Associa ions o physical ac i i y and sc een ime wi h whi e ma e
mic os uc u e in child en om he gene al popula ion
Ma ía Rod iguez-Ayllon
a
, I onne P.M. De ks
b
,
c
, Michiel A. an den D ies
b
,
c
,
I ene Es eban-Co nejo
a
,
d
, Je emy A. Lab ecque
e
, Junwen Yang-Huang
c
,
, Hein Raa
,
Meike W. Ve nooij
e
,
g
, Tonya Whi e
b
,
g
, F ancisco B. O ega
a
, Henning Tiemeie
b
,
h
,
*
,
Ryan L. Mue zel
b
,
e
a
PROFITH “PROmo ing FITness and Heal h h ough physical ac i i y” esea ch g oup, Spo and Heal h Uni e si y Resea ch Ins i u e (iMUDS), Depa men o Physical
and Spo s Educa ion, Facul y o Spo Sciences, Uni e si y o G anada, G anada, Spain
b
Depa men o Child and Adolescen Psychia y, E asmus MC –Sophia Child en’s Hospi al, Ro e dam, he Ne he lands
c
Gene a ion R S udy G oup, E asmus MC –Sophia Child en’s Hospi al, Ro e dam, he Ne he lands
d
Cen e o Cogni i e and B ain Heal h, Depa men o Psychology, No heas e n Uni e si y, Bos on, MA, USA
e
Depa men o Epidemiology, E asmus MC, Ro e dam, he Ne he lands
Depa men o Public Heal h, E asmus MC, Ro e dam, he Ne he lands
g
Depa men o Radiology and Nuclea Medicine, E asmus MC, Ro e dam, he Ne he lands
h
Depa men o Social and Beha io al Science, Ha a d T.H. Chan School o Public Heal h, Bos on, MA, Uni ed S a es
ARTICLE INFO
Keywo ds:
MRI
Di usion enso imaging
B ain de elopmen
Seden a y beha io
Tele ision iewing
Video games
Ac i e commu ing
ABSTRACT
Physical ac i i y and seden a y beha io s ha e been linked o a a ie y o gene al heal h benefi s and p oblems.
Howe e , ew s udies ha e examined how physical ac i i y du ing childhood is ela ed o b ain de elopmen ,
wi h he majo i y o wo k o da e ocusing on ca dio-me abolic heal h. This s udy examines he associa ion be-
ween physical ac i i y and sc een ime wi h whi e ma e mic os uc u e in he gene al pedia ic popula ion. In a
sample o 2532 child en (10.12 0.58 yea s; 50.04% boys) om he Gene a ion R S udy, a popula ion-based
coho in Ro e dam, he Ne he lands, we assessed physical ac i i y and sc een ime using pa en - epo ed
ques ionnai es. Magne ic esonance imaging o whi e ma e mic os uc u e was conduc ed using di usion
enso imaging. To al physical ac i i y was posi i ely associa ed wi h global ac ional aniso opy (β¼0.057, 95%
CI ¼0.016, 0.098, p ¼0.007) and nega i ely associa ed wi h global mean di usi i y (β¼0.079, 95%
CI ¼0.120, 0.038, p <0.001), wo commonly de i ed scala measu es o whi e ma e mic os uc u e. Two
componen s o o al physical ac i i y, ou doo play and spo pa icipa ion, we e posi i ely associa ed wi h global
ac ional aniso opy (β¼0.041, 95% CI¼(0.000, 0.083), p ¼0.047; β¼0.053, 95% CI¼(0.010, 0.096),
p¼0.015, espec i ely) and in e sely associa ed wi h global mean di usi i y (β¼0.074, 95% CI¼(0.114,
0.033), p <0.001; β¼0.043, 95% CI¼(-0.086, 0.000), p ¼0.049, espec i ely). No associa ions we e obse ed
be ween sc een ime and whi e ma e mic os uc u e (p >0.05). This s udy p o ides new e idence ha physical
ac i i y is modes ly associa ed wi h whi e ma e mic os uc u e in child en. In con as , complemen ing o he
ecen e idence on cogni ion, sc een ime was no associa ed wi h whi e ma e mic os uc u e. Causal in e ences
om hese modes associa ions mus be in e p e ed cau iously in he absence o longi udinal da a. Howe e , hese
da a s ill o e a p omising a enue o u u e wo k o explo e o wha ex en physical ac i i y may p omo e heal hy
whi e ma e de elopmen .
Abb e ia ions: MRI, magne ic esonance imaging; METs, me abolic equi alen s; DTI, di usion enso imaging; FA, ac ional aniso opy; MD, mean di usi i y; RCT,
andomized con ol ial; EPI, di ec ion echo plana imaging; AD, axial di usi i y; RD, adial di usi i y; BMI, body mass index; IQ, Non- e bal in elligence quo ien ;
SON-R 2.5–7, Snijde s-Oomen Nie - e bale in elligen ie Tes - Re isie; CBCL/6–18, Child Beha io Checklis school-age e sion; FDR, alse disco e y a e; ZonMw,
Ne he lands O ganiza ion o Heal h Resea ch and De elopmen .
* Co esponding au ho . Depa men o Social and Beha io al Science, Ha a d T.H. Chan School o Public Heal h Bos on, Massachuse s, Uni ed S a es.
E-mail add ess: [email p o ec ed]a a d.edu (H. Tiemeie ).
Con en s lis s a ailable a ScienceDi ec
Neu oImage
jou nal homepage: www.else ie .com/loca e/neu oimage
h ps://doi.o g/10.1016/j.neu oimage.2019.116258
Recei ed 4 Feb ua y 2019; Recei ed in e ised o m 1 Oc obe 2019; Accep ed 7 Oc obe 2019
A ailable online 9 Oc obe 2019
1053-8119/©2019 Else ie Inc. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/).
Neu oImage 205 (2020) 116258
1. In oduc ion
Despi e compelling e idence sugges ing physical ac i i y plays an
impo an ole in gene al heal h (Lee e al., 2012), a subs an ial p o-
po ion o you h do no mee he ecommended le els o physical ac i i y
(Hallal e al., 2012). Du ing childhood and adolescence, he b ain un-
de goes a a ie y o de elopmen al changes in whi e and g ay ma e
s uc u e (Len oo and Giedd, 2006;Schmi ho s and Yuan, 2010), which
also coincide wi h changes in beha io and cogni ion. Du ing his sen-
si i e pe iod o ma u a ion, a numbe o en i onmen al ac o s ha e been
shown o be ela ed o he b ain’s whi e ma e mac os uc u e and
mic os uc u e (F odl e al., 2012;Hanson e al., 2013;Bick and Nelson,
2016), ye li le wo k has explo ed o wha ex en physical ac i i y and
seden a y beha io , associa e wi h whi e ma e in child en.
Physical ac i i y and seden a y beha io a e he wo independen
beha io s ha occupy all waking hou s o a day. Physical ac i i y,
defined as any body mo emen ha inc eases ene gy expendi u e (e.g.
ac i e commu ing, ou doo play, o spo pa icipa ion) (Caspe sen e al.,
1985), has been consis en ly linked o men al heal h benefi s ac oss a
pe son’s li espan (Biddle e al., 2018;Chek oud e al., 2018). On he
o he hand, seden a y beha io , defined as any waking beha io cha -
ac e ized by an ene gy expendi u e 1.5 me abolic equi alen s (METs),
while in a si ing, eclining o lying pos u e (T emblay e al., 2017), has
become a cen al componen o he daily li es o child en. The e o e, he
deba e abou whe he seden a y beha io , specifically ec ea ional
sc een ime, nega i ely impac s child en men al heal h is becoming
inc easingly impo an . Recen wo k has sugges ed ha while nega i e
associa ions a e obse ed be ween sc een ime (i.e., echnology use and
playing ideogames) and men al heal h and cogni ion in young people,
hey a e likely oo small in magni ude o wa an policy change (Fe gu-
son, 2017;O ben and P zybylski, 2019). Though p e ious wo k has
s udied he associa ion o hese wo beha io s wi h indica o s o men al
heal h in childhood, li le wo k has examined any neu al co ela es.
Magne ic esonance imaging (MRI) o e s an in i o iew in o he
de eloping b ain. Whi e ma e neu onal issue consis s o axons w ap-
ped in he lipid- ich myelin shea h and is esponsible o p o iding as
and e ficien connec ions h oughou co ex and subco ex. Di usion
enso imaging (DTI) is able o sample ea u es o he mic os uc u al
a chi ec u e o whi e ma e . F ac ional aniso opy (FA) and mean
di usi i y (MD) a e wo commonly de i ed scala me ics om DTI. FA
ep esen s he deg ee o which wa e di uses p e e en ially along one
axis (i.e., he di usion is hinde ed by s uc u es such as myelin and
igh ly packed axons), and has shown o inc ease wi h age du ing child
and adolescen b ain de elopmen (Gio gio e al., 2010;Schmi ho s and
Yuan, 2010;Tamnes e al., 2018) and in many cases o be lowe in he
con ex o a ious neu ological and psychia ic diseases (Hul e sho n
e al., 2011;Ayling e al., 2012;Aoki e al., 2018). MD is he simple
a e age di usion, wi h highe le els indica ing ela i ely unimpeded
di usion (i.e., i is nega i ely co ela ed wi h FA). Nume ous s udies
ha e demons a ed ha de elopmen al changes in whi e ma e mic o-
s uc u e occu h oughou childhood (Schmi ho s and Yuan, 2010;
S iles and Je nigan, 2010), and he echnique has been shown o be
sensi i e o sub le ea u es o psychopa hology (Mue zel e al., 2017).
Howe e , li le wo k has explo ed whe he physical ac i i y o sc een
ime a e associa ed wi h whi e ma e mic os uc u e.
In one andomized con ol ial (RCT) o o e weigh 8–11 yea -old
child en, he e ec o an 8-mon h exe cise in e en ion on whi e ma -
e mic os uc u e was examined (K a e al., 2014;Schae e e al.,
2014). This s udy showed ha FA inc eased in he uncina e and supe io
longi udinal asciculus in he in e en ion g oup. Simila ly, ano he RCT
examined he e ec s o an a e -school exe cise p og am on he mic o-
s uc u e o whi e ma e ac s in 7- o 9-yea -old child en. This s udy
ound ha child en who pa icipa ed in he exe cise p og am showed
inc eased whi e ma e mic os uc u e in he genu o he co pus callosum
(Chaddock-Heyman e al., 2018). In addi ion, a c oss-sec ional s udy
demons a ed ha , in 9- o-10 yea -old child en, highe le els o ca dio-
espi a o y fi ness we e associa ed wi h g ea e FA in sec ions o he
co pus callosum, co ona adia a, and supe io longi udinal asciculus
(Chaddock-Heyman e al., 2014). Howe e , g ea e ca dio espi a o y
fi ness was also associa ed wi h lowe FA in he co icospinal ac
(He ing e al., 2014). Collec i ely, i is di ficul o d aw conclusions om
his limi ed li e a u e, which la gely ocuses on he ela ion be ween
ca dio espi a o y fi ness, exe cise and whi e ma e mic os uc u e,
omi ing he cons uc s o physical ac i i y (e.g., ou doo play, ac i e
commu ing, and spo pa icipa ion). Fu he , o ou knowledge, no o he
s udies ha e examined whe he sc een ime is associa ed wi h whi e
ma e mic os uc u e in child en.
The p esen s udy examined he associa ions o physical ac i i y and
sc een ime wi h whi e ma e mic os uc u e in 10-yea old child en
om he gene al popula ion. Based on p e ious li e a u e, we hypo he-
sized highe le els o physical ac i i y would be ela ed o highe FA and
lowe MD. We hypo hesized inc eased sc een ime would be ela ed o
lowe FA and highe MD, howe e , in line wi h p e ious li e a u e
(Fe guson, 2015,2017;O ben and P zybylski, 2019), we expec hese
ela ionships o be ela i ely small.
2. Ma e ials and me hods
2.1. S udy design and pa icipan s
The s udy was pa o he Gene a ion R S udy, a p ena al popula ion-
based coho . A de ailed desc ip ion o he s udy design and me hods has
been published elsewhe e (Kooijman e al., 2016). In o al, 3992 child en
isi ed ou s udy-dedica ed imaging acili y o an MRI scan a he mean
age o 10 (Whi e e al., 2018). O he 3992 child en, a o al o 942 we e
excluded due o missing a comple e DTI scan (n ¼285), image a i ac s
(n ¼37), poo image quali y (n ¼406), an inciden al finding (n ¼13) o
hei da a we e collec ed using di e en pa ame e s on he MRI sys em
(n ¼201), lea ing 3050 pa icipan s o analysis. A e excluding chil-
d en wi h missing in o ma ion on physical ac i i y (n ¼518), he s udy
sample included 2532 child en (mean age 10.12 0.58 yea s; 50.04%
boys). Supplemen al Table S1 shows he sample cha ac e is ics o chil-
d en included in analyses o sc een ime (N ¼2346), which is highly
simila o hose included in analyses o physical ac i i y. A flow cha
illus a ing he exclusion o da a is depic ed in Fig. 1. The Medical E hics
Commi ee o he E asmus Medical Cen e app o ed he s udy p ocedu es
and pa icipan s p o ided w i en in o med consen .
2.2. Physical ac i i y and sc een ime assessmen s
In o ma ion on he le el o physical ac i i y and sc een ime we e
ob ained h ough a pa en - epo ed ques ionnai e adminis e ed when
child en we e 10 yea s old. The ques ionnai es we e in ended o he
p ima y ca egi e who was mos o en he mo he (97%). To assess he
le el o physical ac i i y, esponden s indica ed bo h he numbe o days
pe week and du a ion pe day hei child engages in: (i) walking o
cycling o/ om school, (ii) ou doo play, and (iii) spo s. Time pe week
spen on each ac i i y was calcula ed by using he ollowing o mula:
weekly ime spen on he ac i i y ¼(days pe week) * (hou s pe day). A
o al physical ac i i y sco e was calcula ed by adding he hou s o ac i e
commu ing, ou doo play, and spo pa icipa ion pe week.
Responden s we e also asked o indica e he numbe o days and
hou s pe day hei child: (i) wa ches ele ision (including ideos/DVDs)
and (ii) uses a compu e o simila de ice (including ideo games).
Sc een imes we e assessed sepa a ely o weekdays and weekend days
bu we e combined o es ima e he o al hou s pe week spen in each
ac i i y. A o al weekly sc een ime sco e was calcula ed by adding he
hou s o playing ideo games and wa ching ele ision.
M. Rod iguez-Ayllon e al. Neu oImage 205 (2020) 116258
2
2.3. MRI
2.3.1. Image acquisi ion
MRI da a we e acqui ed wi h a 3 Tesla GE MR-750W sys em (Gene al
Elec ic, Milwaukee, WI). The DTI sequence consis ed o a 35 di ec ion
echo plana imaging (EPI) sequence using he ollowing sequence pa-
ame e s: TR ¼12,500 m s, TE ¼72 m s, flip angle ¼90, ma-
ix ¼120 120, FOV ¼240 mm 240 mm, slice hickness ¼2 mm,
numbe o slices ¼65 and oxel esolu ion ¼222mm
3
(Mue zel
e al., 2017).
2.3.2. Image p ep ocessing
Image p ep ocessing was conduc ed using he Func ional MRI o he
B ain’s So wa e Lib a y (Jenkinson e al., 2012) and he CAMINO oolki
(Cook e al., 2006) h ough py hon in e aces (h ps:// sl. m ib.ox.ac.uk)
(Go golewski e al., 2011). Images we e fi s adjus ed o mino head
mo ion and eddy-cu en induced a i ac s (Haselg o e and Moo e, 1996;
Jenkinson and Smi h, 2001). In o de o accoun o o a ions applied o
he image da a (Leemans and Jones, 2009;Jones and Ce cignani, 2010),
he esul ing ans o ma ion ma ices we e used o o a e he di usion
g adien di ec ion able. Non-b ain was emo ed using he FSL B ain
Ex ac ion Tool (Smi h, 2002). The di usion enso was fi using he
RESTORE me hod (Chang e al., 2005;Cook e al., 2006), and common
scala maps (i.e., FA, MD, Axial di usi i y (AD), adial di usi i y (RD))
we e subsequen ly compu ed. Fully au oma ed p obabilis ic ac og-
aphy was un using a p edefined se ies o seed- and a ge -masks om
he FSL Au oP x plugin (De G oo e al., 2015;Mue zel e al., 2017).
B iefly, ollowing a nonlinea egis a ion o he FA map o s anda d
space (FMRIB58 1 mm), a p edefined lib a y o seed, a ge , and exclu-
sion masks we e wa ped o each indi idual’s na i e space FA map. FSL’s
Bayesian Es ima ion o Di usion Pa ame e s using Sampling Techniques
(BEDPOSTx) and P ob ackx we e used o conduc p obabilis ic fibe
ac og aphy, accoun ing o wo fibe o ien a ions (Beh ens e al.,
2003). Resul ing connec i i y dis ibu ions we e no malized based on
he o al numbe o success ul seed- o- a ge a emp s, and we e h esh-
olded based on es ablished alues o emo e oxels wi h a low p oba-
bili y (Mue zel e al., 2017). A e age DTI scala me ics we e ex ac ed
o each ac (see Supplemen al Ma e ial), wi h each oxel being
weigh ed by he no malized connec i i y alue om p obabilis ic ac-
og aphy. Global, whole b ain es ima es o DTI me ics (i.e., FA, MD, RD,
AD) we e calcula ed using a confi ma o y ac o analysis ac oss mul iple
ac s desc ibed in de ail elsewhe e (Mue zel e al., 2017).
2.3.3. Image quali y assu ance
Raw image quali y was assessed wi h bo h an au oma ed so wa e and
wi h a isual inspec ion (Mue zel e al., 2017). B iefly, slice-wise a ia-
ions in signal in ensi y we e examined using he DTIp ep package (h
ps://www.ni c.o g/p ojec s/d ip ep). The sum-o -squa es e o (SSE)
Fig. 1. Flow cha indica ion da a inclusion/exclusion. No e: Box wi h do ed lines indica e he sample used in he cu en s udys. QC ¼quali y con ol, IF ¼inciden al
o finding, PA ¼physical ac i i y, ST ¼sc een ime, MRI ¼magne ic esonance imaging, DTI ¼di usion enso imaging.
M. Rod iguez-Ayllon e al. Neu oImage 205 (2020) 116258
3
maps om he enso es ima ion we e also calcula ed and isually
inspec ed o s uc u ed noise. Las ly, nonlinea egis a ion o s anda d
space was inspec ed o accu acy o ensu e seed and a ge masks we e
p ope ly aligned o na i e space. Da ase s de e mined o be o insu ficien
quali y o s a is ical analyses we e excluded (n ¼285 om au oma ed
quali y con ol o slice-wise a ia ion in signal and n ¼121 om an
addi ional isual inspec ion o SSE maps and egis a ion quali y).
Example images o FA maps om child en ep esen a i e o he sample
a e p esen ed in he Supplemen a y Ma e ial (see Fig. S1).
2.4. Co a ia es
Age a MRI scanning and sex we e included as co a ia es. Fu he ,
ma e nal educa ion le el and e hnici y we e assessed by ques ionnai es.
E hnici y was based on he coun y o bi h o he mo he and mo he ’s
pa en s. Ma e nal educa ion le el was defined by he highes comple ed
educa ion and di ided in o 3 ca ego ies anging om low ( om no ed-
uca ion o p ima y school), middle (high school o oca ional aining) o
high educa ion le el ( om highe oca ional educa ion o uni e si y).
Heigh and weigh we e measu ed a he age o 10 yea s a he esea ch
cen e and body mass index (BMI) was calcula ed using s anda dized
sco es acco ding o he Du ch e e ence g ow h cu es (h ps://g ow ha
nalyse .o g)(F ed iks e al., 2000). A non- e bal in elligence quo ien
(IQ) was assessed a app oxima ely 6 yea s o age using he
Snijde s-Oomen Nie - e bale in elligen ie Tes - Re isie (SON-R 2.5–7)
(Tellegen e al., 2005). Emo ional and beha io al p oblems we e assessed
a age o 10 yea s by pa en - epo using he alida ed Child Beha io
Checklis school-age e sion (CBCL/6–18) (Achenbach and Resco la,
2003). Apa om non- e bal IQ (12%), he pe cen age o missing alues
did no exceed 10%.
2.5. S a is ical analysis
All analyses we e pe o med using he S a is ical Package o Social
Sciences (IBM SPSS S a is ics o Windows, e sion 22.0, A monk, NY, p
se a <0.05). Mul iple impu a ion was used o impu e missing da a o
co a ia es. In o al, 10 impu ed da ase s we e c ea ed and pooled esul s
a e p esen ed. Mul iple linea eg ession analyses we e pe o med wi h
physical ac i i y o sc een ime measu es as independen a iables and
DTI scala me ics (i.e., FA, and MD) as dependen a iables. Indepen-
den ly, as hey p o ide added in o ma ion in he in e p e a ion o he
unde lying whi e ma e mic os uc u e, we also es ed he associa ion o
physical ac i i y and sc een ime a iables wi h global RD and global AD.
Linea eg ession analyses we e hie a chically adjus ed o co a ia es by
c ea ing wo models. Model 1 included age a he ime o scanning, sex,
e hnici y, ma e nal educa ion, and BMI. Model 2 was addi ionally
adjus ed o beha io p oblems and non- e bal IQ. In o de o de e mine
whe he he associa ion wi h whi e ma e mic os uc u e was indeed
only global o es ic ed o a pa icula se o whi e ma e bundles, as-
socia ions wi h FA and MD wi hin indi idual ac s we e also es ed i
exposu es showed an associa ion wi h global DTI me ics. Fo ac -
specific analyses, alse disco e y a e (FDR) co ec ion was applied o
accoun o he numbe o es s pe o med.
Addi ionally, a numbe o sensi i i y analyses we e un. Fi s , o al
physical ac i i y and o al sc een ime we e en e ed in o he model
simul aneously o adjus es ima es o one ano he . Second, we di ided
he o al sample in ou subg oups o pa icipan s acco ding o hei
physical ac i i y and sc een ime le els o compa e global FA and MD
amongs he g oups. Physical ac i i y and sc een ime g oups we e
defined acco ding o he sample median (high/low physical ac i i y/
sc een ime). Thi d, di e en in e ac ion e ms we e es ed o asce ain
whe he associa ions we e di e en ac oss sub-g oups o subjec s (i.e.,
sex, pa en al educa ional le el, ances al backg ound). Las ly, we es ed
quad a ic and cubic age e ms, as well as an age-by-sex in e ac ion e m
(using a quad a ic age e m). We also es ed quad a ic sc een ime and
physical ac i i y e m, as well as he in e ac ions be ween quad a ic o al
physical ac i i y a iable and quad a ic o al sc een ime a iable in as-
socia ion wi h whi e ma e mic os uc u e.
3. Resul s
Table 1 p esen s pa icipan demog aphic cha ac e is ics. Di e ences
be ween physical ac i i y and sc een ime le els be ween boys and gi ls
a e shown in Table S2. Cha ac e is ics o included and excluded pa ic-
ipan s a e shown in Table S3.
3.1. Associa ion o physical ac i i y and sc een ime wi h global whi e
ma e mic os uc u e
To al physical ac i i y was posi i ely associa ed wi h global FA
(β¼0.051, 95% CI¼(0.010, 0.092), p ¼0.016) when he model was
adjus ed o sociodemog aphic ac o s. Fu he , he posi i e associa ion
be ween physical and global FA emained a e addi ional adjus men o
beha io p oblems and non- e bal IQ (β¼0.057, 95% CI¼(0.016,
0.098), p ¼0.007). Resul s om analyses o global FA and MD a e p e-
sen ed in Table 2, and ollow-up analyses wi h global RD and AD o be e
desc ibe he di usion p ofile a e p esen ed in Table S4. To de e mine
whe he a pa icula ype o physical ac i i y (i.e. ac i e commu ing,
ou doo play and spo pa icipa ion) was esponsible o he o al PA
associa ion wi h global FA, each ype o physical ac i i y was examined
sepa a ely. In he ully adjus ed model (model 2), posi i e associa ions
be ween ou doo play and global FA (β¼0.041, 95% CI¼(0.000, 0.083),
p¼0.047) and be ween spo pa icipa ion and global FA we e obse ed
(β¼0.053, 95% CI¼(0.010, 0.096), p ¼0.015).
To al physical ac i i y was in e sely associa ed wi h global MD
(β¼0.079, 95% CI¼(0.119, 0.038), p <0.001) when he model
was adjus ed o sociodemog aphic co a ia es (model 1). A e , addi-
ional adjus men o beha io al p oblems and non- e bal IQ he asso-
cia ion emained simila (model 2) (β¼0.079, 95% CI¼(0.120,
0.038), p <0.001). Each ype o physical ac i i y was examined sepa-
a ely o de e mine whe he all o a subse o ac i i ies we e esponsible
o he associa ions wi h o al physical ac i i y. In he ully adjus ed
Table 1
Sample cha ac e is ics.
N Mean/% SD
Sex
Boys,% 1267 50.04
Age a MRI assessmen ,yea s 2532 10.12 0.58
Age a CBCL assessmen , yea s 2495 9.71 0.28
E hnici y, %
Du ch 1671 66.63
O he Wes e n 213 8.49
Non-Wes e n 624 24.88
BMI, kg/m
2
2526 17.36 2.50
Beha io p oblems, sum sco e CBCL 2475 16.76 14.63
Non- e bal IQ, sum sco e SON-R 2218 104.32 14.59
Ma e nal educa ion,%
Low 187 8.06
Medium 618 26.65
High 1514 65.29
Exposu es cha ac e is ics
To al physical ac i i y, h/w 2532 9.06 5.10
To al sc een ime, h/w 2346 17.10 11.63
*No e: 86 pa icipan s had no da a on physical ac i i y bu hey we e included in
analyses o sc een ime. MRI ¼magne ic esonance imaging, CBCL¼Child
Beha io Checklis school-age, BMI¼Body mass index, IQ ¼in elligence quo-
ien , SON-R¼ he Snijde s-Oomen Nie - e bale in elligen ie Tes - Re isie, h/w
¼hou s pe week. To al physical ac i i y ¼hou s o ac i e commu ing, ou doo
play, and spo pa icipa ion pe week. To al sc een ime ¼hou s o compu e
ime, playing ideo games, and wa ching ele ision. Ma e nal educa ion le el
was defined by he highes comple ed educa ion and di ided in o h ee ca e-
go ies anging om low ( om no educa ion o p ima y school), middle (high
school o oca ional aining) o high educa ion le el ( om highe oca ional
educa ion o uni e si y).
M. Rod iguez-Ayllon e al. Neu oImage 205 (2020) 116258
4
model (model 2), ou doo play and spo pa icipa ion we e in e sely
associa ed wi h MD (β¼0.074, 95% CI¼(0.114, 0.033), p <0.001;
β¼0.043, 95% CI¼(0.086, 0.000), p ¼0.049, espec i ely). In o de
o be e desc ibe hese associa ions wi h FA and MD, u he analyses
explo ed which unde lying di usi i y me ics (i.e., RD and/o AD) we e
associa ed wi h physical ac i i y. Bo h RD and AD we e significan ly
associa ed wi h o al physical ac i i y (β¼0.079, 95% CI¼(0.120,
0.039), p <0.001; β¼0.054, 95% CI¼(0.094, 0.014), p ¼0.008,
espec i ely).
No associa ion was ound be ween indi idual o agg ega e sc een
ime a iables and global DTI me ics (all p >0.05) (Table 2).
3.2. Associa ion be ween physical ac i i y, sc een ime and ac -specific
FA and MD
Associa ions be ween o al physical ac i i y and ac -specific FA and
MD a e shown in Table S5. B iefly, no associa ion was ound be ween
o al physical ac i i y and FA wi hin indi idual ac s when significance
le els we e adjus ed o mul iple es ing. Howe e , o al physical ac i i y
was associa ed wi h MD in nea ly all ac s when adjus ed o mul iple
compa isons. Fig. 2 g aphically ep esen s he significan nega i e asso-
cia ions be ween o al physical ac i i y and MD ac oss indi idual ac s.
Las ly, explo a o y analyses es ing he associa ion be ween o al
sc een ime and ac -specific FA and MD a e shown in Table S6.
3.3. Sensi i i y analyses
Resul s emained simila when models o physical ac i i y and global
whi e ma e mic os uc u e we e addi ionally adjus ed o o al sc een
ime, sugges ing ha physical ac i i y is posi i ely associa ed wi h whi e
ma e mic os uc u e, independen o o al sc een ime (Table S7).
Sc een ime was s ill un ela ed o global DTI me ics a e addi ional
adjus men o o al physical ac i i y (Table S7).
Nex , when ca ego ically subdi iding he sample based on physical
ac i i y and sc een ime le els (e.g., high sc een ime, low physical ac-
i i y), he subg oup wi h high physical ac i i y (>8.4 h/week) and high
sc een ime (>14.8 h/week seem) showed lowe MD compa ed o he
es o subg oups (Fig. S2 and Fig. S3, espec i ely).
Then, di e en in e ac ion e ms we e es ed o asce ain whe he
associa ions we e di e en ac oss sub-g oups o subjec s. The associa ion
be ween physical ac i i y and whi e ma e mic os uc u e was consis-
en ac oss pa en s’educa ion ca ego ies. Simila ly, no in e ac ion be-
ween sex o e hnici y and physical ac i i y was obse ed.
Las ly, we ha e included in o he model nonlinea age e ms, spe-
cifically a quad a ic age e m (Table S8) and also included a cubic age
e m and esul s emain highly simila (Table S9). We also es ed age-by-
sex in e ac ion e ec s wi h hese a iables (i.e., age
2
and age
3
) and he
in e ac ion e m was no significan (all P >0.470). Impo an ly, he
model es ima es o he associa ion wi h physical ac i i y and sc een ime
also emained highly simila . Finally, nonlinea sc een ime and physical
ac i i y e ms we e no associa ed wi h FA o MD (See Supplemen al
Ma e ial).
4. Discussion
Using neu oimaging da a om o e 2500 child en, we ound ha
physical ac i i y is associa ed wi h whi e ma e mic os uc u e, speci -
ically ou doo play and spo pa icipa ion ime. On he o he hand, no
associa ion was obse ed be ween sc een ime and whi e ma e mic o-
s uc u e. In he con ex o he li e a u e, his s udy expands upon he
compelling e idence o gene al heal h benefi s o physical ac i i y by
demons a ing a new associa ion wi h whi e ma e mic os uc u e in
child en.
P e ious wo k on ypical b ain de elopmen has shown a posi i e
associa ion be ween FA and age, as well as a nega i e associa ion wi h
MD (Ba nea-Go aly e al., 2005;Elu a hingal e al., 2007;Asa o e al.,
2010;Gio gio e al., 2010;Schmi ho s and Yuan, 2010;B ouwe e al.,
2012;Tamnes e al., 2018). Fu he , a simila pa e n o associa ion has
been shown wi h cogni i e unc ion, whe e whi e ma e mic os uc u e
is associa ed wi h be e neu opsychological pe o mance (Mue zel e al.,
2015). Wi hin his con ex , he posi i e link be ween physical ac i i y
and whi e ma e mic os uc u e shown in he p esen s udy could
explain he imp o emen s obse ed in cogni ion (Hillman e al., 2008,
2015). Impo an ly, specific aspec s o physical ac i i y, namely ou doo
Table 2
Associa ion be ween physical ac i i y and sc een ime wi h global ac ional aniso opy and mean di usi i y.
F ac ional aniso opy
Model 1 Model 2
β95% CI p βCI p
Physical ac i i y (n ¼2532)
To al physical ac i i y, h/w 0.051 (0.010, 0.092) 0.016 0.057 (0.016, 0.098) 0.007
Ac i e commu ing, h/w 0.021 (-0.020, 0.062) 0.325 0.023 (-0.018, 0.064) 0.272
Ou doo play, h/w 0.035 (-0.006, 0.076) 0.093 0.041 (0.000, 0.083) 0.047
Spo pa icipa ion, h/w 0.052 (0.009, 0.094) 0.017 0.053 (0.010, 0.096) 0.015
Sc een ime (n ¼2346)
To al sc een ime, h/w 0.021 (-0.065, 0.023) 0.347 0.010 (-0.054, 0.035) 0.668
Playing compu e games, h/w 0.003 (-0.045, 0.039) 0.880 0.000 (-0.041, 0.042) 0.985
Wa ching ele ision,h/w 0.028 (-0.073, 0.017) 0.219 0.014 (-0.060, 0.031) 0.532
Mean di usi i y
Model 1 Model 2
β95% CI p βCI p
Physical ac i i y (n ¼2532)
To al physical ac i i y, h/w 0.079 (-0.119, 0.038) <0.001 0.079 (-0.120, 0.038) <0.001
Ac i e commu ing, h/w 0.005 (-0.045, 0.036) 0.821 0.005 (-0.046, 0.036) 0.812
Ou doo play, h/w 0.073 (-0.114, 0.032) <0.001 0.074 (-0.114, 0.033) <0.001
Spo pa icipa ion,h/w 0.043 (-0.086, 0.001) 0.045 0.043 (-0.086, 0.000) 0.049
Sc een ime (n ¼2346)
To al sc een ime, h/w 0.028 (-0.072, 0.015) 0.203 0.031 (-0.075, 0.013) 0.170
Playing compu e games, h/w 0.024 (-0.066, 0.017) 0.250 0.026 (-0.067, 0.016) 0.230
Wa ching ele ision, h/w 0.022 (-0.067, 0.022) 0.325 0.025 (-0.070, 0.020) 0.280
*No e: Model 1 was adjus ed o sex, age a he ime o scanning, ances al backg ound, body mass index and ma e nal educa ion. Model 2 was addi ionally adjus ed o
emo ional and beha io p oblems and non- e bal in elligence quo ien . h/w ¼hou s pe week.
M. Rod iguez-Ayllon e al. Neu oImage 205 (2020) 116258
5

play and spo pa icipa ion, we e associa ed wi h whi e ma e mic o-
s uc u e. The associa ion be ween physical ac i i y and whi e ma e
mic os uc u e has no been s udied p e iously, which hampe s u he
compa isons wi h simila s udies. None heless, his wo k complimen s
p e ious s udies ocused on he associa ion be ween ca dio espi a o y
fi ness and exe cise wi h whi e ma e mic os uc u e. Fo ins ance,
p e ious s udies demons a ed ha , in 9- o-10 yea -old child en, highe
le els o ca dio espi a o y fi ness we e associa ed wi h highe FA in
sec ions o he co pus callosum, co ona adia a, and supe io longi udinal
asciculus (Chaddock-Heyman e al., 2014). In con as , adolescen s wi h
be e ca dio espi a o y fi ness showed g ea e numbe o s eamlines,
especially in he co icospinal ac and o ceps mino (He ing e al.,
2014), bu also lowe FA in he co icospinal ac (He ing e al., 2014).
Addi ionally, an 8-mon h exe cise in e en ion showed inc eased FA in
sec ions o he uncina e asciculus and supe io longi udinal asciculus in
o e weigh child en in he exe cise g oup when compa ed o con ols
(K a e al., 2014;Schae e e al., 2014). Mo eo e , an 9-mon h exe -
cise in e en ion showed inc eased whi e ma e mic os uc u e in he
genu o he co pus callosum in 7- o 9-yea -old child en in he exe cise
g oup when compa ed o con ols (Chaddock-Heyman e al., 2018).
In he p esen s udy, no associa ion was ound be ween ac i e
commu ing and whi e ma e mic os uc u e. P e ious wo k has also
shown ha ac i e commu ing was no associa ed wi h cogni i e pe o -
mance in child en (Van Dijk e al., 2014). Thus, esul s a e in line wi h an
inc easing li e a u e sugges ing ha inc eases in cogni i e unc ioning in
childhood due o physical ac i i y a e mos clea ly obse ed in asks ha
in ol e execu i e unc ioning (e.g., spo pa icipa ion) (Tompo owski
e al., 2008).
P e ious wo k has demons a ed ha inc eased le els o physical
ac i i y migh imp o e ce eb al blood flow (Hillman e al., 2008), and
DTI has p o en o be sensi i e o whi e ma e mic os uc u al changes
ha may esul om ca dio- and neu o- ascula isk ac o s (Lee e al.,
2009;She e e al., 2013). A possible physiological mechanism could be
he posi i e influence physical ac i i y has on ca dio-me abolic isk
ac o s, such as insulin esis ance, blood lipids, blood p essu e and in-
flamma o y p o eins (Eisenmann, 2004). Mo eo e , p e ious li e a u e
showed highe le els physical ac i i y a e associa ed wi h be e men al
heal h in child en (Biddle and Asa e, 2011;Biddle e al., 2018). As
childhood is a pe iod whe e many physiological and psychological
changes occu , public heal h ad oca ion o no el app oaches o
inc easing physical ac i i y in child en could be use ul o imp o ed
(neu o) physiological and psychological heal h. In his line, a ecen la ge
Fig. 2. Associa ion be ween o al physical ac i i y and
ac -specific MD. Colou ba ep esen s s anda dized
be a coe ficien s wi h ligh e blue e e ing o nega i e
associa ion. Ligh e blue e e ing o s onge associ-
a ion be ween o al physical ac i i y and MD. Co i-
cospinal ac (CST), acous ic adia ion (AR), an e io
halamic adia ion (ATR), supe io longi udinal
asciculus (SLF), in e io longi udinal asciculus (ILF),
in e io on o-occipi al asciculus (IFOF), uncina e
asciculus (UNC), cingula e gy us pa o cingulum
(CGC), hippocampal pa o he cingulum (CGH), o -
ceps mino (FMI), and supe io halamic adia ions
(STR).
M. Rod iguez-Ayllon e al. Neu oImage 205 (2020) 116258
6
s udy o physical ac i i y and cogni ion showed highe le els o physical
ac i i y we e associa ed wi h be e global cogni ion (Walsh e al., 2018).
Ou esul s sugges ha hese imp o emen s in cogni ion could be
acili a ed by be e unde lying whi e ma e mic os uc u e.
Ano he impo an finding was ha sc een ime was no associa ed
wi h whi e ma e mic os uc u e. To he bes o ou knowledge, his is
he fi s s udy o examine he associa ion be ween sc een ime and whi e
ma e mic os uc u e in child en. These esul s u he suppo he wo k
om Fe guson e al. and O ben e al. (Fe guson, 2017;O ben and P zy-
bylski, 2019) who showed ha he ela ionship be ween sc een ime and
di e en men al heal h ou comes (e.g., ex e nalizing p oblems, in e -
nalizing p oblems and academic pe o mance) was null o e y small.
O e all, he associa ion be ween sc een ime and men al heal h a e likely
nonlinea , and mode a e engagemen in ce ain sc een ime ac i i ies
may no lead o beha io al o emo ional p oblems (Fe guson, 2017). Fo
ins ance, p e ious esea ch ound ha mee ing he 2 h o less ec ea-
ional sc een ime pe day ecommenda ions was associa ed wi h supe-
io global cogni ion (Walsh e al., 2018). In con as , equen weekly
use o ideo games was associa ed wi h conduc p oblems, as well as,
inc eased le els o ele ision iewing we e nega i ely associa ed wi h
neu ocogni i e de elopmen o child en (Takeuchi e al., 2015). In
addi ion o hese disc epancies in he li e a u e, ad ances in echnology
(e.g., a ailabili y o hand-held media de ices, and social media)
compa ed o he cons uc o pu ely passi e ele ision iewing, u he
unde sco e he impo ance o main aining well-cha ac e ized measu es
o sc een ime, as di e ing amoun s/ ypes o sc een ime could influence
he b ain di e en ly. In e es ingly, associa ions be ween physical ac i i y
and whi e ma e emained a e adjus ing o le els o sc een ime. Thus,
hough pu ely specula i e, he benefi s o physical ac i i y may no be
nega i ely influenced by playing compu e games and wa ching ele i-
sion mode a ely, which has been epo ed p e iously o o he gene al
ca diome abolic ou comes (Rezende e al., 2014).
Key s eng hs o he cu en s udy a e he la ge sample size, and
inco po a ion o popula ion-based neu oimaging. The na u e and size o
he coho alloca es us wi h he da a and powe o adjus o mul iple
con ounding ac o s. Fu he , he popula ion-based sampling o e s
inc eased gene alizabili y o he findings compa ed o p e ious s udies.
Howe e , se e al limi a ions equi e discussion. Fi s , his is a c oss-
sec ional s udy, limi ing in e ences abou causali y and di ec ionali y o
any o he associa ed ac o s. Fu he , hough esidual con ounding e-
mains a possibili y, e ec es ima es we e no subs an ially changed a e
adjus ing o a numbe o po en ial con ounding ac o s. Fu u e wo k
should conside o he en i onmen al con ounde s including well-
cha ac e ized measu es o socioeconomic s a us. Second, physical ac i -
i y and sc een ime le els we e assessed by pa en al- epo ed ques ion-
nai es, lending o he possibili y o unde - o o e es ima ions o he
beha io s. The e o e, objec i e measu es such as accele ome y and
expe ience sampling should be u ilized in u u e s udies. Las ly, he e ec
sizes o he associa ion be ween physical ac i i y and whi e ma e
mic os uc u e a e ela i ely small. Howe e , simila e ec sizes a e
obse ed in s uc u e- unc ion associa ions wi h cogni ion and whi e
ma e mic os uc u e (Mue zel e al., 2015), and he clinical ele ance o
such e ec sizes in he con ex o DTI has ye o be o mally e alua ed.
5. Conclusion
This s udy demons a es ha highe le els o physical ac i i y a e
associa ed wi h g ea e whi e ma e mic os uc u e in child en ages 9-
o-10 yea s old om he gene al popula ion. No associa ion was
obse ed be ween sc een ime and whi e ma e mic os uc u e. Fu u e
wo k should con inue o explo e longi udinal da a in o de o mo e
conc e ely deciphe he empo ali y o he associa ions, so ha educa-
ional and heal h ins i u ions can conside whe he o p omo e physical
ac i i y du ing childhood as a po en ial (modifiable) p o ec i e ac o in
he con ex o b ain heal h.
Funding
This s udy was suppo ed by he Sophia Founda ion (S18-20 awa ded
o RM) and Ne he lands O ganiza ion o Heal h Resea ch and De el-
opmen (ZonMw) (p ojec 016.VICI.170.200, awa ded o HT and TOP
91211021, awa ded o TW). Supe compu ing esou ces we e suppo ed
by he Ne he lands O ganiza ion o Scien ific Resea ch (Exac e We en-
schappen) and SURFsa a (Ca esius Compu e Clus e , www.su sa a.nl).
The Gene a ion R S udy is conduc ed by he E asmus Medical Cen e in
close collabo a ion wi h he School o Law and he Facul y o Social
Sciences o he E asmus Uni e si y Ro e dam, he Municipal Heal h
Se ice Ro e dam a ea, and he S ich ing T ombosediens en A senla-
bo a o ium Rijnmond. The gene al design o he Gene a ion R S udy was
made possible by financial suppo om he E asmus Medical Cen e ,
Ro e dam, ZonMw, he Ne he lands O ganiza ion o Scien ific
Resea ch, and he Minis y o Heal h, Wel a e, and Spo . The au ho s
g a e ully acknowledge he con ibu ions o he pa icipa ing child en
and pa en s, gene al p ac i ione s, hospi als, midwi es, and pha macies
in Ro e dam. MRA ecei ed a schola ship om he Uni e si y o G an-
ada om he PhD In e na ional Mobili y P og am o a b ie s ay in he
E asmus Medical Cen e in Ro e dam (The Ne he lands). IEC is sup-
po ed by a g an om he Alicia Koplowi z Founda ion. This wo k is pa
o he Ma ía Rod iguez-Ayllon Ph.D. Thesis conduc ed in he Biomedi-
cine Doc o al S udies o he Uni e si y o G anada, Spain.
Acknowledgmen s
The au ho s hank child en and pa en s who pa icipa ed in his
s udy. The au ho s epo no biomedical financial in e es s o po en ial
conflic s o in e es .
Appendix A. Supplemen a y da a
Supplemen a y da a o his a icle can be ound online a h ps://doi.
o g/10.1016/j.neu oimage.2019.116258.
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