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MR Imaging Methods for Assessing Fetal Brain Development Mary Rutherford, 1 Shuzhou Jiang, 1 Joanna Allsop, 1 Lucinda Perkins, 1 Latha Srinivasan, 1 Tayyib Hayat, 1 Sailesh Kumar, 2 Jo Hajnal 1 1 Robert Steiner MR Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College, Hammersmith Campus, Du Cane Road London W12 OHS, United Kingdom 2 The Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College, Hammersmith Campus Received 29 August 2007; accepted 14 December 2007 ABSTRACT: Fetal magnetic resonance imaging provides an ideal tool for investigating growth and de- velopment of the brain in vivo. Current imaging meth- ods have been hampered by fetal motion but recent advances in image acquisition can produce high signal to noise, high resolution 3-dimensional datasets suitable for objective quantification by state of the art post ac- quisition computer programs. Continuing development of imaging techniques will allow a unique insight into the developing brain, more specifically process of cell migration, axonal pathway formation, and cortical mat- uration. Accurate quantification of these developmental processes in the normal fetus will allow us to identify subtle deviations from normal during the second and third trimester of pregnancy either in the compromised fetus or in infants born prematurely. ' 2008 Wiley Periodi- cals, Inc. Develop Neurobiol 68: 700–711, 2008 Keywords: fetal; brain; magnetic resonance imaging BACKGROUND Magnetic resonance imaging (MRI) is an ideal tool for the in vivo study of the developing brain. Fetal MRI has been used for over 20 years with the first report in 1983. Initial studies required the use of pa- ralysis or sedation of the fetus to obtain nonmotion artifacted images. Original image acquisition times were long and image quality poor. The advent of fast T2 weighted single shot imaging techniques has transformed image quality so that fetal MRI has now become an accepted technique in many antenatal clinics. MRI has an excellent safety record; issues for the developing fetus include heat absorption and exces- sive noise. Current guidelines recommend that MR should be avoided in the first trimester of pregnancy unless there are compelling maternal reasons for imaging studies. This is a precautionary measure as there have been no documented side effects to the developing embryo and fetus when operating under standard clinical conditions. There are however very few studies looking at the acute and longer term effects of MR on the developing fetus and more stud- ies are justified as it becomes a routine clinical tool. Recently, the regional pattern of heat absorption within the mother and fetus was reported using a mathematical model for both 1.5 and 3 Tesla showing that maximum heat deposition was in the mother (Hand et al., 2006). To date, studies have shown no sustained increases in fetal heart rate during MRI and no evidence of hearing impairments in children who had undergone MRI as a fetus (Myers et al., 1998; Vadeyar et al., 2000; Kok et al., 2004). In contrast there are many studies comparing the ability of MRI Correspondence to: M. Rutherford ([email protected]). ' 2008 Wiley Periodicals, Inc. Published online 28 March 2008 in Wiley InterScience (www. interscience.wiley.com). DOI 10.1002/dneu.20614 700

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MR Imaging Methods for Assessing FetalBrain Development

Mary Rutherford,1 Shuzhou Jiang,1 Joanna Allsop,1 Lucinda Perkins,1 Latha Srinivasan,1

Tayyib Hayat,1 Sailesh Kumar,2 Jo Hajnal1

1 Robert Steiner MR Unit, Imaging Sciences Department, MRC Clinical Sciences Centre,Imperial College, Hammersmith Campus, Du Cane Road London W12 OHS, United Kingdom

2 The Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College,Hammersmith Campus

Received 29 August 2007; accepted 14 December 2007

ABSTRACT: Fetal magnetic resonance imaging

provides an ideal tool for investigating growth and de-

velopment of the brain in vivo. Current imaging meth-

ods have been hampered by fetal motion but recent

advances in image acquisition can produce high signal

to noise, high resolution 3-dimensional datasets suitable

for objective quantification by state of the art post ac-

quisition computer programs. Continuing development

of imaging techniques will allow a unique insight into

the developing brain, more specifically process of cell

migration, axonal pathway formation, and cortical mat-

uration. Accurate quantification of these developmental

processes in the normal fetus will allow us to identify

subtle deviations from normal during the second and

third trimester of pregnancy either in the compromised

fetus or in infants born prematurely. ' 2008 Wiley Periodi-

cals, Inc. Develop Neurobiol 68: 700–711, 2008

Keywords: fetal; brain; magnetic resonance imaging

BACKGROUND

Magnetic resonance imaging (MRI) is an ideal tool

for the in vivo study of the developing brain. Fetal

MRI has been used for over 20 years with the first

report in 1983. Initial studies required the use of pa-

ralysis or sedation of the fetus to obtain nonmotion

artifacted images. Original image acquisition times

were long and image quality poor. The advent of fast

T2 weighted single shot imaging techniques has

transformed image quality so that fetal MRI has now

become an accepted technique in many antenatal

clinics.

MRI has an excellent safety record; issues for the

developing fetus include heat absorption and exces-

sive noise. Current guidelines recommend that MR

should be avoided in the first trimester of pregnancy

unless there are compelling maternal reasons for

imaging studies. This is a precautionary measure as

there have been no documented side effects to the

developing embryo and fetus when operating under

standard clinical conditions. There are however very

few studies looking at the acute and longer term

effects of MR on the developing fetus and more stud-

ies are justified as it becomes a routine clinical tool.

Recently, the regional pattern of heat absorption

within the mother and fetus was reported using a

mathematical model for both 1.5 and 3 Tesla showing

that maximum heat deposition was in the mother

(Hand et al., 2006). To date, studies have shown no

sustained increases in fetal heart rate during MRI and

no evidence of hearing impairments in children who

had undergone MRI as a fetus (Myers et al., 1998;

Vadeyar et al., 2000; Kok et al., 2004). In contrast

there are many studies comparing the ability of MRI

Correspondence to:M. Rutherford ([email protected]).

' 2008 Wiley Periodicals, Inc.Published online 28 March 2008 in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/dneu.20614

700

to detect and assess abnormalities suspected on ante-

natal ultrasound and all conclude that the two techni-

ques are complimentary (Fig. 1) with MRI confirming

or detecting new abnormalities in many cases

(Whitby et al., 2001, 2004; Levene et al., 2003; Die-

trich et al., 2006).

Postmortem imaging, whether from a terminated

pregnancy or from a stillbirth or early neonatal death,

can also provide valuable insights into the nature of

acquired or congenital abnormalities (Griffiths et al.,

2005, Cohen et al., 2007; Nicholl et al., 2007). Con-

ventional post mortem examination after the death of

a fetus may be limited by autolysis and the effects of

delivery on the brain; image examination of the brain

within the skull prior to conventional post-mortem

helps confirm the presence and the inter-relationship

of individual brain structures.

There are now many studies reporting the visual

appearances of the developing brain in infants born

preterm. The majority of studies that have used

advanced imaging techniques have assessed the pre-

term infant at term equivalent age. It is difficult to

obtain good quality MR imaging of the sick very pre-

term infant soon after delivery and the majority of

published studies have reported the visual findings

alone (Maalouf et al.,1999). Despite the wealth of in-

formation about the developing brain from these stud-

ies it is clear that the effects of prematurity on the

brain are more widespread than originally appreciated

even in the absence of overt visual abnormalities and

the information cannot, therefore, be taken as repre-

sentative of normal development. We now know that

when compared with term born controls, the preterm

infant at term equivalent age without obvious focal

pathology may have reduced cortical folding (Kape-

liou et al., 2006) reduced thalamic size (Boardman

et al., 2006) and abnormalities in white matter micro-

structure (Counsell et al., 2006; Anjari et al., 2007).

While these studies provide invaluable information

about the effects of prematurity on the developing

brain, we are unable to time the onset of these

changes. Current serial studies imaging preterm

infants from 23 weeks gestation until term require

control data that could be provided by similar serial

studies in normally developing gestationally aged

matched fetuses.

Fetal MRI is fast developing as a clinical tool but

progress in image acquisition and subsequent quanti-

fication has been very slow with the majority of stud-

ies reporting the results of visual analysis only. There

is an urgent need to take advantage of imaging

applications that are being developed for postnatal

imaging.

Fetal MRI has the potential to provide several

invaluable roles in perinatal medicine

� It is an ideal technique to investigate the normal

development of the brain in vivo, its excellent

safety record allowing serial examinations to be

performed in the same subject.

� A thorough knowledge of these normal develop-

mental processes, their timing and their objective

quantification will allow detection of subtle early

but clinically significant deviations in development.

� An objective assessment of subtle changes in

brain development will also allow us to use

Figure 1 Coronal plane. Examples of antenatal ultra-

sound (top row) and magnetic resonance images obtained

with new Snapshot magnetic resonance imaging (MRI)

with Volume Reconstruction (SVR), taken at 32 weeks

(bottom row). The MRI shows residual areas of high SI

subplate (short black arrow), \caps" of low SI consistent

with resident microglia (long black arrow) and high SI WM

crossroads (thick black arrow) (Judas et al. 2005). Low SI

within the cerebellum (*) correspond to myelin within the

central vermis and the bilateral dentate nuclei.

MRI for Assessing Fetal Brain Development 701

Developmental Neurobiology

MRI as a tool to monitor and assess the effects

of interventions designed to promote normal fe-

tal growth and development.

MAGNETIC RESONANCE IMAGING:BASIC CONCEPTS

MRI relies on the presence of protons (hydrogen

nuclei) within body water. The magnetic resonance

scanner provides a static magnetic field, which in

fetal imaging is usually at a strength of 1.5 Tesla.

When a body part is placed inside an MR scanner, the

resonance frequency of protons within it is altered

and they realign to give a net magnetization parallel

to the static field. Magnetic resonance pulse sequen-

ces consist of radio frequency (RF) pulses and gradi-

ent magnetic fields generated by coils within the

scanner which are then applied to the body in a sys-

tematic way. The changing magnetization produced

by a sequence induces a small voltage in a receiver

coil that is placed around the body part being exam-

ined. This electrical signal is known as free induction

decay (FID). The initial magnitude of the FID relates

to the number of protons within the tissue. It decays

with the constant T2, the transverse relaxation time,

which reflects the interaction of nuclei with one

another. The time taken for the net magnetization to

return to the original position parallel to the main

static magnetic field is known as T1 or the longitudi-

nal relaxation time. The echo time is the interval

between the applied RF pulse and the collection of

the MR signal. The repetition time is the interval

between RF pulses. Conventional MR sequences are

described in terms of T1 and T2. T1 weighted

sequences are acquired with a short echo time and a

short repetition time to distinguish between tissues

with different T1 relaxation times. In contrast T2

weighted sequences are acquired with a long TE but a

long TR to distinguish between tissues with different

transverse relaxation times. Sequences are already set

in modern scanners although it is possible to change

the parameters to optimize acquisition for the tissue

being imaged.

CONVENTIONAL IMAGING SEQUENCES:CURRENT STATUS IN FETAL IMAGING

Most reported fetal studies have been performed on 1.5

Tesla scanners. Newer 3 Tesla magnets may have

advantages for fetal imaging but the safety for imaging

the developing nervous system at higher field strengths

still needs to be fully investigated (Hand et al., 2006)

The higher the field strength, the greater the signal to

noise for a given acquisition time. The increased field

strength could therefore be used to either improve sig-

nal to noise or to decrease acquisition time both of

which would improve imaging of the fetus.

No specific preparation of the mother is necessary

although early studies relied on paralysis via the

umbilical vessels or sedation of the mother and

consequently the fetus. The latter is still used in some

centers. Normal exclusion criteria apply and safety

checks for the presence of internal or external metal

must always be performed prior to entering the scan-

ner room. Occasionally, attempts at imaging are

unsuccessful because the mother is too claustropho-

bic or too large to fit into the bore of the magnet.

Fetal imaging is a relatively new technique

because fast scanning required to image the moving

fetus is a recent phenomenon. Each slice through the

brain may be acquired in less than a second; a total

acquisition through the brain lasting *30 s. Fetal

MR examinations take *30 min to perform. Clini-

cally, images show good signal to noise and are

adequate for identifying both normal features in the

brain, including areas of early myelination and

appearances consistent with glial cell migration

within developing white matter, (Fogliarini et al.,

2005a; Glenn, 2006; Prayer et al., 2006) (Fig. 2) and

abnormalities in brain development (Levine et al.,

2003; Fogliarini et al., 2005b) (Figs. 3–5). However

Figure 2 Conventionally acquired T2 weighted MRI in a

fetus of 20 weeks gestation in the coronal plane. Slices

across the entire brain are acquired in less than 40 s. Bands

of altering SI within the hemispheres correspond to an out-

ermost low SI cortex, an adjacent high SI subplate, a thicker

layer of low SI corresponding to migrating cells within the

developing WM, an innermost very low SI corresponding

to the germinal or subependymal layer and the high SI cen-

tral ventricle. The low SI rounded inferior colliculi are seen

in the central brainstem.

702 Rutherford et al.

Developmental Neurobiology

adequate signal to noise is often only possible by

acquiring images with a slice thickness of 4 mm. This

results in partial volume effects. In addition, to pre-

vent \cross talk" data is usually acquired with a gap

between slices resulting in incomplete sampling

across the brain. Small individual structures may not

be well visualized and the data is not suitable for vol-

umetric quantification. Some of these problems can

be addressed by reducing the slice thickness but this

result in poorer signal to noise and longer acquisition

times, the latter further increases the chance of fetal

motion.

Fetal motion poses the biggest problem for

attempts to advance imaging techniques and obtain

data that can be accurately and objectively quantified.

It must be assumed that a degree of fetal motion has

taken place even if there appears to be a parallel se-

ries of imaging slices across the brain. More often the

presence of motion is obvious with rotation occurring

through planes during the acquisition (Fig. 6). This

may hamper clinical visual analysis and excludes the

possibility of more objective quantification.

While current T2 weighted images provide suita-

ble data for clinical analysis the status of T1 weighted

data acquisition is less advanced. Image contrast is

usually inadequate and the data are easily degraded

by motion artifact (Fig. 5). At the present time the ac-

quisition of a T1 weighted dataset is still clinically

useful to confirm the signal intensity of an abnormal-

ity already detected on T2 weighted images. This is

particularly important for the presence of hemorrhage

(Fig. 5) or fat e.g., a lipoma that may accompany

agenesis of the corpus callosum (Ickowitz et al.,

2001). T1 weighted imaging is excellent for detecting

myelin in the more mature brain e.g., >35 weeks ges-

tation. T2 weighted images are superior for detecting

sites of very early myelination e.g., brainstem, den-

tate nucleus, thalami which are present on MR by

27 weeks gestation. Of interest no new sites of myeli-

nation are detected until at least 35 weeks gestation

Figure 3 Conventionally acquired T2 weighted images. Fetus of 27 weeks with bilateral

ventriculomegaly on antenatal ultrasound. There are bilateral foci of abnormal signal intensity in

subependymal lining of the posterior horns (white arrows). These are consistent with foci of

subependymal lining heterotopia. There is also a unilateral cerebellar hypoplasia (black arrow).

Figure 4 Conventionally acquired T2 weighted images. Fetus of 27 weeks gestation with unilat-

eral ventriculomegaly on antenatal ultrasound. The left hemisphere is enlarged, shows abnormal

accelerated cortical folding and a region of abnormal low signal intensity which may represent a

densely cellular area or abnormal myelination.

MRI for Assessing Fetal Brain Development 703

Developmental Neurobiology

(Counsell et al., 2002). Current fetal imaging proto-

cols would be considerably improved by optimized

T1 weighted imaging sequences.

ADVANCED IMAGING TECHNIQUES:CURRENT STATUS

Diffusion weighted (DW) imaging provides a

measure of the random or Brownian motion of

water within a tissue. This motion governs the signal

intensity within the images and is exploited by apply-

ing diffusion sensitive gradients in different planes

across the tissue being scanned. DWI allows us to

quantify tissue microstructure by measuring two pa-

rameters the overall diffusivity, the apparent diffusion

coefficient (ADC) and the directionality or anisotropy

of the water motion (FA). ADC may markedly reduce

in the presence of acute ischemia, which may be evi-

denced by overt increased signal intensity changes on

the raw DW images. Measuring the directionality or

Figure 5 Conventionally acquired T2 weighted images. Fetus of 25 weeks gestation with an

antenatal ultrasound diagnosis of cerebellar hypoplasia. MRI showed hemorrhagic infarction of the

cerebellum. (white arrows) This was easiest to visualize as abnormal high signal intensity on the

T1 weighted images (bottom row). There was an additional parenchymal cleft superiorly, probably

ischemic in origin, which resembles a schizencephaly. This can be clearly seen in all three planes

(black arrows) Antenatal cytomegalovirus infection was suspected but not proven conclusively.

704 Rutherford et al.

Developmental Neurobiology

anisotropy within the tissue can identify more subtle

abnormalities in tissue microstructure and in white

matter tract formation.

Fetal motion is a major problem for any DWI tech-

nique. A standard DW sequence with sensitization in

three planes through the fetal brain can be obtained in

about 10 s using echo planar imaging (EPI) and

allows measurement of ADC. However, signal to

noise is limited and datasets often motion artifacted.

Gross motion makes images uninterpretable, lesser

degrees of motion which may not be visually obvious

will lead to erroneous results in quantification. Sev-

eral studies have now reported values for ADC in the

developing brain showing the expected decrease with

increasing gestational age, reflecting a decrease in the

overall water content (Righini et al., 2003; Schneider

et al., 2007; Manganaro et al., 2007). However, to

obtain accurate quantification of even ADC, datasets

from the individual planes of sensitization need to be

corrected for eddy current distortions and fetal head

motion. A more sophisticated sequence; diffusion

tensor imaging (DTI), with sensitization in at least six

noncollinear planes is required for measurement of

anisotropy. One study aiming to acquire DTI dis-

carded 50% of its datasets because of overt fetal

motion, despite the fact that maternal sedation was

used. (Bui et al., 2006) The requirements for mapping

white matter tracts, tractography are greater still in

terms of numbers of planes of sensitization and signal

to noise ratios, and are not yet available for fetal

imaging. DTI has been used to assess the post-mor-

tem fetal brain where motion is not an issue and

where acquisition times can be prolonged to maxi-

mize signal to noise required to obtain tractography.

(Huang et al., 2006) DTI studies have been performed

in the preterm infant showing decreases in anisotropy

with increasing maturation of the cortex, as a result

of increasing synaptic formation, (Deiployi et al.,

2005). Studies in the preterm infant at term equiva-

lent age have documented differences in anisotropy

in white matter tracts compared with term born con-

trols (Counsell et al., 2006; Anjari et al., 2007).

Image quality sufficient to support accurate measure-

ments of ADC and FA of the normal fetal brain is

now required so that comparisons with preterm

infants of similar gestations can be made to ascertain

at what time point white matter development deviates

away from normal in infants born preterm.

MAGNETIC RESONANCE PROTONSPECTROSCOPY

MR spectroscopy (MRS) follows the same principles

as MRI but has the ability to assess metabolic proc-

esses in the normal and abnormal brain. For MRS,

the free induction decay (FID) is resolved into a

frequency spectrum by fourier transformation. The

local magnetic environment of a nucleus, such as

Figure 6 Conventionally acquired fast single shot T2

weighted images of a fetal brain The fetus has rotated from

transverse to coronal planes during the 40 second acquisi-

tion time.

Figure 7 Proton spectra (TE 136ms) acquired in a fetus

21 weeks GA with normal brain appearances and in a dif-

ferent fetus at 33 weeks GA with mild ventricular dilata-

tion. Peaks identifiable can be attributed to lactate

(1.31ppm) (arrows), N-Acetyl-aspartate (NAA 2.02 ppm)

Creatine (Cr 3.03 ppm) and Choline (Cho 3.22 ppm) and

Myo-inositol (3.56).

MRI for Assessing Fetal Brain Development 705

Developmental Neurobiology

hydrogen, and therefore its resonance frequency is

subtly influenced by its immediate chemical environ-

ment. The relative frequency position is described by

the parameter known as chemical shift. This is a

dimensionless unit which accounts for the strength of

the static magnetic field. The intensity of the metabo-

lite signal relates to its concentration. It is measured

in parts per million (ppm). Absolute quantification is,

however, difficult and in practice results are usually

reported in terms of ratios. It is possible with modern

scanners to obtain proton spectra within a few

minutes but this is still a long acquisition time during

which a fetus is very likely to have moved. It may be

difficult to appreciate fetal motion that has \contami-

nated" a spectrum. This may be partly overcome by

collection of signal averages separately and editing

out individual spectra where motion has resulted in a

shift of the water peak. Some groups use maternal

sedation to decrease fetal motion during image and

spectral acquisition. (Girard et al., 2006a) others have

only imaged fetuses over 30 weeks with the fetal

head engaged in pelvis. At present it is only possible

to obtain spectra with adequate signal to noise

by using a fairly large central region of interest e.g.

4.5 cm3 (Girard et al., 2006a,b,c) and it is not possible

to reliably obtain data from different tissue types as

fetal motion during the acquisition will result in inad-

vertent sampling of adjacent tissues. Proton spectros-

copy in the fetal brain has shown several main peaks

attributable to N-acetyl aspartate (NAA), choline

(Cho), creatine (Cr), glutamate (Glx) myo-inositol,

and lactate (Fig. 7). NAA is a putative marker of neu-

ronal activity representing both dendrite and synapse

formation (Kato et al., 1997; Moffet et al., 2007). It

may also be a marker for oligodendrocyte, prolifera-

tion, and differentiation (Bhakoo et al., 2000) and

would be expected to increase with increasing gesta-

tion. Choline (Cho) is a constituent of membranes

and plays a role in myelination. As the fetus matures

levels of NAA have been shown to increase and Cho

to decrease (Girard et al., 2006b,c). Creatine is

involved in cellular energy metabolism. There is still

debate as to whether lactate should be detectable in

the normal fetal brain (Roelants-van Rijn et al., 2004;

Wolfberg et al., 2007) Myo-inositol acts as an osmo-

lyte. It is also thought to be a marker of astrocytes

shown to decrease with increasing gestation (Girard

et al., 2006b,c) Myo-inositol has been shown to be

reduced in fetal ventricular dilation although the

volume of interest included cerebrospinal fluid (Kok

et al., 2001) MR proton spectroscopy is not being

used as a routine clinical tool in fetal imaging and its

potential needs to be fully explored.

FUNCTIONAL IMAGING

Functional MRI (fMRI) studies brain activity in

response to various stimuli and is based on the BOLD

(blood oxygen level dependent) effect. Local neuro-

nal activity increases in response to a stimulus, induc-

ing an increase in local blood flow and consequently

an increase in venous blood oxygenation and in blood

volume. This leads to an increase in local MR signal

known as BOLD contrast. fMRI is performed using

echo-planar imaging, which is very sensitive to dif-

ferences in magnetic susceptibility. The difference

between oxy- and deoxyhaemoglobin generates the

fMRI signal. The growth of studies in functional MR

imaging in adult populations has been exponential

over recent years. There have been a limited number

of studies trying to obtain truly functional data from

the fetus and neonate. The developmental status in

these populations means that paradigms are largely

restricted to visual and auditory sensory domains

with variable results. Using a vibroacoustic stimulus

Figure 8 Fetal brain in the coronal plane at 22 weeks

gestation showing layered hemisphere with a band of high

signal intensity consistent with the hydrophilic subplate

(arrows) (Perkins et al., accepted).

Figure 9 Fetal brain parenchymal layer diameters in the

parietal lobe against gestational age (Perkins et al.).

706 Rutherford et al.

Developmental Neurobiology

with headphones strapped to the maternal abdomen a

sound level of 95–100 dB produced some activation

in the temporal lobe of 7 of 15 fetuses (Fulford et al.,

2004). Using a visual stimulus provided by a red

LED cluster on the maternal abdomen, five of eight

fetuses showed some activation, in four of these, the

area was found within the frontal region. There was

no significant activation detected within the visual

areas (Fulford et al., 2003).

The hemodynamic response in the fetus is differ-

ent from that in adults. This may reflect differences in

the oxygen affinity of fetal and adult hemoglobin,

immaturity of vascular control mechanisms, differen-

ces in activation in the immature brain (immaturity of

the synaptic connections precluding neuronal activity

in the usual cortical area of interest), and low sensi-

tivity of the fetal fMRI technique (Gowland et al.,

2004). In addition, while the study of mature fetuses

decreases the likelihood of major fetal motion, any

degree of motion will compromise the data obtained.

The application of techniques that can allow the pro-

duction of quantifiable fMRI data in the presence of

Figure 10 Snapshot magnetic resonance imaging (MRI) with Volume Reconstruction (SVR).

Fetus of 32 weeks gestation scanned at 1.5 Tesla. One loop of dynamic scanning in plane of acqui-

sition (a) and reformatted planes (b,c). Combination of four loops of data (d–f). Registration of

combined loops (g) and reformatted registered data (h,i) Ex utero scan of a preterm at 32 weeks

acquired at 3 Tesla (Jiang 2007b).

MRI for Assessing Fetal Brain Development 707

Developmental Neurobiology

fetal motion would provide an exciting advance for

understanding function within the developing brain.

NEW DEVELOPMENTS AND RESEARCH

Current image quality allows improved detection and

assessment of abnormalities compared with ultra-

sound (Levine et al., 2003). Imaging quality and the

range of sequences available are still limited com-

pared with the postnatal examination of the neonate,

the major barrier to this is fetal motion with fetal

brain size and fetal position deep in the maternal

body being important secondary issues.

Volumetric datasets: Visual analysis of images has

allowed us to document many processes within the

developing brain that have not been visualized with

antenatal ultrasound e.g., cortical folding, subplate

involution, myelination. With an optimal data set of

images, 2-dimensional (2D) measures are possible

and this approach has been used to obtain measures

of individual brain structures e.g., total brain and CSF

volumes (Kazan-Tannus et al., 2007), the transcere-

bellar diameter (Garel, 2003; Triulzi et al., 2005) cer-

ebellar vermis height, cortical subplate (Perkins et al.,

accepted) establishing their relationship with gesta-

tional age (Figs. 8 and 9). It is currently not possible

to obtain adequate quality 3-dimensional datasets for

either standard or advanced imaging sequences.

Volumetric data has been obtained using EPI images

having low resolution and are only able to provide

measures of whole brain (Duncan et al., 2005). We

are currently unable, therefore, to perform absolute

quantification of the volume of individual brain struc-

tures in the fetus.

Figure 11 Manual segmentation of reformatted dynamic scans. Region of interest encompassing

the whole brain, the ventricular system and the cerebellum were drawn in the transverse plane and

checked on the reformatted sagittal and coronal images. Courtesy of Tayyib Hayat.

Figure 12 Preterm infant scanned at 27 weeks postmenst-

rual age. T2 weighted image in the sagittal plane showing

subplate layer (arrows). Fractional anisotropy map obtained

with 15 collinear direction diffusion tensor imaging

sequence. Arrows point to the cortex which shows obvious

anisotropy at this age. (Courtesy of Latha Srinivasan).

708 Rutherford et al.

Developmental Neurobiology

Until recently it has not been possible to obtain

coherent datasets of whole fetal brain with adequate

signal to noise (Rousseau et al., 2006). We have

addressed these issues with a novel methodology,

snapshot MRI with volume reconstruction (SVR).

This allows us to image the fetal brain at high resolu-

tion and high signal-to-noise ratio (SNR) (Jiang et al.,

2007b). The method combines registered 2D slices

from sequential dynamic single-shot scans. The SVR

approach requires that the anatomy in question is not

changing shape or size and is moving at a rate that

allows snapshot images to be acquired. Imaging the

target volume repeatedly guarantees sufficient sam-

pling everywhere. We have implemented a robust

slice-to-volume registration that achieves alignment

of each slice within 0.3 mm. Multilevel scattered

interpolation is then used to obtain high-fidelity

reconstruction with root-mean-square (rms) error that

is less than the noise level in the images. Fine struc-

ture of the in-utero fetal brain can be visualized and

substantial SNR improvement realized by having

many individually acquired slices contribute to each

voxel in the reconstructed image (Fig. 10).

We have used these volumetric datasets to mea-

sure absolute brain, ventricular and cerebellar vol-

umes in a small pilot study (Rutherford et al., 2007).

This quantification was achieved with manual techni-

ques (Fig. 11). Automatic segmentation would allow

us to quantify a large number of scans more rapidly

but techniques need optimizing and validating. We

are currently adapting a newly optimized method of

automatic segmentation of the neonatal brain (Xue

et al., 2007) to the fetal datasets. This technique will

provide tissue volumes and will also allow us to

quantify parameters of cortical growth and develop-

ment including thickness and curvature in unprece-

dented detail.

Diffusion imaging: DW imaging can produce data-

sets in a short acquisition time but because of fetal

motion these are not suitable for accurate quantifica-

tion of regional ADC let alone FA and definitely not

suitable for tractography. The production of maps of

ADC and FA requires correction for distortions from

both eddy currents and fetal head motion. Current

studies often do not report whether such correction

was performed (Ringhini et al., 2003; Erdem et al.,

2007; Schneider et al., 2007) We are currently apply-

ing a similar dynamic approach to the acquisition of

data to produce diffusion weighting in 15 planes.

This has allowed us to produce faithful maps of ADC

and less robust maps of FA, although these are able

to identify individual tracts within the very immature

brain (Jiang et al., 2007a). Optimization of this tech-

nique is continuing and will eventually allow us to

obtain data suitable for ADC and FA maps as well as

for tractography that is comparable to that obtained

ex -utero in the preterm infant (Fig. 12).

CONCLUSIONS

The field of fetal MRI is in its infancy. There are

many possibilities for exploiting existing techniques

and for developing intelligent new approaches that

may overcome the major issues inherent in obtaining

MR data form a small moving object. These advances

will enhance our knowledge allowing new insights

into the normally and abnormally developing brain.

We would like to thank the Medical Research Council,

The Health Foundation, Philips Medical Systems, Action

for Medical Research and The European Leucodystrophy

Association for their support.

REFERENCES

Anjari M, Srinivasan L, Allsop JM, Hajnal JV, Rutherford

MA, Edwards AD, Counsell SJ. 2007. Diffusion tensor

imaging with tract-based spatial statistics reveals local

white matter abnormalities in preterm infants. Neuro-

image 35:1021–1027.

Bhakoo KK, Pearce D. 2000. In vitro expression of N-ace-

tyl aspartate by oligodendrocytes: implications for proton

magnetic resonance spectroscopy signal in vivo. J Neuro-

chem 74:254–262.

Boardman JP, Counsell SJ, Rueckert D, Kapellou O, Bhatia

KK, Aljabar P, Hajnal J, et al. 2006. Abnormal deep grey

matter development following preterm birth detected

using deformation-based morphometry. Neuroimage

32:70–78.

Bui T, Daire JL, Chalard F, Zaccaria I, Alberti C, Elmaleh

M, Garel C, et al. 2006. Microstructural development of

human brain assessed in utero by diffusion tensor imag-

ing. Pediatr Radiol 36:1133–1140.

Cohen M, Paley M, Griffiths P, Whitby E. 2007. Less inva-

sive autopsy: Benefits and limitations of the use of mag-

netic resonance imaging in the perinatal post-mortem.

Pediatr Dev Pathol 22:1.

Counsell SJ, Maalouf EF, Fletcher AM, Duggan P, Battin

M, Lewis HJ, Herlihy AH, et al. 2002. MR imaging

assessment of myelination in the very preterm brain.

AJNR Am J Neuroradiol 23:872–881.

Counsell SJ, Shen Y, Boardman JP, Larkman DJ, Kapellou

O, Ward P, Allsop JM, et al. 2006. Axial and radial diffu-

sivity in preterm infants who have diffuse white matter

changes on magnetic resonance imaging at term-equiva-

lent age. Pediatrics 117:376–386.

Deipolyi AR, Mukherjee P, Gill K, Henry RG, Partridge

SC, Veeraraghavan S, Jin H, et al. 2005. Comparing

microstructural and macrostructural development of the

MRI for Assessing Fetal Brain Development 709

Developmental Neurobiology

cerebral cortex in premature newborns: Diffusion tensor

imaging versus cortical gyration. Neuroimage 27:579–

586.

Dietrich RB, Cohen I. 2006. Fetal MR imaging. Magn

Reson Imaging Clin N Am 14:503–522. Review.

Duncan KR, Issa B, Moore R, Baker PN, Johnson IR, Gow-

land PA. 2005. A comparison of fetal organ measure-

ments by echo-planar magnetic resonance imaging and

ultrasound. BJOG 112:43–49.

Erdem G, Celik O, Hascalik S, Karakas HM, Alkan A, Firat

AK. (2008). Diffusion-weighted imaging evaluation of

subtle cerebral microstructural changes in intrauterine fe-

tal hydrocephalus. Magn Reson Imaging 30:211–220.

Fogliarini C, Chaumoitre K, Chapon F, Fernandez C, Lev-

rier O, Figarella-Branger D, Girard N. 2005a. Assess-

ment of cortical maturation with prenatal MRI. I. Normal

cortical maturation. Eur Radiol 15:1671–1685.

Fogliarini C, Chaumoitre K, Chapon F, Fernandez C, Lev-

rier O, Figarella-Branger D, Girard N. 2005b. Assess-

ment of cortical maturation with prenatal MRI. II. Abnor-

malities of cortical maturation. Eur Radiol 15:1781–

1789. Review.

Fulford J, Vadeyar SH, Dodampahala SH, Moore RJ,

Young P, Baker PN, James DK, et al. 2003. Fetal brain

activity in response to a visual stimulus. Hum Brain

Mapp 20:239–245.

Fulford J, Vadeyar SH, Dodampahala SH, Ong S, Moore

RJ, Baker PN, James DK, et al. 2004. Fetal brain activity

and hemodynamic response to a vibroacoustic stimulus.

Hum Brain Mapp 22:116–121.

Garel C. 2003. MRI of the Fetal Brain: Normal Develop-

ment and Cerebral Pathologies. Springer. Berlin and Hei-

delberg.

Girard N, Chaumoitre K, Confort-Gouny S, Viola A, Levrier

O. 2006a. Magnetic resonance imaging and the detection

of fetal brain anomalies, injury, and physiologic adapta-

tions. Curr Opin Obstet Gynecol 18:164–176.

Girard N, Fogliarini C, Viola A, Confort-Gouny S, Fur YL,

Viout P, Chapon F, et al. 2006c. MRS of normal and

impaired fetal brain development. Eur J Radiol 57:217–

225.

Girard N, Gouny SC, Viola A, Le Fur Y, Viout P, Chau-

moitre K, D’Ercole C, et al. 2006c. Assessment of nor-

mal fetal brain maturation in utero by proton magnetic

resonance spectroscopy. Magn Reson Med 56:768–775.

Gowland P, Fulford J. 2004. Initial experiences of perform-

ing fetal fMRI. Exp Neurol 2004; 190 (Suppl 1):S22–S27.

Glenn OA. 2006. Fetal central nervous system MR imaging.

Neuroimaging Clin N Am 16:1–17, vii.

Griffiths PD, Paley MN, Whitby EH. 2005. Post-mortem

MRI as an adjunct to fetal or neonatal autopsy. Lancet

365:1271–1273.

Hand JW, Li Y, Thomas EL, Rutherford MA, Hajnal JV.

2006. Prediction of specific absorption rate in mother and

fetus associated with MRI examinations during preg-

nancy. Magn Reson Med. 2006; 55:883–893.

Heerschap A, Kok RD, van den Berg PP. 2003. Antenatal

proton MR spectroscopy of the human brain in vivo.

Childs Nerv Syst 19:418–421.

Huang H, Zhang J, Wakana S, Zhang W, Ren T, Richards

LJ, Yarowsky P, et al. 2006. White and gray matter de-

velopment in human fetal, newborn and pediatric brains.

Neuroimage 33:27–38.

Heerschap A, Kok RD, van den Berg PP. 2003. Antenatal

proton MR spectroscopy of the human brain in vivo.

Childs Nerv Syst 2003; 19:418–421.

Ickowitz V, Eurin D, Rypens F, Sonigo P, Simon I, David

P, Brunelle F, et al. 2001. Prenatal diagnosis and post-

natal follow-up of pericallosal lipoma: Report of seven

new cases. AJNR Am J Neuroradiol 2001; 22:767–772,

Erratum in: AJNR Am J Neuroradiol 2001; 22:1446.

Jiang S, Counsell S, Xue H, Allsop J, Rutherofrd M, Rueck-

ert D, Hajnal J. 2007a.In utero 3-D high resolution fetal;

brain diffusion tensor imaging. Abstract 622 ISMRM.

Jiang S, Xue H, Glover A, Rutherford M, Rueckert D, Haj-

nal JV. 2007b. MRI of moving subjects using multislice

snapshot images with volume reconstruction (SVR):

Application to fetal, neonatal, and adult brain studies.

IEEE Trans Med Imaging 26:967–980.

Judas M, Rados M, Jovanov-Milosevic N, Hrabac P, Stern-

Padovan R, Kostovic I. 2005. Structural, immunocyto-

chemical, and mr imaging properties of periventricular

crossroads of growing cortical pathways in preterm

infants. AJNR Am J Neuroradiol 26:2671–2684.

Kato T, Nishina M, Matsushita K, Hori E, Mito T, Taka-

shima S. 1997. Neuronal maturation and N-acetyl-L-as-

partic acid development in human fetal and child brains.

Brain Dev 19:131–133.

Kapellou O, Counsell SJ, Kennea N, Dyet L, Saeed N,

Stark J, Maalouf E, et al. 2006. Abnormal cortical devel-

opment after premature birth shown by altered allometric

scaling of brain growth. PLoS Med 3:e265.

Kazan-Tannus JF, Dialani V, Kataoka ML, Chiang G, Feld-

man HA, Brown JS, Levine D. 2007. MR volumetry of

brain and CSF in fetuses referred for ventriculomegaly.

AJR Am J Roentgenol 189:145–151.

Kok RD, de Vries MM, Heerschap A, van den Berg PP.

2004. Absence of harmful effects of magnetic resonance

exposure at 1.5 T in utero during the third trimester of

pregnancy: A follow-up study. Magn Reson Imaging

22:851–854.

Kok RD, van den Bergh AJ, Heerschap A, Nijland R, van

den Berg PP. 2001. Metabolic information from the

human fetal brain obtained with proton magnetic reso-

nance spectroscopy. Am J Obstet Gynecol 185:1011–

1015.

Levine D, Barnes PD, Robertson RR, Wong G, Mehta TS.

2003. Fast MR imaging of fetal central nervous system

abnormalities. Radiology 229:51–61.

Maalouf EF, Duggan PJ, Rutherford MA, Counsell SJ,

Fletcher AM, Battin M, Cowan F, Edwards AD. 1999.

Magnetic resonance imaging of the brain in a cohort of

extremely preterm infants. J Pediatr 135:351–357.

Manganaro L, Perrone A, Savelli S, Di Maurizio M, Maggi

C, Ballesio L, Porfiri LM, De Felice C, Marinoni E, Mar-

ini M. 2007. Evaluation of normal brain development by

prenatal MR imaging. Radiol Med (Torino) 112:444–

455.

710 Rutherford et al.

Developmental Neurobiology

Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri

AM. 2007. N-Acetylaspartate in the CNS: From neuro-

diagnostics to neurobiology. Prog Neurobiol 81:89–131.

Myers C, Duncan KR, Gowland PA, Johnson IR, Baker PN.

1998. Failure to detect intrauterine growth restriction fol-

lowing in utero exposure to MRI. Br J Radiol 71:549–

551.

Nicholl RM, Balasubramaniam VP, Urquhart DS, Sella-

thurai N, Rutherford MA. 2007. Postmortem brain MRI

with selective tissue biopsy as an adjunct to autopsy fol-

lowing neonatal encephalopathy. Eur J Paediatr Neurol

11:167–174.

Perkins L, Hughes E, Srinivasan L, Allsop J, Glover A,

Kumar S, Fisk N, et al. 2008. Exploring cortical subplate

evolution using magnetic resonance imaging of the fetal

brain. Dev Neurosci 30:211–220.

Prayer D, Kasprian G, Krampl E, Ulm B, Witzani L, Prayer

L, Brugger PC. 2006. MRI of normal fetal brain develop-

ment. Eur J Radiol 57:199–216. Review.

Righini A, Bianchini E, Parazzini C, Gementi P, Ramenghi

L, Baldoli C, Nicolini U, Mosca F, Triulzi F. 2003.

Apparent diffusion coefficient determination in normal

fetal brain: A prenatal MR imaging study. AJNR Am J

Neuroradiol 24:799–804.

Roelants-van Rijn AM, Groenendaal F, Stoutenbeek P, van

der Grond J. 2004. Lactate in the foetal brain: Detection

and implications. Acta Paediatr 93:937–940.

Rousseau F, Glenn OA, Iordanova B, Rodriguez-Carranza

C, Vigneron DB, Barkovich JA, Studholme C. 2006.

Registration-based approach for reconstruction of high-

resolution in utero fetal MR brain images. Acad Radiol

13:1072–1081.

Rutherford M, Jiang S, Zavadenko A, Allsop J, Hajnal J.

2007.Snapshot MRI with Volume Reconstruction of the

Fetal Brain. ISMRM proceedings Abstract 391.

Schneider JF, Confort-Gouny S, Le Fur Y, Viout P, Benna-

than M, Chapon F, Fogliarini C, Cozzone P, Girard N.

2007. Diffusion-weighted imaging in normal fetal brain

maturation. Eur Radiol 17:2422–2429.

Triulzi F, Parazzini C, Righini A. 2005. MRI of fetal and

neonatal cerebellar development. Semin Fetal Neonatal

Med 10:411–420.

Vadeyar SH, Moore RJ, Strachan BK, Gowland PA, Shake-

speare SA, James DK, Johnson IR, Baker PN. 2000.

Effect of fetal magnetic resonance imaging on fetal heart

rate patterns. Am J Obstet Gynecol 182:666–669.

Wolfberg AJ, Robinson JN, Mulkern R, Rybicki F, Du

Plessis AJ. 2007. Identification of fetal cerebral lactate

using magnetic resonance spectroscopy. Am J Obstet

Gynecol 196:e9–e11.

Whitby E, Paley MN, Davies N, Sprigg A, Griffiths PD.

2001. Ultrafast magnetic resonance imaging of central

nervous system abnormalities in utero in the second and

third trimester of pregnancy: Comparison with ultra-

sound. Br J Obstet Gynaecol 108:519–526.

Whitby EH, Paley MN, Sprigg A, Rutter S, Davies NP,

Wilkinson ID, Griffiths PD. 2004. Comparison of ultra-

sound and magnetic resonance imaging in 100 singleton

pregnancies with suspected brain abnormalities. Br J

Obstet Gynaecol 111:784–792.

Xue H, Srinivasan L, Jiang S, Rutherford M, Edwards AD,

Rueckert D, Hajnal JV. 2007. Automatic cortical seg-

mentation in the developing brain. Inf Process Med

Imaging 20:257–269.

MRI for Assessing Fetal Brain Development 711

Developmental Neurobiology