Speed of Processing (SoP) Training Plus α-tACS in people with mild cognitive impairment: a double blind, parallel, placebo controlled trial study protocol

STUDY PROTOCOL published: 14 July 2022 doi: 10.3389/ nagi.2022.880510 Edi ed by: Hakuei Fujiyama, Mu doch Uni e si y, Aus alia Re iewed by: Be ina Pollok, Hein ich Heine Uni e si y o Düsseldo , Ge many Sophie Clai e And ews, Neu oscience Resea ch Aus alia, Aus alia *Co espondence: Jo ge Lei e [email p o ec ed] Special y sec ion: This a icle was submi ed o Neu ocogni i e Aging and Beha io , a sec ion o he jou nal F on ie s in Aging Neu oscience Recei ed: 21 Feb ua y 2022 Accep ed: 02 June 2022 Published: 14 July 2022 Ci a ion: Lei e J, Gonçal es ÓF and Ca alho S (2022) Speed o P ocessing (SoP) T aining Plus α- ACS in People Wi h Mild Cogni i e Impai men : A Double Blind, Pa allel, Placebo Con olled T ial S udy P o ocol. F on . Aging Neu osci. 14:880510. doi: 10.3389/ nagi.2022.880510 Speed o P ocessing (SoP) T aining Plus α- ACS in People Wi h Mild Cogni i e Impai men : A Double Blind, Pa allel, Placebo Con olled T ial S udy P o ocol Jo ge Lei e1,2*, Ósca F. Gonçal es2,3 and Sand a Ca alho2,4,5 1Po ucalense Ins i u e o Human De elopmen —INPP, Po ucalense Uni e si y, Po o, Po ugal, 2Po uguese Ne wo k o he Psychological Neu oscience, Po ugal, 3P oac ion Labo a o y, CINEICC, Facul y o Psychology and Educa ional Sciences, Uni e si y o Coimb a, Coimb a, Po ugal, 4Depa men o Educa ion and Psychology and William James Cen e o Resea ch, Uni e si y o A ei o, Campus Uni e si á io de San iago, A ei o, Po ugal, 5The Psychology Resea ch Cen e (CIPsi), School o Psychology, Uni e si y o Minho, B aga, Po ugal Se e al cogni i e aining p og ams, alone o in combina ion wi h non-in asi e b ain s imula ion ha e been es ed in o de o amelio a e age- ela ed cogni i e impai men s, such as he ones ound in Mild Cogni i e Impai men (MCI). Howe e , he e ec s o Cogni i e T aining (CT)—combined o no —wi h se e al o ms o non-in asi e b ain s imula ion ha e been modes a mos . We aim o assess i Speed o P ocessing (SoP) aining combined wi h alpha ansc anial al e na ing cu en s imula ion (α- ACS) is able o inc ease speed o p ocessing as assessed by he Use ul Field o View (UFOV), when compa ing o SoP aining o ac i e α- ACS alone. Mo eo e , we wan o assess i hose changes in speed o p ocessing ans e o o he cogni i e domains, such as memo y, language and execu i e unc ioning by using he NIH EXAMINER. We also wan o es he mechanisms unde lying hese in e en ions, namely b ain connec i i y and cohe ence as assessed by elec oencephalog aphy (EEG). To ha pu pose, ou p oposal is o en oll 327 elde s diagnosed wi h MCI in a double-blinded, pa allel andomized clinical ial assessing he e ec s o combining SoP wi h alpha endogenous ACS (ei he ac i e o sham) in people wi h MCI. Pa icipan s will pe o m an in e en ion ha will las o 15 sessions. Fo he i s 3 weeks, pa icipan s will ecei e nine sessions o he in e en ion, and hen will ecei e wo sessions pe week (i.e., boos e ) o he ollowing 3 weeks. They will hen be assessed a 1, 3, and 6 mon hs a e he in e en ion has ended. This will allow us o de ec he immedia e, and long- e m e ec s o he in e en ions, as well as o p obe he mechanisms unde lying i s e ec s. Clinical T ial Regis a ion: Clinical ials.go , Iden i ie : NCT05198726. Keywo ds: ACS ( ansc anial al e na ing cu en s imula ion), cogni i e aining, MCI (mild cogni i e impai men ), NIBS and cogni ion, EEG F on ie s in Aging Neu oscience | www. on ie sin.o g 1July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI INTRODUCTION The majo p edic o o cogni i e decline is age (Til is e al., 2004; Schae e beke e al., 2021). Despi e he e ogenous p o iles in e ms o p og ession and se e i y, a dysexecu i e synd ome ha can be de ec ed in ea ly onse a ian s o Alzheime ’s disease (Townley e al., 2020), o in mild cogni i e impai men (i.e., MCI; Blanco Ma ín e al., 2016) has been commonly epo ed. This dysexecu i e synd ome ansla es o di icul ies in e ms o c ys alized and luid in elligence, p ocessing speed, a en ion, memo y, language, and execu i e unc ioning (Ha ada e al., 2013), and as such, cons i u e po en ial a ge s o cogni i e aining (CT) in hese popula ions. In he absence o o icial numbe o he li e ime p e alence o MCI, a ecen me a-analysis sugges ed ha MCI can a ec om 22.5 (aged 75–79) o 60.1 pe sons (aged 85 yea s o olde ) pe 1,000 pe sons-yea (Gillis e al., 2019). Mo eo e , se e al s udies sugges ed ha people wi h MCI a e mo e p one o de elop demen ia (Bake e al., 2008), especially i he deg ee o unc ional baseline is accoun ed o (Fa ias e al., 2009). Howe e , he e a e also some epo s ha people wi h MCI e e ed hei cogni i e condi ion o a no mal s age (Hu e al., 2020). This is especially impo an because, his may end up lowe ing he isk o de eloping demen ia o some people wi h MCI. Fu he mo e, e en wi h he ecen ad ances in e ms o medica ion, especially he aducanumab, i s impac on cogni ion is s ill a ma e o in ense deba e (Walsh e al., 2021). In ha sense, se e al in e en ions unde he gene al umb ella o CT ha e been ex ensi ely s udied in o de o es i CT, will be able o minimize o e e he e ec s o age- ela ed cogni i e decline in olde adul s (I azoki e al., 2020 o e iew; Willis e al., 2006). Fo ins ance, a p og am using cogni i e aining in people wi h MCI ha consis ed o 60-min sessions, 3 imes a week, du ing 6 mon hs was able o induce a medium size e ec imp o emen in he Alzheime ’s Disease Assessmen Scale-Cogni i e Subscale (ADAS-Cog; T ain he B ain Conso ium, 2017). Mo eo e , p e ious me a-analyses sugges ed ha cogni i e aining in heal hy olun ee s can indeed inc ease luid in elligence (Ka bach and Ve haeghen, 2014; Au e al., 2015). Howe e , o he me a-analysis sugges ed ha he e ec s o CT in he elde ly a e modes a mos (Teixei a-San os e al., 2019). In e es ingly enough, a ecen andomized clinical ial (RCT) wi h 10 yea s o ollow-up, compa ed he e icacy o h ee ypes o cogni i e aining in 2,802 olde adul s. In his ial, pa icipan s ecei ed ei he Wo king memo y, Reasoning o Speed o P ocessing aining compa ed o a wai ing lis . The CT consis ed o 10 sessions du ing six weeks, and hen up o ou boos e sessions a he 11 h mon h, and inally ano he up o ou boos e sessions a he 35 h mon h. Wo king memo y o easoning aining did no educe he isk o de eloping demen ia [43% me he diagnosis o demen ia c i e ion, 28% me he Mini Men al S a e Examina ion (MMSE) c i e ion, 12% me he psychome ic c i e ion; 15% and 2% me all h ee c i e ia] when compa ed o con ols, bu ha was no he case o speed o p ocessing (SoP) aining (Edwa ds e al., 2017). In ano he s udy, SoP aining inc eased pa icipan ’s ins umen al e e yday abili ies, including d i ing abili ies (Ball e al., 2007). Mo eo e , ans e e ec s o o he cogni i e domains (e.g., a en ion, memo y) and inc eases in connec i i y wi hin he b ain’s cen al execu i e ne wo k ollowing SoP aining we e also epo ed (Lin e al., 2016). This is no su p ising, as SoP has been shown o be an impo an ma ke o indi idual di e ences in e ms o s uc u al connec i i y (Benne and Madden, 2014). Mo eo e , highe o de cogni i e unc ions, such as execu i e unc ioning, ely on e icien communica ion be ween b ain egions, and as such, dec eases in SoP a e a s ong p edic o o age- ela ed decline in se e al cogni i e domains (Gao e al., 2020). This e lec s a connec ion de e io a ion be ween dis al b ain egions in wha has been called he ‘‘disconnec ed b ain’’ amewo k (Fjell e al., 2013). Thus, an inc ease o a ge engagemen may be possible by uning-in he neu al popula ion owa ds he ained abili y, by using non-in asi e b ain s imula ion (NIBS). We ha e p e iously shown ha we we e able o modula e cogni ion using ansc anial di ec cu en s imula ion ( DCS), namely on execu i e unc ioning (Lei e e al., 2011, 2013), wo king memo y (Ca alho e al., 2015a), empa hy (Rêgo e al., 2015), app oach/a oidance mo i a ion unde lying c a ing (Ca alho e al., 2018), a en ion and pain (Sil a e al., 2017; San os e al., 2018). Fu he mo e, by unde s anding he unde lying mechanisms o he in e en ion in he b ain, i is possible o de elop neu al based in e en ions, whose ul ima e aim is o op imize he a ge engagemen (Ca alho e al., 2015b). One possible way o doing so, is o combine SoP aining wi h ano he echnique— ansc anial al e na ing cu en s imula ion ( ACS) —which has been shown o en ain b ain ac i i y (An al and He mann, 2016). En ainmen e e s o he equency dependen esponse o b ain wa es in o de o ma ch he equency o he s imulus ha a e being applied o he b ain (Huang and Cha y on, 2008). Alpha en ainmen may be o pa icula in e es o SoP. Fo ins ance, a s udy has al eady showed ha speed o p ocessing is associa ed wi h changes in his speci ic band (Hilla e al., 2020). By combining he wo in e en ions, i will be hypo he ically possible o op imize b ain communica ion be ween dis al egions, and hus, inc ease cogni i e pe o mance. Acco ding o he Communica ion h ough Cohe ence hypo hesis (CTC), e ec i e connec i i y equi es hy hmic synch oniza ion be ween p e and pos synap ic neu ons and hei cohe ence. Thus, in he absence o cohe ence, inpu s a i e a andom phases o he exci abili y cycle, which esul in lowe connec i i y (and e iciency; F ies, 2015). The e o e, cohe ence be ween p e and pos synap ic neu ons is equi ed o e icien communica ion. In he case o absence o cohe ence (as in he case o a ‘‘disconnec ed b ain due o ageing), pe o mance is impai ed. In his sense, alpha ACS (α- ACS) may be a sui able combina ion o SoP aining. Fo ins ance, α- ACS induces p e e en ial phase synch oniza ion o as spiking neu ons, hus esul ing in an en ainmen p ocess o alpha oscilla ions (Huang e al., 2021). Mo eo e , alpha band is hough o wo k as a b ain ime , se ing up exci a ion and/o inhibi ion mic os a es, which will op imize incoming in o ma ion p ocessing o inhibi ion (Ma hewson e al., 2011). Fu he mo e, α- ACS is able F on ie s in Aging Neu oscience | www. on ie sin.o g 2July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI o modula e empo al esolu ion o human ision by ac ing o e he seg ega ion/in eg a ion ime window o isual in o ma ion, hus inducing pa icipan s o in eg a e mo e o en wo s imuli in o one pe cep (Ba aglini e al., 2020); o e en o modula e in o ma ion ans e in he p emo o -ce ebella loop du ing lea ning (Schube e al., 2021). In e es ingly enough, alpha ac i i y seems o be one o he mos dis inguishable al e a ions in he human b ain due ageing, wi h se e al s udies showing changes in e ms o alpha powe , cohe ence and peak equency in olde adul s, when compa ing o younge ones (Pu don e al., 2015; Beese e al., 2019; Elsha ei e al., 2020). He e he goal is o use each pa icipan ’s endogenous peak alpha equency o guide endogenous alpha phase- ACS (α- ACS) o u he inc ease b ain connec i i y wi hin b ain ne wo ks (Bächinge e al., 2017). In his sense, he cu en p oposal aims o combine wo in e en ions ha ha e al eady shown p omising esul s: a speci ic SoP aining ha has been shown o p oduce esul s in he elde ly (Edwa ds e al., 2017) and an in e en ion ha has been shown o en ain b ain ac i i y (Huang e al., 2021), as a means o inc easing b ain connec i i y (Bächinge e al., 2017). METHODS Pu pose, P ima y, and Seconda y Ou comes P ima y Ou comes The p ima y ou come will be changes om baseline in he Use ul Field o View (UFOV) Assessmen a week 3. UFOV is a good indica o o isual p ocessing speed (Ball e al., 1988). The endpoin a week 3 was chosen because i is a he end o he in ensi e phase, and will be complemen ed by a co-p ima y endpoin a week 6 (a e boos e sessions). Long- e m e ec s will be assessed a 1, 3, and 6 mon hs a e he s imula ion has ended. Seconda y Ou comes NIH Execu i e Abili ies: Measu es and Ins umen s o Neu obeha io al E alua ion and Resea ch (NIH EXAMINER) Aims a p o iding a obus measu e o execu i e unc ioning, namely in e ms o wo king memo y, inhibi ion, se shi ing, luency, insigh , planning, social cogni ion, and beha io (K ame e al., 2014). Mo eo e , i seems o be sensi i e enough o de ec cogni i e changes e en in p e-symp oma ic on o empo al loba degene a ion (S a a oni e al., 2020). I will be used o assess o po en ial ans e e ec s om speed o p ocessing owa ds se e al co e skills unde lying execu i e unc ion. Elec oencephalog aphy (EEG) Da a EEG can be used as an ou come p edic o o he in e en ion, o p ospec i ely in o de o de e mine he chance o p og essing owa ds MCI o o he Demen ia-like s a e (Poil e al., 2013). Mo eo e , EEG can be used o assess changes in b ain connec i i y in people wi h MCI (Tó h e al., 2014). T ial Design, Se ing, and Regis a ion The ial will be an explo a o y h ee a m pa allel g oup, double blinded con olled ial, wi h an 1:1 alloca ion (see Figu e 1). Da a will be collec ed om clinical ou pa ien se ices om he No he n and Cen e Regions o Po ugal. This ial has been egis e ed a Clinical ials.go wi h he iden i ie : NCT05198726. Pa icipan s will pe o m a p e-sc eening p ocedu e in o de o assess hei eligibili y o he s udy. I hey a e eligible, hey will be sc eened by a ained clinician (neu ologis o neu opsychologis ) in o de o assess i he e is e idence o modes cogni i e decline om a p e ious le el o pe o mance; ha hese de ici s do no impai pa icipan ’s independence; ha he cogni i e decline is no a esul o a deli ium, o be e explained by o he men al diso de such as dep ession o schizoph enia as sugges ed by DSM-V (Ame ican Psychia ic Associa ion, 2013). Pa icipan s ha sc een in, will pe o m a baseline assessmen , which will consis o he UFOV, he NIH EXAMINER, and he EEG da a. Then hey will pe o m an in e en ion ha will las o 15 sessions. Fo he i s 3 weeks, pa icipan s will ecei e nine sessions o he in e en ion, and hen will ecei e wo sessions pe week (i.e., boos e ) o he ollowing 3 weeks. We will hen conduc h ee ollow-up assessmen s a 1, 3, and 6 mon hs a e he s imula ion has ended. Assessmen s will be simila ac oss all s udy poin s. Pa icipan s Pa icipan s will be communi y-dwelling adul s aged 65 yea s and olde , wi h cogni i e complains in memo y o o he unc ions, which ha e declined o e ime. Pa icipan s will be excluded i hey a e less han 65, sco e in he mini men al examina ion less han 23 (o o e 28), diagnosis o Alzheime ’s Disease, any o he medical condi ion ha may p edispose pa icipan s o a o hcoming decline in unc ion, o ha may inc ease hei isk o mo ali y du ing he du a ion o he s udy. Pa icipan s will also be excluded i hey ha e any con a- indica ion o ACS, se e e senso y losses o communica ion di icul ies ha will p e en hem om success ully comple e he aining o had any cogni i e aining in he pas . Volun a y and w i en in o med consen will be ob ained om he pa icipan s by a esea che , which will explain in de ail he p ocedu es in ol ed in he s udy. Desc ip ion o he In e en ions Speed o P ocessing (SoP) The e will be a o al o 15 sessions (30-min pe session) o SoP aining. These sessions will be pe o med h ee imes a week o he i s 3 weeks and wo imes a week o he ollowing 3 weeks, and will consis o ou condi ions. In condi ion 1, pa icipan s will be asked o iden i y objec s a inc easingly b ie exposu es (see Figu e 2A). Fo condi ion 2, iden i ica ion o s imulus on he cen e o he sc een will be eques ed om pa icipan s, while a second s imulus will appea somewhe e in pe iphe al ision—s imulus du a ion, di icul y o he cen al localiza ion ask o he a ea in which a ge s may be loca ed, will be used o change he le el o di icul y (see Figu e 2B). Condi ion 3 is simila o condi ion 2, bu isual dis ac o s a e added. Finally, F on ie s in Aging Neu oscience | www. on ie sin.o g 3July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI FIGURE 1 | Schema ic ep esen a ion o he p o ocol. FIGURE 2 | Schema ic ep esen a ion o he wo i s condi ions o he Speed o P ocessing (SoP) ask. Panel (A) ep esen s condi ion 1, wi h only one a ge . Panel (B) ep esen s condi ion 2, in which a second a ge is added (i.e., diamond). o condi ion 4, an audi o y iden i ica ion componen will be supe imposed o e he isual ask (Jobe e al., 2001). Objec s ime exposu e will dec ease by 50 ms i in he p eceding block o 20 ials, pa icipan s success ully ecognized he objec in a leas 75% o ials. I no , ime exposu e o objec s will go up by 50 ms. Once exposu e o objec s canno be educed o h ee consecu i e blocks o 20 ials, pa icipan s may p oceed o he nex condi ion. Visual a ge s will be app oxima ely 2 cm F on ie s in Aging Neu oscience | www. on ie sin.o g 4July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI in wide and heigh , which ep esen s a isual angle o 1.9◦a a 60 cm dis ance. Fo he sham e sion o he ask, objec s ime exposu e will be ixed ac oss all ials (i.e., 500 ms). Endogenous Alpha-T ansc anial Al e na ing Cu en S imula ion (α- ACS) Pa icipan s will do a un-in phase (EEG wi hou α- ACS) du ing he i s 5-min o each aining session in o de o ace he indi idual alpha equency (IAF) o e occipi al egions (de ined as he maximum alpha alue wi hin he 7–13 Hz ange), which will hen be used o deli e he 2 mA α- ACS (based on he IAF) o e he p e on al co ex (PFC; i.e., F3 and F4) o 20- min, using 35 cm2sponges. The PFC was chosen due o his age- ela ed decline (Fjell e al., 2013) and o his in ol emen in isual a ge p ocessing (Madden e al., 2004). Fo he sham ACS, a 45-s o ac i e α- ACS will be applied. This will allow o mimic he ini ial sensa ion o ACS. The compu e sc een will andomly licke ac oss he expe imen o he sham ACS, because ac i e ACS bellow 40 Hz is likely accompanied by isual licke sensa ions. Thus, we plan o use he compu e sc een o mimic his licke ing o he sham ACS condi ion. In o de o con inuously moni o elec oencephalog aphic (EEG) ac i i y and deli e α- ACS du ing ask pe o mance, a cus om Loop-IT solu ion om Neu oca e (Ge many) will be used. Ou comes Main ou come will be he Use ul Field o View (UFOV) es o speed o p ocessing and a en ion (Ball e al., 1988). The UFOV is a es ha was designed o e alua e daily li e di icul ies expe ienced by he elde ly, such asks ha equi e di ided isual a en ion and ha e o be unde aken apidly (speed o p ocessing). The ou -sub es s imulus will be used o he compu e ized e sion, namely iden i ica ion alone; di ided a en ion; selec i e a en ion; selec i e a en ion in conjunc ion wi h same/di e en disc imina ions will be used (Edwa ds e al., 2006). UFOV is expec ed o be comple ed in 10 min and pa icipan s a e asked o ouch he sc een as soon as hey iden i y a a ge (i.e., a ca silhoue e inside a box), wi h he a ge exposu e anging om 16.67 o 500 ms. In o de o p obe di ided a en ion, a pe iphe al a ge is added o he cen al a ge . Fo he selec i e a en ion, dis ac o s a e added; while o he mo e demanding e sion, he e a e wo cen al a ge s, and pa icipan a e asked o make a judgmen i hey a e simila o no . The NIH EXAMINER ba e y will be used o assessing ans e e ec s o he in e en ion o un ained domains. The NIH EXAMINER comp ises cogni i e con ol, e bal luency, and wo king memo y assessmen s (Possin e al., 2013). Namely, NIH EXAMINER is a compu e ized e sion o se e al asks a ge ing wo king memo y, inhibi ion, se shi ing, luency, insigh , planning, social cogni ion, and beha io , which allows o he calcula ion o a composi e sco e (K ame e al., 2014). As he ime o comple e se e al asks is pe o mance dependen , we expec pa icipan s o comple e he NIH EXAMINER be ween 30 and 60 min. Res ing s a e EEG will be used as a su oga e ou come, and will be pe o med be o e and immedia ely a e he in e en ion in o de o assess powe spec al densi y changes, c oss equency couplings and cohe ence among elec odes. Pa icipan s will also pe o m a sho audi o y oddball ask (Fz, Cz, Pz, and Oz) because he P3 wa e is a good ma ke o b ain’s speed o p ocessing. Analysis will be conside ed explo a o y i he d opou a e eaches 20%. A week 3 and 6 ou comes will be collec ed he ollowing business day, due o pa icula cha ac e is ics o he sample. Sample Size No p e ious s udies using ACS and SoP ha e used UFOV as a p ima y ou come, and as such, we a e using he UFOV es - e es da a om Ben ley e al. (2012). Fo olde adul s he mean (SD) es - e es di e ence (i.e., consis ency be ween measu emen s a wo di e en imepoin s on he same sample) be ween UFOV applica ions was 56.2 (74.8). In o de o show an e ec , ou in e en ion should a leas su pass he mean es - e es di e ence. So we an h ee di e en scena ios: 0.50, 0.75, and 1.00 SD below mean di e ence o olde adul s, wi h a powe o 0.8 and alpha o 0.05. In hese scena ios, a minimum o 17 pa icipan s and a maximum o 64 pe g oup would be equi ed in o de o de ec a Cohen’s d o 1 and 0.5, espec i ely. Howe e , hese alues we e abo e he mean es - e es di e ence o younge adul s, namely 31.5 (43.7). As such we used his alue as ou cu o poin , and wi h a powe o 0.8 and alpha o 0.05 we would need a leas 98 pa icipan s pe g oup. I an a i ion a e o 10% is conside ed, 109 pa icipan s pe g oup will be equi ed. Howe e , ha ing ial easibili y in o conside a ion, we decided o conduc a in e im analysis o u ili y as soon as 19 pa icipan s pe g oup a e eached, hen a 32 pa icipan s pe g oup and inally a 71 pa icipan s pe g oup (always conside ing he 10% a i ion a e). Rec ui men Rec ui men will be made in he no h and cen e egions o Po ugal, using b oad communi y ad e isemen s a egies (i.e., Facebook page, lye s) and by a ge ing speci ic o ganiza ions ha usually wo k wi h he elde ly such as senio uni e si ies and assis ed ca e home acili ies. Randomiza ion Pa icipan s will be block andomized ( andom block sizes o 2, 4 o 6) by a compu e ized so wa e o one o he in e en ions. Alloca ion concealmen will be kep using a me hod o closed en elops, which will only designa e G oup A o B. A o B will hen be used o se up a masked s udy mode on he de ice. Randomiza ion lis will be kep on a secu ed s o age, and he access will be es ic ed o he P incipal In es iga o . En olmen o pa icipan s will be pe o med by a esea che o he ial, and he alloca ion will be pe o med immedia ely p io o he beginning o he s imula ion sessions. Blinding P ocedu es This will be a double blind design, in which ial pa icipan s, esea che s p o iding he in e en ions and ou come assesso s will be blinded o he in e en ion. This will be achie ed using s udy mode o he de ices and employing sham p ocedu es o he α- ACS. Pa icipan s will be unblinded i hey expe ience any unexpec ed ad e se e ec s. A he end o hei pa icipa ion, F on ie s in Aging Neu oscience | www. on ie sin.o g 5July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI blinding assessmen will be pe o med o bo h pa icipan s and esea che s who assessed he ou comes, namely by asking abou he s imula ion ha hey hough hey had ecei ed (o applied) and o a e how con iden hey a e in hei guesses. Assessmen s Use ul Field o View (UFOV) UFOV is a e y well alida ed ins umen o assess speed o p ocessing and will be adminis e ed be o e he in e en ion and a he end o week 3 (see Figu es 1,2). This ime poin was chosen in o de o minimize loss o ollow-up. As he e is some e idence ha he e may be a ceiling e ec o CT (which may be he case o SoP also), we will also collec a co-p ima y endpoin a he end o he aining (i.e., week 6; see Figu es 1,2). NIH EXAMINER The NIH Execu i e Abili ies: Measu es and Ins umen s o Neu obeha io al E alua ion and Resea ch-EXAMINER ba e y will be used o assess ans e e ec s o un ained domains, such as execu i e unc ion, insigh o social cogni ion and beha io (K ame e al., 2014). The NIH EXAMINER was p e iously de eloped o be used as a ial endpoin , and is o ganized in o sub es s a ge ing wo king memo y, inhibi ion, se shi ing luency, insigh , planning, social cogni ion and beha io , ha allows us o ob ain an execu i e composi e sco e o each indi idual. EEG Da a EEG da a will be acqui ed using a 8-channel Loop-IT (Neu oca e, Ilmenau, Ge many) ollowing he 10/20 sys em, in a con inuous mode a a digi iza ion a e o 500 Hz, wi h a bandpass il e o 0.01–100 Hz. The EOG will be eco ded om wo addi ional bipola channels. Elec ode impedances will be kep below 5 kΩ. We will be especially in e es ed in changes in α- powe , P300 om he oddball ask, E en Rela ed Desynch oniza ion (ERD; o alpha a enua ion) and Phase ampli ude coupling (PAC; mainly α-γ). MOCA, MMSE, and GDS Pa icipan s will be sc eened using he Mon eal Cogni i e Assessmen (MOCA; Nas eddine e al., 2005) and he Mini-men al S a e Examina ion (MMSE; Fols ein e al., 1975). The Ge ia ic Dep ession Scale (GDS) sho e sion (Yesa age and Sheikh, 1986) o ack dep ession le els ha could be used as a co a ia e in he analysis. Da a Managemen and Access o Da a Collec ed da a will be handled and s o ed acco dingly o na ional and in e na ional egula ions, always espec ing he bes (and s ingen ) p ac ices a ailable. All pe sonal da a will be de-iden i ied and coded. The code will be s o ed in a locked s o age wi h es ic ed access. Digi al da a will be s o ed using REDCap. A secu e enc yp ed OneD i e will be used o he EEG da a. We will use EEGLab, Ma lab and SPSS e sion 28 o pe o m he da a analysis. All u he p ocessing o da a will ollow an e hics commi ee app o al and he da a used will emain de-iden i ied and coded, ollowing he da a-sha ing ag eemen . S a is ical Analysis P ima y Ou come We expec ha all g oups, a e he in e en ion, ha e inc eased pe o mance in he UFOV sco es, howe e we also expec ha he g oup wi h he combined ac i e α- ACS and SoP aining would p esen he la ges inc ease in sco es, when compa ing o ei he in e en ion alone. This will be es ed by calcula ing he del a (week 3 o 6—baseline), and by pe o ming independen one-way ANOVAS wi h in e en ion as a ac o . Mo eo e , wi h he p esen design, we can ack he in e en ion e ec s in se e al ime poin s, namely be ween baseline, a week 3 and 6 o he in e en ions. This will be pe o med by means o an explo a o y mixed model-ANOVAS, wi h ime as wi hin subjec ac o and in e en ion as be ween subjec ac o . As we canno con ol a his poin o se e al a iables such as gende , dep ession o yea s o educa ion, i he e a e signi ican di e ences be ween g oups a e andomiza ion, we will include hose co a ia es in he analysis, pe o ming ANCOVAS ins ead o ANOVAS. Seconda y Ou comes NIH Examine The NIH EXAMINER ba e y is impo an o add ess ans e e ec s o un ained domains, such as execu i e unc ion, insigh o social cogni ion and beha io . Chi-squa e es s will be used o week 3 and 6 eliable change indexes. Reliable Change Index (RCI) will be calcula ed by using he s anda d de ia ion o he e e ence da a-se , and he es - e es eliabili y (C onbach’s alpha). As we wan he RCI, he di e ence be ween measu emen s will be compa ed o he SDi mul iplied by 1.96 (Jacobson and T uax, 1991). This will allow o a ca ego ial YES/NO a iable o he chi-squa e es s. Mo eo e , wi h he p esen design, we can ack he in e en ion e ec s in se e al ime poin s, namely a baseline, week 3 and 6 o he ea men . This will be pe o med by means o chi-squa es, wi h ime as wi hin subjec ac o and in e en ion as be ween subjec ac o . EEG Da a EEGLab1will be used o EEG da a p e-p ocessing and analysis. Independen Componen Analysis (ICA) will be used o a i ac ejec ion and IAF. IAF will be de e mined in he i s 5 min o a 10-min un in phase in which pa icipan will no ecei e any s imula ion, wi h al e na ing cycles be ween eyes open and eyes closed. Fas Fou ie T ans o ma ion (FFT) will be applied o pos e io α. Powe es ima es will be ob ained by squa ing il e ed EEG signals and hen band powe alues will be a e aged o bo h he p e-s imulus e e ence pe iod and he ask in e als. We will hen segmen he ials in blocks o 5-s, and a e age he b ain ac i i y o hose blocks. In o de o p e en he misma ch be ween α- ACS and measu ed α,αpeak will be measu ed always du ing he i s 5-min o he session (wi hou aining) and in he 5-min immedia ely a e s imula ion has ended (see Figu e 3). Sou ce in o ma ion oolbox2will be used o he cohe ence and connec i i y analysis be ween he eigh elec odes (FP1, FP2, C3, C4, T3, T4, O1, and O2) wi hou p e-speci ying speci ic Region o In e es (ROI) compa isons. 1h ps://eeglab.o g/ 2h ps://sccn.ucsd.edu/wiki/SIFT F on ie s in Aging Neu oscience | www. on ie sin.o g 6July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI FIGURE 3 | Schema ic ep esen a ion o he o e all p ocedu e, including session p ocedu e. Follow-up assessmen s will s a 1 mon h a e he in e en ion has ended. Long-Te m E ec s Assessmen s a 3 and 6 mon hs o ollow-up will be c i ical o unde s anding he long e m e ec s o he in e en ion. We will use he eliable change index (RCI; Fe guson e al., 2002) o he p ima y (i.e., UFOV) and seconda y endpoin s such as he NIH EXAMINER. By assessing i he changes in es sco es a e eliable ac oss hose ime poin s, ou unde s anding abou he long las ing e ec s o he in e en ion will imp o e, while po en ial placebo e ec s ha a e no expec ed o pe sis o ha long will be mi iga ed. This will be pe o med by means o Chi-squa es, wi h ime as wi hin subjec ac o and in e en ion as be ween subjec ac o . A he 1, 3, and 6 mon h ollow-ups, pa icipan s will also pe o m he EEG, in o de o allow o he co ela ion be ween changes in α- powe , E en Rela ed Desynch oniza ion (ERD; o alpha a enua ion), Phase ampli ude coupling (PAC; mainly α-γ) and wi h he eliable change indexes (RCI) om he p ima y (UFOV) and seconda y ou comes (NIH EXAMINER), which will inc ease ou unde s anding abou he mechanisms unde lying his in e en ion. E hics and Dissemina ion The ial is cu en ly unde going clinical ials egis y and is app o ed by he local e hics commi ee—Comissão de É ica pa a a Saúde–CES02/21. Con iden iali y Da a collec ion o ms will be de-iden i ied and pa icipan s will be gi en codes, composed by le e s and numbe s o which all da a will be linked. File eco ds con aining pe sonal da a will be s o ed in a ile cabine oom, wi h es ic ed access. Elec onic da a will be kep in secu e local se e s du ing he pe iod o he s udy and up o 5 yea s a e he s udy has ended. Sensi i e da a will be handled and s o ed acco ding o na ional and Eu opean GDPR egula ions. Dissemina ion Policy Deiden i ied and coded da a will be a ailable o esea che s upon eques . Resul s o he s udy will be p esen ed in scien i ic mee ings, as well as in sessions o he gene al public. Resul s o his s udy will be published in pee e iewed jou nals. DISCUSSION The cu en wo k desc ibes a p o ocol o a pa allel, andomized, double-blind sham con olled ial o es he e ec s o he combina ion o ac i e α- ACS wi h Speed o P ocessing (SoP) aining, in ained (as measu ed by he UFOV) and un ained domains (as measu ed by he NIH EXAMINER), in people wi h Mild Cogni i e impai men (MCI). Assessing ained ans e e ec s o o he cogni i e domains (and e en o daily li e ac i i ies) a e ex emely impo an , as he cu en li e a u e is ull o mixed esul s conce ning he ans e e ec s o cogni i e aining (Sala and Gobe , 2017). Wi h he p esen design we expec ha all g oups will imp o e, howe e we expec ha he combined in e en ion will be be e a a ge engagemen , and as such, pa icipan s on ha speci ic a m, will imp o e mo e han he o he s. So wha we aim o add ess wi h he cu en p o ocol is i he combina ion o SoP and ac i e α- ACS is be e han any in e en ion alone. I is impo an o no e, ha he cu en design is no a ull ac o ial (i.e., he e is no placebo in e en ion alone). This was a choice, as an inclusion o ano he g oup would inc ease he cos s o ial, jeopa dizing i s easibili y. Mo eo e , he cu en p o ocol also aims a s udying he unde lying mechanisms o he in e en ion. By s udying he F on ie s in Aging Neu oscience | www. on ie sin.o g 7July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI mechanisms unde lying he in e en ions, i is possible o unde s and he ole o he unde lying neu al ci cui y (Gonçal es e al., 2016) as well as o de ec speci ic candida es o b ain bioma ke s, which could be used o guide in e en ions, o o se e as ou come p edic o (Ya a i e al., 2016; O adia-Ca o e al., 2019). Fo ins ance, by using elec ophysiological measu es, du ing baseline and pos -in e en ion, i will be possible o p obe o connec i i y changes wi hin he b ain, especially in he es ing s a e ne wo ks. Mo eo e , i will be possible o un a el how hose changes in connec i i y ela e o cogni i e pe o mance wi hin he ‘‘disconnec ed b ain’’ amewo k (Fjell e al., 2013, 2016). Fu he mo e, i will be possible o s udy po en ial phase ampli ude coupling (PAC) be ween he alpha and o he EEG bands, such as he gamma (γ;Canol y and Knigh , 2010), which is hough o be esponsible o memo y and a en ional p ocesses (He mann and Mecklinge , 2001). By unde s anding such changes in he b ain, he equi ed algo i hms o EEG guided s imula ion closed-loops can be u he de eloped (Lei e e al., 2017). Ano he impo an aspec o his s udy p o ocol is he unde s anding o he long- e m e ec s o he in e en ion. The i s ollow-up assessmen will occu a 1 mon h a e he in e en ion has ended, and will be epea ed a 3 and 6 mon hs (see Figu e 2). These long- e m assessmen s a e ex emely impo an , as he e is subs an ial e idence o placebo e ec s in heal hy olun ee s due o CT. In a ecen s udy, pa icipan s ha esponded o a ca chy lye , sugges ing ha hey we e going o unde ake a 1 h CT ha would imp o e hei cogni i e pe o mance and hei luid in elligence, imp o ed be ween 5 and 10 poin s in a s anda d IQ scale; while hose ha esponded o a nonsugges i e lye (i.e., pa icipa ing in a 1 h session in exchange o cou se c edi s) did no (Fo oughi e al., 2016). This s udy highligh s he impo ance o accoun ing o placebo e ec s when assessing he e ec s o CT. Despi e he ac ha he e is no clea amewo k o es ima ing he du a ion o placebo e ec s, he e a e sugges ions ha he placebo e ec s may las up o 6 o 12 mon hs (Hansen e al., 1996; P e i ali e al., 2021). We will be using eliable change index (RCI) in o de o assess i he changes in pa icipan ’s pe o mance ac oss ime a e eliable o no (Ba ke -Collo and Pu dy, 2013). By using mul iple assessmen s and especially he RCI we expec o mi iga e any possible con ounde s a ising om placebo e ec s. The main challenge will be he loss o ollow-up. None heless, he eam will ocus on de eloping s a egies o minimize his, such as sending eminde s (phone, le e o email), by in ol ing ca egi e s in he p ocess, among o he s. I pa icipan s a e no able (o willing o pe o m he EEG du ing ollow-up), hey will be o e ed he oppo uni y o pe o m he emaining ollow-up assessmen s emo ely, using ideocon e ence sys ems, by phone o by he means o se e based cogni i e asks. This p oposal has some e hical conce ns ha need o be add essed acco ding o na ional and in e na ional egula ions. The pa icipa ion o subjec s will always be in o med, consen ed and olun a y. I pa icipan s a e ulne able indi iduals o g oups hen esea ch ac i i ies will only be pe o med i all po en ial isks a e minimized, and he ou come o esea ch is aluable enough ha can ha e an impac in hei quali y o li e, men al heal h o well-being. The cu en p oposal in ol es he use o physical echniques, which a e no in asi e and do no ep esen mo e han minimal isk. The e o e, he cu en p oposal aims a combining speed o p ocessing aining (SoP) wi h endogenous alpha ACS, by de eloping an EEG- ACS closed loop solu ion. Addi ionally, we plan o use execu i e measu es o assess i speed o p ocessing aining ans e s o o he highe o de cogni i e domains. Fu he mo e, we wan o explo e how changes in cogni ion a e ela ed o changes in he b ain, as assessed by he EEG, namely connec i i y ac oss p oximal and dis al egions, and coupling wi h o he equencies o in e es , such as he alpha-gamma ampli ude coupling. In sum, he esul s o his p ojec will u he p o ide impo an insigh s in o he mechanisms unde lying EEG- ACS closed-loop coupled wi h cogni i e aining o enhance Speed o P ocessing in people wi h MCI. This p oposal will allow us o es a new in e en ion, a he same ime ha we explo e he mechanism by which he in e en ion wo ks, and o p obe o po en ial bioma ke s ha may be use ul o guide u u e in e en ions. AUTHOR CONTRIBUTIONS JL and SC designed he p o ocol. JL d a ed he ini ial e sion o he manusc ip . SC and ÓG con ibu ed o he inal e sion o he manusc ip . All au ho s con ibu ed o he a icle and app o ed he submi ed e sion. FUNDING This wo k was suppo ed by Na ional Funds h ough he Po uguese Founda ion o Science and Technology (FCT) and co- unded h ough COMPETE 2020—PO Compe i i idade e In e nacionalização/Po ugal 2020/União Eu opeia, FEDER (Fundos Eu opeus Es u u ais e de In es imen o—FEEI) unde he numbe : PTDC/PSI-ESP/30280/2017. REFERENCES Ame ican Psychia ic Associa ion. (2013). Diagnos ic and S a is ical Manual o Men al Diso de s: DSM-5 (Vol. 5). Washing on, DC: Ame ican Psychia ic Associa ion. An al, A., and He mann, C. S. (2016). T ansc anial al e na ing cu en and andom noise s imula ion: possible mechanisms. Neu al Plas . 2016:3616807. doi: 10.1155/2016/3616807 Au, J., Sheehan, E., Tsai, N., Duncan, G. J., Buschkuehl, M., and Jaeggi, S. M. (2015). Imp o ing luid in elligence wi h aining on wo king memo y: a me a-analysis. Psychon. Bull. Re . 22, 366–377. doi: 10.3758/s13423-014 -0699-x Bächinge , M., Moisa, M., Polania, R., Man ini, D., Ru , C., and Wende o h, N. (2017). Changing es ing s a e connec i i y measu ed by unc ional magne ic esonance imaging wi h ansc anial al e na ing cu en s imula ion. B ain S imul. 10:e5. doi: 10.1016/j.b s.2016.11.033 F on ie s in Aging Neu oscience | www. on ie sin.o g 8July 2022 | Volume 14 | A icle 880510 Lei e e al. ACS Plus SoP T aining in MCI Bake , M., Ak o i, K., Schi e , R., and Boyle, M. W. O. (2008). EEG pa e ns in mild cogni i e impai men (MCI) pa ien s. Open Neu oimag. J. 2, 52–55. doi: 10.2174/1874440000802010052 Ball, K. K., Bea d, B. L., Roenke , D. L., Mille , R. L., and G iggs, D. S. (1988). Age and isual sea ch: expanding he use ul ield o iew. J. Op . Soc. Am. A 5, 2210–2219. doi: 10.1364/josaa.5.002210 Ball, K., Edwa ds, J. D., and Ross, L. A. (2007). The impac o speed o p ocessing aining on cogni i e and e e yday unc ions. J. Ge on ol. B Psychol. Sci. Soc. Sci. 62, 19–31. doi: 10.1093/ge onb/62.special_issue_1.19 Ba ke -Collo, S. L., and Pu dy, S. C. (2013). De e mining he p esence o eliable change o e ime in mul iple scle osis. In . J. MS Ca e 15, 170–178. doi: 10.7224/1537-2073.2013-007 Ba aglini, L., Mena, F., Ghiani, A., Casco, C., Melche , D., and Ronconi, L. (2020). The e ec o alpha ACS on he empo al esolu ion o isual pe cep ion. F on . Psychol. 11:1765. doi: 10.3389/ psyg.2020.01765 Beese, C., Vassileiou, B., F iede ici, A. D., and Meye , L. (2019). Age di e ences in encoding- ela ed alpha powe e lec sen ence comp ehension di icul ies. F on . Aging Neu osci. 11:183. doi: 10.3389/ nagi.2019.00183 Benne , I. J., and Madden, D. J. (2014). Disconnec ed aging: ce eb al whi e ma e in eg i y and age- ela ed di e ences in cogni ion. Neu oscience 276, 187–205. doi: 10.1016/j.neu oscience.2013.11.026 Ben ley, S. A., Leblanc, R. P., Nicolela, M. T., and Chauhan, B. C. (2012). Validi y, eliabili y and epea abili y o he use ul ield o iew es in pe sons wi h no mal ision and pa ien s wi h glaucoma. In es . Op halmol. Vis. Sci. 53, 6763–6769. doi: 10.1167/io s.12-9718 Blanco Ma ín, E., Uga iza Se ano, I., Elco oa is izabal Ma ín, X., Galdos Alcelay, L., Molano Salaza , A., Be eincua Ganda ias, R., e al. (2016). Dysexecu i e synd ome in amnesic mild cogni i e impai men : a mul icen e s udy. BMC Neu ol. 16:88. doi: 10.1186/s12883-016-0607-2 Canol y, R. T., and Knigh , R. T. (2010). The unc ional ole o c oss- equency coupling. T ends Cogn. Sci. 14, 506–515. doi: 10.1016/j. ics.2010.09.001 Ca alho, S., Boggio, P. S., Gonçal es, Ó. F., Vigá io, A. R., Fa ia, M., Sil a, S., e al. (2015a). T ansc anial di ec cu en s imula ion based me aplas ici y p o ocols in wo king memo y. B ain S imul. 8, 289–294. doi: 10.1016/j.b s.2014.11.011 Ca alho, S., Gonçal es, Ó. F., Soa es, J. M., Sampaio, A., Macedo, F., F egni, F., e al. (2015b). Sus ained e ec s o a neu al-based in e en ion in a e ac o y case o ou e e synd ome. B ain S imul. 8, 657–659. doi: 10.1016/j.b s.2014. 12.008 Ca alho, S., Sampaio, A., Mendes, A. J., Lema, A., Viei a, D., Gonçal es Ó, F., e al. (2018). Pola i y speci ic e ec s o c oss-hemisphe ic DCS coupled wi h app oach-a oidance aining on chocola e c a ing. F on . Pha macol. 9:1500. doi: 10.3389/ pha .2018.01500 Edwa ds, J., Ross, L., Wadley, V., Clay, O., C owe, M., Roenke , D., e al. (2006). The use ul ield o iew es : no ma i e da a o olde adul s. A ch. Clin. Neu opsychol. 21, 275–286. doi: 10.1016/j.acn.2006.03.001 Edwa ds, J. D., Xu, H., Cla k, D. O., Guey, L. T., Ross, L. A., and Un e zag , F. W. (2017). Speed o p ocessing aining esul s in lowe isk o demen ia. Alzheime s Demen . (N Y) 3, 603–611. doi: 10.1016/j. ci.2017.09.002 Elsha ei, H. A., Fo noni, L., Masson, R., Be and, O., and Bide -Caule , A. (2020). Age- ela ed modula ions o alpha and gamma b ain ac i i ies unde lying an icipa ion and dis ac ion. PLoS One 15:e0229334. doi: 10.1371/jou nal.pone. 0229334 Fa ias, S. T., Mungas, D., Reed, B. R., Ha ey, D., and Deca li, C. (2009). P og ession o mild cogni i e impai men o demen ia in clinic- s communi y- based coho s. A ch. Neu ol. 66, 1151–1157. doi: 10.1001/a chneu ol.2009.106 Fe guson, R. J., Robinson, A. B., and Splaine, M. (2002). Use o he Reliable Change Index o e alua e clinical signi icance in SF-36 ou comes. Qual. Li e Res. 11, 509–516. doi: 10.1023/a:1016350431190 Fjell, A. M., Mce oy, L., Holland, D., Dale, A. M., Walho d, K. B., and Alzheime ’s Disease Neu oimaging Ini ia i e. (2013). B ain changes in olde adul s a e y low isk o Alzheime ’s disease. J. Neu osci. 33, 8237–8242. doi: 10.1523/JNEUROSCI.5506-12.2013 Fjell, A. M., Sne e, M. H., G ydeland, H., S o s e, A. B., and Walho d, K. B. (2016). The disconnec ed b ain and execu i e unc ion decline in aging. Ce eb. Co ex 27:bhw082. doi: 10.1093/ce co /bhw082 Fols ein, M. F., Fols ein, S. E., and McHugh, P. R. (1975). ‘‘Mini-men al s a e’’. A p ac ical me hod o g ading he cogni i e s a e o pa ien s o he clinician. J. Psychia . Res. 12, 189–198. doi: 10.1016/0022-3956(75)90026-6 Fo oughi, C. K., Mon o , S. S., Paczynski, M., Mcknigh , P. E., and G eenwood, P. M. (2016). Placebo e ec s in cogni i e aining. P oc. Na l. Acad. Sci. U S A 113, 7470–7474. doi: 10.1073/pnas.1601243113 F ies, P. (2015). Rhy hms o cogni ion: communica ion h ough cohe ence. Neu on 88, 220–235. doi: 10.1016/j.neu on.2015.09.034 Gao, M., Wong, C. H. Y., Huang, H., Shao, R., Huang, R., Chan, C. C. H., e al. (2020). Connec ome-based models can p edic p ocessing speed in olde adul s. Neu oimage 223:117290. doi: 10.1016/j.neu oimage.2020.117290 Gillis, C., Mi zaei, F., Po ashman, M., Ik am, M. A., and Mase ejian, N. (2019). The incidence o mild cogni i e impai men : a sys ema ic e iew and da a syn hesis. Alzheime s Demen . (Ams ) 11, 248–256. doi: 10.1016/j.dadm.2019. 01.004 Gonçal es, Ó. F., Ca alho, S., Lei e, J., Fe nandes-Gonçal es, A., Ca acedo, A., and Sampaio, A. (2016). Cogni i e and emo ional impai men s in obsessi e- compulsi e diso de : e idence om unc ional b ain al e a ions. Po o Biomed. J. 1, 92–105. doi: 10.1016/j.pbj.2016.07.005 Hansen, B. J., Meyho , H. H., No dling, J., Mensink, H. J., Mogensen, P., and La sen, E. H. (1996). Placebo e ec s in he pha macological ea men o uncomplica ed benign p os a ic hype plasia. The ALFECH S udy G oup. Scand. J. U ol. Neph ol. 30, 373–377. doi: 10.3109/00365599609181313 Ha ada, C. N., Na elson Lo e, M. C., and T iebel, K. L. (2013). No mal cogni i e aging. Clin. Ge ia . Med. 29, 737–752. doi: 10.1016/j.cge .2013.07.002 He mann, C. S., and Mecklinge , A. (2001). Gamma ac i i y in human EEG is ela ed o highspeed memo y compa isons du ing objec selec i e a en ion. Vis. Cogn. 8, 593–608. doi: 10.1080/13506280143000142 Hilla, Y., on Mankowski, J., Föcke , J., and Sauseng, P. (2020). Fas e isual in o ma ion p ocessing in ideo game s is associa ed wi h EEG alpha ampli ude modula ion. F on . Psychol. 11:599788. doi: 10.3389/ psyg.2020.599788 Hu, C., Wang, L., Guo, Y., Cao, Z., Lu, Y., and Qin, H. (2020). S udy o he isk and p e en i e ac o s o p og ess o mild cogni i e impai men o demen ia. Am. J. Alzheime s Dis. O he Demen. 35:153331752092532. doi: 10.1177/1533317520925324 Huang, T. L., and Cha y on, C. (2008). A comp ehensi e e iew o he psychological e ec s o b ainwa e en ainmen . Al e n. The . Heal h Med. 14, 38–50. Huang, W. A., S i , I. M., Negahbani, E., Passey, D. J., Ahn, S., Da ey, M., e al. (2021). T ansc anial al e na ing cu en s imula ion en ains alpha oscilla ions by p e e en ial phase synch oniza ion o as -spiking co ical neu ons o s imula ion wa e o m. Na . Commun. 12:3151. doi: 10.1038/s41467-021- 23021-2 I azoki, E., Con e as-Somoza, L. M., To ibio-Guzmán, J. M., Jena o-Río, C., an de Roes , H., and F anco-Ma ín, M. A. (2020). Technologies o cogni i e aining and cogni i e ehabili a ion o people wi h mild cogni i e impai men and demen ia. A sys ema ic e iew. F on . Psychol. 11:648. doi: 10.3389/ psyg. 2020.00648 Jacobson, N. S., and T uax, P. (1991). Clinical signi icance: a s a is ical app oach o de ining meaning ul change in psycho he apy esea ch. J. Consul . Clin. Psychol. 59, 12–19. doi: 10.1037//0022-006x.59.1.12 Jobe, J. B., Smi h, D. M., Ball, K., Tenns ed , S. L., Ma siske, M., Willis, S. L., e al. (2001). Ac i e: a cogni i e in e en ion ial o p omo e independence in olde adul s. Con ol. Clin. T ials 22, 453–479. doi: 10.1016/s0197-2456(01)00139-8 Ka bach, J., and Ve haeghen, P. (2014). Making wo king memo y wo k: a me a-analysis o execu i e-con ol and wo king memo y aining in olde adul s. Psychol. Sci. 25, 2027–2037. doi: 10.1177/0956797614548725 K ame , J. H., Mungas, D., Possin, K. L., Rankin, K. P., Boxe , A. L., Rosen, H. J., e al. (2014). NIH EXAMINER: concep ualiza ion and de elopmen o an execu i e unc ion ba e y. J. In . Neu opsychol. Soc. 20, 11–19. doi: 10.1017/S1355617713001094 Lei e, J., Ca alho, S., F egni, F., Boggio, P. S., and Gonçal es, Ó. F. (2013). The e ec s o c oss-hemisphe ic do sola e al p e on al co ex ansc anial di ec cu en s imula ion ( DCS) on ask swi ching. B ain S imul. 6, 660–667. doi: 10.1016/j.b s.2012.10.006 Lei e, J., Ca alho, S., F egni, F., and Gonçal es, Ó. F. (2011). Task-speci ic e ec s o DCS-induced co ical exci abili y changes on cogni i e and mo o sequence se shi ing pe o mance. PLoS One 6:e24140. doi: 10.1371/jou nal. pone.0024140 Lei e, J., Mo ales-Quezada, L., Ca alho, S., Thibau , A., Do uk, D., Chen, C.-F., e al. (2017). Su ace EEG- ansc anial di ec cu en F on ie s in Aging Neu oscience | www. on ie sin.o g 9July 2022 | Volume 14 | A icle 880510