In utero tractography of fetal white matter development
Introduction
Magnetic resonance imaging (MRI) in living human fetuses has revolutionized our ability to investigate human brain development in vivo. Since its introduction in the early eighties (Smith et al., 1983), the technical prerequisites for fetal MR have continuously improved (Brugger et al., 2006).
Initially, the use of sedative medication was indispensable for diagnostic fetal MRI. The advent of ultrafast MR sequences (Yamashita et al., 1997, Lan et al., 2000, Chen and Levine, 2001) led to acquisition times of less than 20 s and reduced the problem of fetal motion artifacts. A complete MR examination of a living human fetus can now be performed within 45 min, without sedating mother or fetus (Brugger et al., 2006).
Due to the good T2-weighted tissue contrast and resolution, subtle structures of the fetal brain can be readily visualized in utero from 18 gestational weeks onward (Garel et al., 2001, Baldoli et al., 2002, Garel, 2004, Prayer et al., 2006a, Prayer et al., 2006b). Moreover, it has been shown that diffusion-weighted imaging (DWI) can be used in utero to investigate normal and pathological brain development (Baldoli et al., 2002, Prayer and Prayer, 2003, Righini et al., 2003, Agid et al., 2006, Bui et al., 2006). As image contrast of DWI is generated by the hindered (anisotropic) or non-hindered (isotropic) diffusivity of protons, this technique provides two-dimensional microstructural information about the examined tissue. By measuring the directionality of diffusion, the technique of diffusion tensor imaging (DTI) also enables visualization of three-dimensional morphology (Le Bihan et al., 1986, Basser et al., 1994). Therefore, DTI is a noninvasive tool by which to investigate the axonal/fiber connectivity of the central nervous system, and which is especially applicable to the study of the age-related dynamic microstructural changes associated with brain growth and maturation (Hüppi et al., 1998, Childs et al., 2001, Mukherjee et al., 2002, Zhai et al., 2003, Maas et al., 2004, Partridge et al., 2004, Partridge et al., 2005, Berman et al., 2005, Yoo et al., 2005, Bui et al., 2006, Huang et al., 2006, Anjari et al., 2007, Dubois et al., 2008).
During the second trimester of pregnancy, important anatomical and functional neuronal networks are established in the fetal brain. The structural knowledge about these processes on a macroscopic and microscopic level is mainly documented by postmortem data (Flechsig, 1920, Yakovlev and Lecours, 1967, Brody et al., 1987, Kostovic et al., 2002, Kostovic and Jovanov-Milosevic, 2006a, Kostovic and Judas, 2006b, Bayer and Altman, 2004, Bayer and Altman, 2005, Judas et al., 2005). In addition to the correlation of these data with in vitro MR examinations (Judas et al., 2005, Rados et al., 2006), recent in vivo MRI studies used DTI to gain insights into the changing MR diffusion properties of extremely pre-term brains from 25 gestational weeks onward (Hüppi et al., 1998, Mukherjee et al., 2002, Zhai et al., 2003, Maas et al., 2004, Partridge et al., 2004, Partridge et al., 2005, Berman et al., 2005, Yoo et al., 2005). As MR studies in pre-term infants are logistically and clinically challenging, the sample size is often small and the majority of pre-terms are older than 28 gestational weeks at MR imaging. Moreover, extreme pre-term birth is associated with high mortality, morbidity, and a high incidence of gross brain pathologies (Childs et al., 2001, Zhai et al., 2003, Maas et al., 2004, Dyet et al., 2006, Counsell et al., 2007). The developing white matter, in particular, is extremely vulnerable to the influences of pre-term transition to extrauterine life (Childs et al., 2001, Dyet et al., 2006, Counsell et al., 2007). Thus, in vivo data about normal white matter maturation are rarely available. Because of the limited sensitivity of prenatal ultrasound to detect and depict the maturational processes of the developing white matter, fetal MRI can be considered the most promising in vivo method to study the natural course of human white matter development.
The primary aim of this cross-sectional study was to assess the potential of DTI and tractography to visualize the main projection and commissural pathways in living human fetuses between 18 and 37 gestational weeks (GW) of age, in utero and in vivo. Using in utero DTI, the morphology and age specific anatomy of developing left and right sensorimotor trajectories, the genu, the truncus, and the splenium of the corpus callosum were studied in a group of living fetuses without structural evidence of brain pathology. To assess the microstructure and maturity of specific white matter regions, different diffusion parameters (apparent diffusion coefficient — [ADC], fractional anisotropy — [FA], axial [λ1] and transverse [λ2, λ3] eigenvalues) of various brain regions were measured. We aimed to demonstrate whether these in utero DTI data mirror the unified pattern of prenatal white matter maturation found on histological postmortem (Flechsig, 1920, Yakovlev and Lecours, 1967, Brody et al., 1987) and MR studies (Hüppi et al., 1998, Mukherjee et al., 2002, Partridge et al., 2005, Huang et al., 2006).
As regional differences of brain maturation involve more than anatomically defined fiber pathways, the issue of laterality will be addressed as well. There is structural (Bracco et al., 1984) and functional evidence (Chiron et al., 1997) for hemispheric asymmetry of the fetal brain, most pronounced in the developing language regions (Chi et al., 1977, Kasprian, 2006). Thus, the detection of significant left/right differences in MR diffusion measures of fetal motor and sensory connectivity could clarify whether maturation of the main projection pathways is asymmetrical in utero.
Section snippets
Fetuses
The present cross-sectional study was approved by the local ethics committee. Forty pregnant women were informed about the procedure and the possible risks of the examination, and gave written, informed consent for a prenatal MR study. Gestational age was determined by a previous sonography at 12 post-ovulatory weeks. Only singleton pregnancies were included in the study.
MR studies were performed between September 2006 and September 2007 at gestational ages between 18 and 37 GW (mean age: 28.17 ±
Results
Three-dimensional visualization of the developing right and left sensorimotor tracts was successful in 70% (28/40, right) and 62.5% (25/40, left), respectively (Fig. 4). Bilateral sensorimotor tract depiction was possible in 57.5% (23/40), whereas, in 17.5%, the corticospinal and thalamocortical projections were visible only unilaterally (Fig. 4). Despite regular white matter morphology of the CP, PCI and developing centrum semiovale on T2-weighted sequences, visualization of the remaining
Discussion
Modern intrauterine MRI is a safe and noninvasive imaging method, which offers a structural and chemical characterization of microscopic fetal brain structures. Extending the “conventional” fetal MR sequence repertoire with diffusion-weighted sequences holds the potential to obtain new important morphological and functional insights into normal and abnormal fetal brain development. In particular, the high sensitivity of in utero DW MRI in identifying acute hypoxic ischemic fetal brain lesions
Conclusion
DTI and tractography allows visualization of the 3D appearance of the main commissural and projection tracts in the developing fetal brain in utero between 19 and 37 GW. Consistency with postmortem and ex utero data emphasizes the potential of in utero DTI and tractography to characterize structural and functional aspects of human brain maturation.
Extending the “conventional” fetal MR sequence repertoire with diffusion tensor sequences holds the potential to obtain new important morphological
Acknowledgments
The authors thank Valentina Ribeiro, M.D., Servico de Neuroradiologia, Hospital Geral de Santo Antonio, Porto, Portugal, for her assistance in the reassessment of our tractography results, and the MR technicians of the Department of Neuro- and Musculoskeletal Radiology of the Medical University of Vienna (particularly Fritz Stuhr and Christian Lindner), for their enthusiastic and dedicated support.
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