| Background, Objective and MeaningEssential Hypertension (essential hypertension,EH, referred to as hypertension) is a unknown aetiology to elevated blood pressure as the main clinical manifestations of the syndrome, an important etiology and risk factor of a variety of cardiovascular and cerebrovascular disease, it affects structure and function of the heart, brain, kidney and other important organs, and untimately lead to failure of the above organs. Currently, there are about 200 million of the patients with hypertension in our country, and 2 in every 10 adults suffering from hypertension. Therefore, it is a major public health problem to control the blood pressure for reducing the harm of cardiovascular disease.At present, the research on the pathogenesis of EH is still not perfect, and EH is not curable. Clinically, in order to reduce the morbidity and mortality of cardiovascular and cerebrovascular disease of patients with EH, symptomatic treatment to lower blood pressure in the clinical occupies an important position.To control blood pressure within the normal range, most of patients with EH should be long-term take antihypertensive drugs, but the long-term taking antihypertensive agents may cause gastrointestinal adverse reactions, even damage to the liver and kidney function, and blood pressure level tends to rebound after discontinuing medication.As a complementary and alternative therapy, acupuncture therapy of traditional Chinese medicine(TCM) is simple, effective, economic, safe and other advantages, clinically which is often used alone or with other therapies to treatment hypertension.There is no name of "hypertension" in TCM, according to its clinical symptoms and syndrome characteristics, it belongs to the category of "dizziness" or "headache".Most physicians deem that the incidence of hypertension is the result of both internal and external factors.Internal factors is the essence decline, yin deficiency and yang hypeactivity of inborn endowment, external factors include emotional disorder, improper diet, fatigue due to overexertion and excessive sexual intercourse, its main pathogenesis is the imbalance of Yin and Yang of Liver and Kidney, the disease location in liver and kidney, relate to spleen, heart, brain, collaterals et al..Clinically, hypertension often divided into the hyperactivity of liver Yang, Yin deficiency and Yang hyperactivity, deficiency of both Yin and Yang, accumulation of phlegm-dampness andobstruction of channels by stagnant blood. Yin deficiency and Yang hyperactivity type is more common, its main manifestations are dizziness, headache, soreness of waist, weak knee, feverish sensation over the five centers, palpitation, insomnia, tinnitus, amnesia, red tongue with little coating, string, thready and number pulse. Taichong(LR3) is Shu-stream point and Yuan-primary point of Liver Meridian of Foot-Jueyin(LR), it can regulation of Qi and Blood, soothe the liver and regulate Qi, and suppressing hyperactive liver for calming endogenous wind. Taixi(K13) is Shu-stream point and Yuan-primary point Kidney Meridian of Foot-Shaoyin(KI), it can strengthen the kidney Qi and nourishing kidney Yin. Yuan-primary point can adjust deficiency and excess of itself zang-fu viscera, LR3 combination KI3(LR3+KI3), LR3 can stabilize liver Yang, KI3 can nourish kidney Yin, both of them together can enrich water to moisten wood, nourishing Yin for suppressing hyperactive Yang. Therefore, acupuncturing at LR3+KI3 can treat hypertension of Yin deficiency and Yang hyperactivity.Recently, functional magnetic resonance imaging(fMRI) with high temporal and spatial resolution, accurate localization of brain function and noninvasive, the changes of brain functional activity of real-time response in vivo, et al., it has been widely applied to the research of brain basic, clinical neuroscience and other aspects. Based on fMRI can visually research on the activity and changes of brain function, which has become one of the most important methods of the acupoints specificity and acupuncture mechanism research. Acupoints compatibility is the main form of acupuncture treatment, however, the brain integration mechanism and difference of between acupoints compatibility and single acupoint in treating the disease is not yet clear, the direct relation of studies on the observed phenomenon of previous studies and acupoints compatibility are not penetrated and systematic enough, and the modulating mechanism of acupoints compatibility on the disease also need to further study. So far, the fMRI studies on acupuncture at LR3+KI3 has certain preliminary foundation, such as rest state functional magnetic resonance imaging(Rs-fMRI) study on healthy subjects of acupuncture at LR3+KI3, single LR3 or single KI3 is ongoing. Therefore, to explore the mechanism of acupoints compatibility, this study applies Rs-fMRI to observe changes of the brain functional activities of patients with EH by acupuncture at acupoints compatibility and single acupoint.In summary, patients with EH as subjects, this study is a single blind, randomized and controlled clinical research. This study through comparing to the impacts of SBP, DBP, score of quality of life(SF-36),Yin deficiency and Yang hyperactivity scale score on EH patients by acupuncture at LR3+KI3, single LR3 and LR3 combination sham acupoint (LR3+Sham), and then, evaluate the change of blood pressure by acupuncture at LR3+KI3, the improvement of the quality of life and Yin deficiency and Yang hyperactivity symptoms on patients, to explore the similarities and differences of effective acupoints compatibility, single acupoint and invalid acupoints compatibility. Simultaneously, Rs-fMRI was used to observe the changes of the brain functional activities of patients with EH by acupuncture at LR3+KI3, single LR3 and LR3+Sham after and before the first acupuncture, after and before acupuncture treatment, to explore possible mechanism of brain integration by acupuncture LR3+KI3 treating hypertension, in order to provide the objective basis for central regulation mechanism for acupoints compatibility treatment diseases in the future.Methods1. Clinical observationAccording to inclusion and exclusion standard,45 patients with â… or â…¡ level EH were screened. According to the statistical software (SPSS 20.0) generating random numbers table and the participated sequence,45 subjects were randomly divided into three groups, LR3+KI3 group, LR3 group and LR3+Sham group.1.1 Intervention method1.1.1 Acupuncture acupointLR3+KI3 group:LR3(double) and KI3(double), LR3 group:LR3(double), LR3 +Sham group:LR3(double) and sham acupoint (double).1.1.2 Acupuncture operation and courseInserting needle by claw cut methoding, then using lifting, thrusting, twirling manipulation, needles were twirled at an angle of 90～180° and a frequency of 60～90 times/min, needles were lifted and thrust in the range of 0.3～0.5 cm and frequency of 60～90 times/min. After needling sensation, needles were manipulated for 1 min. Sham acupoints insert a certain depth according to the needling requirements, without lifting, thrusting and twirling manipulation. The retaining needle for 30 min, the needles were manipulated for 1 min every 10 min during this period.Acupuncture treatment once a day, for 5 days, rest 2 days, and then for another 5 days, a total of 10 times.1.1.3 Blood pressure measurementMeasuring blood pressure values after the subjects calmly rest 5 min, subjects take seat, bare arms, palm facing upward, elbow abduce 45。, elbow and the right atrium with the same level, the cuff proper around the right upper arm, the lower edge of cuff 2-3cm above the elbow, proper tightness, and then start measurement, measured twice, an average of 2-3 min between measurements, calculate the average and record data.Time points of measurement:(1) the previous 3 days, the diagnosis mainly based on blood pressure measurement in a fixed time. (2) on the first day of acupuncture therapy,20 min before acupuncture(pre-acupuncture or pre-treatment) and 5 min after withdrawing the needles(post-acupuncture), blood pressure was measured respectively. (3) the next day after the acupuncture treatment course(post-treatment).1.2 Outcome measures1.2.1 Main outcome measuresBlood pressure changes:to compare mean systolic blood pressure and diastolic blood pressure changes before and after the first acupuncture, and after the acupuncture treatment course.1.2.2 Secondary outcome measures(1) Brief Quality of Life Scale (SF-36) assessment(2) Yin deficiency and Yang hyperactivity self-evaluated scales1.3 Statistical analysisUsing SPSS 20.0 for Windows statistical software for statistical analysis. Two-tailed test with α=0.05 and 95% confidence interval were used to inference all statistical. The parameters method was used as much as possible, when the data was not the normal distribution, through the method of data transformation to meet the normal distribution, if the transformed data still did not conform to the normal distribution, non-parametric test could be use.2. Rs-fMRI research45 patients with EH were included according to include and exclude criteria, they were randomly divided into three groups, respectively, LR3+KI3 group, LR3 group and LR3+Sham group.2.1 Interventions2.1.1 Acupuncture acupoints, acupuncture manipulation, course and blood pressure measurement (see:1 Clinical observation)2.1.2 Scanning solutionsUsing 3.0 T MRI scanner (Company Fairfield, GE, Connecticut, America) and standard GE 8 channel head coil for collecting whole brain functional magnetic resonance data of three groups of subjects.1) Transverse T1-weighted image (T1WI) sequence:1 min,51 s, Fast Spin Echo sequence; OAx T1 FLAIR, repetition time 1750 ms/echo time 24 ms, inversion time 960 ms, field of view 24 cm × 24 cm/Z, matrix 320 × 224/number of excitations= 1, thickness 5.0 mm/interval 1.0 mm,30 slices total, echo train length 8, and bandwidth 31.25.2) Resting-state fMRI BOLD data collection:gradient echo-echo-planar imaging sequence scanning was conducted for 6 min in accordance with the following parameters:repetition time 3,000 ms/minimum, echo time minimum, flip angle 90°, field of view 240 mmx240 mm, matrix 96× 96/number of excitations= 1.Image collection time points:on the first day of acupuncture therapy,15 min before the first acupuncture(pre-acupuncture or pre-treatment),15 min after withdrawing the needles(post-acupuncture), the next day after the acupuncture treatment course(post-treatment).2.2 Data Analysis and Processing2.2.1 Image processingData analysis and processing based on R2009a MATLAB platform, using Processing Assistant for Resting-State fMRI fMRI (DPARSF) on the resting state Data for raw data preprocessing. Preprocessing including format conversion, the first 10 point data removing, time horizon calibration, realign, space standardization and spatial smoothing six steps.2.2.2 Data statistical analysisThe REST 1.8 software was used to analyse amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo) of whole brain. Standardized ALFF values and ReHo values of each group two time points of post-acupuncture and post-treatment was compared with pre-acupuncture by the paired t-test in each group respectively. The comparision of ALFF values and ReHo values among 3 groups pre-acupuncture using one-way ANOVA, if there are significant difference, A1FF values and ReHo values of 3 groups pre-acupuncture will be used as covariates respectively, the two independent sample t-test will be used to compare pre-acupuncture and post-acupuncture difference, pre-treatment and post-treatment of 3 groups between every two groups. Using xjview8.0 set statistical threshold probability is 0.05, AlphaSim correction was applied (P= 0.05, the cluster size= 228), the changes of ALLF and ReHo between different groups in different groups pre-treatment and post-treatment were obtained, and the brain areas with statistical significance were showed in the form of images.Results1. Clinical observation1.1 Blood pressure1.1.1 Intra-group comparison(1) In LR3+KI3 group, compared to SBP(136.33± 17.43) and DBP(89.47±8.43) of pre-acupuncture, SBP and DBP of both post-acupuncture and post-treatment obviously reduced, the SBP and DBP comparison of three time points was significant difference(P<0.05), SBP of both post-acupuncture(131.87±17.90) and post-treatment(130.00±13.44) significantly reduced(P<0.05), DBP of pos-treatment(87.87±5.04) significantly reduced(P< 0.05).(2) In LR3 group, compared to both pre-acupuncture(134.93±9.05) and post-acupuncture(134.14±9.94), SBP(129.71±8.60) of post-treatment obviously reduced, the SBP comparison of three time points was significant difference(P <0.05), SBP of post-treatment significantly reduced (P< 0.05).(3) In LR3+Sham group, compared to both pre-acupuncture(84.00±6.37) and post-treatment(84.14±4.54), DBP(82.36±5.05) of post-acupuncture obviously reduced, the DBP comparison of three time points was significant difference(P<0.05), DBP(82.36±5.05) of post-acupuncture significantly reduced (P< 0.05).1.1.2 Comparison among groupsThe comparision of DBP difference of pre-treatment and post-treatment among three groups showed significant difference (P<0.05), compared to the other groups(-0.43±4.45,0.7±1.49), DBP difference(1.60±7.14) of the LR3+KI3 group pre-treatment and post-treatment was significant difference (P<0.05).1.2 Comparsion of SF-36 scale score(1) In LR3+KI3 group, compared to pre-treatment, VT and MH score of post-treatment significantly increased(.P<0.05). (2) In LR3+Sham group, compared to pre-treatment, SF score(97.62±4.73) and MH score(79.43±13.67) of post-treatment significantly increased (P<0.05). (3) MH score of both pre-treatment and post-treatment of the LR3+KI3 group obviously changed, compared to the LR3 group(-2.57±1.70), MH score difference(12.80±19.02) of both pre-treatment and post-treatment of the LR3+KI3 group was significant difference (P<0.05).1.3 Comparsion of Yin deficiency and Yang hyperactivity scores(1) In LR3+KI3 group, compared to pre-treatment(10.47±4.70), Yin deficiency and Yang hyperactivity scores of post-treatment(7.80±3.47) was significant differencet(P<0.05). (2) The comparision of Yin deficiency and Yang hyperactivity scores difference of both pre-treatment and post-treatment among three groups showed no significant difference(P>0.05).2 Rs-fMRI research2.1 Intra-group comparison2.1.1 LR3+KI3 group(1) Compared to pre-acupuncture, post-acupuncture the ALFF value of right inferior temporal gyrus, inferior occipital gyrus, cerebellum posterior lobe superior cerebellar peduncle 1, middle frontal gyrus, dorsolateral superior frontal gyrus, and left fusiform gyrus and lingual gyrus was significantly increased. The ReHo value of left calcarine, lingual gyrus, superior occipital gyrus, precentral gyrus, postcentral gyrus, inferior parietal gyrus, and right postcentral gyrus, supramarginal gyrus and superior temporal gyrus was significantly increased, while the ReHo value of left dorsolateral superior frontal gyrus, anterior and paracingulate gyrus, precuneus, superior parietal gyrus and middle occipital gyrus was significantly decreased.(2) Compared to pre-treatment, post-treatment the ALFF value of left isula, inferior frontal gyrus in orbital part, median cingulate and paracingulate gyrus and supplementary motor area was significantly increased, the ReHo value of left inferior frontal gyrus in triangular part and opercular part, postcentral gyrus, inferior parietal(excluding supramarginal and angular gyrus) and supramarginal gyrus and right inferior occipital gyrus was significantly increased, while the ReHo value of right isula, superior temporal gyrus, precuneus, anterior and paracingulate gyrus, median and paracingulate gyrus, medial superior frontal gyrus was significantly decreased.2.1.2 LR3 group(1) Compared to pre-acupuncture, post-acupuncture the ALFF value of right middle temporal gyrus, middle occipital gyrus was significantly decreased. the ReHo value of both calcarine, lingual gyrus and fusiform gyrus was significantly increased, while the ReHo value of left cerebellum posterior lobe culmen was significantly decreased.(2) Compared to pre-treatment, post-treatment the ALFF value of left calcarine and right middle frontal gyrus was significantly increased, while the ALFF value of left median cingulate and paracingulate gyrus was significantly decreased. the ReHo value of right hippocampus, temporal pole in superior and inferior temporal gyrus and precuneus was significantly increased, while the ReHo value of right inferior parietal(excluding supramarginal and angular gyrus) and supramarginal gyrus, left paracentral lobule, median cingulate and paracingulate gyrus was significantly decreased.2.1.3 LR3+Sham group(1) Compared to pre-acupuncture, post-acupuncture the ALFF value of left fusiform and lingual gyrus was significantly increased, the ReHo value of right putamen, middle frontal gyrus, inferior frontal gyrus in triangular part and supplementary motor area was significantly increased, while the ReHo value of left rectus gyrus was significantly decreased.(2) Compared to pre-treatment, post-treatment the ALFF value of left superior parietal gyrus was significantly increased, the ReHo value of left fusiform, inferior occipital gyrus, hippocampus and parahippocampal gyrus, right dorsolateral superior frontal gyrus was significantly increased, while the ReHo value of right cerebellum anterior lobe 4 and 5, middle temporal gyrus, postcentral gyrus and inferior parietal gyrus was significantly decreased.2.2 Comparison among groups2.2.1 Comparison difference of post-acupuncture and pre-acupuncture(1) Compared to the LR3 group, the LR3+KI3 group showed that the ALFF value of left putamen and caudate was significantly increased, while the ALFF value of right cerebellum posterior lobe 6, middle and inferior occipital gyrus, left superior and middle frontal gyrus and precentral gyrus was significantly decreased, the ReHo value of left middle and inferior frontal in orbital part, inferior frontal in triangular part was significantly increased.(2) Compared to the LR3+Sham group, the LR3+KI3 group showed that the ALFF value of double middle frontal gyrus, left superior and middle occipital gyrus, precentral gyrus, superior frontal gyrus was significantly increased, while the ALFF value of both insula and right inferior frontal in orbital part was significantly increased, the ReHo value of right superior, middle and inferior occipital gyrus, calcarine was significantly increased, while the ReHo value of right cerebellum posterior lobe 3 was significantly decreased.(3) Compared to the LR3+Sham group, the LR3 group showed that the ALFF value of right middle temporal gyrus, precuneus and left inferior frontal gyrus in opercular part, middle occipital gyrus, supramarginal gyrus and inferior parietal(excluding supramarginal and angular gyrus) was significantly decreased, the ReHo value of right cerebellum posterior lobe 8, left cerebellum anterior lobe 9, putamen and caudate was significantly increased, while the ReHo value of right precuneus was significantly decreased.2.2.2 Comparison difference of post-treatment and pre-treatment(1) Compared to the LR3 group, the LR3+KI3 group showed that the ALFF value of left fusiform was significantly increased, while the ALFF value of left median cingulate and paracingulate gyrus, paracentral lobule was significantly decreased, the ReHo value of right precuneus, median cingulate and paracingulate gyrus was significantly increased, while the ReHo value of right postcentral gyrus and paracentral lobule was significantly decreased.(2) Compared to the LR3+Sham group, the LR3+K.I3 group showed that the ALFF value of right medulla, left temporal pole in superior temporal gyrus, inferior frontal in orbital part, median cingulate and paracingulate gyrus, supplementary motor area was significantly increased, while that the ALFF value of double superior parietal gyrus, right superior and middle occipital gyrus was significantly decreased, the ReHo value of left middle and inferior frontal in orbital part, putamen and caudate was significantly increased.(3) Compared to the LR3+Sham group, the LR3 group showed that the ALFF value of right fusiform, middle temporal gyrus was significantly increased, the ReHo value of right middle frontal gyrus, middle and inferior frontal in orbital part, inferior frontal in triangular part was significantly decreased.Conclusion1. LR3 combination K13 maybe have effect of instant and short-time continuous reduction blood pressure, LR3 single maybe have effect of short-time assistant reduction blood pressure, LR3 combination invalid sham acupoint maybe only immediately reduce blood pressure, and its effect of reduction blood pressue is not continuous. LR3 combination KI3 can improve the patient’s VT and MH, LR3 combination invalid sham acupoint can improve the patient’s VT and SF, therefore, this study speculated that acupuncture may have certain advantages in improving the psychological mood of patients, and the central mechanism of acupuncture auxiliary reduction blood pressur may be related to the regulation of acupuncture in psychological and emotional aspects. Simultaneously, LR3 combination KI3 can improve the symptoms of Yin deficiency and Yang hyperactivity, so we suggests that LR3 combination KI3 may has synergy effect.2. The number of brain regions changes in the LR3+KI3 group is remarkablely more than the LR3 group and the LR3+Sham group, this study suggested that the treatment of EH patients with LR3 combination KI3 may hs synergistic effects. Effect of LR3 combination KI3 influenced brain regions of relation with physical movement and sensory function, which may be reflected the synergetic effect of acupoints compatibility.3.Double dorsolateral superior frontal gyrus, middle frontal gyrus, supplementary motor area, inferior frontal gyrus in triangular part, median cingulate and paracingulate gyrus, temporal pole in superior temporal gyrus, left insula, superior, middle and inferior frontal gyrus in orbital part, inferior frontal gyrus in opercular part, right medulla, parahippocampal gyrus, temporal pole in inferior temporal gyrus, cerebellum posterior lobe, et al., these bain regions may be targeting effect brain regions in acupuncture auxiliary reduction blood pressure.4. Acupuncture LR3 combination K.I3 targetting to role in the prefrontal cortex (supplementary motor area) and insula, and so on, these brain regions belong to limbic system, which maybe the central mechanism of acupuncture LR3 combination KI3 auxiliary reduction blood pressure. |
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