Study characteristics of the acupuncture neuroimaging studies on AD
The included studies aimed to explore whether acupuncture could cause brain activation, alternation of the brain network, and brain neuronal activity. Nine of the 13 neuroimaging studies explored whether acupuncture could cause brain activation. However, there is no consensus regarding these alterations. In addition, four studies investigated whether acupuncture could affect brain functional networks, and one study evaluated acupuncture-induced brain neuronal activity. However, only two studies determined the correlation between acupuncture effects and functional network/neuronal activity.
Based on previous study [
54], the sample size may affect the treatment effect evaluation. All included studies had a sample size of less than 30, which may have affected the stability and replicability of the findings; thus, future studies should be conducted with larger sample sizes to confirm the findings of the current review. Additionally, there were more female than male with AD. According to previous studies [
55‐
57], sex is a vital feature influencing physiopathological mechanisms and therapies for patients with AD. Nevertheless, no study explored on the sex-disaggregated neural mechanism of acupuncture in AD. Therefore, sex-disaggregated neuroimaging trials are supposed to carry out.
In terms of the acupuncture details, of the included 13 neuroimaging studies, LR 3 (Taichong) and LI 4 (Hegu) LR 3 and LI 4 were the most frequently used acupoints. In traditional Chinese medicine theory, LI 4 and LR 3 are named the Siguan [
58]. Siguan points are recommended for future neuroimaging studies on acupuncture interventions in AD. In addition, eight studies adopted manual acupuncture, but only two recorded the details of the acupuncturists. Researchers should pay more attention to acupuncturists [
59,
60]. Moreover, the cerebral response is associated with the degree of sensation in neuroimaging; consequently, the response sought should be carefully documented. Finally, based on the STRICTA, several factors may have affected the study findings; therefore, future studies should apply standardized acupuncture procedures based on the STRICTA.
Only three comparison models, acupuncture versus healthy volunteers, self-controlled before and after acupuncture, and acupuncture versus sham acupuncture, were adopted in the included studies. The acupuncture versus healthy volunteer model explores the distinct cerebral activities between patients with AD and healthy people before and after acupuncture, the self-control comparison investigates the alterations in brain areas affected by acupuncture, and acupuncture versus sham acupuncture evaluates the specific cerebral alterations between acupuncture and placebo. However, according to the STRICTA criteria, these models are insufficient for exploring the numerous effects of acupuncture in AD. For instance, according to the STRICTA, the depth, response sought, acupuncture stimulation, practitioners, and other factors affecting acupuncture efficacy require further research.
Regarding the outcome measurements, the cognitive outcome measures applied in the included studies were MMSE, MoCA, CDR, and AVLT, which have been commonly applied to detect cognitive impairment. MMSE and CDR are suggested for evaluating dementia, MoCA is recommended for evaluating mild cognitive impairment (MCI) [
61], and AVLT is recommended to measure episodic memory function in AD [
62]. However, none of these scales comprehensively assess the cognitive function of patients with AD. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as a gold standard, was developed to assess the level of cognitive dysfunction in AD [
63,
64]. Accordingly, it is recommended that ADAS-Cog be used to assess the cognitive function of patients with AD in future studies.
Current methodology of the included studies
Seven of the 13 neuroimaging studies were designated as low risk; five studies were ranked as serious risk; and others were ranked as some concerns about the quality of the methodology used. The one RCT included had some concerns due to issues in the randomization process and selection of the reported results. Of the 12 non-RCTs included, the risk of bias in five studies was serious due to the potential bias of confounding and measurement of the outcomes. Therefore, future studies should strictly conform to the Cochrane Handbook. For instance, according to the Cochrane Handbook, future RCTs should pay more attention to implementing the randomization process and selecting the reported results. Future non-RCTs should provide sufficient details regarding confounding and missing data. Also, due to the unsatisfactory methodological quality, it is suggested that more high quality neuroimaging studies should be conducted to improve the quality and confirm the findings of the current review. In addition, RCTs are considered the gold standard for evaluating the efficacy of interventions; thus, more RCTs are required to confirm that acupuncture protocols employed in neuroimaging studies are effective in AD treatment.
The neuroimaging findings of acupuncture for AD
All of the 13 studies included concentrated solely on brain functional alterations. The neuroimaging method used in the included studies was fMRI. fMRI indirectly measures brain alterations to study the nervous system via hemodynamic and neurovascular coupling [
65]. According to previous studies [
66‐
69], AD is a multidimensional central nervous system disease that affects brain structure and function. Although fMRI is a powerful approach for brain activity analysis, it is not comprehensive enough for neural processing. Numerous neuroimaging techniques have been used to assess neural processing in AD. For instance, diffusion tensor imaging (DTI) is an advanced MRI technique that has been used to provide qualitative and quantitative white matter microarchitecture information of AD [
70]. Furthermore, electroencephalography (EEG), the measurement of the brain’s electric fields, has been used in diagnosing, assessing, and monitoring medical treatment in patients with AD [
71]. PET, a tool used to quantify physiological processes, has proven useful for diagnosing and predicting AD [
72]. It is well known that these approaches have their own characteristics, so integrating multiple approaches allows for a more comprehensive assessment of the effects of acupuncture on AD. Thus, integrating multiple approaches (such as fMRI with DTI, fMRI with EEG, and fMRI with PET) can be a comprehensive way to study acupuncture in AD. Multimodal neuroimaging methods are urgently needed to provide an opportunity to understand the comprehensive neural mechanisms of acupuncture for AD and guide clinical treatment options for patients with AD.
In this review, all of the included studies also explored the instant acupuncture effect, demonstrating that the top ten brain regions affected were the cingulate gyrus, middle frontal gyrus, cerebellum, superior temporal gyrus, inferior parietal lobule, superior frontal gyrus, inferior frontal gyrus, middle temporal gyrus, postcentral gyrus, superior parietal lobule, precentral gyrus, and hippocampus. These brain areas are associated with AD. Accumulating evidence [
73,
74] suggests that the cingulate gyrus is a neurodegenerative biomarker for understanding the neural mechanisms of AD. In addition, numerous studies [
75‐
77] have reported increased FC in the middle frontal gyrus and other brain regions in AD. Moreover, previous reports [
78‐
81] have illustrated that the cerebellum contributes to cognitive and neuropsychiatric deficits in AD. Previous studies have revealed that the cortical thickness of the superior temporal gyrus and inferior parietal lobule changes during AD progression [
82,
83]. In addition, the superior frontal gyrus and inferior frontal gyrus were positively associated with cognitive function [
77,
84]. Moreover, word fluency and naming were correlated with the cortical thickness of the middle temporal gyrus [
85]. Valera-Bermejo also found that the postcentral and precentral gyri volumes were correlated with episodic and semantic memory [
86]. Accumulating research [
87‐
89] has illustrated a change in FC in the superior parietal lobule and other brain regions in AD. Numerous studies have demonstrated that the hippocampus, one of the first structures affected by AD, was regarded as a sensitive neurodegenerative neuroimaging biomarker [
90‐
92]. Meanwhile, previous neuroimaging studies [
93‐
98] illustrated that adjusting these brain regions is a crucial neural mechanism of acupuncture treatment in cognitive impairment diseases. Since acupuncture can promote neuroplasticity and repair these damaged brain areas [
99,
100], the changes in these brain regions are due to an interaction between acupuncture and AD pathology. In addition, the top ten brain areas of most included studies were emerged naturally with data-driven approaches, and only one region (hippocampus) was specifically analysed in a study [
36]. Therefore, these brain areas are genuinely changing with acupuncture in AD compared to other regions. Based on the findings, future acupuncture studies should pay more attention to these brain regions.
The included neuroimaging studies of acupuncture for AD showed that instant acupuncture might adjust the brain networks. Significant pathways related to acupuncture for AD in the included studies are displayed. The results showed that the essential regions of DMN, CEN, FPN, DAN, and SMN are included in the brain regions that undergo alterations due to acupuncture for AD. These brain networks are correlated with cognitive and motor function. DMN plays an important role in cognitive function and internally directed thoughts. Moreover, it is closely connected with AD due to its association with AD atrophy modes and tau sedimentation [
101‐
103]. CEN is a significant network obsessed with cognitive control and episodic memory [
104,
105]. DAN is involved in the externally oriented actions and perceptions [
106‐
108]. Numerous studies have demonstrated that altered DMN, CEN, and DAN are prominent biomarkers of AD [
109]. FPN was shown to play an outstanding role in executive and language functions [
110,
111]. Many studies [
110‐
113] have illustrated that abnormal FC and compensation in the FPN might coexist in AD. SMN was characterized by a hypoactivation phase in patients with AD [
114], while the altered FC of the sensorimotor cortical network was associated with a phenotype conversion from MCI to AD [
115]. Previous studies [
116,
117] have demonstrated disrupted large-scale resting-state FCs in the above networks in patients with AD. Meanwhile, multiple neuroimaging studies [
118‐
122] have suggested that regulating the alterations of these networks is a vital mechanism of acupuncture treatment. Therefore, cognitive-related and motor-associated brain areas are involved in the acupuncture mechanism of AD, implying that acupuncture may modulate these associated networks.
Strengths and weaknesses
To our knowledge, previous systematic reviews have focused on the efficacy and safety of acupuncture for AD. This is the first systematic review to explore the acupuncture mechanism for AD. Moreover, this review may provide specific insights into the neurocentral mechanism of acupuncture in AD subjects by summarizing the findings of recent clinical neuroimaging studies. In addition, the review was registered in PROSPERO and followed the PRISMA and AMSTAR-2 statement to improve the reporting and methodological quality. Nonetheless, this review had several limitations. First, the studies included used multiple analytical imaging approaches; therefore, quantitative meta-analyses were impossible. Furthermore, while 13 studies were included, only one was an RCT, and the others were non-RCTs, indicating low evidence. Due to the small sample size of the included studies, the findings are potentially biased. Moreover, the included studies only focused on the effects of instant acupuncture. Nevertheless, while the instant effect of acupuncture is still important to consider, the constant acupuncture effect must be explored. Finally, acupuncture has not only been used in clinical practice but is usually combined with other therapies for AD; accordingly, studies that investigate the mechanism of acupuncture combined with other therapies for AD should be conducted in the future.