The Impact of Physical Activity on Brain Structure and ......brain structure and function in children and adolescents is examined. DATA SOURCES: Six electronic databases (PubMed, PsychINFO,

The Impact of Physical Activity onBrain Structure and Function in Youth:A Systematic ReviewSarah Ruth Valkenborghs, PhD,a Michael Noetel, PhD,b Charles H. Hillman, PhD,c,d Michael Nilsson, PhD,e Jordan J. Smith, PhD,a

Francisco B. Ortega, PhD,f David Revalds Lubans, PhDa

abstractCONTEXT: Advances in neuroimaging techniques have resulted in an exponential increase in thenumber of studies investigating the effects of physical activity on brain structure and function.Authors of studies have linked physical activity and fitness with brain regions and networksintegral to cognitive function and scholastic performance in children and adolescents butfindings have not been synthesized.

OBJECTIVE: To conduct a systematic review of studies in which the impact of physical activity onbrain structure and function in children and adolescents is examined.

DATA SOURCES: Six electronic databases (PubMed, PsychINFO, Scopus, Ovid Medline, SportDiscus,and Embase) were systematically searched for experimental studies published between 2002and March 1, 2019.

STUDY SELECTION: Two reviewers independently screened studies for inclusion according topredetermined criteria.

DATA EXTRACTION: Two reviewers independently extracted data for key variables and synthesizedfindings qualitatively.

RESULTS: Nine studies were included (task-based functional MRI [n = 4], diffusion tensorimaging [n = 3], arterial spin labeling [n = 1], and resting-state functional MRI [n = 1]) in whichresults for 5 distinct and 4 similar study samples aged 8.7 6 0.6 to 10.2 6 1.0 years andtypically of relatively low socioeconomic status were reported. Effects were reported for 12regions, including frontal lobe (n = 3), parietal lobe (n = 3), anterior cingulate cortex (n = 2),hippocampus (n = 1), and several white matter tracts and functional networks.

LIMITATIONS: Findings need to be interpreted with caution as quantitative syntheses were notpossible because of study heterogeneity.

CONCLUSIONS: There is evidence from randomized controlled trials that participation in physicalactivity may modify white matter integrity and activation of regions key to cognitiveprocesses. Additional larger hypothesis-driven studies are needed to replicate findings.

aPriority Research Centre for Physical Activity and Nutrition, University of Newcastle, University Drive, Callaghan, New South Wales, Australia; bFaculty of Health Sciences, School ofBehavioural and Health Sciences, Australian Catholic University, Banyo, Queensland, Australia; cDepartments of Psychology and dPhysical Therapy, Movement, and Rehabilitation Sciences,Northeastern University, Boston, Massachusetts; eCentre for Rehab Innovations, University of Newcastle and Hunter Medical Research Institute, New Lambton Heights, New South Wales,Australia; and fDepartment of Physical Education and Sports, Faculty of Sports Sciences, University of Granada, Granada, Spain

Dr Valkenborghs conducted the search, screening, extraction, and synthesis processes in addition to drafting the manuscript; Dr Noetel screened articles, extracteddata, and critically reviewed the manuscript; Drs Hillman, Nilsson, and Smith contributed to the conceptualization of the review and critically reviewed (Continued)

To cite: Valkenborghs SR, Noetel M, Hillman CH, et al. The Impact of Physical Activity on Brain Structure and Function in Youth: A Systematic Review. Pediatrics. 2019;144(4):e20184032

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Many children and adolescents arenot sufficiently active to accrue theextensive cardiovascular, metabolic,musculoskeletal, and mental healthbenefits of physical activity.1,2

Habitual physical activity isassociated with a variety of health-related fitness traits (ie,cardiorespiratory, morphologic,muscular, motor, and metabolic),3 andemerging evidence suggests thatparticipation in physical activity andimproving physical fitness mayenhance cognitive health across thelife span.4–9

Specifically, acute physical activitycan enhance children’s attention(g = 0.43; 95% confidence interval[CI] = 0.09–0.77) and on-taskbehavior in the classroom (d = 0.77;95% CI = 0.22–1.32).10–12 Similarly,authors of experimental studies havedemonstrated longer-term benefitsof physical activity for executivefunctions (g = 0.24; 95% CI =0.09–0.39),11 attention (g = 0.90;95% CI = 0.56–1.24),11 and academicperformance (g = 0.26; 95% CI =0.02–0.49).5,11,13 Higher levels ofcardiorespiratory fitness are alsopositively associated with youngpeople’s academic achievement.13

Although awareness of the positiveeffects of physical activity oncognitive and/or academic outcomeshas increased rapidly in the last5 years, the mechanisms responsibleremain relatively untested in youngpeople.14

Animal studies have provided initialinsight into the neurobiologicalchanges induced by physical activity.Molecular effects include epigeneticregulation of gene expression andrelated changes in concentrations offactors such as brain-derivedneurotrophic factor (BDNF) andvascular endothelial growth factor,known to underpin brain plasticityand cellular changes such asneurogenesis, synaptogenesis, andangiogenesis.15–19 There is nowempirical evidence that the samemolecular effects exist in humans (eg,

increases in BDNF and vascularendothelial growth factor) and maybe responsible for the positive effectsof physical activity on cognitivehealth.20–23

In addition, a seminal randomizedcontrolled trial (RCT) in older adultsdemonstrated that 12 months ofaerobic exercise increasedhippocampal volume and improvedmemory, with these improvementsbeing mediated by increases inBDNF.24 Since the publication of thesefindings, there has been anexponential increase in the number ofstudies employing MRI techniques toexamine associations and explore theimpact of physical activity on brainstructure and function in humans.Authors of many cross-sectionalstudies have linked physical activitywith brain regions and networksintegral to cognitive function andscholastic performance in childrenand adolescents.25–28

To date, there has been no systematicreview of experimental MRI studies inwhich the impact of physical activityon brain structure and function inchildren and adolescents isinvestigated. A recent review of 84studies in which the effects ofphysical activity on cognitivefunctioning and neuroimagingfindings were investigated onlyincluded 5 MRI studies because thesearch was conducted in July 2017and it only included RCTs.29 Toprovide a more in-depth and up-to-date summary of evidence of MRIstudies specifically, our reviewincluded all designs of experimentalstudies. Given the importance ofcognitive development, clarifying theeffects of physical activity on brainstructure and function may motivatekey stakeholders to address thecurrent physical inactivity pandemic.Therefore, our aim with this studywas to conduct a systematic review ofMRI studies in which the impact ofphysical activity on brain structureand function in school-aged childrenhave been examined.

METHODS

The conduct and reporting of thisreview adhere to the guidelinesoutlined in the Preferred ReportingItems for Systematic Reviews andMeta-Analysis statement.30 Thereview protocol was registered withthe International Prospective Registerof Systematic Reviews(CRD42017081804).

Study Eligibility Criteria

1. Types of participants: participantswere typically developing school-aged children (usually 5–18 yearsof age; however, children outsidethis age range were included ifthey were recruited withinschools). Studies includingpopulations with learningdifficulties, cognitive deficits, anddevelopmental disorders wereexcluded.

2. Types of studies: experimentalstudies were eligible if the authorsreported statistical analyses ofchanges in brain structure orfunction before and aftera physical activity intervention.

3. Measure of physical activity,cardiorespiratory fitness, ormuscular fitness: studies withobjective (eg, accelerometers andpedometers) or subjectivemeasures of physical activity (eg,exercise session attendance andself-report questionnaires);cardiorespiratory fitness (eg,maximum oxygen consumption[VO2max] test, Progressive AerobicCardiovascular Endurance Run,and predictive equations); and/ormuscular fitness (eg,dynamometry, standing long jump,and push up test) were eligible.

4. Brain imaging techniques: studiesthat reported findings from MRItechniques (eg, functional MRI[fMRI], diffusion tensor imaging[DTI], and arterial spin labeling[ASL]) that have been used toidentify structural and functional

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mechanisms that may explain therelationship between physicalactivity, cardiorespiratory fitnessor muscular fitness, and cognitionor academic achievement wereeligible.

Information Sources and SearchStrategy

Six electronic databases (PubMed,PsychINFO, Scopus, Ovid Medline,SportDiscus, and Embase) weresearched for studies published withinthe last 16 years (2002–March 1,2019) (Supplemental Table 4).Additional searches of recentlypublished systematic reviews inwhich the associations betweenphysical activity, cardiorespiratoryfitness or muscular fitness, andcognitive outcomes were examinedwere conducted, and the referencelists of all retrieved studies werereviewed. The search was restrictedto articles published in the Englishlanguage.

Study Selection

The study screening and selectionprocess was performed onCovidence.31 One reviewer screenedthe titles and abstracts of recordsretrieved by the search strategy andclassified these as possibly relevantor definitely irrelevant. The full-textarticles of records classified aspossibly relevant were retrieved andindependently reviewed by 2reviewers. Studies were classified asinclude or exclude. If there wasdisagreement between reviewers,consensus was sought throughdiscussion. Reasons were providedfor excluding any possibly relevantstudies.

Data Extraction

Both reviewers independentlyextracted data from included studiesinto a purpose-built data extractiontemplate in excel. Data extractionincluded (1) sample data (includingsample size, age, sex, and education);(2) study details (location, design,setting, duration, and assessment

points); (3) assessment of physicalactivity, cardiorespiratory, and/ormuscular fitness (objective,subjective, laboratory-based, or field-based); (4) neuroimaging data (MRImodality, analysis methods, regions ofinterest, etc); (5) data analysis(statistical methods used,confounders adjusted for, etc); and(6) study findings (quantitative andqualitative).

Risk of Bias Assessment

All studies were independentlyassessed by 2 reviewers and werescored as low, high, or unclear for 8criteria according to the Cochranecollaboration risk of bias tool andscoring.32 Any disagreementconcerning risk of bias assessmentbetween the 2 reviewers wasresolved through discussion.Consensus was reached on all articlesincluded in the review.

RESULTS

Overview of Studies

Figure 1 displays the flow of studiesthrough the review process. After theexclusion of duplicates, thesystematic search yielded 9508potentially relevant citations, ofwhich 153 were retained for full-textreview. There was almost-perfectinterrater agreement for the full-textreview (k = 0.97).33 A total of 9articles satisfied the inclusion criteriaand were included in the review,reporting results for 5 distinct and 4similar samples of participantsranging from 8.7 6 0.634 to 10.2 61.035 years of age and typically ofrelatively low socioeconomic status.The sample size ranged from 936 to143.34 The studies were conducted inNorth America (8 in the UnitedStates) and Asia (1 in China). Of theincluded studies, 7 were RCTs and 2were acute before and after studies.Detailed information about eachincluded study is presented inTable 1.

Risk of Bias

Detailed information about the risk ofbias for the included studies ispresented in Table 2. In summary, all9 (100%) were deemed to be atunclear risk of selection bias, withunclear description of (1) sequencegeneration process, (2) concealedallocation processes, and [in 5 (56%)studies] (3) subgroup selectionprocesses. Seven (78%) studies weredeemed at unclear risk of reportingbias because of lack of availability ofa protocol published by means ofeither an article or trial registration.Six (67%) studies were deemed athigh risk of attrition bias because ofsignificant dropout with inadequateanalyses. Overall, only 2 (22%)studies scored as low risk of bias for$3 (of the 8 criteria.34,35 There wassubstantial interrater agreement forthe risk of bias assessment (k =0.61).33

Measures of Brain Structure andFunction

Four different MRI modalities wereused across the 9 included studies.Four (44%) studies used task-basedfMRI, 3 (33%) studies used DTI, 1(11%) study used ASL, and 1 (11%)study used resting-state fMRI. Datafor 12 regions were reported acrossthe 9 included studies: anteriorcingulate cortex, cerebellum, corpuscallosum, frontal lobe, hippocampus,parietal lobe, superior longitudinalfasciculus, uncinate fasciculus,cognitive control network, defaultmode network, executive controlnetwork, and motor network.

Measures of Physical Activity andFitness

Authors of seven (78%) studiesprovided physical activityinterventions and investigated effectson brain structure or function.34,37–42

The duration of the interventionsranged from 3 to 9 months andgenerally consisted of moderate-to-vigorous physical activity (eg,70%–80% maximum heart rate

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[HRmax]) either twice a week or eachschool day for 20 to 120 minutes. Ofthese, 4 studies measuredcardiorespiratory fitness by means ofoxygen uptake during a maximalgraded treadmill test (modified Balkeprotocol).34,37,39,42 Authors of 2studies investigated changes in brainfunction in response to acute bouts ofaerobic exercise at 60% to 70%HRmax.

35,36 Details of all interventionsare outlined in Table 1.

The Impact of Physical Activity onBrain Structure or Function

Findings from each included studyare presented by brain region belowand Table 1, with effects furthersummarized in Table 3.

Frontal Lobe

Authors of 3 RCTs with distinct butsimilarly aged samples reportedresults for changes in activation of thefrontal lobe in response to physical

activity interventions which rangedfrom 20 to 77 minutes each schoolday over 3 to 9 months. Authors of 2of the RCTs assessed prefrontalactivation during cognitive tasks(antisaccade [n = 2] and flanker[n = 2]) and found changes pre- andpost- intervention but the effectswere in opposite directions in bothcases. Davis et al38 reported thatincreased bilateral prefrontal (anddecreased posterior parietal) cortexactivity was observed duringantisaccade performance in thephysical activity group, whereas Krafftet al39 reported decreased activationduring antisaccade performance inseveral prefrontal (and parietal)regions including medial frontal gyrus,right inferior frontal gyrus, andbilateral precentral gyrus. Krafft et al39

also observed increased activation ofthe superior frontal gyrus of theprefrontal cortex during incongruenttrials of the flanker task in the

physical activity group, whereasauthors of the third RCT (Chaddock-Heyman et al37) observed decreasedactivation in the right anteriorprefrontal cortex during incongruenttrials of the flanker task in thephysical activity intervention groupbut no changes in the control group.Note that although both Chaddock-Heyman et al37 and Davis et al38

adjusted for baseline during theirregion of interest analyses, Krafftet al39 did not report if/whatcovariates were adjusted for andemployed a whole-brain analysisapproach, which could contribute tothe disparate results.

Parietal Lobe

Authors of 3 studies reported resultsfor the parietal lobe from task-basedfMRI paradigms. Authors of 2 RCTswith similarly aged samples andrelatively similar type, frequency,intensity, and duration of physicalactivity interventions founddecreased parietal cortex activityduring antisaccade performance aftera physical activity intervention.38,39

Both studies used comparable clustersize thresholds but it should be notedthat while Davis et al38 adjusted forbaseline in their analyses, Krafftet al39 did not report if and whatcovariates were adjusted for.

Chen et al36 investigated the acuteeffects of a 30-minute bout of cycling(60%–69% HRmax) during task-basedfMRI and reported improved n-backperformance and increased activationof bilateral parietal cortices (as wellas the left hippocampus and bilateralcerebellum).

Anterior Cingulate Cortex

Authors of 2 RCTs reported task-based fMRI results for the anteriorcingulate cortex. Authors of 1 RCTfound that participation in a physicalactivity intervention did not changeactivation of anterior cingulate cortexduring neutral or incongruentconditions of a flanker task.37 Theother RCT found that although there

FIGURE 1Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram.


TABLE1Summaryof

Included

Studies

FirstAuthor

andYear

StudyandSample

Characteristics

(Design,n,Age(y),%

MaleSex,SES,

Country)

Exposure

Measure

ofPhysical

Activity

and/or

Fitness

ImagingTechniqueandAnalysis

ConfoundersAdjusted

forin

Analyses

KeyFindings

Frontallobe:executive

processes,cognition,

attention,

and

language

processing

Chaddock-Heyman

etal

2013

37RCT,23,8.96

5.8,71,

2.06

0.9,aUnited

States

2h(76.8min

MVPA)

aerobicand

muscle-and/or

bone-strengthening

activities

aftereach

schooldayfor

150outof

170school

days.M

ean

(SD)

attendance

=82%

613.3%

VO2m

ax(m

odified

Balke)

Task-based

fMRI:FSL,R

OIapproach,

motioncorrectionviaarigidbody

algorithm

inMCFLIRT.Primary

thresholdlevelinput(z):.6.00;

correctedclustersignificance

threshold:P,

.05;familywisea

level:P=.05

Baseline

Interventionparticipants

show

eddecreasesinfMRIbrainactivationin

therightanterior

prefrontal

cortex

(Z=6.2)

during

aflankertask

Daviset

al2011

38RCT,19,9.66

1.0,58,

notreported,U

nited

States

Daily

afterschoolexerciseprogram

includingrunninggames,jum

prope,and

modified

basketballand

soccer

at1666

8beatsper

minute(∼79%

HRmax).20–40

min/

dfor14

61.7wk.Mean

attendance

=85%

613%

HRmonitors

and

attendance

Task-based

fMRI:AFNIand

ROI

approach.Volum

eswereregistered

toarepresentativevolume,and6

regressors

werecalculated

(rotationalandtranslationalhead

motionin

3planes),Monte

Carlo

simulations

threshold-clustermethod

familywiseaat

P=.05preserved

with

individualvoxelthresholdat

P=

.05andaclustersize

of40

voxels

Baseline

Increasedprefrontal

(and

decreasedposteriorparietal)

cortex

activity

during

antisaccade

performance

was

observed

inthe

exercise

group

Krafftet

al2014

39RCT,43,9.86

0.8,35,

4.96

1.1,bUnited

States

8moinstructor-ledafterschool

intervention(eg,tagandjump

rope)40

min

each

school

dayat

161beatsperminute(m

ean;∼77%

age-predictedHR

max)

VO2peak(m

odified

Balke)

Task-based

fMRI:AFNI,whole-brain

approach.Volum

eswereregistered

toarepresentativevolumeand

regressedforrotationin

x,y,andz

planes.M

onte

Carlosimulations

threshold-clustermethod:familywise

aof

.05preservedwith

3Dcluster

size

of35

(antisaccade)or

37(flanker)

voxels.

Notreported

Exercise

ledto

decreasedactivation

inseveralprefrontal

(and

parietal)

regionssupportingantisaccade

performance,including

bilateral

precentral

gyrus,medialfrontal

gyrus,paracentrallobule,and

right

inferior

frontalgyrus.Theexercise

groupalso

show

edincreased

activationin

severalregions

supportingflankerperformance,

includingsuperior

frontalgyrus

and

theanterior

cingulate

Parietallobe:perception

andintegrationof

somatosensory

inform

ation

Chen

etal

2016

36Acutebefore

andafter,

9,10,56,notreported,

China

30min

cyclingat

60%–69%

age-

predictedHR

max

HRmonitors

Task-based

fMRI:SPM

8,whole-brain

approach,m

otioncorrected.

Statistical

threshold:

P,

.025;

clustersize

threshold=100voxels,

Baseline

Acutemoderate-intensity

aerobic

exercise

benefitedperformance

inthen-back

task,increasingbrain

activities

oftheleftparietal

cortex

(T=8.64),rightparietalcortex

(T=


TABLE1

Continued

FirstAuthor

andYear

StudyandSample

Characteristics

(Design,n,Age(y),%

MaleSex,SES,

Country)

Exposure

Measure

ofPhysical

Activity

and/or

Fitness


ConfoundersAdjusted

forin

Analyses

KeyFindings

equivalent

tocluster-levelP,

.05.

AlphaSim

corrected

6.57),lefthippocam

pus(T

=8.23),

leftcerebellum

(T=7.18),andright

cerebellum

(T=6.47)

Daviset

al2011

38RCT,19,9.66

1.0,58,

notreported,U

nited

States

Daily

afterschoolexerciseprogram

includingrunninggames,jum

prope,and

modified

basketballand

soccer

at1666

8beatsper

minute(∼79%

HRmax)for

20–40

min/d

for14

61.7wk.Mean

attendance

=85%

613%

HRmonitors

and

attendance

Task-based

fMRI:AFNI,RO

Iapproach.

Volumes

wereregistered

toarepresentativevolume,and6

regressors

werecalculated

(rotationalandtranslationalhead

motionin

3planes).Monte

Carlo

simulations

threshold-clustermethod

familywiseaat

P=.05,preserved

with

individualvoxelthresholdat

P=

.05andaclustersize

of40

voxels

Baseline

Decreasedposteriorparietal

cortex

(and

increasedprefrontal

cortex)

activity

during

antisaccade

performance

was

observed

inthe

exercise

group

Krafftet

al2014

39RCT,9.86

0.8,35,4.9

61.1,bUnitedStates

Instructor-ledafterschool


rope)40

mindaily

at161beatsper

minute(m

ean:∼77%

age-

predictedHR

max)

VO2peak(m

odified

Balke)

Task-based


approach.Volum

eswereregistered



x,y,andz

planes.M

onte

Carlosimulations


aof

.05preservedwith

3Dcluster

size

of35

(antisaccade)or

37(flanker)

voxels

Notreported

Exercise

ledto

decreasedactivation

inseveralparietal

(and

prefrontal)

regionssupportingantisaccade


superior

parietal

lobule,inferiorparietal

lobule,paracentral

lobule,

postcentralgyrus,andleft

precuneus

Anterior

cingulate

cortex:executive

function

Chaddock-Heyman

etal

2013

37RCT,23,8.96

5.8,71,

2.06

0.9,aUnited

States

2h(76.8min

MVPA)

aerobicand

muscle-and/or

bone-strengthening

activities

aftereach

schooldayfor

150outof

170school

days.M

ean

(SD)

attendance

=82%

613.3%

VO2m

ax(m

odified

Balke)

Task-based

fMRI:FSL,R

OIapproach.

Motioncorrectionviaarigidbody

algorithm

inMCFLIRT.Primary

thresholdlevelinput(z):.6.00;

correctedclustersignificance

threshold:P,

.05;familywisea

level:P=.05

Baseline

Interventionparticipantsshow

edno

changesin

fMRI

brainactivationof

theanterior

cingulatecortex

(z=

7.1)

during

aflankertask

Krafftet

al2014

39RCT,43,9.86

0.8,35,

4.96

1.1,bUnited

States

Instructor-ledafterschool


rope)40

mindaily

at161beatsper

minute(m

ean:∼77%

age-

predictedHR

max)

VO2peak(m

odified

Balke)

Task-based


approach.Volum

eswereregistered



x,y,&z

planes.M

onte

Carlosimulations


aof

.05preservedwith

3Dcluster

size

of35

(antisaccade)or

37(flanker)

voxels

Notreported

Exercise

ledto

decreasedactivation

intheanterior

cingulatecortex

(as

wellas

theseveralprefrontal

and

parietal

regions)

during

antisaccade

performance.The

exercise

groupalso

show

edincreasedactivationin

several

regionssupportingflanker


theanterior

cingulateandsuperior

frontalgyrus


TABLE1

Continued

FirstAuthor

andYear

StudyandSample

Characteristics

(Design,n,Age(y),%

MaleSex,SES,

Country)

Exposure

Measure

ofPhysical

Activity

and/or

Fitness


ConfoundersAdjusted

forin

Analyses

KeyFindings

Hippocam

pus:mem

ory

andspatialnavigation

Chen

etal

2016

36Acutebefore

andafter,


China

30min

cyclingat

60%–69%

age-

predictedHR

max

HRmonitors

Task-based

fMRI:SPM

8,whole-brain

approach,m

otioncorrected.

Statistical

threshold:

P,

.025;

clustersize

threshold=100voxels,

equivalent

tocluster-levelP,

.05.

AlphaSim

corrected

Baseline


aerobic

exercise


inthen-back


activities

oftheleftparietal

cortex


(T=

6.57),lefthippocam

pus(T

=8.23),

leftcerebellum

(T=7.18),andright

cerebellum

(T=6.47)

Cerebellum:

coordinationof

voluntarymovem

ent,

motor

learning,

balance,and

sequence

learning

Chen

etal

2016

36Acutebefore

andafter,


China

30min

cyclingat

60%–69%

age-

predictedHR

max

HRmonitors

Task-based

fMRI:SPM

8,whole-brain

approach.S

tatistical

threshold:

P,

.025;cluster

size

threshold=100

voxels,equivalenttocluster-levelP

,.05.AlphaSim

corrected

Baseline


aerobic

exercise


inthen-back


activities

oftheleftparietal

cortex


(T=

6.57),lefthippocam

pus(T

=8.23),

leftcerebellum

(T=7.18),andright

cerebellum

(T=6.47)

Functionalnetworks

Krafftet

al2014

40RCT,22,9.56

0.7,32,

4.66

1.2,bUnited

States



rope)40

min

each

school

dayat

164beatsperminute(m

ean;∼78%

age-predictedHR

max)

HRmonitors

Resting-statefMRI:FSL,ICA

approach.

Visuallyinspectedforabsolute

motion.1-mm

shift,com

ponents

representingnoisewereremoved,

and6motiontim

ecourses

(estimated

rotationandshift

inx,y,

andzplanes)wereremoved.

Uncorrectedvoxelthreshold=P,

.0001.Familywiseaof

.05preserved

with

3Dclusters

of$169voxels

Notreported

Results

show

edapatternof

decreasedsynchronyafterexercise

training

with

3RSNs

(defaultmode

network,cognitive

control,and

motor).Although

themotor

network

show

eddecreasedsynchronyin

the

exercise

groupwith

thecuneus,the

motor

networkwas

theonlyRSNto

also

show

anopposing

patternof

increasedsynchronywithin

the

exercise

group.

Pontifexet

al2018

35Acutecrossover,41,

10.26

1.0,56,0.86

0.2∼,U

nitedStates

20min

fast

walkandslow

jogon

atreadm

illat

70%

age-predicted

HRmax

HRmonitors

ASL:AFNI

andFSL,whole-brain

and

ROIapproaches.Control-label

perfusionweighteddifference

images

werelinearlyalignedto

proton-densityweightedimages

and

None

(nocorrelation

betweenchange

inCBFandage,sex,

pubertal

status,IQ,

orchange

inHR

orbloodpressure)

Findings

revealed

nodifferences

inCBFafterthecessationof

exercise

relativeto

theactivecontrol

condition

across

each

ofthe

networks

exam

ined

(frontoparietal,

executivecontrol,andmotor)


TABLE1

Continued

FirstAuthor

andYear

StudyandSample

Characteristics

(Design,n,Age(y),%

MaleSex,SES,

Country)

Exposure

Measure

ofPhysical

Activity

and/or

Fitness


ConfoundersAdjusted

forin

Analyses

KeyFindings

coregistered

tosubject-andsession-

specificT1-weightedimages

White

matterintegrity

Chaddock-Heyman

etal

2018

34RCT,143,8.76

0.55,

49,1.916

0.78,a

UnitedStates

2haftereach

schooldayfor150d

ofthe170-dschoolyear.There

was

30–35

min

ofsustainedMVPAand

90min

ofinterm

ittentMVPA.

VO2m

ax(m

odified

Balke),H

Rmonitors,and

accelerometers

DTI:FSL,FDTandTBSS,and

ROI

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were no significant correlationsbetween changes in cardiorespiratoryfitness and brain activation duringtask-based fMRI,39 the physicalactivity intervention led todifferential activation across 2inhibition tasks, with decreasedactivation of the anterior cingulatecortex during an antisaccade task andincreased activation of the cingulategyrus during the incongruentcondition of a flanker task.39

Comparatively, the control group

showed decreased activation duringthe flanker task.39 Such differencesacross inhibition tasks highlights thecomplexity of brain activation duringperformance of tasks that tapdifferent aspects of a similar cognitiveconstruct.

Hippocampus

Authors of 1 acute before and afterstudy reported enhancedperformance in an n-back task andincreased brain activity (task-based

fMRI) of the left hippocampus inresponse to an acute 30-minute boutof cycling (60%–69% HRmax).

36

Cerebellum

Authors of 1 acute experimentalstudy investigated the effects ofa 30-minute bout of cycling(60%–69% HRmax) during task-based fMRI and reportedimproved n-back performance andincreased activation of bilateralcerebellum.36

Functional Networks

Authors of 2 experimental studiesreported results for specificfunctional brain networks. Authorsof 1 RCT used an independentcomponent analysis approach andreported that a physical activityintervention caused decreasedsynchrony between the defaultmode network and the cognitivecontrol network with brain regionsoutside of those networks duringresting-state fMRI.40 There was nochange in synchrony of the saliencenetwork, whereas the motornetwork had decreased synchronywith the left cuneus but increasedsynchrony with certain frontalregions.40

TABLE 3 Summary of Studies Which Have Examined the Impact of Physical Activity on BrainStructure or Brain Function

Positively Associated WithPA

Negatively Associated WithPA

Not Associated With PA

Task-based fMRI

Task-positiveregions

Chen et al36,a Krafft et al39,b Chaddock-Heymanet al37

Davis et al38,a — —

Krafft et al39,a — —

Task-negativeregions

— Davis et al38,b —

— Krafft et al39,b —

Resting-state fMRI — Krafft et al40,c —

DTI Chaddock-Heyman et al34,d — —

Krafft et al41,d — —

Schaeffer et al42,d — —

ASL — — Pontifex et al35

PA, physical activity; —, not applicable.a Increased activation.b Decreased activation.c Decreased synchrony of resting-state networks with regions outside those networks.d Increased white matter integrity.

TABLE 2 Risk of Bias Assessment

Study SequenceGeneration

AllocationConcealment

ParticipantBlinding

AssessorBlinding

PersonnelBlinding

SelectiveOutcomeReporting

IncompleteOutcome Data

Other Sourcesof Bias

Chaddock-Heyman et al34

?a ?a ?a 1 1 1 2b 1

Chaddock-Heyman et al37

?a ?a ?a ?a ?a 1 2b 1

Chen et al36 2 2 2 2 2c ?d ? ?a

Davis et al38 ?a ?a 2 1 2c ?d 1 2e

Krafft et al39 ?a ?a ?a ?a ?a ?d 2b 2e,f



Pontifex et al35 ?a ?a 1 ?a 1 ?d 2b 1Schaeffer et al42 ?a ?a ?a ?a ?a ?c 1 2e,f

1 represents low risk of bias, ? represents unclear risk of bias, and 2 represents high risk of bias.a Unclear description in article.b Significant dropout with inadequate analyses.c Authors appeared to provide intervention and control.d No protocol.e Inadequate description of subgroup selection.f Risk of intervention contamination.


Pontifex et al35 investigated the acuteeffects of a 20-minute bout of fastwalking and/or slow jogging (70%HRmax) on cerebral blood flow in10.2 6 1.0 year old (n = 41) andfound no differences across any of thenetworks examined (frontoparietal,executive control, and motornetworks).

White Matter Integrity

Authors of 3 studies reported resultsof 2 RCTs that had examined theeffects of physical activity on whitematter tracts in similarly agedchildren using regions ofinterest analyses.34,41,42 One largeRCT (n = 143) revealed that 2 hoursof physical activity each school dayfor 8 months improved white matterintegrity (ie, increased fractionalanisotropy, which indicates theorientation of diffusion and is higheralong well-defined pathways) anddecreased radial diffusivity (a markerof myelin disintegration) in the genuof the corpus callosum from pretestto post-test, with no changes inestimates of axonal fiber diameter(axial diffusivity).34 There were nochanges in the white matter integrityof the wait list control group,reflective of typical development. Theother RCT (n = 18) also delivered an8-month intervention consisting ofa 40-minute session each school day.Authors of 1 study reported that thephysical activity group showedgreater increases in bilateral uncinatefasciculus fractional anisotropy andgreater decreases in left uncinatefasciculus radial diffusivity comparedwith the control group.42 In thesecond report from this RCT, thephysical activity intervention did notsignificantly increase white matterintegrity in the superior longitudinalfasciculus. However, higherattendance in the exerciseintervention, higher intensity, andgreater total dose of exercise were allassociated with increased fractionalanisotropy and decreased radialdiffusivity of the superior longitudinal

fasciculus in a dose-responsemanner.41

DISCUSSION

In this systematic review, weexamined evidence of the impact ofphysical activity on brain structureand function in youth from MRIstudies. Nine experimental studieswere included in the review, of which7 were RCTs and 2 were acute beforeand after studies, reporting data for12 regions acquired with 4 MRImodalities. All 7 RCT studies (4samples) reported significant changesin either brain structure or functionafter a physical activity interventionin young people.37–42

To date, the parietal cortex is the onlyspecific region that has had .1 RCTreport in which authors found animpact of physical activity on brainstructure or function and for theeffects to be in the same direction (ie,authors of both RCTs founddecreased posterior parietal cortexactivity during antisaccadeperformance after a physical activityintervention38,39). Otherwise, RCTfindings for the impact of physicalactivity on activation during task-based fMRI were inconsistent (ie,authors of 1 study found anassociation and another did not) forthe anterior cingulate cortex,37,39 orconflicting (ie, physical activity had animpact on activation, but authors of 1study reported increased activationand authors of another studyreported a decreased activation in thecase of each task paradigm[antisaccade and incongruentcondition of a flanker task]) forfrontal regions.37–39 It should benoted that although the sample agesand cluster size thresholds weresimilar in these studies, theinterventions varied from 20 to77 minutes per session over 3 to9 months which presentsconsiderable heterogeneity.

The desired direction of the effect ofphysical activity on activation will

differ depending on the region andcontext (eg, task and rest) ofinterest. However, positiveassociations between physicalactivity and activation of task-positive regions during performanceof task paradigms is interpreted as agreater ability to use resources insome studies,36,43,44 whereasnegative associations (ie, lessactivation) are considered torepresent a more efficient use ofresources in others.37,45 There isevidence to support decreasedactivation of a task-positive regionduring task performance beingreflective of a more mature andadult-like brain46–48 but thisshould be interpreted with cautionuntil the findings have beenreplicated by studies adequatelypowered to perform mediationanalyses.49

Authors of 2 RCTs found that physicalactivity caused decreased activationof the posterior parietal cortex duringantisaccade task performance.Although this did not reflecta difference in antisaccadeperformance between the physicalactivity and control group in 1study,39 authors of the other studydid not report data for antisaccadetask performance.38 The inferiorparietal lobule, located within theposterior parietal cortex, forms partof the default mode (task-negative)network,50–52 which is known todecouple from the cognitive controlnetwork during successfulperformance of a cognitive task.53

Therefore, these results may indicatea more refined, adult-like pattern ofactivation in the exercise group whilemaintaining equivalent levels of taskperformance.54–56 A recent meta-analysis revealed that deactivation ofthe default mode network is essentialfor processing information so that itcan later be remembered.57 Thisdiversion of processing resourcesfrom the default mode network tobrain regions involved in the taskperformance has previously been


demonstrated in a cross-sectionalpediatric physical activity study.Despite similar memory performanceto their inactive peers, duringencoding of later remembered versusforgotten word pairs, participantswith high levels of physical activitydisplayed (1) robust deactivation ofthe default mode network, (2) strongnegative coupling with thehippocampus, and (3) a more focalincrease in activation of the lefthippocampus only.45

Decreased synchrony betweena given network and regions outsideof that network is usually anindication of a more focal, coherent,and specialized pattern ofactivation.58,59 Authors of 1 RCT inthis review examined deactivationand activation of functional networksduring resting-state fMRI and foundthat physical activity may beconducive of a more mature efficientbrain by causing decreased synchronyof the default mode network andcognitive control network with brainregions outside of those networksduring resting-state fMRI.40

In terms of structural changes, 1 largeRCT (FITKids2; n = 143) revealed thatparticipation in physical activity canimprove white matter integrity of thecorpus callosum; a region importantfor cognitive processing.34 A secondRCT investigated effects of physicalactivity on white matter integrity anddetected significant improvements inthe bilateral uncinate fasciculus(which usually matures later thanmany other tracts60).42 This wasparticularly evident in the leftuncinate fasciculus, which is linkedwith auditory-verbal memoryproficiency, verbal IQ, and full-scaleIQ.42,61,62

In a second study from the sameRCT,41 changes in white matterintegrity of the superior longitudinalfasciculus were not significantlydifferent between the groups.However, higher attendance atexercise sessions, higher intensity,

and greater total dose of exercisewere positively associated withchanges white matter integrity.41

Similarly, white matter integrity didnot change among adultsparticipating in a 1-year exerciseintervention, but changes in fitnesswere positively associated withwhite matter integrity of prefrontaland temporal regions (which arelinked by the uncinate fasciculus).63

Improvements in fitness were alsoassociated with changes in short-term memory, but increases inwhite matter integrity were notassociated with short‐term memoryimprovement. In another larger-scalestudy involving adults, white matterintegrity in multiple tracts (includingthose that connect medial temporaland prefrontal cortices) mediatedthe relationship between fitnessand spatial working memory.64

Additional support for theimportance of fitness in terms ofwhite matter integrity also exists inpediatric cross-sectional studies,which have found positiveassociations between fitness andfractional anisotropy in several ofthe same white matter tracts inchildren.65

Future Directions

To date, no RCT has examined theimpact of a physical activityintervention on volumes of brainregions in children or adolescents.This is surprising given that a recentmeta-analysis on the effect of aerobicexercise on hippocampal volume inadults included 14 studies.66 Thisreview revealed a significant effect ofaerobic exercise on both left and righthippocampal volume in comparisonwith control conditions in healthyolder adults. The effects were drivenby exercise attenuating normal age-related neurodegeneration, which hasbeen shown to precede and lead tocognitive decline and Alzheimerdisease.67,68 Whether exercise canincrease the volumetric growth of thehippocampus and whether theseincreases in volume subsequently

confer benefits to cognition, memory,and/or academic performance duringchildhood and adolescence has notbeen established.

More studies in adolescents areneeded because all experimentalstudies included in this review wereconducted with children. Futureresearchers should also measurecardiorespiratory and muscularfitness so that (1) baseline fitness canbe adjusted for in analyses and (2)changes in fitness due to physicalactivity interventions can be analyzedfor correlations with changes in brainstructure or function. There isconsiderable scope for differentintensities, frequencies, and types ofphysical activity such as high-intensity interval training, resistanceexercise, exergaming, and cognitivelydemanding physical activity to beexplored.69

Limitations

Although this is the first systematicreview of MRI studies in the area ofpediatric physical activity, there aresome limitations that should benoted. Most notably, because of thesmall number of RCTs andconsiderable heterogeneity ofincluded studies, we were unable toconduct meta-analyses. In addition,we did not check for a file drawereffect so the risk of publication biascannot be ruled out.

There are a number of commonstudy limitations that should benoted. The majority of the includedstudies included small samples and/or relied on statistical significanceanalyses. The P values do not providean indication of the size of aneffect nor the importance of a resultand by themselves are not a goodmeasure of evidence regardinga model or hypothesis.70 As such, thefield needs to progress to promotethe reporting of effect estimates inaddition to the correspondingstatistics.71 Risk of bias was largelyunclear across all domains andstudies. Researchers are encouraged


to adhere to the ConsolidatedStandards of Reporting Trials

guidelines72 to reduce the risk ofbias, particularly in terms of

selection bias and reporting bias.73

Findings need to be interpreted with

caution until additional RCTs can (1)replicate findings and (2) establish

whether exercise-induced changes in

brain structure or function mediate

the cognitive and/or academicbenefits of physical activity.

Conclusions

There is some evidence fromRCTs that participation inphysical activity may enhancebrain structure and function in termsof white matter integrity andactivation of regions key to cognitiveprocesses, respectively. No RCTresearchers have reported on theimpact of physical activity on volumesof brain regions in children oradolescents.

ABBREVIATIONS

ASL: arterial spin labelingBDNF: brain-derived neurotrophic

factorCI: confidence intervalDTI: diffusion tensor imagingfMRI: functional MRIHRmax: maximum heart rateRCT: randomized controlled trialVO2max: maximum oxygen

consumption

the manuscript; Dr Ortega critically reviewed the manuscript; Dr Lubans conceptualized the review and contributed to the design, synthesis, and drafting of the

manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial has been registered with the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/) (identifier

CRD42017081804).

DOI: https://doi.org/10.1542/peds.2018-4032

Accepted for publication Jul 16, 2019

Address correspondence to David Lubans, PhD, Priority Research Centre for Physical Activity and Nutrition, University of Newcastle, University Dr, Callaghan, NSW

2308, Australia. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by an Australian Research Council Future Fellowship grant (FT 140100399).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Supplemental Information

SUPPLEMENTAL TABLE 4 Search Strategy

Search Terms

(child* OR adolescent OR youth OR young person OR young people OR school* OR teen* OR preadolescent OR kid* OR development OR maturation)AND(“physical activity” OR “physical exercise” OR sport OR fitness OR recreation OR walk* OR aerobic activity OR aerobic fitness OR “cardiovascular exercise OR“cardiovascular fitness” OR “cardiorespiratory exercise” OR “cardiorespiratory fitness” OR “VO2” OR “oxygen consumption” OR “aerobic fitness” OR “aerobiccapacity” OR “aerobic exercise” OR “muscular fitness” OR “muscular exercise” OR “resistance training”)

AND(brain OR “brain structure” OR “brain function” OR “brain plasticity” OR neurogenesis OR “stem cell” OR MRI OR “magnetic resonance imaging” OR fMRI OR“functional magnetic resonance imaging” OR DTI OR “diffusion tensor imaging” OR BOLD OR “blood oxygen level dependent” OR VBM OR “voxel basedmorphometry” OR “grey matter” OR “gray matter” OR “white matter integrity” OR volumetry OR “fractional anisotropy” OR “radial diffusivity” OR “restingstate” OR “default mode network” OR “spectroscopy”

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The Impact of Physical Activity on Brain Structure and ......brain structure and function in children and adolescents is examined. DATA SOURCES: Six electronic databases (PubMed, PsychINFO,