b ain
sciences
A icle
De ici s in Ea ly Senso y and Cogni i e P ocessing A e Rela ed
o Phase and Nonphase EEG Ac i i y in Mul iple
Scle osis Pa ien s
Es eban Sa ias-A abal 1,* , Sa a Eichau 2, Alejand o Gal ao-Ca mona 3, El i a Domínguez 4,
Guille mo Izquie do 5and Manuel Vázquez-Ma u o 1


Ci a ion: Sa ias-A abal, E.; Eichau,
S.; Gal ao-Ca mona, A.; Domínguez,
E.; Izquie do, G.; Vázquez-Ma u o,
M. De ici s in Ea ly Senso y and
Cogni i e P ocessing A e Rela ed o
Phase and Nonphase EEG Ac i i y in
Mul iple Scle osis Pa ien s. B ain Sci.
2021,11, 629. h ps://doi.o g/
10.3390/b ainsci11050629
Academic Edi o : F ancesco Di Russo
Recei ed: 22 Ma ch 2021
Accep ed: 11 May 2021
Published: 13 May 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
1Expe imen al Psychology Depa men , Facul y o Psychology, Uni e si y o Se ille, 41018 Se ille, Spain;
[email p o ec ed]
2Uni CSUR Mul iple Scle osis, Hospi al Vi gen Maca ena, 41009 Se ille, Spain; [email p o ec ed]
3Depa amen o de Psicología, Uni e sidad Loyola Andalucía, 41704 Se illa, Spain; [email p o ec ed]
4Uni o Mul iple Scle osis, FISEVI, Hospi al Vi gen Maca ena, 41009 Se ille, Spain;
[email p o ec ed]
5
Uni o Mul iple Scle osis, Hospi al VITHAS, 41950 Se ille, Spain; guille mo.izquie [email p o ec ed]
*Co espondence: [email p o ec ed]; Tel.: +34-676-182-823
Abs ac :
Cu en ly, he e is sca ce knowledge abou he ela ion be ween spec al bands modula ions
and he basis o cogni i e impai men in mul iple scle osis (MS). In his sense, analyzing he e oked
o phase ac i i y can con i m esul s om adi ional e en - ela ed po en ial (ERP) s udies. Howe e ,
s udying he induced o nonphase ac i i y may be necessa y o elucida e hidden compensa o y o
a ec ed cogni i e mechanisms. In his s udy, 30 emi ing- elapsing mul iple scle osis pa ien s and
30 heal hy con ols (HCs) ma ched in sociodemog aphic a iables pe o med a isual oddball ask.
The main goal was o analyze phase and nonphase alpha and gamma bands by applying empo al
spec al e olu ion (TSE) and i s po en ial ela ion wi h cogni i e impai men in hese pa ien s. The
beha iou al esul s showed slowe eac ion ime and poo e accu acy in MS pa ien s compa ed o
con ols. In con as , he ime- equency analysis o elec oencephalog aphy (EEG) e ealed a delay
in la ency and lowe ampli ude in MS pa ien s in e oked and induced alpha compa ed o con ols.
Wi h espec o he gamma band, he e we e no di e ences be ween he g oups. In summa y, MS
pa ien s showed de ici s in ea ly senso ial (e oked alpha ac i i y) and cogni i e p ocessing (induced
alpha ac i i y in longe la encies), whe eas he induced gamma band suppo ed he hypo hesis o
i s ole in ansla ion o a en ional ocus (induced ac i i y) and did no show s ong ac i i y in his
pa adigm ( isual oddball).
Keywo ds: alpha; oddball; EEG; gamma; mul iple scle osis; e oked; induced
1. In oduc ion
Mul iple scle osis (MS) is a neu odegene a i e disease o unknown e iology, in which
he main neu ological damage is demyelina ion and in lamma ion o he cen al ne ous
sys em (CNS) [
1
]. MS is a disease p edominan in women, and i s onse occu s o e a wide
age ange (mainly be ween 20 and 40 yea s) [
2
]. Mo eo e , MS shows di e se cogni i e
de ici s in 40–70% o cases [
1
], and di e en neu opsychological p o iles ha e been ound
by clinical assessmen s. Di e se s udies ha e de ined ha a en ion, p ocessing speed and
memo y a e he cogni i e domains mos equen ly a ec ed [3,4].
One o he cogni i e pa adigms ha has been used o unde s and he neu al basis
o hese cogni i e al e a ions in MS is he oddball ask. Mos s udies ha e ound a delay
in he la ency o e en - ela ed po en ials (ERPs) pos -s imulus (misma ch nega i i y, N1,
P1, P2 and P300) [
5
–
7
]. Howe e , some au ho s ha e no desc ibed di e ences in ERPs
be ween g oups [
8
]. In addi ion, he oddball ask can be a use ul ool because changes
in ERPs co ela e wi h changes in sco es o neu opsychological es s [
9
,
10
] and magne ic
B ain Sci. 2021,11, 629. h ps://doi.o g/10.3390/b ainsci11050629 h ps://www.mdpi.com/jou nal/b ainsci
B ain Sci. 2021,11, 629 2 o 13
esonance imaging (MRI) pa ame e s [
6
,
11
]. E en ERPs ob ained while pe o ming isual
oddball asks p edic cogni i e unc ioning and p ocessing speed in pa ien s wi h MS [
12
].
The combined use o spec al analysis and he oddball ask has been applied in pa ien s
wi h MS [
13
], esul ing in an inc eased powe in be a and gamma bands. This inc ease
is associa ed wi h on o-co ical a ophy as sugges ed by o he au ho s [
6
,
14
]. Howe e ,
hese s udies ha e only analyzed he equency domain wi hou he ime dimension. To
imp o e ou knowledge o he neu al basis o cogni i e impai men in MS pa hology, he
ime- equency domain o he elec oencephalog aphy (EEG) signals should be analyzed o
add empo al in o ma ion o equency domain me hods. To he bes o ou knowledge, he
ime- equency domain has ne e been s udied in MS when applying audi o y o isual
oddball asks.
P io o ocusing on MS, i is impo an o desc ibe he ela ion be ween he ime-
equency ea u es o spec al EEG bands and speci ic cogni i e mechanisms. Wi h espec
o he analyzed bands in his s udy (alpha and gamma), he e is conside able li e a u e
ela ed o hei unc ional ole. The alpha band was o iginally p oposed as an indica o o
a neu al a ea a es [
15
]; howe e , se e al au ho s ha e subsequen ly sugges ed ha i can
also play an ac i e ole in inhibi o y con ol and iming o senso y p ocessing [
16
]. In his
sense, he inc ease (synch oniza ion) in alpha ac i i y in egions i ele an o he ask has
been associa ed wi h inhibi ion p ocesses [
17
]. Addi ionally, some s udies ha e p oposed
ha he synch oniza ion o alpha in la encies o ERPs (P1 and N1) [
18
,
19
] ep esen s he
ea ly senso ial p ocessing o s imulus [
20
]. In con as , he dec ease (desynch oniza ion)
in he alpha band has also been ela ed o psychophysiological oles [
21
]. Speci ically, a
dec ease in alpha has been associa ed wi h gene al a en ion and speci ic p ocesses, such as
seman ic p ocessing [
22
–
25
], which indica es ha a la ge dec ease (desynch oniza ion) in
alpha ac i i y leads o be e beha iou al pe o mance.
Wi h ega d o gamma ac i i y, esea che s ha e ela ed such ac i i y o se e al
cogni i e p ocesses [
26
,
27
]. Howe e , a di e se ange o gamma ac i i ies has been s udied,
which has esul ed in disc epancies. These con adic o y esul s may be based on di e en
cogni i e demands, asks and analyzed anges. The gamma band has been undamen ally
associa ed wi h isual binding [
28
–
30
], spa ial a en ion [
31
], p ocessing a ge s imuli [
32
]
o ansla ion o a en ional ocus [
20
,
33
]. One o he easons ha makes his band sui able
o a en ional mechanisms is i s ine empo al uning o neu onal i ing (10–30 ms ime
p ecision) [34].
Wi h espec o hese spec al bands, mos s udies ha e analyzed he alpha band in
pa ien s wi h MS wi h simila conclusions. These s udies ha e sugges ed ha a smalle
dec ease in he alpha band o MS pa ien s compa ed o heal hy con ols is associa ed wi h a
poo e beha iou al pe o mance [
13
,
35
,
36
]. Howe e , a la ge dec ease (desynch oniza ion)
in alpha ac i i y in pa ien s wi h MS has been desc ibed in ce ain condi ions ha demands
mo e cogni i e esou ces [
20
]. These au ho s ha e sugges ed ha in some condi ions,
MS pa ien s need a la ge dec ease in he alpha band o imp o e cogni i e p ocessing
(compensa o y mechanism).
In he case o he gamma band, o he bes o ou knowledge, ew s udies ha e de-
sc ibed al e a ions in his band in MS pa ien s. I has been p oposed ha al e a ions in he
gamma band may be ela ed o de ici s in cogni i e p ocessing [
37
]. Mo e speci ically, an
inc ease (synch oniza ion) in he gamma band in pa ien s wi h MS compa ed o heal hy con-
ols has been associa ed wi h plas ici y o compensa o y a en ional mechanisms [20,38].
As sugges ed abo e, ime- equency me hods a e be e han equency me hods
o unde s anding he ole o spec al bands. One o hese ime- equency echniques is
empo al spec al e olu ion (TSE) [
39
]. The TSE allows EEG ime- equency in o ma ion
ha includes bo h e oked (phase) and induced (nonphase) modula ions o a spec al
band ela ed o a s imulus p esen a ion o be ob ained ( o a de ailed desc ip ion o he
TSE me hod, see [
40
–
42
]). Bo h e oked and induced ac i i ies ha e been demons a ed o
ep esen di e en cogni i e p ocesses [20].
B ain Sci. 2021,11, 629 3 o 13
Finally, TSE has a ely been applied in pa ien s wi h MS o obse e spec al modula-
ions. Applying he a en ion ne wo k es (ANT), a lowe inc ease (synch oniza ion) in
ampli ude in e oked (phase) alpha ac i i y and a delayed la ency in induced (nonphase)
alpha ac i i y ha e been desc ibed in MS pa ien s [
20
]. Rega ding he gamma band, a
la ge induced (non-phase) gamma ac i i y has been ound in MS pa ien s compa ed o
heal hy con ols [
20
]. Al e a ions in alpha bands ha e been associa ed wi h de ici s in ea ly
senso y and cogni i e p ocessing, and changes in gamma bands ha e been associa ed wi h
de ici s in ansla ion o a en ional ocus.
Conside ing hese p emises, we hypo hesized ha he alpha band would be al e ed
in he MS g oup e en wi h an oddball ask whe e he cogni i e mechanisms in ol ed
a e simple han in he a en ion ne wo k es (ANT) [
20
]. We also hypo hesized ha
he gamma band would no show di e ences be ween he wo g oups because a en ion
ocus does no change h oughou he expe imen (cen al p esen a ion). The e o e, he
main aims o he p esen s udy we e o analyze he po en ial modula ions in alpha and
gamma bands (e oked and induced), as well as o ela e hem o cogni i e impai men in
MS pa ien s.
2. Me hods
2.1. Pa icipan s
Six y subjec s we e en olled o pe o m he expe imen in con olled condi ions. Thi y
pa ien s (22 women and 8 men) wi h elapsing- emi ing MS (RRMS) we e ec ui ed
om he Mul iple Scle osis Uni o he Hospi al Uni e si a io Vi gen Maca ena (Se ille,
Spain). The pa ien s we e be ween he ages o 27 and 59 yea s (mean 41.5, s anda d
de ia ion (SD) 9.04). A heal hy con ol (HC) g oup wi h hi y subjec s was selec ed wi h
sociodemog aphic a iables ma ched o he MS g oup (19 women and 11 men who we e
be ween he ages o 24 and 52 yea s (mean 37.43, SD 10.68) (Table 1). Each g oup had h ee
subjec s who we e le -handed.
Table 1. Sociodemog aphic da a.
MS HC
Sex (m/ ) 8/22 11/19
Age (yea s, mean ±SD) 41.5 ±9.04 37.43 ±10.68
Handedless (le / igh ) 3/27 3/27
Du a ion o disease (yea s, mean ±SD) 8.46 ±4.3 -
EDSS (mean, ange) 2.95 ±1.6 -
Abb e ia ions. MS: Mul iple Scle osis; HC: Heal hy Con ols; SD: S anda d de ia ion; EDSS: Expanded Disabili y
S a us Scale; m: male; : emale.
Rega ding pa ien s wi h RRMS, he de ini e diagnosis was made by a neu ologis
acco ding o McDonald’s c i e ia [
43
]. To be eligible o inclusion in he s udy, pa ien s
we e equi ed o be unde an Expanded Disabili y S a us Scale (EDSS) o 5.5 (mean 2.95,
SD 1.6). The ollowing exclusion c i e ia we e used o his s udy: clinical elapses in he
las mon h; p esence o como bid neu odegene a i e o psychia ic diso de s; se e e signs
o dep ession; his o y o subs ance abuse; head auma; ascula diseases and seizu es;
signi ican uppe limb impai men ; o isual acui y o ield de ici s. The mean du a ion
o he disease (in yea s) and he s anda d de ia ion we e 8.46 and 4.36, espec i ely. All
heal hy subjec s we e decla ed o be ee o neu ological condi ions.
This s udy was pe o med in compliance wi h he Helsinki Decla a ion. All pa ici-
pan s signed in o med consen be o e hei inclusion, and he p o ocol was app o ed by
he E hics Commi ee o he Uni e si y o Se ille (p ojec code: PSI2016–78133-P).
2.2. Cogni i e Task
Pa icipan s we e sea ed in a sound-a enua ed oom in on o a compu e moni o .
S imuli we e c ea ed by E-p ime 2.0 (Psychology So wa e Tools, Inc., Pi sbu gh, PA,
B ain Sci. 2021,11, 629 4 o 13
USA) and p esen ed on a liquid c ys al display (LCD) sc een. The cogni i e ask used
was a “ isual oddball” in which he subjec had o disc imina e uncommon isual s imuli
( a ge ) (p obabili y: 25%) in a sequence o equen s imuli (s anda d). The a ge s imulus
consis ed o a ec angle wi h a checke boa d pa e n ha was comp ised o ed and whi e
squa es. The s anda d ( equen ) s imulus was equi alen in size wi h he same pa e n
bu wi h black and whi e squa es. All s imuli sub ended a 7.98
◦×
9.42
◦
isual angle a
a iewing dis ance o 80 cm. Bo h s imuli we e displayed andomly in he cen e o he
sc een. When a a ge was displayed, he subjec was equi ed o p ess he mouse bu on
wi h he igh index inge and igno e he s anda d s imulus. All s imuli we e p esen ed o
500 ms, and he s imulus onse asynch ony (SOA) was 1 s, du ing which he subjec could
espond. A ixa ion poin was p esen du ing he SOA o a oid changes in eye posi ion
du ing he expe imen . One block wi h 200 ials was used o ob ain good pe o mance
in a a ge /s anda d ask. A he end o he expe imen al session, he eac ion ime and
pe cen age accu acy (including no esponses o he s anda d s imuli) we e calcula ed. All
pa icipan s we e asked o espond as quickly and accu a ely as possible.
2.3. Elec oencephalog aphy (EEG) Reco ding and Analyses
EEG da a we e eco ded om 58 elec odes (Ag/AgCl) in s anda d loca ions o
a
10–10
sys em [
44
] and ampli ied wi h B ainAmp ampli ie s (B ain P oduc s GmbH,
Gilching, Ge many) The de ailed posi ions o elec odes a e shown in Figu e 1. The EEG
signal was il e ed online wi h a bandpass o 0.01 o 100 Hz, digi ized wi h a sampling
a e o 500 Hz and s o ed using B ain Vision Reco de so wa e (B ain P oduc s GmbH,
Ge many). All con inuous da a we e e e enced online o he linked au icula lobes and
o line o a common a e aged e e ence. Impedance was kep below 5 kOhm du ing
he expe imen . Ve ical elec ooculog ams (VEOGs) and ho izon al elec ooculog ams
(HEOGs) we e also eco ded wi h a bipola mon age. T ials wi h a HEOG signal ou side
he
±
50
µ
V ange we e ejec ed. Fo blinking a e ac s, ocula co ec ion was pe o med
in he scalp elec odes using he algo i hm de eloped by he au ho s [
45
]. A con inuous
signal was epoched in segmen s o
−
1000 o 1000 ms wi h ze o being he onse o he a ge .
A baseline co ec ion (
−
200 o 0 ms) was also applied o bo h condi ions. We segmen ed
he signal in in e als o 2000 ms o a oid edge a e ac s in he spec al modula ions
s udied [46].
Figu e 1. Elec ode ma ix selec ed o analyze spec al ac i i y.
A e p ocessing, he ollowing wo possible analyses we e pe o med o he EEG
signal: he a ge condi ion was a e aged independen ly o ob ain e oked ac i i y, and he
signal was il e ed o alpha (8–13 Hz) and gamma (30–45 Hz) bands and ec i ied [
47
]. P io
o he induced ac i i y, he empo al spec al e olu ion (TSE) me hod was calcula ed wi h
B ain Sci. 2021,11, 629 5 o 13
he ollowing s eps: (1) iden ical bandpass il e ing in p e iously de ined alpha and gamma
bands was pe o med o e he EEG epochs, (2) he signal was ec i ied, (3) he a ge s imuli
we e a e aged, and (4) a baseline co ec ion (
−
200 o 0 ms) was also applied. A e his
analysis, a sub ac ion o e oked ac i i y om he TSE was subsequen ly pe o med o
calcula e he induced esponse (nonphase ac i i y) [47] (Figu e 2).
Figu e 2. Tempo al spec al e olu ion (TSE).
Following he guidelines p oposed by Keil and Mülle [
48
], he la ency was calcula ed
a he elec ode wi h he maximum ampli ude (p4p) in he a e age o he a ge condi ion in
bo h g oups. The la ency peak was de e mined indi idually o each pa icipan . Mo eo e ,
he ampli ude was analyzed a di e en in e als o e oked and induced ac i i y a e he
onse s imulus. Fo alpha ac i i y, he ampli ude in he e oked ac i i y was expo ed o he
in e al o 125–155 ms, while o he induced ac i i y, he in e al was
120–220 ms
. These
in e als included he la ency a which bo h g oups eached hei maximum ampli ude
alues. In addi ion, he mean ampli ude alue in he in e al o 220–800 ms was expo ed
in he induced ac i i y because bo h g oups showed a dec ease in induced alpha ac i i y
a e he i s alley obse ed in he a ge condi ion. Fo gamma ac i i y, he ampli ude
in he e oked ac i i y was expo ed o he in e al o 90–160 ms, while o he induced
ac i i y, he in e al was 90–130 ms. All he in e als we e iden ical o bo h g oups. The
mean ampli ude alues we e expo ed o he en i e in e al in a ma ix o 3
×
7 elec odes
ha co e ed he pos e io a ea o he scalp in bo h bands (Figu e 1).
2.4. S a is ical Analyses
2.4.1. Beha iou al Responses
The Shapi o–Wilk es (p> 0.05) was applied o check o no mali y. Pa ame ic (anal-
ysis o a iance, ANOVA) o non-pa ame ic es s (Mann–Whi ney U es ) we e pe o med
o s udy possible di e ences in eac ion ime o accu acy. The analysis o he eac ion imes
was pe o med wi h a single- ac o ANOVA using he ollowing ac o : g oup ac o (le els:

B ain Sci. 2021,11, 629 6 o 13
HC and MS pa ien s). The accu acy o he subjec s’ esponses was de e mined wi h he
Mann–Whi ney U es wi h he same ac o as o he eac ion ime ANOVA.
2.4.2. Alpha Band
In he case o he analysis o alpha ac i i y, e oked and induced la encies we e an-
alyzed oge he . One ANOVA wi h wo a iables was pe o med wi h he ollowing
ac o s: g oup ac o (le els HC and MS pa ien s) and ac i i y ac o (le els: e oked and
induced ac i i y). Rega ding ampli ude, e oked ac i i y o he 125–155 ms in e al was
analyzed wi h ANOVA wi h he ollowing ac o s: g oup ac o (le els: HC and MS pa-
ien s); an e io -pos e io ac o (le els: mid-pa ie al, pa ie al and pa ie al-pos e io ); and
la e al-medial ac o (line 5, line 3, line 1, cen al, line 2, line 4 and line 6). The ampli ude o
he induced ac i i y was analyzed wi h he same ac o s o e oked ac i i y in a di e en
in e al (120–220 ms). Fo he induced ac i i y, ano he empo al window (220–800 ms)
was checked wi h he ac o s desc ibed p e iously.
2.4.3. Gamma Band
In his case, we pe o med he same ANOVAs desc ibed in he alpha sec ion. To
analyze he la ency o e oked and induced gamma ac i i ies, one ANOVA wi h he ollow-
ing wo a iables was pe o med: g oup ac o (le els HC and MS pa ien s) and ac i i y
ac o (le els: e oked and induced ac i i y). Fo he ampli ude a iable, we pe o med
wo ANOVAs (e oked and induced ac i i ies) wi h he same ac o s and le els applied o
alpha ANOVAs. Howe e , he in e als we e di e en o e oked and induced ac i i y.
Fo he e oked ac i i y, he ampli ude was analyzed in he 90–160 ms in e al a e he
onse s imulus ( a ge o s anda d). Fo he induced ac i i y, he in e al used o analysis
was 90–130 ms.
In all he s a is ical analyses desc ibed, sphe ici y was co ec ed wi h G eenhouse–
Geisse , and a s a is ically signi ican esul was conside ed a p< 0.05. Pos hoc analyses
we e pe o med using Bon e oni co ec ion.
3. Resul
3.1. Beha iou al Da a
The analysis showed di e ences be ween g oups in eac ion ime [F (1,29): 25.247;
p< 0.001;
η2
: 0.465]. The heal hy con ols (mean: 338.08; SD: 40.62) we e as e han he
MS pa ien s (mean: 394.05; SD: 38.25). Rega ding accu acy, heal hy con ols (mean 96.66;
SD: 5.31) showed mo e p ecision han he MS pa ien s (mean 78; SD: 26.42) [U: 135.50;
p< 0.001
;
η2
: 0.320]. The eac ion ime and accu acy alues a e p esen ed in Table 2. In an
explo a o y analysis no co ela ion was ound be ween EDSS sco es and beha io al da a.
Table 2. Beha io al esul s.
Reac ion Time Accu acy
G oup Heal hy
Con ols
Mul iple
Scle osis Subjec Heal hy
Con ols
Mul iple
Scle osis
Mean 338 394 Mean 96 78
SD 40.6 38.2 SD 5.3 26.4
p- alue <0.001 p- alue <0.001
The p- alue e e s o he “g oup” ac o di e ence (see ex o de ails). Reac ion ime and accu acy we e measu ed
in milliseconds and pe cen ages, espec i ely. Abb e ia ions: SD: s anda d de ia ion.
3.2. Alpha Band
In la ency, we obse ed di e ences be ween g oups (HC and MS) [F (1,58): 14.552;
p< 0.001
;
η2
: 0.312] (Figu e 2). In addi ion, he pos hoc Bon e oni compa ison con i med
ha he heal hy con ols we e as e han he MS pa ien s in bo h e oked (p= 0.034) and
induced ac i i ies (p< 0.001). The la ency and ampli ude alues a e shown in Table 3.
B ain Sci. 2021,11, 629 7 o 13
Addi ionally, he ac i i y ac o was s a is ically signi ican [F (1,58): 8.301; p= 0.005;
η2
:
0.262] wi h e oked ac i i y being as e han induced ac i i y. No co ela ion was ound
be ween EDSS sco es and spec al ac i i y o alpha band.
Table 3. E oked and induced alues o alpha band (8–13 Hz) and gamma band (30–45 Hz).
Alpha Band
La ency (mean ±SD) Ampli ude (mean ±SD)
HC MS p- alue HC MS p- alue
E oked 132 ±32 167 ±54 0.034 E oked 2.15 ±0.83 1.30 ±1.05 0.003
Induced 136 ±37 189 ±60 <0.001 Induced –1.33 ±0.60 –1.57 ±1.22 0.292
Gamma Band
La ency (mean ±SD) Ampli ude (mean ±SD)
HC MS p- alue HC MS p- alue
E oked 117 ±37 126 ±36 1.000 E oked 0.275 ±0.2 0.142 ±0.16 0.058
Induced 126 ±41 152 ±46 0.098 Induced –0.246 ±0.14 –0.17 ±0.15 0.067
La ency and ampli ude we e measu ed in milliseconds and mic o ol s, espec i ely. Abb e ia ions: MS: mul iple scle osis; HCs: heal hy
con ols; SD: s anda d de ia ion.
Rega ding ampli ude in he e oked ac i i y, he heal hy con ols showed a la ge
ampli ude han ha o he MS pa ien s [F (1,58): 9.390; p= 0.003;
η2
: 0.220]. In he
g oup x an e io –pos e io in e ac ion, pos hoc Bon e oni compa ison showed ha he
pos e io egions (pa ie o-occipi al) o heal hy con ols we e la ge han hose o MS
pa ien s (
p= 0.008)
. In he induced ac i i y, he ANOVA did no ind ampli ude di e ences
be ween g oups in he 120–220 ms in e al. Howe e , in he 220–800 ms in e al a e
onse o s imulus, he s a is ical analysis showed ha he MS pa ien s eached a highe
dec emen o induced ac i i y han ha o he heal hy con ols in he g oup ac o [F (1,58):
6.562; p= 0.013; η2: 0.177] (Figu e 3).
Figu e 3.
Spec al ac i i y o alpha band in bo h g oups. (
A
) E oked and induced wa es o he alpha band (8–13 Hz) in he
isual oddball ask. (
B
) 2D head maps o he peak and alley la encies o e oked and induced ac i i y. Abb e ia ions: MS:
mul iple scle osis; HCs: heal hy con ols; ms: milliseconds; µV: mic o ol s.
B ain Sci. 2021,11, 629 8 o 13
3.3. Gamma Band
Rega ding la ency, we did no obse e di e ences be ween g oups (HC and MS)
(p= 0.158)
. The la ency and ampli ude alues a e shown in Table 3. Simila o he alpha
band, he ac i i y ac o o he gamma band showed signi ican di e ences [F (1,58): 16.142;
p< 0.001;
η2
: 0.376]. In his case, he e oked ac i i y (mean: 122; SD: 36) was also as e
han he induced ac i i y (mean: 139; SD: 45).
Rega ding he ampli ude, he e we e no di e ences be ween g oups in he
90–160 ms
in e al o he e oked ac i i y (p= 0.121) o in he 90–130 ms in e al o he induced
esponse (p= 0.062) (Figu e 4). In an explo a o y analysis no co ela ion was obse ed
be ween EDSS sco es and spec al ac i i y in gamma band.
Figu e 4.
Spec al ac i i y o gamma band in bo h g oups. (
A
) E oked and induced wa es o he gamma band (30–45 Hz)
in he isual oddball ask. (
B
) 2D head maps o he peak and alley la encies o e oked and induced ac i i y. Abb e ia ions:
MS: mul iple scle osis; HCs: heal hy con ols; ms: milliseconds; µV: mic o ol s.
4. Discussion
Some s udies ha e applied he isual oddball ask in pa ien s wi h MS
[5,6,9,10,12,49]
.
Few au ho s ha e compa ed he pe o mance be ween MS pa ien s and heal hy con-
ols
[9,10,49]
. In wo o hese p e ious s udies, no di e ences in eac ion ime in he
isual oddball pa adigm we e obse ed be ween MS pa ien s and heal hy con ols [
9
,
10
].
Howe e , we ound a delay in eac ion ime in MS pa ien s compa ed o heal hy con ols.
As we sugges below, his delay may be explained by gene al slowing, impai ed p epa a-
ion o a esponse o he onse o he a ge o bo h. Rega ding accu acy, we obse ed a
poo e pe o mance in MS pa ien s han in heal hy con ols, sugges ing ha he e was no
speed–accu acy ade-o in his expe imen . The e o e, hese esul s indica ed a cogni i e
de ici in he sample o pa ien s pa icipa ing in he s udy.
4.1. E oked Alpha
In e oked alpha, an inc ease (synch oniza ion) in ac i i y was obse ed in bo h
g oups (Figu e 3). This inc ease ollowing s imulus onse has also been desc ibed in he
isual oddball ask [
25
,
47
] and in o he pa adigms, such as ANT [
20
]. Some au ho s
ha e sugges ed ha e oked alpha ac i i y a la encies wi hin he 100–200 ms in e al
ep esen he spec al con en o ea ly ERPs (P1 and N1) [
16
,
18
,
19
]. In con as , we obse ed
di e ences be ween g oups in he la ency a which he maximal synch oniza ion o alpha
ac i i y was eached. Heal hy con ols showed as e la encies han pa ien s wi h MS
(Table 3)
. The mos plausible cause o he longe la ency may be he demyelina ion
ha MS pa ien s su e [
1
]. I is well known ha MS pa hology can p o oke a delay in
ansmission wi hin a ne wo k o be ween neu al ne wo ks, causing cogni i e de ici s [
50
].
B ain Sci. 2021,11, 629 9 o 13
Ano he al e na i e in e p e a ion may be ela ed o p epa a o y ac i i y. Some
au ho s ha e sugges ed ha a ixed SOA can gene a e expec a ions in he absence o
cues [
51
,
52
]. In his way, subjec s can de elop accu a e expec a ions abou he onse o he
s imulus e en in he absence o empo al and/o spa ial cues. Howe e , a p e ious s udy
has epo ed a poo expec a i e p epa a ion esponse in MS pa ien s e en in pa adigms
wi h empo al and spa ial cues [
53
]. In addi ion, Liu e al. [
54
] demons a ed ha hose
who show a poo e le el o ale ness a e wo se in he empo al es ima ion o he onse o
he s imulus. In ac , di e se s udies ha e desc ibed an impai men in ale ness o MS
pa ien s [
55
–
58
]. The e o e, he delay in la ency obse ed in MS pa ien s may be acili a ed
by de ici s in ale ness and poo e expec a i e mechanisms.
Rega ding ampli ude, he analyses showed signi ican di e ences be ween g oups
(Figu e 3). Heal hy con ols eached highe ampli ude (synch oniza ion) han did pa ien s
wi h MS. This la ge ampli ude in heal hy con ols may ep esen a be e pe o mance
in ea ly senso y p ocessing o he s imulus compa ed o he MS pa ien s [
59
]. The lowe
ampli ude in MS may be due o a de ici in he neu al ec ui men o neu onal i ing causing
a lowe le el o synch oniza ion.
A ophic p ocesses may also be esponsible o a change in he opog aphy o he
spec al modula ions and subsequen ly esponsible o a lowe ampli ude. In ac , MS
pa ien s exhibi ed a lowe ampli ude in he pa ie o-occipi al egions compa ed o he
heal hy con ol g oup. Howe e , he elec ode wi h maximum ampli ude in bo h g oups
was p4p, and no subs an ial change in he gene al dis ibu ion o e he scalp o he e oked
modula ion was p esen in he cu en da a. This easoning is in acco dance wi h p e ious
s udies, in which a ophy measu es and EDSS sco es (cogni i e measu es included) do no
co ela e in he i s s age o he disease [60].
4.2. Induced Alpha
In he induced ac i i y, a dec ease (desynch oniza ion) in he alpha band was obse ed
as in p e ious s udies [
47
,
61
] (Figu e 3). This dec emen ( alley) has been associa ed wi h
he need o educe alpha o allow o he cogni i e p ocesses, ope a ing in alpha o in
o he equencies, o pe o m hei unc ion [
16
,
25
,
36
,
62
]. Wi h ega d o induced ac i i y,
he heal hy con ols eached he maximum desynch oniza ion (dec ease) as e han he
MS pa ien s, sugges ing ha he heal hy con ols can dec ease he induced alpha ac i i y
o allow a mo e e icien cogni i e p ocessing han he MS pa ien s. As o he e oked
esponse, demyelina ion and/o impai ed mechanisms o expec a ion may be esponsible
o his delay.
Su p isingly, no signi ican di e ences we e ound in he maximum ampli ude eached
in ei he g oup in he alley o he induced ac i i y (Figu e 3); his ou come con adic s
p e iously s udies ha ha e epo ed al e a ions in he dec emen o he alpha band
in MS pa ien s [
20
,
35
,
36
]. Howe e , MS pa ien s showed a g ea e dec ease in induced
alpha ac i i y han heal hy con ols in he 220–800 ms in e al (a e alley). A plausible
in e p e a ion is ha he i s dec emen o alpha was simila in his ask because he
cogni i e equi emen s o he ask may no ha e eached he le el in ol ed in o he
cogni i e asks such as he ANT [
20
]. Howe e , he dec emen o induced alpha ac i i y
needs o be main ained in longe la encies (220–800 ms) o allow he pa ien o pe o m he
ask as bes as possible [20,35,36].
4.3. E oked Gamma
In he cu en expe imen , we obse ed a posi i e e oked gamma modula ion in
simila la encies compa ed o p e ious s udies [
63
]. In e es ingly, he da a showed no
di e ences in la ency o ampli ude be ween g oups (Figu e 4). The e o e, based on hese
esul s, we sugges ha he MS pa ien s did no mani es al e a ions in he mechanisms
indexed by he ea ly gamma-e oked esponse as p e iously desc ibed [20].