brain 2009_ p45

BRAINA JOURNAL OF NEUROLOGY

Childhood brain insult: can age at insult helpus predict outcome?Vicki Anderson,1,2,5,6 Megan Spencer-Smith,1,5 Rick Leventer,1,3,6 Lee Coleman,4

Peter Anderson,1,5 Jackie Williams,1,5 Mardee Greenham1 and Rani Jacobs1,5

1 Murdoch Childrens Research Institute,

2 Department of Psychology,

3 Neuroscience,

4 Department of Radiology, RCH, Melbourne,

5 School of Behavioural Sciences and

6 Department of Paediatrics, University of Melbourne

Correspondence to: Vicki Anderson,

Department of Psychology,

Royal Childrens Hospital, Flemington Road,

Parkville, Victoria, 3052, Australia

E-mail: [email protected]

Until recently, the impact of early brain insult (EBI) has been considered to be less signicant than for later brain injuries,

consistent with the notion that the young brain is more exible and able to reorganize in the context of brain insult. This study

aimed to evaluate this notion by comparing cognitive and behavioural outcomes for children sustaining EBI at different times

from gestation to late childhood. Children with focal brain insults were categorized according to timing of brain insult,

represented by six developmental periods: (i) Congenital (n = 38): EBI: rstsecond trimester; (ii) Perinatal (n = 33); EBI: third

trimester to 1 month post-natal; (iii) Infancy (n = 23): EBI: 2 months2 years post-birth; (iv) Preschool (n = 19): EBI: 36 years;

(v) Middle Childhood (n= 31): EBI: 79 years; and (vi) Late Childhood (n = 19): EBI: after age 10. Groups were similar with

respect to injury and demographic factors. Children were assessed for intelligence, academic ability, everyday executive function

and behaviour. Results showed that children with EBI were at increased risk for impairment in all domains assessed.

Furthermore, children sustaining EBI before age 2 years recorded global and signicant cognitive decits, while children with

later EBI performed closer to normal expectations, suggesting a linear association between age at insult and outcome. In

contrast, for behaviour, children with EBI from 7 to 9 years performed worse than those with EBI from 3 to 6 years, and

more like those with younger insults, suggesting that not all functions share the same pattern of vulnerability with respect to

age at insult.

Keywords: brain injury; plasticity; outcome; IQ; executive function; behaviour

Abbreviations: AL= age at lesion; BRIEF = Behavioral Rating Inventory of Executive Function; EBI = early brain insult;ES = emotional symptoms; FSIQ= Full Scale Intelligence Quotient; HYP=Hyperactivity-Inattention Scale; PIQ=PerformanceIntelligence Quotient; SDQ=Strengths and Difculties Questionnaire; SES = Socio-economic status

IntroductionDespite a lively and continuing interest in this area, recovery

from early brain insult (EBI) remains imperfectly understood.

Pathological conditions that would almost certainly lead to

severe cognitive dysfunction in an adult have quite different con-

sequences for children (Aram, 1988; Bates et al., 2001; Jacobs

and Anderson, 2002; Anderson et al., 2005). Children with focal

doi:10.1093/brain/awn293 Brain 2009: 132; 4556 | 45

Received May 20, 2008. Revised September 1, 2008. Accepted October 10, 2008

The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.For Permissions, please email: [email protected]

left-hemisphere insult, for example, may go on to acquire age

appropriate language abilities, free from the symptoms of aphasia

observed following similar lesions in adulthood (Heywood

and Canavan, 1987; Taylor and Alden, 1997). Similarly, early

vascular accidents need not preclude normal or higher

intellectual and academic achievements (Smith and Sugar, 1975;

Ballantyne et al., 2008). Even when an entire cerebral hemi-

sphere is removed, children may develop relatively normal cogni-

tive function (Dennis and Whittaker, 1976). In contrast, children

sustaining generalized cerebral insult (e.g. traumatic brain injury)

display slower recovery and poorer outcome than adults with

similar insults (Anderson and Moore, 1995; Gronwall et al.,

1997; Taylor et al., 2002; Anderson et al., 2004, 2005). These

somewhat unpredictable recovery patterns after EBI are puzzling

and restrict health professionals capacity to identify children at

high risk for sequelae who may need more intensive follow-up

and intervention.

In search of a more accurate prognostic formula, researchers

have considered a range of factors that might reasonably be

assumed to inuence recovery. However, apart from the estab-

lished relationship between insult severity and outcome, these

studies have failed to identify consistent links between outcome

and specic insult characteristics (e.g. diffuse versus focal patho-

logy, laterality) (Bates et al., 2001; Herz-Pannier et al., 2002;

Chilosi et al., 2005; Stiles et al., 2008), presence of residual dis-

ability (e.g. hemiparesis, epilepsy) (Hartel et al., 2004; Chilosi

et al., 2005; Ballantyne et al., 2007), pre-insult child and family

factors (Ponsford et al., 1999; Anderson et al., 2006), and envir-

onmental parameters (e.g. socio-demographics, access to interven-

tions, parent/family function) (Breslau, 1990; Taylor et al., 2002;

Anderson et al., 2006; Catroppa et al., 2008). While each of these

factors appears to contribute incrementally to outcome, we fall

short of providing a complete picture of relevant predictors and

their interactions.

A further potential piece in the puzzle is the developmental

stage of the child at time of insult, with major controversy existing

regarding the potential impact of this dimension for neuro-

behavioural and psychological outcome. This debate is best illu-

strated by the contrasting plasticity versus early vulnerability

approaches, which dispute whether the immature brain has a

greater capacity for recovery than the mature or adult brain.

This debate is argued at both biological and cognitive levels,

although this article will limit its focus to the functional dimen-

sion. Plasticity theorists postulate that the young brain is imma-

ture, less committed and thus less susceptible to the impact of

cerebral damage. Plasticity is thought to be maximal early in

development when the central nervous system (CNS) is less rigidly

specialized (Kennard, 1936, 1940; Huttenlocher and Dabholkar,

1997), and synapses and dendritic connections remain unspecied.

Such exibility provides the capacity for transferring or reorganiz-

ing functions from damaged brain to healthy tissue. In contrast,

early vulnerability proponents postulate that the young brain is

uniquely sensitive to insult, and thus EBI is detrimental to devel-

opment. Donald Hebb (1947, 1949) argued that plasticity theories

ignored the possibility that brain insult will have different conse-

quences at different times throughout development. He concluded

that EBI may be more detrimental than later injury, because

cognitive development is critically dependent on the integrity of

particular cerebral structures at certain stages of development.

Thus, if a cerebral region is damaged at a critical stage of cognitive

development it may be that cognitive skills dependent on that

region are irreversibly impaired (Kolb, 1995; Luciana, 2003).

A review of the literature relevant to these theories provides

little clarication. While it is now evident that the young

brain has some capacity for neural restitution, via either neural

regrowth or anatomical reorganization (Kolb, 2005; Giza, 2006),

there is ongoing controversy as to the implications of these

processes. Even if neural restitution does occur, full recovery

may be limited by either: (i) inappropriate connections being

established (Stein and Hoffman, 2003; Kolb et al., 2004) resulting

in dysfunctional behavioural recovery; or (ii) a crowding effect

(Vargha Khadem et al., 1992; Aram and Eisele, 1994), where

functions normally subsumed by damaged tissue are crowded

into remaining healthy brain areas, with a general depression

of all abilities. In support of such concerns, studies of children

with pre-natal lesions, or those sustaining insults during the

rst year of life, consistently report poorest functional outcomes

(Riva and Cassaniga, 1986; Duchowny et al., 1996; Anderson

et al., 1997; Ewing-Cobbs et al., 1997; Leventer et al., 1999;

Jacobs et al., 2007).

While the debate continues, there is little disagreement that

developmental factors play a central role in outcome from EBI.

The challenge remains to describe the nature of this relationship.

To date, most research has employed single-condition approaches

(e.g. dysplasia, traumatic brain insult), examining age effects

within such conditions. Such designs are unable to investigate

consequences of insults sustained from gestation to adolescence,

as these conditions are necessarily age-specic (e.g. traumatic

brain injury is post-natal). To investigate developmental inuences

comprehensively, studies need to incorporate conditions occurring

throughout gestation and childhood. Further, previous research

has often assumed that age effects will be linear, that is, the

younger the insult the poorer the outcome. Such an assumption

is inconsistent with knowledge of brain maturation, where devel-

opment is step-wise (Casey et al., 2000; Gogtay et al., 2004),

with critical maturational periods for processes such as myelination

and synaptogenesis (Klinberg et al., 1999; Gogtay et al., 2004),

separated by more stable periods. Cognitive theorists describe

similar stage-like processes (Piaget, 1963; Flavell, 1992). It is

likely that disruption during one of these predetermined, neural

or cognitive growth periods will cause ow on effects, as the

establishment of other later emerging skills is thrown off course

(Mosch et al., 2005). To date, insufcient evidence is available

to pinpoint the timing or scope of these critical periods for

humans, however, animal literature provides some insights (Kolb,

1995; Kolb et al., 2005), suggesting that age and recovery are not

linearly related, but are associated, via underlying neural processes

such as synaptogenesis, dendritic aborization and myelination.

This study, we believe, is the rst to attempt to systematically

address these age-related hypotheses, by examining outcomes

from EBI sustained across gestation and childhood, when brain

development is most rapid. To address the potential non-linearity

between age and outcome, we have constructed age at lesion

(AL) groups, dened according to developmental timetables

46 | Brain 2009: 132; 4556 V. Anderson et al.

for key neurological processes in the prefrontal cortex as well as

developmental timetables for cognitive processes which recruit this

region. These groupings are consistent with principles emerging

from animal studies (e.g. Kolb et al., 2004), and preliminary

child studies (Pavlovic et al., 2006; Jacobs et al., 2007) which

identify critical periods for neural development, and account

for parallels in brain structure and function. These parallels are

highlighted by Goldman Rakic (1987), who has shown that skill

emergence is tightly linked to the peak period of synaptogenesis

in the brain region by which it is underpinned. These studies

suggest that both neurological and cognitive developmental

processes occurring at the time of brain insult are central to out-

comes. Of note, these AL groups were necessarily heterogeneous

for cause of insult as many CNS insults occur only at specic

stages of development (e.g. penetrating head injury, developmen-

tal malformations). To minimize any confounding effects caused

by this heterogeneity: (i) only children identied as having focal

abnormalities on MRI scan were included in the sample; and

(ii) AL groups were compared with respect to lesion characteristics

(size, location, laterality). In this context we have addressed the

following questions: (i) Is EBI associated with decits in intelli-

gence, academic achievement, and executive abilities in the daily

context and emotional and psychological function? and (ii) Does

age at brain injury have long-term implications for these outcomes

in later childhood and adolescence?

Method

SampleThe sample comprised 164 children, including 92 (56.1%) males, aged

between 10 and 16 years at recruitment (Mean=13.07, SD=1.88),

with a history of EBI. Participants were ascertained between 2005 and

2007, through the Royal Childrens Hospital, Melbourne, Australia.

Eligible children were identied via hospital records and consecutive

referrals to neuroscience outpatient clinics.

Inclusion criteria were: (i) aged 1016 at assessment; (ii) MRI evi-

dence of focal brain pathology; (iii) brain insult at least 12 months

prior to assessment, to allow for stabilization of recovery processes;

(iv) cognitive skills sufcient to participate in study protocol. Exclusion

criteria were: (i) evidence of diffuse pathology (e.g. closed head injury)

on MRI scan; and (ii) non-English speaking. We did not exclude chil-

dren based on low IQ as we were interested in achieving a represen-

tative sample. Eleven children were excluded based on study criteria.

Approaches were made to 215 families, with 51 declining to partici-

pate (77% participation rate) due to time burden (n=18), lack of

interest (n=29) or distance (n=3). Table 1 provides demographic

information on the sample.

The sample was divided into six AL groups, based on timing of

cerebral growth spurts (van Praag et al., 2000; Kolb et al., 2004):

(i) Congenital (n=38): EBI during rst and second trimester;

(ii) Peri-natal (n=33); EBI within the third trimester to 1 month

post-natal; (iii) Infancy (n=23): EBI 2 months2 years post-birth;

(iv) Preschool (n=19): EBI 36 years of age; (v) Middle childhood

(n= 31): EBI 79 years of age; and (vi) Late childhood (n=19): EBI

after age 10.

Diagnoses were necessarily diverse, in order to provide sufcient

children with EBI across the developmental span of interest, and

included stroke, contusion from falls, penetrating head injury,

tumour, malformation, dysplasias, cyst and abscess. Details of the

mechanism of insult and the extent, laterality and region of lesion

across the groups are provided in Table 2.

Materials

Demographic information

In a structured interview parents provided information on their childs

medical and developmental history, academic progress and parental

occupation and educational level. Socio-economic status (SES) was

determined using Daniels Scale of Occupational Prestige (Daniel,

Table 1 Demographics of sample

Congenital Perinatal Infancy Preschool Mid Childhood Late Childhood Total group

n 38 33 23 19 31 20 164

Gender, n (%) males 19 (50.0) 23 (69.7) 13 (56.5) 12 (63.2) 16 (51.6) 9 (45.0) 92 (56.1)

SES Mean (SD) 4.40 (1.4) 4.07 (0.84) 4.04 (1.06) 4.09 (1.13) 4.21 (1.29) 4.25 (1.11) 4.20 (1.06)

Age at testing Mean (SD) 12.97 (1.86) 13.24 (1.98) 12.48 (1.97) 12.57 (1.72) 12.90 (1.72) 14.45 (1.46) 13.07 (1.86)

Age at insult Mean (SD) NA NA 1.35 (0.93) 4.80 (1.07) 8.30 (0.80) 11.85 (1.60) NA

Time since insult Mean (SD) NA NA 11.10 (2.19) 7.78 (1.98) 4.59 (2.10) 2.50 (1.30) NA

Age at diagnosis Mean (SD) 3.56 (3.91) 1.96 (2.19) 1.60 (1.23) 4.95 (1.03) 8.47 (1.05) 11.91 (1.59) 5.20 (4.27)Time from diagnosis Mean (SD) 9.40 (3.68) 10.97 (3.68) 10.79 (1.85) 7.68 (1.99) 4.30 (2.05) 2.54 (1.28) 7.79 (4.14)Handedness (Right), n (%) 19 (50.0) 23 (69.7) 13 (56.5) 12 (63.2) 16 (51.6) 9 (45.0) 92 (56.1)

Developmental delays

Speech delay, n (%) 16 (42.1) 12 (36.4) 4 (17.4) 0 3 (9.7) 0 35 (21.3)

Motor delay, n (%) 19 (50.0) 15 (45.5) 5 (21.7) 2 (10.5) 2 (6.5) 1 (5.0) 44 (26.8)

No delays, n (%) 14 (36.8) 11 (33.3) 17 (73.9) 17 (89.5) 24 (77.4) 16 (80) 101 (61.6)

Academic assistance

Special school/aide, n (%) 15 (39.7) 16 (48.5) 9 (39.1) 4 (21.1) 9 (29.0) 2 (10.0) 56 (34.1)

Extra tuition, n (%) 12 (31.3) 5 (15.2) 7 (30.4) 3 (15.8) 7 (22.6) 5 (25.0) 39 (23.8)

Normal progress, n (%) 11 (30.0) 12 (36.3) 6 (26.1) 12 (63.1) 15 (48.4) 13 (65.0) 69 (42.1)

Seizures 24 (63.1) 16 (48.5) 14 (60.9) 5 (26.3) 11 (35.5) 5 (25.0) 75 (46.9)

P50.001, P50.01.

Can age at insult predict outcome? Brain 2009: 132; 4556 | 47

1983), which rates parent occupation on a 7-point scale, where a high

score reects low SES.

MRI scans

(i) Acquisition: MRI scans were conducted as part of routine clinical

practice prior to recruitment. For those who had not undergone scan-

ning, or whose scans were unavailable, scans were conducted simul-

taneously with neurobehavioural evaluation. All scans were conducted

on a 1.5 Tesla scanner, and axial and coronal slices were obtained. (ii)

Coding protocol: A coding protocol developed by Leventer et al.

(1999) was employed to describe brain insult characteristics including:

brain regions affected (lobes, subcortical structures), laterality (left,

right, bilateral), extent of insult (focal, multifocal), volume of brain

affected (number of regions) and mechanism of brain insult

(developmental, infective, ischaemic, neuroplasm or traumatic).

Details are provided in Table 3. A subset of four scans was double

coded, demonstrating 97.5% internal consistency.

Brain insult

Timing of brain insult was based on a combination of MRI, brain

biopsy, and medical record (clinical history, medical investigations).

For acquired brain insults, where timing is generally precise, ratings

were based on information provided by clinical history. In contrast,

for pre- and peri-natal events, rating of injury timing was not precise,

but was divided into trimesters, based on current understanding of

the likely timing of specic structural abnormalities. Where timing

of insult was not evident, consensus was reached through discussion

with a paediatric neurologist and neuropsychologist. Ten cases were

double-rated, with 100% consistency. Mechanism of insult was coded

as: developmental, infective, ischaemic, neuroplastic, or traumatic.

Presence of seizure history and neurological abnormalities were

noted. Age at diagnosis indicated the time at which the brain condi-

tion was identied and diagnosed. For acquired injuries age at diag-

nosis and time of insult were identical. For pre- and peri-natal insults,

diagnosis was frequently delayed, although for the majority of children

developmental delay had been detected and early interventions imple-

mented from an early age.

Neurobehavioural measures

(i) Intelligence: The 4-subtest version of the Wechsler Abbreviated

Intelligence Scale (WASI: Wechsler, 1999) was administered.

Scores derived were Verbal (VIQ), Performance (PIQ) and Full

Scale Intelligence Quotients (FSIQ) (Mean= 100, SD=15).

(ii) Academic Ability: The Wide Range Achievement Test-3

(WRAT-3: Wilkinson, 1993) assessed reading, spelling and arith-

metic. Scaled scores were used in analyses (Mean= 10, SD=3).

(iii) Executive function in everyday life: The Behavioral Rating

Inventory of Executive Function (BRIEF: Gioia et al., 2000)

(parent and teacher) provided an index of attention and

Table 3 Insult mechanism across age at lesion groups

Congenital Perinatal Infancy Preschool Middle Childhood Late Childhood Total Group

n 38 33 23 19 31 20 164

Mechanism of pathology

Developmental, n (%) 30 (78.9) 5 (15.2) 0 (0) 0 (0) 0 (0) 0 (0) 35 (21.3)

Infective, n (%) 0 (0) 0 (0) 1 (4.3) 1 (5.3) 1 (3.2) 1 (5.0) 4 (2.4)

Ischaemic, n (%) 2 (5.3) 25 (75.8) 6 (26.1) 6 (31.6) 12 (38.7) 6 (30) 57 (34.8)

Neuroplastic, n (%) 5 (13.2) 3 (9.1) 14 (60.9) 8 (42.1) 10 (32.3) 6 (30) 46 (28.0)

Traumatic, n (%) 0 (0) 0 (0) 2 (8.7) 4 (21.1) 8 (25.8) 7 (35.0) 21 (12.8)

Regiona

Frontal, n (%) 21 (55.3) 23 (69.7) 8 (24.8) 9 (47.2) 14 (45.2) 11 (55.0) 86 (52.4)

Extrafrontal, n (%) 21 (55.3) 23 (69.7) 8 (24.8) 9 (47.2) 14 (45.2) 11 (55.0) 105 (64.0)

Subcortical, n (%) 29 (76.3) 23 (69.7) 17 (73.9) 11 (57.9) 14 (45.2) 11 (55.0) 91 (55.5)

Laterality

Left, n (%) 8 (21.1) 11 (33.3) 9 (39.1) 8 (42.1) 14 (45.2) 4 (20.0) 54 (32.9)

Right, n (%) 9 (23.7) 6 (18.2) 8 (34.8) 5 (26.3) 7 (22.6) 9 (45.0) 44 (26.8)

Bilateral, n (%) 21 (55.3) 16 (48.5) 6 (26.1) 6 (31.6) 10 (32.3) 7 (35.0) 66 (40.2)

Extent

Focal, n (%) 18 (47.4) 18 (54.5) 16 (69.6) 14 (73.7) 18 (58.1) 13 (65.0) 97 (59.1)

Multifocal/diffuse, n (%) 20 (52.6) 15 (45.5) 7 (30.4) 5 (26.3) 13 (41.9) 7 (35.0) 67 (40.9)

a There is some overlap across categories for this variable. P50.001.

Table 2 Summary of terms for brain insult characteristicsand related factors

Variable Denition

Region

Frontal Brain pathology involves the frontal lobe.

Extra-frontal Brain pathology involves the parietal, occipitalor temporal lobe.

Subcortical Brain pathology involves the corpus callosum,thalamus or basal ganglia.

Posterior fossa Brain pathology involves the brain stem orcerebellum.

Laterality

Left hemisphere Brain pathology conned to left hemisphere.

Right hemisphere Brain pathology conned to right hemisphere.

Bilateral Brain pathology located in both left and righthemispheres.

Extent

Focal Brain pathology is conned to one area.

Multifocal Brain pathology involves two or more areas.

Diffuse Brain pathology involves the whole brain.


executive abilities in everyday life. The BRIEF comprises 86 items

over two subscales: (i) Behavioral Regulation (BRI); and (ii)

Metacognition (MCI). A Global Executive Composite (GEC)

was also calculated (Mean=50, SD=10).

(iv) Psychological function: The Strengths and Difculties Question-

naire (SDQ: Goodman, 1997) (parent and teacher) rated childrens

behaviour over the previous 6 months. The SDQ is scored on a

likert scale and includes 25 items, providing ve subscales: Emo-

tional Symptoms (ES), Conduct Symptoms (CS), Hyperactivity-

Inattention (HYP), Peer Problems (PP), Prosocial Behaviour

(PSB). A Total Difculties (TOT) score was derived and ranked

as normal, borderline and abnormal, as per scoring instructions.

ProcedureThis study was approved by the Human Research Ethics Committee,

Royal Childrens Hospital, Melbourne, Australia. Eligible children were

identied via medical records, neuroradiology meetings or outpatient

clinics. Families were contacted to seek their participation and mailed

details of the study and requests for written consent. Consenting

families were seen at an outpatient clinic, with a small number of

children assessed at home, for family convenience. Children were eval-

uated on an individual basis, by a trained child psychologist.

Assessments lasted approximately one hour and during this time par-

ents completed questionnaires.

Statistical analysisFor the WASI and WRAT-3, some children were unable to complete

measures due to low functioning. In these cases, missing data were

recoded conservatively to two SDs below the mean. For the WASI,

eight children in the Prenatal and one in the Perinatal group were

recoded. For the WRAT-3, eight children in the Prenatal, two in the

Perinatal and one in the Infancy group were recoded. Data missing

for other reasons (e.g. failure to return a questionnaire) were not

recoded.

Quantitative analyses were conducted using SPSS (version 14.0). AL

groups were compared (ANOVA) to identify demographic differences.

To address hypothesis 1, the total sample was compared to published

test norms, using single sample t-tests. For hypothesis 2, preliminary

analyses were conducted to determine group differences for demo-

graphic and medical variables, using ANOVA. Tukeys HSD analyses

were used to identify individual group differences. MANOVA was

used to compare AL groups across each domain. Effect size was deter-

mined by 2. When group differences were observed, Tukeys HSD

was calculated.

Power analysis was conducted prior to study commencement,

based on results from our previous studies (Anderson et al., 2004,

2005), and indicated that the study required a sample of 20 partici-

pants per group (one-tailed alpha 0.05, power set at 0.95) to detect

a difference of 2/3 to 1 SD, that is a clinically signicant difference,

between the groups. AL group size was determined accordingly.

Individual impairment scores were also derived, based on test man-

uals. For the WASI and WRAT-3: (i) normal function: within 1 SD

of test mean; (ii) mild impairment: one to two SD below test mean;

(iii) severe impairment: 42 SD below test mean. For the BRIEF:(i) normal function: 565; and (ii) clinical range: 65 or above. Forthe SDQ, total scores were classied as normal, borderline or abnor-

mal, using the following cut-offs: parent version: normal: 013;

borderline 1416; abnormal: 1740; teacher version: normal: 011;

borderline 1215; abnormal: 1640. Chi-square analyses were

conducted on these data. Due to small numbers in some cells, mild

and severe impairment groups were collapsed for these analyses.

Results

Sample characteristicsNo group differences were identied for gender, SES or handed-

ness. A signicant age at test difference was identied,

F(5,158) = 3.21, P=0.009, 2 = 0.09, revealing that Late

Childhood group was older than the Congenital (P= 0.04),

Infancy (P=0.007), Preschool (P=0.02), and Middle Childhood

(P=0.037) groups. Age was not used as a covariate in analyses,

however, as all measures reported are age-standardized. As

expected given the nature of the groups, group differences were

also present for age at diagnosis, F(5,149) = 64.25, P50.001,2 = 0.68, and time since diagnosis, F(5,149) = 39.95, P50.001,2=0.57. AL groups also showed distinct differences with respect

to outcomes. Risk of developmental delay, as reported by primary

caregiver, was associated with earlier AL, 2(20, n= 163) = 39.12,

P50.001, V= 0.50, with high frequency of such delays inCongenital and Peri-natal groups. For academic assistance, again

the earlier AL groups (Congenital, Peri-natal and Infancy) had

high rates, but group differences failed to reach signicance,

2(10, n= 162) = 17.93, P=0.06, V= 0.24. Finally, signicant

group differences were identied for presence of seizures, 2(5,

n=158) = 17.44, P=0.004, V=0.332, with a large proportion

of children in the Congenital group with epilepsy/seizures

(SR=1.7) and a small proportion in the Preschool group (Table 1).

Mechanisms of insult are provided in Table 2, illustrat-

ing signicant group differences, 2(20, n= 163) = 150.10,

P50.001, V= 0.48, consistent with the heterogeneity ofthe sample. There were no group differences for region of insult

[frontal, 2(5, n= 164) = 7.84, P=0.17, V= 0.22; extrafrontal,

2(5, n= 164) = 9.74, P=0.08, V= 0.24; subcortical, 2(5,

n= 164) = 5.08, P=0.41, V= 0.18], or extent of insult (unifocal/

multifocal), 2(5, n= 164) = 5.46, P=0.36, V= 0.18, suggesting

that groups did not differ signicantly with respect to lesion

characteristics.

Comparing EBI to normativeexpectationsAs illustrated in Table 4, using total group data, children with EBI

achieved poorer scores than the normal population (P50.001) onall measures. For the WASI, the EBI group means ranged from

approximately 3/5 to 1 SD below normative means, with greatest

discrepancies recorded for VIQ (14.12 points). For academic abil-

ity, all mean differences were signicant (P50.001) and greaterthan 2/3 SD. Of note, Arithmetic abilities were particularly poor

in the EBI group (scaled score = 6.13), with group mean 41SDbelow expectations.

Parent ratings of executive function (BRIEF) were elevated rela-

tive to test expectations (all P50.001). BRI, MCI and GEC were all41 SD above the test mean. Teacher ratings indicated evengreater deviation from normal (all P50.001) for BRI, MCI and


GEC. For both parent and teacher SDQ ratings, group differences

were signicant (P50.001).

Comparisons across AL groups

A. Comparison of group means

Intellectual ability

MANOVA detected a signicant multivariate effect, Wilks

K=0.785, F(15,420) = 2.57, P50.001, 2=0.08. Univariateanalyses showed group differences for three measures: FSIQ:

F(5,154) = 5.11, P50.001, 2 = 0.14; VIQ: F(5,154) = 5.08,P50.001, 2 = 0.14; and PIQ: F(5,154) = 5.77, P50.001,2 = 0.16 (Table 5). For FSIQ, the Congenital group performed

more poorly than the two older AL groups (Middle

Childhood: P=0.01; Late Childhood: P=0.04). The Infancy and

Perinatal groups recorded lower scores than the Middle Childhood

group (P=0.02 and 0.03, respectively). The Congenital group

achieved signicantly lower VIQ and PIQ scores than the three

older AL groups (Preschool: P=0.04; Middle Childhood: P=0.01;

Late Childhood: P=0.02). For PIQ, the pattern was identical, with

the Congenital groups results poorer than the three older AL

groups (Preschool: P=0.01; Middle Childhood: P50.001; Late

Childhood: P=0.02). A signicant group difference was also

found between the Perinatal and Middle Childhood groups

(P=0.03), in favour of the latter. These results indicate that

children with insults prior to preschool are at greater risk for

long-term intellectual problems than those sustaining later insults,

especially those with congenital lesions.

Table 5 Performances across groups

Congenital Perinatal Infancy Preschool Mid Childhood Late Childhood Total group


n 38 32 22 19 30 19 160

FSIQ Mean (SD) 79.05 (16.10) 81.00 (18.40) 79.91 (17.53) 93.79 (13.67) 94.41 (19.99) 94.53 (17.08) 87.93 (20.10)VIQ Mean (SD) 81.58 (16.70) 86.44 (19.34) 86.41 (20.66) 100.32 (20.62) 102.00 (18.11) 98.68 (21.74) 85.88 (18.53)PIQ Mean (SD) 80.63 (18.68) 82.41 (18.27) 81.59 (19.73) 95.16 (16.54) 98.17 (20.22) 96.32 (19.99) 91.19 (20.49)Academic achievement

Reading Mean (SD)+ 6.71 (4.61) 6.70 (4.07) 6.50 (4.75) 8.58 (3.36) 9.48 (3.85) 9.15 (3.48) 7.74 (4.24)

Spelling Mean (SD)+ 6.66 (4.09) 7.06 (4.09) 7.05 (4.12) 8.21 (3.87) 9.55 (3.68) 8.85 (3.42) 7.81 (4.01)

Arithmetic Mean (SD) 4.94 (3.16) 5.55 (3.96) 4.50 (3.66) 7.53 (2.88) 7.71 (3.55) 7.15 (3.31) 6.13 (3.65)Executive function

Parent ratings

BRI Mean (SD) 63.63 (12.75) 67.65 (18.44) 63.05 (11.52) 52.94 (12.14) 63.33 (13.74) 55.80 (13.17) 62.23 (14.67)MCI Mean (SD)+ 67.13 (11.89) 66.87 (12.46) 64.68 (7.56) 58.11 (12.31) 63.40 (10.83) 58.33 (12.16) 63.97 (11.66)

GEC Mean (SD) 66.88 (12.09) 68.58 (14.90) 64.95 (8.44) 56.67 (12.14) 64.30 (11.71) 57.87 (12.42) 64.27 (12.72)Teacher ratings

BRI Mean (SD) 70.88 (21.81) 67.14 (18.33) 67.60 (14.80) 57.83 (10.47) 66.00 (16.99) 61.64 (18.50) 66.12 (17.90)

MCI Mean (SD) 75.18 (16.08) 73.21 (18.82) 73.60 (13.62) 65.11 (14.11) 69.63 (15.01) 68.21 (19.40) 71.46 (16.31)

GEC Mean (SD) 75.91 (18.07) 72.68 (19.15) 73.10 (13.09) 63.44 (12.80) 71.07 (15.22) 67.43 (19.76) 71.47 (16.85)

P50.001, P50.01, +P50.05.

Table 4 Differences between clinical sample and test means for outcome domains

Measure Variable Test mean Sample mean SD t df P Mean difference

WASI FSIQ 100 87.93 20.10 7.60 159 50.001 12.08VIQ 100 85.88 18.53 9.64 159 50.001 14.12PIQ 100 91.19 20.49 5.44 159 50.001 8.81

WRAT-3 Reading 10 7.74 4.24 6.74 159 50.001 2.26Spelling 10 7.81 4.01 6.90 159 50.001 2.19Arithmetic 10 6.13 3.65 13.44 159 50.001 3.86

BRIEF parent BRI 50 62.23 14.67 10.14 147 50.001 12.23MCI 50 63.97 11.66 14.57 147 50.001 13.97GEC 50 64.27 12.72 13.65 147 50.001 14.27

BRIEF teacher BRI 50 66.12 17.90 10.77 142 50.001 16.12MCI 50 71.46 16.31 15.74 142 50.001 21.46GEC 50 71.47 16.85 15.23 142 50.001 21.47

SDQ parent TOT 8.2 13.65 7.25 9.48 158 50.001 5.45SDQ teacher TOT 6.5 10.85 6.36 8.32 147 50.001 4.35

Means for SDQ are Australian norms based on a sample of 717 years old. From website www.sdqinfo.com which sites this reference: Mellor, D. Normative data forthe Strengths and Difculties Questionnaire in Australia. Aust Psychol 2005; 40: 21522.


Academic ability

MANOVA detected a signicant multivariate effect, Wilks

K=0.84, F(15,420) = 1.81, P50.03, 2=0.06. Univariate analysesshowed group differences for Reading: F(5,154) = 3.01, P=0.013,

2 = 0.089, Spelling: F(5,154) = 2.56, P=0.03, 2 = 0.08; and

Arithmetic: F(5,154) = 4.21, P=0.001, 2 = 0.12. Despite the

signicant group difference for Reading, and the trend for earlier

AL groups (Congenital, Perinatal, Infancy) to perform more poorly,

comparisons were not signicant. The Congenital and Middle

Childhood groups differed signicantly, in favour of the older AL

group on tests of Spelling (P=0.04) and Arithmetic (P= 0.02).

In addition, a signicant difference between the Infancy and

Middle Childhood groups was identied on Arithmetic (P=0.01).

These ndings highlight a trend towards poorer academic abilities

in children with earlier lesions.

Executive abilities

(a) Parent ratings: For all three summary indices AL group means

were abnormally elevated (460) with the exception of thePreschool and Late Childhood groups. MANOVA detected a sig-

nicant multivariate effect, Wilks K=0.85, F(15,387) = 1.62,

P=0.06, 2 = 0.06, with univariate analyses detecting consistent

differences: BRI: F(5,142) = 3.19, P=0.01, 2 = 0.101; MCI:

F(5,142) = 2.63, P=0.03, 2 = 0.09; and GEC: F(5,142) = 3.28,

P=0.01, 2 = 0.10. For BRI and GEC, a single difference was

found between the Perinatal and Preschool groups (P=0.01,

P=0.02, respectively), with the Perinatal group more impaired.

For GEC, the difference between Congenital and Preschool

groups approached signicance (= 0.06); (b) teacher ratings:

MANOVA detected no differences, Wilks K=0.91, F(15,373) =

0.89, P=0.57, 2 = 0.03, and univariate analyses were also

non-signicant: BRI: F(5,137) = 1.49, P=0.20, 2 = 0.05; MCI:

F(5,137) = 1.22, P=0.30, 2 = 0.04; GEC: F(5,137) = 1.5, P=0.18,

2 = 0.05.

Psychological status

MANOVA identied no signicant multivariate AL group effect,

for either parent, F(5,153) = 2.0, P=0.08, 2 = 0.06 or teacher

ratings on the SDQ, F(5,142) = 1.22, P=0.30, 2 = 0.04, despite

the observation that total group results were signicantly elevated

in comparison to normative expectations (Table 6). Univariate

analyses revealed a signicant group difference on the HYP sub-

scale of the parent SDQ, F(5,153) = 2.70, P=0.02, 2 = 0.08, with

Post hoc analyses revealing a signicant difference between

Perinatal and Late Childhood groups (P50.01), in favour of thelatter. For teacher ratings only, the ES subscale showed group

differences, F(5,142) = 2.52, P=0.03, 2 = 0.08, with the

Congenital group more impaired than the Preschool

group (P=0.04).

B. Analysis of frequency of impairments


Figure 1 illustrates the proportion of children in each AL group

falling within the normal, mildly impaired and severely impaired

ranges. For FSIQ, 2(5, 160) = 15.60, P50.01, V= 0.31, therewas a larger proportion of children with impairments in the

Congenital group (SR=1.5), and a smaller proportion in the

Middle Childhood group (SR=1.5) than expected. For VIQ,

2(5, 160) = 16.37, P50.01, V= 0.32, the proportion of childrenwith impairments from the Late Childhood group was smaller than

expected (SR=1.7). For PIQ, 2(5, 160) = 22.56, P50.001,V= 0.38, impairment rates also differed across groups, with

more children with impairments in the Congenital group

(SR=2.1), and less in the Preschool (SR=1.7) and MiddleChildhood groups (SR=1.8).Academic ability

Figure 2 illustrates the proportion of children in each group

within the normal, mildly impaired and severely impaired ranges.

Chi-square analysis for Reading, 2(5, 160) = 16.19, P50.01,V= 0.32, revealed more children with impairments in the

Perinatal group (SR=1.7), and less in the Middle Childhood

group (SR=1.5) than expected. For Spelling, 2(5, 160) =15.26, P50.01, V= 0.31, the proportion of children with impair-ments from both the Middle (SR=1.8) and Late Childhood

Table 6 Psychological function across groups (parent and teacher reports)

Congenital Perinatal Infancy Preschool Middle Childhood Late Childhood Total group

SDQ results

Parent ratings

ES Mean (SD) 3.33 (2.32) 3.82 (2.53) 4.00 (2.99) 2.95 (2.68) 3.40 (2.34) 2.28 (2.05) 3.38 (2.50)

CS Mean (SD) 2.25 (2.13) 2.48 (1.91) 2.30 (2.16) 1.47 (2.17) 2.53 (1.87) 2.22 (2.29) 2.26 (2.06)

HYP Mean (SD)+ 5.08 (2.84) 5.91 (2.87) 4.78 (2.28) 4.32 (2.61) 4.70 (2.65) 3.17 (2.46) 4.83 (2.74)

PP Mean (SD) 3.44 (2.22) 3.91 (2.80) 3.22 (1.83) 3.00 (1.94) 3.47 (1.98) 2.00 (2.17) 3.30 (2.26)

PSB Mean (SD) 6.78 (2.36) 7.06 (2.61) 6.96 (1.85) 8.32 (1.77) 7.40 (2.01) 7.06 (2.39) 7.19 (2.24)

TOT Mean (SD) 14.11 (7.41) 15.67 (8.26) 14.30 (6.57) 11.74 (7.29) 13.97 (5.71) 9.67 (6.98) 13.65 (7.25)

Teacher ratings

ES Mean (SD)+ 3.49 (2.05) 2.28 (1.94) 3.43 (2.46) 1.67 (1.37) 2.77 (2.53) 2.67 (1.80) 2.79 (1.16)

CS Mean (SD) 1.49 (2.11) 1.69 (2.14) 1.14 (1.74) 0.72 (0.90) 1.33 (1.81) 0.87 (1.69) 1.23 (1.85)

HYP Mean (SD) 4.37 (2.59) 4.10 (2.58) 4.43 (1.99) 3.44 (2.57) 4.23 (2.49) 3.47 (2.85) 4.09 (2.50)

PP Mean (SD) 3.09 (2.38) 3.14 (2.49) 2.00 (2.19) 2.67 (2.00) 2.27 (2.10) 1.87 (1.55) 2.60 (2.23)

PSB Mean (SD) 6.23 (2.81) 6.17 (2.93) 6.76 (1.92) 7.56 (1.98) 6.33 (2.82) 7.80 (1.57) 6.64 (2.56)

TOT Mean (SD) 12.43 (7.62) 11.21 (6.67) 11.00 (5.60) 8.56 (4.53) 10.93 (6.18) 8.87 (5.36) 10.85 (6.36)

P50.001, P50.01, +P50.05.CS=Conduct Symptoms Scale; HYP=Hyperactivity-Inattention Scale; PP= Peer Problems Scale; PSB= Prosocial Behaviour Scale; TOT=Total Difculties.


groups was smaller than expected (SR=1.5). For Arithmetic,2(5, 160) = 11.79, P=0.04, V= 0.27, there was a larger

proportion of non-impaired children in the Preschool group

(SR=1.9).

Executive abilities and psychological function

No signicant group differences were recorded on any of the

BRIEF or SDQ measures, as seen in Figs 3 and 4.

DiscussionThis study explored neurobehavioural and psychological impair-

ment after EBI to determine the impact of such insults and if

developmental stage at insult had a differential inuence on out-

come, in order to add to the plasticity-early vulnerability debate.

Children sustaining EBI during six different developmental periods,

from gestation to late childhood, were compared across a range of

Percentage impaired on Full Scale IQ across groups

*based on test norms

Percentage impaired on Verbal IQ across groups


Percentage impaired on Performance IQ across groups


100%

A

B

C

75%

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Normal Mildly impaired Severely impaired



Fig. 1 Impairment ratings for AL groups for IQ. (A) FSIQ, (B)VIQ, (C) PIQ.

Percentage impaired on WRAT-3 Reading across groups


Percentage impaired on WRAT-3 Spelling across groups


Percentage impaired on WRAT-3-Arithmetic across groups





Cong

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100%

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Fig. 2 Impairment ratings for AL groups for academicachievement. (A) Reading, (B) Spelling, (C) Arithmetic.


outcome domains. These AL groups were derived from animal

literature to correspond with documented periods of neural

growth, and were similar on key demographic (gender, SES) and

lesion variables (lesion size, extent, laterality). Assessments were

conducted during late childhood/adolescence, when recovery pro-

cesses had subsided and maturational processes were largely

complete.

Comparisons between the total EBI sample and normative

expectations revealed signicant impairments across all domains

under studyintelligence, academic ability, everyday executive

function and psychological function. Results conrm that children

with EBI are at increased risk of impairment when compared to

population expectations. The second aim of the study examined

the impact of EBI at different stages of development. As predicted,

results indicated that, depending on age at insult, outcomes dif-

fered signicantly. Patterns of impairment also varied across

domains, suggesting that different stages of brain development

may be critical for different functions.

Do children with EBI differ frompopulation expectations?As previously noted, children with EBI, as a group, performed

consistently poorly for all domains studied, in keeping with

much previous research (Ewing-Cobbs et al., 1997; Jacobs et al.,

2007). Mean scores for the EBI group were not severely impaired,

but fell approximately 1 SD below expectations, representing per-

formances hovering at the lower end of average. Further, for

cognitive and academic measures, between 50% and 60% of

children recorded scores within the normal range. The exception

to this pattern was Arithmetic, where 63.1% of the EBI sample

recorded impaired function.

Percentage impaired on BRIEF-BRI across groups


Percentage impaired on BRIEF-MCI across groups


Percentage impaired on BRIEF-GEC across groups


Normal Clinical range



Cong

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Fig. 3 Impairment ratings for AL groups for everyday attentionusing the BRIEF. (A) BRI, (B) MCI, (C) GEC.

Percentage impaired on SDQ (parent form) across groups


Percentage impaired on SDQ (teacher form) across groups


100%

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Normal


Borderline Abnormal

Fig. 4 Impairment ratings for AL groups for psychologicalfunction using the SDQ. (A) Parent rating, (B) Teacher ratings.


While it may be argued that the use of normative data rather

than an appropriately constructed healthy comparison group limits

the interpretability of our data, these results are consistent with

previous research with other populations (Kinsella et al., 1997;

Catroppa and Anderson, 2000), and indicate that arithmetic

skills are differentially vulnerable to brain injury, regardless of

when it occurs during childhood, perhaps because of the complex

range of skills recruited in these activities. In contrast, for everyday

executive skills and behaviour, mean scores were consistently

outside the normal range. For executive skills, parents rated their

children as experiencing difculties, with teacher ratings even

higher. For these measures, impairment rates were consistently

between 45% and 55%, signifying high risk and emphasizing

the need for formal evaluation to extend further than intellectual

and academic domains.

These results support previous research documenting

the detrimental effects of EBI (Anderson and Moore, 1995;

Anderson et al., 2005), and provide little evidence to corroborate

plasticity notions, which argue for good outcome from EBI.

Does age at insult inuence long-termoutcome?Age at insult does impact on long-term outcome, although this

relationship may be more complex than expected. Firstly, with

respect to broad outcomes, children with earlier lesions were at

elevated risk for a number of disabilities, including developmental

delay and epilepsy, and with a trend to high risk for academic

difculties. Further, within the cognitive domain (intelligence, aca-

demic ability) group differences were substantial, with a dichot-

omy between EBI sustained before and after age 2, and with

younger AL associated with poorer outcome. This pattern was

consistent across group means and impairment ratings. In particu-

lar, children with Congenital and Perinatal insults performed uni-

formly very poorly, achieving signicantly lower scores than those

injured after age 7 years on all intellectual measures and spelling

and arithmetic. These results demonstrate that brain insult prior to

age 2 leads to poorest cognitive outcome, with later childhood

insult resulting in lesser impact.

For everyday executive function and behaviour the pattern was

somewhat different, and the discrepancy between earlier and

later AL groups was not as well dened. Once again, the Late

Childhood group appeared relatively intact, with Congenital and

Perinatal groups demonstrating signicant problems. In contrast,

the Middle Childhood group, with insults between 7 and 9 years,

was at greater risk, tending to function closer to those early lesion

groups. Children with Preschool insults (36 years) performed

best, and closest to normative expectations, while the Infant

group (1 month to 2 years) showed better outcome in executive

function.

These results support an early vulnerability perspective, with

children sustaining insults prior to and around the time of birth

being most at risk for global decits, while children with insults in

the second decade of life escape relatively unscathed. In contrast

to animal data, which suggests a non-linear relationship between

AL and outcome, our ndings illustrate a relatively linear pattern,

at least for cognitive and academic skills. For behaviour, where

animal researchers might argue skills are more complex, this rela-

tionship is more complex, and children with AL between 7 and

9 years have increased vulnerability, perhaps due to growth spurts

in frontal lobes during this period (Gogtay et al., 2004).

While early recovery issues have been addressed in the animal

literature (Kolb, 2005; Giza, 2006), there are concerns about

whether such data translates directly to humans, where brain

insults are less circumscribed and where cognitive abilities are

more complex. To date, human research has only contributed

partially to the eld, due to difculties in identifying children

with brain insults across development, and challenges controlling

for potential confounders such as insult severity, pathology volume

and environment. This study chose to address these previous

obstacles by recruiting children based on AL rather than the

traditional condition-based approach. In doing so, the resultant

sample necessarily included children for whom mechanism of insult

varied, creating the risk that ndings might reect differences

in brain pathology rather than AL. In order to minimize this risk,

we conned our recruitment to children with focal brain patholo-

gies and collected detailed information on brain pathology (extent,

laterality, lesion size), allowing us to control for these potential

confounds. We believe that this approach has provided important

data to assist in understanding the impact of EBI from an empirical

perspective. Of note, we employed a categorical approach to

quantifying developmental stage. While these categories reect

CNS growth spurts, they are necessarily inexact and may mask

specic critical developmental periods. To extend these ndings,

prospective, multi-centre research facilitating larger sample sizes

is required.

Additionally, in this study we focussed our hypotheses on the

timing and characteristics of the structural lesion, with less empha-

sis on their neurological consequences. Thus, while some research

has demonstrated that presence of seizures has a negative inu-

ence on development (Hartel et al., 2004; Chilosi et al., 2005;

Ballantyne et al., 2007), we chose to conceptualize presence of

seizures as a negative outcome of EBI, similar to speech delay

or motor impairment, in that it would restrict the childs capacity

to acquire skills and knowledge and function adequately within

his/her environment. Supplementary analyses, demonstrating

that presence of seizures is most frequent in earlier insults, sug-

gests that early brain injury, together with seizures, may confer

added risk for the child, indicating that seizures should be seen

as a potential mediator of long-term function. However, as we

did not collect detailed data on age at seizure onset, frequency

and type of seizures, or medication, we are unable to examine the

specic relationships further.

A further limitation of previous literature is a failure to account

for age at testing. In the animal literature, researchers have shown

that even when keeping AL constant, different outcomes are seen

depending on the age at which outcome is assessed. In their rat

studies, Kolb and colleagues (Dallison and Kolb, 2003) showed

that, if they assessed function on a single post-natal day, recovery

seemed complete, however, if they evaluated animals on a later

post-natal day, their results were less positive. This pattern has

recently been noted in childhood stroke literature, where children

assessed at 5 years appear intact, but when tested several years


later, clear impairments are observed (Bates et al., 2001; Stiles

et al., 2008).

Finally, while our results are consistent with increased vulner-

ability of the young brain, we did identify different patterns of

vulnerability, even using a limited range of outcome measures.

This suggests that inclusion of a broader range of outcome

domains may identify still more differences, reecting either

regions specic to brain development or, alternatively, critical per-

iods for the emergence of particular behaviours.

ConclusionsOur study supports an early vulnerability model for EBI. Results

showed that children with EBI are at increased risk for impairment

in all domains assessed. Children sustaining EBI before age 2 years

recorded global and signicant cognitive decits, with pre- and

perinatal insult being particularly detrimental. Children with EBI

after age 2 functioned closer to normal expectations, suggesting

a roughly linear association between AL and outcome. In contrast,

within the behavioural domain, children with EBI from 7 to 9 years

performed worse than those with EBI from 3 to 6 years, and more

like those with younger insults, suggesting that not all functions

share the same pattern of vulnerability with respect to age at

insult. These ndings have important implications for clinical

practice, suggesting that children who sustain very EBIs will have

long-term impairments and require additional support and man-

agement across cognitive, academic and psychological domains.

FundingNational Health and Medical Research Council of Australia;

Australian Research Council.

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