Marleen Verhoye

Estimation of the Noise in Magnitude MR Images

Magnitude magnetic resonance data are Rician distributed. In this note a new method is proposed to estimate the image noise variance for this type of data distribution. The method is based on a double image acquisition, thereby exploiting the knowledge of the Rice distribution moments.

Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice

Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115–specific functions, underlie neurological alterations in Williams syndrome.

Watershed-based segmentation of 3D MR data for volume quantization

The aim of this work is the development of a semiautomatic segmentation technique for efficient and accurate volume quantization of Magnetic Resonance (MR) data. The proposed technique uses a 3D variant of Vincent and Soilles immersion-based watershed algorithm that is applied to the gradient magnitude of the MR data and that produces small volume primitives. The known drawback of the watershed algorithm, oversegmentation, is strongly reduced by a priori application of a 3D adaptive anisotropic diffusion filter to the MR data. Furthermore, oversegmentation is a posteriori reduced by properly merging small volume primitives that have similar gray level distributions. The outcome of the proceeding image processing steps is presented to the user for manual segmentation. Through selection of volume primitives, the user quickly segments of first slice, which contains the object of interest. Afterwards, the subsequent slices are automatically segmented by extrapolation. Segmentation results are contingently manually corrected. The proposed segmentation technique is tested on phantom objects, where segmentation errors less than 2% are observed. In addition, the technique is demonstrated on 3D MR data of the mouse head from which the cerebellum is extracted. Volumes of the mouse cerebellum and the mouse brains in toto are calculated.

Functional connectivity fMRI of the rodent brain : comparison of functional connectivity networks in rat and mouse

At present, resting state functional MRI (rsfMRI) is increasingly used in human neuropathological research. The present study aims at implementing rsfMRI in mice, a species that holds the widest variety of neurological disease models. Moreover, by acquiring rsfMRI data with a comparable protocol for anesthesia, scanning and analysis, in both rats and mice we were able to compare findings obtained in both species. The outcome of rsfMRI is different for rats and mice and depends strongly on the applied number of components in the Independent Component Analysis (ICA). The most important difference was the appearance of unilateral cortical components for the mouse resting state data compared to bilateral rat cortical networks. Furthermore, a higher number of components was needed for the ICA analysis to separate different cortical regions in mice as compared to rats.

Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells

Objectives Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. Results First, we demonstrated that TNFΔARE mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNFΔARE mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. Conclusions These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

Optimal Experimental Design for Diffusion Kurtosis Imaging

Diffusion kurtosis imaging (DKI) is a new magnetic resonance imaging (MRI) model that describes the non-Gaussian diffusion behavior in tissues. It has recently been shown that DKI parameters, such as the radial or axial kurtosis, are more sensitive to brain physiology changes than the well-known diffusion tensor imaging (DTI) parameters in several white and gray matter structures. In order to estimate either DTI or DKI parameters with maximum precision, the diffusion weighting gradient settings that are applied during the acquisition need to be optimized. Indeed, it has been shown previously that optimizing the set of diffusion weighting gradient settings can have a significant effect on the precision with which DTI parameters can be estimated. In this paper, we focus on the optimization of DKI gradients settings. Commonly, DKI data are acquired using a standard set of diffusion weighting gradients with fixed directions and with regularly spaced gradient strengths. In this paper, we show that such gradient settings are suboptimal with respect to the precision with which DKI parameters can be estimated. Furthermore, the gradient directions and the strengths of the diffusion-weighted MR images are optimized by minimizing the Crame¿r-Rao lower bound of DKI parameters. The impact of the optimized gradient settings is evaluated, both on simulated as well as experimentally recorded datasets. It is shown that the precision with which the kurtosis parameters can be estimated, increases substantially by optimizing the gradient settings.

More accurate estimation of diffusion tensor parameters using diffusion kurtosis imaging

With diffusion tensor imaging, the diffusion of water molecules through brain structures is quantified by parameters, which are estimated assuming monoexponential diffusion‐weighted signal attenuation. The estimated diffusion parameters, however, depend on the diffusion weighting strength, the b‐value, which hampers the interpretation and comparison of various diffusion tensor imaging studies. In this study, a likelihood ratio test is used to show that the diffusion kurtosis imaging model provides a more accurate parameterization of both the Gaussian and non‐Gaussian diffusion component compared with diffusion tensor imaging. As a result, the diffusion kurtosis imaging model provides a b‐value‐independent estimation of the widely used diffusion tensor parameters as demonstrated with diffusion‐weighted rat data, which was acquired with eight different b‐values, uniformly distributed in a range of [0,2800 sec/mm2]. In addition, the diffusion parameter values are significantly increased in comparison to the values estimated with the diffusion tensor imaging model in all major rat brain structures. As incorrectly assuming additive Gaussian noise on the diffusion‐weighted data will result in an overestimated degree of non‐Gaussian diffusion and a b‐value‐dependent underestimation of diffusivity measures, a Rician noise model was used in this study. Magn Reson Med, 2010.

In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system

Injection of manganese (Mn(2+)), a paramagnetic tract tracing agent and calcium analogue, into the high vocal center of starlings labeled within a few hours the nucleus robustus archistriatalis and area X as observed by in vivo magnetic resonance imaging. Structures highlighted by Mn(2+) accumulation assumed the expected tri-dimensional shape of the nucleus robustus archistriatalis and area X as identified by classical histological or neurochemical methods. The volume of these nuclei could be accurately calculated by segmentation of the areas highlighted by Mn(2+). Besides confirming previously established volumetric sex differences, Mn(2+) uptake into these nuclei revealed new functional sex differences affecting Mn(2+) transport. A faster transport was observed in males than in females and different relative amounts of Mn(2+) were transported to nucleus robustus archistriatalis and area X in males as compared to females. This new in vivo approach, allowing repeated measures, opens new vistas to study the remarkable seasonal plasticity in size and activity of song-control nuclei and correlate neuronal activity with behavior. It also provides new insights on in vivo axonal transport and neuronal activity in song-control nuclei of oscines.

Magnetic Resonance Imaging and Spectroscopy Reveal Differential Hippocampal Changes in Anhedonic and Resilient Subtypes of the Chronic Mild Stress Rat Model

BACKGROUND Repeated exposure to mild stressors induces anhedonia-a core symptom of major depressive disorder-in up to 70% of the stress-exposed rats, whereas the remaining show resilience to stress. This chronic mild stress (CMS) model is well documented as an animal model of major depressive disorder. We examined the morphological, microstructural, and metabolic characteristics of the hippocampus in anhedonic and stress resilient rats that may mark the differential behavioral outcome. METHODS Anhedonic (n = 8), resilient (n = 8), and control (n = 8) rats were subjected to in vivo diffusion kurtosis imaging, high-resolution three-dimensional magnetic resonance imaging and proton magnetic resonance spectroscopy. RESULTS Diffusion kurtosis parameters were decreased in both CMS-exposed groups. A significant inward displacement in the ventral part of the right hippocampus was apparent in the resilient subjects and an increase of the glutamate:total creatine ratio and N-acetylaspartylglutamate:total creatine was observed in the anhedonic subjects. CONCLUSIONS Diffusion kurtosis imaging discloses subtle substructural changes in the hippocampus of CMS-exposed animals irrespective of their anhedonic or resilient nature. In contrast, proton magnetic resonance spectroscopy and magnetic resonance imaging-based shape change analysis of the hippocampus allowed discrimination of these two subtypes of stress sensitivity. Although the precise mechanism discriminating their behavior is yet to be elucidated, the present study underlines the role of the hippocampus in the etiology of depression and the induction of anhedonia. Our results reflect the potency of noninvasive magnetic resonance methods in preclinical settings with key translational benefit to and from the clinic.

Neonatal neuronal overexpression of glycogen synthase kinase-3β reduces brain size in transgenic mice

Glycogen synthase kinase-3beta (GSK-3beta) is important in neurogenesis. Here we demonstrate that the kinase influenced post-natal maturation and differentiation of neurons in vivo in transgenic mice that overexpress a constitutively active GSK-3beta[S9A]. Magnetic resonance imaging revealed a reduced volume of the entire brain, concordant with a nearly 20% reduction in wet brain weight. The reduced volume was most prominent for the cerebral cortex, without however, disturbing the normal cortical layering. The resulting compacted architecture was further demonstrated by an increased neuronal density, by reduced size of neuronal cell bodies and of the somatodendritic compartment of pyramidal neurons in the cortex. No evidence for apoptosis was obtained. The marked overall reduction in the level of the microtubule-associated protein 2 in brain and in spinal cord, did not affect the ultrastructure of the microtubular cytoskeleton in the proximal apical dendrites. The overall reduction in size of the entire CNS induced by constitutive active GSK-3beta caused only very subtle changes in the psychomotoric ability of adult and ageing GSK-3beta transgenic mice.