Alterations in social reward and body perception brain circuits in anorexia nervosa: a functional and structural neuroimaging investigation

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(1)Alterations in social reward and body perception brain circuits in anorexia nervosa: a functional and structural neuroimaging investigation Esther Via Virgili. Aquesta tesi doctoral està subjecta a la llicència ReconeixementSenseObraDerivada 3.0. Espanya de Creative Commons.. NoComercial. –. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial – SinObraDerivada 3.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercialNoDerivs 3.0. Spain License..

(2) !. $ $ $ $ $ Esther$Via$ $$$$$$$$$$ $$$$$$$$$$$$$$$$$ $. $ $. $ PhD$Thesis)2015$$. $. $. !. !. !. !. !. Clinical and Experimental Neuroscience Psychiatry and Mental Health Research Group (IDIBELL) University of Barcelona November 2015. Esther'Via'Virgili' '. A functional and structural neuroimaging investigation.. Alterations in social reward and body perception brain circuits in anorexia nervosa:.

(3) School of Medicine University of Barcelona Department of Clinical Sciences DOCTORATE IN MEDICINE Clinical and Experimental Neuroscience. Psychiatry and Mental Health Research Group (IDIBELL).. ALTERATIONS IN SOCIAL REWARD AND BODY PERCEPTION BRAIN CIRCUITS IN ANOREXIA NERVOSA: A FUNCTIONAL AND STRUCTURAL NEUROIMAGING INVESTIGATION. DOCTORAL THESIS ESTHER VIA VIRGILI. Supervisors: NARCÍS CARDONER ÁLVAREZ CARLES SORIANO-MAS Tutor: JOSÉ M. MENCHÓN MAGRIÑÁ. -SEPTEMBER 2015!.

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(5) Supervisors:! ! ! Dr.$Narcís$Cardoner$Álvarez$ $ Director!of!the!Depression!and!Anxiety!Program!&!OSAMCAT! Mental!Health!Department.!Parc!Taulí!Sabadell.!Hospital!Universitari! Universitat!Autònoma!de!Barcelona!(UAB)! Parc!Taulí!1!08208!Sabadell,!Barcelona,!Spain! Email:!ncardoner@tauli.cat!/!Tel:!+34937231010!. ! ! ! Dr.$Carles$Soriano$Mas$ $ Research!Group!Leader,!Laboratory!of!Neuroimaging!and!Mental!Health!! Department!of!Psychiatry,!Bellvitge!University!HospitalZIDIBELL! Feixa!Llarga!s/n!08907!Hospitalet!de!Llobregat,!Barcelona,!Spain! Email:!csoriano@idibell.cat/!Tel:!+34!932607500!ext!2864!. ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Doctors! Narcís! Cardoner! Álvarez! and! Carles! SorianoZMas! certify! that! they! have! guided! and! supervised!this!doctoral!thesis,!entitled!“ALTERATIONS!IN!BRAIN!CIRCUITS!FOR!SOCIAL!REWARD! AND! BODY! PERCEPTION! IN! ANOREXIA! NERVOSA:! A! FUNCTIONAL! AND! STRUCTURAL! NEUROIMAGING!INVESTIGATION”,!which!is!presented!in!order!to!obtain!the!title!of!doctor!by! the!candidate!Esther!Via.!They!thereby!assert!that!this!thesis!fulfills!all!the!required!criteria.! !. !.

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(7) L’homme sociale “Je!ne!mange!pas!de!pain.!Le!blé!pour!moi!est!inutile.!Les!champs!de! blé!ne!me!rappellent!rien.!Et!ça,!c'est!triste!!Mais!tu!as!des!cheveux!couleur!d'or.! Alors!ce!sera!merveilleux!quand!tu!m'auras!apprivoisé!!Le!blé,!qui!est!doré,!me! fera!souvenir!de!toi.!Et!j'aimerai!le!bruit!du!vent!dans!le!blé...!! Le!renard!se!tut!et!regarda!longtemps!le!petit!prince:!! Z!S'il!te!plaît...!apprivoiseZmoi!!ditZil.”! ! (Antoine!de!SaintZExupéry,!Le!Petit!Prince)!. Man and identity El!yo!individual!es!aquello!que!se!diferencia!de!lo!general,[…]!lo!que!no!puede!ser! adivinado!y!calculado!de!antemano,!lo!que!en!el!otro!es!necesario!descubrir,! desvelar,!conquistar.! ! (Milan!Kundera,!La!insoportable!levedad!del!ser)! ! ! ! Be!yourself;!everyone!else!is!already!taken.! ! (Oscar!Wilde). !.

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(9) The importance of this work lies in the person that one day will sit in front of you…. …the patient.. !.

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(11) Table of contents! !"#$%"#&'(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((')*' +,-."%/$&0$1$.23'(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((')4' 5632'"7'899#$:6826".3'((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((');' <=8>2$#')?'@.2#"&A,26".'((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((')B' "#!$%&'()*+!%(',&-+!###################################################################################################################!."! .#!/0*1(2*&3&45!#########################################################################################################################!..! 6#!783%('+9*3*:5!;+<:&'-!*%!$=!(:*&3&45!#######################################################################################!.6! !"#"$%&'&()*+$,'-$.&/)(,0)1)(2$"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$3!! !"3"$4&/+5',1)(2$""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$3!! !"!"$65*),1$,'-$*71(7/,1$8,*(5/+$"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$39! !"9"$:&7/5-&;&15<=&'(,1$8/,=&>5/?$""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$39! >#!?'+*%!%(:@&'A-!*%,&3,(1!*%!:B(!0+:B&0B5-*&3&45!&;!$=!########################################################!.C! 9"#"$@1(&/,()5'+$)'$0/,)'$*)/*7)(+$<7(,();&12$7'-&/12)'A$,1(&/,()5'+$)'$05-2$-)+(5/()5'$"""""""""""$3B! 9"#"#"$C&8)')()5'$,'-$*5'*&<(7,1)D,()5'$58$05-2$-)+(5/()5'$"""""""""""""""""""""""""""""""""""""""""""""""""$3B$ 9"#"3"$C&+*/)<()5'$58$(.&$'&7/5,',(5=)*,1$<,(.>,2$58$05-2$<&/*&<()5'$"""""""""""""""""""""""""""$3E$ 9"#"!"$:&7/5*5A')();&$,1(&/,()5'+$/&1,(&-$(5$,0'5/=,1$05-2$<&/*&<()5'$)'$@:$""""""""""""""""""$3F$ 9"#"9"$G7'*()5',1$HIJ$8)'-)'A+$/&1,(&-$(5$,0'5/=,1$05-2$<&/*&<()5'$)'$@:$"""""""""""""""""""""""$3K$ 9"#"L"$M5-2$)=,A&N$)-&'()(2N$/&1,()5'$(5$(.&$>5/1-$,'-$+5*),1$*5==7')*,()5'$"""""""""""""""""""$!O$ 9"3"$I&>,/-$,'-$=5();,()5'$"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!#! 9"3"#"$I&>,/-$+2+(&=$)'$(.&$0/,)'P$/&+<5'+&+$(5$-)88&/&'($+()=71)$""""""""""""""""""""""""""""""""""""""$!#$ 9"3"3"$I&>,/-$,'-$<7')+.=&'($"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!3$ 9"3"!"$@1(&/,()5'+$58$(.&$/&>,/-$+2+(&=$)'$@:$""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!!$ 9"3"9"$65*),1$)'(&/,*()5'+$)'$@:$,'-$)(+$/&1,()5'+.)<$>)(.$/&>,/-$,'-$<7')+.=&'($""""""""""""$!9$ 9"3"L"$67==,/2$58$87'*()5',1$HIJ$8)'-)'A+$""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!9$ 9"3"B"$J'(&A/,()5'$58$/&>,/-$+2+(&=$,1(&/,()5'+$(5$,$-2+87'*()5',1$MJ6PM@6$+2+(&=$""""""""""$!9$ 9"!"$65*),1$*5A')()5'$'&(>5/?$"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!L! 9"!"#"$65*),1$)=<,)/=&'($)'$@:$"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!L$ 9"!"3"$C&8)')()5'$58$(.&$+5*),1$*5A')()5'$+2+(&=$""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!B$ 9"!"!"$6&18P/&8&/&'*&N$(.&$-&8,71($=5-&$'&(>5/?$,'-$(.&)/$/&1,()5'+.)<$>)(.$+5*),1$*5A')()5' $""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""$!E$ !.

(12) 4.3.5.&Summary&of&functional&MRI&findings&........................................................................&37& 4.4.&Network&identification&in&structural&MRI&studies&............................................................&38! 5.!Main!questionnaires!used!in!this!work!..................................................................................!49! 5.1.&Eating&Disorder&Inventory&(EDIP2)&....................................................................................&49! 5.2.&Temperament&and&Character&Inventory&(TCIPR)&..............................................................&49! 5.3.&The&Sensitivity&to&Punishment&and&Sensitivity&to&Reward&Questionnaire&(SPSRQ)&..........&49! 6.!Neuroimaging!methods!and!techniques:!..............................................................................!49! 6.1.&Magnetic&resonanceP&Structural&analyses&(sMRI)&............................................................&51! 6.1.1.&Principles&of&MRI&....................................................................................................................&51& 6.1.2.&VoxelPbased&morphometry&(VBM);&DARTEL&normalization&....................................................&51& 6.1.3.&Diffusion&tensor&imaging&(DTI)Pquantitative&..........................................................................&51&. 6.2.&Functional&magnetic&resonance&(fMRI)&...........................................................................&52! 6.2.1.&TaskPbased&BOLD&signal&differences&between&conditions&......................................................&52& 6.2.2.&TaskPbased&connectivity&analyses:&analysis&of&Psychophysiological&interaction&analysis&(PPI)52& 6.2.3.&TaskPindependent:&functional&resting&state&connectivity&analyses&........................................&53& 6.2.3.1.&Resting&state&networks&(RSN)&–&default&mode&network&(DMN)&.....................................&53&. 6.3.&Statistical&correction&in&sMRI&and&fMRI&studies&...............................................................&53! 6.3.1.&Corrected&versus&uncorrected&values&.....................................................................................&53& 6.3.2.&Voxel&versus&cluster&significance&............................................................................................&54&. 6.4.&Accounting&for&confounding&factors&in&MRI&studies&........................................................&54! 6.5.&Summary&and&unanswered&questions&.............................................................................&56!. Chapter$2:$Aims$and$hypotheses$..............................................................................$57$ 1.!Aims!.......................................................................................................................................!59! 2.!Hypotheses!............................................................................................................................!60!. Chapter$3:$STUDY$1:$Disruption$of$brain$white$matter$microstructure$in$women$with$ anorexia$nervosa$.....................................................................................................$61$ Chapter$4:$STUDY$2:$Abnormal$social$reward$responses$in$anorexia$nervosa:$an$fMRI$ study$.......................................................................................................................$75$ Chapter$5:$STUDY$3:$Default$mode$network$alterations$during$selfSother$body$ perception$and$restingSstate$in$anorexia$nervosa$..................................................$101$ Chapter$6:$Summary$of$results$...............................................................................$147$ Chapter$7:$General$discussion$................................................................................$151$ 1.!PrefrontoZparietal!system!....................................................................................................!153! !.

(13) 2.!RewardZinhibition!system!and!social!motivation!................................................................!155! 3.!Body,!self,!other,!reward!and!social!relationships.!Integration!within!previous!models!and!the! new!contribution!of!the!present!results.!.................................................................................!157! 4.!Global!considerations!..........................................................................................................!158! 5.!Future!investigations!...........................................................................................................!159! 6.!Limitations!...........................................................................................................................!160!. Chapter$8:$General$conclusions$..............................................................................$161$ Chapter$9:$Summary$in$Catalan$SResum$en$català$..................................................$165$ Reference$list$.........................................................................................................$187$ Appendices$............................................................................................................$207$ List!of!publications!...................................................................................................................!209! Curriculum!vitae!......................................................................................................................!211! ! ! !. ! ! !. $ $ $ $. !.

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(15) Foreword$ The!work!presented!in!this!Doctoral!Thesis!was!undertaken!in!the!Neuroimaging!group,!at!the!Psychiatry! department!Z!Bellvitge!University!Hospital!and!Bellvitge!Biomedical!Research!Institute!(IDIBELL,!Catalan! acronym),! Barcelona,! Spain.! It! was! conducted! in! collaboration! with! the! Melbourne! Neuropsychiatry! Center,! Melbourne,! Australia,! and! within! the! framework! of! the! Ciències! Clíniques! group,! University! of! Barcelona,!Medical!school,!Barcelona,!Spain.! Enclosed!are!two!peerZreviewed!published!journal!articles!and!a!third!one!in!review.!It!has!been!written! in!accordance!with!the!procedures!indicated!by!the!University!of!Barcelona!and!it!is!presented!in!order! to! obtain! the! International! Doctorate! title,! which! is! granted! by! this! Institution.! The! supervisors! of! this! Thesis!are!Dr.!Narcis!Cardoner!and!Dr.!Carles!SorianoZMas,!and!Dr.!JM!Menchón!Magriñá,!the!tutor.! Personal! funding! for! this! work! includes:! IDIBELL! Scholarship! (2010Z2013),! personal! contract! linked! to! a! research! project! (2013Z2014)! and! Endeavour! Research! Scholarship,! Australian! education! department! (2014Z2015).! Project! funding! is! dependent! on! the! Institute! Carlos! III! (Ministry! of! Economy! and! Competitiveness,!Spain),!grants:!PI!081549,!PI!11210.!! The! present! work! includes,! in! the! following! order:! a! general! introduction,! aims! and! hypotheses,! the! three!original!articles,!a!summary!of!results,!a!general!discussion!with!a!presentation!of!a!new!theoretical! model!based!on!the!findings,!conclusions,!a!summary!in!Catalan!and!list!of!references.! These!years!of!research!have!produced!several!scientific!articles.!Among!those,!the!ones!included!in!this! work:! 1.$Disruption$of$brain$white$matter$microstructure$in$women$with$anorexia$nervosa.$ Via!E,!Zalesky!A,!Sánchez!I,!Forcano!L,!Harrison!BJ,!Pujol!J,!FernándezZAranda!F,!Menchón!JM,!SorianoZ Mas!C,!Cardoner!N,!Fornito!A.!J!Psychiatry!Neurosci.!2014!Nov;39(6):367Z75.! 2.$Abnormal$Social$Reward$Responses$in$Anorexia$Nervosa:$An$fMRI$Study.$ Via!E,!SorianoZMas!C,!Sánchez!I,!Forcano!L,!Harrison!BJ,!Davey!CG,!Pujol!J,!MartínezZZalacaín!I,!Menchón! JM,!FernándezZAranda!F,!Cardoner!N.!PLoS!One.!2015!Jul!21;10(7):e0133539! 3.$Default$Mode$Network$alterations$during$selfSother$body$perception$and$restingSstate$in$anorexia$ nervosa.$ ! Esther!Via,!Ximena!Goldberg,!Isabel!Sánchez,!Laura!Forcano,!Ben!J!Harrison,!Christopher!G.!Davey,!Jesús! Pujol,!Ignacio!MartínezZZalacaín,!Fernando!FernándezZAranda,!Carles!SorianoZMas,!Narcís!Cardoner,!José! M.!Menchón.!In!review,!Social!Cognitive!and!Affective!Neuroscience!Journal.!! In!addition,!these!results!have!been!presented!in!several!international!congresses!as!poster!and!abstract! publications:! Society! of! Biological! Psychiatry,! May! 2014,! New! York;! European! Congress! of! Psychopharmacology,! Barcelona,! 2013;! European! Congress! of! Psychopharmacology,! Vienna,! 2012;! International! Conference! on! Eating! Disorders,! Austin,! Texas,! USA,! 2012.! Moreover,! portions! of! them! were!presented!as!an!oral!presentation!(Dr.!Fernando!FernándezZAranda)!in!the!SIPB!Società!Italiana!di! Psichiatria!Biologica,!Naples,!Italy,!September!2013.!. Doctoral!ThesisZ!Esther!Via!!. !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Foreword!!. !. 13!.

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(17) Acknowledgements$ Voldria agrair a tota la gent sense la qual aquest treball no hagués estat posible, i que espero contribueixi a la recerca actual en anorexia nerviosa. En primer lloc, a les pacients amb anorèxia nerviosa, sobretot a aquelles que van participar en aquest estudi. Espero, sincerament, que el camí us hagi conduït a un lloc millor. Gràcies també a tots els controls sans que van atrevir-se a col.laborar amb nosaltres. Als directors de tesi, Narcís i Carles, Carles i Narcís, aquells genios locos. Per ser tant complementaris i haver-los enganxat en el seu millor moment com a parella professional. Narcís, des dels primers dies buscant-te pels passadissos de la sisena planta fins a avui. Gràcies per la confiança i per l'aposta, tot i que no sempre ha estat fàcil. Mil gràcies per les teves idees i saber escoltar. Carles, amb tu vam començar junts la neuroimatge a Bellvitge, amb tot de canvis i no poc esforç. El primer dia, aprop de Nadal, va ser la meva primera vegada de fer anar allò tant anomenat, SPM, amb les teves instruccions telefòniques mentre compraves regals. És la mostra de tanta dedicació, de tot el que m'has ensenyat, sempre amb aquella broma a punt. Gràcies als dos per la implicació que heu tingut amb mi, no només amb la feina, us agraeixo que hàgiu estat presents i ajudat una mica més enllà. Gràcies per la formació en neuroimatge, que estaré molt orgullosa de dir que he fet amb vosaltres. Al tutor de tesis, cap de departament i director científic d’IDIBELL, Dr Menchón. Gràcies pel lideratge, per donar-me l’oportunitat de treballar en el grup i per comptar amb mi per la recerca, per acollir-me i donar-me suport en la beca que m’ha permès estar fent aquest camí a l’Hospital. Gràcies a la Unitat de Trastorns de l'alimentació. Gràcies Fernando per estar sempre pendent, per estar disposat a escoltar i ajudar, per la motivació per la recerca i per obrir-nos la oportunitat de conèixer d’aprop les pacients amb aquest trastorn. Isabel, gràcies per la teva participació, per les ganes, les idees, la companyia i la motivació pel canvi. Un gran agraïment també als professionals de la unitat de MRI de l’Hospital del Mar, liderat per Jesús Pujol, que tant d’esforç i hores han dedicat en tota aquesta feina. També, i sobretot, per la participació en les idees i els disenys dels estudis. Ben Harrison, thank you for giving me the opportunity to work with you at the MNC, twice!, the first time without even knowing me. You have taught me many important things about research, in a broad sense, which I expect to be ‘carrying’ with me whatever the circumstances of research. Thank you because Melbourne is already like a second home for me. Alex Fornito, Andrew Zalesky, thank you for the opportunity to work with a completely new technique at the MNC; you greatly contributed to make the most of it in a very short time. To the rest of co-authors of the articles, thank you for your work in the studies, ideas, questions and suggestions! Your contribution in the design, patient recruitment and preparation of the articles themselves made possible the present work. Als coPhds i altres becaris i estudiants del despatx. Clara i Marta, excel·lents professionals i millors amigues. Clara, gràcies per ser aquell puntal tant important en els moments més difícils, aportar aquells granets de serenitat, comprensió i escolta. Marta, companya d'aquest 'perfil professional' que ens agrada i ens fa enyorar altres coses, colze a colze, moltes gràcies pel sentit comú i el pràctic, escoltar i estar present. Rosa, gràcies per l’entusiasme, per tirar endavant amb tot, per la presència i, sobretot, perquè per tu va ser que vaig pensar que la. Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Acknowledgements!. !15!.

(18) neuroimatge tenia el seu què. Als altres, Nacho, que vas entrar casi al mateix temps amb mi, amb l’E-Prime i el LCF, gràcies per salvar-nos d’alguns lios tècnics!.. Ximena, Marta Cano, Andrés, Arantxa,... gràcies!. També a Ester Cerrillo, Vero i Eva, les altres embolicades en tot aquest món de la recerca, per la vostra persistència i esforç, pels vostres consells i seguir en el que crèieu. Gràcies a tots els altres companys clínics. Tot i que fora de la tesi, gràcies per tot el que em vau enseyar, durant la residència, del món de la psiquiatria i sobre com ser un bon professional. No puc oblidar el David Mataix i el Quim Raduà. Va ser amb ells amb qui vaig tenir la meva primera experiència en recerca. Us agraeixo haver-ho fet tant fàcil, ensenyar-me amb paciència i metòdicament tots els passos per fer un article i el que significa la recerca. No ho oblido. Gràcies als amics, als que han vingut i marxat, als que encara hi són, als que hi han estat sempre i als que han tornat!…i sobretot als que, a més a més han estat companys de pis i han viscut d’aprop el procés de la tesi, Guns, Pel, Aingeru, provaAna, Ben, Athena, Simon,... Ben, this work was always present; thank you for your inconditional support and acceptance in every sense, irrespective of the length of the distance and changes of life circunstances, I can’t be more thankful for all of what I learned. Valentina! Thank you for your support, your suggestions, for believing in me and empowering me! Thank you for your deep honest friendship. A big thank you to the rest of the MNC and Melbourne family! A la meva família, la gran i, també, el nucli petit, Josep, Elisa, Cristina i Víctor. La família no s’escull, però si ho hagués hagut de fer, no n’hagués pogut trobar una de millor! El suport que em doneu és sempre incondicional, i espero algun dia poder-vos retornar tot el que heu fet per mi.. Finalment, gràcies per tot el que he après de vosaltres. Me n’alegro que aquesta feina també ha contribuït a canviar una part de mi.. Per les coses que es guanyen i les que es queden pel camí, que en fan créixer d’altres. !. Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Acknowledgements!. !16!.

(19) List$of$abbreviations$ ACC$ AI$ Amy$ AN$ BMI$ Cau$ CCQ$ DLFPC$ DTI$ DWI$ EBA$ EDIS2$ FA$ FBA$ FEye$ FFA$ fMRI$ HTH$ ICA$ IFG$ IPC$ LSAS$ MD$ MFG$ MNS$ mPFC$ MRI$ OFC$ OT$ Pc$ PCC$ PFC$ PPC$ PPI$ PMC$ Put$ RHI$ SMFG$ sMRI$ SPC$ SPM$ SPSRQ$ SSens$. !anterior!cingulate!cortex! !anterior!insula! !amygdala!! !anorexia!nervosa! !body!mass!index! !caudate! !crossZcultural!questionaire!! !dorsolateral!prefrontal!cortex! !diffusion!tensor!imaging! !diffusion!weighted!imaging!! !extrastriate!body!area!! !eating!disorder!inventory! !fractional!anisotropy! !fusiform!body!area!! !frontal!eye!fields! !fusiform!face!area! !functional!magnetic!resonance! !hypothalamus! !independent!component!analysis! !inferior!frontal!gyrus! !inferior!parietal!cortex! !liebowitz!Social!Anxiety!Scale! !mean!diffusivity! !middle!frontal!gyrus!! !mirror!neuron!system!! !medial!prefrontal!cortex! !magnetic!resonance!imaging! !orbitofrontal!cortex! !occipitoZtemporal!cortex!! !precuneus!! !posterior!cingulate!cortex! !prefrontal!cortex! !posterior!parietal!cortex! !psychophysiological!interaction! !premotor!cortex! !putamen! !rubber!hand!illusion!! !superior!medial!frontal!gyrus!! !structural!magnetic!resonance! !superior!parietal!cortex!! !statistical!parametric!mapping! !sensitivity!to!punishment!and!sensitivity!to!reward!questionnaire! !somatoZsensorial!cortex!. Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!List!of!abbreviations!. !!!!!!. !. !. !!!!!!!!!!!!17!.

(20) STS$ TCISR$ ToM$ TPJ$ V1$ VBM$ vlPFC$ vmPFC$ vPMC$ VS$ MR$ MRI$ DMN$. !superior!temporal!sulcus! temperament!and!character!inventory! !theory!of!mind! !temporoZparietal!junction!! !primary!visual!cortexZarea!V1! !voxelZbased!morphometry! !ventrolateral!prefrontal!cortex! !ventromedial!prefrontal!cortex! !ventral!premotor!cortex! !ventral!striatum! magnetic!resonance! magnetic!resosonance!imaging! default!mode!network!. $ ! !! ! ! ! ! ! ! ! ! !. $ $ $ $ Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!List!of!abbreviations!. !!!!!!. !. !. !!!!!!!!!!!!18!.

(21) "#$%&'(!!!. )! INTRODUCTION.

(22) !!.

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

(25) 3.!Vulnerability!factors!in!AN!etiology!! In!the!widely!accepted!multifactorial!model!of!AN,!both!genetic/heritable!and!social/cultural!factors,!in! conjunction! with! certain! personality! traits,! are! considered! vulnerability! factors.! There! is! a! complex! interplay!between!psychological,!environmental!and!neurodevelopmental!factors!which!may!trigger!and! maintain!the!disorder.!!. 3.1.!Genetics!and!heritability! There!is!a!substantial$genetic$component!in!the!etiology!of!AN,!suggested!by!strong!familiar!aggregation,! the!crossZcultural!presence!of!the!disorder!and!the!estimated!heritability$percentages!from!twin!studies,! ranging!between!50$to$80%!(Brandys!et!al.,!2015;!Bulik!et!al.,!2006).!Additionally,!there!is!an!aggregation! with! other! psychiatric! disorders;! for! example,! there! is! an! increased! risk! of! affective! disorders! within! family!members!of!patients!with!AN!(Steinhausen!et!al.,!2015).!! As!it!is!the!case!for!other!mental!disorders,!there!is!no!evidence!for!large!effect!stemming!from!singleZ gene!mutations,!and,!instead,!it!has!been!suggested!that!development!of!AN!may!be!due!to!the!additive! presence!of!small$effects$involving$multiple$genes,$in$conjunction$with$environmental$factors$affecting! their!expression.!In!this!context,!a!few!alterations!in!singleZnucleotide!polymorphisms!(SNPs)!have!been! reported,!for!example!related!to!bodyZweight!regulation!hormones,!oxytocin!and/or!serotoninergic!and! dopaminergic!transmission,!among!others!(CastroZFornieles,!2015;!Trace!et!al.,!2013),!although!there!is!a! long! way! to! explore! (Brandys! et! al.,! 2015).! Most! likely,! an! inheritable$ phenotype$ of$ continuous$ behavioural$traits!might!be!present!in!AN!(Connan!et!al.,!2003).!. 3.2.!Personality! Some! personality! traits! have! been! found! to! be! characteristic! of! AN,! and! some! studies! have! suggested! that!they!occur$prior$to$the$development$of$the$disorder$and$persist$after$symptom$recovery!(Casper,! 1990;!Kaye!et!al.,!2013;!Srinivasagam!et!al.,!1995;!Wagner!et!al.,!2006b).!Most!of!these!traits!are!linked! to!anxiety$and$neurotic$or$obsessive$personality$traits,!such!as!harm$avoidance,$perfectionism,$rigidity$ or$obsessionality!(Anderluh!et!al.,!2003;!Friederich!and!Herzog,!2011;!Kaye!et!al.,!2013;!Lilenfeld!et!al.,! 2006).! Other! suggested! predisposing! factors! are! poor$ interoceptive$ awareness$ and$ alexithymia,$ high$ drive$for$thinness$and$ineffectiveness!(Beadle!et!al.,!2013;!Espina,!2003;!Kaye!et!al.,!2013;!Lilenfeld!et! al.,!2006).!It!is!also!relevant!to!highlight!the!high$comorbidity$with$anxiety$disorders!(Kaye!et!al.,!2004)! and! the! high! prevalence$ of$ anxiety$ symptoms$ or$ diagnoses,$ mostly$ for$ social$ anxiety$ disorder,$ even$ before$disorder$onset!(Godart!et!al.,!2000;!Kaye!et!al.,!2004).!Finally,!obsessiveZcompulsive!traits!have! been!associated!with!a!worse$outcome!(Crane!et!al.,!2007).! ! In!relation!to!diagnostic!subtypes,!the!few!studies!that!evaluated!personality!trait!differences!found!that! the! restrictive$ subtype$ presented! higher! anticipatory$ worry$ and$ persistence$ but$ low$ attachment! (a! subdimension! of! reward! dependence)! and! selfZdirectness! (Fassino! et! al.,! 2002).! By! contrast,! bingeS purging$ subtype$ AN! patients! are! considered! to! represent! the! most$ impulsive$ group! of! patients! in! the! spectrum!of!AN!(Brooks!et!al.,!2011;!DaCosta!and!Halmi,!1992).!Nevertheless,!at!least!one!study!did!not! find!any!difference!between!diagnostic!subgroups!(Anderluh!et!al.,!2003).!! !. Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Chapter!1Z!Introduction!. !!!!23!.

(26) 3.3.!Social!and!cultural!factors! AN!has!been!described!in!all!cultures,!and!previous$debates$about$it$being$a$cultureSbound$syndrome$ have$been$refuted!(Keel!and!Klump,!2003).!However,!cultural$influences$on$AN$are$well$recognized.!For! example,!two!studies!about!the!incidence!of!AN!in!the!Netherlands!Antilles!(Curaçao)!(Hoek!et!al.,!2005)! and!among!Netherlands!Antilles!natives!living!in!the!Netherlands!(van!Hoeken!et!al.,!2010)!showed!that,! while!the!incidence!of!AN!in!the!black!population!of!Curaçao!was!nil,!within!the!minority!of!mixed!and! white!population!it!was!similar!to!those!described!in!the!Netherlands.!Moreover,!among!those!migrated! to! the! Netherlands,! the! incidence! was! similar! as! compared! to! native! Dutch.! Authors! pointed! to! the! influence! of! the! Western$ idealization$ of$ thinness,! as! well! as! possible! migrationZrelated! stress! effects! (van! Hoeken! et! al.,! 2010)! as! causative! factors.! However,! some! diagnostic! criteria! should! probably! be! reconsidered! to! better! adjust! to! different! expressions! of! the! disorder! across! cultures,! for! example,! in! black!populations!(Taylor!et!al.,!2013).!!. 3.4.!Neurodevelopmental!framework! The! neurodevelopmental! framework! suggests! that! some! predisposing$ factors,! in! addition! to! environmental$effects,!create!a!continuum$of$vulnerability!features,!with!the!disorder!establishing!itself! after!surpassing$a$specific$threshold$[multifactorial$threshold$model,$(Connan!et!al.,!2003;!Kaye!et!al.,! 2009)].!In!this!context,!certain!developmental!periods!are!more!prone!to!the!emergence!of!AN,!such!as! adolescence,! when! the! brain! undergoes! major! changes$ in$ development$ (important$ synaptogenesis,$ pruning$ and$ myelination).! Within! these! changes,! those! in! frontal$ and$ limbic$ circuits$ are! of! particular! relevance,!which!are!underpinning!the!integration!of!cognition!and!emotion!processing!(Connan!et!al.,! 2003;! Pfeifer! and! Peake,! 2012).$ For! example,! emotion$ recognition! and! cognitive$ control! improve! with! frontal$ efficiency$ and$ associated$ functional$ and$ structural$ connectivity$ changes! (Liston! et! al.,! 2006;! McGivern!et!al.,!2002),!while!improvement!in!other!functions,!such!as!attentional$set$shifting!has!been! associated,! for! example,! with! volume! increase! in! the! anterior$ cingulate$ cortex! (Casey! et! al.,! 1997).! Importantly,! functional! and! structural! alterations! in! all! these! regions! have! been! suggested! to! be! relevantly!involved!in!AN!(Kaye!et!al.,!2009).!However,!there!is!a!lack!of!understanding!to!what!extent! these!factors!might!be!evidenced!in!adolescence!while!conforming!part!of!a!susceptibility$package,!or,! alternatively,! they! might! be! the! consequence$ of$ severe$ starvation$ during! a! sensitive! period! of! brain! development!(Connan!et!al.,!2003).!! Moreover,! adolescence! is! a! period! during! which! major! changes$ in$ psychological$ –including$ important$ changes$ in$ one’s$ own$ identity$ construction$ (Kłym! and! Cieciuch,! 2015;! Sollberger,! 2014)S$ and$ sociocultural$aspects,$as!well!as!purely$biological!factors!develop!within!the!individual.!These!changes! are! important,! among! other! aspects,! to! the! learning! about! social! relationships;! indeed,! developmental! changes!in!different!brain!areas!are!dedicated!to!improvement!in!social$information$processing.!Nelson! et! al.! (Nelson! et! al.,! 2005)! described! three! main! circuits! important! to! social! processes! which! develop! during! this! period,! namely:! a! ‘detecting$ node’! (fusiform! area,! superior! temporal! sulcus! and! anterior! temporal! lobe,! already! mature! by! adolescence),! an! ‘affective$ node’,! (amygdala,! the! hypothalamus,! ventral!striatum,!septum,!orbitofrontal!cortex!and!bed!nucleus!of!the!stria!terminalis),!and!a!‘cognitiveS regulatory$ node’! (dorsomedial! prefrontal! cortex! and! ventral! prefrontal! cortex).! In! addition,! developmental! changes! associated! with! fear$ learning! and! habituation$ to$ changes$ and$ novelty! might! also!be!relevant!to!the!consolidation!of!these!circuits!in!adolescence!and!associated!to!some!personality$ traits$ linked$ to$ AN! (high! harm! avoidance,! low! novelty! seeking! and! low! reward! dependence)! (Strober,! Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Chapter!1Z!Introduction!. !!!!24!.

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

(28) Maudsley! Hospital! and! Institute! of! Psychiatry! –IOPZ! in! London,! UK! (Prof.! Janet$ Treasure! and! Dr.! Kate$ Tchanturia),!is!centred!on!alterations!in!cognitive$and$socioSemotional$domains!in!AN!(Oldershaw!et!al.,! 2011;!Tchanturia!et!al.,!2014).! In!recent!years,!the!arrival!of!new!available!therapies!in!psychiatry,!such!as!deep$brain$stimulation$(DBS)$ or$transcranial$magnetic$stimulation$(TMS)!recently!applied!to!patients!with!AN![see!(McClelland!et!al.,! 2013)],! has! stressed! the! need$ of$ better$ networkSbased$ models$ of$ the$ underlying$ pathophysiology$ of$ AN.!Indeed,$an!intense!debate!has!emerged!about!the!opportunity!and!ethical!implications!of!applying! these! techniques! without! conclusively! defined! neurobiological! models! of! the! disorder! (Coman! et! al.,! 2014;! Oudijn! et! al.,! 2013).! At! present,! data! from! neurocognitive! and! imaging! studies! suggest! that! patients! with! AN! have! impairments! in! neural! systems! implicated! in! executive$ functions,! visuoSspatial$ processing,! selfSimage$ perception,! fear$ and$ anxiety,$ (socioS)$ emotional$ regulation! and! reward$ processing! (Kaye! et! al.,! 2009).! In! the! following! lines,! and! with! the! purpose! of! introducing! the! three! studies! presented! in! this! work,! alterations! in! visuoZspatial! processes! and! selfZimage! perception! within! the!framework!of!body$perception,!as!well!as!alterations!in!reward$and$socioSemotional$processing!and! the!brain!networks!subserving!these!functions!will!be!reviewed.!. 4.1.!Alterations!in!brain!circuits!putatively!underlying!alterations!in!body!distortion! 4.1.1.$Definition$and$conceptualization$of$body$distortion$ Body$ distortion! is! a! core$ feature! ofZ! and! a! required! diagnostic! criterion! forZ! AN! (American! Psychiatric! Association,! 2013;! American! Psychiatric! Association! and! Association,! 2000).! Relevantly,! the! specific! evaluation!of!this!symptom!is!not!only!key!for!the!diagnosis!of!AN!but!is!also!a!putative!marker$of$eating$ disorders$ (Gardner! and! Bokenkamp,! 1996)! and! its! development$ (Jacobi! et! al.,! 2004),! as! well! as! a! predictor! of! relapse! (Keel! et! al.,! 2005).! It! describes! the! overestimation$ of$ body$ representation,! specifically! defined! as! a! “Disturbance! in! the! way! in! which! one’s! body! weight! or! shape! is! experienced,! undue! influence! of! body! weight! or! shape! on! selfZevaluation,! or! persistent! lack! of! recognition! of! the! seriousness! of! the! current! low! body! weight”! (American! Psychiatric! Association,! 2013;! American! Psychiatric! Association! and! Association,! 2000),! or! a! “dread! of! fatness! that! persists! as! an! intrusive,! overvalued! idea”! (World! Health! Organization! (WHO),! 1992).! ! It! becomes! noticeable! in! the! literature,! however,!that!this!conceptualization!is!rather!vague!and!the$nature$of$body$image$distortion$has$long$ been$ controversial.! Partially,! this! problem! arises! from! its$ complexity! and! the! lack$ of$ a$ wellSdefined$ concept$of$body$representation!in!nonZclinical!populations!(de!Vignemont,!2010).!! Evidence!from!neurological!damage!to!the!brain!and!neurocognitive!evaluations!have!distinguished!two! main! components! of! body! perception:! one! for! postural! and! sensory–motor! capacities,! involving! action! (body!schema)!and!another!including!a!broad!system!of!perceptions,!attitudes!and!beliefs!pertaining!to! one’s! own! body! and! involved! in! the! sense! of! body! ownership! and! selfZconsciousness! (body! image)! (Berlucchi! and! Aglioti,! 1997;! Berlucchi! and! Aglioti,! 2010;! Gallagher,! 2005).! Most! definitions! in! AN! have! mainly! focused! on! alterations! of! body$ image,! conceptualized! in! two! main! subcomponents:! lowSlevel$ perceptual! processing! (e.g.! involving! body! size! and! weight! estimation)! and! a! higherSorder$ attitudinal! component,!which!involves!attitudes$and$feelings$towards$the$body!(Cash!and!Deagle,!1997;!Fernández! et!al.,!1994;!Fisher!and!Cleveland,!1958;!Skrzypek!et!al.,!2001).!In!other!words,!‘sensory$and$nonSsensory$. Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Chapter!1Z!Introduction!. !!!!26!.

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c76I>+5$("F("5+\,(G"6E(,-R+?(,*&2+(&56(G"6E(O+-I*$(%+'&$-H+( $"(&#$7&'(2%"2"%$-"5,(:-5F+%-"%(2&%-+$&'(#"%$+M?(2%+#75+7,(&56("##-2-$".$+>2"%&'(#"%$+MB( 8C =>>;M8NO;. MPQKPR;R8S( VFF+#$-H+( %+,2"5,+( $"( "5+d,( "O5( G"6ET( F++'-5I,( &56( ,&$-,F&#$-"5W6-,,&$-,F&#$-"5( "F( "5+\,( "O5( G"6EC( :2%+F%"5$&'( #"%$+M.-5,7'&.&>EI6&'&( .&56( V11(&56(H+5$%&'(,$%-&$7>B YC MPGRN8NO;.MPQKPR;R8S(<+'-+F,(#"5#+%5-5I(G"6E(->&I+(&56(&22+&%&5#+?(&,(O+''(&,($*+( >+5$&'( %+2%+,+5$&$-"5( "F( "5+\,( "O5( G"6EC( :'&#=( "F( ,$76-+,C( &>EI6&'&?( $*+( >+6-&'( 2%+F%"5$&'(#"%$+M(&56($*+(2",$+%-"%(:-5F+%-"%B(2&%-+$&'(#"%$+MB(. X/D1/X)SVe( X/D1/X)SVe ( V))4)S!4fVe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`(H,(_&$$-$76-5&'`("%(_+>"$-"5&'`(&56(_#"I5-$-H+`?(,-5#+(&''(#">2"5+5$,( &%+(-5H"'H+6(-5($*+(2+%#+2$7&'(+M2+%-+5#+C(["O+H+%?($*+(>",$(F%+Z7+5$'E(%+2"%$+6($+%>,(O-''(G+(7,+6(-5($*-,(O"%=C( 8 (45($*+(%7GG+%(*&56(-'7,-a5?(2&%$-#-2&5$,(H-+O(&(%7GG+%(*&56(2'&#+6(-5(F%"5$("F($*+>?(,'-I*$'E($"("5+(,-6+(G7$(-5(&(,->-'&%(2",-$-"5($"($*+-%("O5( *&56?(*-66+5(F%">(H-+OC(<"$*($*+(%7GG+%(*&56(&56($*+(2&%$-#-2&5$\,("O5(*&56(&%+($*+5(,$%"=+6?(+-$*+%(,E5#*%"5"7,'E("%(&,E5#*%"5"7,'EC(b*+5(. !"#$"%&'()*+,-,.(/,$*+%(0-&((((((((((((((((((((((((((((((((1*&2$+%(3.(45$%"67#$-"5(. ((((89(.

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(31) 2014;!Skrzypek!et!al.,!2001;!Smeets!et!al.,!1999).!Indeed,!one!important!critique!of!the!models!used!to! evaluate!alterations!in!body!size!perception!in!these!experiments!is!the!lack!of!a!direct!comparison!with! a!picture!of!the!body!size!of!the!affected!person,!but!rather!rely!on!the!body!size!storage!that!she/he!has! in! her/his! memory! (Stein! and! Corte,! 2003).! However,! most! of! the! authors! would! agree! in! that! body! distortion!is$not$a$perceptual$disturbance$per(se!(Skrzypek!et!al.,!2001).! Alterations! of! body! image! processing! in! AN! have! mostly! been$ evaluated$ through$ the$ presentation$ of$ own$sizeSdistorted$body$image.$However,!this!response!seems!to!be!highly!variable,!with!overZ!but!also! underestimation! of! body! sizes! (Hennighausen! et! al.,! 1999;! Probst! et! al.,! 1995),! or! no! differences! (Gardner! and! Brown,! 2014).! This! variability! of! results! is! suggested! to! be! related! to! either! different! methodological! approaches! (Gardner! and! Bokenkamp,! 1996),! to! the! putative! presence! of! altered$ perception$in$a$more$severe$group$of$patients!(Skrzypek!et!al.,!2001),!to!the!influence$of$interceptive$ awareness! on! body! size! estimation! (Kaye! et! al.,! 2009;! Waldman! et! al.,! 2013),! or! to! a! lack$ of$ differentiation$between$the$perceptive$and$the$affective/cognitive$components!(Madsen!et!al.,!2013).! In! this! context,! however,! there! is! at! least! one! clear! cognitive$ bias,$ which$ allows$ for$ the$ accurate$ estimation$ of$ another’s$ body$ shape! estimation! as! opposed! to! an! inaccurate$ estimation$ of$ one’s$ own! body!shape!(Benninghoven!et!al.,!2007;!Vartanian!and!Germeroth,!2011).!! ! To! evaluate! perceptive! functions! irrespective! of! the! interference! of! different! functions! associated! with! body! processing,! some! other! studies! evaluated! visuoSspatial$ cognitive$ functions! irrespective$ of$ body$ size,!mostly!using!the!corresponding!subscores!of!the!Wechsler!Adult!Intelligence$Scale!(Wechsler,!2008)!! and! the! Rey–Osterreith! Complex! Figure! (RCFT,! (Meyers! and! Meyers,! 1995)),! which! suggested! subS optimal$performance!in!AN$and$at$riskSpopulations!(Madsen!et!al.,!2013),!although!the!interpretation!of! these!findings!in!the!context!of!body!(visual)!perception!is!unclear.!For!example,!RCFT!is!often!used!to! evaluate!alterations!in!central$coherence,!a!specific!perceptual!cognitive$style!which!describes!enhanced! attention! to! local! details! at! the! expense! of! global! processing! (Lopez! et! al.,! 2009),! which! has! been! observed! in! both! active$ and$ recovered$ AN! participants! and! their! unaffected! sisters,! and! in! adults$ and$ adolescents! (Roberts! et! al.,! 2013;! Tenconi! et! al.,! 2010).! Interestingly,! a! few! studies! have! suggested! instead! greater! difficulties! in! the! integration$ of$ multimodal$ information! [i.e.! visualZtactile! and! visuoZ propioceptive!(Case!et!al.,!2012;!Keizer!et!al.,!2011)];!for!example,!AN!patients!underestimated!whether! an! aperture! was! wide! enough! to! pass! through! in! Guardia! et! al.! and! Keizer! et! al.! (Guardia! et! al.,! 2010;! Keizer!et!al.,!2013),!or!presented!increased!sensitivity!to!the!and!rubber!hand!illusion2!!in!Eshkevari!et!al.! (Eshkevari!et!al.,!2012).!However,!further!research!in!this!area!will!be!needed.! ! In! summary,! there! is! no! conclusive! evidence! of! purely! perceptive! (or! bottomZup)! alterations! in! body! perception!in!AN,!and!some!of!the!positive$results$derived$from$neurocognitive$tasks$are$likely$to$be$ influenced$by$attitudinal$components$of$body$distortion!(Epstein!et!al.,!2001;!Keizer!et!al.,!2011).!! $ 4.1.4.$Functional$MRI$findings$related$to$abnormal$body$perception$in$AN$ fMRI!studies!on!AN!have!rarely!conceptualized$body$image$perception$as$a$multidimensional!construct,! and,! instead,! have! evaluated! responses! to! body! stimuli! as! unitary.! In! their! review,! Gaudio! and! Quattrocchi! (Gaudio! and! Quattrocchi,! 2012)! summarized! the! results! of! fMRI! studies! using! body! image! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 2. !In!the!rubber!hand!ilusión,!participants!view!a!rubber!hand!placed!in!front!of!them,!slightly!to!one!side!but!in!a!similar!position!to!their!own! hand,!hidden!from!view.!Both!the!rubber!hand!and!the!participant’s!own!hand!are!then!stroked,!either!synchronously!or!asynchronously.!When! the! fake! hand! is! stroked! in! synchrony! with! one’s! own! hand,! one! feels! the! touch! on! the! fake! hand! as! if! the! fake! hand! belonged! to! oneself.! However,!this!illusion!is!reduced!if!the!stroking!of!the!fake!and!real!hand!is!asynchronic.!. Doctoral!ThesisZ!Esther!Via!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Chapter!1Z!Introduction!. !!!!29!.