Multiparametric MRI changes persist beyond recovery in

Kathryn Y ManningMSc

Amy Schranz BMScRobert Bartha PhDGregory A Dekaban

PhDChristy Barreira BScArthur Brown PhDLisa Fischer MDKevin Asem MDTimothy J Doherty MD

PhDDouglas D Fraser MD

PhDJeff Holmes PhDRavi S Menon PhD

Correspondence toDr Menonrmenonrobartsca

Supplemental dataat Neurologyorg

Multiparametric MRI changes persistbeyond recovery in concussed adolescenthockey players

ABSTRACT

Objective To determine whether multiparametric MRI data can provide insight into the acute andlong-lasting neuronal sequelae after a concussion in adolescent athletes

Methods Players were recruited from Bantam hockey leagues in which body checking is firstintroduced (male age 11ndash14 years) Clinical measures diffusion metrics resting-state networkand region-to-region functional connectivity patterns and magnetic resonance spectroscopyabsolute metabolite concentrations were analyzed from an independent age-matched controlgroup of hockey players (n 5 26) and longitudinally in concussed athletes within 24 to 72 hours(n 5 17) and 3 months (n 5 14) after a diagnosed concussion

Results There were diffusion abnormalities within multiple white matter tracts functional hyper-connectivity and decreases in choline 3 months after concussion Tract-specific spatial statisticsrevealed a large region along the superior longitudinal fasciculus with the largest decreases in dif-fusivity measures which significantly correlated with clinical deficits This region also spatiallyintersected with probabilistic tracts connecting cortical regions where we found acute functionalconnectivity changes Hyperconnectivity patterns at 3 months after concussion were present on-ly in players with relatively less severe clinical outcomes higher choline concentrations and dif-fusivity indicative of relatively less axonal disruption

Conclusions Changes persisted well after playersrsquo clinical scores had returned to normal and theyhad been cleared to return to play Ongoing white matter maturation may make adolescent ath-letes particularly vulnerable to brain injury and they may require extended recovery periods Theconsequences of early brain injury for ongoing brain development and risk of more serious con-ditions such as second impact syndrome or neural degenerative processes need to be elucidatedNeurologyreg 2017892157ndash2166

GLOSSARYAD 5 axial diffusivity CST 5 corticospinal tract DMN 5 default mode network DTI 5 diffusion tensor imaging FA 5fractional anisotropyMD5mean diffusivityMRS5magnetic resonance spectroscopy RD5 radial diffusivity ROI5 regionof interest RS 5 resting-state RSN 5 resting-state network SLF 5 superior longitudinal fasciculus

Concussion remains a critical health problem and the developing brain may be uniquely sus-ceptible1 In Canada hockey-related concussions account for nearly half of all sports teamndash

related concussions and disproportionately affect adolescents2 The neuronal mechanisms thatunderlie concussion remain poorly understood A complex cascade of structural functional andmetabolic changes are secondary to rotational acceleration of the brain3 MRI studies have re-ported neuronal vulnerabilities that persist after athletes have been cleared to return to play4ndash7

Without full recovery players may have increased susceptibility to injury and may be at risk ofserious conditions such as second impact syndrome8 Therefore it is essential to understand the

From the Department of Medical Biophysics (KYM AS RB RSM) Department of Microbiology and Immunology (GAD CB)Department of Anatomy and Cell Biology (AB) Department of Physical Medicine and Rehabilitation (TJD) and School of OccupationalTherapy (JH) University of Western Ontario Centre for Functional and Metabolic Mapping (KYM RB RSM) and Molecular Medicine(GAD CB AB) Robarts Research Institute Primary Care Sport Medicine (LF KA) Family Medicine Fowler Kennedy Sport Medicineand Paediatrics Critical Care Medicine (DDF) London Health Sciences Centre London Ontario Canada

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the articleThe Article Processing charge was funded by Canadian Institutes of Health Research Foundation Grant 353372 to RS Menon

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially without permission from the journal

Copyright copy 2017 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 2157

immediate effects of concussion on the ado-lescent brain and the nature of any long-lastingneuronal changes detectable with noninvasivemultiparametric imaging

In this study concussed adolescent malehockey players were evaluated longitudinallyafter concussion and compared to independentage-matched nonconcussed players as controlsWhile clinical measures in this population indi-cate recovery and prompt return to play givenprevious imaging findings we hypothesized thatthere would be persistent MRI-detectable neu-ronal changes that reflect long-lasting damageto white matter fibers and compensatory recov-ery mechanisms Given this multiparametricMRI dataset we were able to directly relateresting-state (RS-fMRI) changes with underly-ing structural abnormalities through diffusiontensor imaging (DTI)9 brain metabolic changesthrough magnetic resonance spectroscopy(MRS) and acute clinical deficits

METHODS Players diagnosed with a mild traumatic brain

injury or concussion (age 133 6 06 years) were assessed within

24 to 72 hours of their injury (n 5 17) and again 3 months later

(n 5 14) An independent group of healthy age-matched

nonconcussed male hockey players were assessed and acted as

our controls (n 5 26 age 1306 1 years) Portions of this study

design have been described previously10 Further clinical methods

are described in appendix e-1 at Neurologyorg The numbers of

included participants for each portion of the study are summa-

rized in table e-1 MRI acquisition parameters are outlined in

appendix e-2

Standard protocol approvals registrations and patientconsents Ethics approval was obtained through the University

of Western Ontariorsquos Health Sciences Research Ethics Board

All participants and parentsguardians provided informed written

consent

RS-fMRI analysis RS-fMRI data were analyzed with FSL

(FMRIB Software Library) 506 (Oxford England) with 2 major

aims to investigate RS network (RSN) reorganization and whole-

brain region-to-region connectivity patterns Standard pre-

processing steps included brain extraction a high-pass filter (001

Hz) spatial smoothing with a 5-mm full-width half-maximum

gaussian filter and motion correction using linear image regis-

tration relative to the middle volume Data with excessive motion

(1-mm maximum displacement or 05-mm relative mean

displacement) were excluded from further analyses Preprocessed

images were denoised with single-session independent compo-

nent analysis and automatic dimensionality estimation Compo-

nents that were designated as noise (related voxels outside the

brain within the corticospinal fluid primarily high-frequency

profile or motion artifacts) were regressed from the data Each

dataset was registered to standard space with a 2-stage affine

registration technique that first registered the low-resolution

functional data to the brain-extracted anatomic image and then

to a 2-mm isotropic Montreal Neurologic Institute T1-weighted

reference image using 12 df

Multisession temporal concatenationndashindependent compo-

nent analysis was used to create average RSN maps followed by

dual regression to generate session-specific networks11 In partic-

ular the visual occipital pole default mode (DMN) sensorimo-

tor executive control and cerebellar networks were investigated

The FSL randomize permutation-testing tool was implemented

to assess group differences according to a general linear model

with threshold-free cluster enhancement and multiple-

comparison Bonferroni-corrected p values (p 0001) In addi-

tion a regional connectivity analysis was performed on the

preprocessed data with the CONN toolbox12 because of the

statistical advantages as it complements the network analysis

and expands to look at whole-brain regional connectivity

Participant-specific CSF and white matter masks were used as

regressors Data were parcellated into 136 functionally relevant

regions with the Harvard-Oxford cortical atlas and cerebellar

regions with the Automated Anatomical Labeling atlas Whole-

brain region-to-region connectivity differences were assessed with

false discovery rate correction

Diffusion tensor and tractography analysis Raw diffusion

datasets were corrected for eddy current distortions and relative

head motion with the eddy command line tool The nonndash

diffusion-weighted (b 5 0) volume was used to create a modestly

extracted brain mask A diffusion tensor was fit voxel-wise with

the use of specific inputs of the gradient directions and b values

(b 5 1000 smm2) directly from the scanner Several diffusion

metric spatial maps were created including fractional anisotropy

(FA) and mean (MD) axial (AD) and radial (RD) diffusivity With

the use of the John Hopkins University high-probability white

matter tractography atlas13 these DTI metrics were extracted and

analyzed within the superior longitudinal fasciculus (SLF) cingulum

forceps major and minor of the corpus callosum uncinate

fasciculus corticospinal tract (CST) anterior thalamic radiation

and inferior fronto-occipital and longitudinal fasciculus

Once tracts with significant changes were identified with

a multivariate analysis of variance an iterative randomization tool

within FSL was used to spatially quantify where the greatest

changes occurred along those tracts while regressing for age

DTI metrics within the regions with the greatest changes were ex-

tracted and analyzed These regions are referred to as DTImax and

are described in Results Probabilistic tractography with iterative

Monte Carlo simulations of principal diffusion tensor vectors was

used to quantify a probabilistic streamline between regions of

interest (ROIs) Probabilistic structural connections were inves-

tigated between relevant parceled RS-fMRI regions to spatially

relate structural and functional changes To quantify these results

2 identical spherical ROIs (5-mm radius) were placed before and

after DTImax (that overlapped along the probabilistic tract con-

necting acute RS-fMRI ROIs that we identified figure 1A) The

probability distribution was displayed per participant and quan-

tified the probability of a structural connection between the seed

and waypoint masks (normalized by the total number of tracts

modeled)

MRS analysis Spectra were postprocessed with in-house software

to measure absolute N-acetylaspartate choline creatine glutamate

glutamine and myo-inositol as previously described14ndash16 Briefly

analysis software created in our laboratory in IDL (version 54

Research Systems Inc Boulder CO) was used to correct spectral line

shapes by combined QUALITY deconvolution and eddy current

correction17 Spectra were fitted in the time domain with the use of

a Levenberg-Marquardt minimization routine14 with prior knowl-

edge of metabolic line shapes Prior knowledge was acquired from

in vitro spectra obtained from aqueous solutions of metabolites before

the study14 We report absolute metabolite levels using unsuppressed

2158 Neurology 89 November 21 2017

water from the ROI as an internal standard as previously described in

detail1416 In addition absolute concentrations included a correction

for tissue partial volume and T1 and T2 relaxationndashrelated signal loss

Statistical analysis Statistical analysis was performed with

a multivariate analysis of variance with Tukey post hoc testing

using GraphPad Prism (version 60) A hypothesis-driven 2-

tailed Pearson correlation analysis was explored between data

that had a significant effect for group (p 005 after false dis-

covery rate correction)

RESULTS Clinical results are summarized in appendixe-3 and figure e-1

RS-fMRI resultsWe found significant increases in con-nectivity at 3 months after concussion in several RSNsIn particular there was significantly increased connec-tivity at 3 months after concussion compared to con-trols with the occipital pole visual network andcerebellar network (figure 2 B and C) Compared to24 to 72 hours after concussion there were significantincreases in connectivity by 3 months with the senso-rimotor network (figure 2D) and cerebellar network

There was increased DMN connectivity at 3 monthscompared to controls that did not survive statisticalBonferroni correction (p 001 figure 2A) and nosignificant differences were found within the executivecontrol network or between controls and the 24- to72-hour postconcussion group in any network

There were a few subtle changes in region-to-region connectivity within 24 to 72 hours after con-cussion compared to controls (figure 1B) howeversome were striking with a large effect size (08) andprompted further analysis to directly relate with ourDTI findings (figure 1C) Specifically there were sig-nificant anticorrelations between the anterior supra-marginal gyrus and areas that mimic the DMNincluding the angular gyrus and frontal pole (p

005 including portions of the medial prefrontal cor-tex figure 1C) This was not found in our networkanalysis possibly as a result of statistical power (voxel-level correction) or the dominance of the frontal poleThere was an increase in regional connectivity imme-diately after concussion compared to controls

Figure 1 Acute connectivity changes spatially relate to axonal damage

(A) Frontal pole (FP) and anterior supramarginal gyrus (aSMG) are shown in yellow with the probabilistic tractography con-necting them shown in red DTImax region is overlaid in blue showing the spatial relationship between structural abnormal-ities and resting-state fMRI connectivity (B) Significant whole-brain region-to-region connectivity differences betweencontrols and the 24- to 72-hour postconcussion (PC) group Blue indicates a decrease and red indicates an increase inregion-to-region connectivity (C) Voxel-wise connectivity pattern using the right aSMG (green arrow) as a seed displayingthe enhanced anticorrelation (blue) with the FP and regions that mimic the default mode network AG 5 angular gyruspPaHC 5 posterior parahippocampus ROI 5 region of interest

Neurology 89 November 21 2017 2159

between the cerebellum and parahippocampal gyrusThe significant whole-brain region-to-region connec-tivity changes are shown in figure 3 and similar to theRSN results there were increases in connectivity at 3months compared to both the control and 24- to 72-hour postconcussion groups between regions thatcomplimented our network-level connectivitychanges

Diffusion results There was a significant main effectfor group differences in the CST cingulum andSLF (F 418 p 005 figure 4) Along theCST the greatest diffusion changes were located infe-riorly near the brainstem (p 01) and there weresmall more scattered maximums along the cingulum(p 01) A large region along the right SLF shownin figure 1 had significant MD RD and AD changesat 3 months after concussion (p 001) and a maskwas created over this localized hotspot of compro-mised neuronal integrity DTImax Within DTImaxthe MD and RD values were significantly decreased atboth 24 to 72 hours and 3 months after concussioncompared to controls (F 100 p 001) further-more there were decreases in AD at both time points

(F 5 667 p 5 0060 and p 5 0003 respectively)with increases in FA by 3 months (F 5 391 p 5

0025) Using the anterior supramarginal gyrus asa seed and the frontal pole as a waypoint we con-firmed that probabilistic tracts structurally connectedregions where we found acute RS-fMRI differences(figure 1) The probability of a structural connectiondid not significantly decrease after concussion

Spectroscopy results The spectroscopy voxel wasplaced in the prefrontal region with the followingmean 6 SD tissue content gray matter 19 6

7 white matter 78 6 8 and CSF 3 6

2 The tissue composition of the voxel did notsignificantly change across participants or sessions

No changes in N-acetylaspartate were foundbetween any of the groups Choline was significantlyreduced at 3 months relative to controls (F 5 42p5 002 figure 4) with a 10 decrease in the meanobserved (p5 0035) A reduction in glutamine levelswas observed but was not significantly different fromcontrols (F 5 23 p 5 009) Correlation results aresummarized in detail in table e-2 and examples areshown in figure 5

Figure 2 RSN hyperconnectivity at 3 months after concussion

Each column represents the average resting-state network (RSN) for each of the 3 groups (scaled by z statistic) with areasthat are significantly more highly correlated with that network at 3 months compared to (AndashC) controls or (D) the 24- to 72-hour postconcussion (PC) group (p 0001 except for [A] where p 001) Results are shown for the (A) default modenetwork (B) occipital pole visual RSN (C) cerebellar RSN and (D) sensorimotor RSN


DISCUSSION In this study of adolescent hockeyplayers from Bantam leagues in which body checkingis first introduced we found acute and longitudinalmultiparametric MRI changes after concussion com-pared to controls As expected clinical compositescores elevated immediately after concussion andwithin weeks of injury they returned to control levelsand players were cleared to return to play Howeverwe found persistent RS-fMRI connectivity changesdiffusion-related white matter abnormalities andMRS metabolite decreases in the prefrontal whitematter at 3 months after concussion

The adolescent brain is still not fully developedduring this age range (11ndash14 years) and as it contin-ues to grow and mature it may be more vulnerable tobrain dysfunction and elongated periods of recoveryafter an acceleration-related injury It has been shownthat this heightened vulnerability may be due to bothbiomechanical (neck strength) and neurobiological(incomplete white matter myelination) characteris-tics18 Axonal excitability and electrophysiologic

recordings in a rat fluid percussion brain injury modelhave been used to assess differences in axonal vulner-ability between myelinated and unmyelinated fibersduring injury response and functional recovery19 Inthis animal model myelinated axons recovered within7 days and were relatively protected compared tounmyelinated fibers which were more severelyinjured and took longer to recover It is critical tounderstand how the adolescent human brain reactsand recovers from concussion A recent review ofconcussion-related MRI findings demonstrated theadvantages of relating multiple MRI modalities20

and here we aim to do just that to better understandthe meaning of these changes

We found diffuse changes in DTI metrics along 3major white matter tracts However the tract-specificspatial changes were localized to a single central regionalong the SLF (DTImax) where we found decreased ADMD and RD at both times after concussion In vivoanimal studies have been able to directly relate histologywith MRI diffusion specifically finding a direct

Figure 3 Region-to-region hyperconnectivity at 3 months

Significantly increased connectivity (red lines) is shown using (A) connectome rings with regions labeled around the perim-eter and (B) 3-dimensional brain volumes in which the color of the spheres and the transparency of the connecting lines indi-cate the strength of the effect using a t statistic after false discovery rate correction (corrected p 005) aSMG5 anteriorsupramarginal gyrus Cereb 5 cerebellum CO 5 central opercular cortex dmnMPFC 5 default mode network medialprefrontal cortex HG 5 Heschl gyrus MedFC 5 medial frontal cortex MidFG 5 middle frontal gyrus OFusG 5 occipitalfusiform gyrus OP 5 occipital pole PaCiG 5 paracingulate gyrus pMTG 5 posterior middle temporal gyrus PO 5 parietaloperculum cortex PrePostCG 5 precentralpostcentral gyri sLOC 5 superior lateral occipital cortex SPL 5 superiorparietal lobule toITG 5 temporoccipital inferior temporal gyrus TP 5 temporal pole Ver 5 vermis


relationship between AD and axonal injury throughpostmortem neurofilament immunostaining and confir-mation of the presence of b-amyloid precursor pro-tein21 Diffuse axonal pathology has been observed inall traumatic brain injury severities in which transport isdisrupted and axonal bulb formations occur22 The de-creases in AD observed after concussion may reflect thisaxonal pathology because they relate directly to imme-diate symptoms The AD within DTImax at 24 to 72hours after concussion was significantly correlated withtotal symptom scores and the number of errors during

balance testing indicating that a more severe injury isassociated with more severe axonal damage This re-mained true at 3 months after concussion when thesustained decrease in AD within DTImax was associatedwith a higher symptom severity score

The most common injury mechanism in ourcohort was falling affecting the back of the head In-vestigations of the biomechanical deformations andshearing forces after even minimal acceleration ofthe human head have reported deformation of thehuman brain Rapid deceleration directed to the back

Figure 4 Diffusion and MRS results

(AndashE) Average diffusion metrics within standard atlas-derived white matter tracts and (F) absolute metabolite concentrations with the prefrontal whitematter voxel SDs are shown with error bars Significant multivariate analysis of variancendashcorrected post hoc differences (p 005) DTI5 diffusion tensorimaging MRS 5 magnetic resonance spectroscopy PC 5 postconcussion


of the head results in anterior shortening and poste-rior elongation as well as deformations in the axialplane23 These results correspond to regions wherewe found diffusion changes indicative of structuraldamage to the long tracts running anterior to poste-rior This acceleration injury and the consequentstrain and shearing forces between brain tissues maydamage axons themselves The decrease in AD was

concurrent with decreases in RD and MD and in-creases in FA within the same region This couldreflect different pathologies such as axonal disruptioncytotoxic edema axonal swelling or changes in myelinat the site of injury24 These findings are similar to someprevious DTI studies5925ndash27 but not all2829 Cohorts ofdifferent ages injury severity and acquisition timing allmay play a role in the direction of these changing

Figure 5 Examples of correlation results

Relating data at (A and B) 24 to 72 hours postconcussion (PC) (C and D) 3 months PC and (E and F) between 24 to 72 hours PC (x-axis) and 3 months PC (y-axis) data Further details are provided in table e-2 The 95confidence interval is shown using the dashed curves and all relationships shown here have p

005 after false discovery rate correction AD 5 axial diffusivity CHO 5 choline DTI 5 diffusion tensor imaging ImPACT 5 Immediate Post-ConcussionAssessment and Cognitive Testing MRS 5 magnetic resonance spectroscopy SLF 5 superior longitudinal fasciculus


diffusion metrics Fluid-attenuated inversion recoveryand turbo spin echo sequences were used to confirma mild traumatic brain injury with no cerebral edemaWe observed region-to-region RS-fMRI hyperconnec-tivity at 3 months after concussion compared to bothcontrols and 24 to 72 hours after concussion This wasalso true at the network level Previous studies havevariably found this pattern and hyperconnectivity hasbeen proposed to be involved in recovery and compen-sation for underlying white matter disruption430ndash33

Here we demonstrate the strength of multipara-metric MRI by relating our connectivity findingsdirectly to DTI and clinical data Acute regional con-nectivity changes with the cerebellum correlated withall of the significant measures reflecting acute posturalbalance deficits and directly relate the role of the cer-ebellum in balance performance34 The average ADalong the SLF and within DTImax was correlated withchanges in interregional connectivity in which ingeneral more axonal injury (lower diffusivity) anda more severe injury as quantified by number andseverity of symptoms or more days required to recoverwere associated with lower absolute values of connec-tivity Only those players with a less severe injury asindicated by these acute clinical measures exhibitedregional hyperconnectivity at 3 months after concus-sion similar to previous work focused on the DMNin more severe and older patients with traumaticbrain injury 6 months after their injury35 This pos-sible recovery mechanism may be compensating forthe underlying damaged avenues of structural con-nections by recruiting regions of connectivity andenhancing both correlated and inhibitory communi-cation It is possible that some players have not yetreached or completed the recovery phase and furtherlongitudinal data are needed to understand the timingand potential long-term consequences of thesemechanisms

A 10 reduction in the MRS choline signal wasobserved at 3 months relative to controls The cholinesignal is made up of different components mainlyphosphorylcholine (a precursor to membrane synthe-sis) and glycerophosphorylcholine (a breakdownproduct of the membrane)36 This change is particu-larly interesting because reductions in blood plasmaglycerophospholipids at 24 to 72 hours were reportedin a subset of these hockey players10 Other studieshave also reported reduced choline levels in the motorcortex after a month of high school football in non-concussed players37 This was suggested to be due toa decrease in membrane turnover as a result of repet-itive subconcussive impacts The correlations with theMRS data support similar interpretations The cho-line concentration at both 24 to 72 hours and 3months after concussion was significantly correlatedwith RS-fMRI connectivity in particular a lower

choline concentration was associated with a lowerabsolute interregional connectivity value Given therelationship between choline concentrations and theclinical diffusion and connectivity measures wehypothesize that the decrease in choline is related toreduced membrane turnover rate36

There are limitations in the present study thatwill motivate future MRI investigations of adoles-cent concussion The average changes we reporthere represent a heterogeneous population whoseindividual injury mechanisms severities and recov-ery times vary We followed up with players3 months after their injury however the playershad clinically recovered and were cleared to returnto play at different times It is possible that return-ing to play may affect the brain and any ongoingneuroreparative mechanisms Given the long-lastingchanges we found at 3 months future longitudinal stud-ies should continue to follow this demographic as theydevelop to understand exactly how long the recoveryperiod lasts as a function of age and the consequencesif any later in life including increased vulnerabilityto future concussions and the development ofneurodegenerative diseases such as chronic traumaticencephalopathy3839

The persistent changes we observed in this studyprovide evidence of prolonged axonal disruption ina localized area along the SLF This result was spa-tially related to acute RS-fMRI connectivity changesand choline metabolite decreases and correlated sig-nificantly with clinical deficits Diffuse hyperconnec-tivity patterns were present 3 months afterconcussion well after clearance to return to playand symptomatic recovery This adolescent popula-tion may be particularly vulnerable to injury while ax-ons continue to myelinate and mature and ourresults suggest that they may require longer recoveryperiods

AUTHOR CONTRIBUTIONSAll authors approved the manuscript and provided critical edits KYM

manuscript preparation analysis and interpretation of data statistical

analysis AS analysis and interpretation of data RB study concept

and design GAD overall project design CB study coordinator

AB overall project design LF overall project design patient evaluation

KA patient evaluation TJD interpretation of data DDF overall pro-

ject design JH overall project design clinical acquisition RSM overall

project and image acquisition design interpretation of data

ACKNOWLEDGMENTThe authors acknowledge Sandra Shaw for her efforts in organizing patient

appointments They also thank and commend the players and their pa-

rentsguardians for their willingness to participate in this study and the

coaches and MRI technicians for their excellent support

STUDY FUNDINGFunding was provided by a grant from the Childrenrsquos Health Foundation to

Dr DD Fraser and a grant from the Western University Schulich School

of Medicine and Dentistry (co-principal investigators Dr DD Fraser and

GA Dekaban)


DISCLOSUREK Manning and A Schranz report no disclosures relevant to the manu-

script R Bartha is funded by CIHR Project Grant 152927 Canadian

Consortium on Neurodegeneration in Aging 003658 Natural Sciences

and Engineering Research Council of Canada grant 250313-2013

Ontario Institute for Cancer Research Grant 00807 Smarter Imaging

Program Ontario Brain Institute grant ONDRI2013 and an Alzheimer

Foundation of London and Middlesex Premier Research Grant G Deka-

ban is funded by CIHR project grant PJT 148651 is condashprincipal

investigator on the London Health Sciences Centre Childrenrsquos Health

Foundation grant LHR F7806 R-13-116 CHRI (funded the work pre-

sented in this publication) is condashprincipal investigator or applicant on 3

additional CIHR grants and receives funds from the NSE BioCanRx

C Barreira A Brown L Fischer and K Asem report no disclosures

relevant to the manuscript T Doherty receives research support from

Allergan Canada D Fraser receives funding through the Childrenrsquos

Health Foundation J Holmes is funded by CIHR operating grant

326065 and an Alzheimerrsquos Association International Research Grant R

Menon is funded by CIHR Foundation Grant 353372 Natural Sciences

and Engineering Research Council of Canada grant 261701-2012 and

a Brain Canada Platform Support Grant has sold a patent to Siemens

Healthcare and receives research support from Siemens Healthineers Go

to Neurologyorg for full disclosures

Received April 19 2017 Accepted in final form September 6 2017

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3 Bigler ED Maxwell WL Neuropathology of mild

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patterns of brain activity in young carriers of the APOE-

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12 Whitfield-Gabrieli S Nieto-Castanon A Conn a func-

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13 Mori S Oishi K Faria AV White matter atlases based on

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14 Bartha R Drost DJ Williamson PC Factors affecting the

quantification of short echo in-vivo 1H MR spectra prior

knowledge peak elimination and filtering NMR Biomed

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nance spectroscopy of the motor cortex in cervical

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Duggal N N-acetylaspartate in the motor and sensory

cortices following functional recovery after surgery for cer-

vical spondylotic myelopathy J Neurosurg Spine 201625

436ndash443

17 Bartha R Drost DJ Menon RS Williamson PC Spectro-

scopic lineshape correction by QUECC combined

QUALITY deconvolution and eddy current correction

Magn Reson Med 200044641ndash645

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and concussion imaging as a biomarker for diagnosis

and prognosis Neurosci Biobehav Rev 201236

1510ndash1531

19 Reeves TM Phillips LL Povlishock JT Myelinated and

unmyelinated axons of the corpus callosum differ in vul-

nerability and functional recovery following traumatic

brain injury Exp Neurol 2005196126ndash137

20 Shin SS Bales JW Edward Dixon C Hwang M Struc-

tural imaging of mild traumatic brain injury may not be

enough overview of functional and metabolic imaging of

mild traumatic brain injury Brain Imaging Behav 2017

11591ndash610

21 MacDonald CL Dikranian K Song SK Bayly PV

Holtzman DM Brody DL Detection of traumatic axonal

injury with diffusion tensor imaging in a mouse model of

traumatic brain injury Exp Neurol 2007205116ndash131

22 Johnson VE Stewart W Smith DH Axonal pathology in


23 Bayly PV Cohen TS Leister EP Ajo D Leuthardt EC

Genin GM Deformation of the human brain induced by

mild acceleration J Neurotrauma 200522845ndash856

24 Wright AD Jarrett M Vavasour I et al Myelin water

fraction is transiently reduced after a single mild traumatic

brain injury a prospective cohort study in collegiate

hockey players PLoS One 201611e0150215

25 Chu Z Wilde EA Hunter JV et al Voxel-based anal-

ysis of diffusion tensor imaging in mild traumatic brain

injury in adolescents Am J Neuroradiol 201031

340ndash346

26 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 Hum Brain

Mapp 2016373821ndash3834

27 Wilde EA McCauley SR Hunter JV et al Diffusion

tensor imaging of acute mild traumatic brain injury in

adolescents Neurology 200870948ndash955

28 Koerte IK Kaufmann D Hartl E et al A prospective

study of physician-observed concussion during a varsity

university hockey season white matter integrity in ice

hockey players part 3 of 4 Neurosurg Focus 201233E3


29 Goetz P Blamire A Rajagopalan B Cadoux-Hudson T

Young D Styles P Increase in apparent diffusion coeffi-

cient in normal appearing white matter following human

traumatic brain injury correlates with injury severity

J Neurotrauma 200421645ndash654

30 Czerniak SM Sikoglu EM Liso Navarro AA et al A

resting state functional magnetic resonance imaging study

of concussion in collegiate athletes Brain Imaging Behav

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31 Hillary FG Slocomb J Hills EC et al Changes in resting

connectivity during recovery from severe traumatic brain

injury Int J Psychophysiol 201182115ndash123

32 Iraji A Benson RR Welch RD et al Resting state functional

connectivity in mild traumatic brain injury at the acute stage

independent component and seed based analyses


33 Tang CY Eaves E Dams-OrsquoConnor K et al Diffuse

disconnectivity in tBi a resting state fMri anD Dti study

Transl Neurosci 201239ndash14

34 Morton SM Bastian AJ Cerebellar control of balance and

locomotion Neurosci 200410247ndash259

35 Sharp DJ Beckmann CF Greenwood R et al Default

mode network functional and structural connec-

tivity after traumatic brain injury Brain 2011134

2233ndash2247

36 Maddock RJ Buonocore MH MR spectroscopic studies

of the brain in psychiatric disorders Curr Top Behav

Neurosci 201211199ndash251

37 Poole VN Breedlove EL Shenk TE et al Sub-concus-

sive hit characteristics predict deviant brain metabolism

in football athletes Dev Neuropsychol 20154012ndash17

38 Anderson V Catroppa C Morse S Haritou F Rosenfeld

J Functional plasticity or vulnerability after early brain

injury Pediatrics 20051161374ndash1382

39 Daneshvar DH Riley DO Nowinski CJ McKee AC

Stern RA Cantu RC Long-term consequences effects

on normal development profile after concussion Phys

Med Rehabil Clin N Am 201122683ndash700

Get Connected Stay ConnectedConnect with the American Academy of Neurologyrsquos popular social media channels to stay up-to-date on the latest news and breakthroughs in neurology and network with peers and neurologythought leaders Visit AANcomConnect

This Weekrsquos Neurologyreg PodcastMultiparametric MRI changes persist beyond recovery inconcussed adolescent hockey players (see p 2157)

This podcast begins and closes with Dr Robert Gross Editor-in-Chief briefly discussing highlighted articles from the November21 2017 issue of Neurology In the first segment Dr Ted Burnstalks with Dr Kathryn Manning and Dr Ravi Menon about theirpaper regarding the effects of concussion on adolescent hockeyplayers In the second part of the podcast Dr Burns focuses hisinterview with Dr Christopher Goodman on a recent NeurologyToday article featuring Dr Goodman which discussed the increasein gabapentinoid prescription

Disclosures can be found at Neurologyorg

At Neurologyorg click on ldquoRSSrdquo in the Neurology Podcast box to listen to the most recentpodcast and subscribe to the RSS feed

CMEOpportunity Listen to this weekrsquosNeurology Podcast and earn 05 AMA PRA Category 1 CMECreditstrade by answering the multiple-choice questions in the online Podcast quiz


DOI 101212WNL00000000000046692017892157-2166 Published Online before print October 25 2017Neurology Kathryn Y Manning Amy Schranz Robert Bartha et al

playersMultiparametric MRI changes persist beyond recovery in concussed adolescent hockey

This information is current as of October 25 2017

ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2017 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

httpnneurologyorgcontent89212157fullincluding high resolution figures can be found at

Supplementary Material

669DC2httpnneurologyorgcontentsuppl20171127WNL0000000000004

669DC1httpnneurologyorgcontentsuppl20171025WNL0000000000004Supplementary material can be found at

References httpnneurologyorgcontent89212157fullref-list-1

This article cites 39 articles 7 of which you can access for free at

Citations httpnneurologyorgcontent89212157fullotherarticles

This article has been cited by 3 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionmrsMRS

httpnneurologyorgcgicollectionmriMRI

httpnneurologyorgcgicollectionfmrifMRI

httpnneurologyorgcgicollectiondwiDWI

httpnneurologyorgcgicollectionbrain_traumaBrain traumafollowing collection(s) This article along with others on similar topics appears in the

Errata

content90221039fullpdf or page

nextAn erratum has been published regarding this article Please see

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online



Disputes amp Debates Editorsrsquo ChoiceSteven Galetta MD FAAN Section Editor

Reader response Pilocytic astrocytoma with anaplasia arising fromthe optic chiasm in a very elderly patientAndrea Wasilewski (Rochester)

Neurologyreg 2018901037 doi101212WNL0000000000005596

As alluded to by the authors of this NeuroImage1 few studies have investigated pilocytic astro-cytoma (PA) in adults given the rarity of these tumors One study suggested anaplastic PAs havea more aggressive clinical course when compared to juvenile PAwith a higher incidence of tumorrecurrence (from 30 to 42) and progression2 Specifically PA with anaplastic featuresare more aggressive and associated with decreased survival when compared with typical PA3 Nostandard of care exists for treatment of PA especially in the elderly Anti-angiogenic treatmentsuch as bevacizumab (a humanized monoclonal antibody directed against vascular endothelialgrowth factor) should be considered in patients with recurrent or unresectable PA The highlyvascular nature of these tumors suggests they may be uniquely responsive to bevacizumaband may have a similar response as seen in glioblastoma including decreased permeability ofvasculature and decreased perilesional edema4 Case series demonstrated clinical and radiographicimprovement as well as disease control with the use of bevacizumab5

1 Hayashi S Akao N Nakazato Y Okamoto K Pilocytic astrocytoma with anaplasia arising from the optic chiasm in a very elderly patientNeurology 2017891840

2 Ellis JA Waziri A Balmaceda C et al Rapid recurrence and malignant transformation of pilocytic astrocytoma in adult patientsJ Neurooncol 200995377ndash382

3 Rodriguez F Scheithauer BW Burger PC Jenkins S Giannini C Anaplasia in pilocytic astrocytoma predicts aggressive behavior Am JSurg Pathol 201034147ndash160

4 Gilbert MR Dignam JJ Armstrong TS et al A randomized trial of bevacizumab for newly diagnosed glioblastoma N Engl J Med 2014370699ndash708

5 Green R Woyshner E Quan J Pope W Cloughesy T Treatment of unresectable adult pilocytic astrocytoma with bevacizumab with orwithout temozolomide (P01097) Neurology 201380P01097

Copyright copy 2018 American Academy of Neurology

Editorsrsquo note Pilocytic astrocytoma with anaplasia arising from theoptic chiasm in a very elderly patientIn reference to the NeuroImage ldquoPilocytic astrocytoma with anaplasia arising from theoptic chiasm in a very elderly patientrdquoDr Wasilewski comments that there are few studiesand no standard of care guidelines in the treatment of pilocytic astrocytoma in adultsHowever bevacizumab a monoclonal antibody against vascular endothelial growth factorhas shown to be beneficial in case series Author Hayashi reports on the course of theirpatient in the NeuroImage who received radiation and oral temozolomide He agrees thatbevacizumab may be useful in patients with anaplastic pilocytic astrocytoma and micro-vascular proliferation

Megan Alcauskas MD and Steven Galetta MD


NeurologyorgN Neurology | Volume 90 Number 22 | May 29 2018 1037

Author disclosures are available upon request (journalneurologyorg)

Copyright ordf 2018 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Author response Pilocytic astrocytoma with anaplasia arising fromthe optic chiasm in a very elderly patientShintaro Hayashi (Sawatari Japan)


I thank Dr Wasilewski for the valuable comments on our NeuroImage1 Our patient receivedirradiation (576 Gy32 fractions) and oral temozolomide (100 mg for 5 dmo for 14 months)however the tumor gradually extended to the hypothalamus and he was transferred to anotherhospital for terminal care We agree with Dr Wasilewskirsquos comment that alternative regimens foradult patients with anaplastic pilocytic astrocytoma (APA) especially showing recurrent or ag-gressive nature are to be explored and established and antiangiogenic treatment is one of thepowerful tools In our view alternative treatments such as bevacizumab might be justified onlywhen patients with APA showmicrovascular proliferations as observed in our patient1 We are notfully confident whether tests for BRAF V600E mutant proteins are mandatory because the genemutations are found in 6ndash8 of extracerebellar pilocytic astrocytomas2 as well as in otherdisorders (eg pleomorphic xanthoastrocytoma or ganglioglioma)3


2 Tanboon J Williams EA Louis DN The diagnostic use of immunohistochemical surrogates for signature molecular genetic alterationsin gliomas J Neuropathol Exp Neurol 2016754ndash18

3 Shindler G Capper D Meyer J et al Analysis of BRAF V600E mutation in 1320 nervous system tumors reveals high mutationfrequencies in pleomorphic xanthoastrocytoma ganglioglioma and extra-cerebellar pilocytic astrocytoma Acta Neuropathol 2011121397ndash405


Reader response ELAPSS score for prediction of risk of growth ofunruptured intracranial aneurysmsJoshua Z Willey (New York)

Neurologyreg 2018901038ndash1039 doi101212WNL0000000000005595

In the article by Backes et al1 the primary outcome was defined as greater than 1 mm growthas measured at local sites The use of this cutoff was not referenced and a 1 mm change couldbe subject to potential measurement error Furthermore if different imaging modalities in onepatient (magnetic resonance angiography vs CT angiography) were used to measure growth

Editorsrsquo note ELAPSS score for prediction of risk of growth ofunruptured intracranial aneurysmsIn ldquoELAPSS score for prediction of risk of growth of unruptured intracranial aneurysmsrdquothe authors established a 6-predictor risk score for aneurysm growth In their study theydefined significant aneurysm growth as greater than 1 mm Dr Willey discusses thepossibility of measurement error and bias as a result of this methodology He alsoquestions whether the readers were blinded how aneurysm ruptures were treatedstatistically and how ELAPSS compares to other existing classification systems Theauthors did not respond



1038 Neurology | Volume 90 Number 22 | May 29 2018 NeurologyorgN



their results could also lead to measurement error An additional source of error and bias is if thephysician carrying out the measurement was aware of the prior size In that instance the inter-preting physician may judge an aneurysm that is larger to be more likely to grow thereby biasingmeasurement The potential sources of measurement error and bias may affect the results itwould be helpful to know if there was a blinded central reading center

In the analysis it was also unclear how aneurysm rupture was treated statistically It appears thata stable aneurysm in 2 scans before rupture was treated as not having grown Would this patientbe treated as censored in survival analysis and not contribute information on aneurysm growthAneurysm rupture is a clinical outcome indicating a change in the aneurysm more serious thana 1 mm growth and with similar risk factors The estimates which had a large standard errorwere heavily weighted toward size and location which are well-known risk factors To interpretthe clinical and additive utility of ELAPSS a statistical comparison to a traditional score withreceiver operating characteristics or net reclassification would help In other words howmuch better was patient risk stratified with ELAPSS compared to a simple classification (egposterior circulation and size greater than 7 mm)

1 Backes D Rinkel GJE Greving JP et al ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms Neurology2017881600ndash1606


CORRECTION

Multiparametric MRI changes persist beyond recovery in concussedadolescent hockey playersNeurologyreg 2017901039 doi101212WNL0000000000004909

In the data supplement for article ldquoMultiparametric MRI changes persist beyond recovery inconcussed adolescent hockey playersrdquo by KY Manning et al1 there is an error in the ldquoMRIAcquisitionrdquo section on page 4 The first sentence should read ldquoAll MRI data were acquiredusing a 32-channel human head coilrdquo rather than ldquo64-channel coilrdquo as originally published Theauthors regret the error

Reference1 Manning KY Schranz A Bartha R et al Multiparametric MRI changes persist beyond recovery in concussed adolescent hockey players

Neurology 2017892157ndash2166




immediate effects of concussion on the ado-lescent brain and the nature of any long-lastingneuronal changes detectable with noninvasivemultiparametric imaging

In this study concussed adolescent malehockey players were evaluated longitudinallyafter concussion and compared to independentage-matched nonconcussed players as controlsWhile clinical measures in this population indi-cate recovery and prompt return to play givenprevious imaging findings we hypothesized thatthere would be persistent MRI-detectable neu-ronal changes that reflect long-lasting damageto white matter fibers and compensatory recov-ery mechanisms Given this multiparametricMRI dataset we were able to directly relateresting-state (RS-fMRI) changes with underly-ing structural abnormalities through diffusiontensor imaging (DTI)9 brain metabolic changesthrough magnetic resonance spectroscopy(MRS) and acute clinical deficits

METHODS Players diagnosed with a mild traumatic brain

injury or concussion (age 133 6 06 years) were assessed within

24 to 72 hours of their injury (n 5 17) and again 3 months later

(n 5 14) An independent group of healthy age-matched

nonconcussed male hockey players were assessed and acted as

our controls (n 5 26 age 1306 1 years) Portions of this study

design have been described previously10 Further clinical methods

are described in appendix e-1 at Neurologyorg The numbers of

included participants for each portion of the study are summa-

rized in table e-1 MRI acquisition parameters are outlined in

appendix e-2

Standard protocol approvals registrations and patientconsents Ethics approval was obtained through the University

of Western Ontariorsquos Health Sciences Research Ethics Board

All participants and parentsguardians provided informed written

consent

RS-fMRI analysis RS-fMRI data were analyzed with FSL

(FMRIB Software Library) 506 (Oxford England) with 2 major

aims to investigate RS network (RSN) reorganization and whole-

brain region-to-region connectivity patterns Standard pre-

processing steps included brain extraction a high-pass filter (001

Hz) spatial smoothing with a 5-mm full-width half-maximum

gaussian filter and motion correction using linear image regis-

tration relative to the middle volume Data with excessive motion

(1-mm maximum displacement or 05-mm relative mean

displacement) were excluded from further analyses Preprocessed

images were denoised with single-session independent compo-

nent analysis and automatic dimensionality estimation Compo-

nents that were designated as noise (related voxels outside the

brain within the corticospinal fluid primarily high-frequency

profile or motion artifacts) were regressed from the data Each

dataset was registered to standard space with a 2-stage affine

registration technique that first registered the low-resolution

functional data to the brain-extracted anatomic image and then

to a 2-mm isotropic Montreal Neurologic Institute T1-weighted

reference image using 12 df

Multisession temporal concatenationndashindependent compo-

nent analysis was used to create average RSN maps followed by

dual regression to generate session-specific networks11 In partic-

ular the visual occipital pole default mode (DMN) sensorimo-

tor executive control and cerebellar networks were investigated

The FSL randomize permutation-testing tool was implemented

to assess group differences according to a general linear model

with threshold-free cluster enhancement and multiple-

comparison Bonferroni-corrected p values (p 0001) In addi-

tion a regional connectivity analysis was performed on the

preprocessed data with the CONN toolbox12 because of the

statistical advantages as it complements the network analysis

and expands to look at whole-brain regional connectivity

Participant-specific CSF and white matter masks were used as

regressors Data were parcellated into 136 functionally relevant

regions with the Harvard-Oxford cortical atlas and cerebellar

regions with the Automated Anatomical Labeling atlas Whole-

brain region-to-region connectivity differences were assessed with

false discovery rate correction

Diffusion tensor and tractography analysis Raw diffusion

datasets were corrected for eddy current distortions and relative

head motion with the eddy command line tool The nonndash

diffusion-weighted (b 5 0) volume was used to create a modestly

extracted brain mask A diffusion tensor was fit voxel-wise with

the use of specific inputs of the gradient directions and b values

(b 5 1000 smm2) directly from the scanner Several diffusion

metric spatial maps were created including fractional anisotropy

(FA) and mean (MD) axial (AD) and radial (RD) diffusivity With

the use of the John Hopkins University high-probability white

matter tractography atlas13 these DTI metrics were extracted and

analyzed within the superior longitudinal fasciculus (SLF) cingulum

forceps major and minor of the corpus callosum uncinate

fasciculus corticospinal tract (CST) anterior thalamic radiation

and inferior fronto-occipital and longitudinal fasciculus

Once tracts with significant changes were identified with

a multivariate analysis of variance an iterative randomization tool

within FSL was used to spatially quantify where the greatest

changes occurred along those tracts while regressing for age

DTI metrics within the regions with the greatest changes were ex-

tracted and analyzed These regions are referred to as DTImax and

are described in Results Probabilistic tractography with iterative

Monte Carlo simulations of principal diffusion tensor vectors was

used to quantify a probabilistic streamline between regions of

interest (ROIs) Probabilistic structural connections were inves-

tigated between relevant parceled RS-fMRI regions to spatially

relate structural and functional changes To quantify these results

2 identical spherical ROIs (5-mm radius) were placed before and

after DTImax (that overlapped along the probabilistic tract con-

necting acute RS-fMRI ROIs that we identified figure 1A) The

probability distribution was displayed per participant and quan-

tified the probability of a structural connection between the seed

and waypoint masks (normalized by the total number of tracts

modeled)

MRS analysis Spectra were postprocessed with in-house software

to measure absolute N-acetylaspartate choline creatine glutamate

glutamine and myo-inositol as previously described14ndash16 Briefly

analysis software created in our laboratory in IDL (version 54

Research Systems Inc Boulder CO) was used to correct spectral line

shapes by combined QUALITY deconvolution and eddy current

correction17 Spectra were fitted in the time domain with the use of

a Levenberg-Marquardt minimization routine14 with prior knowl-

edge of metabolic line shapes Prior knowledge was acquired from

in vitro spectra obtained from aqueous solutions of metabolites before

the study14 We report absolute metabolite levels using unsuppressed







































































GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















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20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION













































































GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION




























































GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION

















































GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION









































GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION



































GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION





























GA Dekaban)
































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION






































e58868




















1371











7214






362ndash369




199912205ndash216








436ndash443








1510ndash1531









11591ndash610

















340ndash346





Mapp 2016373821ndash3834

















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION
















20149323ndash332
















2233ndash2247









































Errata





Reprints








































CORRECTION




























Errata





Reprints








































CORRECTION























Errata





Reprints








































CORRECTION












































CORRECTION




























CORRECTION












CORRECTION








Documents

Multiparametric MRI changes persist beyond recovery in