| Acupuncture, a traditional Chinese therapy with thousands of years of history, hasbeen universally accepted and recognized worldwide nowadays. As a greencomplementary and alternative therapy, acupuncture has been demonstrated to be ofsignificant effect on many diseases, especially on functional diseases. However, themechanism of acupuncture remains elusive, which greatly restricts the improvements ofthe understanding of acupuncture. As a result, acupuncture theories update slowly andfurther restrict the development of maximum clinical effects of acupuncture. Therefore,to clarify the mechanisms, especially the central mechanisms of acupuncture as soon aspossible play a vital role in the development of the entire acupuncture field. fMRI basedacupuncture studies have gone through more than fifteen years, during which hundredsof high-level international journal articles have been released, which play a significantrole in promoting the development of acupuncture central mechanisms. Owing to thecomplexity of acupuncture, as well as the precision of fMRI technology in dataprocessing and statistical analysis, many fatal questions exist in previous fMRI basedacupuncture studies. More researchers start to cautiously inspect the questions that existin study hypothesis, experimental design, experimental control, data processing,statistical analysis, and interpretation of results. However, studies that evaluate validityof the method and reliability of the results from the height of methodology are stilllimited. The article commences the work exactly from this standpoint.The details of researches and the main innovations were listed as follows:Firstly, this study comprehensively discusses the main questions in fMRI basedacupuncture studies from three aspects: Research ideas, analytical methods andinterpretation of results. This article also put forward an objective framework of fMRIbased acupuncture studies. In terms of research ideas, selecting healthy subjects toexplore the effectiveness-related BOLD responses pattern of acupuncture and assumingthe acupuncture response meets the "ON-OFF" mode are the two main problems in thefMRI based acupuncture studies. We believe that:1) we should select patients withdiseases, which are proved to be effective by acupuncture treatments and explore thecentral regulation mechanism of acupuncture based on the clinical efficacy;2) fMRIbased acupuncture studies on healthy subjects should focus on the central processingmechanism of acupuncture stimulation;3) We should base on real-time recordingsubjective sensory information as the reference vector to explore the needling sensationdependent central response pattern. In terms of analytical methods,1) we should use group analysis method that can be generalized to the population, such as random effectsor mixed effects, and increase the attention on the individual results;2) We need to usemultiple comparison correction threshold values as the reported results, which can avoidthe possible false positive interference;3) We need a large enough sample size to ensurethe reliability of the results and guarantee sample consistency from two aspects ofsubjective behavior and evaluation of individual differences degree on BOLD patterns.In terms of results interpretation,1) acupuncture specificity should be interpreted basedon the comparison results between the acupuncture group and the control group, andshould not be based on just the visual comparison between the two one sample results;2)We should use more effective experimental design and experimental control and try toavoid reverse inference discussions that are commonly used in previous fMRI basedacupuncture studies;3) We should be more cautious on the evaluation and interpretationof deactivations in fMRI based acupuncture results, as unreasonable experiment controland data preprocessing will introduce a wide range of false deactivations. All in all, weneed to create a brand-new fMRI based research framework to safeguard the objectivity.Secondly, this study comprehensively and detailedly discuss the impact of globalnormalization, a preprocessing step, on the results of fMRI based acupuncture studies.Global normalization is often used as a preprocessing step for dispelling the “nuisanceeffects.” However, it has been shown in cognitive and emotion tasks that thispreprocessing step might greatly distort statistical results when the orthogonalityassumption of global normalization is violated. The present study examines this issue infMRI acupuncture studies. Thirty healthy subjects were recruited to evaluate theimpacts of the global normalization on the BOLD responses evoked by acupuncturestimulation during de-qi sensation and tactile stimulation during nonpainful sensations.To this end, we compared results by conducting global normalization (PSGS) and notconducting global normalization (NO PSGS) based on a proportional scaling model.The orthogonality assumption of global normalization was violated, and significantchanges between BOLD responses for NO PSGS and PSGS were shown in mostsubjects. Extensive deactivations of acupuncture in fMRI were the non-specificallypernicious consequences of global normalization. The central responses of acupunctureduring de-qi are non-specifically activation dominant at the somatosensory-related brainnetwork, whose statistical power is specifically enhanced by PSGS. In conclusion,PSGS should be unjustified for acupuncture studies in fMRI. The differences includingthe global normalization or not may partly contribute to conflicting results andinterpretations in previous fMRI acupuncture studies. Thirdly, this study Initially indicate that the de-qi related and shap pain relatedBOLD response patterns are partly separated. Nowadays, functional magnetic resonanceimaging (fMRI) has become one of the most important ways to explore the centralmechanism of acupuncture. Among the hundred or so fMRI-based acupuncture studies,activations around the somatosensory related brain network had the most robust bloodoxygen level-dependent (BOLD) responses. However, due to the insufficient control ofthe subjective sensations during acupuncture stimulation, whether these robustactivations reflected the pattern of de-qi, sharp pain, or mixed (de-qi+sharp pain)sensations was largely unknown. Furthermore, the relationship between the de-qi relatedand the sharp pain related BOLD responses was also unclear. The current studyrecruited50subjects and grouped them into the de-qi group or the mixed groupaccording to whether he/she experienced sharp pain during acupuncture stimulation togive a definite answer to the following two questions. First, what are the de-qi relatedBOLD responses, that is, are they dominated by activation or deactivation? Second,what is the relationship between the de-qi related and the sharp pain related BOLDresponses? Our results indicated that for the first question, BOLD responses associatedwith de-qi during acupuncture stimulation at ST36were activation dominated. For thesecond question, both the quantitative and qualitative differences of BOLD responsesbetween de-qi and mixed sensations evoked by acupuncture stimulation were significant.The pattern of BOLD responses of sharp pain might be partly separated from that ofde-qi in the spatial distribution. Therefore, we proposed that in order to explore thespecific central mechanism of acupuncture, subjects with sharp pain should be excludedfrom those with only de-qi.Finally, we evaluate the degree of individual differences of immediate centralresponse pattern during acupuncture stimulation, and evaluate the impact of outliers,defined based on central BOLD response pattern, on the group analysis results.Acupuncture at ST36and checkerboard stimulation was applied to16subjects. Wecalculated the mean distance using beta values in a generalized linear model (GLM)analysis and employed it to study the group homogeneity by detecting the outliers. Amore significant individual difference was presented in acupuncture stimulationcompared with visual stimulation through evaluation of the mean distance. From thegroup results, we found that the activations were more significant in the homogeneousgroup results. Combining the behavior and fMRI results, there was no direct correlationbetween deqi index and mean distance in acupuncture stimulation. The deqi index of theoutlier was in the normal range and did not differ significantly from others. Traditional group results without removing outliers were not sensitive enough to detect the realacupuncture effect. We suggest that individual difference should be taken intoconsideration for future acupuncture studies. Also, group analysis paralleled withindividual analysis is critical for a full understanding of acupuncture effects.Overall, this article discusses the methodological problems existing in acupuncturefMRI studies from two aspects of data pre-processing and statistical analysis. Thearticle indicates that the preprocessing step of global normalization is not suitable forthe fMRI based acupuncture studies; We should assurance reliability of group analysisresults by controlling consistency of subjective feeling and central response pattern. Themain findings of this article can improve our understanding of the current problemsexisting in acupuncture fMRI studies and provide help for the exploration a newresearch framework that guarantee results specificity and reliability in the future. |
PDF Full Text Request