MRI of normal fetal brain development

European Journal of Radiology 57 (2006) 199–216 MRI of normal fetal brain development Daniela Prayer a,∗ , Gregor Kasprian a , Elisabeth Krampl b , Barbara Ulm c , Linde Witzani a , Lucas Prayer d , Peter C. Brugger e b a Department of Radiodiagnostics, Medical University of Vienna, Vienna, Austria Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria c Department of Prenatal Diagnosis, Medical University of Vienna, Vienna, Austria d Diagnosezentrum Urania, Vienna, Austria e Center of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria Received 11 November 2005; received in revised form 14 November 2005; accepted 16 November 2005 Abstract Normal fetal brain maturation can be studied by in vivo magnetic resonance imaging (MRI) from the 18th gestational week (GW) to term, and relies primarily on T2-weighted and diffusion-weighted (DW) sequences. These maturational changes must be interpreted with a knowledge of the histological background and the temporal course of the respective developmental steps. In addition, MR presentation of developing and transient structures must be considered. Signal changes associated with maturational processes can mainly be ascribed to the following changes in tissue composition and organization, which occur at the histological level: (1) a decrease in water content and increasing cell-density can be recognized as a shortening of T1- and T2-relaxation times, leading to increased T1-weighted and decreased T2-weighted intensity, respectively; (2) the arrangement of microanatomical structures to create a symmetrical or asymmetrical environment, leading to structural differences that may be demonstrated by DW-anisotropy; (3) changes in non-structural qualities, such as the onset of a membrane potential in premyelinating axons. The latter process also influences the appearance of a structure on DW sequences. Thus, we will review the in vivo MR appearance of different maturational states of the fetal brain and relate these maturational states to anatomical, histological, and in vitro MRI data. Then, the development of the cerebral cortex, white matter, temporal lobe, and cerebellum will be reviewed, and the MR appearance of transient structures of the fetal brain will be shown. Emphasis will be placed on the appearance of the different structures with the various sequences. In addition, the possible utility of dynamic fetal sequences in assessing spontaneous fetal movements is discussed. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Fetal magnetic resonance imaging; Fetal brain development; Cell density 1. Introduction A firm knowledge of the magnetic resonance (MR) appearance of fetal brain maturation is mandatory to be able to recognize impairment of fetal brain development. While even subtle anatomical details of the fetal brain can be visualized by ultrasound (US) [1,2], the layers of parenchyma do not display enough impedance differences to be delineated ∗ Corresponding author at: Department of Radiodiagnostics, Medical University of Vienna, Waehringerguertel 18-20, A 1090 Vienna, Austria. Tel.: +43 1 40400 4895; fax: +43 1 40400 4864. E-mail address: Daniela.prayer@meduniwien.ac.at (D. Prayer). 0720-048X/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2005.11.020 sonographically. Thus, the assessment of the processes associated with the formation of the cerebral mantle lies beyond the methodological capabilities of US. MR studies, however, can combine information about structural and ultrastructural brain development [3,4]. 2. Background Fetal MRI is usually done after the 17th gestational week (GW) when the main steps of organogenesis are completed [5]. At this stage, the fetal brain consists, histologically, of seven layers that may readily be displayed by MRI in vitro [6]. The thickness and number of these layers changes until 200 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 1. Decrease in ventricular size between 18 and 24 GW. T2-weighted axial sections at the level of the interventricular foramen of an 18-week-old (a), 20-week-old (b), 22-week-old (c) and 24-week-old (d) fetus. Note the wide ventricles and thin brain parenchyma in the 18 GW fetus (a). The increasing thickness of the pallium results in a reduced ventricular size and the five-layered appearance of the fetal brain (arrows in b and d) compare with Fig. 2b. the 36th GW [6]. Supratentorially, in the 18th GW, the ventricles appear rather large compared to the thickness of the brain parenchyma [7]. Later, the cerebral mantle increases more in thickness than do the lateral ventricles in width. In addition, the formation of the basal ganglia leads to the typical shape of the supratentorial ventricular system. These processes contribute to an apparent decrease in ventricular size between the 18th and 24th GW (Fig. 1). Hemispherical growth and beginning sulcation and gyration also lead to an increase of the skull size. In infratentorial regions, the bony posterior fossa is formed independently of cerebellar growth [8]. 3. Methods For optimal image quality, the fetal head must be in the center of the coil. This means a centered positioning of a mobile coil (such as the cardiac coil) around the mother, or, in case of the use of the body coil, a proper positioning of the pregnant woman within the magnet. Sequences used for the assessment of normal fetal brain development are selected based on their ability to: 1. delineate surface structures, such as gyri, sulci, contours of the brainstem and cerebellum, and cranial nerves; this information is best provided by T2-weighted contrast; 2. show differences in cell density (as evolve, for instance, during development of the basal ganglia); this may be done using T1-weighted information; 3. display the maturing processes of the layers of brain parenchyma, which is reflected by different signal behaviors on the various sequences; 4. visualize the predominantly premyelinating processes of the primary white matter tracts. As described in a previous work [9], T2-weighted, ultrafastspin-echo sequences, T1-weighted gradient-echo sequences, steady-state free precession sequences, and diffusion-weighted sequences are used, with their parame- ters adjusted to the changing ultrastructural composition of the developing brain. MR signals of the different layers of the brain mantle depend, on the one hand, on cellular density [10], and, on the other hand, on the amount of extracellular matrix [6], and the spatial course of ultrastrucural elements [11]. 4. Supratentorial cortical development Primitive cerebral hemispheres can be detected as early as 3 weeks after conception [12], with the beginning of formation of the cortical plate after the 7th GW, in the most lateral aspect of the cerebral wall [13]. Production of future cortical neurons starts with symmetric divisions of neuroepithelial cells [14] that are located in the germinal ventricular zone, as early as five GW [15], and reaches peak performance until GW 16 [16]. This time period also marks the end of neuroblast generation in the ventricular zone [17]. Cells originating from the ventricular zone are direct descendants of the neural plate [18], differentiating to both glia cells and neuroblasts. At first, a preplate is formed in the peripheral aspect of the brain, and contains the first postmitotic neurons, the so-called pioneer neurons [19]. The outermost layer of the cortical plate is called the marginal zone, the future layer I of the mature cerebral cortex [20]. Layer I is also the result of the first postmitotic cell generation from the ventricular zone [21], and has an impact on the future establishment of the laminar organization of the cerebral cortex [22]. While the germinal ventricular zone is the source of cells during embryology and early fetal life, this task is transferred eventually to the subventricular zone during the latter third of pregnancy [18]. Deep layer neurons of the future six-layered cortex are produced in the ventricular zone, the subventricular zone gives rise to more superficially located neurons [23] and, later in development, is the major source of glia cells [22]. The subventricular zone lies between the ventricular zone and the intermediate zone. Four distinct regions of the ventricular/subventricular D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 201 Fig. 2. Sagittal (a), coronal (b), and axial (c) T2-weighted sections of a 20 GW fetus. The black arrows indicate the hypointense signal in the superior and inferior parts of the ganglionic eminence. The laminar organization of the fetal brain is visible—the hypointense cortical plate (CP), the hyperintense signal of the subplate (SP), the slim hypointense intermediate zone (IZ), and the hypointense ventricular zone (VZ). The subventricular zone can also be identified in the frontal regions (asterisks). zone have been identified: the medial; lateral; caudal ganglionic eminences; and the fetal neocortical subventricular zone. The ganglionic eminences are thickened parts of the ventricular and subventricular zones, partly protruding into the ventricular lumina [18]. Anatomically, the ganglionic eminences are a single structure, but due to the C-shaped form, which follows the expansion of the hemispheres, the structure is cut twice on transversal sections [24] and coronal sections (Fig. 2). Thus, a superior (medial) and inferior (lateral) part may be distinguished [18,24]. Neurons originating from these ganglionic eminences create the transient gangliothalamic body [25], the amygdala, the basal nucleus of Meynert [24], and the basal ganglia and thalamus. Neurons originating from the neocortical parts of the subventricular zones are thought to migrate directly toward the cortical plate. Until the 20th GW, a cortical plate (giving rise to cortical layers II–IV [20]) is formed within the preplate, by radially and tangentially migrating neurons, accompanied by an exponential increase in cell numbers [16,21,26]. This layer is rich in cells, and thus, appears hyperintense to the underlying subplate on T1-weighted images, hypointense on T2weighted images, and hyperintense on diffusion-weighted source (isotropical) images. In addition, the cortical plate shows anisotropic behavior [27,28]. This is due to the fact that the cortical plate is predominantly composed of radially orientated elements that create an anisotropic environment. The subplate can be visualized adjacent to the cortical plate. The subplate (the remnants of which form the future layer VII of the mature cortex [20]), is a transient structure of the developing human brain, widest around the 22nd GW (about four times thicker than the cortical plate at that time) and gradually dissolving after the 30th GW [6]. The subplate serves as reservoir for neurons that form temporary neuronal circuits in this region [29], which provide thalamocortical connectivity. The thickness of the subplate also varies in different brain regions [6] (Figs. 1 and 2). Cells of this zone are generated in the ventricular zone. Together with the marginal zone and the cortical plate, the subplate builds the anlage of the future cortex [30]. Cortical organization and cellular differentiation is accompanied by increasing synaptogenesis. Few synapses are built earlier than the beginning of the eighth GW, and are built more frequently with the building of the subplate [30]. When migration is completed, neurons are locked in position by the formation of specific axon–target interaction [21]. 4.1. MRI The germinal zone appears hyperintense on T1-weighted images, markedly hypointense on T2-weighted [28,31], and hyperintense on diffusion-weighted, and is associated with a low ADC and medium-graded fractional anisotropy on postnatal scans of preterm babies [28]. The bright periventricular band on diffusion-weighted source images (corresponding to a dark band on ADC maps) corresponds to the intermediate zone, subventricular zone, periventricular zone, and germinal zone [28] (Figs. 3 and 4). These signal qualities may be ascribed to the high cell densities in this region, and also to the microvessel density that is higher in the germinal zone than in any other region of the developing brain [32], and to the inconsistent radial alignment in these layers [28]. In the frontal regions, where the subventricular zone is thick [23], it can be delineated from the adjacent layers [28] (Figs. 2 and 3). On T2-weighted images, the hypointense periventricular rim is thinner than the diffusion-weighted periventricular band (Fig. 3). There, the intermediate zone appears as a hypointense band between the subventricular zone and the subplate [16] (Fig. 2). The subplate appears hypointense to the cortical plate on T1-weighted images, hyperintense on T2-weighted, and hypointense on diffusion-weighted source images, without showing anisotropy. These signals may be explained by a high content of extracellular matrix in the cells, on the one hand, 202 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 3. Coronal diffusion-weighted sequence of a fetus at 24 GW compared to similar sections of a T2-weighted sequence. On sections marked with the slim arrows, the anisotropic cortical plate, the intermediate, and the ventricular zones can be identified. Note the isotropic appearance of the subplate on DW images and the difference in width on T2-weighted images (wider) and DW images (more narrow). The thick arrow indicates the anisotropy in the posterior limb of the internal capsule. Asterisks indicate frontal crossroads. and, on the other hand, by the variety of synapses composed of ultrastructural elements that have random alignment, preventing anisotropical behavior. However, on diffusion-weighted sequences, the subplate appears thinner than on T2-weighted images. This is due to the fact that the subplate is not a homogeneous layer of tissue, with the more internal hyperintense part corresponding to the bundle of fibers emerging from the thalamus, which enters the subplate in a curved course (Fig. 4). The cortical plate displays anisotropical behavior on diffusion-weighted sequences, as primarily radially migrating neurons create an asymmetrical environment [27,28] (Figs. 4 and 5). A thickening of the brain parenchyma, and a consecutive decrease in ventricular width can be detected later, when the cortex becomes isotropical on diffusionweighted images, as synaptogenesis causes an isotropically behaving network. Anisotropy is lost earliest in the central regions, followed by the occipital cortex, while continuing D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 203 Fig. 4. Axial diffusion-weighted sequence of a fetus at 28 GW, compared to similar sections of a T2-weighted sequence. The germinal zone (upper line, arrowheads) and the posterior limb of the internal capsule (PLIC) (lower line, arrows) display anisotropy. On T2-weighted images, the PLIC does not show hypointensity at that age. to be present in the frontal and temporal regions until around the 35th GW [27,28]. This development mirrors the sequence of maturation of the primary cortical areas [16] (Figs. 5 and 6). Recently, DWI revealed different values of fractional anisotropy in the right and left frontal cortex, indicating a faster maturation of the right side [33]. On MR images, gyration starts with the appearance of a shallow indentation of the fetal brain in the temporal regions at the 18th GW. At the same time, the anterior cingular fissure and the parietooccipital fissure occur. The central sulcus begins to be visible at 24 GW (Fig. 6). Fissures then become deeper, tighter, and gyri bulge into the subarachnoid space. Until the 35th GW, all primary, and most of the secondary sulci, are present [4,16], with secondary sulci appearing from the 24th GW, and tertiary after the 28th GW. Certain sulci may be used as “landmarks” for a respective gestational age [34,35], enabling the determination of age-related cortical development (Figs. 5 and 6). 5. White matter development The prospective white matter appears primarily between the ventricular zone and the marginal zone, and is thus called the intermediate zone [6,21]. This layer results from the second postmitotic wave of cells, generated in the ventricular zone [21]. The intermediate zone increases by a factor of 3.8 between the 13th and 20th GW [21]. Oligodendrocyte progenitor cells have their greatest proportional presentation in this layer, guided by glial fibers [36]. Early afferents and efferents to and from the cortical plate run through this area, and migrating immature neurons have to pass through here as well [22,37]. During midgestation, as many as 30 generations of radially migrating axons, along a single glial shaft, have been identified in the intermediate zone [38]. In addition, zone cell groups have also been found, migrating perpendicular to the radial glia, in a tangential direction [37,39]. Neurons at the border between the subventricular zone and the intermediate zone may constitute a path for callosal axons [40]. Between the 15th and 29th GW, the intermediate zone contains the sagittally orientated radiation of the external capsule, an intermediate stratum of thalamocortical afferent and cortical efferent fibers, and a deep stratum that holds the fibers of the callosal projections [30]. 6. White matter tract formation The directed growth of axons is an important step for appropriate neural connectivity [41]. Thus, the phylogenetically older internal capsule and pyramidal tract form earlier than the phylogenetically younger corpus callosum [41,42]. A primitive internal capsule is already shaped by the thalamic axons, which emerge at the time of preplate formation [43]. Thus, an internal capsule can already be distinguished in the late embryonic period [44]. However, in the 20th GW, the internal capsule is only a space, filled with undifferentiated blastic cells [45]. Later, internal capsule-forming axons are mainly derived from the subplate [42]. The development of pyramidal tracts also starts in the late embryonic period [22], with axons that come from the subplate. Pyramidal decussation is complete by GW 17, and myelination is partly present in this region at GW 25. Corticospinal fibers reach the spinal cord by 24 GW [46]. The corpus callosum does not develop before GW 11 in the commissural plate, collecting axons from the cortical plate. However, the first cells to send axons across the corpus callosum are located in the cingulate cortex [42]. Cerebral myelination is a predominantly postnatal process [47], progressing in a craniocaudal direction and centrifugal manner [35,48]. While histological evidence of myelin in the fetal spinal cord shows a spurt phase between the 15th and 21st GW [49], the first histological proof of brain myelination appears in the 21st GW, in the brainstem and internal 204 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 5. Development of the primary visual cortex. Coronal T2-weighted sequences of fetuses at 18 GW (a), 20 GW (b), 26 GW (c), and 28 GW (d). Beginning with 20 GW, the calcarine fissure can be visualized. Based on the short distance between the cortical surface and the ventricle, the laminar organization of the brain is densely aggregated at area 17. On DW images, the cerebellum is homogeneously hyperintense. capsule [50], and in the 22nd GW, in the thalamus [36]. As oligodendrocyte progenitors are already formed during embryonic stages, there is a considerable delay between the generation of myelin-building cells and the onset of their activity [36,51]. As early as about 3 months before the onset of myelination, the number of immature oligodendrocytes increases [51], a phase that has been called myelination gliosis [52]. Premyelinating changes, such as the appearance of proteolipidprotein in the globus pallidus and pallidothalamic fibers, occur in the 20th GW [53]. This reflects the phase of transformation of the oligodendrocyte progenitors into oligodendrocytes. Recently, three phases of myelination have been identified in the human brain [51]: 1. the formation of the “premyelin sheath” produced by immature oligodendrocytes, with no myelin basic protein (MBP), which is a characteristical component of mature myelin sheaths; D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 205 Fig. 6. Development of primary sensory and motor cortex. Axial (upper row) and parasagittal (lower row) T2-weighted sequences of fetuses at 20 GW (a), 25 GW (b), 27 GW (c), and 32 GW (d). Beginning with 25 GW, the central sulcus can be delineated as a slight indentation of the posterolateral aspects of both hemispheres. 2. the building of a “transitional sheath”, which already contains MBP in some layers; 3. the formation of a mature myelin sheath, which contains MBP in all parts. dinal fasciculus at the level of the brainstem (Fig. 4), the internal capsule, the corpus callosum, and the optic chiasm (Figs. 3 and 4). 6.1. MRI 7. Transient structures of the fetal brain On MR images, the intermediate zone and the subventricular zone cannot be separated from each other [6]. They show intermediate signals on T1- and T2-weighted sequences, and no anisotropy (Figs. 1–3). This is probably attributable to the different directions of fibers traversing this layer. The borders between the intermediate zone and subplate zone begin to blur after the 27th GW, as the high water content in the subplate diminishes. Myelination-corresponding signals are seen on MR images after a delay of several weeks [11,54]. However, diffusion-weighted imaging allows recognition of premyelinating stages as well [55–57] (Figs. 3 and 4). White matter tract anisotropy appears before the onset of myelination, probably due to preceding microscopic changes and to the establishment of an axon potential [59]. The latter has been recognized as a promoter of differentiation of immature oligodendrocytes, and a stimulator of myelination [58]. White matter tract maturation is associated with an increase in diffusion anisotropy [59]. Based on these qualities, diffusiontensor imaging may be used to demonstrate white matter tracts in the postnatal setting [28,55,60]. Prenatally, the slice thickness (with a minimum of 2 mm) does not allow following the thin fiber tracts continuously. However, anisotropy images provide information about premyelinating changes in the corticospinal tract, the longitu- In addition to the subplate that has already been discussed above, other transient structures of the fetal brain are known, the integrity of which are crucial for normal brain development [25,61,62]. The histological and in vitro presentation of most of these structures are discussed in “In vitro MRI of Brain Development.” [63] The perireticular nucleus lies among the fibers of the internal capsule and serves as an intermediate target for outgrowing axons [62]. The neurons of the perireticular nucleus are thought to act as guidepost cells, which may sort corticofugal from corticothalamic fibers, directed toward either the dorsal thalamus or toward the brain stem. In addition, the pioneer axons, originating in the internal capsule and moving to the thalamus, could form a substrate for thalamo-cortical connections [64]. Involution of the perireticular nucleus has been ascribed to apoptosis of the cells, migration [65], and the growing of the fibers of the internal capsule, spreading the cells further apart [45]. The neuronal axis of the perireticular cells has been found to be parallel to the reticular nucleus axis, and to the fibers of the internal capsule [45] (Fig. 4). Quantitatively, the average number of cells, consisting of neurons, and non-orientated glial cells in a relationship of 1:3, was higher in the posterior crus of the internal capsule than in the anterior crus [45]. Thus, the number of cells increases between the 20th and the 32nd GW to sharply decrease subsequently. 206 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 7. At 26 GW: the T2-weighted hypointensity and the T1-weighted (T1-weighted FLAIR sequence) hyperintensity of the basal ganglia on axial images reflect cellularity. The gangliothalamic body is a transient structure present between 15 and 34 GW that extends from the ganglionic eminence to the pulvinar thalami, and consists of a stream of migrating neurons [25]. It is located under the external surface of the thalamus. The disappearance of this structure is probably due to cell migration [25]. Crossroads are regions characterized by immature fibers that result from radial and tangential migration, with a transiently high content of extracellular matrix [66]. 7.1. MRI On in vitro MR scans, the formation of a ganglionic eminence was observed by 10 GW [67]. The peak volume of the germinal zone is reached at about 26 GW, to diminish subsequently, persisting longest at the level of the superior ganglionic eminence [31,62].On in vivo fetal MR images, the internal capsule is homogeneously hypointense to the adjacent basal ganglia on T1-weighted images and hyperintense on T2-weighted images until the 28th [47] and 30th GW [35] (Fig. 4), when T2-weighted hypointensity and T1hyperintensity appears in the posterior crus of the internal capsule. However, diffusion-weighted anisotropy in the posterior crus can be detected from the 22nd GW onward (Fig. 4). In addition, the posterior crus of the internal capsule was shown to present with lower mean diffusivity and higher fractional anisotropy in preterm brains than most of the other unmyelinated white matter tracts [55]. These signal changes may be attributed, on one hand, to the increased cell density provided by perireticular-nucleus neurons and microglia, and, on the other hand, by the creation of an asymmetrical environment enhanced by the alignment of perireticular nucleus neurons in this region (Fig. 4). On MR scans, the gangliothalamic body cannot be delineated from the adjacent gray matter nuclei and the ganglionic eminence: the ganglionic body equally displays T1-weighted Fig. 8. Coronal T2-weighted images (GW 26 (a) and GW 30 (b)) depict hyperintense frontal crossroads (asterisks). D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 hyperintensity, and T2-weighted hypointensity (Fig. 7). The lack of anisotropy may be explained by the non-linear course of the stream of migrating neurons. Crossroads appear on fetal MR scans in the frontal and occipital white matter, appearing hypointense on T1weighted, and hyperintense to the surrounding white matter on T2-weighted images. Crossroads do not show diffusionweighted anisotropy. On fetal MR scans, these crossroads become detectable around GW 24 and persist to postterm stages (Fig. 8). They have also been described on MR scans of preterm babies [68], where they have a “cap-like” appearance on MR scans [69]. Crossroads may also be visible on MR scans in the region lateral to the posterior crus of the internal capsule, adjacent to the caudal part of the ganglionic eminence. They have signals identical to crossroads in the frontal and occipital region, but appear in normal subjects between the 20th and 30th GW, to blur subsequently with the surroundings [70] (Figs. 1d and 2c). 8. Temporal lobe development In the ninth GW, the hippocampal primordial can be identified histologically by its position on the medial aspect of the developing cerebral hemisphere. The four-layered structure consists of the ventricular zone, the intermediate zone, the hippocampal plate, and a wide and pronounced marginal zone [71]. Specifically, the hippocampus of primates and humans lacks a subventricular zone; thus, its anterior transition to the subiculum is demarcated early [72]. According to the developmental pattern of the cortical plate almost all neuronal and glial hippocampal precursors are derived from the ventricular zone [73,74], and will subsequently assemble in the same “inside out” spatiotemporal manner to create the pyramidal cell layer of the hippocampus [72]. Beginning with the second half of gestation, the thickness of the pyramidal cell layer decreases from the designated first hippocampal subfield toward the hilus of the forming dentate gyrus. This gradient is mirrored by the intrinsic order of subfield maturation and differentiation, beginning with the first subfield (CA1) and ending with CA4 and the dentate gyrus, respectively [75]. Macroscopically, the hippocampus appears as an upright “S” shaped structure at 15 GW. At this early stage, the first axons, reportedly derived from neurons located in the entorhinal cortex [76] and supramammillary nucleus [77], form synapses in the marginal zone [78]. These early synapses are organized by Cajal Retzius cells [79,80], and later, by GABAergic interneurons [81] derived from the ganglionic eminence [82]. During the 15th to 24th GW, cell proliferation and horizontal migration toward CA 4 [83], together with the enlargement of subicular and parahippocampal cortices, result in a changing topology of the hippocampus. Until the 24th GW, the vertical orientation is gradually lost, and resembles the adult morphology positioned inferomedially in the temporal horn. 207 The subsequent period is characterized by an increase in the volume of the hippocampal formation. As most of the pyramidal cells have already formed and are currently undergoing the process of differentiation, the cellular components that increase in number are mainly of glial or endothelial origin. Furthermore, the majority of dentate gyrus granule cells, which began to develop by 13 weeks, are born during the third trimester and the first year of life [84]. Ongoing granule cell production in the adult human brain has been detected [85], but the dimensions and consequences are still a subject of dispute [86]. In addition, the production of endothelial cells in the developing hippocampus must not be neglected, as the process of hippocampal neurogenesis is intimately associated with active vascular recruitment [87]. During the last gestational months, the most prominent developmental processes are represented by the establishment of hippocampal fiber connections, paralleled by the functional maturation of the hippocampal network. GABAergic interneurons play an eminent role in this process, according to recent findings, which postulate an early fetal excitatory function of this important inhibitory neurotransmitter in the adult brain [88]. Correlative animal studies have suggested that early, synchronized activity in the hippocampal or neocortical networks is present during late gestation [89]. Moreover, recent studies with full-band EEG recordings [90] have demonstrated the presence of these events in human preterm babies as well. They disappear soon after term age, together with the appearance of hyperpolarizing (“inhibitory”) GABAergic transmission [91], roughly coinciding with the time, when long range cortical afferent systems have reached high enough maturity for activity-dependent plasticity to occur. 8.1. MRI On in vitro MR images, the immature hippocampal formation may be recognized, as evidenced in 13- and 14-week-old specimens that showed an unfolded hippocampus along the medial surface of the temporal lobe, bordering a widely open hippocampal sulcus [92]. While the depiction of the intrinsic details of the hippocampal formation of fetuses in vivo is technically limited, coronal T2-weighted sequences can be used to determine the gross anatomic position [93]. As early as 18 GW, the hippocampus appears as a slim “S” shaped hypointense structure. A deep horizontally oriented indentation between the parahippocampal gyrus and the forming cornu ammonis (CA), the hippocampal sulcus can be delineated in vitro [92] and in vivo (Fig. 9). According to Humphrey [94], the borders of the hippocampal sulcus fuse in its medial aspects approximately at the 20th week. In the depth of the sulcus, this process is partially incomplete, leaving residual cysts that are occasionally detectable by MRI in adults [95,96]. At this stage, the hippocampus is still the most prominent structure of the medial temporal lobe. Coronal T2-weighted images of 208 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 9. Coronal T2-weighted sequences of fetuses at 18 GW (a), 21 GW (b), 26 GW (c), and 31 GW (d). On the left, the region anterior to the hippocampal head is depicted. Please note the hypointense signal of the amygdaloid nucleus (black arrow). On the right, the changing morphology of the hippocampus is shown. At 18 weeks, the hippocampal fissure can be delineated (white arrowhead). D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 209 Fig. 10. Axial T2-weighted (left) and T1-weighted sequence of a fetus at 32 GW. The amygdaloid nucleus (black arrow) can be delineated as a T2-weighted hypointense and T1-weighted hyperintense structure anterior to the hippocampal head. After 28 GW, a T2-weighted hyperintense and T1-weighted hypointense signal is visible in the temporopolar subcortical region (white arrow). fetuses between 20 and 24 GW can be used to demonstrate the growth of the parahippocampal gyrus, paralleled by the changing morphology of the hippocampus (Fig. 9). After 24 GW, the hippocampus shows its adult position as a horizontally oriented structure at the inferior ventricular border of the temporal horn (Fig. 9). The hippocampus then increases in thickness and volume. On axial T1-weighted sequences (Fig. 10), a marked hyperintense signal is visible throughout all areas, which most probably reflects the increasing amount of cellular components (glial, endothelial, neuronal). According to Arnold and Trojanowski [83], myelination of hippocampal axons does not start before 39 weeks and primarily occurs during the first postnatal year [84]. Therefore, it is less likely to cause a bright signal on T1-weighted images. In the future, proof of this hypothesis should be provided by direct correlation of imaging and histological data. After 24 GW, the different gyri of the temporal lobe are beginning to form. The appearance of the superior temporal gyrus (STG) correlates well with gestational age [97] and serves as marker of the regular progress of gyral development. The posterior part of the STG develops as early as 25 GW [98], and as the STG is detectable in the temporopolar area at 32–34 weeks, its formation is complete [93]. The collateral sulcus appears slightly after or at the same time as the STG. All primary sulci of the temporal lobe are visible after 34 weeks [34]. Subcortically, a prominent T2-weighted hyperintensity within the temporopolar white matter appears around 28 weeks (Fig. 10). This coincides with the formation of amygdalo-cortical tracts and the reorganization of the temporal cortical plate [99]. 9. Development of the amygdala Neurons destined for the amygdaloid complex are among the earliest postmitotic cells in the primate telencephalon [100,101]. They are mainly derived from the ganglionic eminence [102] and migrate toward the amygdaloid nucleus. Histologically, clustered migratory neurons are visible as radially oriented columnar cell aggregations [102] at 12 GW [103,104] in the lateral amygdaloid nucleus, where they persist until 24 GW [103]. After 24 GW, the basolateral nuclei of the amygdala begin to lose their contacts to the ganglionic eminence [102], which begins to gradually diminish by 26 GW. From now on, the macroscopic aspect of the amygdaloid complex remains unchanged until birth, whereas major developmental events take place at the level of cell differentiation [102]. 9.1. MRI By 18 GW, the amygdaloid complex appears as a poorly defined hypointense area rostral to the temporal horn of the lateral ventricle on coronal T2-weighted MR sequences (Fig. 9). The resolution of axial as well as coronal MR sequences is actually insufficient to depict the narrow borders of the inferiorly located hypointense ganglionic eminence. The rostral parts of the complex cannot be separated from the thick and hypointense ribbon of the piriform cortex [105]. Before the convolution and formation of the anterior temporal lobe gyri begins by 31 GW, different structures (amygdala, piriform cortex, hippocampal head) are depicted as a continuous hypointensity at the medial temporopolar area on axial T2-weighted sequences (Fig. 10). Later, growth of the temporal lateral neocortex advances and displaces this area more posteromedially within the temporal lobe. A hyperintense appearance of the amygdala on in vivo T1weighted images is present by 18 weeks and persists until the end of gestation (Fig. 10). This appearance is comparable to the signal properties of the cortical plate and the hippocampus and most likely reflects cellularity. 210 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 11. Sagittal T2-weighted sequence of a fetus at 25 GW (a). The primary fissure of the cerebellum (black arrow) separates the anterior and posterior lobes of the cerebellum. Please note the hypointense signals at the tips of the cerebellar foliae. Coronal T2-weighted sequence of a fetus at 35 GW. The flocculonodular lobe is visible by its marked hypointense signals (white arrow). 10. Cerebellar development The first of four steps of cerebellar formation consists of the characterization of the cerebellar territory from the hindbrain. Arising from the metencephalon as well as the mesencephalon, the brainstem and cerebellum share their originating structures. The pontine flexure develops simultaneously with the cerebellar hemispheres during embryonic stages [106]. Compared with the telencephalon, the cerebellum shows a delayed maturation [107]. Cerebellar development starts as early as the 5th to 6th GW, but continues after birth [108,109]. The rate of development of the cerebellum varies as a function of the region [110]. At the end of the 8th GW, the vermis is formed at the time of the fusion of the cerebellar hemispheres that, later, grow faster than the vermis [106], with the vermis and cerebellar hemispheres having their newborn-shape (but not yet size) by GW 22 [106]. As developing cerebellar structures are very small, their detection by MRI lags behind histological proof [106,111]. On in vitro MR, it was possible to trace the development of the rhombencephalic vesicle or primitive fourth ventricle from 10 weeks onward, as the first morphological correlate of the developing cerebellum [111]. The second developmental step is cell production, also occurring during embryologic stages. There are two primary regions (germinal zones, which disappear at birth [112]) that are thought to give rise to neurons that make up the cerebellum. The first region is the ventricular zone (the roof of the fourth ventricle). This area produces Purkinje cells, Golgi cells, and deep cerebellar nuclear neurons that migrate between GW 9 and 13 [112] radially into the body of the cerebellar anlage [113]. These cells are the primary output neurons of the cerebellar cortex and cerebellum, respectively. The second germinal zone is known as the external granular layer. Originating at the caudal portion of the 4th ventricle, starting at GW 11–13, a second wave of migrating cells moves at the surface, to give birth postnatally to the granule cell layer [113]. The third developmental step is characterized by inward migration of the granule cells, starting in the 16th GW and continuing through the whole fetal period [108,112]. Between 20 and 32 GW, a transient zone appears, the lamina dissecans [114], consisting of a meshwork of migrating cells [108,112] that separates the external granular cell layer from an internal granular cell layer. Abraham et al. [115] observed the highest proliferation rate in this zone between GW 28 and 34. The external granule cell layer is also a transient structure, but only involutes after birth [112]. The fourth step consists of further cell differentiation and formation of circuits [108], necessary for the cerebellar function as a coordination center [116]. The first anatomical area to form is the flocculonodular lobe [109]. The first fissure to appear in the cerebellum is the posterolateral fissure, visualized by 12/13 GW [106] and separating the “corpus cerebelli” [117] from the flocculonodular lobe (Fig. 11). The development of the primary fissure, deepest in the midline (Fig. 11), follows at GW 14/15. Subsequently, the prepyramidal, preculminate, and precentral fissures are seen by GW 15/16, and the horizontal fissure by GW 21 [106]. The foliation of the vermis starts in GW 14, and, between 24 and 37 GW, the number of foliae in each lobule accounts for 50% of the amount in adults [110]. The deep gray-matter nuclei of the cerebellum are derived from the ventricular zone [117]. The dentate nucleus can be detected within the cerebellar white matter by 11 [118] or 16 GW [119]. 10.1. MRI Compared to other brain regions, the developing cerebellum has an extremely high cell density [120]. Thus, it appears rather hypointense on T2-weighted, hyperintense on T1-weighted, and bright on diffusion-weighted source images. The lack of anisotropy is probably due to the different courses of migrating neurons as described above (Fig. 5). On MR images, the primary fissure can be recognized from GW 20 (Fig. 11). The other fissures appear afterward, and their delineation is strongly dependent on image quality D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 [109]. The peripherical tips of the cerebellar foliae are more hypointense on T2-weighted images than is the depth. This might be due to the higher density of Purkinje cells in the periphery [110] (Fig. 11). The foliae of the vermis can be discriminated on T2-weighted images around the 24th GW, and those of the hemispheres at the 30th GW [121]. T2-weighted hypointensity in the depth of the cerebellar hemispheres, recognized best on sagittal images around GW 21, has been attributed to the cell-dense dentate nucleus [109]. The gyration of the dentate nucleus, visible from GW 30, appears hypointense on T2-weighted images, compared to the hyperintense core (Fig. 11). The other deep cerebellar nuclei can hardly be differentiated on fetal MR scans. 11. Brainstem maturation The human brainstem is formed around the sixth to seventh GW and matures caudally to rostrally, thus forming the medulla, pons, and midbrain [122]. Medullary functions appear prior to those of the pons, which precede those of the midbrain [122]. Brainstem development is not complete before the seventh postnatal month [123]. The medulla houses the descending motoric tracts and the nuclei of cranial nerves VIII–XII. The somatotopic organization of gray and white matter in the developing medulla oblongata is rather complex. The most important structure of the medulla oblongata is the nucleus of the solitary tract, an important site of central integration and control and vital functions [124]. Anatomically, lying in the dorsal part of the medulla, this nucleus has a craniocaudal orientation. This is also true for the corticospinal tract that is situated more ventrally (Fig. 12). 211 12.1. MRI From the 24th/25th GW, the dorsal part of the pons is hypointense on T2-weighted (Fig. 11) images and hyperintense on T1-weighted images, while the ventral part stays hyperintense on T2-weighted and hypointense on T1weighted images until after birth on fetal MR scans [47,111]. On diffusion-weighted images, the pons appears homogeneously hyperintense with no anisotropy. 13. Midbrain maturation The midbrain, which is least differentiated during fetal life, contains the substantia nigra, the inferior and superior colliculi, the nuclei of cranial nerves III–VI, and structures that continue from the pons [122]. The most mature structures in the fetal midbrain are related to the auditory pathways [122]. This is mirrored, for instance, by early maturational changes of the inferor colliculi, the relay station for auditory input. The development of the inferior colliculi accelerates after 18 GW with regard to columnar volumes and lengths, areas of neurons and circularity ratios, and matures gradually after 33 GW with regard to the maturation of Nissl bodies [125]. 13.1. MRI On MR images, the inferior colliculi appear hypointense on T2-weighted images from GW (Figs. 3, 5 and 11), and are barely delineable on other sequences because of their small size. 14. Infratentorial myelination 11.1. MRI Both structures can be delineated on fetal MR images as early as in the 18th GW. While the ascending sensory tracts are hypointense on T2-weighted images, due to cell density and myelination, the pyramidal tract is hyperintense to its surroundings. T1-weighted contrast is usually not sufficient to allow a delineation of these structures. On DW-images, both behave anisotropically (Fig. 12). 12. Pontine maturation The pons begins to emerge after the medulla, around the eighth week of gestation [122]. The pontine structures include the nuclei of cranial nerves V–VIII, the tegmentum, the raphe nucleus, the locus coeruleus, and the medial longitudinal fasciculus. Pontine functions (reactions to acoustic stimulation, vibration) gradually evolve after 26 GW [122]. The ventral and dorsal spinocerebellar tracts and the tectocerebellar tracts are already formed during the early embryonic stages [117]. Myelination begins between the 20th and 24th GW. The first structures to myelinate are the vestibular fibers, the floccular region, and the vermian commissure [117]. 14.1. MRI On fetal MR images, the flocculonodular lobe can be recognized as a hypointense structure on T2-weighted images from GW 22, preceding myelination of the spinocerebellar system (Fig. 11). The inferior and superior cerebellar peduncles show T2-weighted hypointensity at 28 GW. Subsequently, the primary, secondary, and prepyramidal fissure myelinate, followed by hemispherical myelination of the anterior and biventral lobe. Then, the remainder of the hemisphere is myelinated gradually, with the superior and inferior semilunar lobes and the medial parts of the tonsilla myelinated last [117]. 212 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 Fig. 12. At GW 28: axial DW- and T2-weighted images at the level of the mesencephalon. Arrowheads indicate premyelination in the corticospinal tract. Arrows point at premyelinating ascending sensory tracts. 15. Fetal behavior Fetal behavior is characterized by spontaneous and reflective movement [126]. Fetal movements require a certain neuromuscular development and a normal metabolic state of the central nervous system [127]. Thus, movements are regarded as the output of the developing fetal CNS. Evaluation of fetal behavior adds accuracy to the overall assessment of the fetal central nervous system. The first fetal movements, consisting of flexion and extension of the vertebral column, causes a passive displacement of arms and legs, occurring at 7.5–8 GW [128]. Thus, unprovoked movements predate reflectory patterns, predating afferent information that later modulates movement patterns [126]. Coordinated, so-called general movements are complex movements that involve the whole body in a variable sequence of arm, leg, neck, and trunk movements, which are observed from the 9th GW onward [129]. At these stages, movement is not yet influenced by cerebral input, as cortical areas important for target-oriented behavior and their connections to functionally important subcortical areas, are not developed before GW 19 [30]. At 12 GW, isolated, random-appearing movement of the extremities is observed [130]. Hand-to-head movements occur from the 12th GW onward, with increasing frequency [131]. From 14 GW, movements become more “organized”, the uterine wall is touched by palms, and legs extend. Around the 20th GW, bilateral movement is favored over unilateral movement, and hands are held preferably near the face [130]. Between GW 26 and 32, extremities are moved independently to all parts of the uterus, and extremity movement follows a distal proximal pattern [130]. During late gestation (GW 37 and 38), movement frequency decreases, and the dorsum of the hands rest against the uterine wall [130]. In early stages, while singular movements occur randomly, later rest-activity stages alternate [132]. Coordinated movement gradually develops by synchronization and evolves into the so-called behavioral states [133] that are linked to specific parameters of the fetal heart rate pattern and eye movements [132]. Fetal mouth movements may occur in the form of pure mouth movements (opening and closing, swallowing, protruding the tongue, etc.) [133], or as so-called “mouthing” movements, which are mouth movements characterized by a specific rhythm and frequency [133]. These movements represent ingestive cycles that have been recognized as the core movement of human motor speech development [134]. “Mouthing” is increasingly seen in late fetal stages (after the 34th GW), and occurs preferentially during “quiescent stages” [135]. Fig. 13. Single acquisitions of a dynamic sequence show the head-turning movement of a fetus at 28 GW. D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 15.1. MRI Gross fetal movements and intrinsic movements, such as mouthing and swallowing, can be visualized by dynamic MR sequences. An observation period of 3 × 30 s during the MR examination time of 30–45 min has been estimated to allow a qualitative assessment of fetal general movements [127]. However, when movement is absent during this period, it is not necessarily indicative of a developmental abnormality of the fetus (Fig. 13). 16. Conclusion Normal fetal brain development, and its functional expression in the form of spontaneous movement patterns, can now readily be assessed in vivo. The interpretation of the findings is based on a knowledge of the histological background, the temporal appearance and disappearance of transient structures, and their characteristic presentation on MR images. Acknowledgment The authors want to thank Sampsa Vanhatalo, Department of Biological and Environmental Sciences, University of Helsinki, Finland for his valuable input. References [1] Achiron R, Achiron A. Development of the human fetal corpus callosum: a high-resolution, cross-sectional sonographic study. Ultrasound Obstet Gynecol 2001;18:343–7. [2] Toi A, Lister WS, Fong KW. How early are fetal cerebral sulci visible at prenatal ultrasound and what is the normal pattern of early fetal sulcal development? Ultrasound Obstet Gynecol 2004;24:706–15. [3] Righini A, Bianchini E, Parazzini C, et al. Apparent diffusion coefficient determination in normal fetal brain: a prenatal MR imaging study. Am J Neuroradiol 2003;24:799–804. [4] Garel C, Delezoide AL, Elmaleh-Berges M, et al. Contribution of fetal MR imaging in the evaluation of cerebral ischemic lesions. Am J Neuroradiol 2004;25:1563–8. [5] Moore KL. The developing human: clinically oriented embryology. Philadelphia: WB Saunders; 1982. [6] Kostovic I, Judas M, Rados M, et al. Laminar organization of the human fetal cerebrum revealed by histochemical markers and magnetic resonance imaging. Cereb Cortex 2002;12:536–44. [7] Farrell TA, Hertzberg BS, Kliewer MA, et al. Fetal lateral ventricles: reassessment of normal values for atrial diameter at US. Radiology 1994;193:409–11. [8] Griffiths PD, Wilkinson ID, Variend S, et al. Differential growth rates of the cerebellum and posterior fossa assessed by post mortem magnetic resonance imaging of the fetus: implications for the pathogenesis of the chiari 2 deformity. Acta Radiol 2004;45:236–42. [9] Prayer D, Brugger PC, Prayer L. Fetal MRI: techniques and protocols. Pediatr Radiol 2004;34:685–93. [10] Felderhoff-Mueser U, Rutherford MA, Squier WV, et al. Relationship between MR imaging and histopathologic findings of the brain inextremely sick preterm infants. Am J Neuroradiol 1999;20:1349–57. 213 [11] Prayer D, Prayer L. Diffusion-weighted magnetic resonance imaging of cerebral white matter development. Eur J Radiol 2003;45:235–43. [12] Muller F, O’Rahilly R. The first appearance of the future cerebral hemispheres in the human embryo at stage 14. Anat Embryol (Berl) 1988;177:495–511. [13] Bystron I, Molnar Z, Otellin V, et al. Tangential networks of precocious neurons and early axonal outgrowth in the embryonic human forebrain. J Neurosci 2005;25:2781–92. [14] Fishell G, Kriegstein A. Cortical development: new concepts. Neuron 2005;46:361–2. [15] Levitt P. Structural and functional maturation of the developing primate brain. J Pediatr 2003;143:S35–45. [16] Fogliarini C, Chaumoitre K, Chapon F, et al. Assessment of cortical maturation with prenatal MRI. Part I. Normal cortical maturation. Eur Radiol 2005;15:1671–85. [17] Encha-Razavi F, Sonigo P. Features of the developing brain. Childs Nerv Syst 2003;19:426–8. [18] Brazel CY, Romanko MJ, Rothstein RP, et al. Roles of the mammalian subventricular zone in brain development. Prog Neurobiol 2003;69:49–69. [19] Super H, Uylings HB. The early differentiation of the neocortex: a hypothesis on neocortical evolution. Cereb Cortex 2001;11: 1101–9. [20] Marin-Padilla M. Cajal-Retzius cells and the development of the neocortex. Trends Neurosci 1998;21:64–71. [21] Samuelsen GB, Larsen KB, Bogdanovic N, et al. The changing number of cells in the human fetal forebrain and its subdivisions: a stereological analysis. Cereb Cortex 2003;13:115–22. [22] ten Donkelaar HJ. Major events in the development of the forebrain. Eur J Morphol 2000;38:301–8. [23] Zecevic N, Milosevic A, Rakic S, et al. Early development and composition of the human primordial plexiform layer: immunohistochemical study. J Comp Neurol 1999;412:241–54. [24] Ulfig N. The ganglionic eminence—a putative intermediate target of amygdaloid connections. Brain Res Dev Brain Res 2002;139:313–8. [25] Letinic K, Kostovic I. Transient fetal structure, the gangliothalamic body, connects telencephalic germinal zone with all thalamic regions in the developing human brain. J Comp Neurol 1997;384:373–95. [26] Corbin JG, Nery S, Fishell G. Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain. Nat Neurosci 2001;4(Suppl):1177–82. [27] McKinstry RC, Mathur A, Miller JH, et al. Radial organization of developing preterm human cerebral cortex revealed by non-invasive water diffusion anisotropy MRI. Cereb Cortex 2002;12:1237–43. [28] Maas LC, Mukherjee P, Carballido-Gamio J, et al. Early laminar organization of the human cerebrum demonstrated with diffusion tensor imaging in extremely premature infants. Neuroimage 2004;22:1134–40. [29] Arber S. Subplate neurons: bridging the gap to function in the cortex. Trends Neurosci 2004;27:111–3. [30] Kostovic I, Judas M, Petanjek Z, et al. Ontogenesis of goal-directed behavior: anatomo-functional considerations. Int J Psychophysiol 1995;19:85–102. [31] Kinoshita Y, Okudera T, Tsuru E, et al. Volumetric analysis of the germinal matrix and lateral ventricles performed using MR images of postmortem fetuses. Am J Neuroradiol 2001;22:382–8. [32] Ballabh P, Braun A, Nedergaard M. Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res 2004;56:117–24. [33] Gupta RK, Hasan KM, Trivedi R, et al. Diffusion tensor imaging of the developing human cerebrum. J Neurosci Res 2005;81:172–8. [34] Garel C, Chantrel E, Brisse H, et al. Fetal cerebral cortex: normal gestational landmarks identified using prenatal MR imaging. Am J Neuroradiol 2001;22:184–9. 214 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 [35] Garel C, Chantrel E, Elmaleh M, et al. Fetal MRI: normal gestational landmarks for cerebral biometry, gyration and myelination. Childs Nerv Syst 2003;19:422–5. [36] Jakovcevski I, Zecevic N. Sequence of oligodendrocyte development in the human fetal telencephalon. Glia 2005;49:480–91. [37] Menezes JR, Luskin MB. Expression of neuron-specific tubulin defines a novel population in the proliferative layers of the developing telencephalon. J Neurosci 1994;14:5399–416. [38] Rakic P. Elusive radial glial cells: historical and evolutionary perspective. Glia 2003;43:19–32. [39] Ulfig N. Expression of calbindin and calretinin in the human ganglionic eminence. Pediatr Neurol 2001;24:357–60. [40] Del Rio JA, Martinez A, Auladell C, et al. Developmental history of the subplate and developing white matter in the murine neocortex. Neuronal organization and relationship with the main afferent systems at embryonic and perinatal stages. Cereb Cortex 2000;10:784–801. [41] Richards LJ, Koester SE, Tuttle R, et al. Directed growth of early cortical axons is influenced by a chemoattractant released from an intermediate target. J Neurosci 1997;17:2445–58. [42] Koester SE, O’Leary DD. Axons of early generated neurons in cingulate cortex pioneer the corpus callosum. J Neurosci 1994;14:6608–20. [43] Molnar Z, Blakemore C. How do thalamic axons find their way to the cortex? Trends Neurosci 1995;18:389–97. [44] O’Rahilly R, Muller F. Minireview: summary of the initial development of the human nervous system. Teratology 1999;60:39–41. [45] Tulay CM, Elevli L, Duman U, et al. Morphological study of the perireticular nucleus in human fetal brains. J Anat 2004;205:57–63. [46] Eyre JA, Miller S, Clowry GJ, et al. Functional corticospinal projections are established prenatally in the human foetus permitting involvement in the development of spinal motor centres. Brain 2000;123:51–64. [47] Counsell SJ, Maalouf EF, Fletcher AM, et al. MR imaging assessment of myelination in the very preterm brain. Am J Neuroradiol 2002;23:872–81. [48] Kinney HC. Human myelination and perinatal white matter disorders. J Neurol Sci 2005;228:190–2. [49] Grever WE, Weidenheim KM, Tricoche M, et al. Oligodendrocyte gene expression in the human fetal spinal cord during the second trimester of gestation. J Neurosci Res 1997;47:332–40. [50] Shiraishi K, Itoh M, Sano K, et al. Myelination of a fetus with Pelizaeus-Merzbacher disease: immunopathological study. Ann Neurol 2003;54:259–62. [51] Back SA, Luo NL, Borenstein NS, et al. Arrested oligodendrocyte lineage progression during human cerebral white matter development: dissociation between the timing of progenitor differentiation and myelinogenesis. J Neuropathol Exp Neurol 2002;61:197–211. [52] Girard N, Raybaud C, du Lac P. MRI study of brain myelination. J Neuroradiol 1991;18:291–307. [53] Iai M, Yamamura T, Takashima S. Early expression of proteolipid protein in human fetal and infantile cerebri. Pediatr Neurol 1997;17:235–9. [54] van der Knaap MS, Valk J. Magnetic resonance of myelination and myelin disorders. Berlin: Springer; 2005. [55] Partridge SC, Mukherjee P, Henry RG, et al. Diffusion tensor imaging: serial quantitation of white matter tract maturity in premature newborns. Neuroimage 2004;22:1302–14. [56] Prayer D, Barkovich AJ, Kirschner DA, et al. Visualization of nonstructural changes in early white matter development on diffusion-weighted MR images: evidence supporting premyelination anisotropy. Am J Neuroradiol 2001;22:1572–6. [57] Wimberger DM, Roberts TP, Barkovich AJ, et al. Identification of “premyelination” by diffusion-weighted MRI. J Comput Assist Tomogr 1995;19:28–33. [58] Fields RD. Volume transmission in activity-dependent regulation of myelinating glia. Neurochem Int 2004;45:503–9. [59] Huppi PS, Maier SE, Peled S, et al. Microstructural development of human newborn cerebral white matter assessed in vivo by diffusion tensor magnetic resonance imaging. Pediatr Res 1998;44:584–90. [60] Yoo SS, Park HJ, Soul JS, et al. In vivo visualization of white matter fiber tracts of preterm- and term-infant brains with diffusion tensor magnetic resonance imaging. Invest Radiol 2005;40:110–5. [61] Kostovic I, Judas M. Transient patterns of organization of the human fetal brain. Croat Med J 1998;39:107–14. [62] Ulfig N, Neudorfer F, Bohl J. Transient structures of the human fetal brain: subplate, thalamic reticular complex, ganglionic eminence. Histol Histopathol 2000;15:771–90. [63] Rados M, Judas M, Kostovic I. In vitro MRI of brain development. Eur J Radiol 2006, this issue. [64] Coleman KA, Mitrofanis J. Does the perireticular thalamic nucleus project to the neocortex? Anat Embryol (Berl) 1999;200:521–31. [65] Earle KL, Mitrofanis J. Genesis and fate of the perireticular thalamic nucleus during early development. J Comp Neurol 1996;367:246–63. [66] Judaš M, Radoš M, Jovanov-Miloševic N, et al. Structural, immunocytochemical and MRI properties of periventricular crossroads of growing cortical pathways in preterm infants. Am J Neuroradiol 2005;26:2671–84. [67] Brisse H, Fallet C, Sebag G, et al. Supratentorial parenchyma in the developing fetal brain: in vitro MR study with histologic comparison. Am J Neuroradiol 1997;18:1491–7. [68] Battin MR, Maalouf EF, Counsell SJ, et al. Magnetic resonance imaging of the brain in very preterm infants: visualization of the germinal matrix, early myelination, and cortical folding. Pediatrics 1998;101:957–62. [69] Rutherford M. MRI of the neonatal brain. London: WB Saunders; 2002. [70] Prayer D, Brugger PC, Judas M, et al. Triangular crossroads: a “Wetterwinkel” of the fetal brain. Toronto: American Society of Neuroradiology; 2005. [71] Humphrey T. The development of the human hippocampal formation correlated with some aspects of its phylogenetic history. In: Hassler RS, Heinz, editors. Evolution of the forebrain: phylogenesis and ontogenesis of the forebrain. Stuttgart: Georg Thieme Verlag; 1966. p. 104–17. [72] Rakic P, Nowakowski RS. The time of origin of neurons in the hippocampal region of the rhesus monkey. J Comp Neurol 1981;196:99–128. [73] Angevine Jr JB. Time of neuron origin in the hippocampal region. An autoradiographic study in the mouse. Exp Neurol 1965;(Suppl 2):1–70. [74] Reznikov KY. Cell proliferation and cytogenesis in the mouse hippocampus. Adv Anat Embryol Cell Biol 1991;122:1–74. [75] Altman J, Bayer SA. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 1990;301:365–81. [76] Hevner RF, Kinney HC. Reciprocal entorhinal–hippocampal connections established by human fetal midgestation. J Comp Neurol 1996;372:384–94. [77] Berger B, Esclapez M, Alvarez C, et al. Human and monkey fetal brain development of the supramammillary-hippocampal projections: a system involved in the regulation of theta activity. J Comp Neurol 2001;429:515–29. [78] Kostovic I, Seress L, Mrzljak L, et al. Early onset of synapse formation in the human hippocampus: a correlation with NisslGolgi architectonics in 15- and 16.5-week-old fetuses. Neuroscience 1989;30:105–16. [79] Ceranik K, Zhao S, Frotscher M. Development of the entorhinohippocampal projection: guidance by Cajal-Retzius cell axons. Ann NY Acad Sci 2000;911:43–54. [80] Del Rio JA, Heimrich B, Borrell V, et al. A role for Cajal-Retzius cells and reelin in the development of hippocampal connections. Nature 1997;385:70–4. D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 [81] Gozlan H, Ben-Ari Y. Interneurons are the source and the targets of the first synapses formed in the rat developing hippocampal circuit. Cereb Cortex 2003;13:684–92. [82] Pleasure SJ, Anderson S, Hevner R, et al. Cell migration from the ganglionic eminences is required for the development of hippocampal GABAergic interneurons. Neuron 2000;28:727–40. [83] Arnold SE, Trojanowski JQ. Human fetal hippocampal development. I. Cytoarchitecture, myeloarchitecture, and neuronal morphologic features. J Comp Neurol 1996;367:274–92. [84] Seress L, Abraham H, Tornoczky T, et al. Cell formation in the human hippocampal formation from mid-gestation to the late postnatal period. Neuroscience 2001;105:831–43. [85] Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313–7. [86] Rakic P. Adult neurogenesis in mammals: an identity crisis. J Neurosci 2002;22:614–8. [87] Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000;425:479–94. [88] Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci 2002;3:728–39. [89] Khazipov R, Esclapez M, Caillard O, et al. Early development of neuronal activity in the primate hippocampus in utero. J Neurosci 2001;21:9770–81. [90] Vanhatalo S, Voipio J, Kaila K. Full-band EEG (FbEEG): an emerging standard in electroencephalography. Clin Neurophysiol 2005;116:1–8. [91] Vanhatalo S, Matias Palva J, Andersson S, et al. Slow endogenous activity transients and developmental expression of KCC2 in the immature human cortex. Eur J Neurosci 2005;11:2799– 804. [92] Kier EL, Kim JH, Fulbright RK, et al. Embryology of the human fetal hippocampus: MR imaging, anatomy, and histology. Am J Neuroradiol 1997;18:525–32. [93] Kasprian G, Brugger PC, Prayer D. Temporal lobe development investigated using fetal MRI. In: Proceedings of the European congress on radiology. 2005. [94] Humphrey T. The development of the human hippocampal fissure. J Anat 1967;101:655–76. [95] Bronen RA, Cheung G. MRI of the normal hippocampus. Magn Reson Imaging 1991;9:497–500. [96] Sasaki M, Sone M, Ehara S, et al. Hippocampal sulcus remnant: potential cause of change in signal intensity in the hippocampus. Radiology 1993;188:743–6. [97] Larroche JC. Morphological criteria of central nervous system development in the human foetus. J Neuroradiol 1981;8:93–108. [98] Chi JG, Dooling EC, Gilles FH. Gyral development of the human brain. Ann Neurol 1977;1:86–93. [99] Krmpotic-Nemanic J, Kostovic I, Nemanic D. Prenatal and perinatal development of radial cell columns in the human auditory cortex. Acta Otolaryngol 1984;97:489–95. [100] McConnell J, Angevine Jr JB. Time of neuron origin in the amygdaloid complex of the mouse. Brain Res 1983;272:150–6. [101] Kordower JH, Piecinski P, Rakic P. Neurogenesis of the amygdaloid nuclear complex in the rhesus monkey. Brain Res Dev Brain Res 1992;68:9–15. [102] Ulfig N, Setzer M, Bohl J. Ontogeny of the human amygdala. Ann NY Acad Sci 2003;985:22–33. [103] Nikolic I, Kostovic I. Development of the lateral amygdaloid nucleus in the human fetus: transient presence of discrete cytoarchitectonic units. Anat Embryol 1986;174:355–60. [104] Humphrey T. Development of the human amygdaloid complex. In: Eleftherion BE, editor. The neurobiology of the amygdala. Plenum Press; 1972. p. 21–77. [105] Bayer SA, Altman J. The human brain during the third trimester. Boca Raton: CRC Press/Taylor & Francis Group; 2005. [106] Nakayama T, Yamada R. MR imaging of the posterior fossa structures of human embryos and fetuses. Radiat Med 1999;17:105–14. 215 [107] Simonati A, Tosati C, Rosso T, et al. Cell proliferation and death: morphological evidence during corticogenesis in the developing human brain. Microsc Res Technol 1999;45:341–52. [108] ten Donkelaar HJ, Lammens M, Wesseling P, et al. Development and developmental disorders of the human cerebellum. J Neurol 2003;250:1025–36. [109] Adamsbaum C, Moutard ML, Andre C, et al. MRI of the fetal posterior fossa. Pediatr Radiol 2005;35:124–40. [110] Isumi H, Mizuguchi M, Takashima S. Differential development of the human cerebellar vermis: immunohistochemical and morphometrical evaluation. Brain Dev 1997;19:254–7. [111] Chong BW, Babcook CJ, Pang D, et al. A magnetic resonance template for normal cerebellar development in the human fetus. Neurosurgery 1997;41:924–8 [discussion 8–9]. [112] Nakamura Y, Yamamoto M, Oda E, et al. A novel marker for Purkinje cells, KIAA0864 protein. An analysis based on a monoclonal antibody HFB-16 in developing human cerebellum. J Histochem Cytochem 2005;53:423–30. [113] Hynes RO, Patel R, Miller RH. Migration of neuroblasts along preexisting axonal tracts during prenatal cerebellar development. J Neurosci 1986;6:867–76. [114] Rakic P, Sidman RL. Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. J Comp Neurol 1970;139:473–500. [115] Abraham H, Tornoczky T, Kosztolanyi G, et al. Cell formation in the cortical layers of the developing human cerebellum. Int J Dev Neurosci 2001;19:53–62. [116] Chizhikov V, Millen KJ. Development and malformations of the cerebellum in mice. Mol Genet Metab 2003;80:54–65. [117] Larsell O, Jansen J. The comparative anatomy and histology of the cerebellum. In: The human cerebellum, cerebellar connections and cerebellar cortex. Minneapolis: The University of Minnesota Press; 1972. [118] Yamaguchi K, Goto N. Three-dimensional structure of the human cerebellar dentate nucleus: a computerized reconstruction study. Anat Embryol (Berl) 1997;196:343–8. [119] Mihajlovic P, Zecevic N. Development of the human dentate nucleus. Hum Neurobiol 1986;5:189–97. [120] Corrales JD, Rocco GL, Blaess S, et al. Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development. Development 2004;131:5581–90. [121] Triulzi F, Parazzini C, Righini A. MRI of fetal and neonatal cerebellar development. Semin Fetal Neonatal Med 2005;10:411– 20. [122] Joseph R. Fetal brain behavior and cognitive development. Dev Rev 2000;20:81–98. [123] Yakovlev P, Lecours A. The myelogenesis cycles of regional maturation of the brain. In: Davis F, editor. Regional development of the brain in early life. Philadelphia: A Minkowski; 1967. [124] Zec N, Kinney HC. Anatomic relationships of the human nucleus of the solitary tract in the medulla oblongata: a DiI labeling study. Auton Neurosci 2003;105:131–44. [125] Nara T, Goto N, Hamano S, et al. Morphometric development of the human fetal auditory system: inferior collicular nucleus. Brain Dev 1996;18:35–9. [126] Sparling JW. Concepts in fetal movement research. New York: The Haworth Press, Inc.; 1993. [127] Olesen AG, Svare JA. Decreased fetal movements: background, assessment, and clinical management. Acta Obstet Gynecol Scand 2004;83:818–26. [128] Prechtl HF. Ultrasound studies of human fetal behaviour. Early Hum Dev 1985;12:91–8. [129] Prechtl HF, Einspieler C. Is neurological assessment of the fetus possible? Eur J Obstet Gynecol Reprod Biol 1997;75: 81–4. [130] Sparling JW, Van Tol J, Chescheir NC. Fetal and neonatal hand movement. Phys Ther 1999;79:24–39. 216 D. Prayer et al. / European Journal of Radiology 57 (2006) 199–216 [131] de Vries JI, Wimmers RH, Ververs IA, et al. Fetal handedness and head position preference: a developmental study. Dev Psychobiol 2001;39:171–8. [132] Nijhuis IJ, ten Hof J, Nijhuis JG, et al. Temporal organization of fetal behavior from 24 weeks gestation onwards in normal and complicated pregnancies. Dev Psychobiol 1999;34:257–68. [133] D’Elia A, Pighetti M, Moccia G, et al. Spontaneous motor activity in normal fetuses. Early Hum Dev 2001;65:139–47. [134] MacNeilage PF, Davis BL. Motor mechanisms in speech ontogeny: phylogenetic, neurobiological and linguistic implications. Curr Opin Neurobiol 2001;11:696–700. [135] Pillai M, James D. Human fetal mouthing movements: a potential biophysical variable for distinguishing state 1F from abnormal fetal behavior; report of 4 cases. Eur J Obstet Gynecol Reprod Biol 1991;38:151–6.