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FEMALESEXUALDYSFUNCTIONANDDISORDERS(MCHIVERSANDCPUKALL,SECTIONEDITORS)BrainImagingofHumanSexualResponse:RecentDevelopmentsandFutureDirectionsGerbenB.
Ruesink1&JannikoR.
Georgiadis1Publishedonline:23October2017#TheAuthor(s)2017,correctedpublicationNovember/2017.
ThisarticleisanopenaccesspublicationAbstractPurposeofReviewThepurposeofthisstudyistoprovideacomprehensivesummaryofthelatestdevelopmentsintheexperimentalbrainstudyofhumansexuality,focusingonbrainconnectivityduringthesexualresponse.
RecentFindingsStablepatternsofbrainactivationhavebeenestablishedfordifferentphasesofthesexualresponse,espe-ciallywithregardtothewantingphase,andchangesinthesepatternscanbelinkedtosexualresponsevariations,includingsexualdysfunctions.
Fromthissolidbasis,connectivitystud-iesofthehumansexualresponsehavebeguntoaddadeeperunderstandingofthebrainnetworkfunctionandstructureinvolved.
SummaryThestudyof"sexual"brainconnectivityisstillveryyoung.
Yet,byapproachingthebrainasaconnectedorgan,theessenceofbrainfunctioniscapturedmuchmoreaccurately,increasingthelikelihoodoffindingusefulbio-markersandtargetsforinterventioninsexualdysfunction.
KeywordsSexualbehavior.
MRI.
Connectivity.
Wanting.
Liking.
InhibitionIntroductionRecentyearshaveseenspectaculardevelopmentsinthefieldofhumanbrainimaging(neuroimaging)thatallowre-searcherstoanalyzehumanbrainstructureandfunctioningreaterdetailthanwaseverpossible.
Theseneuroimagingapproacheshavebeguntobeappliedtothestudyofhumansexualbehavioraswell.
Giventheprevalenceofidiopathicsexualdysfunctions,thisdevelopmentispositive,butforsexresearchersorsexologistsnottrainedtodealwithbraindata,itcanbedifficulttogetagriponthewealthofoftencomplexresults.
Inthisreview,weprovideacomprehensivesummaryofthelatestdevelopmentsintheexperimentalbrainstudyofhumansexuality,withafocusonthesexualresponse.
Wewillarguethatbrainconnectivityapproachesholdthehighestpromisetoprovokebreakthroughsregardingthemechanismsthatgovernfunctionalanddysfunctionalhumansexualresponding.
FromActivitytoConnectivity"Neuroimaging"appliestotheuseofvarioustechniquestovisualizethestructureandfunctionofthenervoussystem.
Thisreviewalmostexclusivelydealswithresultsobtainedbymagneticresonanceimaging(MRI).
StructuralMRIpro-videsinformationaboutthesize,shape,andintegrityofgray(clustersofcellbodies,e.
g.
,inthecortex)andwhite(bundlesofaxons)matter.
Analyticmethodssuchasvoxel-basedmor-phometry(VBM)canprovidereliableestimatesoflocalgrayand/orwhitemattervolumedifferences,eitherwithinorbe-tweensubjects.
Diffusiontensorimaging(DTI)isanimpor-tantstructuralMRIprotocolthatcanreconstructathree-dimensionalstructuralmapofthewhitemattertracts(thestructuralconnections)inthebrain.
Quantitativemeta-ThisarticleispartoftheTopicalCollectiononFemaleSexualDysfunctionandDisorders*JannikoR.
Georgiadisj.
r.
georgiadis@umcg.
nl1DepartmentofNeuroscience(SectionAnatomy),UniversityMedicalCenterGroningen,UniversityofGroningen,AntoniusDeusinglaan1,Box196,9700ADGroningen,TheNetherlandsCurrSexHealthRep(2017)9:183–191https://doi.
org/10.
1007/s11930-017-0123-4analysescancombinemanydatasetstomakemorereliableinferencesaboutmorphologicalbrainfeaturesinlargepopu-lations.
Anexampleofthisisastudyon1400humanbrainsfromfourdifferentdatasetsthatcouldnotsubstantiatetheideaofaclearsexualdimorphisminthehumanbrain[1].
FunctionalMRIenablesthedetectionofneuralactivityovertime,typicallyrelatedtoatask,group,physiologicalorpsychologicalparameter,orindividualtrait,resultinginfunc-tionallocalization(activation).
Again,quantitativemeta-analysismethodssuchasactivitylikelihoodestimationcancombinedataofmultipleactivationstudiesanddistillthemostrobustpatternsofactivation—thosethatarelikelytoresemblefunctionalnetworks[2,3].
Analysisoffunctionalinteractionandcommunicationwithinthebrainistermed"functionalconnectivity"andisessentiallycalculatedascorrelationsbetweenneuralactivitiesofdistinctareas.
Functionalconnectivitycanbemeasuredfortask-basedfMRIdata,butalsoforso-calledrestingstatedata.
Thelatterdoesnotrequireintrusivetasksorparadigmsthatmightkeeppotentiallyinterestingsubjectgroups(e.
g.
,adoles-cents)frombeingstudiedwithregardtotheirsexualbrainfunction.
Therearedifferentmethodsthatcananalyzefunc-tionalconnectivity;somearemodel-based,suchaspsycho-physiologicalinteractionanalysis(PPI)analysis,whichcanevaluateamoreorlessspecificconnectionunderdifferenttaskconditionsand/orbetweengroups,whereasotherslikeindependentcomponentanalysisrequirenotaskperformanceandtypicallycanevaluatelargernetworksormorenetworkssimultaneously[4,5].
Brainnetworksthatareconsistentlyfoundinfunctionalconnectivitystudies,eitherintherestingstateorduringtaskexecution,includethedefaultmodenet-work,visualnetwork,sensory/motornetwork,andtask-positivenetwork[6].
Asanexample,astudyusingrestingstatestudyfoundthatwomenhadstrongerfunctionalconnec-tivityinpartsofthedefaultmodenetworkthanmendidandthatthemenstrualcycledidnotmodulatethisconnectivity.
Itwasconcludedthattransientactivatingeffectsofgonadalhor-monescouldnotaccountforthesexualdimorphisminfunc-tionalconnectivity[7].
Grangercausalityanalysisanddynam-iccausalmodelscanalsoprovideinformationaboutthedirec-tionofcommunicationbetweenbrainareas[8].
Thisdirectedcommunicationbetweenbrainareasiscalled"effective"connectivity.
Themostrecentanalyticdevelopmentsinneuroimagingaimtocapturewhole-brainfunctionalitybyusingtoolsfromthefieldofnetworkscience[9].
Thepremiseisthatthecentralnervoussystembehavesasanetwork,orasystem,thattriestoachieveanoptimalbalancebetweenlocalspecializa-tionandglobalintegration.
Ifanetworkhasbothproperties,itissaidtohaveasmall-worldorganization,andunlessthereisasevereneurologicalcondition,thisusuallyappliestohumanbrains[10,11].
However,withinasmall-worldorganization,thebalancemightbeshiftedtowardslocalspecializationorglobalintegration.
Graphanalysismethodscanprovideade-tailedanalysisofthissmall-worldorganization,forinstancebyinvestigatingthenumberandlocationofnetworkhubs(areasthatfunctiontointegratenetworkactivity).
Atleastintheory,graphanalysisiscapableofprovidingthemostpro-foundinsightsintoneuralmechanismscontributingtohumansexuality.
ModelingSexTheterm"sexualresponse"referstothesetofbehaviorsandfunctionsdirectlyrelatedtosexualstimulationandthepursuitofasexualgoal[12].
Modelsofthehumansexualresponseaimtoprovideatemplatetostudyandcompareavarietyofsexualresponses,relativelyindependentofothersexualitycharacteristics.
Anexampleofthisisthehumansexualplea-surecycle[13,14].
Thismodel(Fig.
1)—whichunderlinesthesignificanceofexternalstimulationnexttothatoftheinternal"drive"state(incentivemotivationtheory)[15,16]—distinguishesthephaseswantingsex,likingsex(orhav-ingsex),andinhibitingsex.
Sexualorientation,sexualprefer-ence,andgenderidentityarethenseenaselementsdetermin-ingwhatkindofstimulitriggerthesexualpleasurecycle.
Clinically,thisfitswithadistinctionbetweensexualdysfunc-tion(i.
e.
,aproblemwiththesexualresponse,e.
g.
,erectiledysfunction)andparaphilia(i.
e.
,anatypicalsexualprefer-ence,e.
g.
,pedophilia).
Theuseofamodellikethisfacilitatescomparisonbetweenneuroimagingstudiesthattrytomodeldifferentelementsofthesexualresponse,whileallowingdif-ferent(neuroscientific)explanationsandmechanismsforsex-ualresponsiveness.
OverviewofRecentNeuroimagingStudiesonHumanSexualityWereviewedrelevanthumanneuroimagingstudiesthatwerepublishedintheperiod2012–2017,distinguishingstudiesrepresentingthesexualresponseitselfandfactorsinvolvedintriggeringaresponse(sexualorientation,preference,orgenderidentity).
Regardingthesexualresponsecategory,wedistinguishedstudiesrepresentingwanting,liking,andinhibi-tionphases.
Studieswerefurthercategorizedaccordingtotheirmethodology,i.
e.
,whethertheyemployedanalyticap-proachesfocusingonseparateactivatedbrainareas,ormoresophisticatedmethodsanalyzingbrainconnectivityandnet-works(seeprevioussection).
Thisroughcategorizationshowedthatinthedomainofthesexualresponse,abouttwiceasmanyneuroimagingstudieswereconductedthaninotherdomainsofhumansexuality,butalsothattherelativecontri-butionofconnectivitystudieswasgreaterinthelatter.
Furthermore,withinthesexualresponsedomain,itisobvious184CurrSexHealthRep(2017)9:183–191thatmostofcurrentresearcheffortsareconcentratedonthewantingphase,butthatconnectivityapproachesarerelativelymorecommoninexperimentsonthelikingphaseofthesex-ualresponse(Fig.
2).
CurrentStatusofHumanSexualResponseNeuroimagingSystematicreviewsofexperimentalbrainimagingstud-iesofthehumansexualresponserevealphase-dependentpatternsofbrainactivity(Fig.
1)[3,13,14,17].
Intheirreview,GeorgiadisandKringelbachdescribea"sexualwantingpattern"includingtheoccipitotemporalcortex,superiorparietallobule,ventralstriatum(VS),amygdala/hippocampus,orbitofrontalcor-tex(OFC),anteriorcingulatecortex(ACC),andanteriorinsula,anda"sexuallikingpattern,"includingthehy-pothalamus,anteriorandposteriorinsula,ventralpremotorcortex,middlecingulatecortex,andinferiorparietallobule[14].
Usingdifferenttermsforbasicallythesamedistinction,verysimilarpatternswereidenti-fiedbyPoepplandcolleaguesperformingaquantitativemeta-analysisonpsycho-andphysiosexualelementsofthesexualresponse[3].
Byandlarge,asexualre-sponseinvolvesverysimilarbrainactivationpatternsacrosssexualpreferencesandgendergroups,aslongaspreferredsexualstimuliareused[18,19].
Thispat-ternwasrefinedbyarecentmeta-analysis,showingalargelyconsistentpatternacrossgendergroupswithsta-tisticallysignificantgenderdifferencesmainlyinsubcor-ticalareas[20].
Inaddition,thereissomeindicationthatphase-dependencyinbrainresponsepatternsoverthecourseofthesexualresponseislessmarkedinwomenthanitisinmen[21].
Nevertheless,thestabilityofthevisuallyevokedsexualwantingpatternwascon-firmedbyscanningsubjectsontwooccasionsseparatedby1–1.
5yearsandshowingthatthebrainresponsewasverysimilarovertime[22].
Furthermore,sexualwant-ingandlikingbrainresponsepatternsreflect(partsof)knownfunctionalbrainnetworks[6].
Thus,wecon-cludethatthesepatternsarerobustandshouldbeabletoprovideasolidbasisfromwhichsexualresponse-relatedbrainconnectivitycanbestudied.
Morethanbefore,experimentaldesignsarebeingdevel-opedthatcanavoidconfoundscausedbyparticipantreactionmanipulation.
Somestudiesusesubliminal(i.
e.
,belowthethresholdofconsciousness)presentationsofsexualstimuli,eliminatingelaboratecognitiveprocessing[23].
Anovelap-proachinvolvesaddingcognitiveloading(mentalrotationtask)toavisualsexualstimulationdesigntodecreasethelikelihoodofcognitivereactionmanipulation[24].
SuchFig.
1Thehumansexualpleasurecycle.
Brainareasrelevanttothisreviewaredepictedperphase(red:increasedbrainactivity;blue:decreasedbrainactivity).
Inhibitioncanbephysiological(pinkshading)ordeliberate(brownshading).
Abbreviations:ACC,anteriorcingulatecortex;Amy,amygdala;dlPFC,dorsolateralprefrontalcortex;HT,hypothalamus,OFC,orbitofrontalcortex;SPL,superiorparietallobule;vmPFC,ventromedialprefrontalcortex;VS,ventralstriatum(Figureusesinformationfrom[3,13])CurrSexHealthRep(2017)9:183–191185approachesmayeliminateunwantedeffectsof,forinstance,adherencetoculturalstandardsonsexualresponding.
WantingSex:Non-connectivityApproachesNeuroscientificinterestinthesexualwantingdomainisin-creasinglynarrowingdownonsexualdesireextremes.
Severalstudiesusingvisualsexualstimulationhaveshownthat(perceived)hypersexualbehavior(akacompulsivesexualbe-havior,sexualaddiction,orproblematicpornographyuse)iscorrelatedwithalterationsinneuralactivationpatterns[25–32]andregionalbrainvolume[33,34],particularlyinareasofthesexualwantingnetwork[14].
IncreasedactivitytosexualcueshasbeendemonstratedintheVS[25,27]andalsointheamygdalainhypersexualmen[25,27,28],whichissuggestiveofsexualcuesensitization.
Thisissometimestak-entosupporttheaddictiontheoryofhypersexuality[35].
Otherstudies,however,showednegativecorrelationsbetweensexualcue-inducedbrainactivityandhypersexualsymptomseverity,suggestingtheinvolvementofdifferentphenomenathatareseeminglyincompatiblewithaddiction,likeresponseextinctionoremotionaldownregulation[26,28–30,34].
Thesedatamaynotbemutuallyexclusive.
Forinstance,menwithhypersexualitymaybebothsensitizedtosexualcuesorcontingencies(afeatureofaddiction)andmoreeasilyloseinterestorself-regulateifthereisnopossibilitytoad-vancethesexualresponse(asalearnedadaptation).
Indeed,inaparadigmwithrepeatedexposureofcuespredictingthepresentationofapornographicpictureoramonetaryreward,cue-inducedactivityintheACCdecreasedfasterwithrepeat-edexposureinmenwithhypersexuality—butonlyforthesexualcues[26].
Attheotherendofthespectrum,sexualinterest/arousaldisorderisassociatedwithstructuralandfunctionalalterationsinthesexualwantingnetwork,especiallyinareasliketheACC,VS,andamygdala,suggestingdecreasedsexualcuesensitivity[36].
Ruppandcolleaguesshowedthatinpostpartumwomen,amygdalaresponsestoemotionalpictures(includingeroticpictures)wassuppressed,indicatingde-creasedsensitivitytoemotionalsalienceduringthepostpar-tumperiod[37].
ArestingstatefMRIstudysuggestedthatantidepressantuseisassociatedwithalteredfunctionalcon-nectivitywithinthesexualwantingnetwork,especiallywithregardtotheconnectivityofthe(extended)amygdala.
Inthisstudy,amygdalaconnectivityprofilepriortoantidepressantusereliablypredictedifasubjectwasgoingtobevulnerableorresilienttoantidepressant-relatedsexualdysfunction[38].
The"sexualwantingnetwork"canberecruitedbyarangeofsalientnon-eroticstimuliaswell[14],includingnegativeones[39].
Thequestionthenbecomeshowgenericandspe-cificfunctionsworktogetherwithinthisnetworktoproduceadistinctsexualinterest.
Althoughthisquestionisfarfrombeinganswered,interestingnewinsightshavebeenpublished,mostlyontheVS.
Forinstance,VSresponsestofoodanderoticimagespredictedindividualdifferencesinbodyweightandsexualactivity,respectively,6monthslater[40].
AnotherstudyreportedthatdifferencesinVSactivationformonetaryversuseroticcuescouldbeexplainedbytheirrelativemoti-vationalvalue[41].
Hence,theVSmightsignalvaluesfordifferentrewardtypes,buttheneuralresponsesforeachre-wardtypeareuniqueandareinfluencedbytheirsalienceforagivenperson.
Indeed,relativetohealthycontrols,menwithhypersexualityshowstrongerVSactivityforpreferredrela-tivetonon-preferredvisualerotica[32].
Anotherareaofin-terestinthiscontextistheOFC,becauserewardsubtypesareprocessedindifferentOFCsubregions[42].
Whileprimaryrewards(likeeroticstimuli)activatetheOFCposteriorly,sec-ondaryrewards(likemoney)activateamoreanteriorportion[43].
TheOFCisthusaprimecandidatetofurtherthestudyhowthebrainproducesdistinctsexualinterestandfeelings.
Sexualresponsivenessshowsnormalshort-termandlong-termvariability.
Thishasbeenstudiedmostlyinthecontextofthesexsteroidmilieu.
Contrarytothebiologicaladagethatfertilitystatusdrivessexualresponsivity,noconsistentpatternFig.
2Overviewofneuroimagingstudiesonthesexualresponsefromtheperiodof2012to2017.
Studieswerecategorizedbyphaseofthesexualresponsecycleinvestigated(wanting,liking,andinhibition)andbymethodology(activationvs.
connectivityapproaches)186CurrSexHealthRep(2017)9:183–191emergesfromstudiestryingtofindarelationshipbetweenvisualstimulation-inducedbrainactivityandmenstrualcyclephase[21].
However,Ablerandcolleaguesincludedanex-pectancyelementintheirstudyandfoundthat,inregularlycyclingwomen,thepredictingstimulus(conditionedcue)ac-tivatedtheACC,OFC,andparahippocampalgyrusmorestronglyduringthelutealphasethanthefollicularphase.
Activationintheseareaswasstrongerinregularlycyclingwomen,ascomparedtothoseonoralcontraceptives[44].
Testosteroneisseenasthegonadalhormonemostpertinenttohumansexualresponsiveness[45,46].
Indeed,brainsofgeneticmenwithoutandrogenfunction(completeandrogeninsensitivitysyndrome,"46XYwomen")respondedinatyp-icalfemale-likefashiontovisualeroticstimulation,thatis,similartomalecontrolsbutatweakerstrength[47].
Becauseinboth46XYandgeneticwomen,thereislesscentraltestos-teronefunctionthaninmen;itwasconcludedthattestosteroneratherthangeneticsexdeterminesbrainactivitypatternsdur-ingsexualstimulation.
Yet,aDTIexperimentstudyingbrainstructureintransgenderandcisgenderwomenandmenfoundwhitemattervariationthatcouldnotbeaccountedforbydif-ferencesintestosteronefunction.
Transpeopleexhibitedwhitemattervaluesmidwaybetweenmaleandfemalecisgendercontrols,despitegonadalhormonelevelsbeingeithertypical-lymaleorfemale(dependingonwhethertheyweretransgen-derwomenortransgendermen)[48].
WantingSex:ConnectivityApproachesFunctionalconnectivitywithinthesexualwantingnetworkhasrecentlybeeninvestigatedusingthePPIapproach,mainlyinthecontextof(perceived)hypersexuality.
Menwithhypersex-ualityandcontrolsbothshowincreasedfunctionalconnectiv-ityoftheACCwithboththerightVSandrightamygdalawhenviewingerotica,butthestrongestpositivecorrelationwithreportedsexualdesirewasfoundforACC-subcorticalconnectivityinhypersexuality[25].
Aftermanyrepetitionsofsexualstimulation,functionalconnectivityoftheACCwiththerightVSandwiththebilateralhippocampuswasstrongerinmenwithhypersexualitythanincontrols.
Intriguingly,thisincreasedfunctionalconnectivitywithinthesexualwantingnetworkoccurredinthepresenceofdecreasedACCactivity[26].
Thiscouldsignifyahabituationeffect,butmoreresearchisrequiredtoexplorethisphenomenon.
Anotherstudyusedadesignwithcuespredictingpornographicornon-eroticstimuliandfounddecreasedfunctionalconnectivitybetweentheVSandventromedialPFCformenwithhypersexualitycomparedtocontrols[28].
SincealteredVS-prefrontalcouplinghasbeenassociatedwithimpulsivitycontrol,substanceabuse,andpath-ologicalgambling[49–51],thesefindingscouldbeanindica-tionofinhibitionimpairmentinmenwithhypersexuality.
Twootherstudiesemployedarestingstatedesign,showingthat(i)reportedhoursofwatchingpornography(perweek)arenegativelycorrelatedwithrestingstateconnectivitybetweentherightcaudatenucleusandleftdorsolateralPFCand(ii)subjectsdiagnosedwithcompulsivesexualbehaviorhavede-creasedfunctionalconnectivitybetweentheleftamygdalaandbilateraldorsolateralPFC[33,34].
Thesestudiesindicatethatincreasesinsexualbehavioraremarkedbyalteredprefrontalcontrolmechanisms.
Together,theseconnectivitystudiesstrengthentheassumptionthatthe"sexualwanting"patternidentifiedbyactivationstudiesisindeedtheresemblanceofatruefunctionalnetwork,becauseasubsetofitsconstituentbrainareasalterstheircommunicationwhensexualincentivesarepresented,whilethestrengthofthisinteractionreflectsthesexualbehavioralphenotype.
Fronto-striatalconnectivityandVSconnectivityholdhighpromiseasresearchavenuesintothefundamentalsof(aberrant)sexualwanting.
LikingSexBrainimagingparadigmsemployingstrongerandmoreprolongedvisualsexualstimulation(forexample,pornmovies),ortactilegenitalstimulation,arelikelytomodel(el-ementsof)havingsex(e.
g.
,evokephysiologicalgenitalre-sponsesandsexualliking).
Asindicatedearlier,thisphaserecruitsabrainnetworkthatisrelativelydistinctfromthatrecruitedduringwantingsex,andthisisespeciallysoinmen[3,13,14,20].
Likingsexhasalsoseenmorestudiesfocusingonbrainconnectivitythanwantingsexhas(Fig.
1).
Onedisorderthatiscurrentlyreceivingparticularattentionispsychogenicerectiledysfunction(pED).
Thisconditionhasbeenassociatedwithincreasedordecreasedgraymattervol-umeinmanybrainareas,includingthosebelongingtosexualwantingandlikingnetworks[52,53].
Ithasalsobeenasso-ciatedwithpersistentsexualwantingnetworkactivation(su-periorparietallobulespecifically),possiblyresultinginafail-uretoshifttothenextphaseofthesexualresponsecycle[54].
Interestingly,pEDisnowpredominantlybeingstudiedwithstructuralorrestingstateneuroimagingresearchparadigms,contrarytoothersexualdisordersthataredominatedbytask-basedparadigms.
Alteredfunctionalconnectivitywithinandbeyondsexualwantingandlikingnetworkshasbeenidenti-fied.
Forinstance,therightlateralOFCwasfoundtohaveaberrantstructuralconnectivitywithareasintheparietallobeinpED[53].
InarestingstatefMRIstudy,pEDsubjectsshowedalteredfunctionalconnectivityoftherightanteriorinsula(anareaintegraltointeroceptionandemotionregula-tion)withthedorsolateralPFCandrightparietotemporaljunc-tion,comparedtocontrols[55].
ThisindicatesthatpEDmaycomewithanabnormalrepresentationofbodilystates(includ-ingerection)and/orexcessiveinhibitioncontrol.
Interestingly,whensubjectsviewedapornmovieforthedurationoftheexperiment(insteadofresting),reducedfunctionalconnectiv-ityoftherightinsulawasalsofoundinindividualswithpEDrelativetohealthyvolunteers[56].
EventhoughtheCurrSexHealthRep(2017)9:183–191187experimentalparadigmsdiffer,theresultsseemcongruent,againinvolvingcomponentsofbothwantingandlikingnet-worksthatalsoshowstructuraldegradationinpED[53].
Noneofthestudiesdiscussedsofarhaveconsideredwhole-brainconnectivity.
Infact,thefirststudytodothiswaspublishedonly2yearsago.
ZhaoandcolleaguesappliedgraphanalysismethodstostructuraldatatostudydivergingbrainconnectivityprofilesinpEDsubjects[57].
Asexpected,thewhole-brainconnectivityprofileofpEDsubjectsandhealthysubjectshadasmall-worldorganizationcharacterizedbybothnetworksforlocalspecializationandglobalintegration.
However,inpED,thebalancewasshiftedtowardslocalspecialization,possiblyresultinginpoorerintegrationofnetworkactivity.
Indeed,fewerhubs(integratingareas)wereidentifiedinpEDthanincontrols,indicatingoverallpoorerglobalintegration.
Genitalstimulationistheprimarysourceofsexualpleasure(liking)inthebrainandisakeycontributortosexualarousal[13].
Yet,verylittleisknownaboutthebrain'sroleinsexualdevelopmentofgenitalsensations.
Somenewinsightsareprovidedbyresearchinspinabifidapatientswhounderwentasurgicalreinnervationoftheirlifelonginsensatepenistoimprovetheirsexualfunction.
Stimulationoftheglanspenis(reinnervatedbyagroinnerve)andtheintactgroinarea(con-tralateraltotheareathatprovidedthedonornerve)activatedthesameareaoftheprimarysomatosensorycortex,asexpect-ed.
However,primarysomatosensorycortexwasfunctionallyconnectedwiththeMCCandoperculum-insularcortexduringpenisstimulation,butnotduringgroinstimulation[58].
Wiseetal.
studiedtowhatextentbrainactivationoverlapsordiffersforbothphysicalandimaginedgenitalstimulationinwomen[59].
Oneofthemoreinterestingresultsisthatimagineddildostimulationactivatedhippocampus/amygdala,insula,VS,ventromedialPFC,andsomatosensorycorticesmorethanimaginedspeculumstimulation.
Anotherrecentstudyinmas-ochistsshoweddecreasedfunctionalconnectivityofthepari-etaloperculumwiththebilateralinsulaeandoperculumwhentheyreceivedpainfulstimuliinmasochisticcontext,indicat-inganetworkforpainmodulationinfavorofsexualarousal[60].
Evenwhencandidateareashavebeensuggested,clearlymoreworkisneededtoidentifythekeyareasthatgovernnotonlythesexualinterpretationofgenitalsensationinrelationtocontext,butalsothetransitionofgenitaltosexualsensationsinnormalsexualdevelopment.
InhibitingSexFromabehavioralpointofview,thepotentialtoinhibitorcontrolasexualresponseisequallycriticalasbeingabletorespondsexually.
Thus,inthebrain,theremustbeacontinu-ousinterplaybetweensystemsthatpromoteapproachandsystemsthatpromoteavoidance.
Amoreorlessconsistentfindingisthatprefrontalareastendtoshowexaggeratedac-tivityinsubjectswithhyposexualbehavior[61–63].
However,breastcancersurvivorswhoreportdistressabouttheirlossofsexualdesireshowedreducedactivityinthedorsolateralPFCandACCwhenviewingpornographicpictures,comparedtonon-distressedbreastcancersurvivors[64].
Thisresultseemscounterintuitive,butchronicstressorsareassociatedwithpre-frontalhyporegulationofsubcorticalareas[65].
Clinicalfind-ingsconfirmthatprefrontalfunctionneedstobewithinanoptimalrangeforsextofunctionnormally[66],illustratingtheveryimportantpointthatnormalbrainfunctionrequiresoptimalbalancingofbrainsystems.
VictorandcolleaguesperformedaninterestingfMRIstudyfocusingontheVS-amygdalabalanceasanindexoftheindi-vidualtraittoinhibitsexualresponding[67].
Theirhypoth-esiswasthatVSrespondingtoappropriatesexualstimuliisonlyhalfofthestory;inorderforasexualresponsetoad-vance,theamygdalashouldalsodeactivateto"releasethebrake.
"Thisisinlinewithstudiesshowingdecreasedmedialtemporallobeactivityduringhighsexualarousal(e.
g.
,see[14]).
Interestingly,highVSandlowamygdalaactivitydur-inganon-eroticimpulsivitytestwasindeedfoundtopredictahighernumberofsexpartners6monthsafterthestudy,butinmaleparticipantsonly;inwomen,thehighestnumberofnewsexpartnerswaspredictedbyacombinationofhighVSandamygdalaactivity[67].
Importantly,VSandamygdalaac-tivitymightalsoreflectaspecificnegativeappreciationofsexualstimulation.
InarecentfMRIstudywhichincludedanimplicitassociationtest,womenviewedimagesofexplicitpenetrativesex.
Contrarytowhatmightbeexpected,VSac-tivity(andthebasalforebrain-amygdalacontinuum)didnotreflectapproachorpositiveinterest;instead,thosesubjectsthatshowedthestrongestautomaticavoidanceofextremepornhadthestrongestporn-inducedVSresponse[68].
Together,thesefindingsclearlydemonstratethatdetectingasalientsexualstimulusisnotsufficienttoadvanceasexualresponse,butrather,thatsexualresponseresultsfromacom-plexinterplaybetweenapproachandavoidance,theneuralmechanismsofwhichareonlybeginningtobeunveiled.
ConclusionandFutureDirectionsHumansexualitydoesnotrelyonasingle"sexnucleus.
"Rather,itinvolvesmany—sometimesquitegeneric—brainfunctionsincludingthoseforarousal,reward,memory,cogni-tion,self-referentialthinking,andsocialbehavior.
Asclearlyshowninthisreviewandelsewhere[3,14,17],thebrainareasthathavebeenassociatedwithhumansexualityarespa-tiallyremote.
Fromthispointofview,studyingtheconnectiv-ityofthebrainismuchmoreintuitivethanstudyingseparate"activations,"andinfact,studyingthenatureoftheconnec-tivitybetweenbrainregionshasbeenacommonpracticeinanimalmodelsofhumansexualbehaviorformanydecadesalready(seee.
g.
,[46]).
Everyfractionofasecond,billionsof188CurrSexHealthRep(2017)9:183–191neurons"talk"toeachotherbyvirtueofanunthinkablewiringcreatingevenmorecomplexneuralnetworks.
Itisbyunder-standinghowthesenetworksoperate—alone,butpreferablyinconjunctionwitheachother—thatwecanbegintounderstandtheneuralmechanismsthatcriticallyregulatehumansexualfunctionandthatcanaccountfornon-organicsexualdysfunc-tion.
Currently,theurgencytotakesuchanapproachseemsmorepertinentinotherfieldsofsexualityresearch,likegenderidentity/transsexualityandchildsexualoffending.
Forin-stance,arecentstudyusedstructuralMRIdatatodefinere-gionswithgraymatterdeficitsinpedophiliaandthenassessedareliablefunctionalconnectivityprofileoftheseareasusingalargebraindatabase(datafrom7500brainexperimentswereused).
Itturnedoutthatmorphologicallyalteredareasinpedo-philiaarefunctionallyconnectedprimarilywithareasimpor-tantforsexualresponsiveness,i.
e.
,areasofthesexualwantingandlikingnetworks[69].
Thisisstronglysuggestiveofasituationwhereafunctionalsexualresponseisconnectedto—orcontrolledby—brainregionswithsignificantmorpho-logicaldeficits.
Asanotherexampleofmoresophisticatedap-plicationofneuroimagingtothestudyofhumansexuality,arecentstudyusedgraphanalysistoshowthat,relativetocisgenders,transgenderpeoplehaveastrongerlocalspeciali-zationoftheirsomatosensorynetwork,characterizedbymoreandstrongerlocalconnections[70].
Mostlikely,thisunderliestheirdifferentialbodyperception.
Byapproachingthebrainasaconnectedorgan,studiessuchasthesecapturetheessenceofbrainfunctionmuchmoreaccurately,increasingthelikelihoodoffindingusefulbiomarkersandtargetsforintervention.
Westronglyencouragethatsuchmethodsbeusedmoretostudythehumansexualresponse,becauseacceptingthatconditionslikesexualpain/penetrationdisorder,sexualinterest/arousaldisorder,hypersexualcomplaints,prematureejaculation,per-sistentgenitalarousaldisorder,andanorgasmiaoriginateinthebrainisnotenough;sexualdysfunctionsarecomplex,multidi-mensional,andmultifactorialandbytheirverynature,suitabletobestudiedfroma"connectivity"perspective.
CompliancewithEthicalStandardsConflictofInterestTheauthorsdeclarethattheyhavenoconflictofinterest.
HumanandAnimalRightsandInformedConsentAllreportedstudies/experimentswithhumanoranimalsubjectsperformedbytheauthorshavebeenpreviouslypublishedandcompliedwithallapplicableethicalstandards(includingtheHelsinkideclarationanditsamendments,institutional/nationalresearchcommitteestandards,andinternational/na-tional/institutionalguidelines).
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