REVIEW

Neuroimaging of cortical development and brainconnectivity in human newborns and animal modelsGregory A. Lodygensky,1,2 Lana Vasung,2,3 Stephane V. Sizonenko2 and Petra S. Huppi2

1NICU, Department of Pediatrics, University of Geneva, Geneva, Switzerland2Division of Development and Growth, Department of Pediatrics, University of Geneva, Switzerland3Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia

Abstract

Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and

a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding

and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white

matter injury have been shown to affect brain growth including specific structures such as the hippocampus,

with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging

(MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white

matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The

use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white

matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state func-

tional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity

in vivo. Results from studies using these methods have for the first time illustrated the structural impact of

antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature

birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction

with histology in animal models of injury in the immature brain. Understanding the histological substrate of

brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imag-

ing phenotype.

Key words DTI; hypoxic-ischemic; inflammatory; MRI; newborn; preterm.

Introduction

Understanding human brain development is clinically rele-

vant as many neurobiological disorders and disabilities have

their origin in early structural, functional development and

plasticity. With the advent of magnetic resonance imaging

(MRI), it has become possible to address the question of

where, when and how adverse conditions in fetal and early

postnatal life and prematurity relate to the maturation of

cortical networks (Ment et al. 2009). MRI has entered the

research arena due to its non-invasiveness and potential for

high-resolution structural brain imaging. It has allowed for

the first time the study of in-vivo brain development in pre-

mature and healthy newborn infants providing full 3D

imaging data sets.The integration of healthy infants in lon-

gitudinal studies has become possible thanks to the absence

of irradiation or other side-effects, thus allowing a wide

and thorough analysis of brain development. This review

presents advanced imaging modalities used to study the

immature brain and discusses their potential for the in-vivo

assessment of cerebral development in both human as well

as animal models established to study the pathophysiology

of early adverse conditions for brain development.

Conventional magnetic resonance imaging

Conventional MRI techniques, including mainly T1- and T2-

weighted images, allow the assessment of brain develop-

ment in vivo with the highly sensitive assessment of gray

and white matter contrast, as well as the differentiation of

unmyelinated and myelinated white matter (Battin et al.

Correspondence

Petra S. Huppi, Division of Development and Growth, Department of

Pediatrics, University Hospital of Geneva, Rue Willy Donze 6 1211

Geneva 14, Geneva, Switzerland. E: petra.huppi@unige.ch

Accepted for publication 12 July 2010

ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland

J. Anat. (2010) 217, pp418–428 doi: 10.1111/j.1469-7580.2010.01280.x

Journal of Anatomy

1998; Counsell et al. 2002; Ferrie et al. 1999). The immature

white matter demonstrates a relatively homogenous low

signal on T1-weighted images and a high signal on T2-

weighted images compared with gray matter (Fig. 1A). This

is mainly due to the higher water content of the immature

white matter. With increasing maturation, the signal of the

white matter increases on T1-weighted images, which is

related to multiple concurrent processes occurring in the

developing white matter with decreasing water content, a

change in the water : macromolecule ratio caused by the

arrival of the lipid precursors of myelination, and finally the

process of myelination itself. Myelination is visualized at dif-

ferent rates and times on T1-weighted and T2-weighted

images with evidence of myelination determined by a low

signal on T2-weighted images and a high signal on T1-

weighted images that is already present at 28 weeks of ges-

tation in regions such as the inferior and superior cerebellar

peduncles or the ventrolateral nuclei of the thalamus. Mye-

lination of the posterior limb of the internal capsule is seen

by 36 weeks with a completion of myelination by 2 years of

age (Battin et al. 1998; Counsell et al. 2002).

Brain MRI of developing animals in correlation to histo-

logical findings gives us the opportunity to better define

the substrates of MRI changes during development and

following injury. The possibility of imaging mouse pups,

although technically challenging, opens a new area of

research where specific changes in imaging can be

addressed using genetically modified animals (West et al.

2009). The majority of correlation studies between MRI

and histology in the developing brain have been carried

out on rat pups at 7–14 days of life, an age closer to

infants born at term. Imaging of immature animals gives

the same contrast in conventional imaging (Fig. 1B) with

an inversion of contrast similar to the human as the ani-

mals mature (Lodygensky et al. 2008a). Ultra-high field

MRI scanners are increasingly used in rodent studies and

are now available at up to 14 T, equivalent to 300 000

times the earth’s magnetic field. They provide a sufficient

signal-to-noise ratio to achieve the required high resolu-

tion in immature rodents but bring new challenges such as

the assembly of stable coils at the given magnetic fields,

worsening susceptibility artifacts and magnetic field inho-

mogeneity.

Since the discovery of the transient subplate zone

(Kostovic & Molliver, 1974) and its significance for the nor-

mal development of the human telencephalon (Kostovic &

Rakic, 1990a), there has been an extensive amount of

effort invested in identification of the subplate by MRI

methods (Kostovic et al. 2002; Rados et al. 2006; Huang

et al. 2006; Prayer et al. 2006; Kasprian et al. 2008; Kosto-

vic & Vasung, 2009). The subplate zone can be clearly dis-

tinguished in ex-vivo T1 MRI after 13 weeks of gestation

as an area of hypointensity (Kostovic et al. 2002; Rados

et al. 2006; Kostovic & Vasung, 2009) and on in-vivo T2

MRI as an area of hyperintensity (Prayer et al. 2006)

between the bordering cortical plate and the intermediate

zone (Fig. 2). The presence of this transient subplate zone

is one of the main signs of cortical immaturity (Kostovic &

Vasung, 2009). It represents the major site of the endoge-

nous circuitry reorganization (Kostovic & Jovanov-Milos-

evic, 2006; Volpe, 2009). The subplate is crucial in

developmental processes such as the ingrowth of thalamo-

cortical axons (Kostovic & Jovanov-Milosevic, 2006), reorga-

nization of the fetal white matter and establishment of

cortical layers. The subplate is rich in extracellular matrix

and serves as a ‘waiting’ compartment for the thalamo-

cortical and cortico-cortical connections (Kostovic & Rakic,

1990b). Its neurons are known to contribute, as early as

24 weeks of gestation, to the appearance of the first

evoked potentials (Hrbek et al. 1973), which play an

important role in the functional maturation of the human

brain. Furthermore, after 32 weeks of gestation, in parallel

A B

Fig. 1 (A) Preterm infant born at 29 weeks of gestation scanned at term equivalent, coronal T2-weighted section with cerebral grey matter and

basal ganglia hypointense and non myelinated white matter with a higher water content appearing hyperintense. (B) Rat pup at 9 days of life,

coronal T2-weighted section with the same contrast as the preterm infant with hypointense cerebral grey matter and hyperintense cerebral white

matter. Image acquired at 9.4 Tesla in collaboration with Gregory Lodygensky and Rolf Gruetter (CIBM, Ecole polytechnique federale de Lausanne,

Switzerland).

ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland

Neuroimaging in human newborns & animal models, G. A. Lodygensky et al. 419

to the gradual decrease in size and extracellular matrix

content, the subplate zone becomes less visible on in-vivo

MRI (Kostovic & Vasung, 2009).

Qualitative image characteristics such as ventricular

dilatation, abnormal white matter signal, increased

subarachnoid space, white matter cysts and thinning of the

corpus callosum have been shown to predict the neurode-

velopmental outcome. These imaging characteristics can

therefore help the clinician in the assessment of the impact

of prematurity and its co-morbidities on brain development

and outcome with better accuracy when compared with

head ultrasound (Woodward et al. 2006; Huppi et al. 1996;

Ramenghi et al. 2007; Huppi, 2002).

Magnetic resonance image analysis: manual

segmentation

Manual segmentation of anatomical structures was the first

method used in quantitative image analysis of the newborn

brain, mostly performed on high-resolution T2-weighted

images during the first months of life and on T1-weighted

images later in life (Toft et al. 1995). This approach was cho-

sen to evaluate subtle differences in quantitative brain

development caused by premature birth. Several structures

quantified by manual segmentation are affected by pre-

term birth especially in children with associated white mat-

ter injury. These structures include the cerebellum, corpus

callosum, thalamic and lentiform volumes (Anderson et al.

2006; Srinivasan et al. 2007, 2006; Limperopoulos et al.

2005) all showing a marked reduction in size due to prema-

ture birth. Intrauterine growth restriction, a condition in

which the placental blood supply to the fetus is reduced

and results in poor growth of the fetus, was shown to have

an impact on hippocampal volume (Lodygensky et al.

2008b). These changes were shown to persist in former pre-

term infants during childhood or adolescence with signifi-

cant alterations in hippocampal volume, the cerebellum

and corpus callosum (Allin et al. 2001; Lodygensky et al.

2005; Abernethy et al. 2002; Narberhaus et al. 2007).

Magnetic resonance image analysis: automated

computational techniques

High-resolution T1- and T2-weighted images are the basis

for the application of mathematically-based segmentation

techniques that allow volume measurement of total cortical

gray matter, white matter and basal ganglia. Segmentation

techniques for the neonatal brain are still challenging due

to: (i) an inversion of the contrast between gray and white

matter and changes during development prohibiting the

use of adult segmentation toolkits; (ii) a strong signal heter-

ogeneity secondary to myelination affecting both cortical

structures and white matter regions; (iii) the small size of

the brain requiring high-resolution MRI, which leads to a

low signal-to-noise ratio; and (iv) thin structures like the

cortex, prone to partial volume effects, which further com-

A B

Fig. 2 Ex vivo T1 and T2-weighted coronal

MRI images acquired 3T of a human brain at

24 weeks of gestation. (A) Coronal T1-

weighted image with a resolution of

1 · 1 · 2 mm, (B) Coronal T2-weighted

image with a resolution of 0.39 · 0.39 ·0.5 mm. Note the subplate zone clearly

distinguished from the bordering fetal zones

in T2-weighted image as a hyperintense area

between the cortical plate and the

intermediate zone and on the T1 weighted

image as a hypointense area between the

cortical plate and intermediate zone. cp,

cortical plate; iz, intermediate zone; sp,

subplate zone; vz, ventricular zone.

ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland

Neuroimaging in human newborns & animal models, G. A. Lodygensky et al.420

plicate segmentation. The combination of a signal-based

k-means classification with a mathematical morphology

approach for shape recognition is currently the preferred

method for neonatal brain segmentation (Anbeek et al.

2008; Cachia et al. 2003; Weisenfeld & Warfield, 2009).

The recent development of specific newborn brain seg-

mentation tools has allowed the quantification of in-vivo

human brain growth showing a fourfold increase in corti-

cal gray matter, a fivefold increase in myelinated white

matter, a linear steady growth rate of the unmyelinated

white matter (Huppi et al. 1998b) and a 70% growth of

the basal ganglia (Mewes et al. 2006). These major

changes underline the importance of this period in brain

growth and its vulnerability as shown by the toxicity of

dexamethasone on cortical gray matter growth (Murphy

et al. 2001) or intrauterine growth restriction with a

reduction of 30% in cortical gray matter volume (Borra-

dori Tolsa et al. 2004). This approach has shown for the

first time that white matter injury in preterm infants was

associated with a significant impact on cortical gray

matter development (Inder et al. 1999, 2005).

Mathematical morphology: primary cortical folding

One of several possible approaches to investigating cortical

folding in preterm infants is based on a mathematical mor-

phology approach that processes and analyzes shape. The

computational approach quantifies both surface area and

cortical gyration through curvature measurements from 3D

reconstruction of the interface between the developing

cortex and white matter (Dubois et al. 2008a,b). The inner

cortical surface is identified between the cortical gray mat-

ter and white matter. A smooth triangle-based mesh of this

surface is then computed and the global area of this inner

cortical surface can be measured. Finally, the local surface

curvature is estimated from the mesh local geometry; posi-

tive curvatures correspond to the gyrus’s top and negative

curvatures to the fold’s bottom (Cachia et al. 2003). The

sulci are then defined as connected components of nega-

tive curvature. These sophisticated image analysis tools

need high-resolution primary input data with no motion

artifacts.

Cortical folding in preterm infants

In the human brain, the morphology of cortical gyri and

sulci is complex and variable among individuals with an

established asymmetry appearing very early on (Dubois

et al. 2010). A significant amount of cortical folding and

gyrification takes place during the last trimester with a

steep increase of brain surface and degree of sulcation

index (Dubois et al. 2008b). Conditions such as twinning

and intrauterine growth restriction have been shown to

alter sulcation and decrease the sulcation index (Dubois

et al. 2008a) (Fig. 3). Alterations in size and cortical

morphology might reflect abnormal functioning or vice

versa, as shown in correlations between surface, gyrification

index at birth and the Assessment of Preterm Infants’

Behavior score at term equivalent age (Dubois et al. 2008a),

a neonatal neurobehavioral test shown to predict later neu-

rofunctional outcome (Feldman & Eidelman, 2006). So far,

the precise mechanisms responsible for such alterations in

cortical phenotype during intrauterine or postnatal devel-

opment are still poorly understood and therefore studies of

cortical folding in selected animal models will provide fur-

ther insight into the mechanisms underlying cortical folding

(Barnette et al. 2009) (Fig. 4).

Diffusion tensor imaging

The technique of diffusion tensor imaging

Diffusion tensor imaging (DTI) assesses water molecule dis-

placement at a microstructural level with displacement of

water in the order of 10 lm. This technique has been used

in the exploration of the structural basis of white matter

development (Neil et al. 1998; Huppi et al. 1998a; Mukher-

jee et al. 2002) and cortical maturation (McKinstry et al.

2002a).

Fig. 3 3D representation of the inner cortical surface for a singleton

and a twin of equivalent age. SI1 represents the average of the

sulcation index. Note the altered cortical gyrification shown to be

significantly affected in twins when compared to singleton of the

same gestational age. Modified from Dubois et al. (2008a).

A

B

Fig. 4 (A) Cortical surface of ferret brains at 4, 10, 17 days of life and

in an adult. (B) Cortical surface of human brains at 25, 30, 33,

39 weeks of gestation and in an adult. Courtesy of Barnettte et al.

(Barnette et al., 2009).

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Neuroimaging in human newborns & animal models, G. A. Lodygensky et al. 421

Based on the tensor model, the main DTI parameters are

the three eigenvalues k1, k2 and k3 representing diffusion

along the three principal axes of an ellipsoid in each voxel.

Eigenvector maps and RGB color-coded maps indicate the

orientation of the major eigenvector providing an indica-

tion of the direction in which water diffusion is highest

(typically parallel to white matter fiber fascicles). The first

eigenvalue, often referred to as axial diffusivity, was shown

to be affected by axonal integrity (Kim et al. 2006). The sec-

ond and third eigenvectors describe diffusivity perpendicu-

lar to the axial diffusivity. Radial diffusivity, defined by the

average of the second and third eigenvectors, was shown

to be affected in adult animals by changes in myelin

ensheathment (Song et al. 2005). From these three eigen-

values is calculated the apparent diffusion coefficient (ADC)

and mathematical measures of anisotropy describing the

degree to which water diffusion is restricted in one direc-

tion relative to all others, referred to as fractional aniso-

tropy (FA) and relative anisotropy (RA) (Fig. 5). FA and RA

are indicators of the degree of water diffusion anisotropy

with a value that is equal to zero for diffusion equal in all

directions and increases with anisotropy.

Fiber tracking: diffusion tensor imaging

Fiber tracking is able to delineate specific cerebral white

matter tracts by following local vector orientation from the

3D vector field (Fig. 6). Different tractography algorithms

have been developed such as the popular streamline deter-

ministic fiber tracking (Mori et al. 1999). The 3D fiber track

is allowed to continue unless it enters a region of FA less

than a predefined value of FA or turns at an angle greater

than a predefined angle between two consecutive voxels.

Fiber crossing causes one of the major downfalls of fiber

tracking. Several algorithms have been proposed to solve

this issue such as the probabilistic index of connectivity

(Parker et al. 2003) or, more recently, the Gibbs tracking

model (Kreher et al. 2008).

Diffusion tensor imaging: analysis strategies

The four main approaches to analyzing DTI data are

region-of-interest quantification, voxel-based approaches,

histogram analyses and tract-based analysis. Manual region-

of-interest selection and quantification is the most fre-

quently used. This method is time-consuming and is charac-

terized by a large inter-rater variability due to a bias in the

selection of the regions of interest. Voxel-based morphome-

try is an alternative method initially designed to quantify

regional changes in volume on conventional imaging

(Ashburner & Friston, 2001; Kesler et al. 2008; Nosarti et al.

2008). Its automated analysis eliminates a-priori knowledge

and user bias but it is not immune to error due to registra-

tion and normalization. Tract-based spatial statistics is an

alternative method (Smith et al. 2006) developed to address

errors in registration by the tools built for conventional

imaging used on DTI data. It is based on the realignment of

the FA maps of all subjects onto a FA map skeleton.

Diffusion tensor imaging studies

During normal brain development, the ADC of the white

matter was shown to decrease together with a steady

increase in anisotropy (Huppi et al. 1998a; Neil et al. 1998;

Dudink et al. 2007). Following a hypoxic–ischemic injury,

ADC also decreases, resulting in values that are much

reduced compared with the age- and region-dependent

normal values (Rutherford et al. 2004; McKinstry et al.

2002b). This ADC restriction is clinically used to detect brain

injury as it appears very early on, preceding conventional

T2 hyperintensity. During white matter development, a

gradual decrease in diffusion is observed principally in k2

and k3 (and much less in k1), which reflect changes in

water diffusion perpendicular to white matter fibers in sin-

gle coherently ordered fiber bundles and may indicate

A B

Fig. 5 (A) Healthy preterm infant born at 29 weeks of gestation

imaged at term equivalent, coronal FA map at the level of the

posterior limb of the internal capsule. (B) P5 live rat pup, coronal FA

map with sufficient in plane resolution to identify major white matter

bundles such as the corpus callosum or the internal capsule. Image

acquired at 11.7 Tesla in collaboration with Gregory Lodygensky and

Jeffrey J Neil (Washington University, St Louis, Missouri).

A B

Fig. 6 (A) 3D representation of the cortical surface of an infant at

term with superimposed fiber tracking through the corpus callosum.

Courtesy Jessica Dubois (CEA/SAC/DSV/DRM/NeuroSpin/Cognitive

Neuroimaging Unit, Gif-sur-Yvette, France) (B) Relative anisotropy map

of a fixed rat brain at 21 days of age with the superimposed fiber

tracking through the corpus callosum. Image acquired at 9.4 Tesla in

collaboration with Gregory Lodygensky and Rolf Gruetter (CIBM, Ecole

polytechnique federale de Lausanne, Switzerland).

ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland

Neuroimaging in human newborns & animal models, G. A. Lodygensky et al.422

changes due to premyelination (change of axonal width)

and myelination (Mukherjee et al. 2002; Partridge et al.

2004; Giorgio et al. 2008). The increase in white matter

anisotropy values during development appears to take

place in two stages. The first increase takes place before

the histologic appearance of myelin (Huppi et al. 1998a;

Neil et al. 1998). This increase has been attributed to

changes in white matter structure that accompany the ‘pre-

myelinating state’ (Wimberger et al. 1995). This state is

characterized by an increase in the number of microtubule-

associated proteins in axons, a change in axon caliber, and

the maturation and organization of oligodendrocytes. It is

also associated with changes in the axonal membrane, such

as an increase in conduction velocity and changes in

Na+ ⁄ K+-ATPase activity. The increase in anisotropy associ-

ated with premyelination is notable in that it takes place in

the absence of changes in T1- or T2-weighted imaging as

well as before the histologic appearance of myelin. Regio-

nal anisotropy is not only clearly influenced by myelination

alone, but also by factors such as axon packing, relative

membrane permeability to water, internal axonal structure

and intra-axonal space as outlined in recent studies of ani-

mal spinal cord using AxCaliber, a model of water diffusion

that estimates the axonal diameter distribution within a

nerve bundle (Assaf et al. 2008).

This is different with intracortical maturation, where mat-

uration is associated with a progressive decrease in FA dur-

ing development (Deipolyi et al. 2005), confirmed by

studies in the developing rat brain (Huang et al. 2008;

Sizonenko et al. 2007b) with sufficient resolution to identify

clearly the microstructural organization in the cortex

(Fig. 5). During rat brain development, ADC and FA changes

were detected in cortical layers between postnatal day 3

and 6. A distinct radial organization of the cortical layers

with the eigenvectors perpendicular to the pial surface was

observed at both ages. This organization was most promi-

nent in the external cortical layers 1–3 compared with the

deep layers 4–6. With cortical maturation, ADC was

reduced, whereas FA was decreased only in the deep layers

of the cortex. Histology revealed maturational differences

in the cortical architecture with increased neurodendritic

density and reduction in the radial glia scaffolding

(Sizonenko et al. 2007b). Similar developmental changes in

anisotropy within the cortex have been shown in primates

at different gestational ages. At 90 days of gestation, diffu-

sion exhibits prolate symmetry and high anisotropy, reflect-

ing apical neuronal dendrites and radial glia. Later in

gestation, with maturation of basal neuronal dendrites,

connections with thalamo-cortical afferents, branching of

interneurons and reduction of radial glia, the water diffu-

sion was modified and reflected by a reduction of diffusion

along the principal eigenvalue k1 and an increase in the

eigenvalues k2 and k3 (Kroenke et al. 2005).

The histological correlate of DTI modifications after

cerebral hypoxic–ischemic injury at 3 days of life in rat

pups (equivalent to a preterm infant born at 24–28 weeks

of gestation) showed that DTI was indeed sensitive to

microstructural changes with an alteration of the radial

organization of the cortex (Fig. 7). The decrease in ADC

and FA at 24 and 72 h after injury corresponded to neuro-

nal cell death, astrogliosis, axonal degeneration, and alter-

ation of the radial glia with early transformation into

astrocytes (Sizonenko et al. 2005, 2007b). Long-term assess-

ment with DTI showed an altered cortical structure and FA

reduction in the corpus callosum and external capsule. The

damage resulting from the hypoxic-ischemic injury corre-

lated with functional alteration of the whisker-elicited

somatosensory response (Quairiaux et al. 2010). Lipopoly-

saccharide administration in the developing animal mimics

the inflammation-induced white matter injury seen in pre-

term infants. Intracallosal injection of lipopolysaccharide in

5-day-old rat pups has shown a similar pattern on mag-

netic resonance-DTI to that seen in a hypoxic–ischemic

injury with an initial decrease of the ADC corresponding

to the peak of maximal injury. At 4 days after lipopolysac-

charide exposure, the ADC was increased together with

radial diffusivity corresponding to a decrease in cell den-

sity and an increase in callosal thickness and a diffuse

astrogliosis. The increase in ADC of the white matter at

4 days after injury reflected diffuse gliosis with increased

extracellular space rather than an arrest in development

(Lodygensky et al. 2009). Translating this knowledge to

white matter assessment in preterm infants with a higher

ADC and lower RA worsened by white matter injury

would imply a significant injury rather than a delayed

development. The acute changes seen in different animal

models of preterm brain injury reflect the initial damage

on brain structures. These initial tissue and cellular altera-

tions will influence the subsequent brain development in

the long term in balance with the intrinsic protective

response of the brain (Sizonenko et al. 2007a).

B

A

Fig. 7 Principal eigenvector plot representing a disruption in the

parietal cortex of the radially organized cortical eigenvectors 24 h

after hypoxia-ischemia. (B) Fluoro-Jade B stain showing degenerating

neurons in the same area. Courtesy of Sizonenko et al. (Sizonenko

et al., 2007b).

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Neuroimaging in human newborns & animal models, G. A. Lodygensky et al. 423

Preterm infants imaged at term even without evidence

of white matter injury were shown to have a decrease of

the RA in the internal capsule when compared with term

infants and a decrease of FA in the splenium of the corpus

callosum and coronal radiata (Rose et al. 2008). White mat-

ter injury in preterm infants was shown to have an even

stronger impact on the microstructural organization with

an arrest in the normally decreasing ADC and increasing

anisotropy of the white matter together with a decrease of

RA in the internal capsule (Huppi et al. 2001; Miller et al.

2002). Tract-based spatial statistics found significant

changes in regions within the centrum semiovale, frontal

white matter and the genu of the corpus callosum that had

a significantly lower FA in preterm infants imaged at term-

equivalent age compared with term-born controls (Anjari

et al. 2007), thus assessing alterations of brain development

in ex-preterm infants. Further experience-related changes

in diffusion characteristics have been shown in practicing

piano players (Bengtsson et al. 2005) or in working memory

training (Takeuchi et al. 2010) and provide evidence in sup-

port of the experience-based structural plasticity in the

brain. Recently, DTI performed before and after a 2-h task

was able to detect a decrease in ADC in the hippocampus

with an increase in FA in the right amygdala, bilateral

entorhinal cortex and left insula (Tavor et al. 2010). The

recent notion that DTI not only can explore microstructural

foundations of the brain, but also appears to be sensitive

to its functional adaptation opens a new domain of

research.

Functional magnetic resonance imaging andfunctional magnetic resonance imagingconnectivity

Functional MRI (fMRI) is based on the detection of regional

changes in signals that are correlated with brain functional

activity. Neuronal activation is fuelled by an increase in-loco

regional blood flow resulting in a decrease of deoxygen-

ated hemoglobin. As deoxygenated hemoglobin has para-

magnetic properties, a change in its concentration results in

a change in signal intensity that can be quantified. This

effect is known as the blood oxygenation level-dependent

contrast (Ogawa et al. 1990). The high spatial resolution

and relatively fast temporal resolution of fMRI has made it

an excellent technique to study brain function in combina-

tion with structural MRI and diffusion MRI. Functional MRI

connectivity (fcMRI) assesses neural processing (Fox et al.

2005; Schafer et al. 2009) using the spontaneous blood oxy-

genation level-dependent signal intensity time-course’s

coherent oscillations within a neuronal network.

Functional magnetic resonance imaging in infants

Previous studies have demonstrated the feasibility of fMRI

in healthy newborns and infants at different ages using dif-

ferent passive tasks (Seghier & Huppi, 2010; Seghier et al.

2006). These studies have mainly used sensory stimuli in the

visual auditory or sensorimotor domain (Born et al. 1998;

Martin et al. 1999; Yamada et al. 1997; Muramoto et al.

2002). Using passive somatosensorial stimulation, somato-

sensory areas have been identified in the precentral and

postcentral gyri but showed weak hemispheric dominance

as compared with the somatosensory system in adults (Erbe-

rich et al. 2006). Remarkably, speech perception in very

young infants showed prefrontal, temporo-parietal, precu-

neus and angular gyri activations with a significant domi-

nance of the left hemisphere as in the adult brain

(Dehaene-Lambertz et al. 2002). The follow-up of perinatal

brain lesions combining fMRI with DTI has shown remark-

able structural and functional recovery in perinatal stroke

(Seghier et al. 2004, 2005). Unresolved issues of fMRI in

newborns and infants are the equivocal hemodynamic

response influenced by sedation and other mechanisms

controlling the cerebral blood flow response to brain activ-

ity (Seghier et al. 2004; Colonnese et al. 2008).

Impact of prematurity evaluated by functional

magnetic resonance imaging connectivity

Preterm infants scanned at term were shown to have

consistent active resting-state networks during sleep in

the primary visual cortex, bilateral sensorimotor areas,

and bilateral auditory cortex, a network including the

precuneus area, lateral parietal cortex, and cerebellum as

well as an anterior network (Fransson et al. 2007). Serial

resting-state fcMRI every 4–5 weeks was performed on

preterms during their initial hospitalization and compared

with full-term infants (Smyser et al. 2010). Smyser et al.

(2010) identified similar networks and defined their

regional growth and their connections with homotopic

counterparts during development. In addition to the net-

works described by Fransson et al. (2007), they demon-

strated the presence of interhemispheric connectivity as

early as 26 weeks of gestation. The comparison with new-

born infants born at term revealed a reduction of long-

range connectivity worsened by gray and white matter

injury. This study underlines the striking changes occur-

ring during the last trimester of gestation and the

extraordinary susceptibility of white matter in children

born prematurely. More studies are needed to evaluate

the specific impact of prematurity-associated brain injuries

such as periventricular venous infarction or diffuse white

matter injury and to determine its utility in the clinical

arena. Although the acquisition itself is performed in a

very short time and holds a mine of unexploited valuable

information on brain function, it remains a very chal-

lenging imaging technique, as the quantified changes in

signal are close to the noise level and susceptible to a vari-

ety of artifacts such as motion cyclic cardiac and respiratory

artifacts.

ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland

Neuroimaging in human newborns & animal models, G. A. Lodygensky et al.424

Functional magnetic resonance imaging connectivity

in animal models

The fcMRI has been studied in rats at 4.7 T (Zhang et al.

2010) with a relatively large voxel size of 0.125 · 0.125

· 1 mm limiting its translation to younger animals with

much smaller brains without using a higher field strength

and stronger gradients. The fcMRI was established

between the prefrontal cortex, thalamus, and retrosplenial

cortex and their connectivity with very precise anatomical

regions such as the visual, auditory, motor, and somato-

sensory cortices. Interestingly, fcMRI was studied in an

adult animal model of stroke, showing that it may be con-

sidered as a new approach to quantify brain plasticity.

Indeed, the recovery of the contralateral baseline activa-

tion correlated with the recovery of the sensorimotor

function (van Meer et al. 2010). The fcMRI not only pro-

vides the opportunity to study in detail connectivity

between different parts of the brain, but also provides

information regarding plasticity after injury, thus opening

a new era of research in brain injury too often focused on

the lesion itself.

Conclusion

The use of advanced MRI techniques has revolutionized the

in-vivo visualization and comprehension of human brain

development and function. The advance in microstructural

and functional evaluation techniques such as DTI and fcMRI

will open up ways to study longitudinally important aspects

of brain plasticity during development. The implementation

of imaging on high-field magnetic resonance systems in ani-

mal models of brain development and injury further allows

the translation of the study of mechanisms of development

and disease based on experimental data to human applica-

tions and the testing of emerging hypothesis coming from

human brain magnetic resonance research in animal experi-

ments.

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