Chronic obstructive pulmonary disease (COPD), a heterogeneous lung condition characterized by respiratory abnormalities and chronic respiratory symptoms including dyspnea, cough, or sputum, has a global prevalence of 10.1% and is the third leading cause of death worldwide (1–3). As one of the most common symptoms experienced by patients with COPD, dyspnea refers to a subjective experience of breathing discomfort that limits the abilities of patients to perform daily activities, resulting in anxiety and depression, which ultimately impacts the patients' quality of life (4–7). It is also an independent risk factor for COPD exacerbation and is associated with increased mortality (8, 9). Pharmacological therapies recommended by the 2023 Global Initiative for Chronic Obstructive Lung Disease for dyspnea relief include bronchodilators and methylxanthines; however, these therapies fail to rectify refractory breathlessness in patients with advanced disease, which may even result in adverse events such as arrhythmia or exacerbation (10–12). Complementary therapy is required for these patients. Acupuncture has been recommended by the Global Initiative for Chronic Obstructive Lung Disease as a non-pharmacological therapy since 2021 (13). A recent meta-analysis revealed that acupuncture may improve breathlessness and quality of life in patients with advanced COPD (14). However, the effect of acupuncture is still controversial, and the potential mechanism of acupuncture employed for relieving dyspnea in patients with COPD is still unclear.

As is well known, dyspnea is a multidimensional subjective experience that is influenced by emotions such as anxiety and depression (4). An increasing number of imaging studies suggest that it may be related to brain responses. Functional neuroimaging has shown that respiratory control and perception are modulated by the corticolimbic system of the brain (4, 15). Breathlessness in healthy individuals, as induced by lower tidal volume, inhaled CO₂, and respiratory occlusions, is related to the activation of brain regions within the anterior insula (AI), which means that various neuronal networks may respond to dyspnea perception (16–18). Compared with healthy controls, patients with COPD exhibit increased neural respiratory drive and decreased gray matter, especially in the anterior cingulate cortex (ACC). These changes are related to disease severity and anticipatory fear of dyspnea and physical activity (19–21). Activation of the medial prefrontal cortex and ACC in COPD patients correlated with the subjective dyspnea (22). The ACC may be the core brain mechanism responsible for dyspnea. Interestingly, it could also be the neural mechanism involved in acupuncture. Studies on humans and animals have revealed that acupuncture exerts multiple beneficial effects on patients with various diseases through its impact on the central nervous system, as evidenced by hemodynamic indicators in the brain (23, 24). Acupuncture can enhance brain network connectivity within the ACC, amygdala, hippocampal formation, and cerebellum, i.e., the default mode network (DMN) and sensorimotor network, to modulate emotion, memory, perception, antinociceptive activity, and sensorimotor functions (23–26). Acupuncture exhibits an additive effect in patients with depressive disorder by increasing functional connectivity in the amygdala and the ACC (27). Breathlessness is typically accompanied by anxiety; anxiety sensitivity is positively correlated with AI activity and affects the Bayesian sensory perception system associated with breathlessness (28). Therefore, acupuncture, dyspnea, and anxiety may involve similar mechanisms in the central nervous system of patients with COPD. The change in the ACC may be the neural mechanism of acupuncture for treating dyspnea in patients with COPD, with emotion also playing a role in the acupuncture treatment process for dyspnea.

However, the evidence from studies on acupuncture for COPD was limited due to methodological heterogeneity, low power, and the potential morphine-sparing effects of acupuncture (14). Additionally, the mechanism underlying the effects of acupuncture on the central nervous system in COPD has not been explored. The clinical efficacy and neural mechanism of acupuncture for reducing dyspnea severity require further assessment in well-designed clinical trials. Therefore, this randomized controlled functional imaging study will examine the effects of acupuncture on the severity of dyspnea, ability to perform physical activity, and affective state in patients with COPD and explore the neurobiological mechanisms underlying the effects of acupuncture through neuroimaging. The purpose of this study is illustrated in Figure 1. We hypothesize that (1) acupuncture is an effective non-pharmacologic treatment for COPD, resulting in improvements in dyspnea, emotional state, and quality of life; (2) the alleviation of dyspnea through acupuncture is associated with abnormal structural changes and functional connections in specific brain regions; (3) acupuncture can improve long-term anxiety and depression in patients with stable COPD, with associated functional connections in specific brain regions, which may also be related to the improvement of dyspnea conditions; and (4) neural mechanisms in patients with stable COPD differ between exertional dyspnea and resting states.

The recognized treatment effects of acupuncture on dyspnea in COPD are acknowledged in the COPD guidelines; however, its clinical application has been hampered by the low quality of evidence supporting its use and the lack of mechanistic studies. This randomized controlled trial aims to (1) conduct a well-designed 8-week acupuncture treatment program to observe its clinical efficacy in patients with stable COPD and to identify the location and pattern of brain activities related to dyspnea before and after treatment via functional and structural neuroimaging; (2) to explore the neural mechanisms of exertional dyspnea in patients with COPD via brain MRI using several graph theory-based or data-driven methods; and (3) to explore the comprehensive impact of acupuncture on dyspnea in multiple dimensions, particularly the affective dimension.

In this study, the acupoints commonly used for the treatment of COPD include Zusanli, Dingchuan, Lieque, Feishu, Pishu, and Shenshu (41). Acupuncture on Dingchuan can reduce the heart rate and dyspneic sensation in acute exacerbations of COPD and improve lung function in terms of forced expiratory volume in 1 s in patients with asthma (42, 43). Acupuncture on Zusanli, Pishu, Feishu, and Shenshu has been shown to improve pulmonary function and CAT scores and suppress inflammation in COPD (29, 44, 45). Acupuncture on Lieque and Zusanli has been reported to reduce nicotine cravings, and activation of the ACC, insula, and prefrontal cortex was found to be related to acupuncture (46). Stimulation of Zusanli evokes long-lasting activation of the supplementary motor cortex and deactivation of limbic/paralimbic and subcortical regions; the effect on these regions was extensive, and they were identified as network hubs related to the regulation of the secondary somatosensory cortex, emotion, and pain (23, 26, 47–49). Acupuncture on Zusanli improved the symptoms of functional dyspepsia by modulating the functional connectivity of the DMN (50). However, the target brain regions regulated by acupoints and the cumulative effects of stimulation were not determined in this randomized controlled trial on dyspnea.

Acupuncture, an important facet of traditional Chinese medicine, has demonstrated clinical efficacy in many conditions, including pain, mood disorders, and stroke, by modulating neural responses in the brain (51–53). Brain activation leads to enhanced blood flow, blood volume, and oxygen saturation in the cerebrum, thereby increasing deoxyhemoglobin levels, which is proportional to the magnetic resonance signal on functional MRI. The involvement of the sensorimotor and corticolimbic structures, which contributes to motor cognitive and emotional processing, in dyspnea perception is widely recognized (4, 25, 54). Among the brain areas related to dyspnea in COPD, the insular cortex is the most consistently reported region of sensory perception, followed by the amygdala, ACC, supplementary motor area, prefrontal cortex, and thalamus, suggesting that different neuronal networks are involved in dyspnea perception (55). According to the Embodied Prediction Interoceptive Coding and Neurovisceral Integration models, limbic cortices can generate predictions by integrating past experiences and updating through comparison with incoming sensory inputs, with the perception of breathlessness derived from the processes of interaction and comparison (56). Objective measures of disease are based on the balance between sensory inputs and predictions; factors such as effects and expectations can disrupt this balance and increase the perception of breathlessness (56). For example, pulmonary rehabilitation reduces dyspnea in patients by modulating the activity of expectation-related brain regions, such as the AI, ACC, and prefrontal cortex. Therefore, we hypothesize that acupuncture may modulate the activity of corticolimbic brain regions, such as the AI, ACC, and prefrontal cortex, to maintain the balance of predictions, thereby directly reducing dyspnea.

Anxiety or depression is experienced by 30%−40% of patients with COPD (57, 58). A self-perpetuating cycle of breathlessness and anxiety occurs in which breathlessness triggers anxiety, which in turn aggravates dyspnea (59). Fatigue and depression influence the perception of dyspnea by acting on the lateral prefrontal cortex, whereas anxiety can impair the sensitivity of resistive respiratory sensation (22, 60). In COPD patients, increased dyspnea is associated with anticipatory neural activation of the hippocampus, insula, and amygdala, which play key roles in emotional enhancement processes and are related to increased levels of anxiety and depression (61, 62). Therefore, the management of dyspnea-related anxiety and depression in patients with COPD has been investigated for its ability to attenuate the perception of dyspnea. Pulmonary rehabilitation has been reported to be the most effective treatment for dyspnea in patients with stable COPD, with a significant reduction in symptoms of depression and anxiety (63, 64). Pulmonary rehabilitation targets the brain network, including the amygdala, hippocampus, ACC, AI, and superior frontal gyrus, modulating the functions of cognitive control, symptom perception, and sensory integration; this modulation may lead to improved cognitive behavioral therapy outcomes for anxiety (65, 66). Another study reported that pulmonary rehabilitation reduced breathlessness–anxiety, which was related to lower activation of attention regulation and motor network function (67). Owing to the substantial overlap of cerebral activation regions and neural functions between anxiety and acupuncture stimulation, we hypothesize that acupuncture may modulate the activity of the lateral prefrontal cortex, hippocampus, ACC, or other brain regions to alleviate dyspnea-specific anxiety and depression and indirectly reduce breathlessness in COPD patients.

Exertional dyspnea is a major symptom of COPD and may be caused by dynamic hyperinflation during exercise (68). The Borg Dyspnea Scale, a measuring tool used during the 6MWT, can identify dynamic hyperinflation in patients with moderate-to-severe COPD with high reliability (69, 70). Exertional dyspnea during the 6MWT may be caused by a mismatch between central drive and mechanical response (71), and it has also been shown to be associated with activation of the prefrontal cortex in COPD (72). A study on cortical hemodynamics in patients with COPD suggested a stronger correlation between the premotor cortex and exertional dyspnea (73). Similar results have been observed in studies on dyspnea in healthy individuals (74). Therefore, in this study, an MRI will be performed after the 6MWT to explore the mechanisms of exertional dyspnea in the brain.

Depression is considered to be associated with more severe breathlessness, and anxiety plays a crucial role in the interplay between dyspnea and depression (75, 76). The unique connection between dyspnea and acute anxiety is considered to depend largely on subjective feelings (77), which are influenced not only by exteroception but also by interception. Interceptive awareness is a set of reciprocal afferent/efferent circuits that can integrate incoming information and engage in body signal regulation, with perceptual accuracy as a component (78). Anxiety sensitivity may reduce the stability of the Bayesian sensory perception system and increase misunderstanding of symptoms and dyspnea variability (28). Different levels of anxiety indicate different AI activities (79). A recent study suggested that AI and the pre-supplementary motor area are potential candidate brain regions for performing self-corrective functions (80). Thus, we assume that AI is key to the impact of anxiety on dyspnea and will explore the functional connections between AI and other brain regions related to exertional dyspnea for explaining the potential mechanism underlying the effects of anxiety on exertional dyspnea in patients with stable COPD.

To the best of our knowledge, this study is the first to investigate the neurobiological mechanisms of acupuncture for the treatment of dyspnea in patients with COPD. Importantly, non-acupoints on the NAM have been included as a placebo control. In this study, various dyspnea assessment scales were used before and after exercise and acupuncture. Additionally, diffusion tensor imaging and functional MRI data were collected to investigate the mechanisms of exertional dyspnea and its emotional impact on patients with stable COPD. Since dyspnea is a complex experience that can be caused or influenced by many factors and dimensions, we evaluated the effects of acupuncture on dyspnea from multiple aspects, including emotions and quality of life.

This article introduces the design and scheme of a clinical trial to study the effects and neurobiological mechanisms of acupuncture treatment of dyspnea in patients with COPD. The results of this innovative research are expected to answer the following questions: As an alternative therapy, can acupuncture effectively alleviate dyspnea in COPD? How can functional and structural imaging explain the occurrence of exertional dyspnea in COPD? Does acupuncture relieve dyspnea by regulating the respiratory-related areas of the brain? Does acupuncture relieve dyspnea by regulating areas related to emotions? The results of this trial will provide novel insights into the mechanisms of dyspnea and provide evidence and principles for the use of acupuncture to alleviate dyspnea in COPD and other diseases involving dyspnea.

The studies involving humans were approved by the Clinical Trial and Biomedical Ethics Committee of West China Hospital of Sichuan University, Medical Ethics Committee of Pidu District Hospital of Traditional Chinese Medicine, and Medical Ethics Committee of Chengdu University of Traditional Chinese Medicine Affiliated Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

XC: Writing – review & editing, Writing – original draft, Methodology, Data curation. CX: Writing – review & editing, Writing – original draft, Resources, Project administration. LD: Writing – review & editing, Writing – original draft, Methodology. WX: Writing – review & editing, Writing – original draft, Methodology. ML: Writing – review & editing, Writing – original draft. YY: Writing – review & editing, Writing – original draft. CL: Writing – review & editing, Writing – original draft. CZ: Writing – review & editing, Writing – original draft. BM: Writing – review & editing, Writing – original draft. YL: Resources, Writing – review & editing, Writing – original draft. JF: Writing – review & editing, Writing – original draft, Supervision, Methodology, Funding acquisition.