Publications by authors named "Michiel Kleinnijenhuis"

12 Publications

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Revealing the spatio-phenotypic patterning of cells in healthy and tumor tissues with mLSR-3D and STAPL-3D.

Nat Biotechnol 2021 Jun 3. Epub 2021 Jun 3.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Despite advances in three-dimensional (3D) imaging, it remains challenging to profile all the cells within a large 3D tissue, including the morphology and organization of the many cell types present. Here, we introduce eight-color, multispectral, large-scale single-cell resolution 3D (mLSR-3D) imaging and image analysis software for the parallelized, deep learning-based segmentation of large numbers of single cells in tissues, called segmentation analysis by parallelization of 3D datasets (STAPL-3D). Applying the method to pediatric Wilms tumor, we extract molecular, spatial and morphological features of millions of cells and reconstruct the tumor's spatio-phenotypic patterning. In situ population profiling and pseudotime ordering reveals a highly disorganized spatial pattern in Wilms tumor compared to healthy fetal kidney, yet cellular profiles closely resembling human fetal kidney cells could be observed. In addition, we identify previously unreported tumor-specific populations, uniquely characterized by their spatial embedding or morphological attributes. Our results demonstrate the use of combining mLSR-3D and STAPL-3D to generate a comprehensive cellular map of human tumors.
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http://dx.doi.org/10.1038/s41587-021-00926-3DOI Listing
June 2021

Joint modelling of diffusion MRI and microscopy.

Neuroimage 2019 11 14;201:116014. Epub 2019 Jul 14.

Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

The combination of diffusion MRI (dMRI) with microscopy provides unique opportunities to study microstructural features of tissue, particularly when acquired in the same sample. Microscopy is frequently used to validate dMRI microstructure models, addressing the indirect nature of dMRI signals. Typically, these modalities are analysed separately, and microscopy is taken as a gold standard against which dMRI-derived parameters are validated. Here we propose an alternative approach in which we combine dMRI and microscopy data obtained from the same tissue sample to drive a single, joint model. This simultaneous analysis allows us to take advantage of the breadth of information provided by complementary data acquired from different modalities. By applying this framework to a spherical-deconvolution analysis, we are able to overcome a known degeneracy between fibre dispersion and radial diffusion. Spherical-deconvolution based approaches typically estimate a global fibre response function to determine the fibre orientation distribution in each voxel. However, the assumption of a 'brain-wide' fibre response function may be challenged if the diffusion characteristics of white matter vary across the brain. Using a generative joint dMRI-histology model, we demonstrate that the fibre response function is dependent on local anatomy, and that current spherical-deconvolution based models may be overestimating dispersion and underestimating the number of distinct fibre populations per voxel.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880780PMC
November 2019

The spatial correspondence and genetic influence of interhemispheric connectivity with white matter microstructure.

Nat Neurosci 2019 05 15;22(5):809-819. Epub 2019 Apr 15.

Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom.

Microscopic features (that is, microstructure) of axons affect neural circuit activity through characteristics such as conduction speed. To what extent axonal microstructure in white matter relates to functional connectivity (synchrony) between brain regions is largely unknown. Using MRI data in 11,354 subjects, we constructed multivariate models that predict functional connectivity of pairs of brain regions from the microstructural signature of white matter pathways that connect them. Microstructure-derived models provided predictions of functional connectivity that explained 3.5% of cross-subject variance on average (ranging from 1-13%, or r = 0.1-0.36) and reached statistical significance in 90% of the brain regions considered. The microstructure-function relationships were associated with genetic variants, co-located with genes DAAM1 and LPAR1, that have previously been linked to neural development. Our results demonstrate that variation in white matter microstructure predicts a fraction of functional connectivity across individuals, and that this relationship is underpinned by genetic variability in certain brain areas.
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http://dx.doi.org/10.1038/s41593-019-0379-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517273PMC
May 2019

Evaluating fibre orientation dispersion in white matter: Comparison of diffusion MRI, histology and polarized light imaging.

Neuroimage 2017 08 8;157:561-574. Epub 2017 Jun 8.

FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Diffusion MRI is an exquisitely sensitive probe of tissue microstructure, and is currently the only non-invasive measure of the brain's fibre architecture. As this technique becomes more sophisticated and microstructurally informative, there is increasing value in comparing diffusion MRI with microscopic imaging in the same tissue samples. This study compared estimates of fibre orientation dispersion in white matter derived from diffusion MRI to reference measures of dispersion obtained from polarized light imaging and histology. Three post-mortem brain specimens were scanned with diffusion MRI and analyzed with a two-compartment dispersion model. The specimens were then sectioned for microscopy, including polarized light imaging estimates of fibre orientation and histological quantitative estimates of myelin and astrocytes. Dispersion estimates were correlated on region - and voxel-wise levels in the corpus callosum, the centrum semiovale and the corticospinal tract. The region-wise analysis yielded correlation coefficients of r = 0.79 for the diffusion MRI and histology comparison, while r = 0.60 was reported for the comparison with polarized light imaging. In the corpus callosum, we observed a pattern of higher dispersion at the midline compared to its lateral aspects. This pattern was present in all modalities and the dispersion profiles from microscopy and diffusion MRI were highly correlated. The astrocytes appeared to have minor contribution to dispersion observed with diffusion MRI. These results demonstrate that fibre orientation dispersion estimates from diffusion MRI represents the tissue architecture well. Dispersion models might be improved by more faithfully incorporating an informed mapping based on microscopy data.
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http://dx.doi.org/10.1016/j.neuroimage.2017.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607356PMC
August 2017

Choice of reference measurements affects quantification of long diffusion time behaviour using stimulated echoes.

Magn Reson Med 2018 02 3;79(2):952-959. Epub 2017 May 3.

Oxford Centre for Functional MRI of the Brain, University of Oxford, Oxford, United Kingdom.

Purpose: To demonstrate how reference data affect the quantification of the apparent diffusion coefficient (ADC) in long diffusion time measurements with diffusion-weighted stimulated echo acquisition mode (DW-STEAM) measurements, and to present a modification to avoid contribution from crusher gradients in DW-STEAM.

Methods: For DW-STEAM, reference measurements at long diffusion times have significant b value, because b = 0 cannot be achieved in practice as a result of the need for signal spoiling. Two strategies for acquiring reference data over a range of diffusion times were considered: constant diffusion weighting (fixed-b ) and constant gradient area (fixed-q ). Fixed-b and fixed-q were compared using signal calculations for systems with one and two diffusion coefficients, and experimentally using data from postmortem human corpus callosum samples.

Results: Calculations of biexponential diffusion decay show that the ADC is underestimated for reference images with b > 0, which can induce an apparent time-dependence for fixed-q . Restricted systems were also found to be affected. Experimentally, the exaggeration of the diffusion time-dependent effect under fixed-q versus fixed-b was in a range predicted theoretically, accounting for 62% (longitudinal) and 35% (radial) of the time dependence observed in white matter.

Conclusions: Variation in the b-value of reference measurements in DW-STEAM can induce artificial diffusion time dependence in ADC, even in the absence of restriction. Magn Reson Med 79:952-959, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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http://dx.doi.org/10.1002/mrm.26711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811793PMC
February 2018

The effect of realistic geometries on the susceptibility-weighted MR signal in white matter.

Magn Reson Med 2018 Jan 10;79(1):489-500. Epub 2017 Apr 10.

Oxford Centre for Functional MRI of the Brain, University of Oxford, Oxford, United Kingdom.

Purpose: To investigate the effect of realistic microstructural geometry on the susceptibility-weighted MR signal in white matter (WM), with application to demyelination.

Methods: Previous work has modeled susceptibility-weighted signals under the assumption that axons are cylindrical. In this study, we explored the implications of this assumption by considering the effect of more realistic geometries. A three-compartment WM model incorporating relevant properties based on the literature was used to predict the MR signal. Myelinated axons were modeled with several cross-sectional geometries of increasing realism: nested circles, warped/elliptical circles, and measured axonal geometries from electron micrographs. Signal simulations from the different microstructural geometries were compared with measured signals from a cuprizone mouse model with varying degrees of demyelination.

Results: Simulation results suggest that axonal geometry affects the MR signal. Predictions with realistic models were significantly different compared with circular models under the same microstructural tissue properties, for simulations with and without diffusion.

Conclusion: The geometry of axons affects the MR signal significantly. Literature estimates of myelin susceptibility, which are based on fitting biophysical models to the MR signal, are likely to be biased by the assumed geometry, as will any derived microstructural properties. Magn Reson Med 79:489-500, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585669PMC
January 2018

Diffusion tensor characteristics of gyrencephaly using high resolution diffusion MRI in vivo at 7T.

Neuroimage 2015 Apr 10;109:378-87. Epub 2015 Jan 10.

Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Nijmegen, The Netherlands; Erwin L. Hahn Institute for Magnetic Resonance Imaging, Essen, Germany; The University of Queensland, Centre for Advanced Imaging, Brisbane, Australia. Electronic address:

Gyrification of the human cerebral cortex allows for the surface expansion that accommodates many more cortical neurons in comparison to other mammals. For neuroimaging, however, it forms a feature that complicates analysis. For example, it has long been established that cortical layers do not occupy the same depth in gyri and sulci. Recently, in vivo diffusion imaging has provided insights into the fibre architecture of the cortex, usually showing radial tensor orientations. This makes it relevant to investigate whether cortical diffusion tensor metrics depend on the gyral pattern. High-resolution (1mm isotropic) diffusion weighted MRI of the medial wall of the hemispheres was performed at 7 T. Diffusion data were resampled to surfaces in the cortex and underlying white matter, where the cortical surfaces obeyed the equivolume principle for cortical laminae over the cortical curvature. Diffusion tensor metrics were averaged over bins of curvature to obtain maps of characteristic patterns in the gyrus. Diffusivity, anisotropy and radiality varied with curvature. Radiality was maximal in intermediate layers of the cortex next to the crown of the gyrus, not in white matter or on the crown. In the fundus, the deep cortical layers had tangential tensor orientations. In the white matter, tensor orientation changed from radial on the crown to tangential under the banks and fundus. White matter anisotropy gradually increased from the crown to the fundus. The characteristic pattern in the gyrus demonstrated here is in accordance with ex vivo diffusion MR microscopy and histological studies. The results indicate the necessity of taking into account the gyral pattern when cortical diffusion data is analysed. Additionally, the data suggest a confound for tractography approaches when reaching the gyrus, resulting in a possible bias towards the gyral crown. The implications for mechanisms that could drive cortical folding are discussed.
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http://dx.doi.org/10.1016/j.neuroimage.2015.01.001DOI Listing
April 2015

Combining fiber dissection, plastination, and tractography for neuroanatomical education: Revealing the cerebellar nuclei and their white matter connections.

Anat Sci Educ 2014 Jan-Feb;7(1):47-55. Epub 2013 Jul 9.

Department of Anatomy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of Neurosurgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

In recent years, there has been a growing interest in white matter anatomy of the human brain. With advances in brain imaging techniques, the significance of white matter integrity for brain function has been demonstrated in various neurological and psychiatric disorders. As the demand for interpretation of clinical and imaging data on white matter increases, the needs for white matter anatomy education are changing. Because cross-sectional images and formalin-fixed brain specimens are often insufficient in visualizing the complexity of three-dimensional (3D) white matter anatomy, obtaining a comprehensible conception of fiber tract morphology can be difficult. Fiber dissection is a technique that allows isolation of whole fiber pathways, revealing 3D structural and functional relationships of white matter in the human brain. In this study, we describe the use of fiber dissection in combination with plastination to obtain durable and easy to use 3D white matter specimens that do not require special care or conditions. The specimens can be used as a tool in teaching white matter anatomy and structural connectivity. We included four human brains and show a series of white matter specimens of both cerebrum and cerebellum focusing on the cerebellar nuclei and associated white matter tracts, as these are especially difficult to visualize in two-dimensional specimens and demonstrate preservation of detailed human anatomy. Finally, we describe how the integration of white matter specimens with radiological information of new brain imaging techniques such as diffusion tensor imaging tractography can be used in teaching modern neuroanatomy with emphasis on structural connectivity.
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http://dx.doi.org/10.1002/ase.1385DOI Listing
September 2014

Tractography demonstrates dentate-rubro-thalamic tract disruption in an adult with cerebellar mutism.

Cerebellum 2013 Oct;12(5):617-22

Department of Neurosurgery, Radboud University Nijmegen Medical Centre, Huispost 636 Neurochirurgie, Postbus 9101, 6500 HB, Nijmegen, The Netherlands,

A 55-year-old female is presented with transient cerebellar mutism caused by a well-circumscribed left pontine infarction due to postoperative basilar perforator occlusion. Although conventional T2 imaging shows a well-demarcated lesion confined to the pontine region, diffusion tensor imaging shows an asymmetry in fractional anisotropy in the superior cerebellar peduncle. This supports the general hypothesis that cerebellar mutism is caused by functional disruption of the dentate-rubro-thalamic tract. Correlating postoperative anatomic changes to a heterogenic clinical syndrome remains challenging, however.
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http://dx.doi.org/10.1007/s12311-013-0473-zDOI Listing
October 2013

Layer-specific diffusion weighted imaging in human primary visual cortex in vitro.

Cortex 2013 Oct 12;49(9):2569-82. Epub 2012 Dec 12.

Department of Anatomy, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands.

One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual cortex, myelinated fibres are so abundant that he could observe them with bare eyes as a white line. Because of its saliency, the stria of Gennari has a rich history in cyto- and myeloarchitectural research as well as in magnetic resonance (MR) microscopy. In the present paper we show for the first time the layered structure of the human neocortex with ex vivo diffusion weighted imaging (DWI). To achieve the necessary spatial and angular resolution, primary visual cortex samples were scanned on an 11.7 T small-animal MR system to characterize the diffusion properties of the cortical laminae and the stria of Gennari in particular. The results demonstrated that fractional anisotropy varied over cortical depth, showing reduced anisotropy in the stria of Gennari, the inner band of Baillarger and the deepest layer of the cortex. Orientation density functions showed multiple components in the stria of Gennari and deeper layers of the cortex. Potential applications of layer-specific diffusion imaging include characterization of clinical abnormalities, cortical mapping and (intra)cortical tractography. We conclude that future high-resolution in vivo cortical DWI investigations should take into account the layer-specificity of the diffusion properties.
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http://dx.doi.org/10.1016/j.cortex.2012.11.015DOI Listing
October 2013

Gray and white matter degeneration revealed by diffusion in an Alzheimer mouse model.

Neurobiol Aging 2013 May 25;34(5):1440-50. Epub 2012 Dec 25.

Department of Anatomy, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

In patients with Alzheimer's disease (AD) the severity of white matter degeneration correlates with the clinical symptoms of the disease. In this study, we performed diffusion-tensor magnetic resonance imaging at ultra-high field in a mouse model for AD (APP(swe)/PS1(dE9)) in combination with a voxel-based approach and tractography to detect changes in water diffusivity in white and gray matter, because these reflect structural alterations in neural tissue. We found substantial changes in water diffusion parallel and perpendicular to axonal tracts in several white matter regions like corpus callosum and fimbria of the hippocampus, that match with previous findings of axonal disconnection and myelin degradation in AD patients. Moreover, we found a significant increase in diffusivity in specific hippocampal subregions, which is supported by neuronal loss as visualized with Klüver-Barrera staining. This work demonstrates the potential of ultra-high field diffusion-tensor magnetic resonance imaging as a noninvasive modality to describe white and gray matter structural changes in mouse models for neurodegenerative disorders, and provides valuable knowledge to assess future AD prevention strategies in translational research.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.11.017DOI Listing
May 2013

Structure Tensor Informed Fiber Tractography (STIFT) by combining gradient echo MRI and diffusion weighted imaging.

Neuroimage 2012 Feb 28;59(4):3941-54. Epub 2011 Oct 28.

Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Kapittelweg 29, 6525 EN Nijmegen, Netherlands.

Structural connectivity research in the human brain in vivo relies heavily on fiber tractography in diffusion-weighted MRI (DWI). The accurate mapping of white matter pathways would gain from images with a higher resolution than the typical ~2mm isotropic DWI voxel size. Recently, high field gradient echo MRI (GE) has attracted considerable attention for its detailed anatomical contrast even within the white and gray matter. Susceptibility differences between various fiber bundles give a contrast that might provide a useful representation of white matter architecture complementary to that offered by DWI. In this paper, Structure Tensor Informed Fiber Tractography (STIFT) is proposed as a method to combine DWI and GE. A data-adaptive structure tensor is calculated from the GE image to describe the morphology of fiber bundles. The structure tensor is incorporated in a tractography algorithm to modify the DWI-based tracking direction according to the contrast in the GE image. This GE structure tensor was shown to be informative for tractography. From closely spaced seedpoints (0.5mm) on both sides of the border of 1) the optic radiation and inferior longitudinal fasciculus 2) the cingulum and corpus callosum, STIFT fiber bundles were clearly separated in white matter and terminated in the anatomically correct areas. Reconstruction of the optic radiation with STIFT showed a larger anterior extent of Meyer's loop compared to a standard tractography alternative. STIFT in multifiber voxels yielded a reduction in crossing-over of streamlines from the cingulum to the adjacent corpus callosum, while tracking through the fiber crossings of the centrum semiovale was unaffected. The STIFT method improves the anatomical accuracy of tractography of various fiber tracts, such as the optic radiation and cingulum. Furthermore, it has been demonstrated that STIFT can differentiate between kissing and crossing fiber configurations. Future investigations are required to establish the applicability in more white matter pathways.
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http://dx.doi.org/10.1016/j.neuroimage.2011.10.078DOI Listing
February 2012
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