Do mirror movements relate to hand function and timing of ...in a prospective cohort of children with unilateral cerebral palsy, and to explore the relationship with hand function

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

Do mirror movements relate to hand function and timing of thebrain lesion in children with unilateral cerebral palsy?

KATRIJN KLINGELS1,2,* | ELLEN JASPERS3,* | MARTIN STAUDT4,5 | ANDREA GUZZETTA6 | LISA MAILLEUX1 |ELS ORTIBUS7 | HILDE FEYS1

1 Department of Rehabilitation Sciences, KU Leuven – University of Leuven, Leuven; 2 Rehabilitation Research Center (REVAL), Biomed, Faculty of Medicine and LifeSciences, Hasselt University, Diepenbeek, Belgium. 3 Neural Control of Movement Lab, Department of Health Sciences and Technology, ETH Zurich, Zurich,Switzerland. 4 Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, T€ubingen; 5 Epilepsy Center for Children andAdolescents, Clinic for Neuropediatrics and Neurorehabilitation, Schoen Klinik Vogtareuth, Vogtareuth, Germany. 6 Department of Developmental Neuroscience, IRCCSStella Maris, Pisa, Italy. 7 Department of Development and Regeneration, KU Leuven – University of Leuven, Leuven, Belgium.

Correspondence to Katrijn Klingels at Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected]

*These authors contributed equally.

PUBLICATION DATA

Accepted for publication 6th October 2015.

Published online

ABBREVIATIONS

CST Corticospinal tract

MACS Manual Ability Classification

System

MMS Mirror movement scores

AIM This study aimed to systematically map the severity of mirror movements in both hands

in a prospective cohort of children with unilateral cerebral palsy, and to explore the

relationship with hand function and brain lesion type.

METHOD Seventy-eight children were included (41 males, 37 females; age 9y 4mo, SD 3y

1mo, range 5–15y). Mirror movements were scored during three repetitive tasks following

Woods and Teuber criteria. Strength, tone, Melbourne Assessment, Jebsen–Taylor test, andAssisting Hand Assessment were evaluated. Lesions were classified into malformations (n=5),periventricular (n=43), cortico–subcortical (n=22), and postnatally acquired lesions (n=8).RESULTS Significantly more mirror movements were observed in the non-paretic versus the

paretic hand (p≤0.003). Higher mirror movement scores in the non-paretic hand significantly

correlated with lower distal strength and lower scores on unimanual and bimanual

assessments (r=0.29–0.41). In the paretic hand, significant differences were found between

lesion types (p=0.03).INTERPRETATION The occurrence of mirror movements in the non-paretic hand seems

related to hand function while mirror movements in the paretic hand seem more related to

the lesion timing, whereby children with earlier lesions present with more mirror

movements.

Children with unilateral cerebral palsy (CP) often experi-ence difficulties in bimanual coordination which affectsdaily life activities. Apart from spasticity, muscle weakness,and sensory deficits the occurrence of mirror movementshas also been suggested as a possible contributing factorthat interferes with bimanual performance.1

Mirror movements are described as ‘involuntary move-ments of one body part that mirror the voluntary move-ment of the contralateral homologous body part’.2,3 Theyare mainly observed in the upper limbs, are symmetrical bynature, and their intensity increases with increasing taskcomplexity or fatigue.4,5 Physiological mirror movementsare present in newborn infants, show a steep decreasebetween 5 years and 8 years of age, and disappear after10 years of age.4,6 These mirror movements are most likelyto be caused by incomplete maturation of the corpus callo-sum and concurrent less effective interhemispheric inhibi-tion. Unilateral tasks thereby invoke activation of bilateralmotor cortices.6–8 Further maturation of the transcallosalpathways with age ensures increasing inhibition of the

motor cortex ipsilateral to the task hand, thus reducing theoccurrence of mirror movements.7

Mirror movements have frequently been described in uni-lateral CP,3,8,9 mostly in the non-paretic hand, albeit withlarge variability.1,3,8–10 The pathogenesis for their occurrenceis not yet fully understood. One potential hypothesis couldbe the activation of bilateral primary motor cortices due todeficient interhemispheric inhibition caused by the underly-ing brain lesion.2,6 Conversely, the persistence of ipsilateralcorticospinal projections between the non-lesioned motorcortex and the paretic hand has also been proposed as apossible mechanism for mirror movements.9–12 Thisreorganization of the corticospinal tract (CST) is unique inchildren with unilateral CP, and depends on both the timingand extent of the lesion.9,13 The importance of lesion timingis further supported by the fact that children with congenitalunilateral CP show more mirror movements compared tothose suffering from childhood stroke.3,13 However, theexact link between lesion type and mirror movements hasyet to be investigated in a larger sample.

© 2015 Mac Keith Press DOI: 10.1111/dmcn.12977 1

Moreover, little is known about the relationship betweenmirror movements and upper limb function. Mirror move-ments have generally been associated with more severeimpairments,10,13 though only one study investigated thisin more detail.1 These authors found no relationshipbetween the occurrence of mirror movements in eitherhand and spasticity, muscle weakness, or impaired dexter-ity. They did report an important relationship with biman-ual skills.1 However, this study was based on a smallsample and lacked standardized testing. Further studyusing reliable and valid upper limb assessments is requiredto better understand the impact of mirror movements onupper limb function.

The first aim of this study was to systematically map theoccurrence and severity of mirror movements in the pareticand non-paretic side during repetitive hand movements ina large sample of children with unilateral CP. Secondly, weaimed to define the relationship between mirror move-ments and upper limb function and the role of brain lesiontype regarding the occurrence of mirror movements.

METHODParticipantsChildren with unilateral CP aged 5 to 15 years and withavailable brain MRIs were recruited consecutively from theUniversity Hospital Pellenberg, Belgium, between 2008and 2013. Children who received upper limb botulinumtoxin A injections within 6 months of testing or who hadprevious upper limb surgery were excluded, as were chil-dren not mentally capable of cooperating with the assess-ments. The Ethical Committee of the University HospitalLeuven approved the protocol and all parents providedwritten informed consent.

Clinical assessmentsTwo trained physiotherapists, blind to the MRI findings,evaluated all children. Functional hand use was classifiedusing the Manual Ability Classification System (MACS).14

Mirror movementsMirror movements were videotaped during three uniman-ual tasks: (1) fist opening and clenching, (2) finger opposi-tion (thumb sequentially touches other four digits), and (3)finger tapping (fingers are sequentially lifted from the tablesurface).1 Children were seated at a height-adjustable tablewith elbows and forearms supported. Each task was exe-cuted five times, first with the non-paretic side. To opti-mize visibility of the hand movements, the video camerawas placed orthogonally to the table surface. The occur-rence of mirror movements in the opposite hand wasscored for each task following the Woods and Teuber cri-teria (total score 0–12): 0, no clear imitative movement; 1,barely discernable repetitive movements; 2, slight mirrormovements or stronger, but briefer repetitive movements;3, strong and sustained repetitive movements; 4, move-ments equal to those expected for the intended hand.5

Videos were scored by a third physiotherapist who was

blind to the child’s clinical examination and MRI findings.Interrater and intrarater reliability of the scoring of themirror movements was assessed using the ICC (2,1), withintraclass correlation coefficients >0.82 (Table SI, onlinesupporting information).

Body function levelAt the body function level, motor impairments wereassessed using a standardized and reliable protocol.15 Mus-cle tone was scored with the Modified Ashworth Scale atthe forearm (pronators; range 0–4) and wrist (wrist/fingerflexors; range 0–8). Muscle strength was evaluated accord-ing to the Medical Research Council rating at the forearm(supinators/pronators; range 0–10) and wrist (flexors/exten-sors; range 0–10). Grip strength was assessed with theJamar dynamometer (Lafayette Instrument Company,Lafayette, IN) as the mean of three maximum contractions.The ratio of the paretic versus the non-paretic hand wasused for further analysis.

Activity levelAt the activity level, the Melbourne Assessment of Unilat-eral Upper Limb Function16 and the Jebsen–Taylor test17

were used to evaluate unimanual capacity. The MelbourneAssessment measures quality of movement during 16 uni-manual tasks (total raw score between 0 and 122, convertedto percentages). The Jebsen–Taylor test provides a mea-sure of manual dexterity by recording the movement time(seconds) required to perform six unimanual tasks with atotal maximum of 720 s. Bimanual performance wasassessed with the Assisting Hand Assessment (AHA).18 TheAHA evaluates the spontaneous use of the paretic handduring bimanual play. Raw scores were converted to logit-based 0 to 100 AHA-units. High levels of reliability andvalidity were established for all activity assessments.16,18,19

Classification of brain lesionsMRI data were acquired using a 1.5T or 3T Philips Inge-nia scanner (Philips Healthcare, Best, the Netherlands); T1(magnetization-prepared rapid gradient-echo), T2, and/orfluid-attenuated inversion recovery images were used forlesion classification. Congenital unilateral CP was definedas a unilateral motor disability due to a pre/perinatal orpostnatal event occurring before the 28th postnatal day.These children’s MRIs were classified as malformation,periventricular white matter lesion, or cortical–subcorticallesion.20 Lesions due to a postnatal event occurring afterthe 28th postnatal day and before 3 years of age were clas-sified as acquired lesions.21 A neuropediatrician blind tothe clinical assessments inspected all of the images.

What this paper adds• More mirror movements are observed in the non-paretic versus the paretic

hand.• Poor hand function correlates with more mirror movements in the non-pare-

tic hand.• Mirror movements in the paretic hand are related to the brain lesion type.

2 Developmental Medicine & Child Neurology 2015

Statistical analysisDescriptive statistics were used to document the children’scharacteristics and the severity of mirror movements. Mir-ror movement scores (MMS) were compared between bothsides with a Wilcoxon signed-rank test. Depending on thetype of data, biserial (rb), or Spearman’s rank correlationcoefficient (q) correlations were calculated between MMSand general characteristics (age, paretic side), motorimpairments, and upper limb activities. In addition, thecorrelation between MMS and the discrepancy of bimanualversus unimanual function was assessed. This discrepancywas calculated as the ratio of AHA (range 0–100) versusMelbourne-scores (range 0–100). Ratios of <1.0 indicatelower AHA compared to Melbourne scores. Correlationcoefficients >0.75 were considered good to excellent, 0.50to 0.75 moderate to good, 0.25 to 0.50 fair, and <0.25 littleor no association.22 A multiple regression analysis for theJebsen–Taylor test and the AHA was used to verify if thereported evidence for the univariate relations was main-tained when combining the variables ‘mirror movementscores in test 1’ (fist opening and clenching) in each handand ‘type of lesion’. p values and squared semi-partial cor-relations (semi R2) for the three predictors were reported.Differences in mirror movements between children withdifferent MACS levels or lesion types were analyzed withthe Kruskall–Wallis tests and post hoc Wilcoxon rank-sumtest. The level of significance was set at p<0.05. Statisticalanalyses were conducted with SAS Enterprise Guide 4.3(SAS Institute, Inc., Cary, NC, USA).

RESULTSParticipantsSeventy-eight children (41 males, 37 females; 41 right-sideparetic; mean age 9y 4mo, SD 3y 1mo) participated in the

study. Twenty-one children were classified in MACS levelI, 46 in level II, and 11 in level III. Descriptive data ofupper limb assessments is provided in Table SII (onlinesupporting information).

Mirror movementsThe distribution of MMS at each side is provided inTable SIII (online supporting information) and Figure 1.

For all three tests, significantly more severe mirrormovements were observed in the non-paretic sidecompared to the paretic side (p≤0.003). Over 60% of thechildren had clear mirror movements (scores ≥2) in thenon-paretic side for each test. Of these children, 10% evenshowed repetitive movements of their non-paretic handequal to those expected of the moving paretic hand duringfist opening/clenching (score 4). Test 1 (fist opening/clenching) also resulted in clear mirror movements in theparetic side (score 2, 3) in half of the children. For theother two tests, clear mirror movements in the paretic sidewere observed in 27% (finger opposition) and 38% (fingertapping) of the children. Significant correlations werefound between MMS in the paretic and non-paretic side(test 1 q=0.51, test 2 q=0.66, test 3 q=0.60).

Correlation analyses further showed a significant butonly fair correlation between mirror movements in theparetic side and age for test 1 (rb=!0.26), with youngerchildren showing more mirror movements. No significantcorrelations were found between age and mirror move-ments in the non-paretic side.

Mirror movements and hand functionFor mirror movements in the non-paretic side, lower val-ues of grip, forearm, and wrist strength in the paretic handwere fairly associated with higher MMS for test 1 (range

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Figure 1: Distribution of the mirror movement scores at the paretic and non-paretic hand for the three tests. Test1, fist opening and clenching; Test2,finger opposition; Test3, finger tapping.

Mirror Movements in Unilateral CP Katrijn Klingels et al. 3

q=!0.38 to !0.32). Similar, though lower, associationswere found for test 3. Muscle tone was not significantlycorrelated with MMS for any test.

Fair correlations were found between all activity mea-sures and mirror movements, whereby children withpoorer unimanual capacity and bimanual performance pre-sented with higher MMS in the non-paretic side. Highestcorrelations were found for test 1 (Melbourne Assessment,q=!0.36; Jebsen–Taylor test, q=0.41; AHA, rb=!0.42).

Mirror movements in the paretic side were not corre-lated with any clinical assessment (Table I).

Figure 2 shows the comparison of MMS between thedifferent MACS levels for test 1. Significantly higher MMSwere seen in the non-paretic side in children in MACSlevels II and III compared to MACS I (p=0.02; Fig. 2b).Post hoc comparison showed significant differences inMMS between children in MACS I and II (p=0.01) and atrend between MACS I and III (p=0.05). No significantdifferences in mirror movements in the paretic side werefound between the different MACS levels (p>0.3; Fig. 2a).

Lastly, the correlation between MMS and the ratio ofbimanual performance versus unimanual capacity wasinvestigated (Table I). Fair correlations between MMS andthis ratio were found for test 2 in the paretic hand andtests 2 and 3 in the non-paretic hand (range rb=!0.31 to0.34). This indicated that children with more mirror move-ments during finger opposition and finger tapping had a

lower performance in bimanual activities compared to theirunimanual capacity.

Mirror movements and brain lesionsFive children had a malformation (6%), 43 childrenshowed periventricular lesions (55%), and 22 had cortico–subcortical lesions (28%). Eight children were diagnosedwith a postnatally acquired lesion (11%).

Mirror movements in the non-paretic side were not sig-nificantly different between the classification groups(Table II).

A comparison of MMS in the paretic side showed signif-icant differences between the four groups for fist opening/clenching (p=0.03; Table II). Visual inspection of theMMS showed more mirror movements in children withmalformations and periventricular lesions compared to cor-tico–subcortical and postnatally acquired lesions (Fig. 2;bottom row). Post hoc comparison confirmed significantlyhigher MMS in children with periventricular lesions versuspostnatally acquired lesions (p=0.01).

Figure 3a and 3b show the individual Jebsen–Taylorscores and individual AHA scores respectively of childrenwith bilateral mirror movements (MMS of ≥2 for fist open-ing/clenching), mirror movements only in the paretic hand,mirror movements only in the non-paretic hand, and chil-dren without mirror movements for each of the brainlesion types. Overall, children without mirror movementsperformed better than children with mirror movementsand the best performance was seen in children withperiventricular lesions without mirror movements. Remark-ably, mirror movements only in the paretic hand occurredexclusively in children with periventricular lesions. Chil-dren with mirror movements in both hands showed a largevariability in unimanual capacity and bimanual perfor-mance ranging from poor assisted hand use and lackingany ability to grasp and release objects to fairly good uni-and bimanual function.

Multiple regression analysis for the AHA showed thehighest squared semi-partial correlation for type of lesion(semi R2=0.21, p<0.001), followed by mirror movements inthe non-paretic hand (semi R2=0.10, p=0.008). For the Jeb-sen–Taylor test, squared semi-partial correlation for typeof lesion was 0.23 (p<0.001) and for mirror movements inthe non-paretic hand was 0.08 (p=0.003). Mirror move-ments in the paretic hand showed a non-significant squaredsemi-partial correlation for the AHA (semi R2=0.07,p=0.56) and for the Jebsen–Taylor test (semi R2=0.04,p=0.99).

DISCUSSIONModerate to strong mirror movements were present inover 60% of the children. In general, one-third showedmirror movements in both hands, another third showedmirror movements only in one hand (mostly the non-pare-tic), and no mirror movements were seen in the remainingthird of the children. This high occurrence of mirrormovements compared to the normative data reported by

Table I: Correlations between mirror movements, motor impairments, uni-manual capacity, and bimanual performance

Tonea Strengtha

Grip ratiobForearm Wrist Forearm Wrist

Paretic handFist opening/clenching

0.14 !0.02 !0.10 !0.04 !0.08

Finger opposition 0.22 !0.06 !0.05 0.00 !0.01Finger tapping 0.15 !0.12 0.01 0.06 !0.01

Non-paretic handFist opening/clenching

0.15 0.19 !0.32c !0.35c !0.38c

Finger opposition 0.06 0.06 !0.12 !0.11 !0.18Finger tapping 0.14 0.09 !0.22 !0.23 !0.30c

Jebsen–Taylor testa Melba AHAb

RatioAHA/Melbb

Paretic handFist opening/clenching 0.11 !0.02 !0.11 !0.18Finger opposition 0.01 0.05 !0.10 !0.31c

Finger tapping 0.00 0.07 !0.03 !0.21Non-paretic handFist opening/clenching 0.41c !0.36c !0.41c !0.17Finger opposition 0.09 !0.08 !0.23 !0.33c

Finger tapping 0.18 !0.17 !0.30c !0.34c

aSpearman’s rank correlation coefficient. bBiserial correlation coeffi-cients. cCorrelation coefficients of 0.25–0.50 indicate a fair relation-ship. Melb, Melbourne Assessment for Unilateral Upper LimbFunction; AHA, Assisting Hand Assessment Ratio; AHA/Melb, dis-crepancy between bimanual performance and unimanual capacityscores.


Koerte et al.4 supports the idea that the mirror movementsseen in our group of children with unilateral CP can beconsidered as abnormal. In line with the literature, wefound no or fair associations between age and the occur-rence of pathological mirror movements.1,9 In contrast,physiological mirror movements are known to decreaseafter 5 years of age and to disappear after 10 years of age.4

It has been suggested that the suppression of mirror move-ments with increasing age is related to increasing inter-hemispheric inhibition through further myelination of thecallosal fibres. However, the mechanism underlying physi-ological mirror movements seems to differ from the mech-anisms responsible for mirror movements in CP.6

In children with unilateral CP, studies thus far gener-ally point towards significantly more mirror movements

in the non-paretic compared to the paretic hand,1 as con-firmed in our study. Although underlying spasticity andmuscle weakness might mask the occurrence of mirrormovements in the paretic side, the lack of significant cor-relations between these impairments and mirror move-ments in the paretic hand does not support thishypothesis. Kuhtz-Buschbeck et al.1 also noted that asym-metric mirror activity in wrist electromyography couldnot only be explained by a difference in maximumstrength. These authors suggested that the higher level ofdexterous ability of the non-paretic hand creates a morerefined and lateralized pattern of cortical brain activity.Such lateralization would lead to increased interhemi-spheric inhibition from the non-lesioned towards thelesioned hemisphere, and hence less mirror movements in

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MACS I MACS II MACS III

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MALF PVL CSC ACQBrain lesion types

MACS levels MACS levels

Figure 2: Median and interquartile ranges of mirror movement scores (MMS) for Test 1 (fist opening and clenching) for the different Manual AbilityClassification System (MACS) levels (top row) at (a) the paretic hand and (b) non-paretic hand and for the different brain lesions (bottom row). MALF,malformations; PVL, periventricular lesions; CSC, cortico–subcortical lesions; ACQ, postnatally acquired lesions.


the paretic hand when moving the non-paretic hand. Athird hypothesis would be that mirror movements in thenon-paretic hand occur partly to assist paretic handmovements. Symmetrical movements are known to beeasier,23 which might help to overcome the lack of selec-tivity and strength of the paretic hand. Mirror movementsin the non-paretic side could thus be considered a non-specific motor ‘overflow’ phenomenon in children withsignificant motor impairments.13 This idea is further sup-ported by the significant correlations between distalstrength deficits, reduced unimanual capacity, and theoccurrence of mirror movements in the non-paretic handduring paretic hand movements. Also, strong mirrormovements in the non-paretic hand were more frequentlyseen in children in MACS levels II and III, i.e. the moreseverely paretic children, which is in line with theliterature.10,13,24

Table II: Mirror movements (median and 25th–75th centiles) for the dif-ferent brain lesion types and the concurrent statistical analyses

Malfn=5

PVLn=43

CSCn=22

Acqn=8 pa

Paretic handFist opening/clenching

2 (1–3) 2 (1–3) 1 (0–2) 0 (0–1) 0.03

Fingeropposition

1.5 (0.5–2) 1 (0–2) 1 (0–1) 0 (0–1) 0.35

Finger tapping 1.5 (0.5–2.5) 1 (1–2) 1 (0–2) 0.5 (0–1) 0.36Non-paretic handFist opening/clenching

2 (2–3) 2 (0–3) 2 (2–3) 2 (0–3) 0.64

Fingeropposition

1.5 (0.5–2) 2 (1–3) 2 (1–2) 2 (1.5–2) 0.54

Finger tapping 2 (0–3) 2 (1–3) 2 (0–3) 2 (0.5–2) 0.93

aKruskall–Wallis test. Malf, malformations; PVL, periventricularlesions; CSC, cortico–subcortical lesions; Acq, postnatally acquiredlesions.

0MALF

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Bilateral MMNo MMNon-paretic hand MMParetic hand MM

Bilateral MMNo MMNon-paretic hand MMParetic hand MM

Figure 3: (a) Individual Jebsen–Taylor (maximum 720s) and (b) Assisting Hand Assessment (AHA) scores of children with bilateral mirror movements(mirror movement scores of ≥2 on fist opening and clenching), children with mirror movements only in the paretic hand, children without mirror move-ments and in those with mirror movements in the non-paretic hand only, plotted for every group of brain lesions. MALF, malformations; PVL, periventric-ular lesions; CSC, cortico–subcortical lesions; ACQ, postnatally acquired lesions.


Mirror movements in the non-paretic hand significantlycorrelated with bimanual performance, confirming theimpact of mirror movements on the performance ofbimanual tasks in which differential roles of the two handsare a prerequisite. Correlations were lower than thosereported by Kuhtz-Buschbeck et al.,1 though this studylacked a standardized assessment for bimanual function.Interestingly, further exploration of the functional out-comes showed that some children had a poor assistance ofthe paretic hand in bimanual tasks, despite good unimanualcapacity. This discrepancy was significantly correlated withthe occurrence of mirror movements in both sides. It thusseems that the symmetric nature of mirror movements dis-rupts the asymmetric requirements of most bimanual tasks.The occurrence of mirror movements will thereby hinder afluent and efficient task execution and the child might pre-fer a unimanual strategy to avoid interference. However,correlations were fair, and other factors such as poor sen-sory function or developmental disuse might also play arole.24

Brain lesion type might offer an additional explanationfor mirror movements. The few available studies havereported more mirror movements in children with earlyversus late lesions;13 however, these did not differentiatebetween mirror movements in the paretic and the non-paretic side. Our analysis showed a significant differencein mirror movements of the paretic hand during openingand clenching of the non-paretic hand between childrenwith different lesion types. Children with early lesions(periventricular lesions) had significantly more mirrormovements compared to children with lesions thatoccurred after birth. Brain lesion type has also beenrelated to the structural reorganization of the CST, whichis the main motor pathway of the upper limb.13,25 Thisreorganization results in ipsilateral control, i.e. the paretichand is controlled by the non-lesioned hemisphere, or inbilateral control of the paretic hand and is typically seenin children with more extensive lesions in the first, second,or early third trimester. In these children, motor functionmay be maintained through the ipsilateral connectionsthough at the expense of producing mirror movements.9

Staudt et al.26 also noted that mirror movements in theparetic hand only occurred in those children with ipsilat-eral CST projections and concluded that only these mirrormovements are a sign for the presence of ipsilateral CSTreorganization. Holmstr€om et al.24 confirmed this byreporting strong mirror movements in the paretic handonly in children with ipsilateral motor projections to theparetic hand. However, these authors also showed thatapart from lesion type or timing, lesion extent and loca-tion also play a role in ipsilateral CST reorganization.24

The results of the current study clearly illustrate the com-plex multifactorial interaction between hand function, theoccurrence of mirror movements, and lesion type (Fig. 3),which might account for the generally fair correlations.Whether or not mirror movements are indeed a reliable

indicator for ipsilateral motor reorganization and its effi-cacy remains to be determined in future research combin-ing transcranial magnetic stimulation, diffusion-weightedimaging, and a quantitative assessment of mirror move-ments.12 Also, larger sample sizes of children in the differ-ent lesion type groups are needed to boost the statisticalpower.

This study also warrants some critical reflections. First,scoring of mirror movements was based on a simple, ordi-nal scale. Although high positive correlations werereported between ordinal ratings and more advanced quan-titative measurements,1 recording of isometric fingertipforces or electromyography measures might prove moresensitive. Secondly, we did not include transcranial mag-netic stimulation although it is considered a valuable, non-invasive tool for mapping the motor output to both handsfrom either cortex. Third, brain lesions were broadly clas-sified. More detailed characterizations of brain lesions arecurrently possible using quantitative post-processing orsemi-quantitative clinical scales27 and are likely to providefurther insights into the underlying mechanisms of mirrormovements in this population.

Still, this is the largest study that systematically assessedmirror movements in children with unilateral CP, basedon a representative sample covering the whole range ofupper limb functionality and lesion types. We reportedmore mirror movements in the non-paretic hand com-pared to the paretic hand, whereby results suggest differ-ent factors playing a role in these phenomena. Theoccurrence of mirror movements in the non-paretic handwhen moving the paretic hand seems related to upper limbfunction. Interestingly, mirror movements seem to inter-fere with bimanual performance, despite good underlyingunimanual capacity. The occurrence of mirror movementsin the paretic hand is more related to brain lesion type,whereby children with earlier lesions present with moremirror movements. However, the relationship with brainlesion and type of reorganization, as well as the impactof these factors on treatment response, needs furtherinvestigation.

ACKNOWLEDGEMENTSThis study received financial support from Research Foundation

Flanders (FWO project, grant G087213N) and by the KU Leu-

ven (Bijzonder onderzoeksfonds, grant OT/14/127). Ellen Jaspers

received a Marie Curie Intra-European Fellowship within the 7th

European Community Framework Programme (FP7-PEOPLE-

2013-IEF/Proposal No. 623396). The authors have stated that

they had no interests that might be perceived as posing a conflict

or bias.

SUPPORTING INFORMATIONThe following additional material may be found online:

Table SI: Intraclass correlation coefficients (ICC [2,1]) and

95% confidence intervals for interrater and intrarater reliability

(n=20).


Table SII: Descriptive data of upper limb assessments of the

study group (n=78).Table SIII: Frequencies (percentage) of mirror movements for

the different tests at the paretic and non-paretic hand.

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January 2016 | Volume 3 | Article 1121

HYPOTHESIS AND THEORYpublished: 06 January 2016

doi: 10.3389/fped.2015.00112

Frontiers in Pediatrics | www.frontiersin.org

Edited by: John R. Mytinger,

The Ohio State University and Nationwide Children’s Hospital, USA

Reviewed by: Shahanawaz Syed,

Dr. D. Y. Patil Vidyapeeth, India Kumar Sannagowdara,

Medical College of Wisconsin, USA

*Correspondence:Ellen Jaspers

[email protected]

Specialty section: This article was submitted to

Neuropediatrics, a section of the journal Frontiers in Pediatrics

Received: 15 July 2015Accepted: 07 December 2015

Published: 06 January 2016

Citation: Jaspers E, Byblow WD, Feys H and

Wenderoth N (2016) The Corticospinal Tract: A Biomarker to Categorize Upper Limb Functional

Potential in Unilateral Cerebral Palsy. Front. Pediatr. 3:112.

doi: 10.3389/fped.2015.00112

The Corticospinal Tract: A Biomarker to Categorize Upper Limb Functional Potential in Unilateral Cerebral PalsyEllen Jaspers1* , Winston D. Byblow2 , Hilde Feys3 and Nicole Wenderoth1,4

1 Neural Control of Movement Laboratory, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland, 2 Movement Neuroscience Laboratory, Department of Sport and Exercise Science, University of Auckland, Auckland, New Zealand, 3 KU Leuven, Department of Rehabilitation Sciences, Research Group of Neuromotor Rehabilitation, Leuven, Belgium, 4 KU Leuven, Department of Kinesiology, Movement Control and Neuroplasticity Research Group, Leuven, Belgium

Children with unilateral cerebral palsy (CP) typically present with largely divergent upper limb sensorimotor deficits and individual differences in response to upper limb rehabilita-tion. This review summarizes how early brain damage can cause dramatic deviations from the normal anatomy of sensory and motor tracts, resulting in unique “wiring patterns” of the sensorimotor system in CP. Based on the existing literature, we suggest that corti-cospinal tract (CST) anatomy and integrity constrains sensorimotor function of the upper limb and potentially also the response to treatment. However, it is not possible to infer CST (re)organization from clinical presentation alone and conventional biomarkers, such as time of insult, location, and lesion extent seem to have limited clinical utility. Here, we propose a theoretical framework based on a detailed examination of the motor system using behavioral, neurophysiological, and magnetic resonance imaging measures, akin to those used to predict potential for upper limb recovery of adults after stroke. This theoretical framework might prove useful because it provides testable hypotheses for future research with the goal to develop and validate a clinical assessment flowchart to categorize children with unilateral CP.

Keywords: cerebral palsy, upper limb, corticospinal tract, reorganization, biomarker, categorization

GENERAL INTRODUCTION

With a prevalence of 1 in 500 newborns, cerebral palsy (CP) is the leading cause of childhood physi-cal disability (1). This review focuses on upper limb function in children with unilateral CP, which accounts for 38% of the CP group (2). These children typically present with delays in sensorimotor development and in the acquisition of gross and fine motor upper limb skills. Irrespective of the severity of the brain lesion, they experience lifelong disabilities that put a high emotional and financial burden on families, caretakers, and society (3, 4). To maximize the child’s functional potential and subsequent independence in life, adequate treatment planning is essential. However, treatment optimization is challenged by the large heterogeneity in the clinical presentation of chil-dren with unilateral CP. Despite the rapid increase of evidence-based therapy management, large variability in treatment response persists; Novak et al. (5) recently showed that 70% of the available interventions for children with CP have highly variable efficacy and the existing clinical assessments and outcome measurements fail to accurately predict treatment response (5). A stratified therapy

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Jaspers et al. Functional Potential in Unilateral CP


approach could further optimize treatment planning, thereby increasing the odds that a child reaches its maximal functional potential within the constraints imposed by the structural dam-age of the brain. The strategic and economic significance of the identification of subgroups or strata of patients based on clinical biomarkers has been clearly demonstrated in other areas, such as oncology (6, 7). Exploring the clinical merit of such an approach in CP seems warranted.

The first step toward stratification is the identification of clinically relevant biomarkers. Literature has indicated that the clinical assessment of sensorimotor function alone is not enough but may be complemented with information about neural, structural and functional integrity. The heterogeneous nature of brain lesions underlying CP might constitute a crucial factor in explaining treatment response variability. Brain lesions range from relatively localized damage to the motor pathways (often seen when lesions occur after 24 weeks of gestation), to severe malformations typically seen when the incident occurs during the first months of pregnancy. Structural MRI has been used to derive neural biomarkers such as lesion location and extent, often combined with the time-point of the insult (8). However, gross anatomy or timing of the lesion remains only a moderate predictor of a child’s sensorimotor function (9, 10), even when applied at the group level. This raises the question why simple markers describing lesion anatomy are relatively uninformative in children with CP. Part of the answer is that the brain is still highly plastic in the early stages of development, undergoing vast time-dependent maturational changes, making specific parts of the brain particularly vulnerable to injury (11). Following injury at this phase of development, plasticity permits alterations from the pre-programmed pathway of brain organization (12, 13). As a result, the final “wiring” of the sensorimotor system might deviate from that expected, a phenomenon that is unique to unilateral CP. If the pattern and extent of “re-wiring” can be identified, it may offer clinical utility.

In the first part of the review, we provide a concise overview of typical and disrupted neural development of the human brain and summarize the available knowledge related to how brain damage impacts on sensorimotor function in unilateral CP. In the second part of this review, we propose the work-ing hypothesis that the initial brain damage and concurrent structural reorganization of the sensorimotor system (and most notably the corticospinal tract, CST) form a primary source of variability among children with unilateral CP, and constrain the maximal functional potential a child can theoretically reach. Since two children can present with similar sensorimotor function yet differ largely regarding the underlying anatomical substrate, we propose a systematic evaluation of the CST to infer the wiring pattern at the level of the individual child with unilateral CP. With this review, we intend to generate testable hypotheses to identify biomarkers that go beyond the traditional clinical assessments and that allow categorizing children based on their CST wiring pattern. Such categorization might prove useful in a clinical context and in the long run, these insights will further advance research in the field of therapy stratification in unilateral CP.

ANATOMICAL PATHWAYS FOR UPPER LIMB MOVEMENTS

Voluntary upper limb movements originate primarily from the contralateral motor cortex, which receives input from frontal and parietal areas that play an important role in higher-order sensorimotor processing. The motor cortex is divided into the primary motor cortex (M1), premotor cortex (PM), cingulate motor area (CMA), and supplementary motor area (SMA) (14). These areas are densely interconnected within one hemisphere via association tracts, and connect with homologous areas of the opposite hemisphere via commissural tracts. The CST constitutes the major motor output pathway. It is formed by large pyramidal neurons from M1, which converge with fibers from SMA, PM, the somatosensory cortex, and the posterior parietal cortex. The CST passes through the corona radiate, the posterior limb of the internal capsule, and the cerebral peduncles, and crosses at the level of the pyramidal decussation into the lateral spinal cord. A small portion (10%) of the CST also descends anteriorly into the ipsilateral spinal cord. These uncrossed anterior projections are thought to primarily innervate proximal and axial muscles, rather than distal forearm and hand muscles (15, 16). However, the exact functional role of the uncrossed anterior projections remains unclear (17, 18).

The afferent cortical input needed for the accurate execution of movements, i.e., the sensory information, is ensured via the thalamocortical radiations into the motor areas and the primary and secondary sensory areas (19). An overview of relevant tracts and structures related to upper limb sensorimotor function is provided in Figure 1.

LESION TYPES AND “RE-WIRING” OF MAJOR TRACTS FOLLOWING EARLY BRAIN DAMAGE

Malformations (Week 0–24)In the first 24 weeks of gestation the brain undergoes major morphological changes, such as the formation of the cerebral hemispheres, the folding of the cortex, and the shaping of the ventricular system (11). Lesions occurring before week 24 there-fore typically result in malformations (Figure 2A), such as a lack of gyri or sulci development or an excessive number of small gyri, unusually thick convolutions, or a disorganization of the cerebral cortex (e.g., schizencephaly). These lesions occur in <10% of the children with unilateral CP (8, 9).

Periventricular White Matter Lesions (Week 24–34)During week 24–34, brain maturation is predominantly char-acterized by white matter tract development. Association tracts (cortical–cortical connections) and afferent/efferent projec-tion tracts (connecting the cortex with subcortical nuclei, the cerebellum, and the spinal cord) arise from the neurepithelium surrounding the lateral ventricles. Importantly, each hemisphere initially develops bilateral crossed and uncrossed descending

FIGURE 1 | Structural connectivity of the sensorimotor system. Schematic overview of relevant tracts and structures (adopted from Ref. 20).




efferent projections that form the CST. During typical develop-ment, the ipsilateral uncrossed projections (CSTipsi) gradually weaken and the contralateral crossed projections (CSTcontra) strengthen. This process, known as competitive withdrawal, occurs at the termination point of corticospinal neurons within the spinal cord (21), resulting in predominantly contralateral control of the upper limb.

White matter tract development is accompanied by a local increase in blood flow around the lateral ventricles. Hence, insults occurring between week 24 and 34 most frequently result in periventricular white matter lesions (Figure 2B), which account for around half of the children with unilateral CP (8, 9). The CST has already reached the cervical cord by 24 weeks of gestation (22), and lesions that occur during this period frequently damage the CST and the internal capsule (23), resulting in reduced integrity of the motor tract and the posterior/reticular limb of the internal capsule (24), for review see Ref. (25). These lesions also compro-mise the typical competitive withdrawal process of the CST (26), thereby causing a unique “re-wiring” within the sensorimotor system in unilateral CP: the existing uncrossed projections from the non-lesioned hemisphere (CSTipsi) gain control of the affected hand (13), and are strengthened during further development and environmental interactions. Conversely, the weaker crossed projections (CSTcontra) from the lesioned hemisphere withdraw, at least partly (12, 26). Eventually, the non-lesioned hemisphere can become equipped with fast-conducting uncrossed projections to the affected upper limb (21, 23, 27). Importantly, this “re-wiring” pattern is influenced by lesion extent, whereby only larger lesions seem to cause a “shift” of the CST toward the non-lesioned hemi-sphere (23, 27) (Figure 2E). However, the functional relevance of

ipsilateral control of the affected hand in children with unilateral CP compared to typically developing children remains ambigu-ous, as there are currently no known associations between neu-rophysiological lateralization indices and upper limb function.

Cortical synapses of the afferent thalamocortical radiations are formed later than the CST (28), such that afferent tracts are much less affected than efferent tracts. Nonetheless, reduced integrity of the posterior thalamocortical radiations has been reported in children with periventricular lesions (29, 30). Thalamocortical radiations also follow a different pattern of reorganization, whereby the sensory afferents seem to bypass even larger lesions to reach the contralateral cortex (13, 31, 32) (Figure 2E). Although the general wiring pattern is preserved for the afferent pathways, and sensory input of each hand is connected to the contralateral cortex, there might be profound reorganization within the pri-mary sensory cortex of the lesioned hemisphere (27).

Cortical-Subcortical Lesions (Week 34–38, and Up To 28 Days After Birth)Week 34–38 of gestation is characterized by further maturation of the tracts (synaptic production and myelination) (33), causing a vast improvement of fetal movement quality, alertness, and visual func-tion (34). This maturation coincides with a migration of the area of blood flow toward the cortical and subcortical areas. Consequently, lesions occurring after 34 weeks of gestation or around birth typically affect cortical or subcortical gray matter of the central and parasagittal areas (Figure 2C) (8, 35). These cortical–subcortical “infarct-like” lesions occur in 20–30% of the children with unilat-eral CP (8, 9) and often do not extend so far medially as to also affect the periventricular white matter (26). As a consequence, crossed

FIGURE 2 | Schematic overview of cerebral development and structures more vulnerable to damage depending on the stage of brain maturation and possible reorganization of the motor and sensory system, based on time-point of occurrence and lesion extent. (A) Malformations, caused by an insult in the first 24 weeks of gestation (schizencephaly); (B) periventricular lesions, which typically occur around week 24–34 of gestation, and affect the corticospinal tract (CST); (C) cortical–subcortical lesions, which typically occur after 34 weeks of gestation and primarily affect the motor and/or sensory cortex; (D) postnatally acquired lesions, which occur after 28 days after birth until age 2 years; (E) different types of motor reorganization are typically seen following periventricular lesions (CST, black), whereby the reorganization pattern depends on the extent of the lesion. The general pattern of the sensory pathways is preserved (thalamocortical radiations, blue); (F) crossed CST projections from the lesioned hemisphere are at least partially intact following cortical–subcortical or postnatally acquired lesions.




CST projections from the lesioned hemisphere are usually at least partially intact and “re-wiring” to the non-lesioned sensorimotor areas is less frequently seen (26, 31, 32) (Figure 2F).

Postnatally Acquired Lesions (Up To Age 2 years)The first 2 years of life are a highly dynamic period and perhaps the most critical phase of postnatal brain development, characterized by structural brain growth and a rapid development of a whole range of cognitive and motor functions (36). Lesions occurring between 28 days after birth and before the age of 2 years are categorized as postnatally acquired and represent around 15% of the lesions in children with unilateral CP (9). Postnatally acquired lesions entail a variety of affected structures, whereby cortical damage in the area of the cerebral medial artery and deep gray matter structures is most prevalent (Figure 2D) (9). Sensory reorganization toward the non-lesioned hemisphere has not yet been described in these children (31) (Figure 2F).

EARLY BRAIN DAMAGE AND UPPER LIMB DEFICITS

At a general level, the severity of upper limb sensorimotor deficits in unilateral CP depends on the time of the insult, as well as on

the location and extent of the lesion (8, 35, 37, 38). For example, periventricular lesions that occur between week 24 and 34 on average lead to fewer motor and tactile deficits and better arm and hand function than cortical–subcortical lesions that occurred after 34 weeks or around birth, or than postnatally acquired lesions (9, 26, 31, 39). However, if the early lesion is large and causes substantial “re-wiring” such that the affected upper limb receives input from the non-lesioned ipsilateral hemisphere, this results in poorer performance compared to children with perive-ntricular lesions with contralateral control of the affected upper limb (26, 31). Additionally, the structural integrity of the CST and thalamocortical radiations might further modulate the extent of upper limb deficits (40, 41). Lastly, basal ganglia/thalamus dam-age often results in poor upper limb sensorimotor function, reach and grasp abilities, and bimanual hand use, irrespective of the timing of the brain lesion and potential reorganization (9, 10, 39, 42).

Upper limb motor deficits typically include muscle weakness, spasticity, dystonia, and muscle shortening (43). More than 75% of children with unilateral CP also experience deficits in exteroception, proprioception, two-point discrimination, and/or stereognosis (44). Together, these sensorimotor deficits compro-mise the acquisition of gross and fine motor skills, resulting in less (effective) use of the affected hand in unimanual and bimanual activities (43). Adequate treatment selection and planning are

FIGURE 3 | Individual treatment responses following a constraint-induced movement therapy (CIMT) program, as measured with the assisting hand assessment (AHA, bimanual hand use). Vast inter-individual variation in treatment response is seen following CIMT (1 h/day, 5 days/week for a period of 10 weeks in children age 4–12 years). Changes in AHA score of 5 or more units surpass the smallest detectable difference (personal communication with Klingels based on study results published in Ref. 46).




important to maximize a child’s upper limb functional abilities. However, there is a lack of strong evidence in favor of any par-ticular upper limb therapy approach in children with unilateral CP (45). This is likely due to the heterogeneous nature of lesions in these children and the highly variable treatment response at the level of the individual child compared to group averages (Klingels, personal communication), as illustrated in Figure 3.

Together, these results have led to a general consensus within the CP community that biomarker-based treatment planning offers a new opportunity to further advance upper limb func-tional outcome. However, it remains unclear what biomarkers are clinically relevant and how they can be combined to guide therapy decisions. Recent research has suggested that neural biomarkers related to the specific wiring pattern of the CST may become predictive for treatment outcome (47, 48). This supports our working hypothesis that the initial brain damage and concur-rent structural reorganization of the sensorimotor system form a major source of variability among children with unilateral CP. In the next paragraph, we propose an approach of how to infer the CST wiring pattern and connectivity strength at the level of the individual child with unilateral CP.

PROBING THE CST

The CST wiring pattern is usually not immediately apparent from how the child presents clinically, and children with unilateral CP might have similar upper limb sensorimotor deficits, despite a different underlying CST wiring pattern. Additionally, CST

wiring might also aid in further explaining the heterogeneity in upper limb outcome within the group of children with unilateral CP. Two questions might be of relevance for clinical decision-making: first, does the affected hand receive significant input from the non-lesioned hemisphere via uncrossed CSTipsi fibers or from the lesioned hemisphere (CSTcontra)? Second, can further important information be derived from estimating the “connec-tivity strength” of the CST in the lesioned hemisphere, i.e., its quality or structural integrity?

Here, we present a theoretical framework, integrating behav-ioral, neurophysiological, and medical imaging measures to allow a systematic evaluation of CST wiring and connectivity strength. The proposed flowchart is purely hypothetical at this point but provides a series of testable ideas on how the individual CST wiring pattern of a child with unilateral CP can be inferred from different measurements. It is important to note, however, that the development of a clinically applicable assessment flowchart requires direct validation in children with unilateral CP, which will be the focus of future research.

A simple behavioral measure to probe CST wiring could be the occurrence of mirror movements (MM). MM refer to involuntary movements of one hand that mirror the intentional movement of the contralateral hand (49, 50). MM are part of the physiological motor pattern in typically developing children up to age 10 years and increase with increasing task complexity (51). The relationship between age and the occurrence of MM is less straightforward in unilateral CP, i.e., MM are driven by different phenomena in the affected and non-affected hand (52). Moreover, it also appears that highly repetitive and simple motor tasks are more appropriate to assess the occurrence of pathological mirror movements (52). MM in the affected hand (i.e., mirroring inten-tional movements of the non-affected hand) have been proposed to be indicative for one motor cortex controlling both hands, i.e., ipsilateral or bilateral “re-wiring” of the CST (26). MM in the non-affected hand seem more related to sensorimotor impair-ment of the affected hand rather than to the CST wiring pattern (50, 53). We propose the assessment of MM in the affected hand as a non-invasive, low-risk clinical biomarker to probe CST wiring and categorize children with unilateral CP (Figure 4). However, adequate interpretation of the frequency and magnitude of MM would benefit from further standardization of the assessment in terms of task complexity (51), but also through the use of a quantitative method based on, e.g., grip force measurements.

The sensorimotor system can also be assessed using single-pulse TMS over the hand area of the motor cortex in the lesioned and non-lesioned hemisphere to elicit MEPs in the affected hand (54). Absence of a descending CST projection from one hemi-sphere is assumed when even high stimulation intensities fail to elicit early MEP responses in the affected hand (23). Based on this neurophysiological biomarker, children with unilateral CP can be further categorized based on whether MEPs in the affected hand are elicited from the lesioned hemisphere only (contralat-eral wiring), from the non-lesioned hemisphere only (pure ipsilateral wiring), or from both hemispheres (bilateral wiring), as illustrated in Figure 4. Single-pulse TMS has been shown to be safe and well tolerated in children, i.e., the occurrence of seizures has not been reported, despite the growing variety of childhood

FIGURE 4 | Categorization based on a stepwise evaluation of CST wiring pattern and structural integrity in unilateral CP. First, if MM are present at the affected hand, this suggests some ipsilateral control of the affected hand. Further investigation with TMS will help to identify whether children have a bilateral or a unique unilateral control of the affected hand. Children with a pure ipsilateral wiring pattern form a first category in this scheme. For those children with bilateral control of the affected hand, DWI allows to determine the structural integrity of the lesioned CSTcontra. Here, a further categorization entails those with good structural integrity vs. poor structural integrity (i.e., affected hand predominantly controlled via the lesioned CSTcontra or via the non-lesioned CSTipsi, respectively). In children with unilateral CP who do not present with MM in the affected hand, TMS will confirm the contralateral control via the lesioned CTScontra. Here, DWI can again be used to further categorize children into those with good vs. poor structural integrity of the lesioned CSTcontra. CST, corticospinal tract; MM, mirror movements; TMS, transcranial magnetic stimulation; DWI, diffusion-weighted imaging; ipsi, ipsilateral hemisphere with respect to the affected hand; contra, contralateral hemisphere with respect to the affected hand; na, not applicable.




neurological conditions being studied (55, 56 and for review see Ref. 57). However, while single-pulse TMS is put forward as a viable technology to increase our understanding of disorders of the developing brain, the application of this technique requires specialized training and should only be delivered by expert asses-sors within a child-friendly environment. One must note that children under age 10 years have a higher (resting and active) motor threshold compared to adults, which only decreases to adult levels by mid-adolescence (56, 58). Although eliciting an MEP in a relaxed muscle in children younger than 6 years might not be possible, even at maximum stimulator output (59), MEPs can certainly be elicited when the target muscle is active (21). On the other hand, TMS might be most informative in older children and certainly biomarker research might benefit most from focusing on older children and adolescents. In children with unilateral CP, the CST is not expected to reorganize after age 2 years (21), and thus information obtained from older children is still expected to generalize to the larger group of children with unilateral CP.

Lastly, in case of contralateral or bilateral “re-wiring,” we hypothesize that the structural integrity of the lesioned CSTcontra will provide further insights that might aid clinical decisions. Structural imaging techniques, particularly diffusion MRI and fiber tracking, might be promising imaging biomarkers to assess the contralateral input to the control of the affected hand. This will allow quantifying CST asymmetry between the lesioned and the non-lesioned hemisphere, using measures of fractional anisotropy or fiber count either at the level of the posterior limb of the internal capsule or cerebral peduncles (for review see Ref. 25). Increased asymmetry between both hemispheres has been related to more severe upper limb deficits in unilateral CP (good vs. poor contralateral wiring) and might help distinguishing predominant ipsilateral vs. predominant contralateral control of

the affected hand in those children with a bilateral wiring pattern (Figure 4). While diffusion imaging provides detailed anatomi-cal information that cannot be accessed with any other currently available imaging method, this technique also implies specific expertise to ensure an adequate and proper interpretation of the diffusion images (for review see Ref. 60). Moreover, given the length and noisiness of diffusion imaging acquisition protocols, it might not always be feasible in younger children. Future research will have to clarify whether or not the implementation of any diffusion-weighted imaging protocol in clinical practice is truly beneficial.

At present, it is speculative whether the biomarkers proposed here can be used to infer the underlying CST “(re-)wiring” pattern and structural integrity for individual children with unilateral CP. However, the utility of several of the suggested biomarkers has been demonstrated previously (see next paragraph). The pro-posed theoretical scheme generates five categories and concurrent hypotheses that can be tested empirically in future studies. Note, however, that the scheme as depicted here is only an example of what such an assessment flowchart might look like and awaits vali-dation in children with unilateral CP. In the long run, this might pave the road for future studies investigating whether treatment allocation based on biomarkers characterizing the neuroanatomy of the individual child’s CST is feasible and advantageous com-pared to traditional approaches (see also Ref. 48).

EXPERIMENTAL EVIDENCE SUPPORTING THE CATEGORIZATION BASED ON THE CST

The five categories described in Figure 4 are based on knowledge about typical brain development, combined with empirical data




from children with unilateral CP (23, 26, 31, 61). Here, we evalu-ate this categorization against existing evidence, based on clinical, (neuro)physiological, or medical imaging parameters. Any future flowchart developed on the basis of the presented hypothesis and concurrent new clinical evidence could benefit from the theoreti-cal framework proposed here. However, the current depiction is only an example of what such an assessment flowchart might look like.

The first premise of our categorization relates to the wiring pattern of the CST, i.e., is the affected hand mainly controlled via the contralateral lesioned hemisphere or via the ipsilateral non-lesioned hemisphere? While the occurrence of ipsilateral control of the affected hand has not yet been systematically assessed, it is estimated to occur in 30–60% of the children with unilateral CP (23, 62, 63), and many children present with a mixed response pat-tern (23, 31, 63). Ipsilateral “re-wiring” ensures the development of (some) upper limb skills despite severe CST damage (23, 26), though it is an insufficient substitute for the typical contralateral control (17) and (near) normal hand function is only seen when the affected hand is controlled via the CSTcontra of the lesioned hemisphere (23, 26, 31). No or minimal MM of the affected hand (23), as well as the absence of ipsilateral control of the affected hand based on TMS (23, 64, 65) have been put forward as predic-tors of better upper limb function in children with unilateral CP.

However, whether or not ipsilateral “re-wiring” forms the basis for differential treatment responses remains a topic of debate (66). While some authors have suggested that children with unilateral CP with pure ipsilateral control are poor responders to intensive unimanual training (61, 67), others could not confirm these findings (68). These discrepancies reflect an on-going debate of how to determine the optimal therapy for the individual child with CP (48, 66). Additionally, the impact of the wiring pattern with respect to therapy outcome following different programs, i.e., bimanual training vs. intensive unimanual training, has not yet been systematically investigated.

The second premise is that if a child has a typical contralateral wiring pattern (i.e., the paretic hand is controlled via crossing fibers from the lesioned hemisphere only) or a bilateral wiring pattern (i.e., the affected hand is controlled by both hemi-spheres), the integrity of the lesioned CSTcontra determines upper limb functional abilities. The structural integrity of descending motor pathways, based on, e.g., diffusion MRI measures of fractional anisotropy or fiber count of the CSTcontra from the lesioned hemisphere to the affected hand, has been reported to predict good motor outcome (47, 69–73). We further hypoth-esize that those children with bilateral control of the affected hand and good structural integrity of the lesioned CSTcontra will have better abilities to develop fine upper limb motor skills. Lastly, CST integrity has been reported to impact on treatment response, as demonstrated in children with acquired brain injuries. In this group of children, good structural integrity of the lesioned CST (measured at the level of the PLIC using DWI) was predictive for better functional gains following constraint-induced movement therapy (CIMT) (74). These results might be extrapolated to children with unilateral CP in case the affected hand is mainly controlled via the contralateral lesioned hemisphere.

Overall, the proposed categorization of children with uni-lateral CP based on their underlying CST wiring and structural integrity seems to be consistent with previous findings that demonstrated the link between clinical outcome measurements and (neuro)physiological, as well as brain MRI parameters at the group level (9, 26, 39). We specifically focus on the CST, given that it predominates skilled voluntary upper limb movements in humans and plays a crucial role in upper limb functional outcome as demonstrated in adult stroke (75, 76). However, inferring whether children exhibit predominantly ipsilateral vs. con-tralateral control of the affected hand is not easy and MM of the affected hand, as proposed in the current review, might only be a first indication of “ipsilateral or bilateral re-wiring” (26). Further research combining the systematic assessment of MM and TMS is an absolute necessity to further clarify the relationship between both measurements. Importantly, additional decision parameters with respect to upper limb functional outcome in children with unilateral CP might include (1) functional and structural con-nectivity patterns between sensory and motor areas, including the thalamocortical radiations (29, 40, 41); (2) functional and structural connectivity patterns between hemispheres (64); (3) underlying sensorimotor deficits, such as distal muscle weak-ness, spasticity, or impaired stereognosis (44); and (4) cognitive abilities and age (46). The importance of these measures and their integration into the proposed assessment to further optimize the categorization remain as future challenges. Lastly, given that the brain lesions occur while the nervous system is still developing, structural and functional connectivity may also be expected to change due to maturation and necessitate an age-corrected approach. If categorizing children with unilateral CP based on their CST wiring and structural integrity allows explaining the variability in treatment response, this may offer a real advantage with respect to individualized treatment planning and may even allow a stratified therapy approach in the future.

SUMMARY AND CONCLUSION

Children with CP present with a striking heterogeneity in senso-rimotor dysfunctions, which has triggered an increasing interest to optimize therapy in light of the specific requirements of the individual child, while keeping in mind that resources available for care and therapy are limited. Here, we advocate the idea that the individual “re-wiring” pattern and structural integrity of the CST might provide important information to further explain upper limb function and treatment outcome in children with unilateral CP and that CST functionality can be inferred from a systematic evaluation, which combines behavioral, neuro-physiological, and medical imaging biomarkers. During the last decades, a large repertoire of neurophysiological and imaging techniques have been developed, but more research is required to identify which techniques are best suited to derive clinically relevant neural biomarkers. We provide a theoretical framework with a series of testable hypothesis for biomarker research and categorization in unilateral CP. Note that this framework has no immediate clinical application but presents a series of anatomi-cally motivated ideas, which need to be tested and validated in future research in children with unilateral CP.




Lastly, we also indicate knowledge gaps regarding the avail-ability of validated behavioral, neurophysiological, and medical imaging parameters, which can be used to further investigate the interaction between the CST wiring pattern, CST integ-rity, and upper limb sensorimotor outcome in unilateral CP. Characterizing whether the sensorimotor wiring pattern imposes a hard constraint on the maximum sensorimotor abilities a child can reach and/or on the response to treatment

might pave the road for an evidence-based stratified therapy approach in CP.

FUNDING

EJ received a Marie Curie Intra-European Fellowship within the 7th European Community Framework Programme [FP7-PEOPLE-2013-IEF/Proposal No. 623396].

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Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Do mirror movements relate to hand function and timing of ...in a prospective cohort of children with unilateral cerebral palsy, and to explore the relationship with hand function