Magnetic resonance methods in fetal neurology

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Seminars in Fetal & Neonatal Medicine 17 (2012) 278e284

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Seminars in Fetal & Neonatal Medicine

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Magnetic resonance methods in fetal neurology

M. Mailath-Pokorny a,*, G. Kasprian b, C. Mitter b, V. Schöpf b, U. Nemec b, D. Prayer b

aMedical University of Vienna, Department of Obstetrics and Gynecology, Vienna, AustriabMedical University of Vienna, Department of Radiodiagnostics, Vienna, Austria

Keywords:FetusFunctional magnetic resonance imagingMagnetic resonance imagingNeurologySpectroscopyTractography

* Corresponding author. Address: Medical UniversObstetrics and Gynecology, Waehringer Guertel 18Tel.: þ431 40400 2821; fax: þ431 40400 2862.

E-mail address: mariella.mailath-pokorny@medPokorny).

1744-165X/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.siny.2012.06.002

s u m m a r y

Fetal magnetic resonance imaging (MRI) has become an established clinical adjunct for the in-vivoevaluation of human brain development. Normal fetal brain maturation can be studied with MRI fromthe 18th week of gestation to term and relies primarily on T2-weighted sequences. Recently diffusion-weighted sequences have gained importance in the structural assessment of the fetal brain. Diffusion-weighted imaging provides quantitative information about water motion and tissue microstructureand has applications for both developmental and destructive brain processes. Advanced magneticresonance techniques, such as spectroscopy, might be used to demonstrate metabolites that are involvedin brain maturation, though their development is still in the early stages. Using fetal MRI in addition toprenatal ultrasound, morphological, metabolic, and functional assessment of the fetus can be achieved.The latter is not only based on observation of fetal movements as an indirect sign of activity of the fetalbrain but also on direct visualization of fetal brain activity, adding a new component to fetal neurology.This article provides an overview of the MRI methods used for fetal neurologic evaluation, focusing onnormal and abnormal early brain development.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

1.1. Overview

Fetal neurology has been defined as morphological, metabolicand functional assessment of the fetus.1 Ultrasound has been theprimary imaging method for the routine evaluation of the fetus andfor the early diagnosis of fetal malformations.2 To date, morpho-logical and functional information has been acquired mainly byultrasound,3 which is still the mainstay of imaging the fetus.4

According to its specific physical background, ultrasound islimited to the visualization of only certain aspects of fetal neuro-logical diseases.

Fetal magnetic resonance imaging (MRI) has evolved in the last25 years since it was first described5 and has become of increasingimportance as an adjunct to prenatal ultrasound,6 especially whenevaluating the fetal brain.7 Because of its higher tissue contrastresolution than prenatal sonography it allows better visualizationof both normal and abnormal tissue7 and may add importantinformation in three specific ways: by quantification of brain

ity of Vienna, Department ofe20, 1090 Vienna, Austria.

uniwien.ac.at (M. Mailath-

All rights reserved.

growth and structural abnormalities, by qualitative evaluation ofcentral nervous system (CNS) microstructure and by qualitativeassessment of dynamic fetal movements in utero.8 Thus, using MRIas a clinical adjunct to ultrasound, all three mentioned areas ofneurologic evaluation can be approached.

Normal fetal brain maturation can be studied by in-vivo MRIfrom the 18th week of gestation to term and relies primarily on T2-weighted sequences. Diffusion-weighted sequences have recentlygained importance in the structural assessment of the fetal brain.Diffusion-weighted imaging provides quantitative informationabout water motion and tissue microstructure and has applicationsfor both developmental and destructive brain processes.9,10

Advanced magnetic resonance techniques, such as spectroscopy,might be used to demonstrate metabolites involved in brainmaturation,11 though their development is still in the early stages.Regarding functional assessment, two possibilities exist: similarlyto ultrasound, MRI may record gross and intrinsic fetal move-ment,12 and MRI may directly assess brain function.13

1.2. Safety of MRI in human studies

It is generally accepted that MRI is safe in pregnancy since noshort- or long-term effects of MRI on mother or fetus have beenreported. Concerns have been raised in some studies about the levelof acoustic noise, biological effects and static field exposure.2

However, several studies failed to show any adverse long-term

M. Mailath-Pokorny et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 278e284 279

effects of fetal MR in children who were imaged as fetuses, thoughthese studies lacked a sufficient sample size.14e17

In 2002, the American College of Radiology stated that pregnantpatients can undergo MRI at any stage of pregnancy if, the risk:-benefit ratio is acceptable.18 However, because of the potential riskof MRI to the developing fetus and the excessive motion of youngerfetuses, the policy of our institute is not to start fetal MRI before 18weeks of gestation. Additionally the patients are extensivelycounseled upfront and an informed consent is signed. All patientsare screened for possible contraindications to MRI before theexamination. Usually, during fetal MRI, no sedation or contrastagents are administered.

2. Fetal brain morphology

2.1. Background

Normal structural brain maturation is a prerequisite for regularfetal neurological development. Using MRI, fetal brain maturationcan be shown from gestational week 17 onwards.19 At this stage, thefetal brain consists of seven layers, which can be displayed byMRI.9

Until 36 weeks of gestation the fetal brain undergoes substantialdevelopment with neuronal migration and formation of gyri andsulci.4 The increasing number and the depth of cortical sulci can beassessed and used as age-related marker of brain development.20

Interestingly, it could be shown that cortical folding occurs not atthe same time in both hemispheres and that asymmetry is a hall-mark of normal brain development.21 In the second trimester, thefetal brain shows a laminar appearance with different layers, whichare transient by nature and disappear during development, leadingto its characteristic neonatal morphology. Premyelination e whichis the state of the axons before the onset of myelination e of theinternal capsule, and the brainstem, as well as cell density in theprimary cortical regions and the basal ganglia can be recognized.9

Diffusion-weighted imaging is sensitive to the normal matura-tional changes and may be of value in the detection of abnormali-ties of brain development that cannot be detected with T2- orT1-weighted images.22

Infratentorial development, which is regarded as crucial for thegeneration of normal movement patterns, can be assessed andquantified with in-vivo fetal MRI.23

Abnormal brain development may be characterized by focal ordiffuse changes of cortical folding. Using MRI, diffuse pathologiessuch as lissencephalies or polymicrogyria may be recognized evenbefore onset of formation of gyri and sulci, as these syndromes areassociated with impaired lamination of the brain parenchyma and/or brainstem abnormalities,10,24 and/or abnormal hemisphericalasymmetry.21 Diffuse abnormalities of cortical formation are asso-ciated with developmental delay, motoric impairment andepilepsy.25,26 Thus early diagnosis of diffuse disorders of corticalmalformation is of prognostic significance.

Focal cortical dysplasia may also lead to epilepsy and/or focalneurological deficits. Their etiology is inhomogeneous.25 Due totheir small size, they may be missed on MRI before the thirdtrimester. This may be also the case in cortical tubera and/or sub-ependymal nodules in tuberous sclerosis.27

Morphological manifestations of acquired brain pathology mayshow an overlap with malformations, especially if caused byinfection such as CMV, that may lead to disorders of corticaldevelopment28 and may cause structural and profound neuro-developmental abnormalities,29 such as microcephaly or ven-triculomegaly and periventricular cystic lesions.30 Ischemic orhemorrhagic lesions have inhomogeneous etiologies.31

The cause of fetal ischemia can be of placental, fetal or maternalorigin.6 Ischemia can be demonstrated shortly after the insult by

a hyperintense diffusion-weighted image signal, whereas chronicchanges appear as increased signal on T1-weighted MR images,which is caused by subcortical leukomalacia.32,33 Spontaneous CNShemorrhage can be caused by congenital coagulation disorders,vascular malformations and pre-existing tumors6 andmay result inan obstructive hydrocephalus or abnormalities of brain develop-ment and neuronal migration.34 MRI is highly sensitive to acuteischemic brain lesions35 as well as to different stages of hemor-rhage. In addition, grading of hemorrhage may be more accuratelypossible using MRI compared with ultrasound,36 leading to betterprognostic information.

2.2. MRI

Fetal MR imaging is routinely performed on 1.5T MR scanners.The mother lies supine or in the left lateral decubitus positionduring the course of the examination. For optimal image quality,the fetal head must be in the center of the coil, which meansa centered positioning of a mobile coil (such as a cardiac coil)around the mother, or in case of the use of the body coil, a properpositioning of the pregnant woman within the magnet.Sequences used for the assessment of normal fetal brain devel-opment are selected based on their ability to delineate surfacestructures and layering, which is best provided by T2 weightedcontrast; to show differences in cell density, which may be doneusing T1-weighted images. Gradient-echo-sequences and echo-planar sequences respectively are sensitive for acute hemorrhageand blood breakdown products. Premyelination may be evalu-ated using diffusion-weighted anisotropy images.33,37

In general, T2-weighted images, ultrafastspin-echo sequences,T1-weighted gradient-echo sequences, steady-state free preci-sion sequences, and diffusion-weighted sequences are used, withtheir parameters adjusted to the changing ultrastructuralcomposition of the developing brain. Because fetal MRI is per-formed without maternal or fetal sedation, image acquisition issusceptible to fetal motion; therefore, fetal MRI is performedprimarily using ultrafast MRI techniques known as single-shot,fast spin-echo (SS-FSE) or half-Fourier acquired single-shotturbo spin-echo (HASTE).

MR signals of the different layers of the pallium depend oncellular density and on the amount of extracellular matrix, and thespatial course of ultrastructural elements.38,39

3. Fetal brain connectivity

3.1. Background

Diffusion tensor imaging (DTI) and tractography are non-invasive tools that enable the study of three-dimensional (3D)diffusion characteristics and their molecular, cellular and micro-structural correlates in the human brain.40 Bundles of unmyelin-ated axons create a strongly anisotropic environment witha diffusion maximum parallel to the orientation of the fiber tracts.Computational postprocessing algorithms use the directionaldiffusion information of each imaged voxel to generate 3D visual-ized ‘fibers’, which allows the 3D reconstruction and depiction ofmain white-matter fiber pathways.41,42 Tractography has alreadybeen used to identify white-matter fiber tracts in healthy preterm43

and term newborns,44 as well as in postmortem samples of fetalbrains.45e47

Using specially tailored DTI sequences it has already beenshown that it is possible to delineate sensorimotor tracts and thecorpus callosum in living, unsedated fetuses in utero and tocompare developmental changes in the morphology of these fibertracts across gestational age.40 Thus, this method will be helpful in

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diagnosing agenesis or hypogenesis of the corpus callosum or inpathologies where an impairment of the corticospinal tract issuspected.48 Recently even association fibers have been demon-strated.49 In the future a better estimation of neuropsychologicaldevelopment might be possible using the information provided bytractography of these bundles.

3.2. MRI

Connectivity can be demonstrated from 18 gestational weeksonwards. At that time, the corticospinal and the frontopontinetracts can be visualized.40 MR tractography is based on theevaluation of diffusion-tensor images.40 A diffusion-tensorsequence with 16e32 diffusion-sensitizing directions is used.Then, the color-coded fractional anisotropy maps are super-imposed with anatomical images. Regions of interest (ROIs) aredrawn in locations where the respective tract passes. A fiber-bundle passing through these ROIs can then be visualized(Fig. 1).40

4. Functional MRI

4.1. Background and MRI

Functional magnetic resonance imaging (fMRI) allows detectionof the brain areas involved in a task, a process, or an emotion. Thus,fMRI gives insights into the spatiotemporal distribution of humanbrain networks. Some of these networks can be detected when thefetus is in a resting state, whereas others have been observed in thecontext of task-focused behavior.50

Resting state networks (RSNs) are always present: during taskperformance and at rest, during sleep and anesthesia and across allages from infants to adults.51e56

It has been shown that structural and functional connectivity ofRSNs can be affected by various neurodegenerative, neurological,psychiatric, motor and chronic pain diseases.57 Moreover it hasbeen hypothesized that RSNs may serve as a classifier or marker forthe course and extent of various diseases.58 The developmentalorigin of these networks is largely unknown.

However, the recent literature shows that resting-statenetworks are shaped and detectable in utero (Fig. 2).13 Furtherinvestigations of resting-state measurements in the fetus maytherefore allow developmental brain activity monitoring and mayprovide insights into the early brain function.

Fig. 1. Axial T2-weighted magnetic resonance images of fetus at 28 weeks of gestation showsplenium of the corpus callosum (blue) and the corticopontine/corticospinal projection fib

5. Metabolic information

5.1. Background

Fetal magnetic resonance spectroscopy (H MRS) is a non-invasive imaging technique that allows in-vivo information aboutthe metabolic status of fetal brain tissue by analyzing the differ-ences in the 1H proton’s absorption of specific radiofrequencies ina static magnetic field. Brain H MRS identifies several metabolites,including lactate.59 Preliminary data show that MRS can be used inthe pediatric population, especially for the detection of hypoxicischemic encephalopathy (HIE), leukoencephalopathies and inbornerrors of metabolism.60,61 Additionally, it has been reported thatimpaired fetal brain development associated with ven-triculomegaly, intrauterine growth restriction (IUGR), and small forgestational age fetuses can be shown by MRS signal changes.

5.1.1. Brain metabolites seen on MRS1H MR spectra at short TE of the healthy neonatal brain reveal

four main groups of metabolites: N-acetyl (NA), creatine (Cr),choline (Cho), and inositol (Ino). Using additional water suppres-sion pulses in vivo, the spectrum in the brain reveals specific peaksdue to the metabolites NAA and N-acetyl-aspartate glutamate(NAAG); creatine þ phosphocreatine (Cr); choline (Cho); Myo-inositol (Myo-ino); glutamine (Gln); glutamate (Glu); glucose (G);taurine (Tau); scylloinositol (Scy-ino); and lactate (Lac).62e64

Normative values for the levels of the fetal brain metabolites, Ino,Cho, Cr, and NA, and their ratios are available65 and can be used asreferences to examine changes in 1HMR spectra due to pathologicalconditions of the fetal brain, for example, neuronal damage due tohypoxia.

5.1.2. Fetal brain maturation on MRSMetabolite levels within the human fetal brain have been shown

to change with increasing gestational age during the thirdtrimester. This finding is thought to reflect maturation, in agree-ment with 1H MRS performed on preterm neonates.66 At 22 weeksof gestation the MRS is characterized by two prominent resonancesassigned to Myo-ino and Cho. The Myo-ino resonance dominatesthe spectrum at short TE from 22 to 28 weeks of gestation and issignificantly reduced with progressing gestational ages in fetuses.67

Choline is also prominent on the MRS spectrum at a short TEfrom 22 to 28 weeks. Cho is involved in synthesis of acetylcholineand membrane phospholipids68,69 and is taken up by both glia andneurons. Cho and the Cho:Cr ratio significantly decrease with

ing three-dimensional fiber tracts projected onto the fetal brain. Note the genu and theers (green).

Fig. 2. Axial T2-weighted magnetic resonance image of a fetus at 33 weeks of gesta-tion with normal brain development. Functional imaging data sets at rest were studiedusing functional connectivity analysis. A seed voxel of interest was placed in the rightcortical plate of the occipital cortex. Image processing was performed in Matlab(Matlab 7.8, R2009a, Mathworks Inc., Sherborn, MA, USA).

M. Mailath-Pokorny et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 278e284 281

increasing gestational age.67 NAA also appears in the spectrum asearly as 22 weeks although the peak intensity is weak67,70 and isthought to be related to the development of dendrites and synapsesas well as proliferation and differentiation of oligodendrocytes.71

NA signal increases significantly with progressing gestationalage.65 Ino shows no significant change in relation to fetal gesta-tional age, which is in agreement with findings in the literature.

Increasing cerebral tissue levels of NA and Cr and decreasinglevels of Cho and Ino are observed with the development of thefetal brain.67 Fetal brain maturation on MRS.62,69,72e75

At 34 weeks of gestation, the spectrum of metabolites is similarto that of the neonate. Three dominant resonances e Cho, Cr, andNAA e are observed at a long TE and five resonances e Myo-ino,Cho, Cr, NAA, and glutamine/glutamate e are dominant at a shortTE.

Recently, lactate was shown on MRS studies in IUGR fetuses andin patients with gastroschisis.76,77 However, as lactate may be partof the normal metabolic spectrum in premature newborns,78 thepathological significance of a lactate peak found in the fetal brainremains unclear.

5.1.3. Impaired fetal brain development demonstrated by MRSImpaired fetal brain development may be caused by a primary

brain malformation, hypoxiceischemic injury, infection, ora combination of factors. The literature gives little informationabout specific metabolic changes in different fetal brain abnor-malities, and specific spectroscopic patterns in different brainanomalies have not yet been identified in utero. However, in

ventriculomegaly, a lower Ino:Cr ratio has been suggested to resultfrom an abnormal hypo-osmolar state.79

The recent literature also suggests that the evaluation of gliosismight be made possible by Cr increases, which can be detected intissue injury and which are not visible by conventional T1 or T2sequences.80 In the future, the evidence of gliosis might help in theevaluation of the timing of an intrauterine injury, as glial reactivityhas been found to be associated with developmental steps in therodent brain.81

5.1.4. Intrauterine growth restrictionAs mentioned before, in IUGR fetuses with normal morphology,

proton MRS of the fetal brain shows lactate and a low NAA:Choindex, metabolic markers of starvation/hypoxia.77 This pattern isconsistent with the metabolic changes seen in hypoxiceischemicinjury in neonates. A recent study additionally shows a significantincrease in Ino:Cho ratio and significantly higher apparent diffusioncoefficient (ADC) values in the pyramidal tract of small for gesta-tional age fetuses compared with age-matched normal fetuses.82

5.1.5. InfectionIn a fetus with cytomegalovirus infection, MRS may show an

increased concentration of lipids, Myo-inos, and possibly alanine,although the white matter may appear normal on conventionalsequences. It has been speculated that this may correlate with anincrease in amino acids, which is associated with brain infection.11

5.2. MRI

MRS is usually acquired using spin echo Point-RESolved Spec-troscopy (PRESS, SE) or STimulated Echo Acquisition Mode (STEAM,ST) sequences with short and long echo times (TE ¼ 20e35 and144 ms). For an optimal signal-to-noise ratio a minimum nominalvolume of interest (VOI) size of 3.4 cm3 (15 mm� 15mm� 15mm)should be used, with the VOI as close to the receiver coil as possible.Care should be taken to avoid inclusion of extracranial structureswithin the VOI.11 The acquisition time for a single spectroscopicsequence may take between 2 and 7 min. The measurement of allnecessary spectra can take up to 15 min.

If fetal movements complicate the examination, it is advisable torepeat scoutMR images between spectral acquisitions to ensure theplacement of spectroscopic VOI within the chosen brain region. Thefetal head should notmove significantly during the acquisition timeperiod.11 Spectroscopy can be done without sedation. However,maternal premedication with flunitrazepam administered orally15min to 1 h before theMR examination has been recommended.83

Short TE acquisitions are used to detect fetal brain metabolites withshort spinespin relaxation times, such as glutamine, glutamate,glucose, taurine and lipids.

Resonances ofN-acetyl aspartate (NAA), choline and creatine arealso visible in short echo spectra. However, because of the longerrelaxation time, a quantification is far more accurate if the TEacquisitions are longer (135, 144 and/or 270 ms). Longer TE acqui-sitions are also used to discriminate between lactate, alanine andlipid resonances in the spectral region around 1.35 and 1.55 ppm.

6. Observation of fetal movement patterns

6.1. Background

Fetal motor activity is a conspicious feature of prenatal devel-opment. The human fetus moves on average once per minute and ismotorically active up to 30% of the time. Spontaneous motoractivity starts in the embryonic period and motor patterns becomeincreasingly complex with continuous pregnancy.84

Fig. 3. Single acquisitions of a dynamic sequence showing the mouthing movements of a fetus at 24 weeks of gestation.

M. Mailath-Pokorny et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 278e284282

Fetal behavior is characterized by spontaneous and reflectivemovements, which require a certain neuromuscular developmentand a normal metabolic state of the CNS.85 Thus, evaluation of fetalmovements may add accuracy to the overall assessment of the fetalCNS.

The first fetal movements consisting of flexion and extension ofthe vertebral column occur around the 8th week of gestation.86

Coordinated movements involving the whole body are observedfrom 9 weeks of gestation.87 At this time the movements are notinfluenced by cerebral input, as the cortical areas, which areimportant for targeted-oriented behavior and the functionallyimportant subcortical areas, are not developed until 19 weeks ofgestation.88 From the 14th gestational week the movementsbecome more organized and at around 20 gestational weeks thefetus shows bilateral movements, whereas the hands are heldpreferably near the face.88 Between gestational weeks 26 and 32,the fetus starts to move extremities independently followinga distal proximal pattern.88 At later gestational weeks betweenweeks 37 and 38, the movement frequency decreases, and the backof the hands rest against the uterine wall.88

Fetal mouth movements may occur as pure mouth movements(opening and closing, swallowing, protruding the tongue, etc.) or asso-called mouthing movements, which are mouth movementscharacterized by a specific rhythm and frequency.89

These movements represent ingestive cycles that have beenrecognized as the core movement of human motor speechdevelopment.90

Mouthing is increasingly seen later in pregnancy, after 34 weeksof gestation, and occurs preferentially during fetal rest (Fig. 3).91

Knowledge about the MRI characteristics of the fetal muscu-lature is limited and there are only a few reports in the litera-ture.12,92 Compared with prenatal MRI, several studies in pediatricpopulations have documented the role of MRI in the visualizationof neuromuscular disorders.93,94 Muscular atrophy on fetal MRI

may also present with T2 signal hyperintensity and has beenattributed to fatty replacement secondary to chronic denerva-tion.12,92,95 The specificity of this finding is unknown. Furthermore,MR spectroscopy might be able to measure abnormal metabolismin fetal muscle tissue, but currently there are no data on this.95

6.2. MRI

Dynamic steady-state free precession (SSFP) sequences usingfour to six images per second may show gross fetal movements12

and intrinsic movements, such as mouthing and swallowing.9 Thedynamic SSFP sequencemay be applied five times at 5, 10, 15, 20, 25and 40 min to study fetal movements and to detect fixed contrac-tures. An observation period of 3� 30 s during an MRI examinationtime of 30e45 min is estimated to be sufficient to show fetalgeneral movements. However, absence of fetal movement patternsduring this time period is not necessarily indicative of a fetaldevelopmental abnormality.

7. Conclusion

Fetal MRI has become established as a clinical adjunct in theevaluation of the developing CNS and has the power to confirm orchange decisions at critical points in daily clinical practice.

Using fetal MRI in addition to prenatal ultrasound, morpholog-ical, metabolic, and functional assessment of the fetus can be ach-ieved. The latter is not only based on observation of fetalmovements as an indirect sign of activity of the fetal brain but alsoon direct visualization of fetal brain activity, adding a newcomponent to fetal neurology. Future research will contributesignificantly to our understanding of early normal and abnormalcerebral development.

Practice points

� Normal fetal brain maturation can be studied with MRI

from the 18th week of gestation to term

� The interpretation of the findings is based on a knowl-

edge of the histological background, the temporal

appearance of transient structures and their character-

istic presentation on MRI

� Using fetal MRI in addition to prenatal ultrasound,

morphological, metabolic, and functional assessment

of the fetus can be achieved.

Research directions

� Normal fetal brain development can now be readily

assessed in different periods of gestation

� Extending the “conventional” fetal MR-sequences with

new imaging techniques, such as diffusion tensor

imaging (DTI), tractography or functional fetal MRI may

provide important morphological and functional

insights into normal and abnormal fetal brain

development.

� Further investigations are needed to prove the diag-

nostic potential of these new imaging techniques.

M. Mailath-Pokorny et al. / Seminars in Fetal & Neonatal Medicine 17 (2012) 278e284 283

Conflict of interest statement

None declared.

Funding sources

None.

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