A Functional Magnetic Resonance Imaging Assessment of Small Animals Phobia Using Virtual Reality as a Stimulus

O iginal Pape A Func ional Magne ic Resonance Imaging Assessmen o Small Animals’ Phobia Using Vi ual Reali y as a S imulus Mi iam Clemen e1, PhD; Bea iz Rey1,2, PhD; Aina Rod iguez-Pujadas3; Juani B e on-Lopez4, PhD; Al onso Ba os-Losce ales3, PhD; Rosa M Baños2,5, PhD; C is ina Bo ella2,4, PhD; Ma iano Alcañiz1,2, PhD; Cesa A ila3, PhD 1LabHuman, I3BH, Uni e si a Poli ecnica de Valencia, Valencia, Spain 2Cibe , Fisiopa ología Obesidad y Nu ición, CB06/03, Ins i u o de Salud Ca los III, Mad id, Spain 3Depa amen o de Psicología Básica, Clínica y Psicobiología, Uni e si a Jaume I, Cas ellon, Spain 4Labpsi ec, Uni e si a Jaume I, Cas ellon, Spain 5Labpsi ec, Uni e si a de Valencia, Valencia, Spain Co esponding Au ho : Mi iam Clemen e, PhD LabHuman I3BH Uni e si a Poli ecnica de Valencia Ciudad Poli écnica de la Inno ación - Cubo Azul - Edi 8B - Acceso N, Camino de Ve a s/n Valencia, 46022 Spain Phone: 34 96 387 75 18 ex 67042 Fax: 34 96 387 95 10 Email: ya [email p o ec ed] Abs ac Backg ound: To da e, s ill images o ideos o eal animals ha e been used in unc ional magne ic esonance imaging p o ocols o e alua e he b ain ac i a ions associa ed wi h small animals’phobia. Objec i e: The objec i e o ou s udy was o e alua e he b ain ac i a ions associa ed wi h small animals’ phobia h ough he use o i ual en i onmen s. This con ex will ha e he added bene i o allowing he subjec o mo e and in e ac wi h he en i onmen , gi ing he subjec he illusion o being he e. Me hods: We ha e analyzed he b ain ac i a ion in a g oup o phobic people while hey na iga ed in a i ual en i onmen ha included he small animals ha we e he objec o hei phobia. Resul s: We ha e ound b ain ac i a ion mainly in he le occipi al in e io lobe (P<.05 co ec ed, clus e size=36), ela ed o he enhanced isual a en ion o he phobic s imuli; and in he supe io on al gy us (P<.005 unco ec ed, clus e size=13), which is an a ea ha has been p e iously ela ed o he eeling o sel -awa eness. Conclusions: In ou opinion, hese esul s demons a e ha i ual s imulus can enhance b ain ac i a ions consis en wi h p e ious s udies wi h s ill images, bu in an en i onmen close o he eal si ua ion he subjec would ace in hei daily li es. (JMIR Se ious Games 2014;2(1):e6) doi:10.2196/games.2836 KEYWORDS neu oimaging; pa ien assessmen ; i ual eali y; phobia In oduc ion Small Animal Phobia Phobias a e one o he mos wide sp ead and common diso de s o mode n li e, a ec ing 1 in 10 people a some poin o hei li es [1-3]. Mo e speci ically, small animals’ phobia is one o he mos disabling ones, due o he possibili y o acing he animal in daily li e. In ac , 40% o speci ic phobias belong o he ca ego y o small animals, including bugs, mice, snakes, and ba s [4]. JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.1h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X E alua ing S a e o he Phobia In o de o e alua e he s a e and e olu ion o he phobia, many s udies ha e been conduc ed using b ain imaging echniques, such as unc ional magne ic esonance imaging ( MRI), posi on emission omog aphy (PET), o elec oencephalog aphy (EEG). To da e, mos o hose s udies used pho og aphs o ideos o eal animals as s imulus o p o oke he eac ion o he subjec . Fo example, Paque e e al [5] used ilm exce p s o eal spide s as s imulus, and exce p s o eal bu e lies as con ol. They aimed o p obe he e ec s o cogni i e beha io al he apy (CBT) on he neu al co ela es o spide phobia. They ound signi ican ac i a ion o he igh do sola e al p e on al co ex and he pa ahippocampal gy us du ing he phobogenic s imulus be o e he CBT, which disappea ed a e i . Rega ding he s udies ha used pic u es as s imulus, se e al o hem analyzed he amygdala ac i a ion when compa ing phobic and nonphobic subjec s. Fo example, Schienle e al [6] s udied he e ec s o a cogni i e he apy, compa ing pic u es o eal spide s wi h images ha p o oked ea , disgus , o images ha we e neu al. Ano he example is he s udy o La son e al [7], who also used pic u es as s imulus. Alpe s e al [8] s udied he amygdala ac i a ion and i s ela ionship wi h a en ion o e spide -phobic women, employing supe imposed images o spide s and bi ds du ing he ask. Apa om he amygdala, se e al s udies ha used pic u es as s imuli we e ocused on o he b ain a eas, such as he insula. S aube e al [9] analyzed insula ac i a ion due o he an icipa o y anxie y, which e e s o he ea you eel when you a e expec ing o ind he animal objec o you phobia. In ano he s udy, Wend e al [10] analyzed he ela ion o he insula ac i a ion o he de ensi e esponse he subjec expe iences be o e he appea ance o hei ea ed objec , using sus ained exposu e o he phobia ele an s imuli. Rega ding o he neu oimaging echniques, Scha mülle e al [11] used EEG o in es iga e he symp oms o spide phobia, again using pic u es as s imulus. They ound sou ces o ac i a ion in a eas ela ed o he isuo-a en ional p ocessing, emo ional p ocessing, and ep esen a ions o a e si e bodily s a es. Vi ual Reali y Bene i s In he ield o phobias, i ual eali y (VR) has been epea edly used o ea he diso de , bu o ou knowledge, i has no been used o he assessmen o he dis u bance ye . VR is a echnology ha comp ises compu e -gene a ed simula ions o eali y [12]. Among mos common ea men s o men al diso de s a e he cogni i e beha io al ea men s, based on he exposu e o he subjec o he objec o hei ea , o make hem adap p og essi ely o he s imulus [13,14]. Howe e , hese di ec -exposing echniques some imes a e conside ed “dange ous and e hically ep ehensible” [14-16] because o he impac ha he di ec exposu e can ha e on he subjec . In his sense, VR allows exposu e o he subjec o he ea ed s imuli in a con olled en i onmen ha is conside ed sa e and mo e e hically accep able [17]. Bo ella e al [18] ga e a lis o he ad an ages ha VR has in psycho he apy; om which we can emphasize he a o emen ioned allowance o unning he he apy in a p o ec ed en i onmen close o eali y, whe e he pa ien can ac wi hou eeling h ea ened ( om a “sa e base”). Fu he mo e, in VR he pa ien can in e ac wi h he con ex , and he psycho he apis can g ade he si ua ion acco ding o he pa ien ’s s a e. Mo eo e , in a mo e echnical way, VR is an excellen sou ce o in o ma ion in pe o mance achie emen s, and allows o an accu a e con ol o he si ua ion. Finally, we can men ion he ecological alidi y o he s imuli p esen a ion. One o VR’s many ad an ages is ha i allows he pa ien o in e ac wi h he phobic objec o si ua ion as i hey a e eal and hey exis he e wi h he ea ed animals. This concep is known as p esence, he sense o being he e, inside he i ual en i onmen , al hough you body is physically loca ed elsewhe e [19-22]. The VR exposu e he apy has been widely used in he ea men o speci ic phobias [23], such as ac ophobia [24], claus ophobia [25], a achnophobia [26], hodophobia [27], and p e ome hanophobia [28]. An example o his kind o ea men in ou ield o in e es (small animals phobia) is he one de eloped by Ga cia-Palacios e al [29], using VR wi h spide phobic subjec s. In ano he s udy, Bo ella e al [30] applied augmen ed eali y, a VR- ela ed echnology, o ea ing cock oach phobic subjec s. Howe e , o da e, VR has no been used inside he MRI scanne as a s imulus o assess he esponses o he phobic subjec s in he p esence o he ea ed elemen s. Ou p oposal is ha he use o VR as a s imulus inside an MRI se ing will en ail he same ad an ages o he phobia e alua ion ha i b ough o he phobia ea men . T adi ionally, he phobia e alua ion has been made using beha io al assessmen s and sel - epo ed scales. Finding he neu al co ela es ela ed o he phobia ac i a ion in each indi idual subjec could help in hei e alua ion p ocess, g ading hei le el o phobia, and gi ing u he in o ma ion abou hei s a e. This knowledge can help he he apis s o decide he mos app op ia e ea men o each pa icula pa ien , aking in o accoun he b ain ac i a ions ha can be obse ed. Besides, he analysis o he b ain ac i a ions ela ed o he phobia once he ea men has inished can be used o e alua e i he ea men has been success ul. Using VR inside an MRI se ing will allow he psychologis s o place he pa ien s in i ual si ua ions ela ed o he objec o hei phobia, whe e hey a e able o in e ac . I can also make he use eel p esen in he en i onmen , c ea ing a mo e “ ealis ic” expe ience han he one induced by he isualiza ion o ideos o pho og aphs. Consequen ly, we expec he ac i a ed b ain a eas o be mo e simila o hose ac i a ed du ing he eal expe ience. Fu he mo e, he expe imen e will ha e he possibili y o con olling he exposu e o he i ual si ua ions in he mos con enien way, cus omizing i acco ding o he pa ien ’s si ua ion, i i is equi ed. Finally, his kind o sys em allows an easy moni o ing o he beha io al esponses o he pa icipan s inside he i ual en i onmen . In o de o alida e his p oposal, ou a ge in he p esen wo k is o examine whe he VR can be used o he assessmen o he phobia, p o oking a mo e ealis ic and imme si e si ua ion han he iew o a s ill pho og aph, which can be manipula ed by he psychologis . We ha e used i ual en i onmen s whe e he subjec can na iga e eely, which should induce a highe sense o p esence due o he sel -con ol o he na iga ion ou e [31]. JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.2h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X As p esen ed p e iously in Clemen e e al [32], ou main hypo hesis is ha he b ain a eas ac i a ed wi h hese en i onmen s will be cohe en wi h he esul s om p e ious s udies based on pic u es o ideos o eal animals (see Mul imedia Appendix 1). Me hods Rec ui men Fo his s udy, we ec ui ed 11 igh -handed phobic women, be ween 20 and 35 yea s old (mean age 24.64). None o hem had any o he medical o psychological diso de s, apa om he phobia. The pa icipan s’hand dominance was es ed using he Edinbu gh Handedness In en o y [33]. Expe clinicians who we e also he he apis s o he pa icipan s ca ied ou he diagnosis and assessmen phases. In o de o be included in he s udy, he ollowing inclusion c i e ia we e conside ed: (1) mee ing Diagnos ic and S a is ical Manual o Men al Diso de s - 4 h edi ion (DSM-IV) [1] c i e ia o speci ic phobia animal ype, speci ically cock oach and spide phobia; (2) ha ing sco es o e 4 in phobic a oidance (on a scale o 0 o 8); (3) ha ing no cu en alcohol o d ug dependency; (4) ha ing no diagnosis o majo dep ession o psychosis; (5) no ha ing been o being ea ed wi h a simila p og am; and (6) ha ing a minimum o 1 yea o du a ion o he p oblem. The Anxie y Diso de s In e iew Schedule [34] speci ic phobia sec ion was used o ca y ou he di e en ial diagnosis o he anxie y diso de s included in he DSM. These women we e s uden s, we e paid o hei pa icipa ion in he s udy, and we e ec ui ed om he Uni e si a Jaume I in Cas ellón. E hical app o al was ob ained om he au ho s’ ins i u ion, and each subjec signed a w i en in o med consen p io o pa icipa ion. En i onmen s The i ual en i onmen s used du ing he ask we e p og ammed using GameS udio so wa e (Coni ec Da ensys eme GmbH), which allowed us o de elop h ee-dimensional objec s and i ual wo lds wi h which pa icipan s could in e ac and na iga e. Fo his s udy, we ha e di ided he ask in o h ee expe imen al condi ions, all o hem in ol ing a oom whe e he subjec can na iga e eely. In he i s o hese condi ions “CLEAN”, he pa ien na iga es h ough a common clean bed oom (wi h a bed, a close , and a desk wi h some books on i ). In he second condi ion “DIRTY”, he na iga ion is pe o med h ough he same oom, bu his ime di y and da ke , gi ing he subjec he eeling ha he ea ed animal could appea in any momen ; his oom in ends o s imula e he anxie y in he use . In he las condi ion “PHOBIC”, he subjec na iga es h ough he same di y oom, bu his ime he e appea ed spide s and cock oaches. Each o hese expe imen al condi ions las ed 20 seconds. Figu e 1 shows he cap u es o each en i onmen . To p e en he subjec s om s aying s ill in he VR du ing he na iga ion pe iods, a sea ch ask was included in o de o o ce hem o mo e h ough he en i onmen and con on he phobic s imulus in he co esponden expe imen al condi ion. This ask consis ed o sea ching and coun ing he numbe o ed keys ha appea ed and disappea ed in he en i onmen . Howe e , hey we e no encou aged o ind hem all, o o ind hem as quickly as possible, hey we e only old o con inue sea ching o hem du ing each pe iod. A e each ask, he subjec s we e ques ioned abou he numbe o keys ha hey had ound ( hey had o answe in a sho pe iod o 4 seconds). While hey we e conduc ing he asks, he esea che checked in he compu e o see ha hey had answe ed p ope ly. The numbe o keys ha hey coun ed was no ele an ; i was jus included o a oid he subjec s emaining s ill du ing he expe imen al condi ions. A black sc een was included be ween phases o gi e he subjec s a es pe iod, du ing which b ain ac i a ion could decay o i s baseline alues (6 seconds). A e his, he label indica ing he nex ask appea ed (2 seconds). The o al ime be ween asks was 12 seconds. Each o he h ee expe imen al condi ions was epea ed six imes in a coun e balanced o de o p e en e ec s p oduced by he o de in which hey we e p esen ed. A he beginning o he expe imen he e we e 14 seconds o black sc een o compensa e o elaxa ion ime (T1) sa u a ion e ec s. The o al ime o he comple e expe imen was 9 minu es and 40 seconds. Figu e 2 shows a scheme o he p o ocol. Be o e en e ing he scanne , he subjec s unde wen a sho aining session whe e hey we e in oduced o he VR na iga ion ask. This aining session was conduc ed in a supplemen a y i ual en i onmen , wi hou any kind o phobic s imuli, o a oid habi ua ion. Du ing he MRI scan, he VR applica ion checked he o al ime ha hey spen mo ing he joys ick in each condi ion o gua an ee ha hey did no emain s ill du ing he phobic s imula ion. Figu e 1. Cap u es o he h ee en i onmen s used in he condi ions: CLEAN (le ), DIRTY (cen e ), and PHOBIC ( igh ). JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.3h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X Figu e 2. Scheme o he p o ocol o he unc ional magne ic esonance imaging ( MRI) ask. Func ional Magne ic Resonance Imaging P ocedu es All he subjec s we e scanned in a 1.5 Tesla Siemens A an o Magne ic Resonance scanning de ice. We used an adap ed magne ic esonance (MR) helme o p e en head mo emen . To display he en i onmen s, we used magne ic esonance imaging (MRI)-compa ible ideo goggles, VisualS im Digi al (Resonance Technology Inc), and o he na iga ion we used an adap ed joys ick (Resonance Technology Inc). Fi s , sagi al T1-weigh ed s uc u al images we e acqui ed (224 x 256 ma ix co e ing he b ain wi h 176 con iguous 1 mm slices, epe i ion ime [TR] = 11 ms, echo ime [TE] = 4.94 ms, lip angle [FA] = 15 , oxel size = 1.04 x 1.04 mm). Then, he unc ional scanning was launched, synch onized wi h he i ual en i onmen s. Func ional images we e ob ained using a elaxa ion ime (T2*) single-sho echo-plana imaging sequence. We used 30 con iguous 4.2 mm in e lea ed axial slices—pa allel o he an e io commissu e – pos e io commissu e line (AC-PC line)—co e ing he en i e olume o he b ain wi h a 64 x 64 ma ix (TR = 2000 ms, TE = 30 ms, FA = 90 , oxel size = 3.5 x 3.5 mm). Da a Analysis We ha e used he s a is ical pa ame ic mapping so wa e (SPM8, Wellcome Depa men o Imaging Neu oscience) o he analysis o he MRI da a, launched wi h he 7.1 e sion o Ma lab (Ma hWo ks). We excluded he i s 7 scans om he analysis o elimina e he decay o he MRI signal ha is associa ed wi h he momen when magne iza ion eaches equilib ium. Fi s we aligned he images o he AC-PC line. Once i was done, we began he p ep ocessing o he da a, ealigning he unc ional images (es ima e and eslice op ion), co egis e ing hem o he s uc u al images, and segmen ing his la e ana omical scan. We hen no malized he esliced unc ional olumes wi h he no maliza ion pa ame e s ha we ex ac ed a e segmen a ion and no maliza ion o he ana omical olumes o each subjec sepa a ely ( he empla e was p o ided by he Mon eal Neu ological Ins i u e, MNI). None o he olun ee s had o be excluded due o mo emen s o dis o ions du ing he MRI. Finally, we smoo hed he images using a Gaussian ke nel ( ull wid h a hal maximum, FWHM, o 8 x 8 x 8 mm). In a i s ixed-e ec le el analysis, he unc ional ime se ies o each subjec and o each condi ion we e modeled wi h a boxca unc ion con ol ed wi h he hemodynamic esponse unc ion. The pa ame e s o he mo ion co ec ion we e employed as eg esso s o nonin e es . To elimina e he low equency componen s in he signal caused by he scanne mo ion and wa ming, we applied a 96 seconds high pass il e . We pe o med g oup es s a a second le el andom e ec analysis. We es ed o ask ela ed ac i a ion by pe o ming a one-sample es , including con as images o es ima ed pa ame e s o he di e ences o in e es be ween condi ions. As we ha e a o emen ioned, ou MRI pa adigm was di ided in o h ee di e en na iga ion asks (clean oom, di y oom, and phobic-s imulus oom) ha we wan ed o compa e in o de o ob ain he con as ing b ain ac i a ions. Al hough he esul s o he h ee con as s ha e been ob ained, he esul s ha show he b ain ac i a ions o he phobic s imulus a e con ained in he “phobic>clean” con as . The “phobic>di y” con as shows phobic ac i a ions a oiding he anxie y eeling caused by he di iness o he oom, and he “di y>clean” con as con ains he anxie y ela ed ac i a ions. JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.4h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X All con as s a g oup le el we e conside ed i mo e han 10 adjacen oxels passed he s a is ical h eshold o P<.005 (unco ec ed). These esul s we e co ec ed a P<.05 using AlphaSim co ec ion (combined heigh h eshold P<.005, and a minimum clus e size= 25) [35]. We used he xjView so wa e u ili y o s a is ical pa ame ic mapping (SPM) which uses he MNI coo dina es sys em o ob ain he speci ic b ain a eas ha we e ac i a ed o each con as . Resul s We selec ed he con as “phobic>clean”, and looked o he main ac i a ed b ain egions. We ound ac i a ions in he le occipi al in e io lobe and middle occipi al gy us bila e ally, among o he s (see “supe io ” pa o Table 1, and Figu e 3 also shows his ac i a ion). B ain egions ha also displayed signi ican ac i a ions du ing he ask we e: (1) he cuneus bila e ally, (2) he supe io on al gy us, and (3) he p ecuneus. In he middle pa o Table 1 (also shown in Figu e 4), we can obse e he esul s ob ained o he “phobic>di y” con as (in e io occipi al lobe bila e ally, and he le supe io , and middle on al lobe); and in he lowe pa o Table 1 (also shown in Figu e 5) a e he esul s o he “di y>clean” con as (le supe io occipi al lobe, and igh middle on al gy us, middle occipi al gy us and cingula e). In he able, apa om he ana omical a ea and b ain hemisphe e, he alues o he loca ion and T sco e o he maximum o each a ea, he size o he clus e ac i a ed in each a ea, and he P alue used as h eshold a e shown. Table 1. B ain a ea ac i a ion esul s. PClus e size 10 (x, y, z)Hemisphe eAna omical egionCon as <.05 co ec ed364,19(-22, 98, -12)La Occipi al in e io lobe“Phobic>clean” <.05 co ec ed295,21(-54,-77, -4)La Middle occipi al gy us (BA19c) <.05 co ec ed1754,76(31, 77, 0)Rb Middle occipi al gy us <.05 co ec ed364,01(20, -91, 9)Rb Cuneus <.05 co ec ed28-11,64(26, -96, 6)Rb BA18c <.05 co ec ed555,82(-8, -95, 30)La Cuneus <.005 unco ec - ed134,52(20, 49, 42)Rb Supe io on al gy us <.05 co ec ed314,59(-1, -46, 68)La P ecuneus <.05 co ec ed545,52(-26, -98, -12)La In e io occipi al lobe“Phobic>di y” <.005 unco ec - ed224,43(48, -84, -8)Rb In e io occipi al lobe <.005 unco ec - ed184,51(-22, 56, 34)La Supe io on al lobe <.005 unco ec - ed185,25(-26, 14, 63)La Middle on al lobe <.05 co ec ed2015,69(-15, -91, 30)La Supe io occipi al lobe“Di y>clean” <.05 co ec ed395,23(24, 53, -8)Rb Middle on al gy us <.05 co ec ed1846,81(27, -84, 13)Rb Middle occipi al gy us <.005 unco ec - ed147,40(17, -35, 30)Rb Cingula e gy us aL=le bR= igh cBA = B odmann a ea JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.5h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X Figu e 3. B ain ac i a ions o he “phobic>clean” con as . Figu e 4. B ain ac i a ions o he “phobic>di y” con as . JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.6h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X Figu e 5. B ain ac i a ions o he “di y>clean” con as . Discussion Main Goal The main goal o ou s udy was o analyze he b ain a eas ac i a ed due o phobic s imulus du ing a subjec ’s na iga ion in a i ual en i onmen h ough he h ee expe imen al condi ions p e iously desc ibed (CLEAN, DIRTY, and PHOBIC). The main esul s, o he pu poses o he s udy, a e hose ob ained when compa ing he b ain ac i a ions be ween he phobic and he clean condi ions (“phobic>clean”), which e lec he ea and anxie y el by he subjec s due o he phobic s imulus when compa ed wi h an emo ionally neu al si ua ion. Bo h he phobic and di y si ua ions may gene a e anxie y in he pa icipan . Howe e , in he di y condi ion, he anxie y is gene a ed by he ac o being in a h ea ening oom (because o he di iness o he oom, he pa icipan may eel ha is a dange ous place o be), and in he phobic condi ion, apa om he di iness o he oom he e a e phobic s imuli. Ou hypo hesis is ha in he “phobic>clean” compa ison, he ac i a ions may be caused by bo h ac o s, while in he “phobic>di y” con as , he ac i a ions would be ela ed o he phobia i sel , and no o he anxie y eeling. In he ollowing pa ag aphs, we will commen on he esul s o he “phobic>clean” con as in compa ison wi h he esul s ob ained in o he s udies abou phobia. A e ha , we will discuss b ie ly he esul s ob ained in he o he wo con as s, “phobic>di y” and “di y>clean”. Finally, he limi a ions o he s udy will be commen ed on, and we will make some o e all conclusions. P incipal Resul s One o he mos impo an ac i a ed a eas in he “phobic>clean” con as is he occipi al lobe, mo e speci ically, he le in e io a ea and in he middle lobe bila e ally. Ano he impo an esul was he ac i a ion ob ained in he supe io on al gy us. Finally, ac i a ions we e also ound in he cuneus and p ecuneus. A mo e de ailed explana ion o he impo ance o hese esul s is ound below. The Occipi al Lobe The occipi al lobe mainly con ols he isual a eas, which a e necessa y o he pe o mance o a na iga ion ask. In he in e io a ea o he occipi al lobe, we ound ac i a ion in he lingual gy us, which is belie ed o play a ole in d eaming as well as in ision, especially in he ecogni ion o wo ds [36]. In his a ea, we also ound ac i a ion in he B odmann a ea 18, pa o he ex as ia e isual co ex. This encompasses mul iple unc ional a eas, including V3, V4, V5/MT, which a e sensi i e o mo ion, o he ex as ia e body a ea used in he pe cep ion o human bodies [37,38]. Paque e e al had al eady ound b ain ac i a ion in he occipi al lobe a ea [5] in a simila s udy ca ied ou using ilm exce p s o spide s as he phobic s imulus, and ilm exce p s o bu e lies as he neu al condi ion. They concluded ha his ac i a ion was ela ed o enhanced isual a en ion o he phobic s imuli, and ha i suppo ed igilance unc ions in anxie y [39,40]. Mo eo e , hose esul s we e consis en wi h hose ob ained in o he simila s udies [41-43]. Mo e ecen ly, he e ha e been se e al MRI [6,8,9] and PET [11] s udies among phobic and nonphobic subjec s ha ha e also ound ac i a ion in he isual co ex. In ac , S aube e al [9] jus i ied i as likely o be caused JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.7h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X by he a en ion subjec s pu on he isual inpu ha e lec an “inc ease in he p ocessing o he cue, bu also he expec a ion o beha io ally ele an senso y inpu ”. Mo eo e , se e al s udies ha e poin ed ou he sp ead o e ime ha he amygdala ac i a ion has o he occipi al a eas, due o he emo ional ele ance o he s imulus [44,45]. The Supe io F on al Gy us The o he impo an ac i a ion in ou esul s was ound in he supe io on al gy us. This a ea has been p e iously ela ed o he eeling o sel -awa eness [46], which is inc eased when he phobic subjec s wa ch he animal ha p o okes hei ea . Du ing he es ing condi ion (CLEAN), he subjec s a e in ol ed in a highly demanding senso y ask du ing which hey elax and a e less conscious o hemsel es [46]. Howe e , when he en i onmen changes, and he phobic subjec s ind hemsel es in a ea ul si ua ion, hei ale s a e inc eases, ying o inhibi hei eac ion in on o he phobic s imulus [5]. The na u al eply o his s imulus is o a oid he ea esponse i p o okes o e hem, and o do so hey con ol hei mind and body, inc easing he consciousness hey ha e o hemsel es. Also acco ding o Du Boisgueheneuc e al [47], he supe io on al gy us is ela ed o he highe cogni i e unc ions and he wo king memo y. Howe e , he e a e some o he s udies ha ela e he isualiza ion o a phobic s imulus o he deac i a ion o he on al a eas, especially o he p e on al and o bi o on al co ices [48,49]. They a gue ha isually elici ed phobic eac ions deac i a e he a eas ela ed o cogni i e con ol o e emo ions, esul ing in mo o eadiness o igh o ligh [49]. Ne e heless, hose deac i a ions a e ela ed o mo e an e io a eas o he b ain, no in ol ing he supe io on al gy us. Mo eo e , in ou s udy he subjec s we e mild phobics, so hey we e able o eac in on o a phobic s imulus wi hou needing o engage mo e ins inc i e eac ions. Al hough Paque e e al [5] did no ind ac i a ion in he supe io on al gy us, hey discussed i s ela ion o he olun a y sel - egula ion o emo ion. Mo e exac ly, hey exposed he esul s ob ained in a PET s udy ca ied ou by Johanson e al [50], whe e an inc ease in he on al egional ce eb al blood low was ob ained which co ela ed wi h he use o cogni i e s a egies o cope wi h he phobic si ua ion. Paque e e al [5] poin ed ou ha he phobic subjec s ac i a ed hei p e on al a eas when a emp ing o con ol hei ea be o e he ilm exce p s o spide s. Goldbe g e al [46] analyzed he subjec i e awa eness eeling, and i s ela ion wi h he on al a eas o he b ain. They ema ked how when wa ching an abso bing mo ie o being in ol ed in a highly demanding senso y ask (as in ou case he i ual na iga ion h ough an imme si e en i onmen ), he s ong subjec i e eeling is o “losing he sel ”, o as hey explained, o disengaging om sel - ela ed e lec i e p ocesses. Accep ing his s a e, he inc ease in he sel -awa eness eeling du ing he isualiza ion o phobic s imulus in a highly demanding na iga ion ask is clea ly ela ed o he highe eeling o you sel when “ igh ing” he ea . In he wo ds o Scha mülle e al [11], inc eased ac i a ion in he supe io on al co ex migh e lec he pa ien s’u ge o lee du ing he con on a ion wi h he ea ed objec ; and his link be ween he senso imo o sys em and he e ec i e/cogni i e unc ion is in line wi h he heo y abou embodied cogni ion [51]. In conclusion, we can conside his ac i a ion essen ially ela ed o he phobia. The Cuneus and he P ecuneus Wi h espec o ou o he esul s, we also ound ac i i y in he cuneus and he p ecuneus. Rega ding he cuneus, i has been ela ed o isual p ocessing, which is di ec ly associa ed wi h he sense o p esence ha he subjec eels while na iga ing h ough a i ual en i onmen [52]. On he o he side, he p ecuneus has been ela ed o sel -consciousness, such as e lec i e sel -awa eness, ha in ol es a ing you own pe sonali y ai s [53,54]. This in o ma ion con inues wi h he idea o an inc ease in he consciousness o you sel while you a e exposed o a phobic s imulus, ying o educe you eac ion be o e i . I has also been in ol ed in di ec ing a en ion in space when planning o pe o ming a mo emen [55,56], which is di ec ly ela ed o he na iga ion h ough a i ual en i onmen . The Amygdala Al hough one o he a eas mos commonly ela ed o phobias is he amygdala, i is no ac i a ed in ou esul s. Se e al p e ious s udies ha e been conduc ed o ind he pa e n o ac i a ion o his a ea [5,7,8], hey ha e concluded ha he amygdala su e s habi ua ion o e ime [7]. This means ha i is ac i a ed o a b ie ime pe iod and hen disappea s. Paque e e al [5] also poin ed ou ha his sugges s ha he amygdala may no be ela ed o he phobic exp ession o expe ience, bu o he ea condi ioning [5,57]. S aube e al [9] also discussed ha he amygdala ac i a ion may occu du ing b ie p esen a ions o he phobogenic s imuli, and in he induc ion o apid beha io al esponses, mo e han in he sus ained and explici p ocessing o he h ea ening s imuli. Alpe s e al [8] also poin ed ou ha hei ac i a ion in he amygdala was helped by he b ie s imulus hey used (200 ms). In ou case, he use o pe iods o na iga ion as s imulus ins ead o pic u es may be he cause o no de ec ing ac i a ion in his a ea (we used a block design o he p o ocol ins ead o an e en - ela ed). In ac , mos o he s udies a ound he amygdala ha e epo ed i s ac i a ion du ing he e y ea ly s ages o he s imulus [6-8]. The “Phobic>Di y” Con as Ha ing exposed he main esul s o he “phobic>clean” con as , we will b ie ly discuss he esul s o he emaining con as s. Rega ding he “phobic>di y” compa ison, we ound ha he in e io occipi al lobe played a majo ole in he ea esponse o he phobic s imulus, bila e ally. This is in conco dance wi h he esul s ob ained o he “phobic>clean” con as , whe e we poin ed ou he ela ion o his a ea wi h he phobic esponse. As we ha e al eady said, he occipi al lobe has been ela ed o enhanced isual a en ion o he phobic s imuli [39,40]. The o he impo an ac i a ion was loca ed in he supe io and middle on al lobe, he esul also con ained in ou p e ious con as , due o i s ela ion o he eeling o sel -awa eness and he ac ion o he senso y sys em [46]. As we can see, he main esul s ha we poin ed ou as being ela ed o he phobia a e s ill ac i a ed when we es ic he condi ions o he con as o a oid he anxie y esul s. JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.8h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X The “Di y>Clean” Con as Rega ding he “di y>clean” con as , he sel -awa eness was s ill high due o he g ea e ea o inding a spide o a cock oach when na iga ing h ough a da k and di y en i onmen han when na iga ing h ough a clean one, which esul ed in he ac i a ion o he middle on al gy us. The ac i a ion o he occipi al lobe was main ained he e due o he highe isual p ocessing when expec ing he appea ance o a ea ed animal. The las ac i a ion was loca ed in he cingula e gy us, which Paque e e al [5] poin ed ou o be mainly associa ed wi h he cogni i e/in e nal gene a ion o he emo ional s a e by e oking isual image y o memo ies. As we a o emen ioned, he ac i a ions in his con as a e due o he e oca ion o he ea , no o he exposi ion o i ; so he meaning o he ac i a ion in he cingula e gy us is clea as a gene a o o he emo ional e oca ions. Limi a ions To inish his discussion, we will add ess some o he limi a ions ha ou s udy p esen s. Fi s o all, i was conduc ed using a speci ic g oup o pa icipan s, namely, 11 igh -handed women. This cons i u es a small sample size, which es ic s he s a is ical powe o he s udy o de ec changes in he blood-oxygen-le el-dependen signal. All o he subjec s we e igh -handed in o de o p e en noise e ec s due o manual la e aliza ion on b ain ac i a ion in he i ual/spa ial p ocessing. Mo eo e , we chose all women in o de o educe he a iabili y gene a ed by gende di e ences. In ac , some p e ious s udies ha e poin ed ou he impo ance o choosing only women, due o hei highe ac i a ion in he p esence o he emo ional s imuli. Canli e al [58] indica ed ha hey chose women because “ hey epo mo e in ense emo ional expe iences, and show mo e physiological eac i i y in conco dance wi h alence judgmen s han men”. Mos o he s udies we ha e a o emen ioned ha e been conduc ed wi h emale subjec s [5,6,9,11]. Scha mülle e al [11] poin ed ou ha hey es ic ed hei s udy o use only emale subjec s since he p e alence o spide phobia is highe in hem. Mo eo e , Schienle e al [6] ema ked ha mos o he spide s’ phobia su e e s we e emales. Ano he limi a ion could be he absence o con ol subjec s o compa e wi h, which could cons i u e a u u e ex ension o he cu en wo k. Conclusions In conclusion, he esul s ha we ha e ob ained wi h VR is simila o he esul s ob ained using eal s imuli, in e ms o MRI b ain ac i a ions. In ac , he main ac i a ions we ound in he occipi al and on al a eas a e consis en wi h hose ound in p e ious s udies ha we e conduc ed wi h spide phobic subjec s using pic u es o ideos o eal animals as s imuli. Mo eo e , he ac i a ion in he cuneus could be ela ed o he sense o p esence elici ed in he subjec s because o he na iga ion h ough he i ual en i onmen . This inding opens he doo o deepe in es iga ions in o he phobias, due o he ac ha VR allows he ec ea ion o no mal li e scenes in a mo e ealis ic and in e ac i e way, ha a e impossible o achie e wi h o he echniques. This kind o si ua ion could allow, o example, he s udy o subjec s wi h a mild phobia, whose ea canno be exci ed by only he use o pho og aphs. Once he alidi y o he use o VR as a s imulus o e oking he phobia is e alua ed, he nex s ep will be o p o e he use ulness o VR du ing he assessmen o he b ain ac i a ions a e he subjec s ha e passed h ough a psychological ea men o cu e he diso de . This will be e alua ed in u u e s udies. Acknowledgmen s This s udy was unded by Vice ec o ado de In es igación de la Uni e si a Poli ècnica de València, Spain, PAID-06-2011, RN 1984; by he Minis e io de Educación y Ciencia Spain, P ojec Game Teen (TIN2010-20187); and pa ially by p ojec s Consolide -C (SEJ2006-14301/PSIC), “CIBER o Physiopa hology o Obesi y and Nu i ion, an ini ia i e o ISCIII”, he Excellence Resea ch P og am PROMETEO (Gene ali a Valenciana. Conselle ia de Educación, 2008-157), and he Consolide INGENIO p og am (CSD2007-00012). Gene ali a Valenciana, unde a VALi+d G an , suppo ed he wo k o MC. Con lic s o In e es None decla ed. Mul imedia Appendix 1 Powe Poin o he p esen a ion done du ing he REHAB 2013 Wo kshop, held in Venice (I aly) on he 5 h o May 2013. [PPT File (Mic oso Powe Poin P esen a ion), 5MB - games_ 2i1e6_app1.pp ] Re e ences 1. Ame ican Psychia ic Associa ion. Diagnos ic and s a is ical manual o men al diso de s: DSM-IV. Washing on, DC: Ame ican Psychia ic Associa ion; 2000. 2. Kessle RC, Be glund P, Demle O, Jin R, Me ikangas KR, Wal e s EE. Li e ime p e alence and age-o -onse dis ibu ions o DSM-IV diso de s in he na ional como bidi y su ey eplica ion. A ch Gen Psychia y 2005 Jun;62(6):593-602. [doi: 10.1001/a chpsyc.62.6.593] [Medline: 15939837] 3. Magee WJ, Ea on WW, Wi chen HU, McGonagle KA, Kessle RC. Ago aphobia, simple phobia, and social phobia in he na ional como bidi y su ey. A ch Gen Psychia y 1996 Feb;53(2):159-168. [Medline: 8629891] JMIR Se ious Games 2014 | ol. 2 | iss. 1 | e6 | p.9h p://games.jmi .o g/2014/1/e6/ (page numbe no o ci a ion pu poses) Clemen e e alJMIR SERIOUS GAMES XSL • FO Rende X