Christian Mitter

In vivo tractography of fetal association fibers.

Association fibers connect different cortical areas within the same hemisphere and constitute an essential anatomical substrate for a diverse range of higher cognitive functions. So far a comprehensive description of the prenatal in vivo morphology of these functionally important pathways is lacking. In the present study, diffusion tensor imaging (DTI) and tractography were used to visualize major association fiber tracts and the fornix in utero in preselected non-motion degraded DTI datasets of 24 living unsedated fetuses between 20 and 34 gestational weeks (GW). The uncinate fasciculus and inferior fronto-occipital fasciculus were depicted as early as 20 GW, while in vivo 3D visualization of the inferior longitudinal fasciculus, cingulum and fornix was successful in older fetuses during the third trimester. Provided optimal scanning conditions, in utero DTI and tractography have the potential to provide a more accurate anatomical definition of developing neuronal networks in the human fetal brain. Knowledge about the normal prenatal 3D association tract morphology may serve as reference for their assessment in common developmental diseases.

Magnetic resonance methods in fetal neurology

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

Disrupted developmental organization of the structural connectome in fetuses with corpus callosum agenesis

Agenesis of the corpus callosum is a model disease for disrupted connectivity of the human brain, in which the pathological formation of interhemispheric fibers results in subtle to severe cognitive deficits. Postnatal studies suggest that the characteristic abnormal pathways in this pathology are compensatory structures that emerge via neural plasticity. We challenge this hypothesis and assume a globally different network organization of the structural interconnections already in the fetal acallosal brain. Twenty fetuses with isolated corpus callosum agenesis with or without associated malformations were enrolled and fiber connectivity among 90 brain regions was assessed using in utero diffusion tensor imaging and streamline tractography. Macroscopic scale connectomes were compared to 20 gestational age-matched normally developing fetuses with multiple granularity of network analysis. Gradually increasing connectivity strength and tract diffusion anisotropy during gestation were dominant in antero-posteriorly running paramedian and antero-laterally running aberrant pathways, and in short-range connections in the temporoparietal regions. In fetuses with associated abnormalities, more diffuse reduction of cortico-cortical and cortico-subcortical connectivity was observed than in cases with isolated callosal agenesis. The global organization of anatomical networks consisted of less segregated nodes in acallosal brains, and hubs of dense connectivity, such as the thalamus and cingulate cortex, showed reduced network centrality. Acallosal fetal brains show a globally altered connectivity network structure compared to normals. Besides the previously described Probst and sigmoid bundles, we revealed a prenatally differently organized macroconnectome, dominated by increased connectivity. These findings provide evidence that abnormal pathways are already present during at early stages of fetal brain development in the majority of cerebral white matter.

Three‐dimensional visualization of fetal white‐matter pathways in utero

Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that probes the threedimensional (3D) tissue architecture by measuring the directionality and amount of motion of water molecules. In the brain, bundles of unmyelinated axons create a strongly anisotropic environment with a diffusion maximum parallel to the orientation of the fiber tracts. Computational postprocessing algorithms use the directional diffusion information of each imaged voxel to generate 3D visualized ‘fibers’. This noninvasive computational technique – ‘tractography’ – thus allows the 3D reconstruction and depiction of main white-matter fiber pathways1,2. Tractography has already been used to identify white-matter fiber tracts in healthy adults3, children and adolescents4, newborns5 and preterm newborns6, as well as in postmortem samples of fetal brains7–9. So far there has been only one published study that used DTI-based tractography to delineate whitematter fiber tracts in a clinical fetal MRI setting. Using specially tailored DTI sequences10, our group was able to successfully delineate both sensorimotor tracts and the corpus callosum in living unsedated fetuses in utero and to compare developmental changes in the morphology of these fiber tracts across gestational age. Apart from the large commissural and projection fiber tracts (Figure 1a), DTI-based tractography can also identify smaller fiber bundles in the living unsedated fetus in utero during a routine fetal MRI examination. As an example we present here the case of a 33-week fetus with normal brain development that was examined at our institution using a 1.5T MRI scanner (Philips, Best, The Netherlands) and a DTI sequence with 16 gradient encoding directions and a reconstructed voxel size of 0.94 × 0.94 × 3 mm. Based on their different course and destination, the internal capsule fibers could be further separated: thalamocortical fibers branch off to enter the thalamus, while corticopontine and corticospinal tracts continue and enter the cerebral peduncles (Figure 1b). Within the thalamocortical fiber system anterior, superior and posterior thalamic radiations could be distinguished, projecting through the internal capsule towards frontal, central and posterior cortical regions, respectively3. In addition to projection and thalamic fibers, which connect the cortex to subcortical structures, and commissural fibers that cross to the contralateral hemisphere, association fiber tracts connecting ipsilateral cortical areas were also successfully visualized (Figure 1c). The latter are essential for the integrative function of specialized cortical areas, and their damage can lead to disconnection syndromes resulting in diverse neuropsychological deficits11. The current potential of in utero DTI to visualize the variety of described white matter pathways and their topographical 3D relationship is illustrated in Figure 1d. We consider DTI-based tractography to be a very promising addition to standard fetal MRI protocols, as it will improve our understanding of fetal subcortical brain architecture and development, and has the potential to acquire diagnostic information in cases of suspected pathology12.

ADEM-like presentation, anti-MOG antibodies, and MS pathology: TWO case reports

Acute disseminated encephalomyelitis (ADEM) mostly occurs in children and can be triggered by infections and vaccinations. Recently, 40% of patients with ADEM were found to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-abs).1 Furthermore, a subgroup of adult patients negative for aquaporin-4 antibody fulfilling diagnostic clinical and radiologic criteria for neuromyelitis optica spectrum disorder (NMOSD) harbor high-titer serum MOG-abs.2 We present clinical, serologic, and histopathologic features of 2 adult patients with a clinical diagnosis of ADEM according to the diagnostic criteria3 associated with intrathecal MOG-abs synthesis. MOG-abs were determined by live-cell immunofluorescence on HEK293T cells expressing full-length human MOG-enhanced green fluorescent protein at a starting dilution of 1:20 in serum and 1:2 in CSF using an epifluorescence microscope and end-point titration as previously described.2

Validation of In utero Tractography of Human Fetal Commissural and Internal Capsule Fibers with Histological Structure Tensor Analysis.

Diffusion tensor imaging (DTI) and tractography offer the unique possibility to visualize the developing white matter macroanatomy of the human fetal brain in vivo and in utero and are currently under investigation for their potential use in the diagnosis of developmental pathologies of the human central nervous system. However, in order to establish in utero DTI as a clinical imaging tool, an independent comparison between macroscopic imaging and microscopic histology data in the same subject is needed. The present study aimed to cross-validate normal as well as abnormal in utero tractography results of commissural and internal capsule fibers in human fetal brains using postmortem histological structure tensor (ST) analysis. In utero tractography findings from two structurally unremarkable and five abnormal fetal brains were compared to the results of postmortem ST analysis applied to digitalized whole hemisphere sections of the same subjects. An approach to perform ST-based deterministic tractography in histological sections was implemented to overcome limitations in correlating in utero tractography to postmortem histology data. ST analysis and histology-based tractography of fetal brain sections enabled the direct assessment of the anisotropic organization and main fiber orientation of fetal telencephalic layers on a micro- and macroscopic scale, and validated in utero tractography results of corpus callosum and internal capsule fiber tracts. Cross-validation of abnormal in utero tractography results could be achieved in four subjects with agenesis of the corpus callosum (ACC) and in two cases with malformations of internal capsule fibers. In addition, potential limitations of current DTI-based in utero tractography could be demonstrated in several brain regions. Combining the three-dimensional nature of DTI-based in utero tractography with the microscopic resolution provided by histological ST analysis may ultimately facilitate a more complete morphologic characterization of axon guidance disorders at prenatal stages of human brain development.

Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy

One major hallmark of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) is the deposition of extracellular senile plaques and vessel wall deposits composed of amyloid-beta (Aβ). In AD, degeneration of neurons is preceded by the formation of Aβ plaques, which show different morphological forms. Most of them are birefringent owing to the parallel arrangement of amyloid fibrils. Here, we present polarization sensitive optical coherence microscopy (PS-OCM) for imaging mature neuritic Aβ plaques based on their birefringent properties. Formalin-fixed, post-mortem brain samples of advanced stage AD patients were investigated. In several cortical brain regions, neuritic Aβ plaques were successfully visualized in tomographic and three-dimensional (3D) images. Cortical grey matter appeared polarization preserving, whereas neuritic plaques caused increased phase retardation. Consistent with the results from PS-OCM imaging, the 3D structure of senile Aβ plaques was computationally modelled for different illumination settings and plaque sizes. Furthermore, the birefringent properties of cortical and meningeal vessel walls in CAA were investigated in selected samples. Significantly increased birefringence was found in smaller vessels. Overall, these results provide evidence that PS-OCM is able to assess amyloidosis based on intrinsic birefringent properties.

Fetal Cerebral Magnetic Resonance Imaging Beyond Morphology.

The recent technological advancement of fast magnetic resonance imaging (MRI) sequences allowed the inclusion of diffusion tensor imaging, functional MRI, and proton MR spectroscopy in prenatal imaging protocols. These methods provide information beyond morphology and hold the key to improving several fields of human neuroscience and clinical diagnostics. Our review introduces the fundamental works that enabled these imaging techniques, and also highlights the most recent contributions to this emerging field of prenatal diagnostics, such as the structural and functional connectomic approach. We introduce the advanced image processing approaches that are extensively used to tackle fetal or maternal movement-related image artifacts, and which are necessary for the optimal interpretation of such imaging data.

Mens inversus in corpore inverso? Language lateralization in a boy with situs inversus totalis

Situs inversus totalis is a rare condition where the visceral organs are organized as a mirror image of default organ position. In this study we picture the co-development between brain and visceral organs in a case of situs inversus totalis from a fetal stage to adolescence and compare our findings to an age-, gender-, and education-matched control with normal position of thoracic and abdominal organs. We show that in this case of situs inversus, functional and structural brain lateralization do not coincide with visceral organ situs. Furthermore, cognitive development in situs inversus is normal. To our knowledge, this is the first report of antenatal cerebral origins of structural and functional brain asymmetry in a case of situs inversus totalis.

OC06.04: MRI appearances of fetal temporal lobe abnormalities in skeletal dysplasias

Objectives: Enlargement and abnormal sulcation of the temporal lobes have been described as a hallmark of thanatophoric dysplasia, while less severe abnormalities of the temporal lobes can be seen in achondroplasia or hypochondroplasia. Compared to fetal neurosonography, fetal MRI offers various advantages in the assessment of brain malformations, and may be of value in the prenatal diagnosis of CNS abnormalities in various skeletal dysplasias. The aim of this study was to describe the spectrum of temporal lobe abnormalities in skeletal dysplasias in a perinatal setting, using fetal MRI as well as postnatal in vivo and postmortem brain MRI. Methods: We included 6 cases of thanatophoric dysplasia in which 1,5T or 3T fetal MRI had been performed between GW17 and 23. In 2 of those cases postmortem MRI at 3T and in 3 cases histological analysis with H&E-staining was available and enabled us to correlate postmortem findings with in utero fetal MRI results. In addition we included 1 fetal MRI and 3 postnatal MRI of fetuses with achondroplasia/hypochondroplasia. Results: Enlargement of the temporal lobes with abnormal sulcation was seen in all 6 subjects of thanatophoric dysplasia in fetal MRI and was confirmed in 2 cases with postmortem MRI and in 3 cases at autopsy. Abnormalities in the 4 subjects with achondroplasia/hypochondroplasia included bilateral or unilateral sagittalisation of the parahippocampal sulcus, seen both in fetal MRI as well as in postnatal MRI. Conclusions: Temporal lobe abnormalities of different severities can be an independent marker of the presence of a skeletal dysplasia, as seen both in thanatophoric dysplasia as well as achondroplasia/hypochondroplasia.