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
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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.
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F on ie s in Aging Neu oscience | www. on ie sin.o g 9July 2022 | Volume 14 | A icle 880510