Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 310591, 12 pages http://dx.doi.org/10.1155/2015/310591 Research Article Discovery of Acupoints and Combinations with Potential to Treat Vascular Dementia: A Data Mining Analysis ShuweiFeng,1YulanRen,1ShilinFan,2MinyuWang,1TianxiaoSun,1 FangZeng,1PingLi,2andFanrongLiang1 1ChengduUniversityofTraditionalChineseMedicine,Chengdu,Sichuan610075,China 2SouthwestPetroleumUniversity,Chengdu,Sichuan610500,China CorrespondenceshouldbeaddressedtoPingLi;[email protected];[email protected] Received18December2014;Revised16February2015;Accepted30April2015 AcademicEditor:ZhixiuLin Copyright©2015ShuweiFengetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense, whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. The prevalence of vascular dementia (VaD) is high among the elderly. Acupuncture, a popular therapeutic method in China, canimprovememory,orientation,calculation,andself-managingabilityinVaDpatients.However,inclinicalacupunctureand acupunctureresearch,theselectionofacupointstotreatVaDremainschallenging.Thisstudyaimedtodiscoveracupointsand acupointcombinationswithpotentialforVaDbasedondatamining.Afterdatabasesearchingandscreeningforarticlesonclinical trialsevaluatingtheeffectsofacupunctureonVaD,238acupunctureprescriptionswereincludedforfurtheranalysis.Baihui(GV 20),Sishencong(EX-HN1),Fengchi(GB20),Shuigou(GV26),andShenting(GV24)appearedmostfrequentlyinthemodern literatureandarepotentialacupointsforVaD.CombinationsbetweenBaihui(GV20),Sishencong(EX-HN1),Fengchi(GB20), Shenting (GV 24), Shuigou (GV 26), and Zusanli (ST 36) were most frequent and represent potential combinations for VaD treatment.TheseresultsprovideareferencefortheselectionandcombinationofacupointstotreatVaDinclinicalacupuncture andacupunctureresearch. 1.Introduction Vasculardementia(VaD)referstocognitiveimpairment caused by changes in theblood circulationofthebrain[5]. Theselectionofacupointsplaysacriticalroleinthetherapeu- Its clinical manifestations include confusion or short-term tic effects of acupuncture. However, the selection of proper memoryproblems,wandering,gettinglostinfamiliarplaces, acupoints remains challenging, contributing to the limited walking with rapid and shuffling steps, losing bladder or therapeutic effects and application of acupuncture. Data bowel control, laughing or crying inappropriately, difficulty mining has been used to discover potential acupoints from infollowinginstructions,andproblemwithcountingmoney theexpansiverelevantliterature.Thismethodhasbeenused andconductingmonetarytransactions.Atthelatestage,VaD tosuggestacupointsontheShaoyangMeridianformigraine patients may have severe impairment of basic activities of treatmentbasedontheirhighfrequencyintheliterature[1]. dailylivingandlackthecapacitytomakeappropriatedeci- Basedontheresultsofdatamining,asubsequentclinicaltrial sions regarding their choices and preferences [6]. A recent confirmed that acupuncture was effective for the treatment of migraine and that acupoints on the Shaoyang Meridian population-basedsurveyreportedthattheprevalenceofVaD were more effective than acupoints on other meridians [2]. among individuals aged 65 years and older was 1.5% [7]. It DatamininghasalsobeenusedtodiscoverpotentialChinese hasbeenpredictedthatdementiawillaffect80millionpeople herbs for the effective treatment of specific diseases [3, 4]. worldwide by 2040 [8]. The annual cost of care per patient Theseresultssupportdataminingasapromisingmethodto is estimated to be US$17,000–55,200 for severe dementia, discoveracupointswithpotentialfortreatingdiseases. placingaheavyeconomicburdenonfamiliesandsociety[9]. 2 Evidence-BasedComplementaryandAlternativeMedicine Acupuncture, a primary therapeutic method in tradi- tional Chinese medicine (TCM), can improve memory, 2121 records identified through database searching orientation, calculation, and self-managing ability in VaD (CNKI: 892, CBM: 1084, PubMed: 145) patients [10–12]. The therapeutic effects of acupuncture are achieved via multiple pathways, including antioxidative effects, antiapoptotic effects, and neurotrophic effects [11, 13–15]. However, acupoint selection remains a challenge in the use of acupuncture to treat VaD. According to our preliminary statistics, more than 100 acupoints distributed in13meridianshavebeenrecordedinthemodernliterature 238 acupuncture prescriptions included in data for the treatment of VaD. The most effective acupoints for mining and network analysis after screening the treatment of VaD and the selection of acupoints for combination remain to be elucidated, representing a major limitationforclinicaltherapeuticeffectsandtheapplication ofacupunctureforVaD. To shed some light on the selection of acupoints and acupointcombinationstotreatVaDinclinicalacupuncture and acupuncture research, this study aimed to discover Data preprocessing: extraction of information about acupointsandacupointcombinationsthathavepotentialto titles, journals, interventions, and main acupoints treatVaDviadatamining. and standardization of acupoint names 2.MaterialsandMethods Theflowofinformationthroughthevariousphasesofdata miningisillustratedinFigure1. 2.1.InclusionCriteriaforConsideringAcupoint Data processing: analysis of frequencies of PrescriptionsforDataMining acupoints and meridians, confidence of acupoint 2.1.1.TypesofStudies. Clinicaltrialsevaluatingtheeffectof TCMacupuncturewithorwithoutrandomizationmethods combination, and network properties were included. Trials with or without controls were also included. The control interventions included no treatment, Figure1:Flowofinformationthroughthedifferentphasesofdata sham acupuncture, Western medicine, TCM herbs, non- mining. traditional acupuncture, and TCM acupuncture containing anotheracupointprescriptionwhichisdifferentfromtheone inobservationgroup.LanguagewasrestrictedtoChineseand Westernmedicine,TCMherbs,nontraditionalacupuncture, English. and TCM acupuncture containing another acupoint pre- scription which is different from the one in observation 2.1.2. Types of Participants. Clinical trials involving adult group. If the studies compared the therapeutic effects of participantsdiagnosedwithVaDwereincluded. differentacupointprescriptions,themosteffectiveacupoint prescriptionwasincluded. 2.1.3. Types of Interventions. Clinical trials evaluating TCM acupuncture were included. Acupuncture can be used alone or in combination with other types of interventions. 2.2.ExclusionCriteria TCMacupunctureinvolvesinsertingneedlesintotraditional meridian acupoints and extraordinary acupoints. Electrical 2.2.1. Types of Studies. Case reports, reviews, systematic stimulation of the needles may be used. Trials using moxi- reviews,andmeta-analyseswereexcluded. bustionaloneorasacointerventionwithacupuncturewere alsoincluded. 2.2.2.TypesofParticipants. Trialsevaluatingthetherapeutic effect of acupuncture for Alzheimer’s disease, traumatic 2.1.4. Effectiveness of Acupoint Prescriptions. Acupoint pre- dementia, and other subtypes of dementia were excluded. scriptions for the disease and not particular syndromes Studiesonanimalswerealsoexcluded. of VaD were included. There should be statistical differ- ences in symptoms between before and after acupuncture. 2.2.3. Types of Interventions. Trials stimulating Ashi points In a controlled trial, patients treated with acupuncture alonewereexcluded. Trialsofdryneedlingortriggerpoint aloneorincombinationshouldreceivegreaterbenefitthan therapy, therapies that are based on principles of western patientswhodonotreceiveacupuncturetherapy.Thecontrol anatomy and physiology, were excluded. Trials of laser interventions included no treatment, sham acupuncture, acupunctureandnoninvasiveelectrostimulation(e.g.,using Evidence-BasedComplementaryandAlternativeMedicine 3 electrodesontheskinratherthanneedlesormoxibustionto and support of acupoint combinations. According to the stimulatetheacupoints)wereexcludedtolimitthefocusto definition of association rules mining [18], the following TCM acupuncture. Trials evaluating acupressure, a form of canbeastatementofassociationrulesminingforacupoint massage,wereexcludedaswell.Finally,trialsofmicropunc- combination. Let 𝐼 = {𝑖1,𝑖2,...,𝑖𝑚} be a set of acupoints. turewereexcludedbecausemicropunctureisanontraditional Let𝐷beasetofacupointprescriptions,whereeachacupoint acupuncturepracticethatisbased ontheprinciplethatthe prescription𝑇isasetofacupointssuchthat𝑇⊆𝐼.Associated head(orear,nose,eye,abdomen,ankle,etc.)isamicrosystem witheachacupointprescriptionisauniqueidentifier,called oftheentirebody. TID. An acupoint prescription 𝑇 contains 𝑋, a set of some acupointsin𝐼,if𝑋 ⊆ 𝑇.Therule𝑋-𝑌hassupport 𝑠inthe 2.2.4. Effectiveness of Acupoint Prescriptions. Acupoint pre- acupointprescriptionset𝐷if𝑠%ofacupointprescriptionsin scriptionsforaparticularsyndromeofVaDwereexcluded. 𝐷contain𝑋∪𝑌. Acupoint prescriptions with no statistical improvement of symptomswerealsoexcluded.Whenthetherapeuticeffects 2.6.3.MeasurementofNetworkProperties.Communitystruc- ofdifferentacupointprescriptionswerecomparedinastudy, ture is a common characteristic of complex networks and allacupointprescriptionsexceptthemosteffectiveonewere is characterized by more dense internal connections within excluded. groups of nodes than with the rest of the network. In this study, a hierarchical agglomeration was adopted to detect 2.3.SearchingMethodsforIdentificationofStudies communitystructureaccordingtoClausetetal.[19].Wealso focusedoninvestigatingthesetofthemostinfluentialnodes 2.3.1.DataSources. PubMed(http://www.pubmed.com(1966 inacupointnetworksofVaD,definedasthenodeswiththe to2012)),theChineseBioMedicineDatabase(CBM)(http:// highest 𝑘-core value [20]. The 𝑘-core method is predomi- www.sinomed.ac.cn (1978 to 2012)), and China National nantly used in analyzing social networks. We employed the KnowledgeInfrastructure(CNKI)(http://www.cnki.net(1912 𝑘-coremethodtoobtainthecoresofdifferentacupoints.The to2012))weresearchedformodernliteratureonacupuncture 𝑘-coremethodwasimplementedasfollows.First,all1-degree treatmentforVaD. nodeswereremoved,andthenodeswerefurtherpruneduntil no 1-degree nodes remained. The remaining nodes formed 2.3.2. Searching Strategy. The searching strategy used the the 2-core node set. The pruning process was repeated in a followingkeywords:(I)“acupuncture”OR“electroacupunc- similar manner for other nodes in the network assigned to ture” OR “moxibustion” OR “meridian” OR “acupoint”; (II) thecorrespondingcores(denotedby𝑘s).Thenodeswiththe “dementia”OR“vasculardementia”OR“Alzheimer’sdisease.” largest 𝑘-core value were defined as the network core. The The searching strategy included literature on acupuncture treatmentforAlzheimer’sdisease(AD)becausethemodern degree of each acupoint was also analyzed to measure the literatureonacupunctureforVaDoverlapswiththatonAD. involvementofthenodeinthenetwork.Thedegreerefersto thenumberofnodestowhichafocalnodeisconnected[21]. 2.4.DataCollection. Tworeviewersindependentlyscreened Betweennesscentralitywasalsousedtoanalyzeanacupoint’s the title and abstract of every record retrieved from the centralityinthenetwork.Centralityisanimportantconcept literature searches. All potentially relevant articles were for the analysis of networks, and betweenness centrality is investigated as full text in English or Chinese. In cases of oneofthemostprominentmeasuresofcentrality.Itisused disagreement, a trial was included or excluded based on to measure the degree to which a node is in a position of discussionbetweenthetworeviewersorafterathirdreviewer brokerage by summing up the fractions of shortest paths reviewed the information. For duplicate publications, the betweenotherpairsofverticesthatpassthroughit[22]. finalpublicationwasused. 3.Results 2.5. Data Preprocessing. Information about titles, journals, interventions, and main acupoints was extracted using the 3.1. Overall Profile of Acupuncture Prescriptions. Database self-establishedDataExcavationPlatformofAcupointSpeci- searching identified 892 records in CNKI, 1084 records in ficity for data mining. Because acupoints have aliases, the CBM, and 145 records in PubMed. After screening, 238 names of acupoints were standardized according to Funda- acupuncture prescriptions in 238 articles were included. mentalsofAcupuncture[16]. Amongthe238trials,185arecontrolledclinicaltrials(CCTs), whiletheother53trialshavenocontrols.Thewholeviewon thestudyqualityofthe185CCTswereshowninFigure2. 2.6.DataProcessing 2.6.1.FrequenciesofAcupoints. Thefrequenciesofacupoints, 3.2.FrequenciesofAcupointsandMeridians. Approximately meridians, and acupoints on different body parts were 109 meridian-acupoints distributed over 13 meridians and analyzed using the Data Excavation Platform of Acupoint 7 extraordinary acupoints have been recorded for 1400 and Specificity. 133times,respectively,inmodernliteratureonacupuncture treatment for VaD. The most frequently used meridian 2.6.2.AssociationRulesMining.AprioriAlgorithmforassocia- was the Governor Meridian (477 times). Other frequently tionrulesmining[17]wasadoptedtoanalyzethefrequencies used meridians included the Gallbladder Meridian of Foot 4 Evidence-BasedComplementaryandAlternativeMedicine Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reporting Another bias 0 20 40 60 80 100 (%) Low risk Unclear risk High risk Figure2:Wholeviewonthestudyqualityofthe185CCTs. 200 180 160 140 120 100 80 60 40 20 0 0) 1) 0) 6) 4) 6) 6) 6) 7) 3) 3) 3) 0) 3) 4) 9) 6) 4) 1) 3) 2Baihui (GV hencong (EX-HN 2Fengchi (GB 2Shuigou (GV 2Shenting (GV Neiguan (PC 3Zusanli (ST Sanyinjiao (SP Shenmen (HT Taixi (KI 1Benshen (GB 2Shenshu (BL 4Fenglong (ST Taichong (LV 1Dazhui (GV 3Xuanzhong (GB 1Fengfu (GV Hegu (LI 1Quchi (LI Yintang (EX-HN Sis Frequency Figure3:The20mostfrequentacupointsandtheirfrequencies. Shaoyang and the Stomach Meridian of Foot Yangming, times),upperlimbs(214times),backandlumbar(127times), which were reported for 218 and 124 times, respectively. andchestandabdomen(43times)(Figures4(a)and4(b)). Extraordinary acupoints were also frequently used. Baihui (GV20),Sishencong(EX-HN1),Fengchi(GB20),Shuigou 3.4.FrequenciesofSpecificAcupoints. Specificacupointsrep- (GV 26), and Shenting (GV 24), which were among the resented78ofthe116acupoints(67.24%).Specificacupoints top five acupoints in frequency, were recorded for 176, 124, havebeenused1292times,representing84.28%ofthetotal 93, 86, and 84 times, respectively. The frequencies of each frequencyofallacupoints(Figures4(c)and4(d)). meridianandacupointareshowninTable1.Thetwentymost frequentlyusedacupointsareshowninFigure3. 3.5.FrequenciesandSupportofAcupointCombinations. Acu- point combinations between Baihui (GV 20), Sishencong 3.3. Frequencies of Acupoints on Different Body Parts. Acu- (EX-HN 1), Fengchi (GB 20), Shenting (GV 24), Shuigou pointsonthehead,face,andneckwereusedmostfrequently, (GV 26), and Zusanli (ST 36) were used most frequently. with a total number of 42 acupoints and a total frequency The15mostfrequentlyusedacupointcombinationsandtheir of766times,followedbyacupointsonthelowerlimbs(383 supportandconfidenceareshowninTable2. Evidence-BasedComplementaryandAlternativeMedicine 5 Table1:StatisticsofmeridiansandacupointsinthemodernliteratureonacupuncturetreatmentforVaD. AcupointsandtheirfrequenciesmberMeridianFrequencyNumberofacupointsBaihui(GV20)176,Shuigou(GV26)86,Shenting(GV24)84,Dazhui(GV14)27,Fengfu(GV16)23,Yintang(EX-HN3)16,Naohu(GV17)13,Shangxing(GV23)11,Mingmen(GV4)8,Yamen(GV15)5,Qiangjian(GV18)5,Qianding(GV21)4,Yaoyangguan(GV3)3,Zhiyang(GV9)3,Jinsuo(GV8)2,GV47726Shendao(GV11)1,Zhongshu(GV7)1,Taodao(GV13)1,Lingtai(GV10)1,Changqiang(GV1)1,Xuanshu(GV5)1,Yaoshu(GV2)1,Shenzhu(GV12)1,Jizhong(GV6)1,Houding(GV19)1,Xinhui(GV22)1Fengchi(GB20)93,Benshen(GB13)47,Xuanzhong(GB39)24,Shuaigu(GB8)7,Wangu(GB12)6,Toulinqi(GB15)6,Qubin(GB7)5,Xuanli(GB6)4,Naokong(GB19)4,Zuqiaoyin(GB44)3,YanglingquanGB21820(GB34)3,Yangbai(GB14)3,Hanyan(GB4)2,Qiuxu(GB40)2,Fengshi(GB31)2,Touqiaoyin(GB11)2,Xuanlu(GB5)2,Muchuang(GB16)1,Zhengying(GB17)1,Zhongdu(GB32)1Sishencong(EX-HN1)123,Taiyang(EX-HN5)4,Wailaogong(EX-UE8)2,Shiqizhui(EX-B8)1,BaxieEX-HN1337(EX-UE9)1,Anmian(EX-HN22)1,Yiming(EX-HN14)1Zusanli(ST36)72,Fenglong(ST40)40,Touwei(ST8)6,Lidui(ST45)2,Sibai(ST2)2,Futu(ST32)1,ST1247Renying(ST9)1Shenshu(BL23)43,Ganshu(BL18)12,Tianzhu(BL10)10,Pishu(BL20)8,Feiyang(BL58)8,Geshu(BL17)7,Xinshu(BL15)4,Zhiyin(BL67)2,Kunlun(BL60)2,Yuzhen(BL9)2,Tongtian(BL7)1,Chengjin(BL56)BL103151,Dazhu(BL11)1,Weizhong(BL40)1,Qucha(BL4)1Sanyinjiao(SP6)71,Xuehai(SP10)14,Taibai(SP3)8,Yinbai(SP1)2,Yinlingquan(SP9)1SP965Neiguan(PC6)73,Zhongchong(PC9)4,Daling(PC7)4,Jianshi(PC5)3,Laogong(PC8)2PC865Taixi(KI3)57,Dazhong(KI4)12,Yongquan(KI1)10,Zhaohai(KI6)8,Rangu(KI2)2KI835Shenmen(HT7)62,Shaochong(HT9)3,Jiquan(HT1)2HT673Hegu(LI4)20,Quchi(LI11)18,Shangyang(LI1)2,Shousanli(LI10)2,Binao(LI14)1,Jianyu(LI15)1,LI457Yingxiang(LI20)1Qihai(CV6)11,Zhongwan(CV12)10,Guanyuan(CV4)9,Danzhong(CV17)9,Shenque(CV8)4CV435Taichong(LV3)37,Dadun(LV1)3LV402Waiguan(TE5)6,Guanchong(TE1)2,Sizhukong(TE23)1,Jiaosun(TE20)1,Sidu(TE9)1TE115Shaoshang(LU11)3,Lieque(LU7)1LU42Shaoze(SI1)2,Yanggu(SI5)1SI32Total1,533116 GovernorMeridian;GB,GallbladderMeridianofFootShaoyang;EX-HN,extraordinaryacupoint;ST,StomachMeridianofFootYangming;BL,BladderMeridianofFootTaiyang;SP,SpleenMeridianofFootn;PC,PericardiumMeridianofHandJueyin;KI,KidneyMeridianofFootShaoyin;HT,HeartMeridianofHandShaoyin;CV,ConceptionVessel;LI,LargeIntestineMeridianofHandYangming;LV,LiverdianofFootJueyin;TE,TripleEnergizerofHandShaoyang;LU,LungMeridianofHandTaiyin;SI,SmallIntestineofHandTaiyang.Frequenciesofmeridiansrefertothetotalfrequenciesofacupointsonthemeridian.Numberofacupointsrefertothetotalnumberofacupointsonthesamemeridian. Nu 1 2 3 4 5 6789 10 111213141516 GV,TaiyiMerisame 6 Evidence-BasedComplementaryandAlternativeMedicine Table2:Statisticsofthe15mostfrequentlyusedacupointcombinationsinthetreatmentofVaD. Number Acupointcombination Frequency Support(%) 1 Baihui(GV20),Sishencong(EX-HN1) 98 41.18 2 Baihui(GV20),Fengchi(GB20) 81 34.03 3 Baihui(GV20),Shuigou(GV26) 72 29.83 4 Baihui(GV20),Shenting(GV24) 70 29.41 5 Baihui(GV20),Zusanli(ST36) 62 26.05 6 Sishencong(EX-HN1),Fengchi(GB20) 60 25.21 7 Baihui(GV20),Sanyinjiao(SP6) 57 23.95 8 Baihui(GV20),Neiguan(PC6) 54 22.69 9 Sishencong(EX-HN1),Shuigou(GV26) 51 21.43 10 Sishencong(EX-HN1),Baihui(GV20),Fengchi(GB20) 51 21.43 11 Baihui(GV20),Shenmen(HT7) 51 21.43 12 Sishencong(EX-HN1),Shenting(GV24) 49 20.59 13 Sishencong(EX-HN1),Neiguan(PC6) 46 19.33 14 Baihui(GV20),Taixi(KI3) 46 19.33 15 Sishencong(EX-HN1),Baihui(GV20),Shuigou(GV26) 43 18.07 Supportreferstothepercentageofacupointprescriptionscontainingtheacupointcombination. 3.6. Community Structure. Community detection resulted (GV24)arepotentialacupointsfortreatingVaD.Intermsof in the division of the 116 acupoints into 5 communities. meridian,acupointsontheGovernorMeridianhavepoten- Nodesofthesamecolorbelongtothesamecommunity.The tialfortreatingVaD.Fromtheperspectiveofcombinations, communitystructureisshowninFigure5(a). combinations between such acupoints as Baihui (GV 20), Sishencong(EX-HN1),Fengchi(GB20),Shenting(GV24), 3.7.Acupoint𝐾-CoreNetwork. Thelargest𝑘-corevaluewas Shuigou (GV 26), and Zusanli (ST 36) have potential for 19.Atthisvalue,therewere28nodes,correspondingtoHegu treating VaD. In addition, acupoints on the head, face, and (LI 4), Quchi (LI 11), Zusanli (ST 36), Fenglong (ST 40), neck have more potential for VaD than acupoints on other Sanyinjiao(SP6),Xuehai(SP10),Shenmen(HT7),Tianzhu regions of the body. Specific acupoints have more potential (BL 10), Xinshu (BL 15), Ganshu (BL 18), Shenshu (BL 23), thannonspecificacupoints.Specificacupoints,withspecific Taixi(KI3),Dazhong(KI4),Neiguan(PC6),Benshen(GB names,areagroupofacupointsonfourteenmeridianswith 13),Fengchi(GB20),Xuanzhong(GB39),Taichong(LV3), specifictherapeuticeffects.Therearetentypesofspecificacu- Mingmen(GV4),Dazhui(GV14),Yamen(GV15),Fengfu points, Five-Shu acupoints, Yuan-Primary acupoints, Luo- (GV16),Baihui(GV20),Shenting(GV24),Shuigou(GV26), Connecting acupoints, Xi-Cleft acupoints, Lower He-Sea Guanyuan(CV4),Sishencong(EX-HN1),andYintang(EX- acupoints, Back-Shu acupoints, Front-Mu acupoints, eight HN3),asshowninFigure5(b). influential acupoints, eight confluent acupoints connecting theeightextrameridians,andconvergentacupoints. 3.8. Degree. The top 20 acupoints in degree are shown Communitydetectiondividedtheacupointsinto5com- in Figure 6(a). Baihui (GV 20), Sishencong (EX-HN 1), munities.Acupointswithinthesamecommunityhavesome Fengchi (GB 20), Shenting (GV 24), and Neiguan (PC 6) characteristicsincommon.Bluenodes(CommunityA)were hadthehighestdegrees,withvaluesof89,76,68,67,and65, respectively. allJing-Wellacupoints.Yellownodes(CommunityB)wereall acupointsonthefaceandhead.Mostgreennodes(Commu- 3.9.BetweennessCentrality. Thetop20acupointsinbetween- nityC)wereacupointsonthefourlimbs.Mostpurplenodes ness centrality are shown in Figure 6(b). Yongquan (KI 1), (CommunityD)wereacupointsbelongingtoGovernorVes- Baihui(GV20),andSishencong(EX-HN1)hadthehighest sel.Mostrednodes(CommunityE)werespecificacupoints betweennesscentrality. or acupoints with specific therapeutic effects, and only this community contained Bach-Shu acupoints and acupoints on the abdomen. Acupoints within the same community 4. Discussion were more densely connected with each other compared 4.1. Potential Acupoints and Combinations for VaD. In this with acupoints from different communities, indicating that study, acupoints and combinations with potential for treat- an acupoint was more often used with acupoints within ing VaD were discovered. These results may provide some thesamecommunitycomparedwithacupointswithinother reference for the selection of acupoints in treatment for communities. VaD, which may promote the therapeutic effects in clinical The19-corenetworkindicatedthat28acupoints,includ- practice.TheresultssuggestthatBaihui(GV20),Sishencong ing Hegu (LI 4), Quchi (LI 11), Zusanli (ST 36), Fenglong (EX-HN1),Fengchi(GB20),Shuigou(GV26),andShenting (ST40),Sanyinjiao(SP6),Xuehai(SP10),Shenmen(HT7), Evidence-BasedComplementaryandAlternativeMedicine 7 45 900 40 800 35 700 30 600 25 500 20 400 15 300 10 200 5 100 0 0 Head, face, Lower Upper Back and Chest and Head, face, Lower Upper Back and Chest and and neck limbs limbs lumbar abdomen and neck limbs limbs lumbar abdomen Number Frequency (a) Thenumbersofacupointsindifferentparts (b) Thefrequenciesofacupointsindifferentparts 40 800 35 700 30 600 25 500 20 400 15 300 10 200 5 100 0 0 Convergent acupoint Five-Shu acupoint Yuan-source point Luo-Connecting point Eight influential point Shu-Back point Eight confluent acupoints Front-Mu point Lower He-Sea point Nonspecifc point Convergent acupoint Five-Shu acupoint Yuan-source point Luo-Connecting point Eight influential point Shu-Back point Eight confluent acupoints Front-Mu point Lower He-Sea point Nonspecifc point Number Frequency (c) Thenumbersofdifferentkindsofacupoints (d) Thefrequenciesofdifferentkindsofacupoints Figure4:Thefrequenciesandnumbersofacupointsindifferentbodypartsanddifferenttypesofacupoints. Tianzhu (BL 10), Xinshu (BL 15), Ganshu (BL 18), Shenshu to 4 different communities, had higher betweenness cen- (BL 23), Taixi (KI 3), Dazhong (KI 4), Neiguan (PC 6), trality.Yongquan(KI1),whichhadthehighestbetweenness Benshen (GB 13), Fengchi (GB 20), Xuanzhong (GB 39), centrality,didnothavearelativelyhighdegree.However,it Taichong(LV3),Mingmen(GV4),Dazhui(GV14),Yamen connectsJing-Wellacupointswithothertypesofacupoints, (GV15),Fengfu(GV16),Baihui(GV20),Shenting(GV24), resulting in a high betweenness centrality. Acupoints with Shuigou(GV26),Guanyuan(CV4),Sishencong(EX-HN1), higher betweenness centrality play an important role in andYintang(EX-HN3)arecoreacupointsinthenetwork. connectingdifferenttypesofacupoints.Jing-Wellacupoints, Baihui (GV 20), Sishencong (EX-HN 1), Fengchi (GB exceptYongquan(KI1),wereoftenusedwithotherJing-Well 20),Shenting(GV24),andNeiguan(PC6)hadthehighest acupointsonly.Yongquan(KI1)wasnotonlyusedwithother degrees.Thisresultindicatesthatthese5acupointshavebeen Jing-Well acupoints but also with other types of acupoints, combinedwithmoreacupointsthanotheracupoints.These such as other types of specific acupoints, nonspecific acu- acupointshavespecifictherapeuticeffectsonVaD.Therefore, points,andacupointsonotherparts.Thehighbetweenness theseacupointscanbeusedtogetherwithotheracupointsto centralitysuggestedthatYongquan(KI1)mayhavemultiple enhancetherapeuticeffects. effectscomparedwithotherJing-Wellacupointsintreatment Yongquan (KI 1), Baihui (GV 20), Sishencong (EX-HN of VaD. From the perspective of TCM theory, Jing-Well 1), Neiguan (PC 6), and Shenting (GV 24), which belonged acupoints can restore consciousness. Yongquan (KI 1) was 8 Evidence-BasedComplementaryandAlternativeMedicine GV6 HT1 GV5 GV4 GV9 GV10 TE20 GV14 EX-B8 GV8 SP6 ST2 EX-HN22 BL56 EX-UE9 GV7 GV16 GV19 GV11 TE23 ST32 GB31 GV22 GV26 GV1 BL11 GV12 GV2 GB40 BL10 BL4 GV15 GV13 PC8 LI14 GB34 EX-HN14 GV20 TE9 BL40 GB39 CV6 SP9 ST36 GV3 GB17 BL60 GB32 GB16 LI11 ST9 CV8 LV3 BL18 CV12 LI15 LI10 TE5 LI4 EX-HN1 PC6 LU7 SI5 PC7 GB8 GB5 EX-HN5 BL9 SP3 ST40 EX-UE8 BL20 GB14 KI3 BL17 GB13 GV23 GB15 GV21 CV4 GB20 CV17 KI4 BL23 KI6 HT7 PC5 ST8 EX-HN3 GV17 BL15 SI1 GB19 LI20 GB7 SP10 BL58 SP1 GV24 GB6 GB12 BL7 GB4 KI2 LV1 ST45 KI1 TE1 GB11 GV18 HT9 LI1 GB44 PC9 BL67 LU11 (a) NetworkstructureofacupointsforthetreatmentofVaD KI4 GV4 GB13 EX-HN3 CV4 GV24 GV16 KI3 GV14 EX-HN1 GB39 ST40 BL23 GV20 PC6 GV26 SP6 GV15 HT7 LI4 GB20 ST36 BL18 LI11 LV3 BL15 BL10 SP10 (b) 19-corenetwork Figure5:(a)NetworkstructureofacupointsforthetreatmentofVaD.Bluenodes(CommunityA)areallJing-Wellacupoints.Yellownodes (CommunityB)areallacupointsonthefaceandhead.Mostgreennodes(CommunityC)areacupointsonfourlimbs.Mostpurplenodes (Community D) are acupoints belonging to Governor Vessel. Most red nodes (Community E) are specific acupoints or acupoints with specifictherapeuticeffects,andonlythiscommunitycontainsBach-Shuacupointsandacupointsontheabdomen.Acupointswithinthe samecommunityaremoredenselyconnectedwitheachotherthanacupointsfromdifferentcommunities.(b)19-corenetwork.Thereare28 acupointsinthe19-corenetwork.TheyarecoreacupointsinthetreatmentofVaD. Evidence-BasedComplementaryandAlternativeMedicine 9 100 90 80 70 60 50 40 30 20 10 0 0 1 0 4 6 6 4 6 6 7 4 3 6 0 3 3 3 0 9 1 GV2 X-HN GB2 GV2 PC SP GV1 GV2 GV1 HT LI KI ST3 ST4 LV GB1 X-HN BL1 GB3 LI 1 E E Degree (a) The20acupointswithhighestdegree 0.16 0.14 0.12 0.1 0.08 0.06 0.04 0.02 0 1 0 1 6 6 0 4 4 6 3 7 4 3 6 0 3 0 6 3 9 KI GV2 X-HN PC GV2 GB2 GV2 GV1 SP X-HN HT LI KI GV1 BL1 LV ST4 ST3 GB1 PC E E Betweenness centrality (b) The20acupointswithhighestbetweennesscentrality Figure6:The20acupointswithhighestdegreeandthe20acupointswithhighestbetweennesscentrality. also used to tonify kidney in treatment of VaD. Therefore, ElectroacupunctureatBaihui(GV20),Dazhui(GV14),and Yongquan (KI 1) is used not only with other Jing-Well Shenshu (BL 23) blocks expression of p53 and Noxa in the acupoints but also with other types of acupoints, such as hippocampal CA1 region of VaD rats [26]. Acupuncture at othertypesofspecificacupoints,nonspecificacupoints,and Baihui (GV 20) can improve neurogenesis via regulating acupointsonotherparts. brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB). BDNF, which 4.2.UnderlyingMolecularMechanismoftheAcupointwiththe is essential for synaptic plasticity and is coupled to CREB MostPotentialtoTreatVaD. Accordingtoourresults,Baihui activation [27], is important for long-term memory storage (GV 20), which had the highest frequency, has the most [28].CREBisrequiredfortheproliferation,growth,survival, potentialtotreatVaD.Asystematicreviewandmeta-analysis anddifferentiationofalltypesofcells.Inthebrain,theCREB alsosuggestedthatBaihui(GV20)isaprincipalacupointfor andCRE-mediatedsystemisinvolvedinmemory,learning, acuteintracerebralhemorrhage(ICH);inanimalmodelsof synaptic transmission, neuron survival, differentiation, and acuteICH,therewasnodifferenceinefficacybetweenBaihui axon growth [29]. Acupuncture at Baihui (GV 20) signifi- (GV20)aloneandBaihui(GV20)plusotheracupoints[23]. cantlyincreasesthelevelsofBDNF[15,30],CREBproteins, Molecular biology studies have provided insights into CREB mRNA [30], and phosphorylated CREB, the active themechanismsunderlyingtheeffectsofBaihui(GV20)in form of CREB [15]. The molecular mechanism underlying VaD treatment, including antioxidant effects, antiapoptotic acupuncture at Baihui (GV 20) also involves cholinergic effects, neurotrophic effects, reduced blood-brain barrier system regulation. Decreased cholinergic function in the (BBB) permeability, and regulation of the cholinergic and brain can result in a decline in memory and cognitive dopaminergic systems. Acupuncture at Baihui (GV 20) in function [31]. Acupuncture at Baihui (GV 20) significantly combination with other acupoints decreases levels of 8- increasesthelevelsofcholineacetyltransferase(ChAT)and 󸀠 hydroxy-2 -deoxyguanosine,aproductofoxidativedamage restores the expression of choline transporter 1 (CHT1) toDNAinducedbyfreeradicals,suggestingthatthebenefit and vesicular acetylcholine transporter (VAChT) [30]. The of acupuncture is partly due to antioxidant effects [11]. dopaminergic system is also involved in the mechanism AcupunctureexertstherapeuticeffectsonVaDviaantiapop- underlyingthetreatmentofVaDwithacupunctureatBaihui tosis.Thetumorsuppressorsp53andNoxaareimportantin (GV 20). Dopamine is a key regulator in specific synaptic regulatingapoptosisandmediatehypoxiccelldeath[24,25]. changes observed at certain stages of learningand memory 10 Evidence-BasedComplementaryandAlternativeMedicine andofsynapticplasticity[32].AcupunctureatBaihui(GV20) 4.4.SingleAcupointorAcupointCombination.Acupointcom- increasesdopaminelevelsinchroniccerebralhypoperfusion binations also influence the therapeutic effects of acupunc- and ischemia-reperfusion injured rats [33]. In addition, ture. An acupoint combination is considered to have a acupunctureatBaihui(GV20)andZusanli(ST36)preserves synergistic effect that enhances the therapeutic effect of the integrity of the BBB, reducing BBB permeability. The acupuncture. For example, a lower prevalence of postoper- BBBisconstructedoftightconjunctions,includingoccludin ative nausea and vomiting in patients treated with Neiguan andclaudin-5,whichformtheendothelialbarrier.Reduced (PC6)plusHegu(LI4)wasobservedcomparedwiththose expression of ZO-1, claudin-5, and occludin mRNA and treatedwithNeiguan(PC6)only[42].Inspiteofextensive protein contributes to BBB breakdown and edema in the evidence suggesting a synergistic effect of acupoint combi- ischemic brain [34]. Electroacupuncture at Baihui (GV 20) nation and supporting its use, some studies have reported antagonistic effects [43–45]. An antagonistic effect occurs and Zusanli (ST 36) reduces brain damage and related whenoneacupointweakensthetherapeuticeffectofanother behavioral deficits via upregulation of tight conjunction acupoint[46].Forexample,electroacupuncturecanimprove proteins,includingZO-1,claudin-5,andoccludin[35].These gastrointestinal movement in rats. The effect of needling findingsrevealpartsofthemolecularmechanismunderlying Pishu (BL 20) alone was better than the effect of needling acupunctureatBaihui(GV20)totreatVaD. Pishu (BL 20) and Zusanli (ST 36) at the same time [44]. Therefore, whether the effect of acupoint combination is 4.3. Acupoints Selection in Treatment for VaD. The proper better than a single acupoint still remains a question and selectionofacupointsisessentialforthetherapeuticeffects needstobefurtherstudied. ofacupuncturebecauseacupointsarespecificwithregardto Some studies have compared single acupoints and an morphologicalstructure,biophysicalproperties,pathological acupoint combination for the treatment of VaD. The thera- response, and stimulating effects [36]. This specificity dif- peutic effect of needling Baihui (GV 20), Shuigou (GV 26), ferentiatesacupointsfromnonacupointsaswellasdifferent and Shenmen (HT 7) in combination was better than the acupointsfromoneanother.Thespecifictherapeuticeffects effects obtained by needling each alone [40]. In addition, ofdifferentacupointshavebeenreportedformigraine[37], needling Baihui (GV 20), Shuigou (GV 26), and Shenmen functionaldyspepsia[38],ischemicstroke[39],andsoforth. (HT 7) simultaneously activated more brain areas related The specificity of acupoints for the treatment of VaD tointellectualactivitiescomparedwithneedlingeachalone, has also been reported. Phosphorylated CREB levels were generatingamoreextensiveeffectonthebrain[41].Antago- significantlyincreasedafteracupuncturetherapyofneedling nisticeffectsinacupuncturetherapyforVaDhavenotbeen Baihui (GV 20) and Zusanli (ST 36) compared to sham reportedbutmayoccur.Mostacupunctureprescriptionsfor acupuncture therapy of needling nonacupoints [15]. Baihui VaDcontainacupointcombinations,andtheuseofacupoint (GV 20), Shuigou (GV 26), and Shenmen (HT 7) are all combinationsissupported.However,acupointcombinations among the 10 acupoints with the most potential. A clinical should be selected carefully to avoid antagonistic effects. It trial demonstrated that needling Baihui (GV 20), Shuigou ishardtotellwhetheracombinationofacupointswillexert (GV26),andShenmen(HT7)werealleffectiveinimproving antagonisticeffectswithcurrentknowledgeorTCMtheory. As abovementioned, acupoints with similar functions can thesymptomsofVaD.However,theirtherapeuticeffectsdif- exertantagonisticeffects.Therearemanyacupoints,andthe fer.NeedlingBaihui(GV20)improvedcalculationabilityand number of acupoint combinations will grow geometrically. short-term memory and corrected the personality changes To test the antagonistic effects of each combination one ofVaDpatients,whileneedlingShuigou(GV26)improved by one is an exhausting job. To avoid antagonistic effects naming ability and short-term memory. The therapeutic as possible, the acupoint prescriptions should be simplified effects of needling Baihui (GV 20) and Shuigou (GV 26) as possible. The general principle is to select acupoints were superior to those of needling Shenmen (HT 7) [40]. with relatively better therapeutic effects and acupoints with APETandSPECTstudyrevealedthatneedlingthesethree multipleindicationsandnottoselectmanyacupoints. different acupoints in VaD patients affected different brain areas.NeedlingBaihui(GV20)activatedtheinnertemporal 4.5.Limitations. Thisstudyhaslimitationsasfollows.First, system, the thalamencephalon system, and the prefrontal otherfactorsthatinfluenceacupuncture,suchasmanipula- corticalsystem.NeedlingShuigou(GV26)activatedthepre- tionandtreatmentduration,werenotanalyzedinthisstudy. frontalcorticalsystem.NeedlingShenmen(HT7)generated These data can be further mined in future studies. Second, an effect similar to but weaker than the effect generated by largelyduetothelackoftreatmentbasedonsyndromediffer- needlingShuigou(GV26)[41].Thesefindingsdemonstrate entiationanddifferentmethodsofsyndromedifferentiation that different acupoints have different therapeutic effects in in modern literature, potential acupoints and combinations acupuncturetreatmentforVaD.Consequently,theselection fordifferentsyndromesofVaDwerenotanalyzed.Although ofacupoints,whichdirectlyinfluencesthetherapeuticeffects treatment based on syndrome differentiation is important ofacupuncture,shouldbeconsideredcarefully.Accordingto andisoftenemphasizedinTCM,treatmentbasedondisease ourresultsbasedondatamining,Baihui(GV20),Sishencong differentiationisequallyimportant.Third,therealtherapeu- (EX-HN1),Fengchi(GB20),Shuigou(GV26),andShenting tic effects of acupoints and combinations on VaD cannot (GV 24), which have higher frequencies in the modern be reflected by frequencies in the literature. However, these literature,mayhavebettertherapeuticeffectsonVaD. resultssuggestsomepotentialacupointsandcombinationsto