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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.
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