The major findings in the present study are as follows: (1) Further clinical evidence for the effect of acupuncture on migraine was provided to consolidate previous findings; (2) We propose a hypothesis of the mechanism of acupuncture in the treatment of migraine; (3) Sham acupuncture is very different from acupuncture in terms of curative effect, affected brain regions and signalling pathways.
Our clinical study revealed that acupuncture can effectively alleviate migraine symptoms, the modes of action and underlying mechanisms of acupuncture therapy may be different from sham acupuncture therapy. Results showed that both acupuncture and sham acupuncture therapy can effectively alleviate migraine symptoms. Based on VAS scores, the effect was more pronounced in the acupuncture group than in the sham acupuncture group, although differences were not statistically significant. This is consistent with the results of previous studies, that is, placebo response is widely observed in clinical trials of pain treatment.17 Furthermore, acupuncture could improve the sleep quality and especially the migraine-specific quality of life. However, our study showed that the GAD-7 index of migraineurs was not significantly affected by acupuncture. We speculate that the psychological state of disease and the pain state interact with each other, but the current psychological assessment scale lacks assessment of pain status, thus making it inadequate for accurate assessment of psychological changes during pain relief.
fMRI data showed that changes in the acupuncture group involved more brain regions than in the sham acupuncture group, indicate that the two treatments have different effects on brain activity. After acupuncture treatment, the ReHo and ALFF values increased in brain regions involved in the processing of pain, including sensory conduction of pain (thalamus), cognitive processing of pain (middle frontal gyrus), emotional processing of pain (cerebellum), and the default mode network (precuneus); In contrast, the ReHo and ALFF values decreased after acupuncture therapy in brain regions involved in the processing of pain (inferior frontal gyrus), emotional processing of pain (insula, cerebellum), default mode network (inferior parietal lobule) and limbic system (cingulate gyrus). Moreover, the ALFF value decreased in the fusiform gyrus but increased in both the lingual gyrus and superior temporal gyrus after acupuncture therapy. Notably, the lingual gyrus in the occipital lobe has been identified as an important structure in cortical spreading depolarization, which is involved in the onset and persistence of migraine.18 Furthermore, the function of thalamus is related to regulating sleep and attention, and the ALFF value in the thalamus was increased after treatment, this phenomenon may explain the effects of acupuncture on sleep quality and migraine-specific quality of life. On the other hand, the brain regions affected by sham acupuncture were limited. Sham acupuncture therapy increased the ALFF value in a part of the brain region that is involved in the default mode network (inferior parietal lobule), but decreased the ALFF value in parts of brain regions that involve emotional processing of pain (insula). This may explain why sham acupuncture has an analgesic effect to some extent.
Migraine is a multifactorial disorder. Initially, researchers focused mainly on the neurovascular system and neurotransmission, until Willem Amery put forward the hypothesis that the pathogenesis of migraine is related to metabolism in 1982.19 Since then, a growing body of evidence shows that migraine is at least partly an energy deficiency syndrome marked by mitochondrial dysfunction.20 Inflammation also plays an important role in migraines. It has been reported that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminal neurovascular system.21 Integrated analysis showed that the mechanism of acupuncture involves complex networks in the body which were mainly related to regulating oxygen supply, energy metabolism, and inflammation. We found that migraineurs' bodies were in a state opposite to hypoxia, compared with the normal control, the hypoxic markers, hypoxanthine and xanthine, were significantly reduced in the migraineur group. Besides, the levels of the upstream and downstream metabolites, inosine and 5-hydroxy acid, were also significantly decreased. Additionally, the pyruvate levels were significantly increased. Furthermore, glyceraldehyde 3-phosphate dehydrogenase, a key enzyme of glycolysis, and lactate increased significantly after acupuncture treatment. Compared with normal controls, there was a downtrend in the levels of GAPDH and lactate in migraineurs. Hypoxanthine and xanthine levels also increased after acupuncture therapy. According to the astrocyte-neuron lactate shuttle theory, neurons activated and release the excitatory neurotransmitter glutamate, stimulate astrocytes to absorb glucose, trigger glycolysis, and produce lactate to provide energy for neurons, which may explain the phenomena that acupuncture can regulate the metabolism of brain energy and alleviate the brain energy imbalance of migraine patients by promote the glycolysis process of astrocytes. Acupuncture treatment resulted in the enrichment of pathways related to inflammation, including the PPAR signalling pathway and linoleic acid metabolism. The levels of (9S)-hydroxyoctadecadienoic acid were upregulated while APO A-II levels were downregulated by acupuncture. We also compared the pathways affected by sham acupuncture with those affected by acupuncture treatment, and found that the two main pathways affected by sham acupuncture involved glycerophospholipid metabolism and regulation of the actin cytoskeleton. Acupuncture exerts complex effects in the human body, and further in-depth research is needed to explore the underlying mechanisms.
In summary, our study is the first to elucidate the anti-migraine mechanisms of acupuncture from the perspectives of clinical effectiveness indices, fMRI, proteomics, and metabolomics. Our findings verified that acupuncture can effectively relieve migraine symptoms, and not merely via the placebo effect. The anti-migraine mechanism of acupuncture involves a complex network which is related to regulating the blood oxygen levels, reversing brain energy imbalance and regulating inflammation. Brain regions of migraineurs affected by acupuncture include the limbic system and default mode network, and regions involved in cognitive and emotional processing of pain, sleep, and attention.