MR imaging of the fetal brain
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Fetal MRI is clinically performed to evaluate the brain in cases where an abnormality is detected by prenatal sonography. These most commonly include ventriculomegaly, abnormalities of the corpus callosum, and abnormalities of the posterior fossa. Fetal MRI is also increasingly performed to evaluate fetuses who have normal brain findings on prenatal sonogram but who are at increased risk for neurodevelopmental abnormalities, such as complicated monochorionic twin pregnancies. This paper will briefly discuss the common clinical conditions imaged by fetal MRI as well as recent advances in fetal MRI research.
KeywordsFetal MRI Brain
MRI is being increasingly used to evaluate the fetal brain, particularly when a fetus is at increased risk for neurodevelopmental disabilities or when an abnormality has been detected on prenatal US. Since its introduction in the early 1980s, studies have consistently shown that fetal MRI can detect abnormalities that are not apparent on prenatal sonography. Moreover, the identification of abnormalities by fetal MRI can influence decisions made about pregnancy management and delivery.
Fetal MRI offers several advantages over prenatal US. It has higher contrast resolution, is not affected by the shadowing from the calvarium or by low amniotic fluid volume, and can be easily performed using commercially available ultrafast T2-W sequences. However, fetal MRI is limited by fetal motion, the small size of the structure being imaged, and the marked distance between the receiver coil and the structure being imaged. Therefore, fetal MRI is typically not performed before 22 gestational weeks.
Because the fetal brain is a dynamic structure, it is important for radiologists to familiarize themselves with the normal appearance of the fetal brain at different gestational ages in order to be better able to identify and characterize abnormalities with fetal MRI. There are several reviews of the topic [1, 2, 3, 4].
Fetal MR technique
Fetal MRI is performed on 1.5-tesla MR scanner using a multi-channel phased array coil to allow increased coverage of the fetal head and increased signal-to-noise ratio. The mother lies supine during the course of the exam (typically 45–60 min). The mother is made as comfortable as possible during the MR exam in order to minimize fetal motion. If the mother is uncomfortable lying on her back (e.g., because of back pain or compression of the inferior vena cava), then the MR exam can be performed with the mother lying on her left side, although this results in lower image quality. At our institution, the mother is also kept NPO for 4 h prior to the MR exam in order to reduce fetal motion.
Because maternal or fetal sedation is not used, most fetal MRI is primarily performed using ultrafast T2-W sequences known as single-shot rapid acquisition with refocused echoes (i.e. single-shot fast spin-echo or half-Fourier acquired single-shot turbo spin-echo). Using these techniques, a single T2-W image is acquired in less than 1 s, decreasing sensitivity to fetal motion. Because each image is acquired separately, motion will affect only the particular image that was acquired while the fetus moved. Typically, an initial localizer is obtained in three orthogonal planes with respect to the mother, using 6- to 8-mm thick slices with a 1- to 2-mm gap and a large field of view. The localizer is used to visualize the position of the fetus and determine fetal sidedness, as well as to ensure that the coil is centered over the region of interest. In certain cases, the coil needs to be repositioned in the middle of the examination, such as when switching from one twin to the other twin, or from the fetal brain to the fetal spine (such as in cases of Chiari II malformation). Typically, 3-mm thick ultrafast T2-W images of the fetal brain are then prescribed from the localizer with no skip. In cases of spine imaging, 2-mm thick slices are acquired because of the small structures being imaged. Images are acquired during maternal free breathing and in an interleaved fashion in order to reduce signal loss due to cross-talk between adjacent slices. Similar to pediatric neuroimaging exams, images are acquired in the axial, sagittal, and coronal planes. Typical imaging parameters are TEeff = 90 ms, TR = 4,500 ms, bandwidth = 25 kHz, matrix = 192 × 160, number of excitations = 0.5, and field of view = 24 cm, although certain parameters, such as field of view, need to be adjusted for increased maternal or fetal size or when aliasing artefact occurs.
Gradient echo-planar T2-W images are performed primarily to detect hemorrhage. Images are acquired in 7 s, during a single maternal breath-hold, in the axial and coronal planes. Typical imaging parameters include TR = 5,290 ms, TE = 94, flip angle = 90, field of view = 30 cm, matrix = 256 × 256, number of excitations = 1, slice thickness = 3 mm, skip = 0 mm. It is important to note that both hemorrhage and normal vessels appear hypointense on this sequence.
Fast multi-planar spoiled gradient-recalled acquisition in the steady state (FMPSPGR) T1-W images are acquired to detect hemorrhage, fat, or calcification. Images are acquired during a single maternal breath-hold with typical parameters of TR = 120 ms, TE = min, flip angle = 70, field of view = 24 cm, matrix = 256 × 160, number of excitations = 1, slice thickness = 5 mm, skip = 1 mm, bandwidth = 31.25 kHz. Images are more susceptible to fetal motion because of their longer acquisition times and are of lower signal-to-noise image quality.
Advanced MR techniques such as diffusion-weighted imaging and parallel imaging have also recently been successfully applied to fetal MR imaging [5, 6, 7, 8]. Diffusion-weighted imaging (DWI) provides quantitative information about water motion and tissue microstructure and can be used to identify focal areas of injury as well as to assess brain development. Single-shot echo planar diffusion-weighted images are acquired in 18 s during a single maternal breath-hold using the following parameters: TR = 4,500 ms, TE = minimum, field of view = 32, matrix = 128 × 128, slice thickness = 5 mm, skip = 2 mm, bandwidth = 167 kHz. Gradients are applied in three orthogonal directions using a b value of 0 s/mm2 and 600 s/mm2. With increasing gestational age and engagement of fetal head in the pelvis, the amount of motion is decreased. Parallel imaging can also be applied to fetal MR imaging in order to decrease the scan time, increase image resolution, or decrease specific absorption rate. Because of their longer acquisition times, diffusion tensor MR imaging and MR spectroscopy are currently limited in their clinical application and are discussed in the Research Application section.
Some manufacturers have interactive scanning programs which allow the technologist to adjust certain scanning parameters (such as scan angle) in real time [9, 10]. This is critical for obtaining true, non-oblique sagittal, axial and coronal images, which results in more accurate assessment of fetal brain structures and identification of abnormalities. As a result, overall image quality is improved and scan time is reduced.
Fetal MRI is most commonly performed to evaluate a suspected abnormality detected by prenatal sonography. By further characterizing the finding and detecting additional abnormalities not seen on prenatal sonography, fetal MRI can provide information that can assist in prenatal counseling of the current pregnancy as well as counseling of the recurrence risk in future pregnancies. The most common indications for imaging the fetal brain will be briefly discussed below and include mild ventriculomegaly, suspected callosal agenesis, complications of monochorionic twinning, and posterior fossa abnormalities.
Ventriculomegaly is defined as atrial width equal to or greater than 10 mm, measured at the posterior margin of the glomus of the choroid plexus on an axial image through the thalami . Measurements of the atrial width on axial MR images have been published [12, 13, 14] and can differ by up to 1 mm to 2 mm compared to US . When the ventricular atrium is measured in the coronal plane, US and MRI measurements are highly concordant .
Ventriculomegaly can be the result of developmental, destructive and obstructive processes, or a combination thereof. In cases of sonographically detected ventriculomegaly, fetal MRI is performed to detect any additional abnormalities, which might give insight into the etiology of the ventriculomegaly as well as neurodevelopmental outcome for the fetus. Fetal MR can detect additional abnormalities in up to 50% of cases of sonographically diagnosed ventriculomegaly [16, 17, 18, 19]. These include agenesis of the corpus callosum, cortical malformations, periventricular heterotopia, cerebellar malformations, hemimegalencephaly, periventricular white matter injury, porencephaly, multicystic encephalomalacia, intraventricular hemorrhage, and germinal matrix hemorrhage [16, 17, 18, 19, 20, 21, 22, 23, 24].
The neurodevelopmental outcome of fetal ventriculomegaly is better when the ventricles are only mildly dilated, defined as measuring ≤15 mm in diameter [25, 26, 27]. Neurodevelopmental outcome is also better when no additional sonographic abnormalities and no genetic abnormalities are identified prenatally or at birth [26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]. When isolated mild ventriculomegaly is confirmed by fetal MRI, normal neurodevelopmental outcome has been observed in 94% of cases with ventricular size of less than 12 mm and in 85% of cases with ventricular size between 12 mm–15 mm . Because of the known limitations of sonography in detecting brain abnormalities, fetal MRI is routinely performed when isolated mild ventriculomegaly is diagnosed by prenatal sonography in order to confirm the isolated nature of the ventriculomegaly.
Abnormalities of the corpus callosum
Fetal MR has been reported to have a greater detection of callosal agenesis as compared with prenatal US . In addition, fetal MR can identify an intact corpus callosum in approximately 20% of cases referred for sonographically suspected callosal agenesis or hypogenesis, which has significant implications for patient counseling . Additional callosal abnormalities, including hypogenesis (or partial agenesis), dysgenesis, and hypoplasia, can also be diagnosed by fetal MRI. Because of the normally thin appearance of the fetal corpus callosum, callosal hypoplasia is more difficult to diagnose, especially during the second trimester.
Posterior fossa abnormalities
Fetal MRI is helpful in evaluating abnormalities of the posterior fossa. It allows direct visualization of the cerebellar hemispheres, vermis, and brainstem in three orthogonal planes and thus allows better assessment of their morphology. Normative measurements of the cerebellum, vermis, and brainstem on fetal MRI are available for different gestational ages [1, 13, 44, 52, 53]. Posterior fossa abnormalities evaluated by fetal MRI include Dandy-Walker continuum, cerebellar hypoplasia, cerebellar dysplasia, cerebellar hemorrhage, and Chiari II malformation [23, 45, 47, 48, 54, 55, 56]. Because many posterior fossa abnormalities are associated with supratentorial abnormalities, fetal MRI is also used to evaluate the supratentorial brain when an infratentorial abnormality is identified. Although fetal MRI can provide additional information about suspected posterior fossa anomalies, it is important to be aware of its limitations, particularly when performed early in gestation .
Normative measurements of the pons on fetal MRI have been published [1, 44], and the pons should be measured in cases of suspected cerebellar or supratentorial abnormalities. The brainstem can also be examined for focal or diffuse morphologic or signal abnormalities (Fig. 10). The dorsal pons and medulla normally appear hypointense on T2-W images and hyperintense on T1-weighted images relative to the ventral brainstem as early as 23–25 gestational weeks [53, 56, 61]. The dorsal midbrain appears hypointense on T2 and hyperintense on T1 later in gestation, by about 31–32 weeks [61, 62]. Diffusion-weighed imaging can be used to evaluate the brainstem, as there is a normal decline in mean diffusivity in the pons with increasing gestational age [59, 60].
Complications of monochorionic twin pregnancies
Although most fetal MRI is performed for evaluation of a sonographically suspected abnormality, fetal MRI is increasingly being performed in cases where sonography of the fetal brain is normal but the fetus is at a known increased risk for neurodevelopmental abnormalities. This occurs in complications of monochorionic twin pregnancy, such as co-twin demise and twin-twin transfusion syndrome. Monochorionic twins share a common placenta that often contains abnormal intertwin vascular connections. Because of the placental vascular anatomy, the overall morbidity and mortality of monochorionic twins is much higher than that of diamniotic twins [76, 77, 78].
Another serious complication of monochorionic twinning is twin-twin transfusion syndrome. Twin-twin transfusion syndrome is characterized by abnormal blood flow from the smaller, donor twin to the larger, recipient twin via placental vascular connections. The recipient twin develops polyhydramnios because of volume overload, and the donor twin develops oligohydramnios resulting in a “stuck twin.” The exact pathophysiology underlying twin-twin transfusion syndrome is complex; however, it appears to be related to an imbalance of intertwin arteriovenous connections . The morbidity rate is very high in twin-twin transfusion syndrome, and both the recipient and the donor twin are at risk for cerebral ischemia and hemorrhage [81, 86, 87, 88, 89, 90, 91, 92, 93]. Fetal MR can be used to identify brain injury in twins affected by twin-twin transfusion syndrome, although imaging the polyhydramniotic twin is difficult because of excessive fetal motion. Brain abnormalities detected by fetal MRI are similar to those seen in survivors of co-twin demise and include encephalomalacia, periventricular white matter injury, germinal matrix hemorrhages, intraventricular hemorrhage, intraparenchymal hemorrhage, and cortical malformation [81, 83, 88, 91, 94, 95]. Laser ablation of the intervascular connections can be performed in cases of twin-twin transfusion syndrome. In such cases, fetal MR is often used to evaluate the brain both before and following surgical intervention.
Although clinically used to evaluate fetuses with either detected brain abnormalities or increased risk for brain abnormalities, fetal MRI is also used to study normal in utero brain development. This is important for establishing normative measures that can be used to better identify cases of abnormal brain development. Using fetal DWI, normative mean diffusivity values during the second and third trimesters have been established [5, 59, 60, 96]. These studies demonstrate that in utero cerebral maturation is characterized by a progressive decline in mean diffusivity in most areas of the fetal brain [5, 59, 60, 96]. Interestingly, the absolute mean diffusivity values, as well as the rates of decline in mean diffusivity with increasing gestational age, vary in different areas of the fetal brain. In particular, mean diffusivity values are higher in the developing white matter as compared to the deep gray nuclei [5, 60]. Moreover, mean diffusivity values decline most rapidly in the cerebellum and thalamus with increasing gestational age [59, 60]. The regional differences in mean diffusivity during gestation likely reflect differences in brain development because of many factors, including increasing cellularity, neuronal maturation, and myelination. Indeed, areas that are known to mature and myelinate earlier have lower mean diffusivity compared to areas that mature later. Thus DWI provides a quantitative marker of in utero brain development. Moreover, diffusion tensor imaging (DTI) has been recently been applied in vivo , although it is more limited by fetal motion. Certain fiber tracts, such as the sensorimotor tracts and the corpus callosum, can be depicted in fetuses during the second and third trimesters . Post-processing methods have also recently resulted in the development of 3D high-resolution diffusion tensor images of the fetal brain . Future studies using DWI and DTI to characterize and identify abnormalities of fetal brain development are needed.
Because of the long acquisition time (several minutes) and size of the voxel relative to the fetal brain size, MR spectroscopy is limited to application in the third trimester when the fetal head is relatively large and engaged in the pelvis. Normal metabolites such as N-acetyl aspartate, creatine, choline, and myo-inositol can be detected, and several studies have shown changes in metabolite levels during gestation [7, 99, 100, 101, 102].
Functional MR studies have also recently been performed in fetuses during the third trimester and have primarily involved the application of an auditory stimulus to the maternal abdomen [103, 104, 105, 106]. These studies have shown temporal lobe activation in response to an auditory stimulus in some fetuses, as early as 33 gestational weeks. A functional MRI study using visual stimulation to the maternal abdomen has also been published . The application of functional MRI in utero, however, is limited by susceptibility artefacts from maternal organs and by fetal motion, requiring either complicated correction algorithms of fetal motion or the administration of maternal sedation (which is not routinely performed in the United States) [103, 104, 105, 106].
An MR technique that has been described recently allows the noninvasive measurement of the oxygen partial pressure of fluids. This has been applied to the fetal cerebrospinal fluid . Because the oxygen content of cerebrospinal fluid can give information about the oxygenation of the surrounding cerebral tissues, this method might offer insight into conditions that result in decreased fetal cerebral oxygenation .
Significant advances in both fetal MRI post-processing and structural analysis methods promise to provide new quantitative biomarkers of early brain development and improve our understanding of in utero brain growth. Because the motion of an unsedated fetus within the deforming tissues of the mother precludes the acquisition of conventional 3-D images that are typically acquired in sedated children, methods have been developed for retrospective motion correction of ultrafast multi-slice fetal data [109, 110]. These methods allow the formation of a single geometrically consistent 3-D image from conventional clinical ultrafast T2 weighted images of a moving fetus by aligning corresponding rigid anatomy of the fetal head in different slices, while discarding matches of the surrounding deforming tissues of the mother. These allow, for the first time, the study of normal in utero brain development at high-resolution and in three dimensions [109, 110, 111, 112]. Moreover, post-processing methods have also recently resulted in the development of 3-D high-resolution diffusion tensor images of the fetal brain .
The developing anatomy of the fetal brain cannot be directly analyzed using methods developed for adult brain studies, and the recent availability of routine 3-D brain image data from fetuses has motivated the development of approaches to the analysis of early developing tissues. These include specific methods to automatically identify and label transient tissue structures such as the germinal matrix within MRI data using computational atlases that capture the developing laminar structure of the brain over time [113, 114, 115]. Such automated tissue segmentation steps allow the morphometric analysis of the developing fetal brain using techniques that quantify tissue volume, surface folding and cortical thickness [116, 117, 118]. These recent advances provide new measures by which normal brain development can be studied. Moreover, they can now be applied to fetuses with specific brain abnormalities, with the goal of being better able to understand and detect brain abnormalities that have their origins in utero.
Fetal MRI is being increasingly used to assess for fetal brain abnormalities. Although significant progress in the field of fetal MR imaging has occurred during the last two decades, continued technical and research advances will likely contribute to significant growth of the field. Because fetal MR involves many disciplines, the promise of fetal MR will be best achieved through continued multidisciplinary collaborative efforts.
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