The chronnectome of musical beat

This is a sel -a chi ed e sion o an o iginal a icle. This e sion may di e om he o iginal in pagina ion and ypog aphic de ails. Au ho (s): Ti le: Yea : Ve sion: Copy igh : Righ s: Righ s u l: Please ci e he o iginal e sion: CC BY-NC-ND 4.0 h ps://c ea i ecommons.o g/licenses/by-nc-nd/4.0/ The ch onnec ome o musical bea © 2019 Else ie Inc. Published e sion Toi iainen, Pe i; Bu una , Iballa; B a ico, El i a; Vuus , Pe e ; Allu i, Vinoo Toi iainen, P., Bu una , I., B a ico, E., Vuus , P., & Allu i, V. (2020). The ch onnec ome o musical bea . Neu oimage, 216, A icle 116191. h ps://doi.o g/10.1016/j.neu oimage.2019.116191 2020 The ch onnec ome o musical bea Pe i Toi iainen a , * , Iballa Bu una a , El i a B a ico b , Pe e Vuus b , Vinoo Allu i c a Finnish Cen e o In e disciplina y Music Resea ch, Depa men o Music, A and Cul u e S udies, Uni e si y o Jy € askyl€ a, Finland b Cen e o Music in he B ain (MIB), Depa men o Clinical Medicine, Aa hus Uni e si y, The Royal Academy o Music Aa hus/Aalbo g (RAMA), Aa hus, Denma k c Cogni i e Science Lab, Kohli Cen e o In elligen Sys ems, In e na ional Ins i u e o In o ma ion Technology, Hyde abad, India ARTICLE INFO Keywo ds: Music Bea MRI Na u alis ic imaging Music in o ma ion e ie al Dynamic connec i i y ABSTRACT Keeping ime is undamen al o ou e e yday exis ence. Va ious isoch onous ac i i ies, such as locomo ion, equi e us o use in e nal imekeeping. This phenomenon comes in o play also in o he human pu sui s such as dance and music. When lis ening o music, we spon aneously pe cei e and p edic i s bea . The p ocess o bea pe cep ion comp ises bo h bea in e ence and bea main enance, hei ela i e impo ance depending on he salience o bea in he music. To s udy unc ional connec i i y associa ed wi h hese p ocesses in a na u alis ic si ua ion, we used unc ional magne ic esonance imaging o measu e b ain esponses o pa icipan s while hey we e lis ening o a piece o music con aining s ong con as s in bea salience. Subsequen ly, we u ilized dynamic g aph analysis and psychophysiological in e ac ions (PPI) analysis in connec ion wi h compu a ional modelling o bea salience o in es iga e how unc ional connec i i y mani es s hese p ocesses. As he main e ec , co ela ion analyses be ween he ob ained dynamic g aph measu es and he bea salience measu e e ealed inc eased cen- ali y in audi o y-mo o co ices, ce ebellum, and ex as ia e isual a eas du ing low bea salience, whe eas egions o he de aul mode- and cen al execu i e ne wo ks displayed high cen ali y du ing high bea salience. PPI analyses e ealed pa ial dissocia ion o unc ional ne wo ks belonging o his pa hway indica ing comple- men a y neu al mechanisms c ucial in bea in e ence and main enance, p ocesses pi o al o ex ac ing and p edic ing empo al egula i ies in ou en i onmen . 1. In oduc ion Humans ha e a p opensi y o engage in isoch onous ac ions, which may be oo ed in e olu iona y adap a ion (Me ke e al., 2009). In addi ion o p oducing sound pa e ns ha a e pe iodic o e ime, we a e able o ex ac empo al egula i ies om he audi o y en i onmen , be i language o music (Ko z e al., 2009;G ube e al., 2013). We a e hus capable o ex ac ing a egula pulse om he audi o y en i onmen , which allows us o p edic u u e hy hmical e en s o which we can hen synch onize ou mo emen s (D ake e al., 2000;Honing, 2012;Maes e al., 2014). When lis ening o music, we a e spon aneously d i en o find a bea , which makes bea pe cep ion undamen al o ou expe ience o music and he e o e key o explaining musical beha io (La ge and Snyde , 2009;Vuus e al., 2018). To da e ou ema kable and possibly uniquely human abili y o e o lessly pe cei e he bea in music keeps challenging cogni i e scien is s, who pu sue o unde s and i s unde lying b ain p o- cesses (La ge and Palme , 2002). A deepe unde s anding he eo would be key o explaining a ange o musical beha io s, such as why mo ing o music is pleasu able (La ge and Palme , 2002;La ge and Snyde , 2009; Za o e and Salimpoo , 2013), o why lis ening o hy hms has a a o - able e ec on pa ien s wi h neu odegene a i e gai diso de s (e.g., Pa - kinson’s disease; Nombela e al., 2013;Ashoo i e al., 2015;Thau e al., 2018), s oke pa ien s (B ad e al., 2010), and au is ic indi iduals (Wan e al., 2011). Such he apeu ic po en ial is he eason why he neu o- science o hy hm has de eloped in o a specificfield o esea ch among clinicians and schola s om many disciplines (An a i e al., 2002; F ançois e al., 2015). Music wi h egula pe iodic pulse exis s in e e y cul u e, a o ding coo dina ion be ween pe o me s and o en a he same ime inducing a synch onized mo o esponse om lis ene s (Ne l, 2000). An ob ious indica o o pulse sensi i i y is ou ins inc i e, almos subconscious, skill o mo o synch oniza ion o music which mani es s a a young age (T ehub, 2001;T aino , 2005). Undeniably, ou p ocli i y o hy hmic mo emen is e idenced in in ancy and o a g ea e ex en o music and o he me ically egula sounds han o speech (Zen ne and Ee ola, 2010). Such a p edisposi ion o mo e wi h music is specula ed o be oo ed in he e olu ion o en ainmen and social beha io , as * Co esponding au ho . E-mail add ess: pe i. oi iainen@jyu.fi(P. Toi iainen). Con en s lis s a ailable a ScienceDi ec Neu oImage jou nal homepage: www.else ie .com/loca e/neu oimage h ps://doi.o g/10.1016/j.neu oimage.2019.116191 Recei ed 20 June 2019; Recei ed in e ised o m 10 Sep embe 2019; Accep ed 11 Sep embe 2019 A ailable online 13 Sep embe 2019 1053-8119/©2019 Else ie Inc. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Neu oImage 216 (2020) 116191 synch oniza ion wi h a bea is he simples o m o en ainmen (Jana a e al., 2012;Madison, 2006;Madison e al., 2011). I is he e o e no su p ising ha music and dance ha e in some cul u es e ol ed oge he (C oss, 2008;Wallin e al., 2000). Bea pe cep ion comp ises wo di e en ypes o subp ocesses (Came on and G ahn, 2016). Fi s , bea induc ion (bea finding) can be defined as gene a ion o pu a i e bea s so as o en ain o synch onize o he isoch onous de ia ions caused due o exp essi e iming in music o , in o he wo ds, ac i e in e ence o pe cei ed bea . Second, bea main- enance (bea con inua ion) can be desc ibed as mechanical, au onomous ime keeping, which in ol es con inual, sus ained measu emen o p e- dic able in e als wi hou significan need o a en ion. The salience o musical bea a ies be ween and wi hin musical pieces, depending on he deg ee o which he music con ains epe i i e hy hmic pa e ns wi h a sui able a e. High bea salience is e oked by musical e en s ha occu a egula in e als a a sui able empo and ha e sha p a acks. The op imal empo o bea salience has been ound o lie in he icini y o 100–120 e en s pe minu e, co esponding o a bea pe iod o 500–600 ms (Pa ncu , 1994;Toi iainen and Snyde , 2003; an Noo den and Moelan s, 1999), which closely co esponds o he spon aneous empo o walking (McDougall and Moo e, 2005) and apping (F aisse, 1982). Bea salience has been ound o be associa ed wi h he u ge o mo e o music (Madison e al., 2011). Compu a ional models o bea salience p oposed so a can be di ided in o wo ca e- go ies based on he kind o music ep esen a ion hey use: symbolic models (e.g., Pa ncu , 1994;Toi iainen and Snyde , 2003), which ope a e on no a ion-like music ep esen a ions, such as MIDI, and audio models (e.g., La illo e al., 2008;Madison e al., 2011), which ake music eco dings as inpu . I can be assumed ha , du ing con inuous lis ening o music, bea in e ence and bea main enance exis concu en ly, wi h bea in e ence being mo e p ominen du ing momen s o low bea salience, and bea main enance du ing momen s o high bea salience. Namely, wi hin he amewo k o ac i e pe cep ion, bea in e ence and main enance can be ega ded as p edic i e coding (Koelsch e al., 2019) wi h low and high ce ain y, espec i ely. Wi hin his amewo k, he wo p ocesses could be conside ed o exis on a con inuum ins ead o being dicho omous. This wa an s he use o a con inuous a iable ha measu es he deg ee o bea salience h oughou he musical pieces a each ime poin . The model by La illo e al. (2008), applied in he p esen s udy, allows he ex ac ion dynamic a ia ion o bea salience. The s eng h o his model is ha i has been pe cep ually alida ed and he e o e a o ds in e - p e abili y o he ound neu al co ela es. Came on and G ahn (2016) p o ide a comp ehensi e e iew high- ligh ing he oles o co ical, subco ical, and ce ebella egions in bea pe cep ion, including in e ence and main enance. They highligh he need o dynamically in es iga ing he ime cou se o hy hm and bea pe cep ion. While neu al co ela es o musical bea ha e been in es i- ga ed using na u alis ic s imula ion on bo h oxel-le el (Allu i e al., 2012,2013;Toi iainen e al., 2014) and ne wo k-le el (Bu una e al., 2017), e ec s o musical bea salience on he empo al dynamics o o e all unc ional connec i i y in he b ain ha e no been s udied so a . 1.1. Bea and neu al ac i a ion When s udying he b ain p ocesses which sus ain iming, se e al mo o - ela ed b ain egions ha e been ound o be in ol ed (G ahn, 2009). This has been conside ed a g oundb eaking finding in music neu oscience, as me ely lis ening o music in he absence o any o e mo emen engages mo o esou ces o he b ain. These include p emo o co ex (PMC), supplemen a y mo o a ea (SMA), and basal ganglia (G ahn and B e , 2007;Chen e al., 2008;Beng sson e al., 2009;G ahn and Rowe, 2009;Geise e al., 2012;Teki e al., 2012;Kung e al., 2013). Rhy hm hus ac i a es he neu al ci cui s in ol ed in mo o p ocessing, which p o ides a possible accoun o he in ima e connec ion be ween music and mo emen (Za o e and Salimpoo , 2013). Bo h he basal ganglia (especially he pu amen) and he SMA seem o be pa icula ly c ucial o bea pe cep ion (Came on and G ahn, 2016; G ahn and B e , 2007). Mo o a eas, pa icula ly he SMA, pe o m ime p edic ion ia op-down connec ions o he audi o y co ex (Cadena-- Valencia e al., 2018;Me chan and Honing, 2014;Me chan e al., 2015a,b;Me chan and Ya ow, 2016). The basal ganglia ha e been implica ed in bo h bea finding (G ahn and Rowe, 2009) and bea con inua ion (Kung e al., 2013). Mo e specifically, inc eased ac i a ion in he basal ganglia du ing hy hm pe cep ion has been epo ed o eflec he in e nal gene a ion o upcoming bea s once he empo al s uc u e o he music has been es ablished and i emains egula . In line wi h his, ac i a ion in he basal ganglia dec eases in esponse o i eg- ula hy hms, as hese lead o modifica ions in bea p edic ion (G ahn and Rowe, 2013), while ce ebella ac i i y inc eases, which is consis en wi h a dis inc ole o he ce ebellum in absolu e iming (G ube e al., 2010;Teki e al., 2012;Came on and G ahn, 2016). In line wi h his, Spence and I y (2013) e iew li e a u e on ce ebellum and iming and conclude ha i s ole is key in “p o iding a p ecise, me ical ep esen- a ion o defined empo al in e als” a he han gi e ise o abs ac empo al ep esen a ions o unde lying hy hms. 1.2. Bea and unc ional connec i i y Keeping ime is likely o be an eme gen ne wo k p ope y, and hence me ely localizing i o pa icula egions p o ides an incomple e pic u e o i s neu al unde pinnings. Consequen ly, unc ional connec i i y s udies in hy hm pe cep ion ha e p o ided new insigh s by iden i ying associa ed audi o y- and mo o - ela ed ne wo ks, which may acili a e he empo al p edic ions in ol ed in hy hm pe cep ion (Za o e e al., 2007;Pa el and I e sen, 2014). Howe e , unc ional connec i i y s udies a e a e and ha e no su ficien ly in es iga ed his phenomenon beyond he Gene al Linea Model (GLM) app oach. In pa icula , a unc ional ne wo k o co ical and subco ical s uc u es, consis ing o audi o y co ex, PMC, pu amen, and SMA, seems o play a ole du ing bea pe cep ion, especially when in e nal gene a ion o he bea is equi ed (G ahn and Rowe, 2009). This co obo a es he hypo hesis ha he PMC and do sal audi o y egions mainly e ol ed o sus ain he mechanisms o empo al sequencing (Lea e e al., 2009;Rauschecke and Sco , 2009). Howe e , as indica ed in Me chan e al. (2015), while one s udy e- po ed inc eased audi o y-p emo o coupling as a unc ion o bea salience in isoch onous sequences (Chen e al., 2006; see also Assaneo and Poeppel, 2018) ano he s udy ound his coupling o dec ease as me ic complexi y inc eased (Kung e al., 2013). Because eal music is a me ical s imulus, which comp ises di e en ially accen ed g oupings and subdi isions o bea and hence di e en ially salien bea s, we should expec a pa e n o connec i i y in ela ion o bea salience ha is di e en om wha p e iously has been obse ed in s udies using isoch onous and equally-salien bea s. On a mo e gene al no e, he lack o consensus does no cu en ly ega d which b ain a eas a e in ol ed in he s udy o iming and hy hm, bu mo e specifically, wha connec ions exis amongs he ele an a eas ha gi e ise o pa icula iming beha io s (G ahn, 2009). Mo eo e , since bea pe cep ion un olds o e ime when one lis ens o music (Came on and G ahn, 2016), i is c ucial o s udy how b ain ne wo ks dynamically o ganize hemsel es in con inuous na u alis ic music lis ening si ua ions. Recen esea ch on bea p ocessing beyond he GLM app oach in es iga ed bea saliency using blind sou ce sepa a ion echniques by means o Independen Componen Analysis (ICA) in combina ion wi h Music In o ma ion Re ie al (MIR) me hods (Bu una e al., 2017). Findings e ealed a obus ac ion-pe cep ion unc ional ne wo k o audi o y and mo o egions associa ed wi h a ia ions in bea salience, which was concealed om a compa a i e GLM analysis. In pa icula , he mo o a eas o he ne wo k we e ound o co ela e nega i ely wi h bea salience. Fu he elucida ion o empo al dynamics o he b ain mecha- nisms pe aining o bea p ocessing will be necessa y o ully cha ac e ize i s na u e. P. Toi iainen e al. Neu oImage 216 (2020) 116191 2 1.3. Bea and ch onnec ome G aph-based me hods p o ide a use ul ool o spa ially cha ac e - izing ne wo k s uc u es (Bullmo e and Spo ns, 2009), by ep esen ing egions o oxels in he b ain as nodes in a g aph. In he domain o music, g aph heo y has been used o in es iga e unc ional ne wo ks du ing music lis ening and hei dependence on musical p e e ence (Wilkins e al., 2014) and aining (Allu i e al., 2017). A g aph- heo e ical mea- su e commonly used in hese s udies is node cen ali y, which indica es he deg ee o which a egion comp ises an impo an hub in he b ain’s ne wo k. Va ious me hods ha e been p oposed o quan i y node cen- ali y. Closeness and be weenness cen ali y a e o en used in analyses conside ing a mos a ew hund ed selec ed egions in he b ain (Loh- mann e al., 2010), bu due o hei compu a ional complexi y hey a e no easible o oxel-based whole-b ain analysis, an app oach necessa y o disen angling unc ional ne wo k s uc u es wi h su ficien spa ial accu acy and o a oid dependence on a pa icula choice o b ain pa - cella ion. Fo his pu pose, Eigen ec o Cen ali y (EC; Bonacich, 2007) is mo e app op ia e. To es ima e EC, a non-nega i e unc ional oxel-by- oxel connec i i y ma ix is fi s calcula ed. A common choice o he connec i i y measu e is Pea son’s co ela ion added by one. Subsequen ly, Singula Value Decomposi ion is applied o he ob ained connec i i y ma ix o ob ain he fi s eigen ec o . This ec o con ains he oxelwise cen ali y alues. EC a ibu es high cen ali y alues o oxels ha a e s ongly connec ed o a la ge numbe o oxels ha hemsel es a e cen al, he eby p o iding a global indi ec measu e o unc ional connec i i y. I he e o e indica es o a gi en condi ion o ask he impo an compu a ional hubs in he b ain’s unc ional ne wo k. An appealing ea u e o EC is ha , unlike closeness and be weenness cen ali y, i does no ely on h esholding and hus is a pa ame e - ee me hod. In p e ious s udies, EC has been ound o change as a unc ion o s imulus (Koelsch and Skou as, 2014), ask (Ga cía-Ga cía e al., 2015), and condi ion (Binnewijzend e al., 2013;Lou e al., 2015). While unc ional connec i i y s udies adi ionally ha e assumed connec i i y pa e ns ha a e s a ic o e ime, dynamic unc ional connec i i y s udies ha e become inc easingly common ( o a e iew, see P e i e al., 2017). Calhoun e al. (2014) ha e coined he e m “ch onnec ome” o e e o ime- a ying whole-b ain connec i i y pa e ns. Dynamic unc ional connec i i y s udies a e mos commonly based on sliding window ap- p oaches (P e i e al., 2017) o phase synch oniza ion es ima es (e.g. Gle ean e al., 2012). The p esen s udy in es iga es he e ec o bea salience on he dy- namics o whole-b ain unc ional ne wo ks du ing con inuous lis ening o music o in es iga e p ocesses unde lying bea in e ence (p e alen du ing low bea salience) and bea main enance (p e alen du ing high bea salience). To his end, i employs dynamic g aph analysis (Eigen- ec o Cen ali y) in andem wi h compu a ional es ima ion o bea salience om he musical s imulus, o ob ain an o e all iew o how unc ional ne wo k cen ali y changes dynamically as a unc ion o musical bea salience. Subsequen ly, a ge ed unc ional connec i i y analyses (Psychophysical In e ac ion) a e ca ied ou o in es iga e how unc ional connec i i y a ies and is modula ed by bea salience wi hin and be ween b ain egions ha ha e p e iously been ound o be in ol ed in bea pe cep ion. Due o sca ci y and lack o consensus in p e ious esea ch, specific hypo heses abou he mani es a ions o he p ocesses o bea in e ence and main enance in whole-b ain unc ional ne wo k connec i i y a e di ficul o d aw. Howe e , we assume ha ne wo k cen ali y in a eas p e iously ound o be ac i a ed by bea pe cep ion, such as co ical, ce ebella , and s ia al mo o a eas, would be modula ed by he p ocess o in e ing a salien bea . Fo specific hypo heses ega ding he depen- dence o unc ional connec i i y on bea salience, we assume, based on esul s ob ained by Kung e al. (2013), ha because music is a me ical s imulus, audi o y-mo o connec i i y inc eases wi h low bea salience. Doya (2000) posi s ha he ce ebello- halamo-s ia o-co ical mo o pa hway can be di ided in o smalle ne wo ks ha play complemen a y oles in lea ning and mo o con ol. The e iew pape highligh s he ole o he ce ebellum as one ha pe o ms supe ised lea ning whe ein an in e nal ep esen a ion o he da a is al eady a ailable. The co ex’s ole is desc ibed as one ha pe o ms unsupe ised lea ning, which can be defined as da a-d i en app oach o lea ning/and esponding o he ex- is ence o lack o pa e ns in i /guided by on he con ex / he s a is ical p ope ies o he s imulus (Bos an e al. 2013). In his app oach, he pa e n o s uc u e has o be lea n based on he a ailable da a and con ex . In his amewo k, one could su mise ha he ce ebello- halamo- co ical mo o pa hway in conjunc ion wi h he audi o y co ex is esponsible o de eloping an in e nal ep esen a ion o bea . Howe e , once his empla e is o med, he ce ebellum con inues o p ocess he bea and ma ch he esul wi h he o med empla e. One could hen hypo hesize ha dec eases in bea salience engende de ia ions om he empla e, which would hen ec ui highe -o de co ical mo o pa h- ways o ake o e and lea n how bes o fill in he gaps based on he audi o y in o ma ion and sho - e m empo al con ex a ailable. In o he wo ds, in he case o low bea salience, highe le el co ical ne wo ks would be ec ui ed o upda e he p edic ion minimizing p edic ion e o ed o wa d om lo e le el a eas. Once he bea is in e ed, he main- enance may no ely on o wa d p edic ion e o om he lowe le els. 2. Me hods 2.1. MRI da a acquisi ion Pa icipan s: Se en y-se en heal hy pa icipan s (age 29.6 8.9, 43 emales, 71 igh -handed, 1 ambidex ous) wi h no his o y o neu olog- ical o psychological diso de s pa icipa ed in he MRI expe imen . The pa icipan s we e sc eened o inclusion c i e ia be o e admission o he expe imen (no e omagne ic ma e ial in hei body; no a oo o ecen pe manen colo ing; no p egnancy o b eas eeding; no ch onic pha - macological medica ion; no claus ophobia). The pa icipan s had a i- able le els o music educa ion, wi h a median o 3.5 yea s and an in e qua ile ange o 11.25 yea s o o mal music educa ion. S imulus & ask: Pa icipan s’b ain esponses we e acqui ed wi h MRI while hey lis ened o an 8-min long piece o A gen inean ango, Adi os Nonino by As o Piazzolla. This s imulus was chosen because i con ains wide a ia ions in he salience o musical bea . Pa icipan s’ only ask was o a en i ely lis en o he music deli e ed ia high-quali y MR-compa ible inse ea phones (A o ec, S ua , FL, USA) while keeping hei eyes open. Foam was used o a enua e he g adien noise. The sound le el o he s imuli was indi idually adjus ed so ha hey we e audible abo e he scanne noise bu he olume s ayed wi hin sa e y limi s (below 80 dB). The s udy p o ocol p oceeded on accep ance by he e hics commi ee o he Coo dina ing Boa d o he Helsinki and Uusimaa Hospi al Dis ic . The da a collec ion was pa o a b oade p ojec (Tun ee ) in ol ing addi ional es s and neu oimaging and neu ophysi- ological measu es (Allu i e al., 2015;Boge e al., 2016;Bu una e al., 2014,2015;Ca lson e al., 2015;Haumann e al., 2016;Kliuchko e al., 2015,2016). Scanning: Scanning was pe o med using a 3T MAGNETOM Sky a whole-body scanne (Siemens Heal hca e, E langen, Ge many) and a s anda d 32-channel head-neck coil, a he Ad anced Magne ic Imaging (AMI) Cen e (Aal o Uni e si y, Espoo, Finland). Using a single-sho g adien echo plana imaging (EPI) sequence hi y- h ee oblique slices (field o iew: 192 192 mm; 64 64 ma ix; slice hickness: 4 mm, in e slice skip: 0 mm; echo ime: 32 ms; flip angle: 75; oxel size: 222mm 3 ) we e acqui ed e e y 2 s, p o iding whole-b ain co e age pe pa icipan . T1-weigh ed s uc u al images (176 slices; field o iew: 256 256 mm; ma ix: 256 256; slice hickness: 1 mm; in e slice skip: 0 mm; pulse sequence: MPRAGE) we e also collec ed o indi idual co egis a ion. P ep ocessing: Func ional MRI scans we e p ep ocessed on a Ma lab P. Toi iainen e al. Neu oImage 216 (2020) 116191 3 pla o m using SPM8 (S a is ical Pa ame ic Mapping), VBM5 o SPM (Voxel Based Mo phome y; Wellcome Depa men o Imaging Neu o- science, London, UK), and cus omized sc ip s de eloped by he p esen au ho s. Fo each pa icipan , low- esolu ion images we e ealigned on six dimensions using igid body ans o ma ions ( ansla ion and o a ion co ec ions did no exceed 2 mm and 2, espec i ely), segmen ed in o g ey ma e , whi e ma e , and ce eb ospinal fluid, and egis e ed o he co esponding segmen ed high- esolu ion T1-weigh ed s uc u al im- ages. These we e in u n no malized o he MNI (Mon eal Neu ological Ins i u e) segmen ed s anda d a p io i issue empla es using a 12-pa am- e e a fine ans o ma ion. Func ional images we e hen blu ed o bes accommoda e ana omical and unc ional a ia ions ac oss pa icipan s as well as o enhance he signal- o-noise by means o spa ial smoo hing using an 8 mm ull-wid h-a -hal -maximum Gaussian fil e . Mo emen - ela ed a iance componen s in MRI ime se ies esul ing om esid- ual mo ion a i ac s, assessed by he six pa ame e s o he igid body ans o ma ion in he ealignmen s age we e eg essed ou om each oxel ime se ies. Following his, spline in e pola ion was used o de end he MRI da a. Nex , empo al fil e ing was pe o med by Gaussian smoo hing (ke nel wid h: 4 s), as i p o ides a good comp omise be ween e ficiency and bias (F is on e al., 2000). 2.2. Musical ea u e ex ac ion Bea salience o he used s imulus was compu a ionally es ima ed using he model p oposed and pe cep ually alida ed by La illo e al. (La illo e al., 2008). The model is based on he use o a mo ing analysis window o ob ain a dynamic es ima e o bea salience. Fo each analysis window, he signal is fi s passed h ough a gamma one fil e bank, a e which he onse s a e de ec ed o each equency channel using ull-wa e ec ifica ion, low-pass fil e ing, ime di e en ia ion and hal -wa e ec ifica ion. Following his, he au oco ela ion unc ion o he en e- lope is calcula ed o each equency channel and hese ob ained unc- ions a e summed ac oss channels o es ima e pe iodici ies p esen in i s. Subsequen ly, he summa y au oco ela ion unc ion is mul iplied by a esonance cu e (Toi iainen and Snyde , 2003), wi h he maximum a he lag o 500 ms, co esponding o he p e e ed empo a he icini y o 120 bpm. Finally, ins an aneous bea salience is es ima ed as he heigh o he highes peak in he au oco ela ion unc ion. The me hod is schema ically p esen ed in Fig. 1. Bea salience depends on se e al musical pa ame e s, including hy hmic complexi y, imb e, and empo. High bea salience is e oked by music ha con ains ones wi h sha p a acks occu ing egula ly a a es close o 120 bpm, while music ha con ains slow a acks o syncopa ion, o is played a low o high empo, yields a lowe bea salience. The p esen bea salience model has been alida ed using a a ing s udy wi h 100 musical excep s ep esen ing a ange o di e en musical s yles (La illo e al., 2008). The pe cep ual da a showed high in e -subjec consis ency and he model could p edic hem wi h high accu acy. This sugges s ha pe cei ed bea salience o he p esen s imulus can be p edic ed by he p esen model. In he p esen s udy we es ima ed he s imulus’bea salience using a 3-s window and a 1-s hop. These ob ained ime se ies had he mean alue o 0.25 and s d o 0.11. Subsequen ly, he ob ained ime se ies was con ol ed wi h canonical double-gamma hemodynamic esponse unc- ion and downsampled o con o m wi h he sampling a e o he MRI da a. The o iginal and con ol ed ime se ies a e p esen ed in Fig. 2. In addi ion o bea salience, 24 o he musical ea u es we e ex ac ed, ep esen ing a ange o musical dimensions. Fo a ull desc ip ion o hese a iables, see Supplemen a y ma e ial. None o hese ea u es co ela ed significan ly wi h bea salience, sugges ing he absence o con ounding ac o s in o he musical dimensions. 2.3. Cen ali y analysis Pa cella ion: To educe he compu a ional bu den, he da a o each pa icipan was spa ially downsampled by a linea ac o o wo, yielding 28,542 cubical oxels wi h 4-mm edges. The connec i i y analysis used in his s udy is schema ically p esen ed in Fig. 3. Windowing: Fo dynamic analysis o connec i i y, we employed a sliding window app oach, which is he mos commonly used app oach o es ima e dynamic unc ional connec i i y (P e i e al., 2017). To his end, each pa icipan ’s da a was windowed using a mo ing Gaussian window wi h a s anda d de ia ion o 10 scan in e als (20 s) and a hop size o one scan in e al. This window has he e ec i e wid h o app ox. 31 secs Fig. 1. Bea salience es ima ion me hod used in he p esen s udy: (a) audio signal; (b) windowed exce p ; (c) ou pu o gamma one fil e bank; (d) onse de ec ion cu es pe equency channel; (e) summa y au oco ela ion unc ion o onse de ec ion unc ions; ( ) au oco ela ion unc ion mul iplied by a esonance cu e (Toi iainen and Snyde , 2003). The la e is displayed as a do ed line. Ins an aneous bea salience (BS) is es ima ed as he heigh o he maximum o he au oco e- la ion unc ion. P. Toi iainen e al. Neu oImage 216 (2020) 116191 4 Fig. 2. Top: bea salience es ima ed om he s imulus used in he s udy. Bo om: bea salience con ol ed wi h hemodynamic esponse unc ion. Uni s o he y axis a e a bi a y and hence a e ma ked as low and high. Fig. 3. Schema ic ep esen a ion o he dynamic cen ali y analysis: (a) BOLD ime se ies da a o oxels i ¼1, …,V, T ime poin s, oxel size 444mm 3 ; (b) Gaussian window cen e ed a ime poin τ ; (c) windowed BOLD ime se ies da a; (d) ins an aneous non-nega i e unc ional connec i i y ma ix a ime poin τ , ob ained using Spea man co ela ion ρ ; (e) fi s eigen ec o o he connec i i y ma ix, ob ained by sol ing he eigenequa ion, ep esen ing cen ali y map a ime poin τ ; ( ) eigen ec o cen ali y ime se ies ob ained by ca ying ou s eps b-e o all ime poin s. P. Toi iainen e al. Neu oImage 216 (2020) 116191 5 (Leona di &Van De Ville, 2015), which lies wi hin he ange o 30–60 s ecommended by P e i e al. (2017). A Gaussian window was used because o i s supe io spec al selec i i y o e a ec angula one (Leo- na di &Van De Ville, 2015). The lowe end o he ecommended ange was used, because he ecommenda ion is based on es ing-s a e da a, and i can be assumed ha connec i i y dynamics wi h he p esen s imula ion a e as e han wi h es ing s a e. Fo each window loca ion, a unc ional connec i i y ma ix was es ima ed by calcula ing he Spea man co ela ion be ween each pai o windowed ime se ies and adding uni y o each elemen o make he ma ix nonnega i e. Eigen ec o cen ali y mapping: Fo each o he hus ob ained ma ices, he fi s eigen ec o was ob ained by powe i e a ion me hod ( on Mises, 1929). Fo each pa icipan , his yielded a se ies o EC maps co e- sponding o each o he imepoin s in he da a. Co ela ion wi h eg esso : To assess he ex en o which he dynamic EC o each oxel was modula ed by he bea salience o he musical s imulus, he EC ime se ies we e co ela ed wi h he bea salience ime se ies using Spea man co ela ion. Fo each pa icipan , his yielded a spa ial map indica ing he s eng h and di ec ion o modula ion a each oxel. Fo significance es ima ion o he hus ob ained co ela ion maps, a Mon e Ca lo simula ion was ca ied ou in which he cen ali y and co ela ion analysis was applied o BOLD ime se ies phase-sc ambled wi h FFT. This was epea ed 10,000 imes o ob ain an empi ical dis i- bu ion o co ela ion alues, which was hen used o con e he co e- la ion o z s a is ics. Subsequen ly, hese maps will be e e ed o as he Cen ali y Modula ion Maps (CMM). Second-le el analysis: Fo g oup-le el in e ence, he pa icipan -le el CMMs we e pooled using S ou e ’s Z-sco e me hod (S ou e , S., DeVinney, L. &Suchmen, 1949). This yielded a g oup-le el CMM o z s a is ics. Subsequen ly, wo ypes o analysis we e pe o med. Fo ne wo k-le el analysis, he g oup-le el CMM was co ela ed wi h es ing-s a e ne wo ks. Fo egional analysis, he map was h esholded, and co ec ion o mul iple compa isons was pe o med wi h clus e -size h esholding, whe e he espec i e h esholds we e ob ained using a null dis ibu ion ob ained wi h a pe mu a ion es . Specifically, we pe o med 10.000 i e a ions, in which we co ela ed he g oup-le el CMM wi h a phase-sc ambled e sion o he bea salience eg esso , pooled and h esholded he hus ob ained map and kep he maximal clus e size. 2.4. Psychophysiological in e ac ions analysis Since cen ali y analysis as such does no p o ide any di ec measu e o in e connec i i y be ween a eas in he b ain and how his migh be modula ed by bea salience, subsequen Psychophysiological In e ac ions (PPI) analyses we e ca ied ou . PPI e alua es how connec i i y be ween wo b ain a eas depends on an ex e nal a iable, ha is, how he p es- ence o absence o an ex e nal a iable modula es he connec i i y. To his end, i employs a mul iple eg ession model ha p edic s he ime- cou se o a a ge egion by he ime-cou se o a seed egion, an ex e nal a iable, and he p oduc he eo . The be a weigh s o he p oduc a iable a e assumed o indica e he s eng h o connec i i y modula ion by he ex e nal a iable ( o mo e de ails, see (F is on e al., 1997)). As audi o y-mo o connec i i y was o key in e es in he p esen s udy, we es ic ed his analysis o egions associa ed wi h he p o- cessing o musical bea belonging o he ce ebello- halamic-s ia o-co ical mo o pa hway, specifically he mo o and audi o y co ices, basal ganglia, halamus, and ce ebellum. The seeds employed in he PPI analyses we e selec ed in a da a-d i en ashion based on he g oup CMM ob ained om he EC analysis. Subsequen ly, o each seed eg esso , PPI analysis was pe o med wi h all oxels wi hin he mo o co ex (MC), audi o y co ex (AC), basal ganglia (BG), hal- amus (TH), and ce ebellum (CE). Fi e sepa a e PPI analyses we e hus ca ied ou , in each o which he a ge egion comp ised he union o he fi e a o emen ioned egions. Significance o pa icipan -le el PPI maps was es ima ed wi h an empi ical dis ibu ion ob ained om a Mon e Ca lo simula ion based on FFT phase-sc ambling o he bea salience ime se ies. Pooling o he maps and clus e -size h esholding we e ca ied ou ollowing he p ocedu e desc ibed in chap e 2.4.2. 3. Resul s 3.1. EC analysis The CMM was h esholded a a significance le el o p <.01 ( wo- ailed, clus e co ec ed a FWE<0.01; clus e size h eshold 100 oxels). Resul s a e p esen ed in Fig. 4 and Table 1a–b. As can be seen, high bea salience was associa ed wi h significan ly inc eased cen ali y in se e al a eas o he DMN, including igh on al a eas, igh angula gy us, and bila e al p ecuneus. Low bea salience, in u n, was associa ed wi h significan ly inc eased cen ali y in mo o a eas, including p ima y mo o co ex, p emo o co ex, and supplemen a y mo o a ea, in igh audi o y a eas, middle occipi al gy us, as well as in mo o a eas o he ce ebellum. To assess he deg ee o which he significan ly co ela ed egions o e lap wi h es ing-s a e ne wo ks, he b ain was pa cella ed acco ding o he es ing-s a e ne wo ks epo ed in Damoiseaux e al. (2006) by assigning each oxel o he ne wo k wi h highes loading and calcula ing, o posi i ely and nega i ely co ela ing clus e s sepa a ely, he p opo - ion o hei o e lap wi h each o he ne wo ks. As can be seen in Fig. 5, highes o e lap o posi i ely co ela ing clus e s was ound wi h DMN (48%) and igh cen al execu i e ne wo k (33%), and ha o nega i ely co ela ing clus e s o senso imo o ne wo k (38%) and audi o y ne wo k (15%). 3.2. Psychophysiological in e ac ions analysis To in es iga e in de ail he modula o y e ec o bea salience on unc ional connec i i y be ween and wi hin b ain a eas p e iously ound o be associa ed wi h musical bea p ocessing, we ca ied ou Psycho- physiological In e ac ions (PPI) analyses in he mo o co ex (MC), audi o y co ex (AC), basal ganglia (BG), halamus (TH), and ce ebellum (CE), wi h he bea salience ime se ies as he psychological eg esso . Fo seeds we selec ed oxels ha displayed highes inc ease in EC du ing low bea salience in each o he a o emen ioned a eas. This esul ed in fi e seed esiding in he le SMA ([-14 -10 64]), igh STG ([58 -14 8]), le cauda e ([-10 0 12]), halamus ([-10 -4 12]) and igh lobule VI ([34–70 -20]). Fo he pu pose o he PPI analyses, each seed eg esso was ob- ained as he mean ime se ies o ac oss oxels wi hin a 6-mm adius om he espec i e seed. Fo each seed eg esso , PPI analysis was pe o med wi h all oxels wi hin MC, AC, BG, TH, and CE. The g oup-le el PPI maps o each seed egion we e h esholded a a significance le el o p <.01 ( wo- ailed, clus e co ec ed a FWE<0.01; clus e size h eshold 264 mm 3 ). To p o ide an o e iew o how bea salience modula ed o e all unc ional connec i i y wi hin and be ween he fi e egions o in e es , Fig. 6 displays he s eng h o in e ac ion o each pai o seed and a ge egion, o bo h nega i e (high connec i i y du ing low bea salience) and posi i e (high connec i i y du ing high bea salience) in e ac ion. As can be seen, du ing low bea salience connec i i y om he AC seed inc eased o a g ea p opo ion o he MC, and o a somewha lesse deg ee o AC, TH, and CE. Fo high bea salience, we obse ed a di e en pa e n. Mos no ably, connec i i y wi hin AC and CE inc eased, and he e was significan connec i i y in- c ease om he TH seed o MC, AC, and CE, and om he BG seed o AC and CE. High bea salience: Clus e s whose unc ional connec i i y wi h he selec ed seeds mani es ed inc eased unc ional connec i i y du ing high bea salience a e shown in Table 2a (a he end o he manusc ip ). As can be seen, mos significan inc ease in unc ional connec i i y was obse ed wi hin he AC and CE egions (z ¼5.7, z ¼5.0, espec i ely) as well as om he TH and BG seeds o igh SMA (z ¼4.4, z ¼3.9, espec i ely). O e all, hese esul s sugges ha unc ional connec i i y be ween audi o y a eas and senso imo o co ex ends o inc ease when P. Toi iainen e al. Neu oImage 216 (2020) 116191 6 music has high bea salience. Low bea salience: Clus e s whose unc ional connec i i y wi h he selec ed seeds mani es ed inc eased unc ional connec i i y du ing low bea salience a e shown in Table 2b (a he end o he manusc ip ). As can be seen, o low bea salience mos significan inc ease in unc ional connec i i y was ound om he AC seed (R STG) o le PoG (z ¼5.8) and le STG (z ¼5.7), as well as om he MC seed (L SMA) o le PoG (z ¼3.5). Mo eo e , g ea e connec i i y was obse ed be ween he igh AC seed and he le STG (z ¼5.7; n¼138) du ing low bea salience whe eas high bea salience was associa ed wi hin he igh STG (z ¼5.7; n¼252) wi h a educed e ec in he le STG (z ¼4.2; n¼71). 4. Discussion Using dynamic Eigen ec o cen ali y analysis, we he e showed ha musical bea a ec s he b ain ne wo ks’cen ali y pa e n du ing music lis ening, wi h high bea salience inc easing cen ali y in he De aul Mode Ne wo k, and low bea salience inc easing cen ali y in he mo o and audi o y co ices. Subsequen Psychophysiological In e ac ions An- alyses wi h seeds selec ed om he Eigen ec o cen ali y analysis esul s showed ha unc ional connec i i y be ween he mo o and audi o y co ices ends o inc ease du ing momen s o low bea salience. This is he fi s s udy o employ dynamic whole-b ain unc ional connec i i y analysis wi h na u alis ic musical s imula ion. The analysis showed ha unc ional connec i i y om he basal ganglia and halamus o senso i- mo o and audi o y co ices as well as ce ebellum ends o inc ease du ing high bea salience. Finally, he esul s showed inc eased con- nec i i y wi hin ce ebellum du ing momen s o high bea salience. 4.1. Dynamic g aph analysis As can be obse ed in he esul s, low bea salience in he s imulus Fig. 4. Regions wi h significan ly inc eased cen ali y du ing (a) high and (b) low bea salience (p <.01, wo- ailed; clus e -size co ec ed a FWE 0.01; clus e -size h eshold 800 mm 3 ). Table 1a Regions wi h inc eased cen ali y du ing high bea salience (p <.01, wo- ailed, FWE<0.01 CS ¼100). Clus e # L/ R egion N MNI (mm) max(Z) BA addi ional egions 1 R MFG 211 34,34,44 4.05 9 IFG, SFG 2 R AG 188 34,14,34 4.01 39 3 R IFG 185 6,42,-8 4.14 11 L ACG, R GR, ACG 4 R P ec 131 2,-54,48 3.93 7 L P ec, MCG 5 R P ec 125 6,-58,24 3.71 23 L P ec, Cun P. Toi iainen e al. Neu oImage 216 (2020) 116191 7 was associa ed wi h inc eased cen ali y in ce ebellum and co ical audi o y-mo o egions while he key hubs o he DMN exhibi ed high cen ali y du ing high bea salience. Specifically, main aining pe cei ed bea du ing musical momen s cha ac e ized by high bea salience was ound o mani es as inc eased cen ali y in egions belonging o he DMN specifically in he bila e al p ecuneus, egions su ounding he igh angula gy us, MPFC, and bila e al pos e io cingula e gy us. Inc ease in ac i i y in hese egions has been p e iously implica ed in dec eased audi o y-cogni i e load (Allu i e al., 2012). Indeed, momen s o high bea salience can be assumed no o equi e a en i e bea finding and hence be conside ed as low load condi ions, implying inc eased mind-wande ing. Ga cía-Ga cía e al. (2015) obse ed inc ease in cen- ali y o he p ecuneus and angula gy us o he DMN in es condi ions e sus ask-based condi ions ( isual) which we e associa ed wi h inc eased cen ali y in isual egions. This esul is in acco dance wi h he p esen findings, assuming ha bea in e ence is conside ed o be a ask which equi es a en i e lis ening, and bea main enance, in con as o bea in e ence, o be a es condi ion. On he o he hand, inc eased cen ali y du ing low bea salience was ound in p emo o co ex, SMA, ce ebellum in conjunc ion wi h audi o y associa ion a eas, sugges ing ha bea in e ence migh be associa ed wi h inc eased global connec i i y in hese a eas. These esul s a e in line wi h se e al s udies ha indica e he ole o co ical mo o egions in ac i e bea finding (Chen e al., 2008;G ahn and Rowe, 2009;Kung e al., 2013). Specifically, he SMA has been implica ed o be c i ical in in e - nal/co e mo emen gene a ion, which equi es en aining o a hy hm (Jenkins e al., 2000;Wu and Halle , 2013). Penhune e al. (1998) demons a ed he impo ance o he igh STG as a locus in sel -cued hy hm ep oduc ion om audi o y sequence/sequen ial empo al memo y (Penhune e al., 1999). Fu he mo e, he pos e io ce ebellum has been implica ed in iming pe cep ion and adjus men o senso y e en s ia in e nal p edic ion models (Doya, 2000). Howe e , he ole o he ce ebellum and basal ganglia in iming pe cep ion has been deba ed upon. The e was no e idence o significan co ela ion be ween cen ali y in he basal ganglia and bea salience, which p obably indica es i s ole bo h in bea main enance and bea finding. In line wi h his, Kung e al. (2013) posi ha BG is ac i e in bo h bea finding and bea main enance/ apping o he bea . Se e al s udies ha e indica ed he BG’s ole in bea p o- cessing when he bea is highly salien and/o in he “p epa a ion o p oduc ion o well-lea ned mo o esponses”(Kung e al., 2013). Teki e al. (2011) demons a e he exis ence o wo dissocia i e ne wo ks unde lying absolu e and ela i e ime keeping: one wi h he ce ebellum as a ocal poin /p ecision clock ha media es absolu e iming; he o he a s ia o- halamo-co ical ne wo k in ol ed in bea -based ime keeping o Table 1b Regions wi h inc eased cen ali y du ing low bea salience (p <.01, wo- ailed, FWE<0.01 CS ¼100). Clus e # L/R egion N MNI (mm) max(Z) BA addi ional egions 1 L PoG 605 18,-34,72 4.61 9 PCL,SPG,P G,SMA,SFG,IPG 2 L PoG 194 50,-18,48 4.86 4 IPG 3 L P G 156 38,-10,60 4.66 6 4 L IFG 141 62,10,12 4.52 6 RO,STG 5 L SOG 118 10,-94,20 3.42 18 Cun, MOG 6 L IFG 113 50,22,4 3.70 45 7 R P G 356 30,.22,60 4.21 6 SMA,PoG,SFG 8 R IOG 306 46,-78,-16 4.95 19 Lob VI, C I-II,FusG 9 R STG 180 58,-14,8 4.05 RO,SMG Fig. 5. P opo ion o o e lap be ween significan clus e s co ela ing posi i ely and nega i ely wi h bea salience, and es ing s a e ne wo ks. DMN –de aul mode ne wo k, AN –audi o y ne wo k, CBLN –ce ebella ne wo k, SN – salience ne wo k, CEN VR – igh cen al execu i e ne wo k, CEN (L) –le cen al execu i e ne wo k, SM –senso imo o ne wo k, VIS (med) –medial isual ne wo k, VIS (la ) –la e al isual ne wo k, VIS (occ) –occipi al isual. Fig. 6. S eng h o in e ac ion (maximal z s a is ic) o each pai o seed and a ge egion, o bo h nega i e (high connec i i y du ing low bea salience) and posi i e (high connec i i y du ing high bea salience) in e ac ion. MC –mo o co ex, AC –audi o y co ex, BG –basal ganglia, TH – halamus, CE –ce ebellum. P. Toi iainen e al. Neu oImage 216 (2020) 116191 8