Journal Pre-proof

Neuroimaging in paediatric mild traumatic brain injury: a systematic

review

Vanessa C Rausa, Jesse Shapiro, Marc L Seal, Gavin A Davis,

Vicki Anderson, Franz E Babl, Ryan Veal, Georgia Parkin, Nicholas
P Ryan, Michael Takagi

PII: S0149-7634(20)30556-X
DOI: https://doi.org/10.1016/j.neubiorev.2020.08.017
Reference: NBR 3891

To appear in: Neuroscience and Biobehavioral Reviews

Received Date: 12 December 2019

Revised Date: 2 August 2020
Accepted Date: 29 August 2020

Please cite this article as: Rausa VC, Shapiro J, Seal ML, Davis GA, Anderson V, Babl FE,
Veal R, Parkin G, Ryan NP, Takagi M, Neuroimaging in paediatric mild traumatic brain injury: a
systematic review, Neuroscience and Biobehavioral Reviews (2020),
doi: https://doi.org/10.1016/j.neubiorev.2020.08.017

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 Neuroimaging in paediatric mild traumatic brain injury: a systematic review

Vanessa C Rausa*, MPsycha, Jesse Shapiro*, BScAdvHonsa,b, Marc L Seal, PhDa,d, Gavin A

Davis, MBBSa, Vicki Anderson, PhDa,b,e, Franz E Babl, MDa,c,d, Ryan Veal, DPsycha, Georgia

Parkina, PhD, Nicholas P Ryan, PhDd,f, and Michael Takagi, PhDa,b

a Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

b Melbourne School of Psychological Sciences, University of Melbourne, Victoria, Australia

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c Emergency Department, Royal Children’s Hospital, Melbourne, Victoria, Australia

d Department of Paediatrics, University of Melbourne, Victoria, Australia

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e Psychology Service, The Royal Children’s Hospital, Melbourne, Australia

f Cognitive -p
Neuroscience Unit, Deakin University, Geelong, Australia
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*co-first authors
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Corresponding Author: Prof Vicki Anderson, Murdoch Children’s Research Institute, 50 Flemington

Road, Parkville. Victoria. AUSTRALIA. 3052.

T: +613 9345 4695; E: vicki.anderson@rch.org.au; ORCID iD: 0000-0001-5233-3149

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Author Emails:

Vanessa C. Rausa, vanessa.rausa@mcri.edu.au

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Jesse Shapiro, jesse.shapiro@mcri.edu.au

Marc L. Seal, marc.seal@mcri.edu.au

Gavin A. Davis, gavin.davis@me.com

Vicki Anderson, vicki.anderson@rch.org.au

Franz E. Babl, franz.babl@rch.org.au

Ryan Veal, rveal@swin.edu.au

Georgia Parkin, georgia.parkin@mcri.edu.au

Nicholas P. Ryan, nicholas.ryan@mcri.edu.au

Michael Takagi, michael.takagi@mcri.edu.au

Running Title: Neuroimaging in paediatric mTBI: a systematic review

Highlights
 Not enough evidence to link paediatric mTBI symptoms with findings on MRI

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 Research in this area is marred by methodological issues and small sample sizes
 Concussed children do not generally have abnormalities on conventional MRI
 In the future, novel MRI techniques could identify children at risk of PCS

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ABSTRACT
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Neuroimaging is being increasingly applied to the study of paediatric mild traumatic brain

injury (mTBI) to uncover the neurobiological correlates of delayed recovery post-injury. The
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aims of this systematic review were to: (i) evaluate the neuroimaging research investigating

neuropathology post-mTBI in children and adolescents from 0-18 years, (ii) assess the
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relationship between advanced neuroimaging abnormalities and PCS in children, (iii) assess

the quality of the evidence by evaluating study methodology and reporting against best
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practice guidelines, and (iv) provide directions for future research. A literature search of

MEDLINE, PsycINFO, EMBASE, and PubMed was conducted. Abstracts and titles were
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screened, followed by full review of remaining articles where specific eligibility criteria were

applied. This systematic review identified 58 imaging studies which met criteria. Based on

several factors including methodological heterogeneity and relatively small sample sizes, the

literature currently provides insufficient evidence to draw meaningful conclusions about the

relationship between MRI findings and clinical outcomes. Future research is needed which
incorporates prospective, longitudinal designs, minimises potential confounds and utilises

multimodal imaging techniques.

Keywords: concussion; mild traumatic brain injury; neuroimaging; paediatric; systematic

review

1.1 INTRODUCTION

The term mild traumatic brain injury (mTBI), of which concussion is a subset, is defined as a

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an alteration in brain function induced by biomechanical forces and manifested by at least

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one or more of a broad range of symptoms (e.g. headache, dizziness, fatigue, cognitive

difficulties).1 mTBI is common among children and adolescents. For example, in a

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multicenter study of 20,000 children with head injuries presenting to the Emergency

Departments (ED), more than 95% of cases were mild.2 Current evidence indicates that the
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recovery period for children and adolescents post mTBI is longer relative to adults.3,4 Long
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term post-concussive symptoms (PCS) can have an impact upon a child’s quality of life,

social, sporting, and academic activities.5

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The neurobiological and physiological mechanisms underpinning PCS are poorly understood.

However, within the research setting, advanced neuroimaging techniques may have
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potential utility to quantify neuroanatomical changes that might prospectively predict

poorer recovery and outcome after mTBI. Indeed, there is growing evidence that high
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resolution brain magnetic resonance imaging (MRI) measures can detect subtle structural,

functional, and perfusion abnormalities following mTBI.6,7 Notwithstanding this, research

examining the relationship between mTBI-related brain abnormalities and persisting PCS

has not yet progressed to a level that it is clinically applicable, and it remains unclear

whether subtle post-mTBI brain abnormalities seen on MRI have any clinical significance.
Previous reviews have attempted to summarise and evaluate the existing landscape of

paediatric mTBI neuroimaging research. Schmidt and colleagues8 systematically reviewed

neuroimaging research of youth (5 to 18 years) with mTBI (22 studies, 448 participants). The

authors examined neuroimaging after mTBI, at any stage post-injury, and the relationship

between neuroimaging findings and behaviour, age, injury mechanism, and recovery.

Findings across imaging modalities were inconsistent, with some revealing differences

between mTBI and control groups and others not.8 Significant correlations between imaging

findings and behaviour (e.g., symptom reporting, emotional distress, cognitive assessment)

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were revealed in nearly 70% of studies examining this relationship. The relationship

between neuroimaging findings and age, injury mechanism and time to recovery could not

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be examined due to study heterogeneity.8 Mayer and colleagues9 also published results in a

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systematic review of biomarker studies following paediatric mTBI. In contrast to Schmidt

and colleagues, these authors included a narrow window post-injury in their inclusion
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criteria. They concluded that there is a scarcity of diagnostic and prognostic biomarker
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studies in the child mTBI literature and substantial heterogeneity within mTBI research.9

While both reviews assessed methodological quality and risk of bias of included studies, a
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thorough critique of specific imaging methodologies was not provided.

Progress in the paediatric mTBI neuroimaging literature has progressed rapidly in recent
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years, with increased use of novel imaging techniques such as arterial spin labelling (ASL)

and perfusion weighted imaging (PWI), which were previously much less common10-12. This
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review updates and expands upon the findings of existing reviews,8,9 summarises findings

from these emerging novel imaging modalities alongside findings within the chronic phase

post-injury, and provides comprehensive quantitative and qualitative critiques of studies

and their imaging methodologies.

The aims of this systematic review were to (i) evaluate the neuroimaging research

investigating neuropathology post-mTBI in children and adolescents aged 0-18, (ii) assess

the relationship between advanced neuroimaging abnormalities and PCS in children, (iii)

assess the quality of the evidence by evaluating study methodology and reporting against

imaging best practice guidelines, and (iv) recommend directions for future research.

2.1 METHOD

2.2 Definitions

Diagnostic criteria and clinical guidelines for the terms mTBI and concussion overlap

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significantly (e.g., the Concussion in Sport Group consensus statement compared to the

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American Congress of Rehabilitation Medicine criteria for mild traumatic brain injury), 1,13

leading to inconsistent terminology and methodological heterogeneity. Many authors do

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not clearly distinguish, or precisely define, their use of these terms. For the purposes of this
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review and to optimise clarity, we use the term mTBI when discussing neuroimaging

findings, recognising that in many studies the terms used to describe patient groups (e.g.
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concussion, mTBI) represent a common diagnosis.

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2.3 Search Strategy and Eligibility Criteria

A literature search using the electronic databases MEDLINE, PsycINFO, EMBASE and
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PubMed for articles published between 01 January 2000 and 15 July 2019 was conducted.

The full search strategy is outlined in Appendix 1. The inclusion criteria were: (i) peer-
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reviewed journal articles written in English, (ii) with a clear definition of mTBI or concussion,

(iii) a minimum of ten participants with a mean age between 0-18 years (maximum age 25

years) and (iv) with a diagnosis of mTBI or concussion and neuroimaging data obtained

subsequent to presentation to the ED (i.e., imaging not used for diagnostic or clinical

purposes). Given that many neuroimaging studies report data across the entire spectrum of
TBI severity in a single study (e.g. mild TBI, moderate TBI, severe TBI in a single study), it was

also necessary that neuroimaging data for the mTBI/concussion participants could be

analysed separately to data from participants diagnosed with other severities of TBI. Other

exclusion criteria were: (i) animal studies, (ii) articles published before the year 2000, (iii)

retrospective analyses, (iv) non-accidental head trauma, and (v) dissertations, case reports

and review papers.

Studies yielded from the searches were imported to Covidence. Two authors independently

screened all titles and abstracts according to the eligibility criteria and independently

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reviewed the full text articles of included studies. Disagreements between the authors at

these two stages were resolved by discussion and consensus agreement. For each eligible

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study, information was extracted for study population characteristics, methodological

characteristics, and outcome related variables. -p

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2.4 Quality Analysis

There is no standardised protocol for assessing the methodological and reporting quality for
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neuroimaging studies. To this end, we employed two different assessment tools to

determine the risk of bias, and the reporting quality of the reviewed papers: the Newcastle-
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Ottawa Scale14 and the Committee on Best Practices in Data Analysis and Sharing (COBIDAS)

Statement on Neuroimaging Research and Data Integrity, 15 16 16 16 15 14 14 14 14 14 14 1414 which was

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translated into criteria that was used to assess the quality of neuroimaging methodology in
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each study.14,15

The Newcastle Ottawa scale is a rating scale used to judge research articles based on three

overarching criteria: sample selection, group comparativeness, and ascertainment of

exposure. Studies receive a score out of nine possible “stars” with more stars indicating a

more robust study design. Although it has high levels of face validity, there are concerns

about its reliability and decision thresholds.16,17 The COBIDAS guidelines are a
comprehensive series of best practice recommendations for the conduct and reporting of

MR neuroimaging research to assist in determining if studies are reproducible, of high

quality, and well reported. Alongside the published guidelines is a checklist for practices and

items to report, with some items judged by COBIDAS to be crucial to the completeness of

the reporting. The items deemed “crucial” were collated, and each study was assessed

against each applicable item, receiving a percentage score relative to the amount of

applicable COBIDAS checklist items (COBIDAS score = number items satisfied/number of

applicable items). Two studies18,19 were not amenable to assessment using the COBIDAS

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checklist as they did not primarily use MRI. The specific criteria from the quality assessment

measures are outlined in Appendix 2.

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3.1 RESULTS
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The literature search yielded 4563 articles. Of these studies, 58 met the inclusion criteria
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(see Figure 1), totalling 2047 mTBI participants and 1243 control participants.
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--- Insert Figure 1 here ---

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A tabled summary of each study is presented in Supplementary Appendix 3, including; the

study aims, number of participants, source of participant recruitment, age at injury, sex,
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timing of MRI acquisition (e.g. acute, sub-acute, chronic), mechanism of injury, and imaging-
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related findings. Appendix 4 includes additional methodological and sample characteristics,

including; definition of concussion, study inclusion and exclusion criteria, sample

comorbidities, history of prior concussions, and non-imaging measures utilised. Examination

of the neuroimaging protocols used by studies showed that most studies used a) Structural

imaging sequences: (i) T1/T2 MRI sequences (n=42), (ii) diffusion imaging (DTI/diffusion

weighted imaging (DWI); n=30), (iii) SWI (n=11), (iv) fluid-attenuated inversion recovery
(FLAIR; n=11) sequences; and (b) fMRI (n=20). Other studies included perfusion sequences

and spectroscopy. Studies that included multiple sequences in their imaging protocols often

failed to report every sequence. The results discussed in this review were limited to those

sequences that were the primary focus of each paper.

3.2 T1- and T2- weighted MRI

T1- and T2-weighted images derived from routine structural MR sequences can provide

detailed anatomical information as well as quantitative characterisation of the volume,

shape, and composition of brain regions. They are commonly utilised in clinical settings and

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are fundamental components of most research neuroimaging protocols.

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3.2.1 Imaging findings

While T1- and T2-weighted images are the most utilized imaging modality, there have been
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mixed findings in relation to grey matter changes post mTBI, and in how these changes are
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related to PCS. Within the studies reviewed, these sequences were typically used to assess

lesion site, or determine severity of mTBI (i.e., uncomplicated or complicated) through

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qualitative rating via visual inspection of these sequences.20-22 MacDonald and colleagues

examined symptomatic 10-14 year old children at 4-6 weeks post injury23, and 1 month and
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6 months post-injury. 24 Quantitative volumetric analysis of 15 primary regions of interest at

4-6 weeks post-injury demonstrated significant differences in the total brain volume, total
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estimated intracranial volume and left hippocampal volume of children with concussion
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compared to controls. However, the authors noted that the volumetric differences observed

did not appear to represent global atrophy and were more in line with indications of

differing stages of growth and development.23 Mayer and colleagues found no difference in

cortical and subcortical grey matter volume between their concussion sample and their

healthy control sample at the two week timepoint of their longitudinal study.25 However at

a four month timepoint, the authors found differences in the rate of cortical thickness
change between the groups within the left superior and medial frontal gyrus, left middle

temporal gyrus, left postcentral gyrus, left inferior parietal lobule, left cuneus, left middle

occipital gyrus, right superior and middle frontal gyri.25 No group differences were found in the

subcortical grey matter.25 A quantitative volumetric segmentation of the whole brain,

cortical, and subcortical regions found minor abnormalities at 6 months post-injury that

were sustained from 1 month post-injury. Reduced left hippocampal volume, as well as

smaller overall intracranial volume and total brain volume, observed amongst concussion

participants at 1 month had resolved by 6 months post-injury.24 Bigler and colleagues26

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similarly did not find any difference in global cortical thickness between children with mTBI

and children with orthopaedic injury (OI) at 6 months post-injury. The authors did, however,

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find a relationship between parental symptom reporting on the PCSI and reduced cortical

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thickness in left frontotemporal regions and the right temporal pole for children in both

mTBI and OI groups where ‘falls’ was the mechanism of injury.26

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Through an analysis of volumetric changes 10 years post-mTBI via T1-weighted, T2-weighted
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and FLAIR-sequence imaging, Beauchamp and colleagues27 reported an increase in CSF

volume and decrease in total gray matter volume. Analysis of specific regions of interest
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revealed significantly smaller grey matter volume in the left hippocampi.27 The authors

argue that the higher CSF volumes in children with mTBI may be suggestive of degenerative
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change, given the absence of focal brain lesions at the time of injury, and that these findings

indicate that mild injuries might be one factor that contributes to long term macrostructural
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brain changes in specific regions, such as the hippocampus.27 The absence of abnormalities

on MRI may also contribute to a child’s outcome post-concussion, as demonstrated by

Antshel and colleagues,28 who compared how parents rated their child’s behaviour before

and after an MRI. They found that children who did not have MRI abnormalities were rated

by their parents as having significantly higher externalizing behaviors at 3 months post-MRI

relative to pre-MRI. In contrast, children who were found to have abnormalities on MRI did

not show a similar increase in parent reported externalising behaviours. Interpreting these

findings in the context of attribution theory, the authors suggest that normal MRI findings

might enhance parental attributions of their child’s behavioural control. They highlight the

importance of education as an intervention in the closed head injury population.28

Ewing-Cobbs and colleagues also investigated the relationship between child functioning

and brain abnormalities post-concussion.29 The authors explored the relationship between

social communication behaviours, including joint attention, gestures, and verbalization, and

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surface area of midsagittal corpus callosum (CC) subregions in children who sustained an

mTBI or moderate-severe TBI prior to 7 years of age. Social communication behaviours were

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measured via video recording of a semi-structured sequence of social interactions between

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child and examiner. Social communication was not affected by injury severity, however the

isthmus was significantly smaller in the moderate–severe group relative to the mTBI
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group.29 These results support Antshel and colleagues’ hypothesis of attribution theory,28
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and suggest that the measure of a child’s behaviour post-concussion may be biased by

parental interpretation. Finally, adopting a qualitative approach (i.e. visual inspection of

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structural MR images), Max and colleagues30-32 examined the relationship between MRI

findings and novel psychiatric disorders (e.g. attention deficit hyperactivity disorder) at
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various time points post-injury. The presence or absence of any lesion (irrespective of

location) at 3 months post-injury was not associated with a novel psychiatric disorder at 6,
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12, or 24 months. However, frontal white matter lesions were significantly associated with a

novel psychiatric disorder at 6 and 24 months post-injury, with those at the 6 month time

point also significantly correlated with poorer processing speed, expressive language, and

overall intellectual functioning.30-32 Loss of consciousness was positively correlated to

abnormalities identified by T1- or T2-weighted sequences, and the presence of parenchymal

lesions was associated with higher ratings of post-concussive cognitive symptoms in

children with lower socioeconomic status.21 However, it is important to note that the

studies by Max and colleagues30-32 included participants who required hospitalisation, had

demonstrated intracranial lesions, and had skull fractures.

3.3 Susceptibility weighted imaging (SWI)

Susceptibility weighted imaging is a newer imaging sequence which makes use of the

paramagnetic properties of hemosiderin – an iron storage complex which is usually found in

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areas of red blood cell catabolism. Hemosiderin clusters are suggestive of prior hemorrhage,

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and some studies have found SWI to be more sensitive than T2*-weighted imaging for

detecting microhemorrhage.

3.3.1 Imaging findings

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Most analyses which report SWI imaging do so on a qualitative basis, with the most

common method being a visual inspection by a radiologist, neurologist, or a

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neuropsychologist. Only two studies reported positive SWI findings.20,33 Attempting to

demonstrate the utility of SWI imaging in a TBI context, Beauchamp and colleagues
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demonstrated a trend of an increase in the number and size of SWI lesions found as the TBI

became more severe20. The authors also found that 11 cases whereby a child with mTBI was
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found not to have any mass lesion on clinical CT or clinical MRI, but was found to have

lesions on SWI imaging.20 Choi and colleagues demonstrated a similar pattern of SWI
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imaging, finding more lesions than standard clinical imaging sequences, however it should

be noted that the authors only used patient GCS as a measure of injury severity, and based

on other clinical evidence reported (such as days spent in ICU and total days spent in

hospital) these patients injuries are likely to represent more severe cases.33 Several other
studies report acquiring SWI imaging as part of larger imaging protocols, and either report

no SWI findings or do not report SWI findings.7,25,34-39

3.3.2 Diagnostic utility

At this stage, there is not enough evidence to suggest that SWI imaging is useful for

differentiating mTBI. While there do appear to be some promising results as to its ability to

detect lesions at the more severe end of mTBI, it is beyond the scope of this review to

discuss its merits in cases of more severe paediatric TBI.

3.4 Diffusion weighted imaging (DWI)

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Diffusion weighted imaging is an established MRI technique that estimates the “diffusion”

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or motion of water molecules within tissue. As myelinated white matter bundles restrict the

free diffusion of water this technique makes it possible to estimate the organisation and
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structure of brain white matter. Diffusion tensor imaging (DTI) is a subtype of DWI that
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measures the magnitude and directionality of water diffusion in tissue, notably of white

matter tracts, and represents a sensitive biomarker of diffuse white matter injury in TBI via
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detection of traumatic axonal injury.38,40 DTI is used to index the microstructural

organisation of white matter tracts in specific brain regions using commonly derived metrics
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including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD, diffusivity

parallel to fibre tracts), and radial diffusivity (RD; diffusivity perpendicular to fibre
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tracts).40,41
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3.4.1 Imaging findings

Analysis techniques for diffusion imaging vary across studies, which included voxel-based

and region of interest (ROI) analyses of diffusion metrics, tract-based spatial statistics (TBSS)

analysis, graph theory (structural connectivity) analysis, and tractography. Despite the

varying approaches to analysis of diffusion metrics, findings across studies consistently

showed higher fractional anisotropy (FA),6,25,42-47 lower mean diffusivity (MD),42,45,48-50 lower
radial diffusivity (RD),42,43,45,46,48 and lower apparent diffusion coefficient (ADC)43,51 for mTBI

participants relative to controls. Exceptions to these results are documented in one study

which found reductions in FA in the left middle frontal gyrus white matter 6 months post-

concussion,24 another which found reductions in left uncinate fasciculus one month post-

concussion,50 and another which found no group differences in FA.48 Variable patterns were

reported for axial diffusivity (AD), with both increases and decreases described.42,44,45,48

Findings from five studies showed that mTBI is associated with altered diffusion properties

in various regions of interest in the subacute phase post-injury,35,43,48 as well as up to 6

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months post-injury.6,24 Murdaugh and colleagues found that participants with a concussion

demonstrated a significant increase in isotopic diffusion along the superior longitudinal

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fasciculus and a segment of the corticospinal tract, imaged within 7 days of injury. No

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differences were identified between groups 21 days post-injury.52 Lancaster and

colleagues48 found significantly decreased MD, AD and RD on DTI in concussed male high
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school and collegiate athletes compared to controls at 24 hours post-injury, which remained
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at 8 days post-injury. Using diffusion kurtosis tensor imaging (DKTI), the authors also found

that the concussion group had increased axial kurtosis (Kax) at both time-points. However,
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there were no group differences in FA, mean kurtosis (MK) or radial kurtosis (Krad). 48

Interestingly, Lancaster and colleagues53 also showed that at 6 months post-injury athletes
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with concussion continued to show decreased MD and AD in a number of white matter

tracts. More specifically, mean and axial diffusivity in several major white matter pathways
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remained significantly lower in concussed athletes at 6 months post-injury compared to

non-concussed athlete controls, consistent with their findings in the acute and early

subacute stages. Unlike their acute findings however, there were no statistically significant

differences between groups on RD or Kax at 6 months post injury. Mayer and colleagues6

compared participants with mTBI with healthy controls across 16 white matter ROIs at both
two weeks and 3 to 5 months, finding a significant (or “at trend levels”) main effect of group

on FA, but no group by time interaction effect for both FA values and cluster metrics.

Bartnik-Olson and colleagues44 only identified differences in diffusion metrics in

symptomatic participants imaged within a range of 3 to 12 months post-injury when

dichotomised according to the presence or absence of cognitive symptoms. Of note, sole

focus on symptomatic participants creates a bias towards more severe injuries, which must

be considered when interpreting study results. Negative results have also been reported;

Maugans and colleagues37 did not identify any differences in diffusion metrics (FA, AD, RD,

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trace) following sport-related mTBI at <72 hours when compared to healthy controls, or

within the concussion group over time (<72 hours, 14 days, or 30 days post-injury).

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Results emerging from structural connectivity analyses were variable, although time points

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post-injury were wide-ranging in the reviewed studies. Within 96 hours of injury, children

with mTBI showed significantly lower global efficiency, and significantly higher normalised
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clustering coefficient, normalised characteristic path length, and small-worldness.54 In
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contrast, Konigs and colleagues55 did not find any impact of mTBI on structural connectivity;

however, time since injury ranged from 9 months to 6 years at the time of imaging, resulting
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in difficulties interpreting these results meaningfully. Yuan and colleagues56 examined the

effectiveness of a 6-week aerobic training intervention compared to stretching exercises at

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approximately 2 months post-injury, and found a significant increase in global efficiency and

a decrease in normalized characteristic path length for the aerobic training group,
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suggesting that recovery may be improved through intervention.

3.4.2 Diagnostic utility

Mayer and colleagues6 demonstrated the potential utility of diffusion imaging to objectively

classify mTBI in children within 21 days post-injury. They found that increased FA was able

to correctly classify patients from controls with 90% accuracy, however these classifications
were not correlated with neuropsychological outcome, calling into question the clinical

utility of this finding. Similarly, Bartnik-Olson and colleagues44 found significant differences

in DTI metrics that were able to differentiate between mTBI participants with and without

cognitive symptoms. Children with subjectively rated cognitive symptoms showed increased

RD and reduced FA in the anterior and posterior limbs of the right internal capsule

compared to those without symptoms. Taken together, while not contributing to diagnosis,

these studies provide an interesting association between DTI metrics and child cognitive

outcomes post-concussion. The findings also indicate that these metrics have potential to

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add prognostic value when used in combination with clinical indicators of injury severity.

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3.5 Functional MRI (fMRI)

Functional MRI is a technique designed to image the functional rather than structural state
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of the brain, and most of the techniques used in fMRI examine changes in BOLD signal
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(blood oxygen level dependent) at rest or when performing cognitive tasks. An increase in

cortical energy demand, such as that required during the completion of a region-specific
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task, requires an increase in oxygenated haemoglobin. A difference in paramagnetic

properties between oxygenated haemoglobin, and deoxygenated haemoglobin, is utilized

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for BOLD MRI. These changes in BOLD signal are attributed to task-induced changes in

cognition or spontaneous processes of the resting brain. While fMRI is typically used within
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a research context, it is also used to inform clinical management and intervention in other

clinical paediatric populations such as seizure disorders and focal epilepsy 57.
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3.5.1 Imaging findings

Mutch and colleagues (2016)58 used controlled CO2 targeting and BOLD MRI to examine

cerebrovascular responsiveness (CVR) in 15 adolescent participants with post-concussion

syndrome, imaged 1 month to 2.7 years post-injury and compared to controls. In response

to a controlled vasodilatory stimulus, regional abnormalities in CVR were identified in all

participants with post-concussion syndrome. Group comparisons demonstrated that an

attenuated response to CO2 challenge is the primary cerebrovascular response. A

distinctive, patient-specific signature of impaired CVR was demonstrated in each participant

with post-concussion syndrome, which was not followed by control participants. Regional

abnormalities in CVR were shown in all participants who, on the graded aerobic treadmill

test, obtained a symptom-limiting threshold. The authors posit that results from ROC curve

analysis indicate the potential utility of examining quantitative biomarker thresholds to

diagnose PCS and define physiological recovery.

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Another widely used technique is to assess brain activity while the brain is at “rest” - so

called resting state fMRI. Typically data acquired from resting state experiments are used to

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estimate the strength and spread of functional networks in the brain. In most studies

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utilising resting state fMRI analysis techniques employed one of two approaches; “model

free” independent component analysis or seed-based functional connectivity analysis.

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Examination of resting-state networks revealed increased functional connectivity in
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executive function and ventral attention networks within 96 hours post-injury,59 as well as

increased connectivity in the default mode network within the first month post-injury for
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children with mTBI relative to controls.59,60 Murdaugh and colleagues found posterior brain

region hyperconnectivity and anterior brain region hypoconnectivity in concussed

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participants relative to controls, imaged within 7 days of injury. No differences were

identified between groups 3 weeks later. 52 On the other hand, while Manning and
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colleagues did not find a significant difference in resting-state network activity at 24-72

hours post-injury, the authors reported significantly increased connectivity within the

occipital pole visual network and cerebellar network for the concussion group relative to

controls at 3 months post-injury. 42 Additionally, using canonical correlation analysis, Iyer

and colleagues found a multivariate association between persistent PCS symptoms and
connectivity within the brain networks. 61 Using fractal geometry analysis, Dona and

colleagues62 found significantly lower grey matter fractional dimension values for mTBI

participants relative to healthy controls, with subsequent ROI analysis revealing significantly

decreased fractional dimension in 11 regions. Participants underwent imaging at a mean of

33 days post-injury (SD = 43·38).

All remaining fMRI studies included in this review involved analysis of task-related cognitive

activation.7,63-70 Yang and colleagues7 found hypoactivation in a number of brain regions of

children with mTBI when examining event-related fMRI (where participants were required

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to complete an auditory-orienting task) within 3 weeks post-injury. In a spatial navigation

task, Holmes and colleagues69 found that even children with few concussive symptoms one

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month post injury showed increased frontal and occipital activation on task. These authors

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also report task based activation differences in the fusiform gyrus when comparing children

with low and high symptom burdens.

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Keightley and colleagues64 used an externally ordered working memory task, and found
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significantly greater activation for healthy controls compared to mTBI participants 9 to 90

days post-injury in bilateral dorsolateral prefrontal cortex, supplementary motor area, left
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premotor cortex, and left superior parietal lobule, with activation in the left dorsolateral

prefrontal cortex significantly correlated with task performance for both groups. Sinopoli
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and colleagues67 identified that the demands of a dual-task working memory and motor

paradigm revealed differences between children with mTBI 3 to 6 months post-injury, who
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showed no deficits on neuropsychological assessment measures, relative to controls.

Westfall and colleagues68 observed that relative to controls, mTBI participants imaged 3 to

12 months post-injury demonstrated greater brain activation on the most complex

condition of a working memory auditory-verbal N-back task. In a similar N-back task,

Khetani and colleagues found that, despite equivocal task performance, children with
delayed recovery from concussion showed decreased activation in the precuneus, anterior

cingulate, and posterior cingulate in the one-back task compared to normally recovering

children.70

3.5.2 Diagnostic utility

In a 2007 study by Lovell and colleagues71, athletes underwent fMRI within the week

following their concussion and again following clinical recovery. They found that global

hypermetabolism during the acute stage of recovery predicted longer recovery times. The

degree of hyperactivation in the region involving the posterior parietal cortex was

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significantly associated with the decrease in cognitive and somatic symptoms from baseline

to recovery. There was also an association between time to return to play and the network

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involving the medial, frontal, and right temporoparietal gyri, and specifically in Brodmann’s

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Area (BA) 6; such that athletes with higher activation in these regions took a significantly

greater time to return to play than those with lower activation in these regions.
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Additionally, Yang and colleagues were able to correctly distinguish mTBI patients from
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controls with 85.7% accuracy based on the BOLD signal patterns during an auditory-

orienting task 2-3 weeks post injury.7

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3.6 Cerebral Blood Flow/Volume

Perfusion weighted imaging (PWI), arterial spin labelling (ASL) and phase contrast
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angiography (PCA) are MR techniques used to investigate cerebral blood flow (CBF) or
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cerebral blood volume (CBV). PWI utilises a dynamic-susceptibility contrast imaging

technique, which calculates cerebral blood flow and volume by detecting changes in signal

intensity. PCA produces images of blood-flow velocity by manipulating magnetisation

phases, while ASL allows for a direct measure of cerebral blood flow through the magnetic

labelling of water molecules within arterial blood.

3.6.1 Imaging findings

Analysis techniques varied between studies adopting perfusion techniques, which included

ROI analysis or estimated whole-brain CBF in grey matter. Findings from these studies

showed patterns of reduced CBF in the bilateral thalami at 3 to 12 months post-injury,44 as

well as abnormal CBF values at <72 hours, 14 days, and 30 days post-injury compared to

healthy controls in unidentified regions, although there was some improvement in

attenuation of the abnormalities over these time-points.37 Brooks and colleagues12

examined the association between history of a diagnosed concussion and CBF. Children with

a history of concussion did not differ from children with an OI in global CBF, however

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regions of hypoperfusion (left and right lingual gyrus, left and right inferior frontal gyrus

[pars triangularis], left fusiform gyrus) and hyperperfusion (left median cingulate gyrus

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[orbital part], right rolandic operculum, left middle temporal pole, right parahippocampal

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gyrus) were identified when compared to the OI group. They also found statistically

significant small to medium correlations between left inferior frontal gyrus hyperperfusion
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and parent reported physical, fatigue and anxiety symptoms, and between right rolandic
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operculum hyperperfusion and parent reported physical and fatigue symptoms. There were

no significant associations between CBF and demographic or pre-injury data. These data
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suggest that previous concussions may affect regional areas of CBF, unrelated to

demographic or clinical history, many years after the concussion. The results by Brooks and
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colleagues are supported by research by Mutch and colleagues,10,58 who examined global

and regional resting CBF. The authors did not identify any differences between youth with
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concussion and controls in mean global resting CBF10,58, which they suggest indicates the

unreliability of mean global resting CBF as a biomarker to distinguish between

physiologically recovered and non-recovered adolescents following sports-related

concussion. The authors found significant group-level differences in mean regional resting

CBF; however, when individual PCS participants were compared with controls, a patient-
specific signature of impaired resting CBF was revealed, which included quantifiable

abnormalities in diffuse brain regions outside of the abnormal regions identified on group

comparisons. Their findings suggest that resting CBF within specific regions of interest may

not reflect the global impairments in cerebrovascular physiology that characterises post-

concussion syndrome. 58 Stephens and colleagues11 found that, at 2 weeks post injury,

adolescents with concussion have significantly higher rCBF than controls in the left insula

and left dorsal anterior cingulate cortex (ACC). At 6 weeks post injury, adolescents with

concussion showed significantly higher rCBF in the left dorsal ACC than controls, although

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significant differences were not shown when controlling for age. Finally, Mutch and

colleagues found no difference in rCBF between the concussion patients and the healthy

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controls.58

3.7 Spectroscopy
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Magnetic resonance spectroscopy estimates the presence and concentration of common

metabolites in tissue, such as N-acetyl aspartate (NAA), creatine (Cr), and choline (Cho).
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Changes to the known objective and relative amounts of these metabolites can be used as

indication of damage to axon and glial cell populations.

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3.7.1 Imaging findings

Magnetic resonance spectroscopic imaging (MRSI) and proton magnetic resonance

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spectroscopy (1H-MRS) were used to examine NAA or gamma-Aminobutyric acid (GABA)

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and their ratios to choline and creatine (NAA, NAA/Cho, NAA/Cr, GABA/Cre). These studies

employed region of interest analysis and multi-tissue spectroscopy techniques. MRSI

findings showed significantly increased GABA/Cre in the frontal lobes following admission

after a first-time concussion,36 reduced NAA/Cr and NAA/Cho ratios in the corpus callosum

and parietal white matter of mTBI participants 3 to 12 months post-injury,44 and reduced

choline (but not NAA) in prefrontal regions 3 months post-injury.42 1H-MRS did not find any
significant changes in NAA or NAA/Cr levels over time at <72 hours, 14 days and 30 days

post-injury.37

3.8 Quality Assessment Findings

The ratings for each study using the NOS and COBIDAS checklists are presented in detail in

Figures 2 and 3 respectively. To assess whether having a higher number of applicable

COBIDAS checklist items impacted on a study’s ability to score highly, a split half

independent samples t-test was carried out, comparing the scores of studies required to

satisfy more than the average number of items (Mscore = 59.69, SD = 10.32) with those

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required to satisfy fewer (Mscore = 57.88, SD = 16.47). No significant difference was found (t =

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-0.50, p > .05). No significant difference was found between the first (Mscore = 54.49, SD =

19.11) and fourth (Mscore = 54.62, SD = 9.91) quartiles (t = -0.02, p > .05), indicating that
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there was no reporting burden effect on the COBIDAS scores, which implies that our rating
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system did not disadvantage studies which were required to report on more items.

In general, according to the NOS scoring, studies included in this review had some form of
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control sample and attempted to account for age and sex effects. Notwithstanding this,

many studies did not recruit prospectively from consecutive presentations, and several
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studies did not report the non-response rate. Collectively, these issues raise the possibility

that the samples in these studies are biased, possibly towards more severely injured
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children or some other unknown latent variable. For the COBIDAS checklist, few studies
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managed to report at a standard that approached the bare minimum level required. Of

most concern were studies failing to report image acquisition parameters and preprocessing

procedures in sufficient detail to enable reproduction. The authors of this review

acknowledge that meeting all of the requirements within the text of a research article can

affect its readability for non-expert readers, and therefore recommend that future studies
adopt the practice of having a highly detailed supplementary methods section which

addresses all of the COBIDAS recommendations published alongside their primary findings.

--- Insert Figures 2 and 3 here ---

4.1 DISCUSSION

In recent years there has been increasing attention to the negative and disruptive effects

mTBI can have for children and their family. Significant advances have been made in

understanding the clinical features and time course for delayed recovery post-injury,72 but

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underlying neurobiological causes remain poorly understood. Advanced MRI offers a unique

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opportunity to elucidate the neurobiological correlates of delayed recovery post-mTBI; thus,

the aims of the present study were to evaluate the neuroimaging research investigating
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neuropathology post-mTBI in children, assess the relationship between advanced
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neuroimaging abnormalities and PCS in children, assess the quality of the evidence by

evaluating study methodology and reporting against best practice guidelines, and
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recommend directions for future research.

The majority of children who sustain an mTBI do not have structural abnormalities identified
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via standard neuroimaging sequences (e.g., CT, T1- or T2- weighted MRI),73 although there

may still be abnormalities at a microstructural level not detected by methods currently

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used. Before concluding that such injuries have no consequences at a brain level,
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application of advanced imaging modalities are required to confirm the absence of

neuroanatomical changes associated with these mild, generalised injuries. Potential targets

for investigation include, but are not limited to, traumatic microhaemorrhages (SWI),

quantifying the integrity of white matter tracts (DTI), assessing the performance of

functional networks (fMRI), and examining post-traumatic neurovascular physiological

changes, such as altered cerebral blood flow and cellular metabolism (e.g., ASL, MRS).
The examination of DTI in relation to mTBI was the primary focus of the majority of studies

in this review. The differences found using advanced MR imaging techniques between

children with mTBI and controls were most consistent using DTI, where findings across

studies reflected a similar pattern of altered diffusion properties.6,25,43-47,49,51 Consistent

patterns of reduced cerebral blood flow or volume were also observed, although this finding

was captured across differing modalities, including PWI, ASL, and PCA.37,44,74 While studies

utilising fMRI typically reported altered functional connectivity, the specific patterns in

resting-state and experimental task-related paradigms demonstrated greater

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variability.7,59,60,62-66,68

The overall body of literature examining neuroimaging in paediatric mTBI has increased over

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time,75 with findings that demonstrate structural and functional changes associated with the

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injury, and this review highlights a number of methodological limitations of existing

research. These limitations, consistent with those identified in previous reviews,8,9 make it
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difficult to collate existing findings that can advance our understanding of the relationship
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between the neurobiological underpinnings of mTBI and functional outcome. In the current

review, there is a lack of methodological consistency characterised by: a paucity of studies

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investigating each of the modalities; variations in outcome measures and approaches to

imaging analysis; discrepant timing of imaging relative to timing of injury; small sample
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sizes; poor control of sex, age, and premorbid IQ; differences in study design; and poor

adherence to best practice recommendations for methodology and results reporting in

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neuroimaging. These caveats can have significant implications on the findings that emerge,

and therefore, findings must be interpreted cautiously. For example, the timing of imaging

post-injury was often conducted with broad windows that spanned acute, semi-acute, and

longer-term recovery periods (e.g., 1 to 11 weeks, 8 to 82 days, 9 to 90 days post-injury).

Similarly, diverse study designs—such as investigation of exclusively symptomatic groups

compared to more representative mTBI injury samples—result in the compilation of

neuroimaging findings for heterogeneous groups of participants. Whether differences in

findings identified across studies can be attributed to injury must be interpreted in

consideration of the inconsistency regarding clinical measures and brain metrics. Moreover,

the paucity of reporting makes reproducibility highly challenging in many cases.

The methodological weaknesses highlighted by this review are consistent with the recent

Consensus Statement on Concussion in Sport,1 which emphasises the need for further

research to establish the clinical utility of high resolution neuroimaging. While this review is

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not positioned to address this point given the absence of homogenous and

methodologically rigorous studies, the findings can provide an indication of their clinical

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potential. For example, from a diagnostic perspective, more sensitive imaging techniques

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may be useful in differentiating children with mTBI from controls. Through the

measurement of FA, DTI was able to objectively classify 90% of mTBI patients from controls
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imaged within the first three weeks post-injury.6,44 Results from fMRI demonstrated similar
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capability to classify mTBI patients from controls through assessment of functional

activation in a combination of regions with relatively high accuracy.7 As a diagnostic marker,

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DTI—as has been suggested previously76,77—and fMRI, may hold promise for identifying

those at risk for persisting PCS and for targeting injury management.
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4.2 Future Directions

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As discussed previously, the methodological heterogeneity of the paediatric neuroimaging

concussion/mTBI literature precludes any robust conclusions. However, the limitations of

the field are well known and several large and methodologically rigorous neuroimaging

studies are currently underway. For example, Yeates and colleagues78 are conducting the A-

CAP study, a prospective, longitudinal cohort study of mTBI in children aged 8-17 years. This

multi-site study is utilizing multiple neuroimaging techniques at several, well-defined time

points to capture acute and post-acute neuroimaging measures. The neuroimaging protocol

includes: three-dimensional T1-weighted volumetric sequences to measure regional

volumes and cortical thickness; DTI to assess white matter microstructure; quantitative

susceptibility mapping to assess haemorrhage and iron deposition; resting state fMRI to

assess functional connectivity; T2-weighted FLAIR for lesion detection; ASL to assess

perfusion; and proton spectroscopy in a single voxel in the dorsolateral prefrontal cortex to

assess metabolite concentrations.

Similarly, the CARE consortium,79 a collaboration between the National Collegiate Athletics

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Association and the US Department of Defence, have recruited over 2000 university-aged

participants who have sustained a concussion. This is a nation-wide collaboration between

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multiple universities and military service academies. Participants are imaged in the acute

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(24-48 hours post-injury), subacute (cleared for return-to-play progression), and post-

concussion periods (7 days following return to play and 6 months post-injury). The
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neuroimaging protocol includes T1-weighted inversion-recovery spoiled gradient-recalled
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echo (MPRAGE/iSPGR) images; T2-weighted FLAIR images; diffusion-weighted MRI using a

‘multishell’ approach (hybrid diffusion imaging); T2-weighted imaging; resting state fMRI
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imaging; pseudo-continuous ASL imaging; as well as sophisticated statistical approaches

combining multiple imaging modalities.

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The results from these well-powered, longitudinal, multi-site studies are likely to

substantially improve our understanding of the neurobiological underpinnings of delayed

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recovery post-mTBI.

4.3 Clinical Application

It is worth noting that most children who sustain an mTBI do not typically receive any

neuroimaging post injury. Additionally, it is important to consider that for the most part,

advanced neuroimaging techniques such as MRI are not widely available and are relatively
costly. Scanning children is logistically complex. Ideally, neuroimaging would provide a

clinician with cheap and reliable answers to several questions:

 Will this child with acute concussion recover quickly or develop persisting PCS?

 Do the imaging changes predict the duration of symptoms?

 Will the post concussive imaging changes indicate appropriate time for the child to

return to school and sport?

 Will the post concussive imaging changes identify those children at risk from repeat

injury if they return to contact sport?

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 Do the neuroimaging changes identify symptom domains and inform clinical

management interventions appropriately in symptomatic children?

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By studying large, representative mTBI samples and employing high quality, reproducible
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advanced MR protocols, future neuroimaging research is likely to address these important

clinical questions, thereby contributing to significant advances in the treatment and

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management of this common childhood condition.
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Author Contributions:
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Rausa, Shapiro, and Takagi were involved in the conceptualisation of the review, literature

search, data extraction and interpretation, and drafting of initial manuscript.

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Seal was involved in the conceptualisation of the review, data extraction and interpretation,

review of interpretation of findings, and critical review of manuscript drafts.

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Davis, Anderson, Babl, Veal, Parkin, and Ryan were involved in the conceptualisation of the

review, review of interpretation of findings, and critical review of manuscript drafts

5.1 ACKNOWLEDGEMENTS
Declaration of Interest: Ms Rausa, Mr Shapiro, Dr Seal, Dr Davis, Dr Anderson, Dr Babl, Mr

Veal, Dr Parkin, Mr Ryan, and Dr Takagi all report no competing financial interests exist.

Funding Source:

This study was funded by The Royal Children’s Hospital Research Foundation. FEB was

funded by The Royal Children’s Hospital Research Foundation (Melbourne Campus Clinician

Scientist Fellowship) and an NHMRC Practitioner Fellowship, and VA by an NHMRC Senior

Practitioner Fellowship.

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The funding source did not have a role in the design and conduct of the study; collection,

management, analysis, and interpretation of the data; preparation, review, or approval of

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the manuscript; or the decision to submit the manuscript for publication.

6.1 REFERENCES

1.
-p
McCrory P, Meeuwisse W, Dvorak J, et al. Consensus statement on concussion in sport—the
re
5th international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med
2017; 51(11): 838-47.
2. Babl FE, Borland ML, Phillips N, et al. Accuracy of PECARN, CATCH, and CHALICE head injury
decision rules in children: a prospective cohort study. Lancet 2017; 389(10087): 2393-402.
lP

3. Davis GA, Anderson V, Babl FE, et al. What is the difference in concussion management in
children as compared with adults? A systematic review. Br J Sports Med 2017; 51(12): 949-57.
4. Zemek R, Barrowman N, Freedman SB, et al. Clinical Risk Score for Persistent Postconcussion
Symptoms Among Children With Acute Concussion in the ED. JAMA 2016; 315(10): 1014-25.
na

5. Ransom DM, Vaughan CG, Pratson L, Sady MD, McGill CA, Gioia GA. Academic effects of
concussion in children and adolescents. Pediatrics 2015; 135(6): 1043-50.
6. Mayer AR, Ling JM, Yang Z, Pena A, Yeo RA, Klimaj S. Diffusion abnormalities in pediatric mild
traumatic brain injury. J Neurosci 2012; 32(50): 17961-9.
ur

7. Yang Z, Yeo RA, Pena A, et al. An fMRI study of auditory orienting and inhibition of return in
pediatric mild traumatic brain injury. Journal of Neurotrauma 2012; 29(12): 2124-36.
8. Julia Schmidt, Kathryn S. Hayward, Katlyn E. Brown, et al. Imaging in paediatric concussion: a
systematic review. Pediatrics 2018; 141(5).
Jo

9. Mayer AR, Kaushal M, Dodd AB, et al. Advanced biomarkers of pediatric mild traumatic brain
injury: Progress and perils. Neurosci Biobehav Rev 2018; 94: 149-65.
10. Mutch WAC, Ellis MJ, Ryner LN, et al. Patient-specific alterations in CO<inf>2</inf>
cerebrovascular responsiveness in acute and sub-acute sports-related concussion. Frontiers in
Neurology 2018; 9 (JAN) (no pagination)(23).
11. Stephens JA, Liu P, Lu H, Suskauer SJ. Cerebral blood flow after mild traumatic brain injury:
associations between symptoms and post-injury perfusion. Journal of neurotrauma 2018; 35(2): 241-
8.
12. Brooks BL, Low TA, Plourde V, et al. Cerebral blood flow in children and adolescents several
years after concussion. Brain Injury 2019.
13. Kay T, Harrington DE, Adams R, et al. American Congress of Rehabilitation Medicine Head
Injury Interdisciplinary Special Interest Group: Definition of mild traumatic brain injury. J Head
Trauma Rehabil 1993; 8(3): 86-7.
14. Wells G, Shea BJ, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the
qualty of nonrandomised studies in meta-analyses. 2000.
http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
15. Nichols TE, Das S, Eickhoff SB, et al. Best practices in data analysis and sharing in
neuroimaging using MRI. Nature neuroscience 2017; 20(3): 299.
16. Hartling L, Hamm M, Milne A, et al. Validity and inter-rater reliability testing of quality
assessment instruments. 2012.
17. Hartling L, Milne A, Hamm MP, et al. Testing the Newcastle Ottawa Scale showed low
reliability between individual reviewers. Journal of clinical epidemiology 2013; 66(9): 982-93.
18. Agrawal D, Gowda NK, Bal CS, Pant M, Mahapatra AK. Is medial temporal injury responsible
for pediatric postconcussion syndrome? A prospective controlled study with single-photon emission
computerized tomography. J Neurosurg 2005; 102(2 Suppl): 167-71.
19. Urban KJ, Barlow KM, Jimenez JJ, Goodyear BG, Dunn JF. Functional near-infrared
spectroscopy reveals reduced interhemispheric cortical communication after pediatric concussion.
Journal of Neurotrauma 2015; 32(11): 833-40.

of
20. Beauchamp M, H., Beare R, Ditchfield M, et al. Susceptibility weighted imaging and its
relationship to outcome after pediatric traumatic brain injury. Cortex: A Journal Devoted to the Study
of the Nervous System and Behavior 2013; 49(2): 591-8.

ro
21. Taylor H, Dietrich A, Nuss K, et al. Post-concussive symptoms in children with mild traumatic
brain injury. Neuropsychology 2010; 24(2): 148-59.
22. Fay TB, Yeates KO, Taylor HG, et al. Cognitive reserve as a moderator of postconcussive
-p
symptoms in children with complicated and uncomplicated mild traumatic brain injury. Journal of
the International Neuropsychological Society 2010; 16(1): 94-105.
23. Mac Donald CL, Barber J, Wright J, et al. Quantitative Volumetric Imaging and Clinical
re
Outcome Characterization of Symptomatic Concussion in 10- to 14-Year-Old Adolescent Athletes.
The Journal of head trauma rehabilitation 2018; 33(6): E1-E10.
24. Mac Donald CL, Barber J, Wright J, et al. Longitudinal Clinical and Neuroimaging Evaluation
of Symptomatic Concussion in 10- to 14-year-old Youth Athletes. Journal of Neurotrauma 2019; 10:
lP

10.
25. Mayer AR, Hanlon FM, Ling JM. Gray matter abnormalities in pediatric mild traumatic brain
injury. Journal of Neurotrauma 2014; 31 (12): A66.
26. Bigler ED, Finuf C, Abildskov TJ, et al. Cortical thickness in pediatric mild traumatic brain
na

injury including sports-related concussion. International Journal of Psychophysiology 2018; Part A.

132: 99-104.
27. Beauchamp M, H., Ditchfield M, Maller J, et al. Hippocampus, amygdala and global brain
changes 10 years after childhood traumatic brain injury. International Journal of Developmental
ur

Neuroscience 2011; 29(2): 137-43.

28. Antshel KM, Malhotra A, Seigers D. Attributions of behavior in the pediatric mild closed head
injury (CHI) population. Psychology, Health and Medicine 2007; 12(1): 48-63.
29. Ewing-Cobbs L, Prasad MR, Swank P, et al. Social communication in young children with
Jo

traumatic brain injury: Relations with corpus callosum morphometry. International Journal of
Developmental Neuroscience 2012; 30(3): 247-54.
30. Max JE, Friedman K, Wilde EA, et al. Psychiatric disorders in children and adolescents 24
months after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci 2015; 27(2): 112-20.
31. Max JE, Pardo D, Hanten G, et al. Psychiatric disorders in children and adolescents six-to-
twelve months after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci 2013; 25(4): 272-82.
32. Max JE, Schachar RJ, Landis J, et al. Psychiatric disorders in children and adolescents in the
first six months after mild traumatic brain injury. The Journal of Neuropsychiatry and Clinical
Neurosciences 2013; 25(3): 187-97.
33. Choi J-I, Kim B-J, Ha S-K, Kim S-H, Lim D-J, Kim S-D. Comparison of subgroups based on
hemorrhagic lesions between SWI and FLAIR in pediatric traumatic brain injury. Child's Nervous
System 2014; 30(6): 1011-9.
34. Babcock L, Byczkowski T, Wade SL, Ho M, Mookerjee S, Bazarian JJ. Predicting
postconcussion syndrome after mild traumatic brain injury in children and adolescents who present
to the emergency department. JAMA Pediatr 2013; 167(2): 156-61.
35. Chu Z, Wilde EA, Hunter JV, et al. Voxel-based analysis of diffusion tensor imaging in mild
traumatic brain injury in adolescents. AJNR Am J Neuroradiol 2010; 31(2): 340-6.
36. Friedman SD, Poliakov AV, Budech C, et al. GABA alterations in pediatric sport concussion.
Neurology 2017; 89(21): 2151-6.
37. Maugans TA, Farley C, Altaye M, Leach J, Cecil KM. Pediatric sports-related concussion
produces cerebral blood flow alterations. Pediatrics 2012; 129(1): 28-37.
38. Wilde EA, Ayoub KW, Bigler ED, et al. Diffusion tensor imaging in moderate-to-severe
pediatric traumatic brain injury: changes within an 18 month post-injury interval. Brain Imaging
Behav 2012; 6(3): 404-16.
39. Urban KJ, Riggs L, Wells GD, et al. Cortical Thickness Changes and Their Relationship to Dual-
Task Performance following Mild Traumatic Brain Injury in Youth. J Neurotrauma 2017; 34(4): 816-
23.
40. Dennis EL, Jin Y, Villalon-Reina JE, et al. White matter disruption in moderate/severe
pediatric traumatic brain injury: advanced tract-based analyses. NeuroImage: Clinical 2015; 12(7):
493-505.

of
41. Huisman TA, Schwamm LH, Schaefer PW, et al. Diffusion tensor imaging as potential
biomarker of white matter injury in diffuse axonal injury. AM J NEURORADIOL 2004; 25(3): 370-6.
42. Manning KY, Schranz A, Bartha R, et al. Multiparametric MRI changes persist beyond

ro
recovery in concussed adolescent hockey players. Neurology 2017; 89(21): 2157-66.
43. Wilde E, McCauley S, Hunter J, et al. Diffusion tensor imaging of acute mild traumatic brain
injury in adolescents. Neurology 2008; 70(12): 948-55.
44. -p
Bartnik-Olson BL, Holshouser B, Wang H, et al. Impaired neurovascular unit function
contributes to persistent symptoms after concussion: A pilot study. Journal of Neurotrauma 2014;
31(17): 1497-506.
re
45. Babcock L, Yuan W, Leach J, Nash T, Wade S. White matter alterations in youth with acute
mild traumatic brain injury. J Pediatr Rehabil Med 2015; 8(4): 285-96.
46. Van Beek L, Ghesquiere P, Lagae L, De Smedt B. Mathematical difficulties and white matter
abnormalities in subacute pediatric mild traumatic brain injury. Journal of Neurotrauma 2015;
lP

32(20): 1567-78.
47. Yallampalli R, Wilde EA, Bigler ED, et al. Acute white matter differences in the fornix
following mild traumatic brain injury using diffusion tensor imaging. J Neuroimaging 2013; 23(2):
224-7.
na

48. Lancaster MA, Olson DV, McCrea MA, Nelson LD, LaRoche AA, Muftuler LT. Acute white
matter changes following sport-related concussion: A serial diffusion tensor and diffusion kurtosis
tensor imaging study. Human Brain Mapping 2016; 37(11): 3821-34.
49. Van Beek L, Vanderauwera J, Ghesquiere P, Lagae L, De Smedt B. Longitudinal changes in
ur

mathematical abilities and white matter following paediatric mild traumatic brain injury. Brain Injury
2015; 29(13-14): 1701-10.
50. King R, Grohs MN, Kirton A, Lebel C, Esser MJ, Barlow KM. Microstructural neuroimaging of
white matter tracts in persistent post-concussion syndrome: A prospective controlled cohort study.
Jo

Neuroimage Clin 2019; 23: 101842.

51. Wu TC, Wilde EA, Bigler ED, et al. Evaluating the relationship between memory functioning
and cingulum bundles in acute mild traumatic brain injury using diffusion tensor imaging. Journal of
Neurotrauma 2010; 27(2): 303-7.
52. Murdaugh DL, King TZ, Sun B, et al. Longitudinal Changes in Resting State Connectivity and
White Matter Integrity in Adolescents With Sports-Related Concussion. Journal of the International
Neuropsychological Society : JINS 2018; 24(8): 781-92.
53. Lancaster MA, Meier TB, Olson DV, McCrea MA, Nelson LD, Muftuler LT. Chronic differences
in white matter integrity following sport-related concussion as measured by diffusion MRI: 6-Month
follow-up. Human Brain Mapping 2018; 39(11): 4276-89.
54. Yuan W, Wade SL, Babcock L. Structural connectivity abnormality in children with acute mild
traumatic brain injury using graph theoretical analysis. Human Brain Mapping 2015; 36(2): 779-92.
55. Konigs M, van Heurn L, Bakx R, et al. The structural connectome of children with traumatic
brain injury. Hum Brain Mapp 2017.
56. Yuan W, Wade SL, Quatman-Yates C, Hugentobler JA, Gubanich PJ, Kurowski BG. Structural
connectivity related to persistent symptoms after mild TBI in adolescents and response to aerobic
training: preliminary investigation. J Head Trauma Rehabil 2017; 32(6): 378-84.
57. Shaikh Z, Torres A, Takeoka M. Neuroimaging in Pediatric Epilepsy. Brain Sciences 2019; 9(8):
190.
58. Mutch WA, Ellis MJ, Ryner LN, et al. Brain magnetic resonance imaging CO2 stress testing in
adolescent postconcussion syndrome. J Neurosurg 2016; 125(3): 648-60.
59. Borich M, Babul AN, Yuan PH, Boyd L, Virji-Babul N. Alterations in resting-state brain
networks in concussed adolescent athletes. J Neurotrauma 2015; 32(4): 265-71.
60. Newsome MR, Li X, Lin X, et al. Functional Connectivity Is Altered in Concussed Adolescent
Athletes Despite Medical Clearance to Return to Play: A Preliminary Report. Front Neurol 2016; 7:
116.
61. Iyer KK, Barlow KM, Brooks B, Ofoghi Z, Zalesky A, Cocchi L. Relating brain connectivity with
persistent symptoms in pediatric concussion. Annals of Clinical and Translational Neurology 2019;
6(5): 954-61.
62. Dona O, Noseworthy MD, DeMatteo C, Connolly JF. Fractal analysis of brain blood

of
oxygenation level dependent (BOLD) signals from children with mild traumatic brain injury (mTBI).
PLoS ONE 2017; 12 (1) (no pagination)(e0169647).
63. Hammeke TA, McCrea M, Coats SM, et al. Acute and subacute changes in neural activation

ro
during the recovery from sport-related concussion. Journal of the International Neuropsychological
Society 2013; 19(8): 863-72.
64. Keightley ML, Singh Saluja R, Chen JK, et al. A functional magnetic resonance imaging study

Neurotrauma 2014; 31(5): 437-51.

65.
-p
of working memory in youth after sports-related concussion: Is it still working? Journal of

Krivitzky LS, Roebuck-Spencer TM, Roth RM, Blackstone K, Johnson CP, Gioia G. Functional
re
magnetic resonance imaging of working memory and response inhibition in children with mild
traumatic brain injury. Journal of the International Neuropsychological Society 2011; 17(6): 1143-52.
66. Saluja RS, Chen J-K, Gagnon IJ, Keightley M, Ptito A. Navigational memory functional
magnetic resonance imaging: A test for concussion in children. Journal of Neurotrauma 2015; 32(10):
lP

712-22.
67. Sinopoli KJ, Chen JK, Wells G, et al. Imaging "brain strain" in youth athletes with mild
traumatic brain injury during dual-task performance. Journal of Neurotrauma 2014; 31(22): 1843-59.
68. Westfall DR, West JD, Bailey JN, et al. Increased brain activation during working memory
na

processing after pediatric mild traumatic brain injury (mTBI). J Pediatr Rehabil Med 2015; 8(4): 297-
308.
69. Holmes SA, Singh-Saluja R, Chen JK, Gagnon I, Ptito A. Evaluating task-based brain network
activity in pediatric subjects with an mTBI: mechanisms of functional compensation are symptom-
ur

level dependent. Brain Inj 2019; 33(3): 383-93.

70. Khetani A, Rohr CS, Sojoudi A, Bray S, Barlow KM. Alteration in Cerebral Activation during a
Working Memory Task after Pediatric Mild Traumatic Brain Injury: A Prospective Controlled Cohort
Study. Journal of Neurotrauma 2019.
Jo

71. Lovell MR, Pardini JE, Welling J, et al. Functional brain abnormalities are related to clinical
recovery and time to return-to-play in athletes. Neurosurgery 2007; 61(2): 352-9.
72. Hearps SJC, Takagi M, Babl FE, et al. Validation of a Score to Determine Time to
Postconcussive Recovery. Pediatrics 2017.
73. McCrory P, Meeuwisse W, Dvořák J, et al. Consensus Statement On Concussion In Sport –
The 5th International Conference On Concussion In Sport Held In Berlin, October 2016. British
Journal of Sports Medicine In Press.
74. Barlow KM, Marcil LD, Dewey D, et al. Cerebral Perfusion Changes in Post-Concussion
Syndrome: A Prospective Controlled Cohort Study. Journal of Neurotrauma 2017; 34(5): 996-1004.
75. Eierud C, Craddock RC, Fletcher S, et al. Neuroimaging after mild traumatic brain injury:
Review and meta-analysis. NeuroImage: Clinical 2014; 4(4): 283-94.
76. Gardner A, Kay-Lambkin F, Stanwell P, et al. A systematic review of diffusion tensor imaging
findings in sports-related concussion. J Neurotrauma 2012; 29(16): 2521-38.
77. Shenton ME, Hamoda HM, Schneiderman JS, et al. A review of magnetic resonance imaging
and diffusion tensor imaging findings in mild traumatic brain injury. Brain Imaging Behav 2012; 6(2):
137-92.
78. Yeates KO, Beauchamp M, Craig W, et al. Advancing concussion assessment in pediatrics (A-
CAP): a prospective, concurrent cohort, longitudinal study of mild traumatic brain injury in children:
study protocol. BMJ Open 2017; 7(7): e017012.
79. Broglio SP, McCrea M, McAllister T, et al. A national study on the effects of concussion in
collegiate athletes and US military service adademy members: The NCAA-DoD concussion
assessment, research and education (CARE) consortium structure and methods. Sports Med 2017;
47(7): 1437-51.

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 Figure 1. PRISMA flow diagram of systematic review

Total number of records identified through database search n = 4563

Duplicate articles n = 1360

Articles excluded following review of titles and abstracts n = 2880

Full articles retrieved for detailed evaluation n = 323

Articles excluded following evaluation n = 265

Exclusion Criteria:

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 Age at injury > 18 yrs (mean ≥ 18 yrs, max > 25 yrs), n = 198
 Moderate-Severe TBI only, or TBI severities combined, n = 22
 No mTBI/concussion diagnosis (e.g., subconcussive injury), n = 17

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 <10 participants in mTBI sample, n = 5
 No clear definition of mTBI/concussion, n = 5
 Conference abstracts, case studies, reviews etc., n = 4
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Retrospective analysis, n = 4
 No neuroimaging, n = 3
 Previously reported data, n = 3
 Non-accidental head trauma included in sample, n = 2
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 Imaging data collected exclusively for diagnostic purposes, n = 1
 mTBI sample exclusively ‘complicated mTBI’, n = 1
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Studies included in this review, n = 58

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Figure 2. Study risk of bias ratings using the Newcastle Ottawa Scale

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Figure 3. Study reporting quality assessed using the COBIDAS best practice guidelines
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