Altered Spontaneous Brain Activity Following Moxibustion in Mild Cognitive Impairment

doi:10.21203/rs.3.rs-2343965/v1

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Research Article

Altered Spontaneous Brain Activity Following Moxibustion in Mild Cognitive Impairment

https://doi.org/10.21203/rs.3.rs-2343965/v1

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published 12 Dec, 2023

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Background

Moxibustion has definite clinical effect in improving the cognitive condition of mild cognitive impairment (MCI) patients, yet its potential neural mechanism remains elusive. This study aimed to investigate the changes of spontaneous brain activity and cognitive function in MCI patients with moxibustion treatment.

Methods

We enrolled a cohort of 30 MCI patients and 30 matched healthy controls (HCs) in this study. MCI subjects were assigned to receive moxibustion treatment for two months. Based on resting state functional magnetic resonance imaging technique, we used regional homogeneity (ReHo) to evaluate changes in brain activity and Mini-Mental State Examination and Montreal Cognitive Assessment to assess changes in the participants' cognitive performance.

Results

There existed aberrant ReHo values in different brain areas mainly involved in the default mode network (DMN) in MCI subjects compared with HCs. After moxibustion treatment, MCI subjects showed an inverse change in ReHo values from baseline in the hippocampus/parahippocampus and insula, as well as an increase ReHo value in the middle frontal gyrus. Furthermore, changes in ReHo values of the left hippocampus/parahippocampus and middle frontal gyrus correlated with cognitive improvement in MCI group.

Conclusion

Abnormal neural activity occurred in MCI subjects mainly within the DMN. Moxibustion therapy may improve the cognitive function of MCI subjects through regulating their brain activity, particularly reversing the neural activity of DMN and salience network at reset, and may hold great potential for the early intervention and treatment of Alzheimer's disease.

mild cognitive impairment

moxibustion

regional homogeneity

functional magnetic resonance imaging

brain activity

Mild cognitive impairment (MCI) is a transitory state in seniors between normal aging and dementia, defined by a deterioration of cognitive function with minimal impairment of daily activities (Langa & Levine, 2014). The prevalence of MCI in adults aged 65 years and older is up to 20%, and the risk increases with age (Langa & Levine, 2014). An early study showed that MCI patients have an annual conversion rate of 10–15% to Alzheimer's disease (AD) (Anderson, 2019), which would be a substantial economic burden and societal impact (Robinson et al., 2017). Many studies have shown that MCI is abnormal in the central nervous system (CNS) (Chandra et al., 2019; Liu et al., 2021). Therefore, CNS-related intervention for MCI patients is of great significance in delaying or preventing the occurrence and development of dementia.

Currently, no medications have produced satisfactory effectiveness for MCI. Acupuncture and moxibustion, as essential parts of Traditional Chinese Medicine (TCM), have been proven to improve the cognitive function and daily living ability of patients with MCI and AD (Zhou et al., 2015; Wang et al., 2020). Moxibustion is a therapeutic method that uses the heat generated by burning moxa to stimulate one or several acupuncture points. Moxibustion has been used in Asia for centuries and is gaining popularity in the Western world. Animal studies and clinical trials have been conducted to explore the mechanisms and benefits of moxibustion in the prevention and treatment of MCI (Yang et al., 2016; Choe et al., 2018). Moxibustion and acupuncture are different in terms of stimulation, but they are thought to produce similar clinical effects. According to TCM, some acupoints, such as Guanyuan (RN4), Baihui (GV20), Xuanzhong (GB39), and Zusanli (ST36), have been shown to improve cognitive-related disorders such as MCI and AD (Zhou & Jin, 2008; Gu et al., 2014; Zhang et al., 2022). Evidence suggested that acupuncture and moxibustion normalized the brain's functional activity (Scheffold et al., 2015; Bao et al., 2016). In particular, moxibustion treatment may delay or prevent the progression of MCI by regulating abnormal CNS responses. However, data on the mechanism of moxibustion is limited. As a result, more research on this subject is required.

Functional magnetic resonance imaging (fMRI) (Bifone & Gozzi, 2011) is an effective technology to assess the changes in brain function, which can provide an opportunity to explore the neural mechanism of moxibustion. In fMRI studies, regional homogeneity (ReHo) (Zang et al., 2004) can be indicative of abnormal coordination and synchronization of spontaneous neural activities in brain regions, revealing pathophysiological changes in the brain. Based on rs-fMRI technology, ReHo has been widely investigated in the mechanisms of a multitude of neuropsychiatric diseases (Zhang et al., 2012; Ma et al., 2019). A recent study confirmed that employing ReHo to detect aberrant patterns of spontaneous brain activity in MCI patients is feasible (Min et al., 2019).

In this study, we aimed at exploring changes in cognitive-related clinical symptoms and neural mechanisms in MCI with moxibustion treatment. We hypothesized that MCI patients might present abnormal brain functions, which could be regulated by moxibustion.

Subjects

A cohort of 30 MCI subjects (aged 55–75 years) were enrolled, screened and assigned to receive the two-month moxibustion treatment. In addition, 30 age, gender and years of education matched controls without treatment were included in the present study. We recruited all participants through advertisements in the local community centers, senior activity centers, as well as the First Affiliated Hospital of Guangxi University of Chinese Medicine. Detailed inclusion and exclusion criteria for MCI patients have been reported in previously published articles (Lai et al., 2022; Liu et al., 2022) and are summarized as follows: 1) the chief complaint was memory impairment, confirmed by an informed individual; 2) general cognitive function is either normal or slightly impaired; 3) there was no effect on the ability of daily living; 4) no dementia; 5) without other illnesses that could impair the brain function; 6) scores for the Mini-Mental State Examination (MMSE) were 24–27 (Folstein et al., 1975), the Montreal Cognitive Assessment (MOCA) was < 26 (Nasreddine et al., 2005), the Clinical Dementia Rating was 0.5, and the Global Deterioration Scale was 2–3; 7) right-handed; 8) without any MRI examination contraindications.

The study was approved by the local medical ethics board, and registered in the Chinese Clinical Trial Registry. All subjects provided informed consent. It was in accordance with the principles outlined in the Declaration of Helsinki.

Moxibustion treatments

Based on previous studies related to moxibustion for cognitive disorders (Yang et al., 2022), six acupoints (RN4, GV20, bilateral GB39, and bilateral ST36) were selected as the acupoints for moxibustion treatment of MCI subjects in this study. In order to fix the moxa-cone and protect the subject's skin, we first applied Vaseline to the corresponding acupoints before moxibustion. One moxa-cone was burned for each acupoint for about 3–4 min. Each moxa-cone weighed 5g, and the dimensions were 1.5cm×3.0cm. MCI patients received a total of two courses of moxibustion intervention with a 3-day break between the two courses. One treatment course consists of 15 times, each one day apart. To ensure that participants felt the same moxibustion sensation during the formal treatment, the same acupuncturist completed all of the above treatment procedures.

Outcome measurement

The improvement in cognitive function was the primary outcome we were looking for as a result of the treatment, which was necessary to measure by validated assessment tools, such as the MoCA and MMSE which are currently accepted tools for assessing cognitive status. A higher score on the MMSE and MoCA generally indicates the improvement of cognitive function. In the present study, a baseline evaluation was conducted for MCI patients and healthy controls (HCs), and a second evaluation was performed after two months of moxibustion intervention for the patients.

MRI data acquisition

All MRI data for this study were obtained from HCs and MCI subjects at baseline as well as after moxibustion for MCI subjects, performed with a 3.0T Siemens Magnetom Verio MRI System (Siemens Medical, Erlangen, Germany). Each subject's head was immobilized with foam pillows in an 8-channel head coil in order to reduce head motion. The resting state fMRI images were acquired with a single-shot gradient-recalled echo-planar imaging (EPI) sequence with the following parameters: repetition time (TR) = 2000ms; echo time (TE) = 30ms; flip angle (FA) = 90°; field of view (FOV) = 240mm × 240mm; matrix size: 64 × 64; slice thickness = 5mm (no-gap); 31 slices and 180 volumes. High resolution T1-weighted images were then obtained with a magnetization- prepared rapid acquisition gradient-echo sequences (3D MPRAGE) with the following parameters: TR = 1900ms; TE = 2.22ms, FOV = 250mm × 250mm, matrix size: 256 × 256, FA = 9^◦, slice thickness = 1mm and 176 slices. All participants were required to remain awake, while remaining still without giving any consideration to anything during the process.

fMRI Data preprocessing

On the MATLAB platform, imaging data were analyzed using the Data Processing & Analysis for Brain Imaging (DPABI, http://rfmri.org/dparbi) along with Statistical Parametric Mapping, version 12 (SPM12, http://www.fil.ion.ucl.ac.uk/spm). The pre-processing steps roughly consisted of the following: discarding the first five time points; correcting the slice timing and head motion; spatial normalizing the corrected images to the Montreal Neurological Institute (MNI) space (EPI template with 3 × 3 × 3mm³ voxel size); removing nuisance signal including global signal, head motion parameters, white matter, cerebrospinal fluid, linear detrended and temporal bandpass filtering (0.01-0.1Hz). A subject was excluded from the final analysis if the rotation or translation of head movement in any direction was more than 2.5 degrees or 2.5mm.

ReHo analysis

ReHo analysis was implemented for each participant by the DPABI software mentioned above. In a voxel-wise approach, individual ReHo maps were computed using the KCC between the voxel's BOLD time series and those of its 26 nearest neighboring voxels (Zang et al., 2004). For standardization, all individual ReHo maps were computed and standardized into ReHo Z-values by subtracting the mean voxel-wise ReHo obtained for the whole brain (i.e., global ReHo), and then dividing the resultant value by the standard deviation (Davis et al., 1998). This subject-wise ReHo normalization has demonstrated a significant improvement in normality and reliability among subjects (Davis et al., 1998). Finally, the ReHo maps were spatially smoothed using a Gaussian kernel with a 4mm full width at half maximum.

Statistical analysis

Demographic and clinical data of the two groups were calculated using SPSS software (Version 22.0; IBM, Armonk, New York). Normally distributed continuous variables were analyzed using two independent samples t-tests, while non-normal continuous variables were analyzed using Mann-Whitney U-tests. The Pearson's Chi-square test was used to compare categorical variables. The statistical significance threshold for all comparisons was set at p < 0.05. In the present study, age, gender, and years of education accounted for insignificant covariates.

At baseline, we applied the two-sample t-test to explore changes in normalized ReHo values in MCI subjects compared with HCs. Using statistical parametric mapping, paired t-tests were used to quantitatively compare the differences in ReHo values between post-moxibustion and baseline within a gray matter mask. To avoid excessively increasing the risk of false negatives, these contrasts were thresholded at a voxel-level significance of p < 0.005 with a cluster extent of k ≥ 15, corresponding to the "expected voxels per cluster" value generated by SPM12. To reveal the association between the altered ReHo values and clinical symptom changes, we performed Pearson's correlation between changed ReHo value and MMSE and MoCA scores in MCI subjects. The significant threshold was set at p < 0.05 (Bonferroni corrected).

Demographic and neuropsychological data

There were 60 subjects (30 MCI subjects and 30 matched HCs) involved in this study. At baseline, no significant differences were found between groups regarding age, gender, and years of education (p > 0.05). Table 1 shows data on demographic and general neuropsychological measures for all subjects. MCI subjects had significantly lower MMSE (p < 0.0001) and MoCA scores (p < 0.0001) than HCs, as well as significantly higher GDepS scores (p < 0.05). After two-month moxibustion treatment, the MMSE and MoCA scores of MCI subjects improved dramatically (p༜0.0001) (Table 2).

Table 1

Baseline clinical characteristics and assessment of participants
	MCI patients (n = 30)	Healthy controls (n = 30)	P value
Age (years)	64.30 ± 6.05	66.07 ± 5.91	0.257^a
Gender (M/F)	10/20	13/17	0.425^b
Education (years)	11(11 ~ 14) ^d	14(8 ~ 15) ^d	0.129^c
Pre-MMSE	26(25 ~ 27) ^d	29(28 ~ 30) ^d	0.000^c
Pre-MoCA	21.83 ± 2.60	25.57 ± 2.06	0.000^a
GDepS	5.63 ± 2.09	3.67 ± 2.43	0.002^a
MCI, mild cognitive impairment; M, male; F, female; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; GDepS, Geriatric Depression Scale; a, stands for two-sample t-test; b, stands for chi-square; c, stands for Mann-Whitney U-test; d stands for median (interquartile range).

Table 2

Changes in cognitive scores in MCI after moxibustion compared to baseline
	MCI treatment (n = 30)	MCI baseline (n = 30)	P value
MMSE change	29.5(28 ~ 30) ^d	26.0(25 ~ 27) ^d	0.000^e
MoCA change	27(25.00 ~ 28.25) ^d	21(20.75 ~ 23.25) ^d	0.000^e
MoCA change indicates that post-treatment MoCA score minus baseline MoCA score. MMSE change indicates that post-treatment MMSE score minus baseline MMSE score. d stands for Median (interquartile range); e stands for Wilcoxon Signed Ranks Test.

ReHo contrasts

In the present study, MCI subjects exhibited decreased ReHo values in the right medial prefrontal cortex, insula, inferior parietal lobe, and left precuneus and temporal pole, and an increased value in the left hippocampus/parahippocampus (Hip/Phip) when compared with HCs (Fig. 1).

The ReHo value in the left Hip/Phip of MCI subjects decreased after a two-month moxibustion intervention, whereas it increased in the right insula and left middle frontal gyrus (MFG) (Fig. 2).

Correlation analysis

After two-month moxibustion treatment of MCI subjects, the increase of MMSE score was negatively associated with a decrease in ReHo value in the left Hip/Phip, and positively associated with an increase in ReHo value in the left MFG (Fig. 3).

The present study aimed to explore the neural mechanism of moxibustion in MCI patients using ReHo analysis from resting state fMRI data. We found that compared with HCs, MCI subjects exhibited aberrant ReHo values in various brain areas, primarily the default mode network (DMN) and salience network (SN), which may be regulated by moxibustion treatment, resulting in the improvement of cognitive performance.

In comparison to HCs, MCI patients showed aberrant ReHo values in different brain areas involved in attention, cognition, and episodic memory. The Hip/Phip, medial prefrontal cortex, inferior parietal lobe, precuneus, and temporal pole are essential components of the DMN, which has been thought to engage in internal concentrated tasks, such as autobiographical memory extraction and envisioning the future, when individuals are not focused on the external environment (Gusnard et al., 2001; Raichle, 2015). The DMN is an important part of brain intrinsic connectivity networks and is vulnerable to AD (Buckner et al., 2009). As the transitional state between normal cognition and early dementia, MCI showed similar patterns of altered activity of the DMN to AD (Eyler et al., 2019). In this study, the abnormal ReHo value in the DMN indicated that MCI patients might show abnormal spontaneous brain activities of the DMN and have dysfunction in detecting episodic memory and internal and external surroundings. The insula is consistently thought to be a critical node of the SN, involved in both attention and interoceptive and affective processes (Sridharan et al., 2008). The decreased ReHo value in the insula revealed that MCI patients might have deficits in attentional control and cognitive function. A recent study has shown that the SN is impaired in patients with MCI and AD (Li et al., 2019). Taken together with these findings, we speculate that dysregulation of the SN and DMN may be essential markers of local neural activity in MCI subjects during the resting state.

As a treatment of complementary and alternative medicine, moxibustion could regulate the nervous, immune, and endocrine systems, potentially exerting significant therapeutic effects (Bao et al., 2016; Xu et al., 2017). In this study, we found that after moxibustion, the Hip/Phip and insula changes were reversed from baseline, and the ReHo changes of the left Hip/Phip and MFG (both included in DMN) were significantly correlated to MMSE scores.

The Hip/Phip, an element of DMN, is well recognized to facilitate episodic memory, memory encoding, and retrieval (Moser & Moser, 1998). It is one of the first cognition-related regions showing pathologic changes. A study indicated increased ReHo value in the bilateral Hip/Phip in MCI patients without lacunar infarctions compared with HCs (Ni et al., 2016). In fMRI studies, increased Hip/Phip activation was observed in conditions that confer risk for AD, including MCI (Yassa et al., 2010; Li et al., 2015). These findings were consistent with this study. A possible explanation was that the overactivation of Hip/Phip directly causes memory deficit, which may be related to extensive degenerative processes in prodromal AD (Putcha et al., 2011). Several fMRI studies based on memory recognition tasks showed that after drug treatment, Hip activity in MCI patients decreased to the level of HCs, and memory performance was improved accordingly (Bakker et al., 2012; Bakker et al., 2015). Notably, the increased MMSE score due to moxibustion intervention was significantly linked with changed ReHo in Hip/Phip, which may further support the beneficial effects of moxibustion on regulating aberrant spontaneous brain activity in DMN and cognitive performance.

Furthermore, we observed that moxibustion treatment dramatically increased the ReHo value in the right insula. The insula, involved in the SN, is anatomically interconnected with extensive cortical and subcortical structures associated with higher-order brain activities including as cognition, decision-making, and pain perception (Nieuwenhuys, 2012). In HCs, activation in the insula was observed to be linked to complicated verbal memory storage tasks and memory encoding tasks (Iidaka et al., 2000). In addition, it has been reported that after acupuncture treatment, more pronounced insula BOLD activation is observed in AD patients (Zhou & Jin, 2008). It could be due to enhanced attention to specific portions of the body. It is suggested that an increase in body attention around the acupoints plays a crucial role in the brain's reaction to acupuncture stimulation. Our finding indicated that moxibustion therapy may have had beneficial intervention effects on the insula of MCI patients. Interestingly, when attention is focused externally, DMN and SN activity is usually anti-correlated, and the greater anti-correlation between SN and DMN, the more effective the cognitive control (Kelly et al., 2008). The changes of the Hip/Phip and insula in reverse from baseline indicated that moxibustion might improve cognitive function by regulating DMN-SN anticorrelation during the resting state.

In addition to the changes in ReHo values in the brain areas described above, we also found an increase ReHo value in the left MFG after treatment. The MFG retrieves information about previously experienced events in rich contextually details, related to a decline of age-related episodic memory retrieval (Rajah et al., 2010). According to a study by Shan et al., acupuncture could elicit brain activation in some cognitive-related regions (including MFG) in MCI patients (Anderson, 2019). Similarly, Kwon et al. found that in the visuospatial N-back task, the subjects showed more activation in the right cerebral hemisphere, such as MFG and inferior frontal gyrus (Kwon et al., 2002). Meanwhile, we found a substantial positive correlation between the MMSE score and the ReHo value in the left MFG. This finding suggests that moxibustion may increase spontaneous brain activity in cognitive-related regions, thereby improving the cognition of MCI patients. As a treatment strategy related to physical touch and verbal interactions, psychological factors may be one of the reasons for its curative effect. More studies are needed to attest to these hypotheses.

There were several issues to be addressed. First, the relatively small sample size may need additional studies with more subjects to confirm the reliability of our results. Second, it was challenging for HCs to complete the entire two-month course of moxibustion. So, no HCs included for comparison after moxibustion, which will be a problem to resolve in our future research. Moreover, due to the validation of fMRI data analysis methods, some scientists emphasized that they had to be precisely designed to reduce possible false-positive results. The combination of fMRI with other techniques in future research could be used to verify the existence of brain activities specificity in moxibustion, such as magnetic resonance spectroscopy and positron emission tomography.

In conclusion, we detected abnormal neural activity mainly within DMN in patients with MCI by the ReHo analysis. Moreover, as an important part of TCM, moxibustion may enhance the cognitive performance of MCI by regulating neural activity particularly reversing the activity of the DMN and SN, and may hold great potential for the early intervention and treatment of AD.

Funding

The study was supported by the National Natural Science Foundation of China (grant no. 82060315 and 82102032) and Guangxi key research and development program (Grant No. AB22080053).

Conflict of interest

The authors have no conflict of interest to report.

Ethics approval and Consent to participate

The study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Guangxi University of Chinese Medicine, Guangxi, China. Informed consent was obtained from each subject before starting this study.

Availability of data and material

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

Code availability

Not applicable.

Author Contributions

D.D.M. contributed design of the study. Z.Q.P., L.Z.Y. and W.Y.C. performed the study and drafted the manuscript. L.L.Y., L.P. and D.G.X. was involved in manuscript editing. L.P. and L.Y.Q. performed data analysis. All authors read and approved the final manuscript.

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No competing interests reported.

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Altered Spontaneous Brain Activity Following Moxibustion in Mild Cognitive Impairment

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Introduction

Methods

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Moxibustion treatments

Outcome measurement

MRI data acquisition

fMRI Data preprocessing

ReHo analysis

Statistical analysis

Results

Demographic and neuropsychological data

ReHo contrasts

Correlation analysis

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Conclusion

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