Insomnia disorder (ID) is the inability to initiate and maintain sleep despite adequate opportunity for sleep, accompanied by significant daytime dysfunction (Battle, 2013). With a prevalence rate of 30–35% and an annual incidence rate of 7–15% (Morin et al., 2015), ID affects our mental and physical health widely (Pigeon et al., 2017; Khan and Aouad, 2022).

As a kind of complementary therapy, acupuncture is widely recognized as a potentially effective treatment method for ID. It has shown a positive effect on improving sleep quality (Zhang et al., 2020; Zhao et al., 2021) and alleviating the symptoms of anxiety and depression brought on by insufficient sleep (Liu C. et al., 2021). While the potential mechanisms remain to be elucidated.

The hyperarousal theory, which proposes increased activation in specific brain regions in insomniacs, is largely recognized as an explanation for the origin of insomnia (Bonnet and Arand, 1997). The locus coeruleus (LC), a crucial part of the ascending activation system, is a major norepinephrine (NE) producer and projects a large number of neurons to the spinal cord and cortex (Benarroch, 2018). LC-NE neurons remain active while awake, and at a resting state during sleep, especially during the rapid eye movement phase (Eschenko and Sara, 2008; Eschenko et al., 2012). Therefore, LC was regarded as an important contributor to promoting wakefulness and maintaining sleep.

Studies using fMRI have shown that LC plays an important role in insomnia. The functional connectivity (FC) between the LC and the posterior cingulate, thalamus, and caudate nucleus alters with the awakening state (Song et al., 2017). In insomniacs, the FC of LC increased in areas of the sensory cortex and default mode network (DMN) while decreased in the prefrontal cortex (Gong et al., 2021). Acupuncture has been shown to regulate the electrophysiology of LC in rat models of insomnia (Lee and Kim, 2017). We hypothesize that regulating the functional activity of LC may be one of the mechanisms for acupuncture to improve sleep. This study aims to investigate the modulation effect of acupuncture on the FC of the LC in ID.

Detailed baseline demographic and clinical characteristics are shown in Table 1. No significant difference between groups was observed (all p > 0.05).

This study aims to explore the effect of acupuncture on the FC of LC in ID patients. The clinical data suggested that acupuncture could modulate the state of arousal and improve sleep quality in insomniacs. Sleep quality was improved in both groups, but more significantly in the RA group. The doctor-patient interaction during acupuncture treatment may relieve the patients’ negative emotions in both groups (Liu, 2007). The fMRI analysis revealed that the FC between the LC and the IFG, insular, and SMG were modulated following acupuncture treatment.

The IFG is considered a key brain region for sleep. Individuals with lower gray matter density in the left IFG are more likely to develop insomnia and wake early (Stoffers et al., 2012). Studies have shown that the activity of the IFG decreases during sleep while increases during sleep deprivation (Vartanian et al., 2014). Li et al. discovered that the amplitude of the low-frequency fluctuation value of the left IFG was reduced in insomnia patients and negatively correlated with the duration of insomnia (Li et al., 2016). Yan et al. discovered that the degree centrality value of the left IFG decreased proportionally to the PSQI score in insomniacs (Yan et al., 2018). The IFG is a fundamental component of the cognitive control network (CCN), which is involved in executive function and cognitive control (MacDonald et al., 2000). In a previous study, we discovered that patients with insomnia had higher LC FC in the middle frontal gyrus than healthy people (Chen et al., 2022). Both the middle frontal gyrus and IFG belong to CNN, demonstrating the importance of CNN in sleep regulation. Abnormal CCN function was found in ID patients, which may account for the heightened sensitivity to external stimulation (Nofzinger, 2004). Our study found that the FC between the LC and IFG was downregulated after acupuncture, which is consistent with the previous findings; thus, acupuncture may inhibit the overactivation of the IFG.

The insula is part of the salience network (SN) and is crucial for decision-making, cognition, emotion regulation, and attention control (Uddin, 2015). Patients with ID exhibited abnormal insular activity during both task execution and resting states. ID patients showed decreased FC between the insula, amygdala, striatum, and thalamus compared to normal sleepers (Martin et al., 2015; Lu et al., 2017). The co-activation of the insula with the SN is increased when ID patients fall asleep (Chen et al., 2014). Prior studies found that the FC value between the bilateral insula in ID patients decreased (Huang et al., 2017; Liu et al., 2018). The anatomical connection between the LC and insula is related to the processing of unexpected events (Dayan and Yu, 2006; Eschenko et al., 2012), and the changes in the FC of the LC-insula may be associated with the modulation of perceptual awareness skills and salience event processing (Liu J. et al., 2021). Our study found the consistent results, real acupuncture could increase the FC of the LC-left insular. But we were unable to establish a significant correlation between this finding and clinical assessments, which may be related to the sample size. Based on the above studies, we speculated that acupuncture may be beneficial for interoceptive and emotional processing in ID by modulating the abnormal functional of the insula.

The ΔFC value of SMG showed differences between groups. And ΔPSQI was negatively associated with the ΔFC value of LC-left SMG. The SMG belongs to the inferior parietal lobule, which is part of the DMN (Husbani et al., 2021) and plays an important role in the adjustment of consciousness (Marques et al., 2018). Kay et al. discovered an inverse correlation between the rate of glucose metabolism in SMG and sleep efficiency (Kay et al., 2016). A voxel-based morphometry study showed that the white matter volume of SMG was negatively associated with the PSQI score (Bai et al., 2022), and the higher volume of SMG was correlated with the longer sleep duration (Cheng et al., 2021). Studies found that the increasement in parietal lobe activity could compensate for the decreased cognition caused by insomnia (Chee and Choo, 2004; Li Y. et al., 2022). Based on these findings, we believe that acupuncture may relieve cognitive decline caused by insomnia by modulating LC-SMG FC.

An earlier study found decreased LC-IFG FC and elevated LC-SMG FC in ID patients (Gong et al., 2021), which appears inconsistent with our findings. This difference may be related to the compensatory mechanism described above and, on the other hand, to the variation in depression and anxiety in the included population. Anxiety and depression were found to affect the FC of IFG and brain regions in DMN (Fang et al., 2016; Yan et al., 2019; Yu et al., 2021). Therefore, it is difficult to determine whether insomnia or anxiety and depression had a greater impact on the FC of LC-IFG and LC-SMG in that study. The FC of LC is also influenced by age, differences in demographic characteristics can also contribute to inconsistent results (Zhang et al., 2016; Song et al., 2021). In addition, the difference in the method of LC localization may also play roles. There are relatively few studies on the FC of LC in insomnia patients, and the results lack uniformity (Gong et al., 2021; Li C. et al., 2022). To obtain more accurate results, a big-scale study focused on ID patients without emotional problems is needed. As for the brain regions that showed differences in the between-group comparisons but did not appear in the within-group comparisons (insula and SMG), it may be related to the non-specific effect of the sham acupuncture, which needs to be further explored. Furthermore, we discovered that the brain regions with FC differences are in the left hemisphere, which is intriguing. We suspect this is because the insomnia patients we recruited were all right-handed. Activation in the left hemisphere of the brain was found to be more dominant than the right in right-handed people (Gut et al., 2007). We will include left-handed patients in our future study to test our hypothesis.

Acupuncture has been found to regulate heart rate variability, indicating that acupuncture can inhibit the sympathetic nerve and activate the vagus nerve (Wang et al., 2002; da Silva and Dorsher, 2014). Acupuncture’s regulation mechanism on the LC FC may be related to afferent vagus nerve stimulation. The nucleus of the solitary tract (NTS) is primarily innervated by vagal afferents, and the NTS projects to the locus coeruleus. The peripheral vagus nerve can be stimulated to further regulate the functional activities of the LC. Future research should be combined with heart rate variability and other indicators to evaluate vagal nerve activity in order to validate this hypothesis.

There are some limitations in our research. First of all, the LC is the main source of NE, but this study did not involve the measurement of NE, and future studies should be combined with relevant examinations. Second, actigraphy relies on exercise to identify the awake period, although it is relatively objective but not accurate enough, polysomnography should be adopted. Thirdly, the LC has only 45,000–50,000 cells, making its precise location difficult. Even though the LC region has been added to AAL3, a more precise map of the Chinese brain is required. Additionally, the sample size was relatively small in this study. Additional studies should be conducted with larger sample sizes to confirm our findings. Lastly, there was no follow-up in this study, in the future, a long-term observation is required.

To our knowledge, this is the first study to investigate the mechanism of acupuncture treatment of insomnia utilizing the FC of LC. We found that the behavioural results of the insomniacs improved after acupuncture, and the imaging results showed that the FC between the LC and IFG, insular and SMG were modulated. The LC, which connects the SN, CCN, and DMN, may be an important target for acupuncture to improve insomnia.

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 Medical Ethical Committee of the Beijing Hospital of Traditional Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.

ZC participated in the conception and design of this study, data collection, organization, and drafting of the paper, and revised the content of the paper. TJ and XY participated in the design, organization, and analysis of this study. ZT participated in the fMRI experimental design. JG and BL participated in the design and implementation of the experiment, participated in the analysis and interpretation of the data, provided guidance on the experiment, provided administrative, technical, and material support, and made key revisions to the academic content of the paper. All authors contributed to the article and approved the submitted version.

This study was funded by the National Natural Science Foundation of China (81774391), Natural Science Foundation of Beijing Municipality (7212170) and the Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China (BZ0437).

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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