Acupuncture induces divergent alterations of functional connectivity within conventional frequency bands: evidence from MEG recordings.

As an ancient Chinese healing modality which has gained increasing popularity in modern society, acupuncture involves stimulation with fine needles inserted into acupoints. Both traditional literature and clinical data indicated that modulation effects largely depend on specific designated acupoints. However, scientific representations of acupoint specificity remain controversial. In the present study, considering the new findings on the sustained effects of acupuncture and its time-varied temporal characteristics, we employed an electrophysiological imaging modality namely magnetoencephalography with a temporal resolution on the order of milliseconds. Taken into account the differential band-limited signal modulations induced by acupuncture, we sought to explore whether or not stimulation at Stomach Meridian 36 (ST36) and a nearby non-meridian point (NAP) would evoke divergent functional connectivity alterations within delta, theta, alpha, beta and gamma bands. Whole-head scanning was performed on 28 healthy participants during an eyes-closed no-task condition both preceding and following acupuncture. Data analysis involved calculation of band-limited power (BLP) followed by pair-wise BLP correlations. Further averaging was conducted to obtain local and remote connectivity. Statistical analyses revealed the increased connection degree of the left temporal cortex within delta (0.5-4 Hz), beta (13-30 Hz) and gamma (30-48 Hz) bands following verum acupuncture. Moreover, we not only validated the closer linkage of the left temporal cortex with the prefrontal and frontal cortices, but further pinpointed that such patterns were more extensively distributed in the ST36 group in the delta and beta bands compared to the restriction only to the delta band for NAP. Psychophysical results for significant pain threshold elevation further confirmed the analgesic effect of acupuncture at ST36. In conclusion, our findings may provide a new perspective to lend support for the specificity of neural expression underlying acupuncture.

Altered topological patterns of brain networks in mild cognitive impairment and Alzheimer's disease: a resting-state fMRI study.

Recent studies have shown that cognitive and memory decline in patients with Alzheimer's disease (AD) is coupled with losses of small-world attributes. However, few studies have investigated the characteristics of the whole brain networks in individuals with mild cognitive impairment (MCI). In this functional magnetic resonance imaging (fMRI) study, we investigated the topological properties of the whole brain networks in 18 AD patients, 16 MCI patients, and 18 age-matched healthy subjects. Among the three groups, AD patients showed the longest characteristic path lengths and the largest clustering coefficients, while the small-world measures of MCI networks exhibited intermediate values. The finding was not surprising, given that MCI is considered to be the prodromal stage of AD. Compared with normal controls, MCI patients showed decreased nodal centrality mainly in the medial temporal lobe as well as increased nodal centrality in the occipital regions. In addition, we detected increased nodal centrality in the medial temporal lobe and frontal gyrus, and decreased nodal centrality mainly in the amygdala in MCI patients compared with AD patients. The results suggested a widespread rewiring in AD and MCI patients. These findings concerning AD and MCI may be an integrated reflection of reorganization of the brain networks accompanied with the cognitive decline that may lead to AD.

Investigation of the effective connectivity of resting state networks in Alzheimer's disease: a functional MRI study combining independent components analysis and multivariate Granger causality analysis.

Recent neuroimaging studies have shown that the cognitive and memory decline in patients with Alzheimer's disease (AD) is coupled with abnormal functions of focal brain regions and disrupted functional connectivity between distinct brain regions, as well as losses in small-world attributes. However, the causal interactions among the spatially isolated, but functionally related, resting state networks (RSNs) are still largely unexplored. In this study, we first identified eight RSNs by independent components analysis from resting state functional MRI data of 18 patients with AD and 18 age-matched healthy subjects. We then performed a multivariate Granger causality analysis (mGCA) to evaluate the effective connectivity among the RSNs. We found that patients with AD exhibited decreased causal interactions among the RSNs in both intensity and quantity relative to normal controls. Results from mGCA indicated that the causal interactions involving the default mode network and auditory network were weaker in patients with AD, whereas stronger causal connectivity emerged in relation to the memory network and executive control network. Our findings suggest that the default mode network plays a less important role in patients with AD. Increased causal connectivity of the memory network and self-referential network may elucidate the dysfunctional and compensatory processes in the brain networks of patients with AD. These preliminary findings may provide a new pathway towards the determination of the neurophysiological mechanisms of AD.

Exploring the effective connectivity of resting state networks in mild cognitive impairment: an fMRI study combining ICA and multivariate Granger causality analysis.

Mild cognitive impairment (MCI) was recognized as the prodromal stage of Alzheimer's disease (AD). Recent neuroimaging studies have shown that the cognitive and memory decline in AD and MCI patients is coupled with abnormal functions of focal brain regions and disrupted functional connectivity between distinct brain regions, as well as losses of small-world attributes. However, the causal interactions among the spatially isolated but function-related resting state networks (RSNs) are still largely unexplored in MCI patients. In this study, we first identified eight RSNs by independent components analysis (ICA) from resting state functional MRI data of 16 MCI patients and 18 age-matched healthy subjects respectively. Then, we performed a multivariate Granger causality analysis (mGCA) to evaluate the effective connectivity among the RSNs. We found that MCI patients exhibited decreased causal interactions among the RSNs in both intensity and quantity compared with normal controls. Results from mGCA indicated that the causal interactions involving the default mode network (DMN) became weaker in MCI patients, while stronger causal connectivity emerged related to the memory network and executive control network. Our findings suggested that the DMN played a less important role in MCI patients. Increased causal connectivity of the memory network and executive control network may elucidate the dysfunctional and compensatory processes in the brain networks of MCI patients. These preliminary findings may be helpful for further understanding the pathological mechanisms of MCI and provide a new clue to explore the neurophysiological mechanisms of MCI.

Modulatory effects of acupuncture on resting-state networks: a functional MRI study combining independent component analysis and multivariate Granger causality analysis.

PURPOSE: To investigate acupuncture specificity by exploring causal relationships of brain networks following acupuncture at GB40 (Qiuxu), with the acupoint KI3 (Taixi) as a control (belonging to the same nerve segment but different meridians). MATERIALS AND METHODS: Needling at acupoints GB40 and KI3 was performed in 12 subjects separately. The specific coherent patterns, resting-state networks (RSNs), were retrieved by independent component analysis (ICA) from functional magnetic resonance imaging (fMRI) data of resting state and post-acupuncture resting states, respectively. Then multivariate Granger causality analysis (mGCA) was applied to evaluate the effective connectivity within and among the detected RSNs-default model, memory, executive, auditory, and motor brain networks. RESULTS: Following acupuncture at GB40, the strength of causal connectivity between the superior temporal gyrus (STG) and anterior insula was enhanced, while the connection strength between the STG and postcentral gyrus increased following acupuncture at KI3. Additionally, the causal influences within the auditory network increased following acupuncture at GB40, in comparison with the executive network following acupuncture at KI3. CONCLUSION: The current study demonstrates that acupuncture at different acupoints could exert different modulatory effects on RSNs. Our findings may help to understand the neurophysiological mechanisms underlying acupuncture specificity.

Investigation of acupoint specificity by multivariate granger causality analysis from functional MRI data.

PURPOSE: To investigate the acupoint specificity by exploring the effective connectivity patterns of the poststimulus resting brain networks modulated by acupuncture at the PC6, with the same meridian acupoint PC7 and different meridian acupoint GB37. MATERIALS AND METHODS: The functional MRI (fMRI) study was performed in 36 healthy right-handed subjects receiving acupuncture at three acupoints, respectively. Due to the sustained effects of acupuncture, a novel experimental paradigm using the nonrepeated event-related (NRER) design was adopted. Psychophysical responses (deqi sensations) were also assessed. Finally, a newly multivariate Granger causality analysis (mGCA) was used to analyze effective connectivity patterns of the resting fMRI data taken following acupuncture at three acupoints. RESULTS: Following acupuncture at PC6, the red nucleus and substantia nigra emerged as central hubs, in comparison with the fusiform gyrus following acupuncture at GB37. Red nucleus was also a target following acupuncture at PC7, but with fewer inputs than those of PC6. In addition, the most important target following acupuncture at PC7 was located at the parahippocampus. CONCLUSION: Our findings demonstrated that acupuncture at different acupoints may exert heterogeneous modulatory effects on the causal interactions of brain areas during the poststimulus resting state. These preliminary findings provided a clue to elucidate the relatively function-oriented specificity of acupuncture effects.

Neural specificity of acupuncture stimulation from support vector machine classification analysis.

Acupoint specificity, as a crucial issue in acupuncture neuroimaging studies, is still a controversial topic. Previous studies have generally adopted a block-based general linear model (GLM) approach, which predicts the temporal changes in the blood oxygenation level-dependent signal conforming to the "on-off" specifications. However, this method might become impractical since the precise timing and duration of acupuncture actions cannot be specified a priori. In the current study, we applied a data-driven multivariate classification approach, namely, support vector machine (SVM), to explore the neural specificity of acupuncture at gall bladder 40 (GB40) using kidney 3 (KI3) as a control condition (belonging to different meridians but the same nerve segment). In addition, to verify whether the typical GLM approach is sensitive enough in exploring the neural response patterns evoked by acupuncture, we also employed the GLM method to the same data sets. The SVM analysis detected distinct neural response patterns between GB40 and KI3--positive predominantly for the GB40, while negative following the KI3. By contrast, group analysis from the GLM showed that acupuncture at these different acupoints can both evoke similar widespread signal decreases in multiple brain regions, and most of these regions were spatially overlapped, mainly distributing in the limbic and subcortical structures. Our findings may provide additional evidence to support the specificity of acupuncture, relevant to its clinical efficacy. Moreover, we also proved that GLM analysis is prone to be susceptible to errors and is not appropriate for detecting neural response patterns evoked by acupuncture stimulation.

Differential neural responses to acupuncture revealed by MEG using wavelet-based time-frequency analysis: a pilot study.

Acupoint specificity, lying at the core of the Traditional Chinese Medicine, still faces many controversies. As previous neuroimaging studies on acupuncture mainly adopted relatively low time-resolution functional magnetic resonance imaging (fMRI) technology and inappropriate block-designed experimental paradigm due to sustained effect, in the current study, we employed a single block-designed paradigm together with high temporal-resolution magnetoencephalography (MEG) technology. We applied time-frequency analysis based upon Morlet wavelet transforming approach to detect differential oscillatory brain dynamics induced by acupuncture at Stomach Meridian 36 (ST36) using a nearby nonacupoint (NAP) as control condition. We observed that frequency power changes were mainly restricted to delta band for both ST36 group and NAP group. Consistently increased delta band power in contralateral temporal regions and decreased power in the counterparts of ipsilateral hemisphere were detected following stimulation at ST36 on the right leg. Compared with ST36, no significant delta ranges were found in temporal regions in NAP group, illustrating different oscillatory brain patterns. Our results may provide additional evidence to support the specificity of acupuncture modulation effects.

Investigation of acupoint specificity by whole brain functional connectivity analysis from fMRI data.

Previous neuroimaging studies on acupuncture have primarily adopted functional connectivity analysis associated with one or a few preselected brain regions. Few have investigated how these brain regions interacted at the whole brain level. In this study, we sought to investigate the acupoint specificity by exploring the whole brain functional connectivity analysis on the post-stimulus resting brain modulated by acupuncture at acupoint PC6, with the same meridian acupoint PC7 and different meridian acupoint GB37. We divided the whole brain into 90 regions and analyzed functional connectivity for each condition. Then we identified statistically significant differences in functional correlations throughout the entire brain following acupuncture at PC6 in comparison with PC7 as well as GB37. For direct comparisons, increased correlations for PC6 compared to PC7 were primarily between the prefrontal regions and the limbic/paralimbic and subcortical regions, whereas decreased correlations were mainly between the parietal regions and the limbic/paralimbic and subcortical regions. On the other hand, increased correlations for PC6 compared to GB37 were primarily between the prefrontal regions and somatosensory regions, whereas decreased correlations were mainly related with the occipital regions. Our findings demonstrated that acupuncture at different acupoints may exert heterogeneous modulatory effects on the post-stimulus resting brain, providing new evidences for the relatively function-oriented specificity of acupuncture effects.

Exploring the evolution of post-acupuncture resting-state networks combining ICA and multivariate Granger causality.

The sustained effects of acupuncture have been widely applied to clinical treatment, thus it can be assumed that the relatively functional specificity of acupoints may evolve as the function of time. In this study, we originally combined ICA and multivariate Granger causality analysis to explore the causal interactions within and among the post-acupuncture resting-state networks (RSNs) at a hearing-related acupoint GB40, with the cognition-related acupoint KI3 as a control. Following acupuncture at GB40, the superior temporal gyrus (STG) and anterior insula (AI) within auditory network appeared persistent bidirectional connection with maximal strength, and the interactions between the auditory network and others became more complex as time passed. For KI3, both the superior parietal lobule (SPL) and dorsolateral prefrontal cortex (DLPFC), as vital nuclei of cognitive function, emerged increased causal outflows and inflows as time went on. We concluded that acupuncture at different acupoints may exert different evolutive effects on causal interactions within and across the RSNs during segmented post-stimulus resting states.

Acupuncture modulates temporal neural responses in wide brain networks: evidence from fMRI study.

BACKGROUND: Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network, large portions of which are overlapped with the pain-related areas. Recently, a striking feature of acupuncture-induced analgesia is found to be associated with its long-last effect, which has a delayed onset and gradually reaches a peak even after acupuncture needling being terminated. Identifying temporal neural responses in these areas that occur at particular time--both acute and sustained effects during acupuncture processes--may therefore shed lights on how such peripheral inputs are conducted and mediated through the CNS. In the present study, we adopted a non-repeated event-related (NRER) fMRI paradigm and control theory based approach namely change-point analysis in order to capture the detailed temporal profile of neural responses induced by acupuncture. RESULTS: Our findings demonstrated that neural activities at the different stages of acupuncture presented distinct temporal patterns, in which consistently positive neural responses were found during the period of acupuncture needling while much more complex and dynamic activities found during a post-acupuncture period. These brain responses had a significant time-dependent effect which showed different onset time and duration of neural activities. The amygdala and perigenual anterior cingulate cortex (pACC), exhibited increased activities during the needling phase while decreased gradually to reach a peak below the baseline. The periaqueductal gray (PAG) and hypothalamus presented saliently intermittent activations across the whole fMRI session. Apart from the time-dependent responses, relatively persistent activities were also identified in the anterior insula and prefrontal cortices. The overall findings indicate that acupuncture may engage differential temporal neural responses as a function of time in a wide range of brain networks. CONCLUSIONS: Our study has provided evidence supporting a view that acupuncture intervention involves complex modulations of temporal neural response, and its effect can gradually resolve as a function of time. The functional specificity of acupuncture at ST36 may involve multiple levels of differential activities of a wide range of brain networks, which are gradually enhanced even after acupuncture needle being terminated.