Integration–segregation dynamics in functional networks of individuals diagnosed with schizophrenia

RESEARCH REPORT In eg a ion–seg ega ion dynamics in unc ional ne wo ks o indi iduals diagnosed wi h schizoph enia Se gio Iglesias-Pa o 1 | Juan Ruiz de Mi as 2 | Ma ia Felipa So iano 3 | An onio J. Ib añez-Molina 1 1 Depa men o Psychology, Uni e si y o Jaén, Jaén, Spain 2 Depa men o So wa e Enginee ing, Uni e si y o G anada, G anada, Spain 3 Men al Heal h Uni , San Agus ín Hospi al de Lina es, Lina es, Spain Co espondence Se gio Iglesias-Pa o, Depa men o Psychology, Uni e si y o Jaén, Jaén, Spain. Email: [email p o ec ed] Funding in o ma ion This esea ch was unded by Agencia Es a al de In es igaci on, AEI, PID2019-105145RB-I00. Edi ed by: John Foxe Abs ac Schizoph enia has been associa ed wi h dys unc ion in in o ma ion in eg a- ion/seg ega ion dynamics. One o he neu al ne wo ks whose ole has been mos in es iga ed in schizoph enia is he de aul mode ne wo k (DMN). In his s udy, we ha e explo ed he possible al e a ion o in eg a ion and seg ega ion dynamics in indi iduals diagnosed wi h schizoph enia wi h espec o heal hy con ols, based on he s udy o he opological p ope ies o he g aphs de i ed om he unc ional connec i i y be ween he nodes o he DMN in he es ing s a e. Ou esul s indica e ha he pa ien s show a diminu ion o he modula - i y o he DMN and a highe global e iciency, in spa se g aphs. Ou da a emphasise he in e es in s udying empo al changes in ne wo k measu es and a e compa ible wi h he hypo hesis o andomiza ion o unc ional ne wo ks in schizoph enia. KEYWORDS EEG, heal hy con ol, in eg a ion, schizoph enia, seg ega ion 1|INTRODUCTION Schizoph enia (SCZ) is a complex, ch onic men al illness cha ac e ized by a se ies o symp oms, including posi i e (e.g., hallucina ions and delusions), nega i e (e.g., diminished emo ional exp ession and a oli ion) and cogni i e symp oms (e.g., diso ganized speech, hough and/o a en ion). E en oday, he causes o schizoph e- nia emain subjec o deba e and esea ch. Ne e heless, i has been p oposed ha he pa hophysiology o schizo- ph enia may be associa ed wi h dys unc ional pa e ns o in eg a ion/seg ega ion in dis ibu ed neu al ne wo ks, a he han wi h he dis up ion o he unc ion wi hin any speci ic s uc u e (F is on & F i h, 1995; Wang e al., 2015; Zhou e al., 2007). One o he neu al ne wo ks whose possible dys unc- ion has been equen ly associa ed wi h diagnosis o SCZ is he de aul mode ne wo k (DMN). The DMN is a la ge-scale ne wo k ha in ol es associa ion co ex and pa alimbic egions bu spa e senso y and mo o co ex, loca ed along he midline o he p e on al co ex, encompassing he os al an e io cingula e co ex, pos e io cingula e co ex and p ecuneus (Buckne e al., 2008). I has been p oposed ha his ne wo k is esponsible o men al simula ions ha a e used adap i ely in in e nally o ien ed asks Abb e ia ion: BEM, bounda y elemen me hod; DMN, de aul mode ne wo k; EEG, elec oencephalog am; HC, heal hy con ols; ICA, independen componen analysis; SCZ, schizoph enia. Recei ed: 10 No embe 2022 Re ised: 16 Ma ch 2023 Accep ed: 16 Ma ch 2023 DOI: 10.1111/ejn.15970 This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use and dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modi ica ions o adap a ions a e made. © 2023 The Au ho s. Eu opean Jou nal o Neu oscience published by Fede a ion o Eu opean Neu oscience Socie ies and John Wiley & Sons L d. Eu J Neu osci. 2023;1–15. wileyonlinelib a y.com/jou nal/ejn 1 (Buckne , 2013; Sp eng e al., 2009). The ac i a ion o he DMN is an i-co ela ed wi h he ac i i y o b ain ne wo ks esponsible o ex e nal in o ma ion p oces- sing (B essle & Menon, 2010). Thus, in passi e asks whe e he expe imen e ’s equi emen s a e minimized, he DMN is mo e ac i e, and he ac i i y in he a eas o he co ex esponsible o senso y p ocessing is educed (Uddin e al., 2009. Likewise, i has been obse ed ha he DMN shows a lowe ac i a ion du ing he pe o mance o cogni i e asks han in he es ing s a e o in asks ha equi e in e nal concen a ion ( an Buu en e al., 2012). DMN al e a ions ha e been associa ed wi h a ious symp oms o schizoph enia, including posi i e (Ro a ska- Jagiela e al., 2010), nega i e (Wang e al., 2015) and cog- ni i e symp oms (Zhou e al., 2016). Indi iduals wi h an SCZ diagnosis ha e a diminished capaci y o deac i a e DMN du ing ask pe o mance ( an Buu en e al., 2012; Whi ield-Gab ieli e al., 2009; Whi ield-Gab ieli & Fo d, 2012) and ele a ed DMN es ing-s a e unc ional connec i i y (Liu e al., 2012; Shim e al., 2010; Skudla ski e al., 2010; Whi ield-Gab ieli e al., 2009). Howe e , he esul s a e no uni ocal, and some s udies epo dec eased low- equency es ing-s a e unc ional connec i i y wi hin he DMN (Hilland e al., 2022)o widesp ead dec eased connec i i y including he DMN (Liang e al., 2006). The idea o coo dina ion dynamics p oposes ha he endency o b ain egions o exp ess hei specialized unc ions (seg ega ion) coexis s wi h endencies o coo - dina e globally o mul iple unc ions (in eg a ion) and ha his in eg a ion/seg ega ion balance may ha e an e olu iona y unc ion (Deco e al., 2015). In his sense, some au ho s ha e p oposed ha an imbalance in in e- g a ion/seg ega ion capaci y may be ela ed o schizo- ph enia (F is on e al., 1995; Hu e al., 2017; Liang e al., 2006). The p esen wo k aims o explo e he possi- ble al e a ion o in eg a ion and seg ega ion dynamics in indi iduals wi h an SCZ diagnosis wi h espec o heal hy con ols (HC), based on he s udy o he opological p op- e ies o g aphs de i ed om he unc ional connec i i y be ween he nodes o he DMN in es ing s a e. We s a om he assump ion ha he b ain can be unde s ood as a complex ne wo k, and we use g aph heo y as a concep- ual amewo k o s udying he opological ea u es o hese ne wo ks. P e ious g aph- heo e ical esea ch in SCZ and o he psychia ic diso de s has demons a ed a dis up ed bal- ance be ween seg ega ion and in eg a ion wi hin he unc ional b ain ne wo ks. Thus, Rubino e al. (2009), analyzing weigh ed g aphs, ound ha he g oup o indi- iduals wi h an SCZ diagnosis displayed lowe clus e ing (an indica o o seg ega ion) and sho e pa h leng hs (an indica o o in eg a ion) in compa ison o he HC g oup. Likewise, Vé es e al. (2012) ound ha opological p ope ies o clus e ing and modula i y (i.e., seg ega ion) we e somewha educed in childhood- onse SCZ-diagnosed indi iduals. S udying he opologi- cal p ope ies o unc ional b ain ne wo ks, (Lynall e al., 2010; Rubino e al., 2009) ound ha hey we e less hie a chical, less small-wo ld, less clus e ed and less e icien ly wi ed in indi iduals wi h an SCZ diagnosis. Compa ing HC and indi iduals wi h an SCZ diagnosis, (Basse e al., 2008) ound educed hie a chy and inc eased connec ion dis ance in SCZ, and (Liu e al., 2008) ound ha indi iduals wi h an SCZ diagnosis exhibi ed lowe clus e ing and lowe pa h leng h han HC, bu no di e ences we e ound be ween g oups in e iciency. Du ing a wo-back wo king memo y ask, Micheloyannis e al. (2006) ound ha indi iduals wi h an SCZ diagnosis did no show small-wo ld p ope ies o alpha, be a and gamma elec oencephalog am (EEG) e- quency bands. All hese wo ks show he bene i s o g aph heo y o cha ac e ize unc ionally complex ne wo ks. Howe e , mos o hem a e ocused on he s udy o he b ain sys em as a whole (e.g., Basse e al., 2008; Rubino e al., 2009) o , a mos , on he cha ac e iza- ion o in e egional unc ional ela ionships (e.g., Liu e al., 2008). Ve y ew include, speci ically, he s udy o unc ional connec i i y wi hin he DMN. On he o he hand, al hough mos o he ci ed wo ks ake ad an age o he high spa ial esolu ion p o ided by MRI, how- e e , his high empo al esolu ion is a he cos o lowe empo al esolu ion. Fu he mo e, MRI measu es ac i a ion- ela ed hemodynamics a he han neu onal ac i i y in i sel (Bullmo e & Spo ns, 2009). Finally, mos o hese pape s o e a s a iona y iew o he unc ional ela ionships be ween ne wo k commu- ni ies, as hey end o calcula e unc ional ela ionships om measu es based on a e ages o he eco dings. Fo hese easons, in he p esen wo k, we will use EEG es ing s a e eco dings o compa e he dynamical opological p ope ies o he DMN in pa ien s wi h SCZ and HC. Speci ically, we wan o compa e he dynamics o in eg a ion (global e iciency) and seg ega ion (modula i y) o he DMN in SC pa ien s and HC. To his end (see Figu e 1, o a de ailed wo k low), we p oceeded o eco d he EEG o indi iduals wi h an SCZ diagnosis and HC du ing 161 s o es ing s a e. We hen pe o med he econs uc ion o he co ical sou ces, which we subsequen ly pa celed in o he 14 DMN egions using he Desikan–Killiany a las (Desikan e al., 2006). Fo each o hese egions and o each subjec , using a sliding win- dow sys em, we ob ained 798 co ela ion ma ices, 2IGLESIAS-PARRO ET AL. 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License co esponding o each one o he 798 sliding windows, ha we bina ized using a ious h esholds ( om 0.1 o 0.6). F om each o hese unc ional ne wo ks o e ime, we ob ained modula i y and o e all e iciency. Fo each ime se ies o hese wo measu es (global e iciency and modula i y) ha epo edly map in eg a ion and seg ega- ion, espec i ely, we calcula ed he coe icien o a ia- ion and he mean and hen p oceeded o compa e hem be ween g oups. 2|METHODS 2.1 |Pa icipan s The sample o his s udy consis ed o a g oup o indi id- uals wi h an SCZ diagnosis and a g oup o heal hy con- ols. The g oup o indi iduals wi h an SCZ diagnosis (he eina e e e ed o as he SCZ g oup) consis ed o 11 pa icipan s who we e ec ui ed a he Hospi al Uni- e si a io San Agus ín (Lina es, Jaén). The inclusion c i- e ia o pa icipa ion we e an ICD-10 diagnosis o schizoph enia (F20), psycho ic diso de (F23) o schizo- ph enic diso de (F25). The pa icipan ’s diagnosis was made by he uni psychologis . The mean age o his g oup was 36.27 yea s (SD =10.28 yea s; min =23, max =53). Ou o all he pa icipan s, wo (18.18%) we e women. All pa icipan s we e dex e ous. Rega ding he educa ional le el o he pa icipan s, wo had p ima y educa ion, eigh had seconda y educa ion and one had highe educa ion. Rega ding he medica ion, all pa icipan s we e ecei ing an ipsycho ic medica ion (all a ypical). In addi ion o an ipsycho ics, one o he pa icipan s was ecei ing an idep essan s. Due o di e - ences in ac i e p inciples, doses and adminis a ion me hods, we con e ed he doses o all an ipsycho ics in o chlo p omazine equi alen s (M=818.18 mg, SD =407.75 mg). Twen y pa icipan s in he con ol g oup (he eina - e e e ed o as he HC g oup) we e ec ui ed om he s uden s o he Uni e si y o Jaén, he s a o he Uni e si y S . Agus in Hospi al o Lina es (Jaén) and an Adul School o Lina es (Jaén). The a e age age o his g oup was 40.72 yea s (SD =11.96 yea s; min =23, max =57). Ou o all pa icipan s, se en (35%) we e women. Only wo pa icipan s we e le -handed. Rega ding he educa ional le el o he pa icipan s, one had p ima y educa ion, 12 had seconda y educa ion and se en had highe educa ion. The e was no signi ican associa ion be ween sex and g oup (χ 2 [1, N =31] =0.97, p=0.32) o be ween g oup and educa ion le el (χ 2 [2, N =31] =3.29, p=0.19). The FIGURE 1 P incipal s eps in he wo k low. (a) EEG measu emen in HC and SCZ. (b) Sou ce modeling. (c) Pa cella ion o he de aul mode ne wo k. (d) We calcula e wi h co ela ion coe icien he unc ional connec i i y in ime (798 ma ices). (e) Bina ize he ma ices wi h h esholds om 0.1 o 0.6. ( ) We cons uc he unc ional ne wo ks (in ime, one o each ma ix and a each h eshold). (g) We ob ain o each ma ix and a each h eshold, ne wo k measu emen s: modula i y and global e iciency. (h) Cha ac e ize he dynamics o he se ies as well as s a iona y measu es. (i) Be ween-g oup compa isons. EEG, elec oencephalog am; HC, heal hy con ols; SCZ, schizoph enia; ROI, egion o in e es . IGLESIAS-PARRO ET AL.3 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License g oups did no di e signi ican ly wi h espec o age ( [29] =1.03, p=0.30). Fo bo h g oups, he exclusion c i e ia we e ei he a concu en diagnosis o neu ological diso de , a concu - en diagnosis o subs ance abuse diso de , a his o y o de elopmen al disabili y, an inabili y o sign in o med consen , ision diso de s ( ision diso de s ha , al hough co ec ed wi h su ge y, glasses o con ac lenses, esul in a loss o isual acui y, e.g., ca a ac s) o hea ing diso de s (unless co ec ed wi h hea ing aids o su ge y). In addi- ion, an exclusion c i e ion o he con ol g oup was he diagnosis o a men al diso de (as epo ed e bally by he pa icipan s). All pa icipan s ga e w i en in o med consen in acco dance wi h he Decla a ion o Helsinki, and he Jaén Resea ch E hics Commi ee app o ed he s udy. The Spanish e sion (Pe al a & Cues a, 1994) o he Posi i e and Nega i e Synd ome Scale (PANSS, Kay e al., 1989) was used o assess psychopa hology. PANSS consis s o 30 i ems ha e alua e schizoph enic syn- d ome, and each i em is sco ed acco ding o a scale o 7 deg ees o in ensi y o se e i y, whe e 1 is equi alen o he absence o he symp om and 7 o he p esence wi h se e i y. PANSS can be di ided in o h ee subscales: he posi i e subscale o 7 i ems (M=13.95, SD =4.5), he nega i e subscale o 7 i ems (M=19.27, SD =8.18), and he gene al psychopa hology subscale o 16 i ems ha e alua es he p esence o o he symp oms in he pa ien (dep ession, anxie y and diso ien a ion, among o he s) (M=29.36, SD =7.06). 2.2 |EEG acquisi ion EEG da a we e acqui ed while he pa icipan s we e ins uc ed o es wi h hei eyes open and look a a s a- iona y c oss on a moni o . An ac i e elec ode cap (ac iCAP™) was used o acqui e da a om he in e na- ional 10–20 sys em o 32 scalp si es. All elec odes we e e e enced o bo h mas oids. Elec ode impedance was kep lowe han 5 kΩ. The EEG da a we e collec ed o 161 s a a a e o 500 Hz h ough a B ainAmps™ampli- ie . Da a p ocessing was pe o med wi h he B ain Vision Analyze so wa e EEGLAB (Delo me & Makeig, 2004) and MATLAB cus om sc ip s. We applied a bandpass il e wi h cu -o equencies o 0.5 and 30 Hz. Blinks and o he a e ac s we e ex ac ed using in omax independen componen analysis (ICA) (Bell & Sejnowski, 1995). ICA componen s wi h a e ac s we e selec ed ia isual inspec ion o he scalp opog aphy, powe spec a and aw ac i i y om all componen s. Once all noisy componen s we e selec ed, hey we e elim- ina ed om he o iginal signals. 2.3 |Sou ce econs uc ion A sou ce model consis ing o 15,002 cu en dipoles was used o calcula e Ke nel in e sion ma ices o each subjec wi h sLORETA implemen ed in B ains o m (Pascual-Ma qui, 2002). As an MRI empla e, we used he ICBM152 b ain, dis ibu ed wi h he B ains o m package. Dipole o ien a ions we e cons ained no mal o he co ex. Using he bounda y elemen me hod (BEM) as implemen ed in he OpenMEEG model (Co si e al., 2020; Kybic e al., 2005), he o wa d EEG model was compu ed o each subjec . We used he iden i y ma ix as he noise co a iance ma ix. 2.4 |Pa cella ion The sou ce model was hen ana omically pa cella ed using he Desikan–Killiany a las (Desikan e al., 2006) a ailable in B ains o m, as no indi idual ana omies o he pa icipan s we e a ailable. Au oma ed pa cella ion by his me hod has been shown o be compa able o manual labelling (Fischl e al., 2004). Acco ding o his pa celing scheme, he DMN was de ined as he ollowing 14 egions o in e es (ROIs): Is hmus cingula e L, Is h- mus cingula e R, La e al o bi o on al L, La e al o bi o on al R, Medial o bi o on al L, Medial o bi o on al R, Pa ahippocampal L, Pa ahippocampal R, Pos- e io cingula e L, Pos e io cingula e R, P ecuneus L, P ecuneus R, Ros al an e io cingula e L and Ros al an e io cingula e R (whe e L s ands o le and R o igh ). 2.5 |Func ional connec i i y We calcula ed he Spea man co ela ion coe icien be ween he 14 nodes o he DMN ha we ob ained a e pa cella ion. To ake ad an age o he empo al esolu- ion o he EEG eco dings and hus be able o explo e he empo al dynamics o in eg a ion and seg ega ion in he DMN, we used a sliding window o 2000 ms wi h a 90% o o e lap on each s ep and ob ained a o al o 798 unc ional connec i i y ma ices o each pa icipan . The du a ion o he ime se ies o which we applied he sliding window was 161 s. The opological p ope ies o he ne wo ks ob ained a e bina izing he ma ix o in e egional co ela ions will depend on he choice o he h eshold alue. In his sense, i he h eshold is high and he esul ing numbe o edges is low, he ne wo k will be poo ly connec ed and some egional nodes may be disconnec ed. On he o he hand, i he h eshold is low, and he numbe o edges is 4IGLESIAS-PARRO ET AL. 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License high, he ne wo k will be mo e densely connec ed bu will also ha e a andom opology (Basse e al., 2008). Following he ecommenda ion o Rubino and Spo ns (2010) ha ne wo ks should ideally be cha ac e ized ac oss a b oad ange o h esholds, in his pape , we used h esholds om 0.1 o 0.6 in s eps o 0.1. Th esholds o 0.1–0.6 p oduce ne wo ks limi ed o 90–40% o he 120 possible edges in a ully connec ed ne wo k o 14 nodes. Following Su e al. (2015), we ha e selec ed his ange o cos s because hey co e he spec um o meaning ul ne wo ks o es ing s a e da a. Thus, we ob ained a o al o 798 bina y ma ices (unweigh ed and undi ec ed) o each o he six h esholds explo ed. In his s udy, we emo ed nega i e connec ions om he ne wo k o a oid in e e ence (Mu phy & Fox, 2017; Rubino & Spo ns, 2010). 2.6 |G aph measu es Fo each bina y g aph, a each h eshold le el, we calcu- la e he global e iciency and he ne wo k modula i y. The g aph measu es we e calcula ed wi h he B ain Con- nec i i y Toolbox, a MATLAB oolbox de eloped by (Rubino & Spo ns, 2010). These da a, anonymized, a e s o ed in Figsha e (DOI: 10.6084/m9. igsha e.21975899) and also he sc ip s (DOI: 10.6084/m9. igsha e.21990005). Bo h will be a ailable upon easoned eques . Acco ding o Rubino and Spo ns (2010), he unc ional seg ega ion me ics cap u e he abili y o a ne wo k o pe o m specialized p ocessing. The p esence o clus e s in unc ional ne wo ks is in e p e ed as an indica ion o seg ega ed neu al p ocessing. In his pape , we will measu e ne wo k seg ega ion using modula i y. Modules in ne wo ks co espond o clus e s o nodes ha a e in e nally s ongly coupled bu ex e nally only weakly coupled (Spo ns & Be zel, 2016). Acco ding o Simon (1962), modula i y is a dis inc i e cha ac e is ic o com- plex sys ems, and he impo ance o modula b ain ne - wo ks in shaping b ain dynamics has been iden i ied as a powe ul incen i e o empi ically s udy changes in b ain modula i y in men al diso de s (Fo ni o e al., 2015). Heu is ically, modula i y compa es he numbe o edges inside a clus e wi h he expec ed numbe o edges ha one would ind in he clus e i he ne wo k we e a an- dom ne wo k (wi h he same numbe o nodes, bu an- domly a ached). Acco ding o Newman and Gi an (2003), modula i y can be quan i ied by he ollowing exp ession: Q¼1 2EX ij Aij eij  δmi,mj  : whe e A ij is he ij elemen o he adjacency ma ix o he g aph G ( he connec ion s a us be ween iand j:A i =1 when link ij exis s; A ij =0, o he wise), e ij is he ac ion o edges in he ne wo k ha connec e ices in he same communi y and δ(m i ,m j ) is he K onecke del a unc ion and equals 1 i nodes iand jbelong o he same module (i.e., m i =m j ) and 0 o he wise. On he o he hand, he in eg a ion me ics cap u e he abili y o apidly combine specialized in o ma ion om dis ibu ed b ain egions. In his wo k, we selec ed global e iciency as he measu e o ne wo k in eg a ion. A la ge global e iciency alue o he b ain ne wo k ep- esen s a highe in o ma ion ansmission e iciency and a highe in eg a ion deg ee o he b ain ne wo k. In unc- ional b ain ne wo ks, global e iciency is in e sely ela ed o he opological dis ance be ween nodes ( he pa h leng h) and p o ides a measu e o he o e all capaci y o pa allel in o ma ion ans e and in eg a ed p ocessing among dis ibu ed componen s o he sys em wi h he ad an age o e he a e age pa h leng h ha i can be calcula ed in disconnec ed ne wo ks (Bullmo e & Spo ns, 2012; La o a & Ma chio i, 2001). The ne wo k can be ep esen ed as a g aph G(N,M) wi h Nnodes and Medges. The global e iciency is de ined as ollows: Eglob ¼1 NN1ðÞ X j≠iG 1 lij whe e l ij is he mean o he sho es pa h leng h ( he a e - age numbe o s eps along he sho es pa hs o all possi- ble pai s o ne wo k nodes) be ween nodes iand j. Fo an undi ec ed g aph o Nnodes, he mean o he sho es pa h leng h is as ollows: lij ¼1 NN1ðÞ X j≠iG dij whe e dij is he leng h o he sho es pa h be ween nodes iand j. Fo a mo e echnical desc ip ion o g aph-based me - ics equen ly used in b ain ne wo ks, see Bullmo e and Spo ns (2009) and Rubino and Spo ns (2010). A g aphic ep esen a ion o hese concep s can be ound in Figu e 2. 3|DATA ANALYSIS AND RESULTS F om he bina y g aphs, we ob ained he dependen a iables (e iciency and modula i y) bo h s a ic and IGLESIAS-PARRO ET AL.5 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License dynamic. These da a we e analyzed using mixed-e ec s analysis o a iance wi h, g oup, h eshold and hei in e ac ion as ixed ac o s and pa icipan s as andom ac o s. Analyses we e pe o med in R using he lme () unc ion o he lme4 package (Ba es e al., 2015). Pos hoc compa isons and in e ac ion analyses we e made using emmeans package (Len h, 2021). To con ol he e o ype I due o he numbe o compa isons we used he d p ocedu e (Benjamini & Yeku ieli, 2001). 3.1 |Dynamic measu es In o de o s udy he empo al dynamics o modula i y and e iciency, o bo h me ics we calcula ed he a ia- ion coe icien (VC), and hese da a we e summi ed o a mixed model wi h in e cep as a andom ac o and g oup and h eshold as ixed ac o s. The VC allows o compa e he a iabili y o he se ies independen ly o he means o each g oup. The esul s o he coe icien o a ia ion o modula i y (see Figu e 3) showed a signi ican e ec o g oup (F[1,31] =5.25; p=0.02), a signi ican e ec o h eshold (F[5155] =9.64; p< 0.01) and a signi ican e ec o he in e ac ion (F[5155] =2.29; p=0.04). Pai wise compa isons o e he in e ac ion e ealed ha o h eshold alues o 0.6, he a iabili y in modu- la i y was signi ican ly highe ( [199] =3.80; p< 0.01) o HC (M=98.6, SD =111.0) han o SCZ (M=36.5, SD =36.3). The esul s o he coe icien o a ia ion o e iciency (see Figu e 4) showed a signi ican e ec o h eshold (F[5155] =3.85; p< 0.01). No signi ican e ec o g oup (F[1,31] < 1) nei he o he in e ac ion (F[5155] =1.03, p=0.39) was ound. Pos hoc compa isons showed he ollowing signi ican di e ences in VC depending on h eshold: T1 < T3 ( [145] =3.39, p< 0.01), T1 < T4 ( [145] =2.95, p< 0.01), T2 < T3 ( [145] =2.32, p=0.02) and T6 < T4 ( [145] =2.41, p=0.01). Signi i- can con as s a e shown in Table 1. 3.2 |S a iona y measu es We also calcula ed he means ac oss all ime windows o modula i y and e iciency and hese da a we e summi ed o a mixed model wi h in e cep as a andom ac o and g oup and h eshold as ixed ac o s. The esul s o he mean o modula i y (see Figu e 5) showed a signi ican e ec o g oup (F[1,31] =7.43; p=0.01) and a signi ican e ec o h eshold (F[5155] =27.69; p< 0.01), bu no signi ican e ec was ound o he in e ac ion (F[5155] =2.25; p=0.051). Pos hoc compa isons showed he mean o modula i y was signi ican ly ( [33.1] =2.63; p=0.01) highe o he HC g oup (M=0.99, SD =0.02) han o he SCZ g oup FIGURE 2 Ne wo k opologies and g aph measu es. (a) Ne wo k opology examples: Random ne wo ks, wi h andomly de e mined connec ions, ha e high global e iciency, as shown by he many connec ions c ossing he cen e o he g aph, and low modula i y, as shown by he ela i ely ew connec ions be ween nea by nodes. La ice ne wo ks show he e e se pa e n. (b) A simula ed ne wo k is used o illus a e common e ms in ne wo k analysis. Nodes a e ep esen ed as ci cles, and edges a e ep esen ed as lines. 6IGLESIAS-PARRO ET AL. 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License (M=0.89, SD =0.03). Signi ican pos hoc compa isons o h eshold a e shown in Table 2. The esul s o he mean o e iciency (see Figu e 6) showed a signi ican e ec o h eshold (F[5155] =342.83; p< 0.01) and a signi ican e ec o in e ac ion (F[5155] =2.41; p=0.03). No signi ican e ec o g oup (F[1,31] < 1) was ound. Pai wise compa isons o e he in e ac ion e ealed ha o a h eshold alue o 0.5, he mean in e iciency was signi ican ly lowe ( [89.5] =2.00; p=0.04) o HC (M=0.16, SD =0.01) han o indi id- uals wi h an SCZ diagnosis (M=0.19, SD =0.01). 3.3 |Rela ionship wi h symp om se e i y To s udy he possible ela ionship be ween schizoph enia symp om se e i y and g aph measu es, we calcula ed FIGURE 4 Main e ec o he coe icien o a ia ion o e iciency depending on h eshold. VC, a ia ion coe icien . FIGURE 3 Main e ec s and in e ac ion o he coe icien o a ia ion o modula i y depending on g oup and h eshold. (a) In e ac ion g oup by h eshold. (b) Main e ec o g oup. (c) Main e ec o h eshold. SCZ, schizoph enia; VC, a ia ion coe icien . IGLESIAS-PARRO ET AL.7 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License Spea man’s co ela ion coe icien be ween PANSS sub- scales and he measu es o in eg a ion and seg ega ion. In addi ion, we included he chlo p omazine equi alen dose and he age o he pa ien s. The esul s a e p esen ed in Table 3. As can be seen in he able abo e, no signi ican ela- ionships we e ound be ween ne wo k measu es and symp oma ology. These esul s a e in line wi h hose ob ained by o he au ho s (Lynall e al., 2010; Shon e al., 2018), who also ound no signi ican ela ionship be ween symp om se e i y and modula i y o e iciency. 4|DISCUSSION The heal hy human b ain ope a es in a pe manen dynamic o seg ega ion and in eg a ion o in o ma ion om in e nal and ex e nal sou ces. This capaci y o dynamic in eg a ion–seg ega ion can be conside ed an e olu iona y success, necessa y o su i al in an e e - changing en i onmen (Deco e al., 2015). The cou se o ce ain men al illnesses, howe e , could a ec his dynamic. In his sense, i has been p oposed ha SCZ could be ela ed o an imbalance in he in o ma ion in eg a ion–seg ega ion dynamics (F is on & F i h, 1995). Speci ically, DMN unc ioning has been ound o be abno mal in schizoph enia (Hu e al., 2017). On he o he hand, esea ch on b ain o ganiza ion based on he es ing s a e has la gely igno ed he po en- ial o empo al a iabili y, implici ly assuming ha he ela ionships be ween and wi hin he di e en b ain ne - wo ks a e s a iona y ac oss he du a ion o he eco dings (Allen e al., 2014). Howe e , some esea ch ha has FIGURE 5 Signi ican Main e ec s o he mean o modula i y depending on g oup and h eshold. (a) Main e ec o g oup. (b) Main e ec o h eshold. SCZ, schizoph enia. TABLE 2 Signi ican pos hoc compa isons o he mean o modula i y depending on h eshold. Con as d a io p alue 0.1–0.4 166 2.71 0.01 0.1–0.5 166 5.72 <0.01 0.1–0.6 166 8.92 <0.01 0.2–0.4 166 2.75 <0.01 0.2–0.5 166 5.76 <0.01 0.2–0.6 166 8.96 <0.01 0.3–0.5 166 4.71 <0.01 0.3–0.6 166 7.91 <0.01 0.4–0.5 166 3.00 <0.01 0.4–0.6 166 6.20 <0.01 0.5–0.6 166 3.20 <0.01 TABLE 1 Signi ican pos hoc compa isons o he mean o e iciency depending on h eshold. Con as d a io p alue 0.1–0.3 166 3.39 <0.01 0.1–0.4 166 2.95 <0.01 0.2–0.3 166 2.32 0.02 0.3–0.6 166 2.84 <0.01 0.4–0.6 166 2.41 0.01 8IGLESIAS-PARRO ET AL. 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License explici ly s udied es ing-s a e unc ional connec i i y dynamics o he DMN has clea ly shown he ime- a ying na u e o connec i i y (Chang & Glo e , 2010), e en in indi iduals wi h an SCZ diagnosis (Sako glu e al., 2010). In he p esen wo k, we aimed o explo e he dynam- ics o in eg a ion–seg ega ion in he DMN o pa ien s and heal hy con ols. Fo his pu pose, om EEG eco dings, we ob ained unc ional ne wo ks o e ime om which we calcula ed he global e iciency and modula i y using di e en h esholds o bina ise he ma ices. To s udy he empo al e olu ion o hese indica o s, we calcula ed he coe icien o a ia ion and compa ed i depending on he g oups o pa icipan s (SCZ and HC), he h esholds (0.1 o 0.6), and he in e ac ion be ween hese ac o s. The esul s we ob ained ega ding he a iabili y o he modula i y, indica e a la ge epe oi e o s a es o connec i i y in he HC g oup han in he g oup o indi- iduals wi h an SCZ diagnosis, pa icula ly in he adja- cency ma ices ob ained a highe h esholds. These esul s could sugges al e ed dynamic pe o mance o b ain g aphs in indi iduals wi h an SCZ diagnosis and a e in line wi h p e ious wo k (Alexande -Bloch e al., 2010; Ro schy e al., 2012; Yu e al., 2015) in which also has been ound ha he connec i i y s a es o HCs FIGURE 6 Signi ican main e ec s and in e ac ion o he mean o e iciency depending on g oup and h eshold. (a) In e ac ion g oup by h eshold. (b) Main e ec o h eshold. SCZ, schizoph enia. TABLE 3 Co ela ion coe icien s and p alues (be ween b acke s) o PANSS, dynamical and s a iona y measu es o modula i y and e iciency, age o pa icipan s and medica ion (CPZ). PANSS P PANSS N PANSS G Modula i y M Modula i y VC E iciency M E iciency VC CPZ PANSS N 0.43 (0.18) PANSS G 0.79* (< .01) 0.74* (0.01) Modula i y M 0.27 (0.43) 0.25 (0.47) 0.01 (0.98) Modula i y VC 0.21 (0.52) 0.26 (0.43) 0.20 (0.55) 0.57 (0.07) E iciency M 0.36 (0.26) 0.21 (0.53) 0.48 (0.14) 0.22 (0.52) 0.71* (0.02) E iciency VC 0.33 (0.31) 0.05 (0.89) 0.48 (0.14) 0.17 (0.61) 0.62* (0.05) 0.90* (< .01) CPZ 0.39 (0.23) 0.44 (0.18) 0.36 (0.28) 0.08 (0.82) 0.42 (0.21) 0.30 (0.37) 0.30 (0.38) Age 0.28 (0.41) 0.31 (0.36) 0.17 (0.63) 0.16 (0.65) 0.36 (0.27) 0.70* (0.02) 0.72* (0.02) 0.51 (0.11) Abb e ia ions: CPZ, chlo p omazine equi alen ; Modula i y and E iciency M, mean measu es o modula i y and e iciency; Modula i y and E iciency VC: a ia ion coe icien measu es o modula i y and e iciency; PANSS, Posi i e and Nega i e Synd ome Scale; PANSS G: gene al psychopa hology; PANSS N, nega i e symp oms; PANSS P, posi i e symp oms. IGLESIAS-PARRO ET AL.9 14609568, 0, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ejn.15970 by Uni e sidad De G anada, Wiley Online Lib a y on [09/05/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License