models.

The Role of Neuroglial Crosstalk and Synaptic Plasticity-Mediated Central Sensitization in Acupuncture Analgesia

Although pain is regarded as a global public health priority, analgesic therapy remains a significant challenge. Pain is a hypersensitivity state caused by peripheral and central sensitization, with the latter considered the culprit for chronic pain. This study summarizes the pathogenesis of central sensitization from the perspective of neuroglial crosstalk and synaptic plasticity and underlines the related analgesic mechanisms of acupuncture. Central sensitization is modulated by the neurotransmitters and neuropeptides involved in the ascending excitatory pathway and the descending pain modulatory system. Acupuncture analgesia is associated with downregulating glutamate in the ascending excitatory pathway and upregulating opioids, 𝛾-aminobutyric acid, norepinephrine, and 5-hydroxytryptamine in the descending pain modulatory system. Furthermore, it is increasingly appreciated that neurotransmitters, cytokines, and chemokines are implicated in neuroglial crosstalk and associated plasticity, thus contributing to central sensitization. Acupuncture produces its analgesic action by inhibiting cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, and upregulating interleukin-10, as well as modulating chemokines and their receptors such as CX3CL1/CX3CR1, CXCL12/CXCR4, CCL2/CCR2, and CXCL1/CXCR2. These factors are regulated by acupuncture through the activation of multiple signaling pathways, including mitogen-activated protein kinase signaling (e.g., the p38, extracellular signal-regulated kinases, and c-Jun-N-terminal kinase pathways), which contribute to the activation of nociceptive neurons. However, the responses of chemokines to acupuncture vary among the types of pain models, acupuncture methods, and stimulation parameters. Thus, the exact mechanisms require future clarification. Taken together, inhibition of central sensitization modulated by neuroglial plasticity is central in acupuncture analgesia, providing a novel insight for the clinical application of acupuncture analgesia.

The Status of the Quality Control in Neuroimaging Studies of Acupuncture Analgesia

Neuroimaging technology is an important technology used to explore the neural mechanisms of acupuncture analgesia. In this study, we extracted original studies published in Chinese and English focusing on the use of neuroimaging technology to explore the mechanisms of acupuncture analgesia from PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, and CNKI databases from January 1999 to August 2020. The extracted data were statistically analyzed in terms of year of publication, country, experimental design, and quality control approaches used, sample size, characteristics of participants, acupuncture operation, and other information. Analysis of the literature revealed that international cooperation promotes scientific research. Flexible experimental design can better explain the mechanism of acupuncture analgesia. Reasonable sample size, strict participant inclusion criteria, and standard acupuncture practices are essential for repeatability of conclusions. These findings show that attention should be paid to quality control in future research to improve the reliability of research on acupuncture analgesia.