ORIGINAL ARTICLE

Neuroanatomical consequences of very preterm birthin middle childhood

Ilyse D. Lax • Emma G. Duerden • Sarah Y. Lin •

M. Mallar Chakravarty • Elizabeth J. Donner •

Jason P. Lerch • Margot J. Taylor

Received: 23 October 2011 / Accepted: 7 April 2012 / Published online: 11 May 2012

� Springer-Verlag 2012

Abstract Individuals born preterm can demonstrate

reductions in brain volume, cortical surface area and

thickness. However, the extent of these neuroanatomical

deficits and the relation among these measures in middle

childhood, a critical developmental period, have not been

determined. We assessed differences in brain structure

by acquiring high-resolution T1-weighted scans in 25

children born very preterm (\32 weeks gestational age)

without significant post-natal neurological sequelae and

32 age-matched term-born children (7–10 years). Children

born very preterm had decreased brain volume, surface

area and cortical thickness compared to term-born chil-

dren. Furthermore, children born preterm did not display

the robust relation between total brain volume and basal

ganglia and thalamic volume apparent in the term-born

children. Cortical thickness analyses revealed that the

cortex was thinner for children born preterm than term-

born children in the anterior cingulate cortex/supplemen-

tary motor area, isthmus of the cingulate gyrus, right

superior temporal sulcus, right anterior insula, postcentral

gyrus and precuneus. Follow-up analyses revealed that

right precuneus thickness was correlated with gestational

age. Thus, even without significant postnatal medical

sequelae, very preterm-born children showed atypical

brain structure and developmental patterns in areas related

to higher cognitive function. Disruptions of the typical

neurodevelopmental trajectory in the third trimester of

pregnancy likely underlie these differences persisting into

middle childhood.

Keywords Preterm � Brain structure � Cortical thickness �Volume � Surface area � Children

Introduction

Premature birth is a significant social and health issue

globally in terms of both associated mortality and long-

term morbidity, as well as financial implications for

health, education and social service sectors. Close to

10 % of all births worldwide were preterm (\37 weeks of

gestation) in 2005 with the highest rates occurring in

Africa and North America, with 11.9 and 10.6 % of

I. D. Lax � E. G. Duerden � S. Y. Lin � M. J. Taylor (&)

Department of Diagnostic Imaging, Hospital for Sick Children,

555 University Avenue, Toronto, ON M5G 1X8, Canada

e-mail: margot.taylor@sickkids.ca

E. G. Duerden � M. Mallar Chakravarty �J. P. Lerch � M. J. Taylor

Department of Neuroscience and Mental Health, Research

Institute, Hospital for Sick Children, Toronto, Canada

S. Y. Lin � J. P. Lerch

Mouse Imaging Centre, Hospital for Sick Children,

Toronto, Canada

M. Mallar Chakravarty

Kimel Family Translational Imaging-Genetics Research

Laboratory, Research Imaging Centre, Centre for Addiction

and Mental Health, Toronto, Canada

E. J. Donner � M. J. Taylor

Department of Neurology, Hospital for Sick Children,

Toronto, Canada

J. P. Lerch

Department of Medical Biophysics, University of Toronto,

Toronto, Canada

M. J. Taylor

Department of Psychology, University of Toronto,

Toronto, Canada

123

Brain Struct Funct (2013) 218:575–585

DOI 10.1007/s00429-012-0417-2

Author's personal copy

births, respectively (Beck et al. 2010). These rates have

dramatically increased over the past 20 years in devel-

oped countries such as the United States, the United

Kingdom, Canada and Scandinavian countries (Pennell

et al. 2007). Although the mortality of very preterm

(\32 weeks of gestation) infants has decreased over

recent years, morbidity has not. Even 50–60 % of healthy

preterm children, whose neonatal period was not marked

by medical complications and who had normal or near-

normal head ultrasounds, are reported to have cognitive

deficits once they enter school (Bohm et al. 2002; Breslau

et al. 2000; Frisk and Whyte 1994; Pharoah et al. 2003;

Taylor et al. 2000). This is not a maturational lag as

children born very preterm continue to experience diffi-

culties as they develop through adolescence (Isaacs et al.

2004; O’Brien et al. 2004). These infants are born in the

third trimester when rapid neurodevelopmental events

take place and are thus vulnerable to primary injury and

secondary maturational disturbances (Volpe 2009).

Recent research using magnetic resonance imaging

(MRI) has demonstrated cerebral volumetric deficits in

preterm infants persisting throughout childhood, adoles-

cence and adulthood (Allin et al. 2004; Fearon et al.

2004; Gimenez et al. 2006; Isaacs et al. 2000; Marti-

nussen et al. 2009; Nosarti et al. 2002, 2004, 2008; Pet-

erson et al. 2000; Taylor et al. 2011). At term equivalent

age, manifestations of brain insults include white matter

abnormalities, reductions in white and gray matter vol-

umes and ventricular enlargement (Inder et al. 2003,

2005; Limperopoulos et al. 2005; Peterson et al. 2003;

Srinivasan et al. 2007; Thompson et al. 2007). MRI

studies of brain volume in childhood, adolescence and

young adulthood reveal similar abnormalities. A study by

Nosarti et al. (2008) found that adolescents (14–15 years

of age) born preterm exhibited reduced gray matter (GM)

volume in the temporal, frontal and occipital cortices and

cerebellum. Additionally, areas of the frontal and tem-

poral lobes have increased GM volume compared to

controls, indicating early overgrowth of these regions or

that typical selective pruning may not be occurring at the

same rate in adolescents born preterm. Reductions in

white matter (WM) were concentrated in the brainstem,

internal capsule, temporal and frontal regions while tem-

poral, parietal and frontal regions showed increased WM

volume. Those with neonatal ultrasound evidence of peri-

ventricular haemorrhage and ventricular dilatation exhib-

ited the greatest GM and WM abnormalities. Additionally,

several areas where very preterm individuals demonstrated

decreased GM and WM volume were associated with ges-

tational age (GA) at birth and may have mediated cognitive

impairment.

More recently, longitudinal MRI investigations have

outlined the development of cortical thickness and its

relation with cognitive functioning across age and clinical

groups (Jones et al. 2000; Shaw et al. 2006, 2007, 2008).

Other studies have specifically examined cortical thick-

ness in adolescents born preterm or with very low birth

weight (VLBW). Martinussen et al. (2005) examined

cortical thickness, surface area and brain volume in

15-year-old adolescents with VLBW or small for gesta-

tional age. Regional thinning was found in the parietal,

temporal and occipital lobes in the VLBW group com-

pared to controls. However, regional thickening was

found in the frontal and occipital lobes. Similarly, Nagy

et al. (2011) found that the cortex was significantly

thinner in adolescents born preterm in focal regions of the

temporal and parietal cortices. Both studies found that

differences in cortical thickness were most pronounced

for those born at the shortest gestation or with the lowest

birthweight.

MRI studies have not examined cortical thickness in

very preterm-born children at school age, a vital period of

development when the cognitive delays associated with

preterm birth are most frequently identified. Previous

volumetric MRI studies have identified differences in

cortical GM and WM volumes as well as subcortical

structures of preterm-born adolescents (Allin et al. 2004;

Gimenez et al. 2006; Nosarti et al. 2008; Martinussen

et al. 2009; Taylor et al. 2011). Thus, the aim of the

present study was to determine whether school-age chil-

dren born very preterm without significant medical

sequelae at birth display structural abnormalities in cor-

tical and subcortical regions. Also, as frontal–striatal

dysfunction is implicated in the cognitive deficits seen

in this population (e.g., Nosarti et al. 2009), we also

measured striatal volumes to determine if there were

anatomical atypicalities of the striatum. In accordance

with the literature, we hypothesised that children born

very preterm would exhibit neuroanatomical differences,

including reduced cortical and subcortical volume, corti-

cal surface area and thickness, particularly in temporal

and parietal regions. During early development efferent

projections from the thalamus connect with migrating

neurons that terminate in the cortical plate (Rakic 1988)

that permit direct neuronal connections between cortical

GM and thalamus. This relation would indicate a strong

volumetric connection between the cortex and the thala-

mus. Thus, we were interested to determine whether

children born preterm would have compensatory changes

in subcortical volume relative to the volume of the whole

brain. Also, thinner cortical regions were expected to be

correlated with GA and birthweight such that those born

earlier and/or with lower birthweight would have more

profound deficits. Similarly, areas of thinner cortex in the

preterm group were hypothesised to be correlated with IQ

and parent ratings of executive function.

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Materials and methods

Participants

The participants were 57 children. Twenty-five, 15 boys

and 10 girls, were born very preterm (mean age = 8.72

years, range 6.92–9.89 years; mean GA = 27.4 weeks,

range 24–31 weeks) and 32 were typically developing

control children, 15 boys and 17 girls (mean age = 8.41,

range 7.06–9.86). The groups did not differ significantly in

terms of age (t = 1.4, p = 0.6) or sex (v2 = 0.97,

p = 0.425). The typically developing children were

recruited through fliers at the Hospital for Sick Children

and announcements in the hospital newsletter, as well as

fliers at public schools in Toronto. All were term-born

without a neurological or psychiatric history or scholastic

difficulties.

The children born very preterm were recruited from the

Neonatology Follow-up Clinics at the Hospital for Sick

Children, and were those who did not experience serious

neurological sequelae during the post-natal period. We

did not include children with periventricular leukomalacia

(PVL) or severe intraventricular haemorrhage (IVH),

grade 3 or 4. Fifteen of these children had normal head

ultrasounds at birth. Four children had grade 1 IVH, two

children had grade 2 IVH, and four children had sube-

pendymal haemorrhage, identified by cranial ultrasound at

birth.

During a recruitment interview, all participants, preterm

and term-born children, were screened for: (1) a medical

history of neurological or developmental disease, (2)

inability to tolerate the MRI environment and (3) having

standard contra-indications for MRI such as metallic or

electronic implants in the body. The Hospital for Sick

Children research ethics board approved the study protocol.

Written informed consent was obtained from parents and

informed assent from the children.

Behavioural assessments

IQ was measured using the 2-subtest Wechsler Abbreviated

Scale of Intelligence [WASI (Wechsler 2003)] for all 25 of

the participants born very preterm, and the majority

(n = 29) of the typically developing controls; participants

had IQs[88. The parents completed the Behaviour Rating

Inventory of Executive Function (BRIEF) which docu-

ments difficulties with executive function of the children

in everyday life. This questionnaire has high internal

consistency (alphas = 0.8–0.98), test–retest reliability

(rs = 0.82) and convergent validity established with a

variety of other measures of executive function (Gioia

et al. 2000).

Imaging parameters

MRI was performed with a 1.5-T whole-body scanner (GE

Excite) using a product 8-channel head coil. An anatomical

scan was obtained for each child using a 3D FSPGR (fast

spoiled gradient recalled) sequence (axial, FOV = 256 cm,

voxel size = 0.93 9 0.93 9 1.5 mm).

Image processing

Anatomical MRI images were analysed with the Cortico-

metric Iterative Vertex-based Estimation of Thickness

(CIVET) image-processing environment, an automated

pipeline (Lerch and Evans 2005). The T1-weighted images

were corrected for MR non-uniformity artefacts (Sled et al.

1998), skull stripped (Smith 2002) and aligned to stereo-

taxic space (Collins et al. 1994). The brain was then tissue

classified into WM, GM and cerebrospinal fluid (CSF)

using a neural net classifier (Zijdenbos et al. 2002; Tohka

et al. 2004). Partial volume effect classification was used to

extract the inner and outer cortical surfaces with 81,924

vertices each. Cortical thickness was then calculated in

native space using the linked distance between the outer

and pial surfaces at each vertex (Lerch and Evans 2005).

Images were smoothed using a 20-mm surface-based dif-

fusion kernel (Chung and Taylor 2006) and non-linearly

registered towards a template surface (Boucher et al. 2009;

Lyttelton et al. 2007). In addition to the measures of cor-

tical thickness calculated at 81,924 vertices across the

cortex for each image, WM, GM and CSF volumes and

surface area were calculated for the whole brain and each

cortical lobe. These estimates were obtained by non-line-

arly warping each T1 image towards a segmented atlas

(Collins et al. 1994; Chakravarty et al. 2008). Subcortical

volumes (striatum, globus pallidus and thalamus) were

obtained by customising a high-resolution subcortical atlas

derived from serial histological data (Chakravarty et al.

2006) using a region-of-interest nonlinear registration

procedure (Chakravarty et al. 2009). These basal ganglia

and thalamus segmentations had been validated using

manual gold-standard segmentations, against other auto-

mated segmentation techniques, and intraoperative elec-

trophysiological recordings in humans during stereotactic

neurosurgery (Chakravarty et al. 2008, 2009).

Statistical analyses

Statistical analyses were performed on the brain volume,

cortical surface area and cortical thickness data. Global

differences in brain volume, including CSF, GM, WM and

total brain volume, were compared by use of MANCOVA

using sex as a covariate. Differences in GM and WM

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volumes as a proportion of total brain volume were cal-

culated and were subsequently tested for between-group

differences using a MANOVA. A similar MANCOVA was

used to investigate between-group differences in basal

ganglia and thalamus volumes and the relation between

total brain volume and subcortical volumes. Global dif-

ferences in cortical surface area and cortical thickness were

also calculated for each hemisphere as well as for the entire

brain. Between-group differences in surface area and cor-

tical thickness at a lobular level were investigated using a

MANCOVA. The anatomical delineations of the lobes

were as follows: the frontal lobe region on the lateral

surface of the brain extended from the frontal pole poste-

riorly to the central sulcus and inferiorly to the lateral fis-

sure; medially the frontal lobe region extended posteriorly

to the central sulcus and inferiorly to the callosal sulcus.

The parietal lobe region on the lateral and medial surfaces

of the brain extended from the central sulcus posteriorly to

the parieto-occipital fissure and on the lateral surface

inferiorly to the lateral fissure. The temporal lobe region

extended from the anterior temporal pole posteriorly to the

preoccipital notch with the superior border being the lateral

fissure and inferior border the inferior temporal sulcus. The

occipital lobe region on the lateral surface of the hemi-

sphere extended from the preoccipital notch posteriorly to

the occipital pole. In the medial surface of the hemisphere

the occipital lobe region included the territory of the

cuneus and the posterior portion of the lingual gyrus.

At a regional level, vertex-based cortical thickness

analyses were conducted to examine group differences

using Surfstat software (Worsley et al. 2009) and thres-

holded for statistical significance using random field theory

(Worsley et al. 1999). The cluster-forming threshold was

set at p \ 0.001. Correlations between average cortical

thickness for significant clusters, from the between-group

cortical thickness analysis, and GA, birthweight, IQ and

BRIEF scores were examined.

Results

Behavioural results

Children born very preterm had significantly lower 2-sub-

test IQ scores (n = 25, M = 101.12, SE = 2.70) than the

subset of term-born children with IQ scores (n = 29,

M = 117.48, SE = 2.60), t(52) = 4.36, p \ 0.001. Also,

the subset of children born very preterm with BRIEF

reports (n = 20, M = 53.40, SE = 2.00) had significantly

higher scores on this measure than the subset of term-born

children with BRIEF reports (n = 28, M = 47.93,

SE = 1.22), t(32.59) = 2.33, p \ 0.05, indicating that the

preterm-born children had poorer behavioural regulation

and metacognition (knowledge and awareness of one’s own

cognitive processes) than the term-born children.

Imaging results

Brain volume

Total brain volume was significantly lower in the very

preterm group than in the control group, F(1, 54) = 16.04,

p \ 0.001, partial g2 = 0.23. WM volume also differed

between groups, with children born preterm showing

decreased volume compared to controls, F(1, 54) = 15.67,

p \ 0.001, partial g2 = 0.23. Similarly, GM volume was

significantly lower in the very preterm group compared to

the control group, F(1, 54) = 8.14, p = 0.005, partial

g2 = 0.13. However, these results were not maintained

when adjusting for total brain volume [WM: F(1,54) =

2.11, p = 0.15, partial g2 = 0.03; GM: F(1,54) = 2.67,

p = 11 partial g2 = 0.05]. CSF volume did not differ

between the two groups, F(1,54) = 0.82, ns (not signifi-

cant; see Table 1a).

Cortical WM, as a proportion of total brain volume,

tended to be higher in the term-born (mean = 0.58,

SD = 0.02) than the preterm-born group (M = 0.57,

SD = 0.03), F(1, 55) = 2.85, ns. Conversely, cortical GM,

as a proportion of total brain volume tended to be higher in

the preterm-born group (mean = 0.396, SD = 0.02) than

the term-born group (mean = 0.389, SD = 0.017), F(1,

55) = 3.60, ns.

Subcortical volumes

Children born preterm had smaller basal ganglia and tha-

lamic volumes than term-born children. The preterm chil-

dren had significantly smaller striatum volumes, F(1,54) =

4.39, p \ 0.05, partial g2 = 0.08, and globus pallidus

volumes, F(1,54) = 11.32, p \ 0.005, partial g2 = 0.17,

than controls. A similar pattern was found for thalamic

volume; children born preterm showed significantly smal-

ler thalamic volumes than control children, F(1,54) =

20.86, p \ 0.001, partial g2 = 0.28 (see Table 1b).

To examine the relation between total brain volume and

subcortical volume within the two groups, Pearson corre-

lations between total brain, basal ganglia (striatum and

globus pallidus segmentations) and thalamic volumes were

examined using a bootstrapping procedure. In the term-

born group, total brain volume was significantly positively

correlated with the striatum (r = 0.65, p \ 0.001), globus

pallidus (r = 0.64, p \ 0.001), and thalamus volumes

(r = 0.81, p \ 0.001) (see Fig. 1a, c, e). These results were

maintained when residualizing out the effects of age (stri-

atum: r = 0.65, p \ 0.001; globus pallidus r = 0.65,

p \ 0.001; thalamus: r = 0.8, p \ 0.001). In contrast, total

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brain volume and striatum (r = 0.27, ns), globus pallidus

(r = -0.11, ns) and thalamus volumes (r = 0.11, ns), were

not correlated in the preterm-born group (see Fig. 1b, d, f).

These findings were also maintained when controlling

for age (striatum: r = 0.27, p = 0.2; globus pallidus:

r = -0.12, p = 0.58; thalamus: r = 0.1, p = 0.61). The

lack of a significant relation between total brain volume

and subcortical volumes, illustrate that the basal ganglia

and thalamus may not develop proportionately with the

whole brain in children born very preterm.

Cortical surface area

Children born preterm had significantly less surface area for

the entire cortex than term-born children, F(1,54) = 14.06,

p \ 0.001, partial g2 = 0.21 (see Table 1c); this was

also the case for the right and left hemispheres separately,

right: F(1, 54) = 14.38, p \ 0.001, partial g2 = 0.21, left:

F(1,54) = 13.42, p \ 0.005, partial g2 = 0.20. At a lobar

level, when averaged across hemispheres, children born

preterm showed reduced surface area in the frontal,

F(1,54) = 6.00, p \ 0.05; temporal, F(1,54) = 10.82,

p \ 0.005; parietal, F(1,54) = 6.09, p \ 0.05; and occipital

lobes, F(1,54) = 16.35, p \ 0.001 (see Table 1c). Group

accounted for 10 % of the variance in frontal and parietal

lobe surface areas, 17 % of the variance in temporal lobe

surface area, and 23 % of occipital lobe surface area (partial

g2 = 0.10, 0.10, 0.17 and 0.23, respectively).

Cortical thickness

Children born preterm showed significantly lower mean

cortical thickness for the entire cortex than term-born

children, F(1,54) = 5.13, p \ 0.05, partial g2 = 0.09 (see

Table 1d). The same pattern was also seen in right and left

hemispheres separately, right: F(1,54) = 4.20, p \ 0.05,

partial g2 = 0.07, left: F(1,54) = 8.08, p \ 0.01, partial

g2 = 0.13.

When examining group differences in cortical thickness

at a lobar level, children born preterm showed decreased

mean cortical thickness in the frontal, F(1,54) = 4.07,

p \ 0.05, temporal, F(1,54) = 5.90, p \ 0.05, and parietal

lobes, F(1,54) = 4.39, p \ 0.05, when averaged across

hemispheres. Group accounted for 8 % of the variance in

parietal lobe cortical thickness, 7 % of the variance in

frontal lobe cortical thickness and 10 % of temporal lobe

cortical thickness (partial g2 = 0.08, 0.07 and 0.10,

respectively). No significant difference in cortical thickness

was found between groups in the occipital lobes,

F(1,54) = 0.74, ns (see Table 1d).

A whole-brain, vertex-based approach was used to

identify the focal regions of reduced cortical thickness. The

cortex was significantly thinner for children born very

preterm in seven distinct clusters. The right anterior cin-

gulate cortex/supplementary motor area (corrected for

multiple comparisons, p \ 0.001), left isthmus of the cin-

gulate gyrus (corrected p \ 0.005), right superior temporal

sulcus (corrected p \ 0.05), right anterior insula (corrected

p \ 0.05), right postcentral gyrus (corrected p \ 0.05) and

precuneus bilaterally (corrected p \ 0.05) were signifi-

cantly thinner in the preterm-born group relative to controls

(see Fig. 2; Table 2). Between-group differences were

similar when IQ was included as a covariate and also when

children with brain abnormalities at birth on ultrasound

Table 1 Group differences in average brain volumes, cortical surface

area and thickness

Preterm-born Term-born F-value

Mean Standard

deviation

Mean Standard

deviation

(a) Brain volume (cm3)

Total brain 1,098.5 77.7 1,188.2 121.4 16.04***

WM 626.4 56.4 689.4 73.5 15.67***

GM 435.1 36.5 460.0 55.0 8.14**

CSF 36.9 9.2 38.8 8.7 0.82

(b) Subcortical volumes (cm3)

Striatum 19.0 1.6 19.7 1.6 4.39*

Globus

pallidus

2.8 0.3 3.0 0.3 11.32**

Thalamus 11.3 0.8 12.2 1.0 20.86***

(c) Cortical surface area (cm2)

Entire

cortex

926.0 60.4 985.7 77.1 14.06***

Frontal

lobes

324.7 22.7 339.7 28.5 6.00*

Temporal

lobes

191.7 17.0 205.9 19.2 10.82**

Parietal

lobes

202.2 18.6 212.4 18.1 6.09*

Occipital

lobes

107.6 9.8 119.1 14.0 16.35***

(d) Cortical thickness (mm)

Entire

cortex

3.59 0.2 3.7 0.16 5.13*

Frontal

lobes

3.79 0.24 3.9 0.18 4.07*

Temporal

lobes

3.79 0.22 3.91 0.15 5.90*

Parietal

lobes

3.42 0.18 3.51 0.15 4.39*

Occipital

lobes

3.28 0.2 3.31 0.2 0.74

Between-group comparisons of average brain volume (a), subcortical

volumes (b), cortical surface area (c) and thickness (d) by use of

MANCOVA with gender as a covariate

Significant differences between groups are indicated by asterisks

(*** p \ 0.001, ** p \ 0.005, * p \ 0.05)

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were excluded. These between-group differences were

strengthened when age was used as a covariate.

Correlations between average cortical thickness for the

seven significant clusters, from the between-groups cortical

thickness analysis, and GA, IQ, BRIEF scores and birth-

weight were examined for the preterm group. The right pre-

cuneus showed a moderate positive relation between

thickness and GA (r = 0.49, p \ 0.01). Individuals born at

an earlier GA had thinner cortices within the right precuneus

than those born later (see Fig. 3). However, this result was

obtained within the context of performing 28 correlations,

and thus needs to be considered a trend. No significant cor-

relations between IQ or BRIEF scores and average cortical

thickness for the seven clusters within the preterm group were

seen. Similarly, no significant correlations were found for

average cortical thickness within the clusters by birthweight.

Discussion

Preterm birth has a profound effect on neuroanatomical

structure in middle childhood that includes decreased brain

volume, surface area and cortical thickness for children

born very preterm when compared to term-born children at

hemispheric and lobular levels. Additionally, preterm-born

children exhibited an altered relation between total brain

volume and thalamic, globus pallidus and striatum volume.

Cortical thickness analyses identifying regional differences

between groups revealed seven distinct areas of thinner

cortex for the preterm-born children within areas respon-

sible for higher cognitive functioning. Furthermore, right

precuneus thickness for those born preterm was positively

related to GA. These results indicate that very preterm-born

children show evidence of neurodevelopmental disruption,

particularly in cortical regions with relatively protracted

maturation (Shaw et al. 2008).

Children born very preterm had smaller whole-brain

volume as well as GM and WM volumes separately.

However, group differences in GM and WM volume were

not maintained after controlling for total brain volume,

indicating that reductions in tissue volume may not be

independent of this variable. Findings are consistent with

previous studies examining brain volume and prematurity

in childhood and adolescence. For example, Peterson et al.

Fig. 1 Graphs of the relation between subcortical volumes (cm3) and

whole-brain volume (cm3). The coloured lines represent the 95 %

confidence interval for the least squares regression line. Striatum(a) for term-born children, a strong positive correlation was found for

the striatum (r = 0.65, p \ 0.001) and 42 % of the variance in

striatum volume was accounted for by whole-brain volume. (b) No

relation between striatum volume and whole-brain volume was found

for the preterm-born children. Globus pallidus: (c) term-born children

showed a strong relation between globus pallidus volume and brain

volume, which accounted for 42 % of the variance in globus pallidus

volume (r = 0.64, p \ 0.001). Children born preterm did not exhibit

a correlation between these volumetric measures (d). Thalamus(e) term-born children exhibited a strong positive relation between

thalamus volume and brain volume (r = 0.64, p \ 0.001) such that

65 % of variance in thalamic volume was explained by brain volume.

(f) Preterm-born children did not display a significant relation

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(2000) found reduced cortical volume in children born

preterm at 8 years of age, although they did not distinguish

GM from WM tissue volumes. Martinussen et al. (2005),

Nagy et al. (2009) and Nosarti et al. (2002) demonstrated

similar results in terms of smaller whole brain, GM and

WM volumes in adolescents born preterm or with very low

birthweight. WM damage accompanied by GM involve-

ment is commonly observed in individuals born preterm

(Inder et al. 2005), when tested in infancy. This finding

illustrates that premature birth may impact myelination,

dendritic connections and corticogenesis through childhood

and adolescence. However, impaired cortical development

may also be associated with low birthweight as this is

likely to influence cortical development. While we did not

find any correlations between low birthweight and altered

cortical morphology in the current study, it is difficult to

dissociate this variable from age of preterm birth.

The children born very preterm exhibited smaller sub-

cortical GM volumes than controls in the present study.

This finding is generally consistent with the existing liter-

ature on subcortical GM and prematurity as the basal

ganglia and thalamus are commonly affected subcortical

GM regions in preterm-born children and adolescents

(Kesler et al. 2008; Nosarti et al. 2008; Sie et al. 2000;

Taylor et al. 2011). Most interestingly, the relation between

subcortical GM volume and total brain volume differed

between groups in the current study. Whole-brain volume

of term-born children was strongly correlated with basal

ganglia and thalamic volume. In contrast, whole-brain

volume of children born preterm was not correlated with

basal ganglia and thalamic volume. Thus, in addition to the

reduced subcortical volumes in children born very preterm,

these children did not demonstrate the robust relation

between whole-brain volume and subcortical volume

exhibited by term-born children. This novel finding sug-

gests that subcortical and cortical regions develop differ-

ently after early exposure to the extrauterine environment

(Volpe 2009).

In the current study, average cortical surface area was

relatively decreased in children born preterm and was

maintained at the lobular level, concordant with the few

studies in this area (Ajayi-Obe et al. 2000; Kapellou et al.

2006; Martinussen et al. 2005). In previous studies, it was

shown that preterm birth and low birthweight were related

to reduced cortical surface area and impairments in cog-

nitive abilities (Kapellou et al. 2006). In the present work

we did not find an association between IQ or BRIEF scores

and surface area; however, more specific deficits in exec-

utive functioning that were not measured in this sample

may be shown to be affected in future studies. An addi-

tional consideration is that our sample was relatively small,

Fig. 2 Whole-brain, vertex-based cortical thickness analysis (cor-

rected p-map): Corrected p values demonstrating regions of signif-

icant regional differences in cortical thickness for term-born versus

children born preterm, controlling for sex and corrected for multiple

comparisons using random field theory (p \ 0.05). Term-born

children had significantly greater cortical thickness in the focal areas

displayed, most significantly in the right anterior cingulate cortex

(ACC)/supplementary motor area (SMA), the isthmus of the cingulate

gyrus, the superior temporal sulcus, the anterior insula (AI), the

postcentral gyrus (POCG), and the precuneus. The colour barindicates corrected p values for significant peaks at the vertex level

(left) as well as at the cluster level (right)

Table 2 Focal areas of significantly thinner cortex in preterm-born children

Brain region Side x y z No. of vertices t value p value (corrected)

Anterior cingulate/supplementary motor area Right 9 14 35 780 5.6 \0.00001

Isthmus of the cingulate gyrus Left -11 -42 4 241 4.6 \0.00001

Precuneus Left -5 -50 51 223 4.2 0.0001

Superior temporal sulcus Right 46 -28 -3 316 4.9 0.02

Precuneus Right 9 -55 46 156 4.4 0.02

Anterior insula Right 30 27 5 105 4.1 0.03

Postcentral gyrus Right 40 -27 46 151 3.9 0.04

Focal regions displaying significant differences in cortical thickness between preterm and term-born children (term born [ preterm born),

controlling for gender and corrected for multiple comparisons using random field theory

Brain Struct Funct (2013) 218:575–585 581

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which may not have provided enough power to address this

issue of impaired cognitive ability and altered cortical

morphology.

The present study is the first that has examined cortical

thickness in school-aged children born very preterm. We

found evidence for an overall decrease in thickness when

averaged across the whole cortex and when averaged

across lobes. Using the more detailed analysis of a vertex-

based approach to examine regional patterns in cortical

thickness across group, we found that the cortex was sig-

nificantly thinner for children born preterm than typical

children in the right anterior cingulate cortex/supplemen-

tary motor area, left isthmus of the cingulate gyrus, right

superior temporal sulcus, right anterior insula, right post-

central gyrus and precuneus bilaterally. These findings

extend those of Martinussen et al. (2005) and Nagy et al.

(2011) as both investigators found focal areas of thinner

cortex within the parietal and temporal regions in preterm-

born adolescents. Within the parietal lobe, Martinussen

et al. (2005) identified the post-central gyri and the supra-

marginal area of the inferior parietal lobule as thinner in

the preterm group, while Nagy et al. (2011) found that the

posterior inferior parietal cortices were significantly thin-

ner in adolescents born preterm. When adolescents born at

fewer than 29 weeks GA were compared to controls, areas

of the medial surface, including the mid-anterior cingulate

and the precuneus/subparietal region, were thinner than

controls (Martinussen et al. 2005); the temporal regions

where cortical thickness was reduced in preterm-born

individuals included the middle temporal gyrus (Nagy et al.

2011; Martinussen et al. 2005), occipito-temporal medial

gyrus, and parahippocampus (Martinussen et al. 2005).

Findings from large-scale longitudinal studies of normal

development show that GM follows an inverted U-shaped

trajectory (Lenroot and Giedd 2006; Shaw et al. 2008); the

cortex reaches peak thickness between 7 and 13 years of age

in a regionally specific manner (Shaw et al. 2008). Hence,

7–13 years of age marks a critical period in terms of GM

development. Due to the narrow age range and relatively

small number of participants in the present study, age did not

significantly contribute to the regional differences in cortical

thickness observed, even though weak quadratic trends

between age and cortical thickness were identified for the

term-born children while those born preterm displayed

divergent trends. Therefore, the observed areas of thinner

cortex may be due to atypical GM development in infancy

and throughout childhood. This important area of further

investigation is reminiscent of atypical GM development in

children with neurodevelopmental and psychiatric disorders.

Shaw et al. (2007) reported that children with attention-

deficit/hyperactivity disorder exhibited a delay in reaching

peak maturational thickness relative to healthy controls.

Also, children with autism spectrum disorders are believed to

experience a period of rapid neuronal overgrowth followed

by a period of arrested growth in early childhood (Cour-

chesne et al. 2007). Whether similar mechanisms occur in

children born preterm remains uncertain; however, based on

the results of the current study, large-scale studies with a

wide age range are warranted.

Gestational age has been shown to be an important

influencing factor on the degree of abnormal cortical

morphology in children born preterm. Martinussen et al.

(2005) reported that adolescents born earlier than 28 weeks

had more profound thinning in several brain regions than

those born later. However, in the present study, the right

precuneus was the only region that was positively corre-

lated with week of birth for the preterm group. Addition-

ally, numerous correlations were calculated to obtain this

result, so it needs to be considered tentative. This dis-

crepancy between the results of our study and that of

Martinussen et al. (2005) can be attributed to differences in

data analysis, the size of the cohort studied as well as other

aspects of the cohort (i.e. maternal and pregnancy factors,

medical complications at birth and perinatal care received).

Fig. 3 The graph illustrates the

relation between gestational age

and average cortical thickness

of the right precuneus for

children born preterm

(mean = 3.73 mm,

SD = 0.22 mm), r = 0.49,

p \ 0.01. The coloured areadenotes the right precuneus

region-of-interest. Average

cortical thickness for term-born

children for this region was

3.97 mm, SD = 0.22 mm

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The exact mechanism underlying the reduction in cortical

thickness, volume and surface area in those born very pre-

term cannot be determined from the current study, although it

is likely that disruptions of the typical neurodevelopmental

trajectory in the third trimester of pregnancy underlie these

differences. During this period the thalamocortical axons

exit the subplate and enter the cortex forming connections in

the deep cortical plate (Kostovic and Jovanov-Milosevic

2006) leading to a substantial increase in volume from

28–40 weeks (Huppi et al. 1998; Kostovic and Judas 2002;

Kapellou et al. 2006). GABAergic cortical neuronal prolif-

eration occurs during this period as well as migration critical

for the expansion of the superficial cortical layers that

underlie an increase in cortical surface area (Volpe 2009). It

is possible that the extrauterine environment of the preterm-

born babies adversely affects these processes and, in turn,

brain structure.

One important aspect of this study pertains to the medical

history of the children included in our sample. The very

preterm-born infants are routinely screened for PVL or severe

IVH using cranial ultrasound and those with PVL, grade 3 or 4

IVH, or other neurological or severe perinatal findings were

not included in the present cohort. Therefore, significant

differences in brain structure between term-born and very

preterm-born children exist even when only those without

serious neurological or medical conditions are considered.

Another strength of the current study is that the same research

team, using the same facilities and scanner, without any

hardware changes, scanned all participants. This standardised

environment is important in reducing unwanted measurement

error, which may increase the sensitivity of analyses.

Future projects should be conducted on cohorts of very

preterm-born children cared for in other health care set-

tings, as multiple studies must be considered together. This

is especially important in this population as outcome can

depend on the neonatal care received (Murphy et al. 2001;

Gressens et al. 2002; Als et al. 2004) and practices can

differ greatly across sites (Van Reempts et al. 2007). To

gain a greater understanding of the related biological

mechanisms across development, longitudinal studies fol-

lowing preterm infants through childhood are essential.

Acknowledgments This work was supported by the Canadian

Institutes of Health Research [Grant Number MOP-81161 to MJT].

The authors thank Wayne Lee for MRI technical and analysis support

and the staff at the Neonatology Follow-Up Clinics, Hospital for Sick

Children. We also sincerely thank the children and their families who

participated in this study.

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