TissueElasticity Imaging
Volume1:TheoryandMethods
Editedby S.KaisarAlam
ImagineConsultingLLC Dayton,NJ,UnitedStates
TheCenterforComputationalBiomedicineImaging andModeling(CBIM) RutgersUniversity Piscataway,NJ,UnitedStates
BrianS.Garra
DivisionofImaging,Diagnostics,andSoftwareReliability
OfficeofScienceandEngineeringLaboratories,CenterforDevices andRadiologicalHealth,FDA,SilverSpring,MD,UnitedStates
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Contributors
SalavatR.Aglyamov
DepartmentofMechanicalEngineering,UniversityofHouston,Houston,TX, UnitedStates
PaulE.Barbone
DepartmentofMechanicalEngineering,BostonUniversity,Boston,MA, UnitedStates
JeremyJ.Dahl
DepartmentofRadiology,StanfordUniversity,Stanford,CA,UnitedStates
MarvinM.Doyley
DepartmentofElectricalandComputerEngineering,UniversityofRochester, Rochester,NY,UnitedStates
BogdanDzyubak
DepartmentofMedicalPhysics,MayoClinic,Rochester,MN,UnitedStates
KevinJ.Glaser
MedicalPhysics,MayoClinic,Rochester,MN,UnitedStates
TimothyJ.Hall
DepartmentofMedicalPhysics,UniversityofWisconsin,Madison,WI, UnitedStates
CarlD.Herickhoff
DepartmentofRadiology,StanfordUniversity,Stanford,CA,UnitedStates
BrendanF.Kennedy
BRITElab,HarryPerkinsInstituteofMedicalResearch,QEIIMedicalCentre, Nedlands,WA,Australia;DepartmentofElectrical,ElectronicandComputer Engineering,SchoolofEngineering,TheUniversityofWesternAustralia,Perth, WA,Australia
RobertM.Lerner
DepartmentofClinicalImaging,UniversityofRochester,Rochester,NY,United States;DepartmentofDiagnosticImaging,RochesterGeneralHospital, RochesterRegionalHealth,Rochester,NY,UnitedStates
AssadA.Oberai
DepartmentofAerospaceandMechanicalEngineering,UniversityofSouthern California,LosAngeles,CA,UnitedStates
KevinJ.Parker
WilliamF.MayProfessorofEngineering,ProfessorofElectricalandComputer Engineering,ofBiomedicalEngineering,andofImagingSciences(Radiology), UniversityofRochester,Rochester,NY,UnitedStates;DeanEmeritus,Schoolof Engineering & AppliedSciences,UniversityofRochester,Rochester,NY,United States
DavidD.Sampson
Optical+BiomedicalEngineeringLaboratory,DepartmentofElectrical,Electronic andComputerEngineering,TheUniversityofWesternAustralia,Perth,WA, Australia;UniversityofSurrey,Surrey,UnitedKingdom
ArseniiV.Telichko
DepartmentofRadiology,StanfordUniversity,Stanford,CA,UnitedStates
TomyVarghese
DepartmentofMedicalPhysicsUniversityofWisconsinSchoolofMedicineand PublicHealthUniversityofWisconsin Madison,Madison,WI,UnitedStates
PhilipWijesinghe
Optical+BiomedicalEngineeringLaboratory,DepartmentofElectrical,Electronic andComputerEngineering,TheUniversityofWesternAustralia,Perth,WA, Australia;BRITElab,HarryPerkinsInstituteofMedicalResearch,QEIIMedical Centre,Nedlands,WA,Australia
Abouttheeditors
S.KaisarAlam,Ph.D.
PresidentandChiefEngineer,ImagineConsultingLLC,Dayton,NJ,UnitedStates
VisitingResearchFaculty,CenterforComputationalBiomedicineImagingand Modeling(CBIM),RutgersUniversity,Piscataway,NJ,UnitedStates
AdjunctFaculty,Electrical & ComputerEngineering,TheCollegeofNewJersey (TCNJ),Ewing,NJ,UnitedStates
Dr.S.KaisarAlamreceivedhisB.Tech(Honors)fromIIT,Kharagpur,India. Followinga3-yearstintasaLectureratRUET,Bangladesh,hecametothe UniversityofRochester,Rochester,NewYork,forgraduatestudiesandreceived hisM.S.andPh.D.degreesinelectricalengineeringin1991and1996,respectively. Afterspending3years(1995 1998)asapostdoctoralfellowattheUniversityof TexasHealthScienceCenter,Houston,Dr.AlamwasaPrincipalInvestigatorat RiversideResearch,NewYork,from1998to2013,workingonavarietyofresearch topicsinbiomedicalimaging.HewastheChiefResearchOfficeratImprolabsPte Ltd,anupcomingtechstartupinSingaporeuntil2017.Thenhefoundedhisown consultingcompanyforbiomedicalimageanalysis,signalprocessing,andmedical imaging.Hehasalsobeeninvolvedintrainingandmentoringhighschoolstudents. HehasbeenavisitingresearchprofessoratCBIM,RutgersUniversity,Piscataway, NewJersey(since2013),avisitingprofessoratIUT,Gazipur,Bangladesh(2010and 2012),andanadjunctfacultyatTheCollegeofNewJersey(TCNJ),Ewing,New Jersey(since2017).
Dr.Alamhasbeenactiveinresearchformorethan30years.Hisresearchinterests includediagnosticandtherapeuticapplicationsofultrasoundandoptics,andsignal/ imageprocessingwithapplicationstomedicalimaging.Theareasofhismostactive researchincludeelasticityimagingandquantitativeultrasound;heisamongafew researcherswithexperienceinbothquasistaticanddynamicelasticityimaging. Dr.Alamhaswrittenover40papersininternationaljournalsandholdsseveralpatents.Heisacoauthorofthetextbook ComputationalHealthInformatics (tobe publishedlate2019orearly2020by CRCPress).HeisaFellowofAIUM,aSenior MemberofIEEE,andaMemberofSigmaXi,AAPM,ASA,andSPIE.Dr.Alamhas servedintheAIUMTechnicalStandardsCommitteeandtheUltrasoundCoordinatingCommitteeoftheRSNAQuantitativeImagingBiomarkerAlliance (QIBA).HeisanAssociateEditorof Ultrasonics (Elsevier)and UltrasonicImaging (Sage).Dr.AlamwasarecipientoftheprestigiousFulbrightScholarAwardin 2011 2012.
BrianS.Garra,M.D.
DivisionofImaging,Diagnostics,andSoftwareReliability,OfficeofScienceand EngineeringLaboratories,CenterforDevicesandRadiologicalHealth,FDA,Silver Spring,MD,UnitedStates
Dr.BrianS.GarracompletedhisresidencytrainingattheUniversityofUtahand spent3yearsasanArmyradiologistinGermanybeforereturningtoWashington DCandtheNationalInstitutesofHealthinthemid1980s.After4yearsatthe NIH,hejoinedthefacultyofGeorgetownUniversityasDirectorofUltrasound. In1998,heleftGeorgetowntobecomeProfessor & ViceChairmanofRadiology attheUniversityofVermont/FletcherAllenHealthcare.In2009,Dr.Garrareturned totheWashingtonDCareaasChiefofImagingSystems & ResearchinRadiologyat theWashingtonDCVeteransAffairsMedicalCenter.InApril2010,healsojoined theFDAasanAssociateDirectorintheDivisionofImagingandAppliedMathematics/OSEL.In2018,helefttheVAandcurrentlysplitshistimebetweenthe FDAandprivatepracticeradiologyinFlorida.
Dr.Garra’sclinicalactivitiesincludespinalMRIandgeneralultrasound.His researchinterestsincludePACS,digitalsignalprocessing,andquantitativeultrasoundincludingDoppler,ultrasoundelastography,andphotoacoustictomography. HewaschairoftheFDAradiologicalDevicesPanelfrom1999to2002andhas beeninvolvedintheapprovalofseveralnewtechnologiesincludinghighresolution breastultrasound,thefirstdigitalmammographicsystem,thefirstcomputer-aided detectionsystemformammography,andthefirstcomputer-aidednoduledetection systemforchestradiographsaswellastheultrasoundcontrastagentalbunex.He alsoledtheteamthatdevelopedtheAIUMbreastultrasoundaccreditationprogram, andhelpeddeveloptheARDMSregistryinbreastultrasound.Heiscurrentlyalso ViceChairmanoftheUltrasoundCoordinatingCommitteeoftheRSNAQuantitativeImagingBiomarkerAlliance(QIBA)andisthePrincipalAuthoroftheforthcomingQIBAUltrasoundShearWaveSpeedProfilewhichwillprovidea standardapproachtoacquisitionofshearwavespeeddataforresearch,clinical application,andregulatorytesting.
Foreword
Giventheheavyrelativelysuccessfuluseofmanualpalpationoverthepastfew thousandyears,theultrasoundcommunity,andmedicineingeneral,wasvery excitedtounderstandandrealizethepossibilityofmeasuringandimagingthestiffnessoftissues.Thisincludedtissuestoodeepformanualpalpation.Improvingthe spatialandquantitativefidelityofelasticityimageswasaddressedaggressively.Also pursuedweremanyextensionsrelatedtoelasticproperties,suchastheanisotropyof elasticity,thecomplexelasticmodulus(viscousandelasticcomponents),andelasticityasafunctionoftimeundercompression.
Thistwo-volumebook TissueElasticityImaging extensivelycoverstheprinciples,implementation,andapplicationsofalltheseapproachestoimagethebiomechanicalpropertiesoftissues.Theachievedandfuturebiomedicalapplicationsof thesemanycapabilitiesarealsowellexplained,asareimportantopticalandmagneticresonanceimagingtechniquesthatfollowed,andthatsometimesleapedahead ofthemanyultrasounddevelopments.
Theserapidadvancesarebroughttolifeforthereaderofthesebooksbyphysiciansandotherimagingscientistsandengineerswhomadeleadingadvancesineach ofthecoveredareas.Iinitiallywishedtolistkeyleadauthorswithasummaryof theircontributions,butthatwouldessentiallyberepeatingmostofthetableofcontents.Theeditorsofthesebooks,Drs.BrianGarraandS.KaisarAlam,excelledin recruitingthemanyluminariestoauthorthevariouschapters,definingthetopics, andeditingtheworkforreadabilitybythetargetaudienceofimagingscientists,engineers,entrepreneurs,clinicians,andoperatorsofthesystems.Theworkshould serveasadefinitivereferenceforthoseteachingandthosewritingshorterexplanationsforvariousgroups.Thisisamuch-neededworkinthefield.Luckily,itwillnot bethelast,asadvancesareandwillcontinuetobemade.
PaulL.Carson,Ph.D.
UniversityofMichigan AnnArbor,Michigan UnitedStates
July14,2019
Preface
Sinceitsmodestbeginninginthelate1980stoearly1990s,elastographyhasgained wideacceptanceinmanyclinicalapplications,e.g.,detection,diagnosis,andtreatmentmonitoring.Toassessthegrowthofelastography,weperformedaPubMed searchfor“elastography.”Thetotalnumberofresultswas4711ifwesearched onlythetitle.Wehaveobservedthatsomepapersonelastographydonotinclude “elastography”inthetitlebutincludeitintheabstract.Accordingly,wealsoperformedatitle/abstractsearchfor“elastography”:thenumberofpaperswentupto 7912.Toprovideaperspectiveontherapidgrowth,thesenumberswere1and1, respectively,ifwelimitedthesearchtoonlytheyear1991.Thesenumbersincreased to16and22(title/abstract)in2001,265and399(title/abstract)in2011,and729and 1305(title/abstract)in2018.Clearlyfromtheseyearlynumbers,theascentofelastographyhasbeenrapid,especiallyduringthelastdecade.
Physicianshaveknownforalongtimethattissueelasticitychangeswith(ordue to)diseaseandroutinelyusedpalpationstoaidindiagnosticevaluations.Ifthe readereverwenttoaphysicianwithanabdominalcomplaint,thephysicianprobably palpatedtheabdomen,includingtheliver.Hippocrates(aGreekphysicianwholived duringGreece’sClassicalperiodandiswidelyregardedasthe“fatherofmedicine”) wroteaboutabdominalswellingsin TheBookofPrognostics:“.Suchswellingsas aresoft,freefrompain,andyieldtothefinger andarelessdangerousthanthe others. then,asarepainful,hard,andlarge,indicatedangerofspeedydeath; butsuchasaresoft,freeofpain,andyieldwhenpressedwiththefinger,are morechronicthanthese.”
Manualpalpation,however,issubjectiveandhighlydependentonthephysician expertise.Themeasurementsarenonquantitativeandnotveryusefulforsmallor deeplesions.Severalresearchersexploredtheclinicaluseoftissueelasticityin the1980s.Eventually,RobertLernerandKevinParkerpublishedthefirstjournal paperondynamicelastography(vibrationsonoelastography)in1988.Jonathan Ophirintroducedquasi-staticelastographyin1991.Manyotherelastographyvariantshavebeeninventedsincethen,andabriefhistorydescribingmanyofthem maybefoundinChapter1ofVolume1.Elastographymethodsdonottypicallysufferfromthelimitationsofmanualpalpation.Furthermore,quantitativeelastography allowsobjectivemonitoringofchangeovertime.Typically,medicalimagingmodalitiesmeasureanddisplayparametersthatvaryonlyafewpercentbetweennormal andpathologicaltissues.Incontrast,elastographymodalities(especiallythemodalitiesthatimageamodulus)canexploitparameterrangesofuptosixordersof magnitude!Elastographyisprobablytheonlymodalitywiththis(verylargedynamicrange)advantage.
Dr.BrianGarraandIhavebeeninvolvedwithelastographysinceitsearlydays. Wediscussededitingareferencebookonelastographyseveraltimesinthepast.We feltafewofyearsagothatthetimewasfinallyrightforustoputthisbooktogether. AsanAssociateEditoroftheElsevierJournal Ultrasonics,IknewourPublisher (atthetime)YsabelErmers.WeapproachedYsabel,andsheputusintouchwith Elsevier’sAcquisitionEditorDr.AnitaKoch.WithAnita’shelp,wefinalizedthe planforthebook.Thebookwasapprovedsoonafterward.BrianandIwantedthe booktobeusefulforintroducingsomeonetoelasticityimagingaswellasareferenceforsomeonemoreadvancedintheart.Someofthespecificsinthechapters ofbothvolumeswillbecomesomewhatoutdatedwithinashorttime.However, thebasicsandthegeneralinformationwillremainuseful.Thereaderscansearch theInternet(e.g.,Google,PubMed,etc.)andcontacttheauthorsinthisbookand otherexpertsforguidanceonthestateoftheart.Thereaderscanalsoconsultthe companionwebsiteforthisbookat https://www.elsevier.com/books-and-journals/ book-companion/978-0-12-809661-1.
Thereweremanyoptionswithrespecttotheorganizationofthebook.We decidedtodividethebookintotwovolumes.Volume1discussestheoryand methodsofelasticityimaging,andVolume2discussesclinicalapplicationsofelasticityimagingmodalities.InVolume1,Chapter1takesthereadersthroughabrief historyofelastography,startingwithsomediscussionaboutpreimagingdays.Chapter2providesaunifiedviewofthegoverningtheoryofelastography.(Individual chaptersinVolume1haveexpandedonthetheoryforeachmodality,asneeded.) Chapter3describesvibrationsonoelastography,thefirstelasticityimagingmethod. Itisfollowedbyadetaileddescriptionofquasi-staticelastographyinChapter4.A thoroughtreatmentofdynamicelastographytechniquesbasedonacousticradiation forceandshearwaveisprovidedinChapter5.Chapter6describesmagneticresonanceelastography.Inverseproblemsandmodulusconstructionarebrieflytreatedin Chapter7.Chapter8describeslateralandshearstrainimaging.Thevolumeconcludeswithadetailedchapteronopticalelastography(Chapter9).
InVolume2,ninechaptersdiscussseveralmajorclinicalapplicationsofelastography.Thisvolumecanalsoservetointroducebasicscientiststoanarrayofclinical applications,theircurrentchallenges,andfutureprospects.Evenafterthreedecades ofdevelopment,elastographyisarapidlyexpandingfield.Giventheever-increasing numberoflabs,researchers,andcommercialendeavors,webelievethatsuch progress(innewmethodsandclinicalapplications)islikelytocontinueformany years.
Werecruitedleadingresearcherstowritethechaptersandwouldliketothankall theauthorswhocontributed.Inaddition,wewouldliketothankthereviewerswho providedhelpfulcommentsforallthechapters.Theirservicewascrucialinensuring
thequalityofthechapters.Thenamesofthereviewersareindicatedbelowinan alphabeticalordertoacknowledgetheirservice.
S.KaisarAlam Dayton,NewJersey,USA October1,2019
Chapterreviewers:
Volume1:Theoryandmethods
ArunK.Thittai
AssadA.Oberai
DavidBradway
EEWVanHouten
GuyCloutier
JamesF.Greenleaf
Jean-LucGennisson
KirillLarin
MarkPalmeri
MarvinM.Doyley
MatthewUrban
MichaelRichards
SalavatAglyamov
ThomasA.Krouskop
TomSeidl
TomekCzernuszewicz
YogeshKannanMariappan
Acknowledgments
Editingthisimportantreferencebookwasmuchharderandatthesametime,much morefulfillingthanIcouldhaveeverimagined.Firstandforemost,Iwanttothank theAlmighty.Hegavemethepowertopursuemydreamsandthisbook.Icould neverhavedonethiswithoutmyfaithinHim.ThisbookhappenedbecauseHe wishedittobe.
Iamevergratefultomydeceasedparentswhoalwaysencouragedmetopursue mydreams.Thankyoumydearwife,daughter,andsonforyourconstantpatience andsupport,especiallyduringdifficulttimes.Myyoungerbrotherandsisterhave beenmysourceofstrengthsincetheywereborn.Theirspousesandchildrenhave beenasourceofinspirationandjoyforme.Ihavealargenumberofuncles,aunts, cousins,nephews,andnieces,whohavealwayssupportedme.Iamluckytohaveall ofyouasmyfamily.
IalsowanttothankmanyindividualswhomIregardasmentorsandfriends. TheyincludemychildhoodmentorDr.KaziKhairulIslam,mydoctoraladvisor Dr.KevinJ.Parker,mypostdocsupervisorlateDr.JonathanOphir,myformer supervisorsDr.ErnieFeleppaandlateDr.FredLizzi,andmycoeditorDr.Brian Garra.(Brianalsoprovidedtheartworkusedtodesignthecover.).
Iamalsoindebtedtomanyfamilymembers,friends,andcolleagues,andit wouldbeimpossibletothankthemallindividually.Iamluckytohavebeenyour family,friend,andcolleague.Thankyouall!
Lastbutnottheleast,thankstoeveryoneintheElsevierteam.Specialthanksto ourAcquisitionEditor(Dr.AnitaKoch),EditorialProjectManagers(LindsayLawrence,JenniferHorigan,andAmyClark),ProjectManager(PaulPrasad Chandramohan),CoverDesigner(MatthewLimbert),andmanyotherindividuals whoworkedbehindthescenestomakethisbookareality.
S.KaisarAlam Dayton,NewJersey,USA October1,2019
2. Earlyhistoryoftissueelasticitydetermination
2.1 Palpation
Palpationistheexaminationofstructuresbytouchingthesurfaceoveranareaof concernwiththegoalofidentifyingandcharacterizingthedeepertissues.Ithas beenanimportantphysicianskillforthedetectionofunderlyinganatomicandpathologicconditionsforthousandsofyears [12].
Palpationcangiveanindicationoforgansizeandalsomaydetectinternalorgan abnormalitiessuchasoverallstiffness(whichmayrelatetofibrosis,scarring,tumor, orinflammation)orfocalabnormalitiessuchastumorsornodules.Abnormalities detectedoutsideorgansincludetumors,fluidcollections(abscesses,hematomas, cysts,seromas),andboneabnormalities.Vascularpulsationsmayalsobedetected byputtingafingeroveranarteryforpulserateandrhythmdeterminationandestimationofbloodpressure.Twoexamplesofmedicalteststhatmaybeviewedas quantitativepalpation(initiallyperformedbyclinicalpalpationbutwithpoorreproducibilityandaccuracy)arebloodpressuremeasurementsandoculartonometry, whichdetectintravascularbloodpressureandintraocularpressurebymeasuringa responsetoanappliedpressureorforce,respectively.Forexample,inbloodpressure measurements,systoleisdeterminedasthelowestpressurethatallowsapulsesound tobedetectedbyastethoscopeorDopplerultrasonographyasthepressureinthe cuffisreducedfromahighenoughpressuretoobstructthepulseorflow.Theintraocularpressureisdeterminedbymeasuringadeformationofthecorneatoaknown pressurepulse(puffofair)andcomparingtoastandard.
Avarietyofearlyattemptstoinvestigatetissuestiffnessinarelativeorquantitativemannerthatwouldcorrelatetopalpationwereexploredforseveraldecadesby researchersusinginstrumentationtoobjectivelymonitorstrain(changeindimensionperunitofinitialdimensionafterstressisapplied)ormotionimpartedtotissues usingvariousperturbingstresses(forcefieldsperunitarea).SeeChapters2and4of thisvolumefordetailsofhowstressandstrainpreciselyrelatetoelasticity.
2.2 OestreicherandvonGierke(1950s)
vonGierkeetal.usedastrobelightandcameratoimagesurfacewavepropagation patternsoverthehumanthigh,producedbyapistonsourceincontactwiththeskin at64Hz.Thepatternswererecordedatadistancefromthefocalharmonicforce appliedtotheskin.Surfacewavelengthandwavespeedweredetermined [13], whichcouldberelatedtomaterialpropertiesofanidealsemi-infinitemedium [14].
Theydidnotrelatethesurfacewavespeedtoshearwaves(slowwaves)orlongitudinalwaves(fastwaves)butitisapparent(fromthewavespeedsrecordedas approximatelyseveralmeterspersecond)thattheywereobservingeffectsofshear
wavedisturbancesinthetissueandthelongitudinalwaveswerenotdetected.This wasthefirstquantitativeexperimentalobservationofsurfacewavepropagationin humans.Surfacewavesarerecognizedtobeassociatedwithspeedsnearshear waves [14].
Thisworkfollowedaveryelegantmathematictreatmentofanoscillatingsphere inaviscoelasticmediumbyOestreicher [15].Theworkwaslargelyunexploiteduntilitsapplicationasafoundationfortissueelasticityimagingwasrecognizedand appliedtoenhancethecurrentunderstandingofthebasicscienceoftissueelasticity imaging [16,17] (alsoseeChapters2,3,and5ofthisvolume).
2.3 Earlytissuemotionstudies(1970tomid-1980s)
Althoughnotexplicitlystated,theimplicationforthesestudieswasthepresumption thattissuemotionresultingfromappliedforcefieldscouldultimatelyallowforthe determinationofobjectiverelative(qualitative)orabsolute(quantitative)tissuestiffness(andothermechanicalproperties,e.g.,viscosity)whenappropriatestress-strain physicalmodelswereapplied.Theappliedforcefieldswerefromavarietyofsourcessuchastransmittedcardiacpulsationsandcontrollableexternalforcesfrommechanicalpistons,acoustichorns,speakers,orpuffsofair.Internaltissuemotionwas detectedbyultrasonographyfortheseearlystudies,althoughsurfacewavemotion hadbeenexploredbyphotographictechniquesalso.
2.3.1 Instrument-enhancedpalpation
Anobjectiverelativeassessmentoftissueresponsetoexternalforcewasattempted intheearlystagesofmedicalultrasonographybyclinicalinvestigatorswhopalpated tissuesduringscanningwithstaticB-scanners,interleavingglobalimageswith selectedareaswheretissuemotionwasdepictedbyM-modeandlaterwithrealtimeB-mode,providingamoreglobalassessmentoftissueresponsetosimultaneous palpationorcompressionbytheultrasoundtransducer [18 23].Theseeffortsto gleanmorestiffnessinformationthanwasreadilyavailablefromastaticimageusing commercialinstrumentationaretobeapplaudedandservedtochallengeresearchers toconceiveofmorereproducibleandobjectivetechniques.Thistechniqueisstill usefulinultrasoundpracticeforthedetectionofslidingmotionoforgansortumors withrespecttootherstructures.
2.3.2
Tissuestimulationbycardiacpulsationsornaturalsources
WilsonandRobinsonpresentedanRFM-modeultrasoundsignalprocessingtechniquetomeasuresmalldisplacementsoflivertissuecausedbytheradialexpansion ofarterieswithintheliverfromcardiacpulsations.Theywereabletocalculatethe velocityoftissuemotionfromthetrajectoryofaconstantphasepointandintegrate thevelocityovertimetoestimatedisplacement [24].
DickinsonandHillusedthecorrelationcoefficientbetweensuccessiveA-scan linestomeasuretheamplitudeandfrequencyoftissuemotion.Theydefinedacorrelationparametertocharacterizethechangesoftheinterrogatedregionbetweenthe
successiveA-scans.Forsmalldisplacements,theyassumedthedecorrelationwas proportionaltodisplacement [25].Tristametal. [26] furtherdevelopedthetechniquetoinvestigatetheresponsesofnormalandcancerouslivertocardiacpulsation. DeJongetal. [27] alsousedamodifiedcorrelationtechniquetomeasuretissue motion.
Fetallungelasticitywasinvestigatedasanimportantparameteroffetallung maturitybyBirnholzandFarrell.Theytriedtoqualitativelydeterminethestiffness offetallungsbyevaluatingthelocalcompressionofthelungadjacenttotheheart comparedtothemoredistantlung,whichwouldcompressrelativelylessdepending onthelungstiffnessanddistancefromtheheart [28].Adleretal.developedmore quantitativeestimatesbyapplyingcorrelationtechniquestodigitizedM-modeimagesandestimatedaparameterthatcharacterizestherangeoftransmittedcardiac motioninfetallungs.Theparameterisameasureofthetemporallyandspatially averagedsystolictodiastolicdeformationperunitepicardialdisplacement [29]
Holenetal. [30] observedacharacteristicBessel-bandDopplerspectrumwhen usingDopplerultrasonographytoexamineunusuallyoscillatingheartvalves.Taylor [31] showedthattheexpressionfortheDopplerspectrumofascatteredDoppler signalfromavibratingtargetissimilartothatofapure-tonefrequencymodulation processundercertainconditions.
CoxandRogersstudiedtheDopplerultrasoundresponseoffishauditoryorgans tolow-frequencysound.ThevibrationamplitudeofthehearingorganwasdeterminedbycomparingtheratioofthecarrierandthefirstsidebandoftheDoppler spectrum [32].
Theseexperimentaltechniquesandmathematicsolutionsallmadecontributions torelativeandabsolutetissuestrainandvelocitymeasurements,butwithoutabsolutemeasuresofstress,strain,andboundaryconditionsofthetargettissues,as wellasappropriatemathematicmodels,intrinsicmaterialelasticityvaluescould notbequantitatedindependentoftheexperimentalsetup.
2.3.3 Tissuestimulationbyexternallycontrollablesources
Eisensheretal. [33] usedM-modeultrasonographytomonitorthefrequencycontent oftissuemotioninducedinbreastandlivertissuesbya1.5-Hzvibrationsource. Theyfoundthatthequasi-staticcompressionresponsefrombenignlesionswascharacteristicallysinusoidal,whereasthatfrommalignanttumorstendedtobemoreflat, i.e.,morenonlinear.
Satoetal. [34] investigatednonlinearinteractionsbetweenultrasoundandlower frequencypumpwavesintissuesatthetimewhenParkerandLerner [11] andKrouskopandLevinson [35] wereusinglinearmethodstoinvestigatethepropagationof vibrationsinsidetissues.
Krouskopetal.reportedoneofthefirstattemptsataquantitativemeasurementof tissueelasticityusinggatedpulseDopplertodetecttissuemotionsubjectedtoan externalvibration.Thesetofequationsrelatingtissuepropertiesandmovementsreducestosimpleformsunderassumptionsofisotropyandincompressibility.Determiningtissueelasticitythenreducestomeasuringpeaktissuedisplacementsand
gradients.Theysuggestedpossibleabsolutetissuestiffnesscouldbedeterminedina verysmallregion,i.e.,0.5 0.5mm,withinahomogeneousmedium [35].
ExceptfortheworkofKrouskop,thetissueelasticitydatawasqualitativeand lackingsufficientdetailforthedeterminationofafundamentaltissuepropertyindependentoftheexperimentalsetupthatcouldtranslatetoanabsolutemeasureoftissuestiffness(elasticity,i.e.,bulkmodulusorYoung’smodulusofelasticity; neglectingdensityvariationsinbiologicalsofttissues,whichareverysmall comparedwithelasticityvariations).Although,ingeneral,absolutestiffnessmeasurementscouldnotbeobtained,relativemeasurementscouldproveveryvaluable todetectfocallesionsintissueifthedatawerereliableoveranextendedareaallowingcomparisonofthetargettissuetotheadjacenttissue.
3. Theearlyeraofimagingtissuestiffness(late1980sto mid-1990s)
3.1 Vibrationamplitudesonoelastography(sonoelasticity)
Toourknowledge,thefirstpublishedimageofrelativestiffnesswasacrudegrayscalemapproportionaltopulse-Doppler-detectedvibrationmotioninatissuemimickingphantomcontainingahardinclusion,whichwassubjectedtoanexternal mechanicalstimulus [2,11].Thistechniquewascalled“sonoelasticity.”Afterinitial proofofconceptinphantomsandinvitroanimalstudies,real-timecolorDoppler vibrationalimagesweredemonstratedinanimalandhumantissues [1,36] (also seeChapter3ofthisvolume).
Real-timemodifiedcolorDopplerobservationoftissuevibrationamplitudeimagesduringdeliberatevariationofthefrequenciesoftheexternalvibrationsourcein therangeof50 200Hzresultedinvariablecentimeter-sizedmodalpatternscorrespondingtowavespeedsof1 3m/s,similartopublishedvaluesofshearwave speedintissues [13,36].Themodalpatternswereverysensitivetothefrequency changesandbecamemorecomplexathigherfrequencies.Hardinclusionsinthe phantomsdisturbedthemodalpatterns.Thissupportedthehypothesisthatthe observedsonoelasticitymodessensitivetotissuestiffnesswererelatedtoshear ratherthanlongitudinalwaves.Thisrecognitionthattissuestiffnesscorrelated morecloselywithshearwavepropagationthanwithlongitudinalwavepropagation waslikelythemotivationforseveralresearchlaboratoriestodirecttheirtissuecharacterizationeffortstowardshearwaves [37] (alsoseeChapter5ofthisvolume).
Areal-timevibrationamplitude(qualitative)imaging(sonoelasticity)studyof invitroprostatespecimensshowedbettersensitivityandpredictivevalueforcancer detectionthanconventionalB-scanalone [8].Thecancerousregionsinthespecimensshowedlessrelativemotionthantheadjacentnormaltissue.Amathematic modelforvibrationamplitudesonoelastographywascompleted,showingthatthe shearwaveelastographiccontrastwasordersofmagnitudegreaterthanthecontrast basedonechogenicity [38 40]
Later,theprinciplesofvibrationsonoelastographywerealsoappliedusingvocal fremitusastheexternalvibrationsourcewiththepatients’ownvoice(asinhummingavowelsound)inconjunctionwithDopplerdisplayofvibration.However, thelimitedcontroloveramplitude,frequency,andthecomplicationsoftheeffect ofvaryingechogenicityontheDopplerdisplayallcontributedtoavariableand patient-dependentresponseusingvocalfremitus [41].
3.2 Compressionelastography
Ophiretal.introducedcompressionelastographyasanimagingmethodtodisplay relativestiffnessbasedonlocaltissuestrainchangesinducedbya“modest”(2%) compressionappliedtoaB-scanreal-timeimagingtransducer.B-scanRFinformationfromthebackscatteredultrasonographybeforeandaftercompressionwasused tocalculatelocalstrainbycorrelationanalysis.Stiffertissueswouldundergoless strainthansofttissuesunderthesameappliedstress.Images,inprinciple,would besimpletointerpretbutrequiredtheapplicationofauniformstresstothesurface andinterveningtissuessuperficialanddeeptothetarget,whichisnoteasilyaccomplishedinpractice.Withintheselimitations,qualitative(relative)stiffnessimages wereobtained [42].
Thisconceptwasinitiallyintroducedinsomecommercialmedicalultrasonographicequipmentandcreatedaplatformforearlyclinicalstudiestoadvancethe fieldofrelativestiffnessimagingoftissues.Thisconceptgainedenoughsuccess tobecurrentlyavailableonnearlyallcommercialclinicalultrasonographicsystems. ThistopicisreviewedinmoredetailinChapter4ofthisvolume.
4. Quantitativetissuestiffnessdeterminationandimaging (1990topresent)
4.1 Quantitativetissuestiffnessdetermination
YamakoshiandSatoetal.developedavibrationphasegradientapproachthatmaps theamplitudeandphaseofthelow-frequencyshearwavepropagationinsidetissues, whichcanbeusedtoderivetheelasticandviscouscharacteristicsofthetissue [37]. Therateofchangeofphasecouldyieldaquantitativeestimateoftissuestiffness(see Chapter3ofthisvolume).
Transientelastography,amethodforthemeasurementoftheshearwaveelastic modulusorshearwavespeedinliver,wasthefirstapplicationofanelastographic methoddevelopedforaspecificapplicationthatmetwithwidespreadclinicalacceptance.Themethod,usinganexternalpistonlikemechanicalstimulationappliedtoa patient’sskin,transmittedshearwavepulsesintotheliverwhereultrasonographic monitoringoftheresultinglivertissuemotionalonganaxialpathyieldedameasure ofshearwavespeed [43].Thetechniquewasincorporatedinaninstrumentcalled FibroScan,whichhashadclinicalsuccessinstagingthedegreeofliverfibrosis 4. Quantitativetissuestiffnessdeterminationandimaging(1990topresent)
[44,45].FibroScandeterminesshearwavespeedbasedonshearwavetissuemotion detectedwithultrasoundwavesalongtheaxialbeamoftheultrasoundtransducer. Intuitively,shearwavespropagateatrightanglestolongitudinalwaves;however, longitudinalshearwavepropagationalongtheaxialpath,anonintuitiveresult,is predictedbytheanalysisofOestreicher’swork [15,17,46].
Therapidacceptanceofshearwavespeed(inmeterspersecond)orelasticity(in kilopascals)asaclinicalparameterforassessingthedegreeofliverfibrosiswas likelythestimulusfortheflurryofactivitythatfollowedwiththegoalofgenerating imagesofabsolutetissuestiffnessintermsoftissueelasticityorshearwavespeed. Shearmodulus G isrelatedtoshearwavespeed vs bytheexpression
Quantitativeimagingoftheelasticpropertiesoftissuesinvolvesperturbationof thetissueandmeasurementofthetissueresponseoverspaceandtime,withdetails dependingonwhetheritisbasedoncompressionelastography,mechanicalimaging, orshearwaveimaging.Knowledgeofthesurfacegeometryofthetissueunderexaminationandthemechanicalstimulationtothetissueasafunctionofspaceand timeisrequiredtomathematicallyprocessthedatausinginversemethodswhen appliedtoanappropriatemodel [47 51] (alsoseeChapter7ofthisvolume).
4.2 Furtherexpansionoftissueelasticityimaging(1994to present)
WorkattheUniversityofParisunderProfessorMathiasFinkdemonstratedthata transientshearwavetrackingapproachcouldproduceclinicallyusefulestimates ofshearwavespeed [43].ThisconceptwassuccessfullycommercializedintoaninstrumentcalledFibroScan.TherecognitionthatFibroScancouldquantifythefundamentaltissuepropertystiffness(i.e.,shearwavespeed[inmeterspersecond]or elasticity[inkilopascals];see Eq.(1.1))ledtoarapidexpansionofdevelopmental workleadingtoresearchinstrumentsandeventuallyclinicaltrialsforothermedical applications.Theensuinginstrumentscouldobtainalocalizedshearwavespeedina regionofinterestdefinedonaB-scanimage.Livercross-sectionalimagesofquantitativeshearwavespeedintissueshadbeenobtainedearlierusingmagneticresonanceimaging(MRI)andanexternallow-frequencysourceofshearwaves. However,duetothelimitedpatientaccesstoMRI,magneticresonanceelastography hadnotyetachievedwidespreadapplicationdespiteitselegantcapabilities [52]
Subsequently,cross-sectionalimagesofshearwavespeedintissueswereobtainedusingotherultrasonographictechniquesandeventuallyopticalmethods. Thesemajordevelopmentsarethesubjectsoflaterchaptersinthisvolumeand includevibrationsonoelastography,quasi-staticelastography,acousticradiation forceimpulse(ARFI)imaging,shearwaveimaging,opticalcomputedtomographic elastography,andMRIelastography.MRIelastography,inprinciple,coulddetect
three-dimensionalmotion,thuspermittinganonisotropicmaterial’sstresstensorto bemeasured.
Longitudinalultrasoundpulsesfocusedintissuesresultinsoundabsorptionleadingtoacousticmomentumtransferthatproducestissuemotionandareasourcefor localizedshearwaves(tissuemotion).Astheshearwavespeedintissuesisapproximately1000timesslowerthanthelongitudinalwavespeed,propagationofthe focaltissuesheardisplacementsormotioncanbedetectedorimagedusing thesametransducerthatappliedtheradiationforce [53 56].Thuspropagationof thefocaltissuedisplacementsandvelocitiescouldbetrackedtoquantitateshear wavespeed.Someoftheseconceptshavebeenusedcommercially(ARFI,shear waveelasticityimaging,andsupersonicimaging)andavoidthe,sometimescumbersome,externallyappliedlow-frequencyshearwavesource.
Useofacousticradiationforceasameansofgeneratingandpropagatingshear wavesintodeeptissuesusingfocusedultrasoundpulsesfromconventionalimaging transducershasbeenamajorcontributionforultrasound-basedimagingofcrosssectionaltissuestiffness [57].Thistechniquecanbetracedtocontributionsby severalinvestigators.Nightingale [58] hadusedacousticradiationforcetoproduce streamingmotionofliquidsforthecharacterizationofcystsinbreasttissue.Using thisconcept,NightingaleandTrahey [59] reportedaclinicalstudytodifferentiate cystsfromsolidlesions.Subsequently,theyappliedittoperturbbreasttissueformotionanalysis.Theyrealizedthatradiationforceitselfcouldbeusedtocreateanimage(ARFI) [56,60].
Sarvazyan [54] appliedacousticradiationforcetoproducelocalizedtissuemotionandtotakeadvantageoftheresultingshearwaves,whichhedetectedpropagatingperpendiculartothelongitudinalaxiallydirectedultrasoundbeam.An advantageofthistechniqueisthatthestimulatedtissueissmallinsizeandtheshear wavepropagationislimitedinrangesothatboundaryconditionsdonotcomplicate theshearwavepropagation [61]
Sarvazyanalsodevelopedanapproachcalledmechanicalimaginginwhichhe appliedanarrayofsurfacemechanicalstimulatorsanddetectorsoftheresponding stresspatternsatthesurfaceproducingdatathatcouldbeprocessedusinginversion modelstoprovidequantitativetissueconstants [62]
Additionalelasticitydeterminationrefinementsandimagingtechniquesthat havehadsuccessinthelaboratoryareshearwavedispersion [63],singletracking locationmethodsthatsuppressspecklenoiseinshearwavevelocityestimation [64],andlaboratoryandclinicaltrialsusingcrawlingwave [65],singletracking location [66],X-rayandcomputedtomographicelastography [67],andphotoacousticelastography [68].
Someofthesetopicsaresubjectsoflaterchaptersofthisvolume.Becauseofthe emerginginterestinelastographyandgivenitsclinicalimportance,KevinParker andcolleaguesattheRochesterCenterforBiomedicalUltrasoundsponsoredaspecialworkshopinWashington,DCinJune1994,invitingDrs.Ophir,Levinson,Bamber,andothersfromtheinternationalcommunitytoshareresearchinsights.This mayhavebeenthefirstdedicatedworkshoponelastography.
Laterinthe1990s,ProfessorsOphirandParkerwouldagreeontheneedfora dedicatedconferencewhereexpertsfrommultipledisciplinesofbiomechanics, cellularbiology,imagingsciences,radiology,andbiophysicscouldhaveextended discussionsabouttherapidlyexpandingworldofelastography.UrgedonbyDr. S.KaisarAlam,whohadworkedwithbothOphirandParker,theInternationalTissueElasticityConferencewaslaunchedwiththefirstconferenceinOctoberof2002 inNiagaraFalls,Canada.Thisconferenceflourishedwithnowover13meetings heldandiscurrentlychairedbyProfessorJeffBamber.
4.3 Microscopictissueelasticityimaging
Extensionofelasticityimagingtothemicroscopicdomainisoccurringthatportends torapidlyexpandknowledgeattheintra-andextracellularlevels.Opticalelastographyhasbeendoneusingopticalcomputedtomography(OCT,seeChapter9of thevolume)andothermethodssuchasMichelsonlaservibrometry [69].ThemechanicalexcitationforOCTcanuseexternalmechanicalstimulationorARFIin additiontoopticalabsorption,leadingtothermallygeneratedacousticwaves.
Thesetechniquesuselightscatteredfromsemitransparenttissuestogenerateimagesdepictedingrayscalesimilartoultrasoundechoimages,butwithmuchfiner resolutionfortrackingmechanicallyexcitedtissuemotionandproductionofmicroscopic(subcellularlevel)tissueelasticityimaging.
Photoacousticelastographycanprovidehigh-resolutionelasticityimages.Inone implementation,thecompressionisappliedmanuallyandtheresultingstrainmapis estimatedfromphotoacousticsignals [68].Photoacousticimaginguseslightpulses focusedwithinatissuetogenerateheatdependingontheopticalabsorptioncoefficientofthespecifictissue,whichcauseslocalthermalexpansiontocreatesharptissuemotionthatresultsinacousticwaves.Therangeofopticalabsorption coefficientsmaybeverywide,permittinganewbasisforcontrastandtissuecharacterizationrelatedtothephotochemicalabsorptioninadditiontotissuestiffness.
Tissueelasticityimagingonthemicroscopiclevelwilllikelyopennewareasof understandingofthefibroticresponseoftissuesattheextracellularmatrixandintracellularlevels.Stemcelldifferentiationhasbeenshowntobesensitivetothestiffnessofitsmilieu,whichmaytriggerstemcellstodifferentiateintocancercellsor fibrocytesthatimpactslivercirrhosis,idiopathicpulmonaryfibrosis,andsystemic sclerosis [70,71].Photoacousticabsorptionmaytargetmelaninorhemewithand withoutoxygentoprovidesuperiorcontrasttotheirneighboringtissues.Perhaps specialstainswithspecificphotoabsorptionfrequenciesandintracellularorganelle affinitiescouldleadtonewapplications.
5. Conclusion/discussion
Imagingandunderstandingtissueelasticityatthemacroscopictissueorganizational level(100micrometerstomillimeters)andmicroscopicintracellularand
extracellularmatrixlevelsportendstosignificantlyimpactourunderstandingof biologyanddiseases.Futureexperimentsandtheoriestounderstandreal(lossless, straininphasewithstress)andimaginary(strainoutofphasewithstress)componentsofshearwavespeedintissuesandsimulatedtissuephantomsasafunction ofrelativeamountsofatwo-phasesystemcomposedoffluidandasupportingsolid matrixsimulatingfibroustissue,cellmembrane,orintracellularorganellesmaybe rewarding.Mathematicmethods,somelabeledas“inverseproblems”(seeChapter7 ofthisvolume),continuetobedevelopedthatallowfortherealitiesofexperimental designssuchasfinitetissueboundaries,realisticstimulatingforceprofilesintime andspace,andanisotropyofthematerialunderevaluationtoobtainabsolutebiomechanicalpropertiesfromelastographydata [51].Thesemethodshavebeenappliedto studyadditionalmechanicaltissuepropertiesthatmayhaveclinicalrelevance,such asshearwavedispersion,anisotropy,porosity,andnonlinearity [51]
Optical/photoacousticelastographymayallowcellularbiologiststotargetintracellularorganellesusingspecialstainsthatcanbetunedtoopticalwavelengthsso thatopticalmodulationandmotiondetectioncouldproduceelastographicimages ofintracellularstructuresandevaluatetheirsurroundingstiffness.
Itisalsoexpectedthatelastographytechniqueswillbeextendedtomoreimaging platformsofdifferentmodalities,andwithspecializedapproachestunedtodifferent applicationsandpathologicconditions,includingthoseaffectingthemusculoskeletalandcardiovascularsystems,alongwithlargeorgansandthebrain.Morecomplexmeasuresoftissueanisotropyandviscositywilladdtotheexisting elastographicassessments.
Tissueelasticityimagingisagreatexampleofhowresearchersworkingwith clinicalcolleaguesadvancedmedicalimagingfromaqualitativeclinicalpattern recognitionsystemtoadiagnosticquantitativeimagingsystem.Fundamentalparameterssuchasshearwavespeedorbulkshearwaveelasticityasobjectivemeasuresofliverfibrosiscouldallowclinicianstotreatandfollow-uppatientswith liverdisease,thusavoidingsomebiopsiesanddirectingbiopsiestoproductivesites. ArecentGoogleinterrogationofelastographyproduced930,000references.Elasticityimagingiscurrentlybeingextendedtootherorgans(breast,thyroid,brain,muscle,kidney,skin,cervix,andplacenta,tonameafew)forimprovedclinical managementandpossiblereducednumbersofbiopsies.Multimodalitydevelopment hasallowedtissueelasticityimagingconceptstoextendbeyondultrasonographyto magneticresonanceandopticaltechniques,wherenewinsightsintofundamental understandingofdiseasesandbiologyaresuretobeforthcoming.
Acknowledgments
ThehelpfulperspectivesfromDrs.JeffreyBamberandKevinParkeraregreatlyappreciated inadditiontovaluableeditorialassistancefromDrs.S.KaisarAlamandBrianGarra.The expertassistancebyLindaWeidmaninthepreparationofthischapterwasessential.
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