Chronic stable angina pectoris (CSAP) is a clinical syndrome characterized by constricting discomfort in the chest, jaw, shoulder, or back, typically aggravated by exertion or emotional stress (Piccolo et al., 2015). As the most common manifestation of coronary artery disease (CAD; Benjamin et al., 2017), CSAP has been identified as a predominant risk of major cardiovascular events and sudden cardiac death, and brings a significant impact on functional capacity and quality of life of patients (Chaitman and Laddu, 2011). Therefore, searching for the effective management of CSAP to reduce the frequency of angina attacks is of great value. Acupuncture is a widely used traditional practice for the prevention and treatment of angina and has been identified as a safe and effective adjunctive therapy for CSAP in several high-quality clinical trials (Zhao et al., 2019, 2021; Huang et al., 2021). It was reported that acupuncture could effectively alleviate symptoms, reduce the frequency of angina attacks, and decrease nitroglycerin use in CSAP patients (Shen et al., 2021). However, the underlying mechanism of acupuncture for CSAP was still unclear.

Recently, the proposal of brain-heart interaction theory (Silvani et al., 2016) provides a new perspective to explore the pathogenesis of cardiovascular diseases and explain the mechanism of intervention. For example, evidence from functional Magnetic Resonance Imaging (fMRI) demonstrated that the dysfunction of autonomic-limbic integration might be the important pathophysiology of takotsubo syndrome (Templin et al., 2019), and the hyperactivity of the temporal gyrus, parahippocampus, fusiform gyrus, and cerebellum played a critical role in pain perception response in CAD patients (Wittbrodt et al., 2020). Furthermore, during the dobutamine-induced angina task, patients with angina manifested increased regional cerebral blood flow in the thalamus, periaqueductal gray, prefrontal cortex, and anterior cingulate cortex (Rosen et al., 1994). These regions overlapped highly with the findings of previous neuroimaging studies about pain (Davis et al., 2017; Mouraux and Iannetti, 2018), which suggested that angina pain, a typical kind of visceral nociception, might share the similarity in pain processing with somatalgia. As an increasing number of studies have detected that acupuncture could modulate the activities of pain processing-related regions, including the thalamus (Chu et al., 2012), hippocampus (Ma et al., 2020), medulla oblongata-brainstem (Chang et al., 2021), middle temporal gyrus (Yu et al., 2019), and occipital gyrus (Ma et al., 2020) in patients with chronic pain, it was necessary and feasible to explore the mechanism of acupuncture for treating CSAP by functional neuroimaging techniques.

Therefore, this resting-state fMRI study was conducted, with the following three aims: (1) comparing the brain spontaneous activity patterns between CSAP patients and healthy subjects (HS), and (2) investigating how acupuncture modulates the abnormal activity pattern of CSAP patients, and (3) exploring the differences of two acupoint prescriptions on regulating resting-state functional connectivity (rsFC) of CSAP patients. We hypothesized that CSAP patients had aberrant functional activity in these brain regions closely associated with pain processing, which could be significantly modulated by acupuncture treatment, and that different acupoint prescriptions had different regulating effects on rsFC of CSAP patients.

To the best of our knowledge, this was the first study to investigate the aberrant brain spontaneous activity patterns of CSAP patients and explore the modulating effects of acupuncture for functional brain activity as well as rsFC in CSAP patients. The findings demonstrated that acupuncture could significantly decrease the elevated spontaneous activity of the left calcarine in CSAP patients. Compared with the acupoints on the meridian indirectly related to the Heart, acupuncturing at the points on the meridians directly related to the Heart had a remarkable effect on the regulation of rsFC between the calcarine and the ITG, cerebellum crus 1, hippocampus, thalamus, and MCC.

Brain-heart interaction plays an important role in the pathophysiology and treatment of cardiovascular diseases (Silvani et al., 2016). On the one hand, the heart receives signals from the brain via the sympathetic and parasympathetic nerves which are controlled by the central autonomic network (Benarroch, 1993). On the other hand, the noxious pain stimulus of angina is mediated by coronary chemoreceptors and transmitted to the brain via vagal afferent nerves, and finally integrated and processed in the cerebral cortex. The current study demonstrated that CSAP patients manifested higher spontaneous activity on the calcarine, MOG, and postcentral gyrus, and that the abnormally elevated functional activity of the calcarine was positively correlated with the McGill pain score in patients. The postcentral gyrus is the cortex center of somatic sensation perception and the crucial part of the pain neural matrix, which is responsible for the adjustment of pain perception, including the positioning and recognition of pain intensity (Mouraux and Iannetti, 2018). Calcarine and MOG are important components of the primary visual cortex and are traditionally thought to be primarily involved in visual processing (Thiebaut de Schotten et al., 2014). However, there is growing evidence in recent years found that several components of the visual cortex, including the calcarine and MOG, were also involved in the processing of pain signals. Results of several fMRI studies have indicated that patients with chronic pain, such as migraine (Wei et al., 2019), low back pain (Bush et al., 2021), and persistent somatoform pain disorder (Liu et al., 2019), exhibited atypical functional activity patterns in the occipital gyrus. For example, (Wei et al., 2019) demonstrated that migraine patients had aberrant spontaneous activity and regional homogeneity in calcarine, as well as atypical rsFC between calcarine and the thalamus, the relay station of sensory signaling. Moreover, these abnormalities of calcarine activity and connectivity patterns were significantly correlated with the pain intensity and affective condition of patients (Wei et al., 2019, 2021). This evidence indicated that calcarine was involved in the processing of pain perception and pain affectivity (Schwedt et al., 2015). In addition to the somatalgia, patients with chronic visceral pain (e.g., irritable bowel syndrome) also exhibited higher spontaneous activity and regional homogeneity in calcarine at resting-state (Chen et al., 2021), and increased activity in the visual cortex during the expectation of rectal pain. These findings suggested that the calcarine was not only associated with pain perception and pain affectivity but was also involved in hypervigilance to pain anticipation (Lee et al., 2012). The typical symptom of CSAP is prolonged, episodic chest dullness and crushing pain. This noxious pain stimulation as well as alertness and excessive fear of angina attacks lead to the hypersensitization of calcarine, manifested as symptoms-associated hyperactivity of the calcarine in CSAP patients.

After acupuncture treatment, the pain experience and anxiety condition were significantly improved, the abnormally elevated functional activity of the calcarine was significantly normalized in CSAP patients, and there were positive correlations between fALFF change in calcarine and improvements of McGill pain, SAS, and SDS score in patients. These findings reverified that acupuncture was an effective adjunctive therapy for CSAP, which was consisted with the previous multicenter randomized controlled trial (Zhao et al., 2019), and suggested that the effects of acupuncture in improving the pain experience of CSAP patients were closely related to the modulation of calcarine activity. In addition, this study also found that acupuncture treatment could significantly regulate the spontaneous activity of the brainstem, hippocampus, parahippocampus, and orbitofrontal cortex in CSAP patients, which were closely related to the transmission, perception, attention, and cognition of pain (Bushnell et al., 2013). These findings indicated that acupuncture for analgesia was not single-targeted. The improvements of symptoms in CSAP patients induced by acupuncture were associated with its multi-targeted modulations of the pain process. These similar results have also been observed in acupuncture treatment of other visceral pains and somatalgia (Ma et al., 2020, 2021; Wen et al., 2021).

Another important finding of this study was the difference in clinical efficacy and modulation of rsFC patterns between acupuncture at points on the meridian indirectly and directly related to the Heart. These results supported the classic acupuncture theory “selecting acupoints along the meridian” (Xing et al., 2013) and explained the potential mechanism of better effects of acupoints on the meridian directly related to the Heart for CSAP from the perspective of brain-heart interaction. This study compared the differences of ROI-voxel rsFC change between these two acupoint prescriptions, finding that acupuncturing at points on the meridian directly related to the Heart could significantly increase the rsFC between the calcarine and the thalamus, hippocampus, MCC, and ITG/Cerebellum crus 1 than acupoints on the meridian indirectly related to the Heart. Pain is a multidimensional and complex experience involving sensory, cognitive, and affective aspects (Fitzcharles et al., 2021). The thalamus is a pivotal node for pain transmission and mediation, the hippocampus and cingulate cortex are responsible for the processing and encoding of pain cognition and affectivity, while the cerebellum and ITG play an important role in pain visual perception and multimodal sensory integration (Saab, 2012; Bushnell et al., 2013; Finnerup et al., 2021). Therefore, the current findings, while confirming the specificity of the acupoint effects, also suggested that better improvement of CSAP symptoms by acupuncturing at points on the meridian directly related to the Heart might be correlated with their multi-threaded modulations to the pain network.

Several limitations should be concerned in this study. First, the sample size was smaller in each acupuncture treatment group. Second, the intervention phase was short. These two factors may account for the non-significant difference in clinical efficacy between two acupoint prescriptions. Third, to be consistent with clinical practice, patients in this study are allowed to receive recommended pharmacological interventions. Therefore, the effects of drugs on functional brain activity are difficult to exclude.

The current study provided neuroimaging evidence for understanding the central pathophysiology of CSAP patients and the mechanism of acupuncture for CSAP. These findings suggested that the elevated spontaneous activity of the calcarine was an important central pathological characteristic of CSAP, and regulation of the aberrant spontaneous activity of the calcarine might be an underlying mechanism of acupuncture treatment for CSAP patients. The multi-threaded modulation of rsFC between calcarine and multiple pain-related brain regions might be a potential mechanism for better efficacy of acupuncture at points on the meridian directly related to the Heart.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Sichuan Traditional Chinese Medicine Regional Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

FL and FZ conceived and designed the study. YL, RS, ZL, MJ, and QW recruited the participants. TY and ZT analyzed the data. LL drafted the manuscript. SL, FL, and FZ revised the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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