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Neonatal White Matter AbnormalitiesPredict Global Executive FunctionImpairment in Children Born VeryPretermLianne J. Woodward a b , Caron A. C. Clark a c , Verena E. Pritchard ab , Peter J. Anderson d & Terrie E. Inder ea Canterbury Child Development Research Group, Department ofPsychology, University of Canterbury, Christchurch, New Zealandb Van der Veer Institute for Parkinson's and Brain Research,Christchurch, New Zealandc Developmental Cognitive Neuroscience Laboratory, University ofNebraska, Lincoln, Nebraskad Murdoch Childrens Research Institute, University of Melbourne,Victoria, Australiae Departments of Paediatrics, Neurology and Radiology, WashingtonUniversity School of Medicine, St Louis, Missouri

Available online: 19 Jan 2011

To cite this article: Lianne J. Woodward, Caron A. C. Clark, Verena E. Pritchard, Peter J. Anderson& Terrie E. Inder (2011): Neonatal White Matter Abnormalities Predict Global Executive FunctionImpairment in Children Born Very Preterm, Developmental Neuropsychology, 36:1, 22-41

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DEVELOPMENTAL NEUROPSYCHOLOGY, 36(1), 22–41Copyright © 2011 Taylor & Francis Group, LLCISSN: 8756-5641 print / 1532-6942 onlineDOI: 10.1080/87565641.2011.540530

Neonatal White Matter Abnormalities Predict GlobalExecutive Function Impairment in Children Born

Very Preterm

Lianne J. Woodward

Canterbury Child Development Research Group, Department of Psychology, University ofCanterbury, Christchurch, New Zealand

Van der Veer Institute for Parkinson’s and Brain Research, Christchurch, New Zealand

Caron A. C. ClarkCanterbury Child Development Research Group, Department of Psychology, University of

Canterbury, Christchurch, New ZealandDevelopmental Cognitive Neuroscience Laboratory, University of Nebraska,

Lincoln, Nebraska

Verena E. PritchardCanterbury Child Development Research Group, Department of Psychology, University of

Canterbury, Christchurch, New ZealandVan der Veer Institute for Parkinson’s and Brain Research, Christchurch, New Zealand

Peter J. AndersonMurdoch Childrens Research Institute, University of Melbourne, Victoria, Australia

Terrie E. InderDepartments of Paediatrics, Neurology and Radiology, Washington University School of

Medicine, St Louis, Missouri

Using prospective longitudinal data from 110 very preterm and 113 full term children, this arti-cle describes the executive functioning abilities of very preterm children at age 4, and examinesrelations between the extent of white matter abnormality on neonatal magnetic resonance imaging(MRI) and later executive function outcomes. Very preterm children performed less well than fullterm children on measures of planning ability, cognitive flexibility, selective attention, and inhibitory

This research was funded from grants from the Neurological Foundation of New Zealand, Health Research Councilof New Zealand, Canterbury Medical Research Foundation, and the Lottery Grants Board.

Correspondence should be addressed to Professor Lianne J. Woodward, Canterbury Child Development ResearchGroup, Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch, New Zealand. E-mail:lianne.woodward@canterbury.ac.nz

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NEONATAL MRI AND LATER EXECUTIVE FUNCTION 23

control. Executive impairments at age 4 were confined to preterm children with mild or moderate—severe white matter abnormalities on MRI. Findings support the importance of cerebral white matterintegrity for later executive function.

Children born very preterm are at an increased risk for global cognitive impairment. They obtainIQ scores that are on average 10.9 points lower than their full term peers (Anderson & Doyle,2008; Aylward, 2002; Bhutta, Cleves, Casey, Cradock, & Anand, 2002), and up to 50% willbe subject to significant cognitive delay by school age (Doyle & Saigal, 2009; Johnson, 2007;Saigal & Doyle, 2008). These high rates of cognitive impairment and their effects on schoolachievement have become a focus of wide international concern. As a result, research effortshave increasingly sought to clarify the specific cognitive difficulties associated with pretermbirth, as well as the neural mechanisms that place some very preterm children at risk of cognitiveimpairment while others remain relatively spared. Such knowledge is vital for preventativeefforts and the development of appropriately targeted interventions to improve the cognitive,educational, and psychological well being of children born very preterm.

The most common form of brain injury affecting children born very preterm consist of diffusenon-cystic white matter abnormalities (Back, 2006; Back, Riddle, & McClure, 2007; Boardman& Dyet, 2007; Inder, Wells, Mogridge, Spencer, & Volpe, 2003). These abnormalities, which arereadily detected with conventional magnetic resonance imaging (MRI) in the neonatal period,include white matter signal abnormalities, enlargement of the lateral ventricles, white matter vol-ume loss, delay in myelination, and thinning of the corpus callosum (Inder, Anderson, Spencer,Wells, & Volpe, 2003; Inder et al., 2003; Maalouf et al., 1999; Woodward, Anderson, Austin,Howard, & Inder, 2006). Recent estimates from MRI studies suggest that about a fifth of infantsborn very preterm are subject to moderate to severe white matter abnormalities and a further50% to mild white matter abnormalities (Cheong et al., 2009; Inder et al., 2003; Miller et al.,2005). These high and relatively stable rates of diffuse white matter abnormalities stand inmarked contrast to recent declines in other forms of brain injury associated with preterm birth andpoor outcome, such as periventricular haemorrhagic infarction (PHI) and cystic periventricularleukomalacia (PVL) (Boardman & Dyet, 2007; Volpe, 2009). Furthermore, these rates are fairlycomparable with the later risks of cognitive impairment in this group (Boardman & Dyet, 2007).

Diffusion tensor imaging (DTI) studies provide support for the validity of conventional MRImeasures as markers of early white matter pathology (Cheong et al., 2009; Huppi & Dubois,2006; Huppi et al., 2001; Inder, Warfield, Wang, Huppi, & Volpe, 2005; Miller et al., 2002;Rose et al., 2008; Skranes et al., 2007). For example, in a recent sample of 111 very preterminfants, Cheong et al. (2009) found that more extensive white matter signal abnormalities onconventional MRI were linearly related to concurrent changes in a number of diffusion parame-ters. Specifically, compared with infants with no or only focal white matter signal abnormalities,infants with more extensive abnormalities showed significantly higher levels of radial diffusion(water movement perpendicular to the axon) across sensorimotor regions bilaterally and in theright internal capsule. Radial diffusion, which is a marker of myelination and the integrity ofoligodendroglial cells, is known to be vulnerable with preterm birth. Corresponding declinesin fractional anisotropy values were also found within the internal capsule, and right frontaland occipital regions, suggesting that preterm infants with more extensive white matter signalabnormalities were characterized by less mature fiber tract organization.

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24 WOODWARD ET AL.

In line with these findings, a serial DTI study found that infants without white matter abnor-malities showed developmentally appropriate increases in anisotropy from birth to near term(Miller et al., 2002). In contrast, these increases were not seen in very preterm infants with mod-erate white matter abnormalities. Infants with mild white matter abnormalities were found to alsoshare some of these risks, but in a more regionally specific way, with the absence of anisotrophicgains seen only in frontal white matter. These results suggest that as cerebral development pro-ceeds, early white matter injury in the preterm infant may adversely impact connectivity andmyelination beyond the site of the initial injury, with some regions being potentially morevulnerable than others.

Collectively, these studies provide valuable insight into the effects of white matter injury onaxonal development and myelination, as well as helping to confirm the validity of clinically use-ful, conventional MRI measures of cerebral white matter abnormality in the high risk pretermneonate (Boardman & Dyet, 2007; Huppi et al., 2001; Volpe, 2009). They also raise the possi-bility that early neonatal exposure to white matter abnormalities could play an important role inthe evolution of later cognitive impairments known to affect a substantial proportion of childrenborn very preterm.

To date, very few studies have examined the impact of these early white matter abnormalitieson later cognitive functioning (Hart, Whitby, Griffiths, & Smith, 2008). Those that do exist havereported on short term outcomes only (Beauchamp et al., 2008; Miller et al., 2005; Nagy et al.,2003; Woodward et al., 2006). There has also been a tendency for studies to focus on severeimpairment or disability without considering the risks of less severe but clinically relevant neu-rocognitive impairments (Aylward, 2002). Nonetheless, converging evidence from a diverse setof studies provides increasing support for the importance of cerebral white matter abnormali-ties as an independent and important predictor of severe cognitive delay (Hack & Taylor, 2000;Miller et al., 2005; Woodward et al., 2006).

One important aspect of cognitive functioning that has been shown to be impaired in preschooland school aged children born very preterm is executive function (Aarnoudse-Moens, Smidts,Oosterlaan, Duivenvoorden, & Weisglas-Kuperus, 2009; Anderson, Howard, & Doyle, 2010;Mulder, Pitchford, Hagger, & Marlow, 2009). Executive function skills that are highly reliant onthe integrity of white matter tracts within sub-cortical and cortical regions (Filley, 2001) enablean individual to manage, self-regulate, and engage in goal-directed behavior (Anderson, 2002;Lezak, 2004). Key components of executive function include inhibitory control, working mem-ory, and cognitive flexibility, as well as more complex planning and organized search abilitiesinvolving the integrated coordination of these core components (Baughman & Cooper, 2007;Huizinga, Dolan, & van der Molen, 2006; Miyake et al., 2000). Importantly, these skills havealso been shown to be predictive of children’s later educational achievement (Blair & Razza,2007; Clark, Pritchard, & Woodward, 2010; Marlow, Hennessy, Bracewell, & Wolke, 2007).

Although relatively few studies have examined the development of executive function abili-ties in preschool children born very preterm, existing studies do suggest that, as a group, thesechildren are at elevated risk for executive impairments (see Howard, Anderson, & Taylor, 2008).Observed impairments in executive function from preschool to early school age have been foundin working memory (Clark & Woodward, 2010; Edgin et al., 2008; Espy et al., 2002; Vicari,Caravale, Carlesimo, Casadei, & Allemand, 2004; Woodward, Edgin, Thompson, & Inder, 2005),inhibitory control (Aarnoudse-Moens et al., 2009; Edgin et al., 2008; Espy et al., 2002), plan-ning, switching, and attention (Anderson & Doyle, 2004; Espy et al., 2002; Taylor, Minich, Klein,

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& Hack, 2004; Vicari et al., 2004), with effect sizes in the small to medium range (Howard et al.,2008). Few studies, however, have examined linkages between the extent and severity of cerebralwhite matter abnormalities on neonatal MRI and the development of executive functioning skillsduring the preschool period. Of those that have considered this issue, most have tended to focuson a single component of executive functioning such as working memory (Clark & Woodward,2010; Woodward et al., 2005) or inhibitory control (Edgin et al., 2008). Although informative,these analyses provide limited information about the specificity or pervasiveness of executiveimpairments among children born very preterm. Given the multidimensional nature of executivefunctions, a comprehensive evaluation of a broad range of skills is needed to fully understandthe profile of executive functions in this population.Late preschool age represents an appropriatetime to attempt a comprehensive assessment of this kind since most executive skills have begunto emerge and are developing rapidly (Garon, Bryson, & Smith, 2008). By this age, children alsohave sufficiently sophisticated language and motor skills to enable the assessment of a broadrange of executive skills.

The overall objectives of the present study were to describe the executive functioning profileof preschool children born very preterm, and to examine the relationship between the severity ofcerebral white matter abnormalities on term MRI and a range of executive functions. The specificaims and hypotheses of the study were as follows.

1. To compare very preterm and full term children’s performance on a range of execu-tive processes assessed at age 4 years (corrected for the extent of prematurity). Theseprocesses included response inhibition, cognitive flexibility and set shifting, planning,organized visual search, and goal-directed behavioral regulation. We hypothesized thatvery preterm children would demonstrate impairment across all executive processes.

2. To examine the relationship between the severity of white matter abnormalities on MRIat term equivalent age and very preterm children’s performance on measures of executivefunction at 4 years of age. We hypothesized that very preterm children with white matterabnormalities on term MRI would demonstrate global executive impairment relative tofull term children, with the degree of this impairment being linearly related to the severityof earlier neurological pathology.

METHODS

Participants

The study sample consisted of two groups of children who are being followed as part of aprospective longitudinal study of the neurodevelopmental consequences of very preterm birth.These two study groups are described below.

Very preterm. The first group was a cohort of 110 children born very preterm (≤32 weeksgestation) who were admitted consecutively into a level III neonatal intensive care unit atChristchurch Women’s Hospital, New Zealand from November 1998 to December, 2000. Duringthe two-year recruitment period, 129 very preterm infants met study criteria. In total (10 deaths,4 missed, 5 refusals), 92% of all eligible infants were recruited at birth, leaving a total n of 110

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infants. Exclusion criteria included congenital abnormalities and non-English speaking parents.Of those children surviving to corrected age 4 years, 98% (n = 107) were seen at followed up.Three further children were excluded from this analysis due to blindness (n = 1), severity ofcognitive impairment (n = 1), and lost MRI data (n = 1).

Full term. The comparison group comprised 113 children born full term (37–41 weeks)who were recruited at age 2 and followed to age 4 years. These children were identified fromhospital birth records (N = 7,200). For each very preterm child born and recruited, the secondprevious or second next child on the hospital delivery schedule was identified and the parentsinvited to participate in the study. Children were matched for gender. Of those identified, 62%(n = 113) were recruited. Reasons for non-participation included: untraceable (47%), movedoverseas (12.5%), refused (12.5%), and agreed but unable to schedule an appointment withinthe 2-week assessment window due to illness or family circumstances (28%). No significant dif-ferences were found between recruited and non-recruited infants on measures of birth weight,gestation, gender, socioeconomic status, family type, or ethnicity. Comparison of the socioeco-nomic profile of families in the full term group with regional census data also showed that thesefamilies were highly representative of the region from which they were recruited. Retentionto age 4 was 96% (n = 108). Of these children, three were not included due to incompletedata. Table 1 describes the infant clinical and family background characteristics of the two studygroups.

TABLE 1Characteristics of the Sample

Full Term(N = 105)

Very Preterm(N = 104) t/χ2 p

Infant Clinical CharacteristicsM (SD) Gestation 39.49(1.19) 27.89(2.31) 30.39 <.001M (SD) Birth weight 3572.87(414.42) 1064.50(309.76) 7.65 <.001% Male 54.3 51.0 .23 .63% Multiple birth 3.8 34.6 32.04 <.001% Small for gestational age 1.0 10.6 8.94 .003% Chronic Lung Disease — 33.7% Sepsis — 29.1% Maternal fever >38◦C 28.8% Postnatal steroids (Dexamethasone only) — 5.8% Grade III/IV Intraventricular haemorrhage — 5.9Cystic periventricular leukomalacia — 5.8

Family Social BackgroundM (SD) Maternal age 31.07(4.49) 30.73(5.28) 3.41 .07% European ethnicity 98.1 89.4 7.28 .009% Mother no formal educational qualifications 18.8 40.0 10.88 .001% Semi/unskilled SES status 10.5 29.8 12.16 <.001% Single parent 11.7 18.8 2.03 .15

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Measures

Magnetic Resonance Imaging (Term)

In addition to comprehensive clinical data collected throughout the hospital period, all chil-dren born very preterm had a structural MRI scan at term equivalent age. Unsedated infantswere settled, wrapped, and placed in a Vac Fix bean bag and then scanned using a 1.5T GESigna System with previously documented sequences (Inder et al., 2003). Each infant’s scanwas graded using a standardized scoring system consisting of five 3-point scales assessing thenature and extent of white matter signal abnormality, periventricular white matter volume loss,the presence of cystic abnormalities, ventricular dilation, and thinning of the corpus callosum.All scans were scored by a blinded pediatric radiologist, and independently reviewed by a pedi-atric neurologist (TI). Inter-rater agreement was 95%, with discrepancies resolved by consensus.Based on their total white matter abnormality scores, preterm infants were classified as follows:(1) no abnormalities (score of 5–7, n = 22), (2) mild abnormalities (score of 8–10, n = 61), or(3) moderate to severe abnormalities (score > 10, n = 19). Further details regarding this scoringsystem are available in the online supplement to Woodward et al. (2006).

Executive Function Measures (4 Years)

At age 4 years (corrected for the extent of prematurity), all participants were invited toattend a neurodevelopmental assessment at our university-based research house. As part of thisassessment, children completed a short form of the Wechsler Preschool and Primary Scales ofIntelligence (WPPSI–R) and a battery of four executive function tasks. The WPPSI–R shortform consisted of two verbal subscale tests (Comprehension, Arithmetic) and two Performancesubscale tests (Picture Completion, Block Design). All measures were administered in a fixedorder to minimize the confounding influence of fatigue. All procedures and measures wereapproved by the regional ethics committee and written informed consent was obtained fromall parents/guardians. The four executive function tasks were as follows.

Tower of Hanoi. The three disk version of the Tower of Hanoi provided a measure of plan-ning ability (Simon, 1975; Welsh, 1991). The task apparatus consisted of two identical platforms(30 cm long and 9 cm wide), one used by the examiner and the other by the child. Each plat-form held three equal sized upright pegs. Placed on these pegs were 2 to 3 disks of varying sizethat allowed for five different pattern configurations across the three pegs. The task involved theexaminer showing the child a series of model configurations and asking them to copy the exam-iner’s model by transferring their own disks from the start home peg to the other pegs. Three ruleshad to be followed: (1) disks could not rest anywhere but on the pegs, (2) only one disk could bemoved at a time, (3) a larger disk could not be placed on top of a smaller disk.Before beginningthe task, each child’s understanding of the task rules was checked on two training trials. Once thiswas confirmed, test trials commenced, with the child asked to replicate a series of increasinglydifficult disk configurations (Levels 2 to 7) in as few moves as possible. The number of movesrequired to complete a configuration ranged from 2 (Level 2) to 7 (Level 7). At each move level(2, 3, 5, and 7) there were two trials, resulting in a total of 8 potential trials overall. Levels 2 to3 used only two disks. At level 5, a third disk was introduced and the task rules were reiterated.

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Children were recorded as passing a trial if they reproduced the required configuration in as fewmoves as possible withoutbreaking a rule. When children failed two consecutive trials at onelevel, the task was discontinued.Task performance was assessed using two measures: successfulpassing of the two training trials and the highest move level at which the child passed both testtrials.

Flexible Item Selection Task. The Flexible Item Selection Task (FIST) was used to assessconcept formation and cognitive flexibility (Jacques & Zelazo, 2001). The task consisted of ninestimulus cards. Each card contained three pictures that varied in terms of shape, color or size.One picture within this triad was able to be matched with the two other pictures on one of theabove dimensions (e.g.,it could be matched with one of the other pictures in terms of shape andthe other in terms of color or size). Each task trial consisted of two phases. During the first phase(pre-switch), the examiner asked the child to “show me two pictures that are the same in oneway,” necessitating the recognition that two pictures could be matched on one dimension (e.g.,color). This phase provided a measure of concept formation and/or abstraction. In the secondphase of each trial (switch), children were asked to now “show me two pictures that are alikein a different way,” necessitating a recognition two pictures could also be matched accordingto a different dimension (e.g., shape). This phase provided a measure of cognitive flexibilityand/or shifting.Two practice trials were administered to allow children to become familiar withthe task. If children did not demonstrate an understanding of the concept of selecting pictures thatwere the “same” or “different” during these practice trials the task was discontinued. Followingpractice trials, the test trials were administered. These were ceased if a child failed more than twoconsecutive trials.Two measures of task performance were recorded: the total number of correctabstractions (score range: 0–9) and the total number of correct cognitive flexibility trials (scorerange: 0–9).

Visual Search. A Visual Search task was used to assess selective attention and organizedsearch (Welsh, 1991). The task consisted of a series of black and white line drawings that werepresented on A3-sized sheets of paper. The objective of the task was for the child to correctly findas many target items (N = 8) within the stimulus array as quickly as possible. The stimulus arrayalso included 32 distractor items. An example of the target item for each trial was presentedat the top of the array. Children were administered eight trials in which they were required toselect eight target items (e.g., bananas). The child was asked, “What is this”? (with the examinerpointing to the picture). When the child had successfully identified the item, they were told,“Find all the _____ as quickly as you can. Tell me when you are finished.” The examiner timedthe length of each search trial using a stopwatch. To minimize the motor demands of the task,children were asked to identify the targets by pointing and then the examiner placed a markacross the stimulus. Total errors were recorded (e.g., child pointing to the same item twice orselecting a non-target item). An efficiency score for each trial was calculated by dividing thetotal correct by the total search time (in seconds). Per trial efficiency scores were then averagedto produce an overall mean efficiency score (Welsh, 1991), with higher scores reflecting greatersearching efficiency.

Shape School. The Shape School task for preschoolers was used to measure inhibitionand cognitive flexibility (Espy, 1997). The task follows a storybook format, depicting cartoon

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drawings of colored, shape figures (red, yellow, and blue; circles and squares) as response stim-uli. There are four task conditions, which are presented in order of increasing difficulty: control,inhibit, switch, and inhibit/switch. Because children younger than 4 years typically under per-form in the inhibit/switch condition (see Espy, 1997), the data for this condition are not reportedhere (see also Aarnoudse-Moens et al., 2009). Prior to each test condition, children were requiredto respond correctly to a set of practice stimuli. If they were unable to do so, the task was discon-tinued. In the first control condition, study children were asked to name as quickly as possiblethe colors of 15 shapes that were arranged on a page in three rows of five. In the inhibit condi-tion, children were told that shapes with happy faces were ready to go for school lunch, whereasthose with sad faces were not. Children were asked to name as quickly as possible the colornames of all the figures who were ready for lunch (i.e., the happy-faced shapes, N = 8), butnot the color names of those that were not ready (i.e., the unhappy- faced shapes, N = 7). Inthe switch condition, six of the shape figures were shown wearing hats, while nine were withouthats. Children were asked to name figures with hats by their shape and figures without hats bytheir color. Successful responding in this condition required the children to switch between twodifferent response rules. Each condition was timed and errors recorded. For the inhibition andswitch conditions, an efficiency score was calculated (efficiency = (number correct – number oferrors)/time taken). The control condition served primarily as a baseline measure of processingspeed (see Espy et al., 2006). The proportion of children who were unable to pass this conditiondue to non-compliance and/or color unfamiliarity was also examined.

Executive function composite. To obtain an overall measure of children’s executive func-tion performance, principal components analysis was used to assess whether the four tasksdescribed above loaded on a single common factor of executive function. A key variable fromeach task was identified for inclusion in this analysis based on two criteria: (1) the score that bestcaptured the executive demand/s of the task and (2) the score that most discriminated betweenvery preterm and full term children. These measures were: the highest move level achieved onthe Tower of Hanoi; the total number of FIST switch trials passed; the overall Visual Searchefficiency score; and the efficiency score for the Shape School inhibit condition. Children whohad been unable to complete a task were allocated the minimum score achieved for the task.Results of this analysis showed that all four measures loaded onto a single common factor thatexplained 52% of the variance. Factor loadings were all above .6 and communalities were accept-able (>.4). Based on this analysis, an executive function composite score was computed for eachstudy child by summing z-scores (based on the mean and SD of the full term group) for each taskand standardizing to a mean of 10 and standard deviation of 2.

Statistical Analysis

Data analysis proceeded in three stages. First, the performance of children born very preterm andfull term was compared on the WPPSI–R and on each of the four executive function tasks inaddition to the composite executive function measure using either a chi-squared test of indepen-dence for dichotomous outcomes or a multivariate analysis of variance (ANOVA) for continuousoutcomes. Multivariate ANOVA was used instead of t-tests in order to minimize Type 1 errorsarising from multiple significance testing. These analyses were then extended to examine theextent to which any between group differences in task performance might be accounted for,

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either in part or in full, by differences in family socioeconomic status (SES). This involved sta-tistically adjusting all bivariate associations between group status and each executive functionoutcome for the effects of family SES using multivariate analysis of covariance (MANCOVA),logistic or ordinal regression models.

In the second stage of analysis, relations between the extent of earlier white matter abnor-malities and later executive function outcomes were examined. For this analysis, all childrenin the very preterm group were classified on the basis of the severity of their cerebral whitematter abnormalities on neonatal MRI (none, mild, moderate–severe). The task performanceof these three preterm groups was then examined in relation to the task performance of chil-dren in the full term comparison group. This involved first examining the overall relationshipbetween the severity of white matter abnormality and EF task performance using either theMantel Haenzel Chi squared statistic or multivariate ANOVA, with tests for linear trends.Also examined were contrasts between each of the three preterm groups and the full termgroup.

In the final stage of the analysis, a multiple regression model was fitted to examine the extent towhich the severity of cerebral white matter abnormalities on term MRI independently predictedglobal executive outcome in the very preterm children after all other social and medical riskfactors shown in Table 1 were taken into account. This analysis was limited to the very pretermgroup given that few of the clinical risk factors associated with preterm birth were relevant forchildren born full term. Global executive outcome was measured using the composite executivefunction score described above. Model fitting was conducted using both forwards and backwardsvariable selection to identify the best fitting and most parsimonious model.

RESULTS

Extent of Cerebral White Matter Abnormalities and Global Cognitive Delay AmongChildren Born Very Preterm

On MRI at term equivalent, 23% (24/103) of very preterm infants showed no white matterabnormalities, 58% (60/103)showed mild, 15% (16/103) moderate and 3% (3/103) severe whitematter abnormalities. Given the small number of children with severe cystic white matter abnor-malities, children in the moderate and severe white matter abnormality groups were combined inall subsequent analyses.

At 4 years corrected age, children born very preterm obtained lower mean IQ scores than theirsame age full term peers (preterm: 95.4 ± 14.7 SD; term: 104.6 ± 13.5 SD, p < .0001), usinga short form of the WPPSI–R. Examination of rates of overall cognitive delay showed that 25%of the very preterm group met criteria for mild cognitive delay, that is, IQ > 1 SD but < 2 SDbelow the full term group mean, and 8.7% for severe cognitive delay, that is, IQ > 2 SD belowthe full term group mean, compared to 11.4% and 1.9% for the full term group, respectively.

Executive Functioning Profile of Children Born Very Preterm at Age 4 Years

Table 2 provides a descriptive profile of the performance of the very preterm and full term groupson the four executive function tasks and the executive function composite measure. Across all

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TABLE 2Performance of Full Term and Very Preterm Groups on Executive Function Measures

MeasureFull Term(N = 105)

Very Preterm(N = 104) p Adj. p∗

Tower of Hanoi†

% Passed training trials 95.2 89.0 .10 .25Mean (SD) Highest move level achieved 1.96 (1.38) 1.41 (1.29) .01 .01

Flexible Item Selection Task% Passed criterion trials 87.6 78.8 .09 .19Mean (SD) Correct abstractions 6.98 (1.97) 6.51 (2.33) .08 .07Mean (SD) Correct cognitive flexibility 3.44 (2.19) 2.83 (2.14) .04 .07

Visual Search% Completed all task trials 98.1 91.3 .03 .05Mean (SD) Total correct 6.71 (1.00) 6.28 (1.24) .01 .01Mean (SD) Efficiency score .25 (.15) .21 (.16) .04 .03

Shape School% Completed control condition 99.0 87.5 .001 .01Mean (SD) total correct on inhibit condition 13.49 (2.33) 12.79 (2.63) .06 .07Mean (SD) Inhibit efficiency score .43 (.27) .33 (.27) .02 .02Mean (SD) Total correct on switch condition 8.46 (3.67) 8.80 (3.28) .53 .87Mean (SD) Switch condition efficiency score .04 (.16) .05 (.15) .65 .56

Executive function composite 10.52 (1.86) 9.46 (2.01) <.0001 <.0001

∗Adj. for household socioeconomic status, †1 very preterm child excluded due to testing error.

measures, very preterm children performed less well than full term children. Effect sizes weregenerally small for individual tasks (d < .4), but in the moderate range for the executive functioncomposite measure (d = .54).

Tower of Hanoi. There was a tendency (p =.10) for very preterm children to have moredifficulty understanding the rules of the Tower of Hanoi task than children born full term. Verypreterm children were also less likely to graduate to the higher move levels of the task, suggest-ing that these children engaged in less planning and displayed more impulsive problem solving(p = .01, d = .34). This between group difference remained significant after adjustment forfamily SES (p = .01).

Flexible Item Selection Task (FIST). After exclusion of those children who failed thetask criterion trials (full term n = 14, very preterm n = 22), results showed the very pretermgroup tended to perform slightly worse on abstraction or concept formation trials (p = .08;d = .22) than the full term group. Both groups experienced difficulties on the cognitive flexi-bility or switch trials, with children in the very preterm group being less able to match a secondset of pictures according to a new dimension (p = .04, d = .31). After adjustment for family SES,this between group difference on the switch phase of the task was reduced slightly (p = .07).

Visual Search. Results from this task revealed that very preterm children experiencedgreater difficulty selectively identifying target stimuli and using an efficient search strategy.Specifically, they were less likely to be able to stay on task to complete all test trials (p = .03),and when they did, correctly identified fewer target stimuli (p = .01) and obtained lower mean

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32 WOODWARD ET AL.

search efficiency scores than their full term peers (p = .04). Effect size comparisons indicatedsmall effect sizes for group differences in the number of correct items nominated (d = .38) andthe efficiency of searching (d = .30). This pattern of results was robust to statistical adjustmentfor the effects of family SES.

Shape School. On the Shape School task, very preterm children were less likely to passthe control condition (p = .001) or to be able to complete all three task conditions (p = .02)than full term children. A MANOVA including the groups’ efficiency scores also revealed thatShape School performance was less efficient in the very preterm group (Wilk’s λ = .96, F(3,169)= 3.41, p = .02), with condition-specific comparisons indicating that the very preterm groupobtained lower mean efficiency scores on the inhibit condition (p = .02, d = .38) but notthe switch condition (p = .65). Closer inspection of the performance of both groups on theswitch condition suggested the presence of a developmental floor effect since almost all childrenobtained low efficiency scores. These findings remained largely unchanged after adjustment forthe effects of family SES.

Executive function composite. Consistent with the findings for each of the individualexecutive function tasks, very preterm children as a group obtained lower performance scoresthan their full term peers on the composite executive function measure (d = .54, p < .0001). Alsoin line with previous findings, this difference remained after statistical adjustment for family SES(p < .0001).

Executive Functioning Outcomes of Very Preterm Children With Varying Degreesof Cerebral White Matter Abnormalities

Table 3 describes the executive task performance of very preterm children with no, mild, andmoderate–severe white matter abnormalities relative to their full term peers. As shown, therewas clear evidence of a relationship between the extent of cerebral white matter abnormalitiesand children’s task performance on the Tower of Hanoi (planning), Visual Search (selective atten-tion), Shape School (inhibitory control), and executive function composite measure. Very pretermchildren in the moderate–severe white matter abnormality group exhibited the most impairedperformance on these four measures, followed by those children with mild abnormalities. Verypreterm children without white matter abnormalities appeared to obtain similar scores to childrenin the full term group. While significant associations between group and FIST task performancewere not observed, except with respect to the proportion of children passing criterion trials andthus capable of completing the task, a generally similar pattern of findings was still evident acrossthe four study groups despite attenuated numbers.

Further statistical evaluation of between group contrasts confirmed the absence of any perfor-mance differences between very preterm children without earlier white matter abnormalities andtheir full term peers across all measures. In contrast, very preterm children with moderate–severewhite matter abnormalities were characterized by the most impaired executive functioning per-formance, with performance impairments found across almost of the primary executive functionmeasures relative to their full term peers at age 4. The only exceptions were abstraction andcognitive flexibility scores on the FIST and the Shape School switch condition. These were too

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TAB

LE3

Exe

cutiv

eF

unct

ioni

ngO

utco

mes

ofC

hild

ren

Bor

nV

ery

Pre

term

Chi

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ndM

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Whi

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atte

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mal

ities

inR

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ren

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ullT

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Ful

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m(F

T)

Very

Pre

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�=(V

PT

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Valu

es

Mea

sure

(n=

105)

No

WM

A(n

=24

)M

ild

WM

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)

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=19

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oi%

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edtr

aini

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ials

95.2

95.8

87.9

82.4

.03

.90

.10

.06

Mea

n(S

D)

Hig

hest

mov

ele

vel

achi

eved

1.96

(1.3

8)1.

92(1

.32)

1.43

(1.2

7)1.

00(1

.02)

.01

.88

.02

.01

Flex

ible

Item

Sele

ctio

nTa

sk%

Pass

edcr

iteri

ontr

ials

87.7

100.

073

.368

.4.0

04.9

9.0

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(SD

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6.29

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.28)

.23

.43

.11

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Vis

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Com

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100.

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10.5

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86)

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8(1

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<.0

001

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33

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34 WOODWARD ET AL.

difficult for most children and therefore discriminated poorly between groups.In general, chil-dren with mild white matter abnormalities on term MRI also performed less well than their fullterm peers, although their performance difficulties appeared to be less marked than children withmoderate–severe white matter abnormalities. Specifically, children with mild white matter abnor-malities were less likely to graduate to the higher move levels of the Tower of Hanoi or completeall three Shape School task conditions. They were also less likely to understand the task require-ments of the FIST (concept formation) and those that did were somewhat poorer in shifting rules(cognitive flexibility).In addition, despite demonstrating efficiency scores on the Visual Searchtask that were comparable to their full term peers and reflective of an efficient search time, theywere less accurate in their identification of target stimuli.

Predictors of Executive Function Outcome Among Children Born Very Preterm

To examine the extent to which the presence and severity of cerebral white matter abnormalitiesdetected on term MRI made a unique and independent contribution to later executive functionrisk for children born very preterm, the above analysis was extended to include a number of othermedical and social risk factors associated with both preterm birth and executive functioningoutcomes. For this analysis the primary outcome was the executive function composite score.The results of this linear regression analysis showed that after taking into account all of theinfant medical and social risk factors shown in Table 1, white matter abnormality status at termequivalent remained a strong independent predictor of overall executive function performance atage 4 years (β = –.34, p = .0001). The only other significant net predictor was child gender (β =.28, p = .002), with females performing better than males. No significant interaction was foundbetween white matter abnormality status and gender. Jointly these two factors explained 19% ofthe variance in children’s executive performance, suggesting a moderate level of prediction. Thisanalysis suggests that early cerebral white matter abnormalities place very preterm children atincreased risk of executive function impairment during the preschool years over and above otherclinical and social background factors.

DISCUSSION

This prospective, longitudinal study of children born very preterm examined a number of keyexecutive functioning processes at age 4. Of particular interest, was the extent to which any iden-tified executive impairments or delays were explained by the presence and severity of cerebralwhite matter abnormalities that are commonly found on neonatal MRI in children born verypreterm. This study extends our understanding of the neuropsychological effects of preterm birthin a number of key ways. First, the examination of a diverse range of executive skills offers valu-able information about the profile of emerging strengths and difficulties in specific aspects ofexecutive function for this cognitively and educationally high risk group of children. Second,in contrast to existing neuroimaging studies, which have typically employed cross sectionaldesigns, the availability of neonatal MRI measures of early brain injury combined with prospec-tive follow-up data is helpful in clarifying the longer term neuropsychological implications ofearly neurological injury in the preterm infant. Finally, given that many preschool measures of

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NEONATAL MRI AND LATER EXECUTIVE FUNCTION 35

executive function do not have good age-based norms, the inclusion of a large, regionally repre-sentative, cohort of full term born comparison children of the same age represents an importantmethodological strength. The major findings from this study and their implications are discussedbelow.

Consistent with existing research, our results demonstrate that children born very pretermare at elevated risk of later executive difficulties, with these difficulties observable by age 4(Bohm, Smedler, & Forssberg, 2004; Edgin et al., 2008; Espy et al., 2002; Matthews, Ellis, &Nelson, 1996; Vicari et al., 2004). Furthermore, extending on previous studies that have tendedto adopt a narrow focus on a specific component of executive function such as working memory(Beauchamp et al., 2008; Luciana, Lindeke, Georgieff, Mills, & Nelson, 1999; Woodward et al.,2005), our results suggest that impairment may indeed be more pervasive, affecting a range ofexecutive abilities, similar to the findings reported by Anderson et al. (2004) in their school-agedcohort. Specifically, findings revealed adverse impacts of very preterm birth on the developmentof children’s planning abilities, selective attention, inhibitory control, and to a lesser extent cog-nitive flexibility. However, it is important to acknowledge that the observed effect sizes werelargely in the small to moderate range.While these small effect sizes could potentially reflect,at least to some extent, the effects of measurement error, this would seem unlikely to accountfor all our findings given the consistent pattern of results across multiple measures. Rather, itwould seem more likely that early impairments in executive function may be relatively subtle, atleast at this early stage of development. Findings also highlight the potential benefit of employ-ing multiple measures of a construct to improve measurement precision especially with youngerchildren.

With respect to the finding that cognitive flexibility appeared to be somewhat less impairedthan other aspects of executive functioning within our cohort of very preterm preschoolers, itis important to note a substantial number of children were unable to follow task requirements.For example, whereas only 12% of full term children failed the control condition, 27% and32%, respectively, of preterm children with mild and moderate–severe white matter abnormal-ities were unable to complete the task due to an inability to master task demands. In addition,it is important to note that cognitive flexibility also represents a higher order executive skillthat relies on the simultaneous engagement of several executive abilities. For instance, the FISTplaces demands on working memory as well as requiring the simultaneous inhibition of incorrectresponse tendencies. Findings from other studies examining cognitive flexibility in children bornvery preterm have tended to yield mixed results, with some demonstrating clear performanceimpairments on measures of shifting and spatial reversal (Aarnoudse-Moens et al., 2009; Bayless& Stevenson,2007; Taylor, Klein, Minich, & Hack, 2000) and others finding no differences(Curtis, Lindeke, Georgieff, & Nelson, 2002; Espy et al., 2002). Given the complex and chang-ing nature of this skill over the course of childhood, it is possible that these differences in resultsmay reflect the age of children at follow-up and/or the relative developmental immaturity of thiscomplex skill at younger ages. Indeed, although it has been shown that the ability to suppress atask irrelevant response can be reliably assessed by age 3 years in typically developing children(Carlson & Wang, 2007; Diamond & Taylor, 1996), the ability to switch flexibly from one stim-ulus dimension to another appears to be an emergent skill, making its accurate assessment belowthe age of 4 years somewhat problematic (Diamond, Carlson, & Beck, 2005; Jacques & Zelazo,2001). This may be particularly true in the case of high risk samples where there is often widevariability in development and in turn, considerable heterogeneity in children’s task performance.

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36 WOODWARD ET AL.

While it is unclear whether these observed impairments in executive functioning reflect devel-opmental delay or a true deficit, our findings are consistent with studies reporting executivefunction outcomes of very preterm children in middle childhood (Anderson & Doyle, 2004),adolescence (Taylor, Minich, Bangert, Filipek, & Hack, 2004), and early adulthood (Nosartiet al., 2007). Further follow-up of this representative cohort should help clarify how individualdifferences in executive functioning develop with age in this high-risk population

The most important finding from this study is that executive impairments appear to be asso-ciated with white matter pathology observed on neonatal MRI. More specifically, the resultsshowed that across all executive outcomes assessed, impairments were confined to those verypreterm children who had either mild or moderate–severe white matter abnormalities at termequivalent. Importantly, very preterm children without MRI white matter abnormalities wereindistinguishable from their full term peer in terms of their performance on tests of planning,cognitive flexibility, selective attention, and inhibitory control. This finding suggests that, at leastduring the preschool years, very preterm children who escape diffuse white matter abnormalitiesmay well be spared the adverse cognitive consequences commonly associated with being borntoo early. Although it is unfortunate that these children represent a relatively small proportion(approximately a quarter) of the total population of children born very preterm, this observationdoes offer considerable hope for parents. It also suggests that reducing white matter injury duringthe neonatal period needs to be an important target for neonatal interventions aimed at reducinglonger term cognitive and educational morbidities associated with preterm birth.

The observation that risks of later executive impairments increased with worsening severityof neonatal white matter abnormalities is of particular relevance here, given the known relationsbetween executive function and educational achievement. Preterm children with the most severeand pervasive executive impairments tended to be those with moderate to severe white matterabnormalities. A larger proportion of these children were likely to fail practice and criteriontrials on each task, suggesting that they did not understand task instructions or were unable tomeet the basic motor or cognitive demands of the task. For those able to complete the tasks,they were more likely to struggle across all measures. In contrast, while children with mild whitematter abnormalities were also characterized by more executive difficulties than their full termpeers, their task completion rates were higher and their performance impairments less severe.

The importance of intact cerebral white matter development for cognition function has beenwell documented (Filley, 2001; Geschwind & Kaplan, 1962; Skranes et al., 2008, 2009). Ashighlighted by Skranes et al. (2008), whereas executive dysfunction is commonly attributed tostructural or functional frontal pathology, the prefrontal cortex relies on the integrity of severalwhite matter tracts that connect it to other brain regions. Our findings suggests that early distur-bances to the development and microstructure of white matter tissue may adversely impact longerterm connectivity, placing very preterm children at increased risk of pervasive impairments inexecutive functioning.

One promising finding to emerge from these results for those responsible for monitoring thedevelopment of these children is that executive problems can be identified prior to school entry,thus allowing for the implementation of intervention programs and remediation strategies. Thisis important since it is well established that executive impairments impact a child’s academicachievement (Bull, Espy, & Wiebe, 2008; Clark et al., 2010) and social functioning (see Riggset al., 2006, for a review). Intervening at an early age, therefore, may help to equip these childrenwith skills and strategies that reduce the risk of later educational and social difficulties.

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Although this study sheds light on some of the challenges facing very preterm children,as well as the predictive value of neonatal white matter abnormalities in the development ofthese difficulties, several methodological limitations should be acknowledged. The first con-cerns the challenge of measuring children’s executive skills during the preschool period, andin particular, the reliance on unstandardized measures with limited psychometric evaluation(Carlson, 2005). This reflects the state of the field, but there is clearly an urgent need forcloser evaluation of what constructs these tasks measure, as well as their reliability and pre-dictive validity. Compounding these challenges is the fact that many of these executive skillsare relatively immature in preschool aged children, posing measurement and interpretationchallenges. Second, the inability of many of the very preterm children to complete all exec-utive function tasks likely served to reduce our statistical power to detect group differences.This also raises questions as to whether these tasks are suited for testing executive functionin children with diverse ability levels. Third, no neonatal MRI was available for children inthe full term comparison group. As a result, the extent of cerebral white matter abnormalitiesin these children is not known. However, unpublished estimates suggest that around 5–10%of the general population may exhibit mild white matter abnormalities, with moderate andsevere abnormalities rarely seen. Fourth, given the exclusive focus of this analysis on execu-tive function, the degree to which white matter abnormalities might influence general cognitivedevelopment, and more importantly, educational under-achievement has yet to be determined.Finally, the extent to which these observed executive function impairments might be secondaryto deficits in lower-level information processing, perceptual and motor skills also remainsunclear.

Nonetheless, study findings do extend our understanding of the nature of the executive func-tion difficulties experienced by children born very preterm and lend further support to therole of early white matter abnormalities in the evolution of later neurodevelopmental risk inthe very preterm infant (Clark, Woodward, Horwood, & Moor, 2008; Woodward et al., 2006;Woodward, Mogridge, Wells, & Inder, 2004). Further, these findings have a number of impli-cations for educators and neonatal care providers. First, for educators, it may be importantto recognize that although very preterm children with severe neurological abnormalities willtypically be identified and monitored from an early age, others may also experience subtle exec-utive impairments that although undetected, will pose challenges for learning and classroommanagement. This is important given the clear links between executive functioning and edu-cational achievement in general population samples (Blair & Razza, 2007; Bull et al., 2008;Clark et al., 2010). Thus, a potentially important avenue for future research would be to assessthe extent to which newly emerging, intensive executive function training strategies might assistvery preterm children in developing core executive skills (Diamond, Barnett, Thomas, & Munro,2007; Klingberg et al., 2005; Thorell, Lindqvist, Bergman Nutley, Bohlin, & Klingberg, 2009)that will support children’s learning, behavior, and social development. Second, for neonatalservice providers, findings suggest that reducing rates of white matter injury among pretermsurvivors needs to be an urgent priority if longer term outcomes are to be improved. Neonatalbrain monitoring may also be helpful in ensuring that cerebral injuries are detected early andappropriate follow-up services implemented to address the needs of these children and theirfamilies.

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ACKNOWLEDGMENTS

Special thanks to Michelle Davey, Jacqueline Knight, and Carole Spencer for assistance withdata collection, and also to study families for their time and support of this project.

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