Nyoman Kurniawan - Profile on Academia.edu (original) (raw)

Papers by Nyoman Kurniawan

Background: Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorder... more Background: Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have
increased in prevalence in the past two decades. Animal models offer the opportunity to understand the biological
basis of these disorders. Studies comparing different mouse strains have identified the inbred BTBR T + tf/J (BTBR)
strain as a mouse model of ASD based on its anti-social and repetitive behaviours. Adult BTBR mice have complete
agenesis of the corpus callosum, reduced cortical thickness and changes in early neurogenesis. However, little is
known about the development or ultimate organisation of cortical areas devoted to specific sensory and motor
functions in these mice that may also contribute to their behavioural phenotype.
Results: In this study, we performed diffusion tensor imaging and tractography, together with histological analyses
to investigate the emergence of functional areas in the cerebral cortex and their connections in BTBR mice and
age-matched C57Bl/6 control mice. We found evidence that neither the anterior commissure nor the hippocampal
commissure compensate for the loss of callosal connections, indicating that no interhemispheric neocortical
connectivity is present in BTBR mice. We also found that both the primary visual and somatosensory cortical
areas are shifted medially in BTBR mice compared to controls and that cortical thickness is differentially altered
in BTBR mice between cortical areas and throughout development.
Conclusions: We demonstrate that interhemispheric connectivity and cortical area formation are altered in an
age- and region-specific manner in BTBR mice, which may contribute to the behavioural deficits previously observed in
this strain. Some of these developmental patterns of change are also present in human ASD patients, and elucidating
the aetiology driving cortical changes in BTBR mice may therefore help to increase our understanding of this disorder.
Keywords: Autism spectrum disorders (ASD), BTBR mice, Agenesis of the corpus callosum, Cortical area patterning,
Diffusion imaging

Brain tissue compartment density estimated using diffusion-weighted MRI yields tissue parameters consistent with histology

Human Brain Mapping, 2015

We examined whether quantitative density measures of cerebral tissue consistent with histology ca... more We examined whether quantitative density measures of cerebral tissue consistent with histology can be obtained from diffusion magnetic resonance imaging (MRI). By incorporating prior knowledge of myelin and cell membrane densities, absolute tissue density values were estimated from relative intracellular and intraneurite density values obtained from diffusion MRI. The NODDI (neurite orientation distribution and density imaging) technique, which can be applied clinically, was used. Myelin density estimates were compared with the results of electron and light microscopy in ex vivo mouse brain and with published density estimates in a healthy human brain. In ex vivo mouse brain, estimated myelin densities in different subregions of the mouse corpus callosum were almost identical to values obtained from electron microscopy (diffusion MRI: 42 ± 6%, 36 ± 4%, and 43 ± 5%; electron microscopy: 41 ± 10%, 36 ± 8%, and 44 ± 12% in genu, body and splenium, respectively). In the human brain, good agreement was observed between estimated fiber density measurements and previously reported values based on electron microscopy. Estimated density values were unaffected by crossing fibers. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.

Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric β-catenin signaling

Kidney international, Jan 14, 2015

Gestational stressors, including glucocorticoids and protein restriction, can affect kidney devel... more Gestational stressors, including glucocorticoids and protein restriction, can affect kidney development and hence final nephron number. Since hypoxia is a common insult during pregnancy, we studied the influence of oxygen tension on kidney development in models designed to represent a pathological hypoxic insult. In vivo mouse models of moderate, transient, midgestational (12% O2, 48 h, 12.5 dpc) or severe, acute, early-gestational (5.5-7.5% O2, 8 h, 9.5-10.5 dpc) hypoxia were developed. The embryo itself is known to mature under hypoxic conditions with embryonic tissue levels of oxygen estimated to be 5%-8% (physiological hypoxia) when the mother is exposed to ambient normoxia. Both in vivo models generated phenotypes seen in patients with congenital anomalies of the kidney and urinary tract (CAKUT). Severe, acute, early hypoxia resulted in duplex kidney, while moderate, transient, midgestational hypoxia permanently reduced ureteric branching and nephron formation. Both models disp...

Proceedings of the National Academy of Sciences, 2015

Venom represents one of the most extreme manifestations of a chemical arms race. Venoms are compl... more Venom represents one of the most extreme manifestations of a chemical arms race. Venoms are complex biochemical arsenals, often containing hundreds to thousands of unique protein toxins. Despite their utility for prey capture, venoms are energetically expensive commodities, and consequently it is hypothesized that venom complexity is inversely related to the capacity of a venomous animal to physically subdue prey. Centipedes, one of the oldest yet least-studied venomous lineages, appear to defy this rule. Although scutigeromorph centipedes produce less complex venom than those secreted by scolopendrid centipedes, they appear to rely heavily on venom for prey capture. We show that the venom glands are large and well developed in both scutigerid and scolopendrid species, but that scutigerid forcipules lack the adaptations that allow scolopendrids to inflict physical damage on prey and predators. Moreover, we reveal that scolopendrid venom glands have evolved to accommodate a much larger number of secretory cells and, by using imaging mass spectrometry, we demonstrate that toxin production is heterogeneous across these secretory units. We propose that the differences in venom complexity between centipede orders are largely a result of morphological restrictions of the venom gland, and consequently there is a strong correlation between the morphological and biochemical complexity of this unique venom system. The current data add to the growing body of evidence that toxins are not expressed in a spatially homogenous manner within venom glands, and they suggest that the link between ecology and toxin evolution is more complex than previously thought. venom evolution | venom-gland morphology | centipede | mass spectrometry imaging | venom optimization hypothesis

lop-DWI: A Novel Scheme for Pre-Processing of Diffusion-Weighted Images in the Gradient Direction Domain

Frontiers in neurology, 2014

We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion... more We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion-gradient directions for high angular resolution diffusion magnetic resonance imaging. Our pre-processing method incorporates prior knowledge about the acquired diffusion-weighted signal, facilitating noise reduction. Periodic spiral sampling of gradient direction encodings results in an acquired signal in each voxel that is pseudo-periodic with characteristics that allow separation of low-frequency signal from high frequency noise. Consequently, it enhances local reconstruction of the orientation distribution function used to define fiber tracks in the brain. Denoising with periodic spiral sampling was tested using synthetic data and in vivo human brain images. The level of improvement in signal-to-noise ratio and in the accuracy of local reconstruction of fiber tracks was significantly improved using our method.

Toxins, 2013

Although known for their potent venom and ability to prey upon both invertebrate and vertebrate s... more Although known for their potent venom and ability to prey upon both invertebrate and vertebrate species, the Barychelidae spider family has been entirely neglected by toxinologists. In striking contrast, the sister family Theraphosidae (commonly known as tarantulas), which last shared a most recent common ancestor with Barychelidae over 200 million years ago, has received much attention, accounting for 25% of all the described spider toxins while representing only 2% of all spider species. In this study, we evaluated for the first time the venom arsenal of a barychelid spider, Trittame loki, using transcriptomic, proteomic, and bioinformatic methods. The venom was revealed to be dominated by extremely diverse inhibitor cystine knot (ICK)/knottin peptides, accounting for 42 of the 46 full-length toxin precursors recovered in the transcriptomic sequencing. In addition to documenting differential rates of evolution adopted by different ICK/knottin toxin lineages, we discovered homologu...

Microscopic diffusion properties of fixed breast tissue: Preliminary findings

Magnetic Resonance in Medicine, 2014

To investigate the microscopic diffusion properties of formalin-fixed breast tissue. Diffusion mi... more To investigate the microscopic diffusion properties of formalin-fixed breast tissue. Diffusion microimaging was performed at 16.4T with 40-μm isotropic voxels on two normal and two cancer tissue samples from four patients. Results were correlated with histology of the samples. Diffusion-weighted images and mean diffusivity maps demonstrated distinct diffusivity differences between breast tissue components. Mean diffusivity (MD) in normal tissue was 0.59 ± 0.24 μm(2) /ms for gland lobule (voxels containing epithelium and intralobular stroma) and 1.23 ± 0.34 μm(2) /ms for interlobular fibrous stroma. In the cancer samples, MD = 0.45 ± 0.23 μm(2) /ms for invasive ductal carcinoma (voxels contain epithelium and intralobular stroma) and 0.61 ± 0.35 μm(2) /ms for ductal carcinoma in situ. There were significant MD differences between all tissue components (P < 0.005), except between gland lobule and ductal carcinoma in situ (P = 0.71). The low diffusivity of epithelium-rich cancer tissue and of normal epithelium relative to its supporting fibrous stroma was similar to that reported for prostate tissue and the esophageal wall. Diffusion microimaging demonstrates distinct diffusivity differences between breast tissue glandular structures. Low diffusivity may be a distinctive feature of mammalian epithelia. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Visualization of mouse barrel cortex using ex-vivo track density imaging

NeuroImage, 2014

We describe the visualization of the barrel cortex of the primary somatosensory area (S1) of ex v... more We describe the visualization of the barrel cortex of the primary somatosensory area (S1) of ex vivo adult mouse brain with short-tracks track density imaging (stTDI). stTDI produced much higher definition of barrel structures than conventional fractional anisotropy (FA), directionally-encoded color FA maps, spin-echo T1- and T2-weighted imaging and gradient echo T1/T2*-weighted imaging. 3D high angular resolution diffusion imaging (HARDI) data were acquired at 48 micron isotropic resolution for a (3mm)(3) block of cortex containing the barrel field and reconstructed using stTDI at 10 micron isotropic resolution. HARDI data were also acquired at 100 micron isotropic resolution to image the whole brain and reconstructed using stTDI at 20 micron isotropic resolution. The 10 micron resolution stTDI maps showed exceptionally clear delineation of barrel structures. Individual barrels could also be distinguished in the 20 micron stTDI maps but the septa separating the individual barrels appeared thicker compared to the 10 micron maps, indicating that the ability of stTDI to produce high quality structural delineation is dependent upon acquisition resolution. Close homology was observed between the barrel structure delineated using stTDI and reconstructed histological data from the same samples. stTDI also detects barrel deletions in the posterior medial barrel sub-field in mice with infraorbital nerve cuts. The results demonstrate that stTDI is a novel imaging technique that enables three-dimensional characterization of complex structures such as the barrels in S1 and provides an important complementary non-invasive imaging tool for studying synaptic connectivity, development and plasticity of the sensory system.

lop-DWI: A Novel Scheme for Pre-Processing of Diffusion-Weighted Images in the Gradient Direction Domain

Frontiers in Neurology, 2015

We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion... more We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion-gradient directions for high angular resolution diffusion magnetic resonance imaging. Our pre-processing method incorporates prior knowledge about the acquired diffusion-weighted signal, facilitating noise reduction. Periodic spiral sampling of gradient direction encodings results in an acquired signal in each voxel that is pseudo-periodic with characteristics that allow separation of low-frequency signal from high frequency noise. Consequently, it enhances local reconstruction of the orientation distribution function used to define fiber tracks in the brain. Denoising with periodic spiral sampling was tested using synthetic data and in vivo human brain images. The level of improvement in signal-to-noise ratio and in the accuracy of local reconstruction of fiber tracks was significantly improved using our method.

NeuroImage, 2012

The recently proposed track-density imaging (TDI) technique was introduced as a means to achieve ... more The recently proposed track-density imaging (TDI) technique was introduced as a means to achieve superresolution using diffusion MRI. This technique is able to increase the spatial resolution of the reconstructed images beyond the acquired MRI resolution by incorporating information from whole-brain fibre-tracking results. It not only achieves super-resolution, but also provides very high anatomical contrast with a new MRI contrast mechanism. However, the anatomical information-content of this novel contrast mechanism has not yet been assessed. In this work, we perform such a study using diffusion MRI of ex vivo mouse brains acquired at 16.4T, to compare the results of the super-resolution TDI technique with histological staining (myelin and Nissl stains) in the same brains. Furthermore, a modified version of the directionally-encoded colour TDI map using short-tracks is introduced, which reduces the TDI intensity dynamic range, and therefore enhances the directionality colour-contrast. Good agreement was observed between structures visualised in the superresolution TDI maps and in the histological sections, supporting the anatomical information-content of the images generated using the TDI technique. The results therefore show that the TDI methodology does provide meaningful and rich anatomical contrast, in addition to achieving super-resolution. Furthermore, this study is the first to show the application of TDI to mouse brain imaging: the high-resolution, high-quality images demonstrate the useful complementary information that can be achieved using super-resolution TDI.

NeuroImage, 2011

The hippocampal formation plays an important role in cognition, spatial navigation, learning, and... more The hippocampal formation plays an important role in cognition, spatial navigation, learning, and memory. High resolution magnetic resonance (MR) imaging makes it possible to study in vivo changes in the hippocampus over time and is useful for comparing hippocampal volume and structure in wild type and mutant mice. Such comparisons demand a reliable way to segment the hippocampal formation. We have developed a method for the systematic segmentation of the hippocampal formation using the perfusion-fixed C57BL/6 mouse brain for application in longitudinal and comparative studies. Our aim was to develop a guide for segmenting over 40 structures in an adult mouse brain using 30 μm isotropic resolution images acquired with a 16.4 T MR imaging system and combined using super-resolution reconstruction.

NeuroImage, 2013

This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 7... more This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 70 μm in-plane resolution, 1 mm slice thickness) to evaluate the spatiotemporal development of severe mid-thoracic contusive spinal cord injury (SCI) in mice. In vivo imaging was performed prior to SCI, then again at 2 h, 1 day, 3 days, 7 days, and 30 days post-SCI using a Bruker 16.4 T small animal nuclear magnetic resonance spectrometer. Cross-sectional spinal cord areas were measured in axial slices and various DTI parameters, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ || ) and radial diffusivity (λ ⊥ ), were calculated for the total spared white matter (WM), ventral funiculi (VF), lateral funiculi (LF) and dorsal columns (DCs) and then correlated with histopathology. Cross-sectional area measurements revealed significant atrophy (32% reduction) of the injured spinal cord at the lesion epicentre in the chronic phase of injury. Analysis of diffusion tensor parameters further showed that tissue integrity was most severely affected in the DCs, i.e. the site of immediate impact, which demonstrated a rapid and permanent decrease in FA and λ || . In contrast, DTI parameters for the ventrolateral white matter changed more gradually with time, suggesting that these regions are undergoing more delayed degeneration in a manner that may be amenable to therapeutic intervention. Of all the DTI parameters, λ ⊥ was most closely correlated to myelin content whereas changes in FA and λ || appeared more indicative of axonal integrity, Wallerian degeneration and associated presence of macrophages. We conclude that longitudinal DTI at 16.4 T provides a clinically relevant, objective measure for assessing white matter pathology following contusive SCI in mice that may aid the translation of putative neuroprotective strategies into the clinic.

NeuroImage, 2012

• We present a methodology for systematic delineation of the C57BL/6J mouse cerebellum in MRI. • ... more • We present a methodology for systematic delineation of the C57BL/6J mouse cerebellum in MRI. • We have successfully delineated 38 cerebellar and cerebellar-related structures.

Magnetic Resonance in Medicine, 2012

Diffusion tensor microimaging with 40 µm isotropic voxels at 16.4 T was used to investigate compa... more Diffusion tensor microimaging with 40 µm isotropic voxels at 16.4 T was used to investigate compartmentation of water diffusion and biexponential diffusion decay in formalin fixed prostate tissue. Tissue samples (~28 mm 3 ) were similar in volume to a typical prostate DWI voxel in vivo and were imaged with ~400,000 voxels. The bulk mean diffusivity ('ADC') of epithelial, stromal, and ductal/acinal compartments was estimated by two methods: manual region of interest (ROI) selection; and Gaussian fitting of whole sample voxel diffusivity histograms.

Magnetic Resonance in Medicine, 2012

Diffusion tensor microimaging at 16.4 T with 40 mm isotropic voxels was used to investigate aniso... more Diffusion tensor microimaging at 16.4 T with 40 mm isotropic voxels was used to investigate anisotropic water diffusion in prostate tissue at spatial resolution approaching the cellular scale. Nine normal glandular tissue samples were collected from the peripheral zone of six formalin fixed radical prostatectomy specimens. Fibromuscular stromal tissue exhibited microscopic diffusion anisotropy (mean fractional anisotropy range 0.47-0.66) significantly higher (P < 0.01, Student's t-test) than in epithelium-containing voxels (mean fractional anisotropy range 0.31-0.54) in six of the seven normal tissue samples in which both compartments could be measured. Fiber tracking demonstrated principle stromal fiber directions consistent with myocyte orientation seen on light microscopy of the same sample. Diffusion tensor microimaging may be valuable for investigation of variable results from attempts to measure diffusion anisotropy in the prostate in vivo. Magn Reson Med 000:000-000, 2012. V C 2012 Wiley Periodicals, Inc.

Journal of Neurotrauma, 2013

Blocking the action of inhibitory molecules at sites of central nervous system injury has been pr... more Blocking the action of inhibitory molecules at sites of central nervous system injury has been proposed as a strategy to promote axonal regeneration and functional recovery. We have previously shown that genetic deletion or competitive antagonism of EphA4 receptor activity promotes axonal regeneration and functional recovery in a mouse model of lateral hemisection spinal cord injury. Here we have assessed the effect of blocking EphA4 activation using the competitive antagonist EphA4-Fc in a rat model of thoracic contusive spinal cord injury. Using a ledged tapered balance beam and open-field testing, we observed significant improvements in recovery of locomotor function after EphA4-Fc treatment. Consistent with functional improvement, using high-resolution ex vivo magnetic resonance imaging at 16.4T, we found that rats treated with EphA4-Fc had a significantly increased cross-sectional area of the dorsal funiculus caudal to the injury epicenter compared with controls. Our findings indicate that EphA4-Fc promotes functional recovery following contusive spinal cord injury and provides further support for the therapeutic benefit of treatment with the competitive antagonist in acute cases of spinal cord injury.

Brain Structure and Function, 2014

The complex pathogenesis of temporal lobe epilepsy includes neuronal and glial pathology, synapti... more The complex pathogenesis of temporal lobe epilepsy includes neuronal and glial pathology, synaptic reorganization, and an immune response. However, the spatio-temporal pattern of structural changes in the brain that provide a substrate for seizure generation and modulate the seizure phenotype is yet to be completely elucidated. We used quantitative magnetic resonance imaging (MRI) to study structural changes triggered by status epilepticus (SE) and their association with epileptogenesis and with activation of complement component 3 (C3). SE was induced by injection of pilocarpine in CD1 mice. Quantitative diffusion-weighted imaging and T2 relaxometry was performed using a 16.4-Tesla MRI scanner at 3 h and 1, 2, 7, 14, 28, 35, and 49 days post-SE. Following longitudinal MRI examinations, spontaneous recurrent seizures and interictal spikes were quantified using continuous video-EEG monitoring. Immunohistochemical analysis of C3 expression was performed at 48 h, 7 days, and 4 months post-SE. MRI changes were dynamic, reflecting different outcomes in relation to the development of epilepsy. Apparent diffusion coefficient changes in the hippocampus at 7 days post-SE correlated with the severity of the evolving epilepsy. C3 activation was found in all stages of epileptogenesis within the areas with significant MRI changes and correlated with the severity of epileptic condition.

Background: Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorder... more Background: Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have
increased in prevalence in the past two decades. Animal models offer the opportunity to understand the biological
basis of these disorders. Studies comparing different mouse strains have identified the inbred BTBR T + tf/J (BTBR)
strain as a mouse model of ASD based on its anti-social and repetitive behaviours. Adult BTBR mice have complete
agenesis of the corpus callosum, reduced cortical thickness and changes in early neurogenesis. However, little is
known about the development or ultimate organisation of cortical areas devoted to specific sensory and motor
functions in these mice that may also contribute to their behavioural phenotype.
Results: In this study, we performed diffusion tensor imaging and tractography, together with histological analyses
to investigate the emergence of functional areas in the cerebral cortex and their connections in BTBR mice and
age-matched C57Bl/6 control mice. We found evidence that neither the anterior commissure nor the hippocampal
commissure compensate for the loss of callosal connections, indicating that no interhemispheric neocortical
connectivity is present in BTBR mice. We also found that both the primary visual and somatosensory cortical
areas are shifted medially in BTBR mice compared to controls and that cortical thickness is differentially altered
in BTBR mice between cortical areas and throughout development.
Conclusions: We demonstrate that interhemispheric connectivity and cortical area formation are altered in an
age- and region-specific manner in BTBR mice, which may contribute to the behavioural deficits previously observed in
this strain. Some of these developmental patterns of change are also present in human ASD patients, and elucidating
the aetiology driving cortical changes in BTBR mice may therefore help to increase our understanding of this disorder.
Keywords: Autism spectrum disorders (ASD), BTBR mice, Agenesis of the corpus callosum, Cortical area patterning,
Diffusion imaging

Brain tissue compartment density estimated using diffusion-weighted MRI yields tissue parameters consistent with histology

Human Brain Mapping, 2015

We examined whether quantitative density measures of cerebral tissue consistent with histology ca... more We examined whether quantitative density measures of cerebral tissue consistent with histology can be obtained from diffusion magnetic resonance imaging (MRI). By incorporating prior knowledge of myelin and cell membrane densities, absolute tissue density values were estimated from relative intracellular and intraneurite density values obtained from diffusion MRI. The NODDI (neurite orientation distribution and density imaging) technique, which can be applied clinically, was used. Myelin density estimates were compared with the results of electron and light microscopy in ex vivo mouse brain and with published density estimates in a healthy human brain. In ex vivo mouse brain, estimated myelin densities in different subregions of the mouse corpus callosum were almost identical to values obtained from electron microscopy (diffusion MRI: 42 ± 6%, 36 ± 4%, and 43 ± 5%; electron microscopy: 41 ± 10%, 36 ± 8%, and 44 ± 12% in genu, body and splenium, respectively). In the human brain, good agreement was observed between estimated fiber density measurements and previously reported values based on electron microscopy. Estimated density values were unaffected by crossing fibers. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.

Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric β-catenin signaling

Kidney international, Jan 14, 2015

Gestational stressors, including glucocorticoids and protein restriction, can affect kidney devel... more Gestational stressors, including glucocorticoids and protein restriction, can affect kidney development and hence final nephron number. Since hypoxia is a common insult during pregnancy, we studied the influence of oxygen tension on kidney development in models designed to represent a pathological hypoxic insult. In vivo mouse models of moderate, transient, midgestational (12% O2, 48 h, 12.5 dpc) or severe, acute, early-gestational (5.5-7.5% O2, 8 h, 9.5-10.5 dpc) hypoxia were developed. The embryo itself is known to mature under hypoxic conditions with embryonic tissue levels of oxygen estimated to be 5%-8% (physiological hypoxia) when the mother is exposed to ambient normoxia. Both in vivo models generated phenotypes seen in patients with congenital anomalies of the kidney and urinary tract (CAKUT). Severe, acute, early hypoxia resulted in duplex kidney, while moderate, transient, midgestational hypoxia permanently reduced ureteric branching and nephron formation. Both models disp...

Proceedings of the National Academy of Sciences, 2015

Venom represents one of the most extreme manifestations of a chemical arms race. Venoms are compl... more Venom represents one of the most extreme manifestations of a chemical arms race. Venoms are complex biochemical arsenals, often containing hundreds to thousands of unique protein toxins. Despite their utility for prey capture, venoms are energetically expensive commodities, and consequently it is hypothesized that venom complexity is inversely related to the capacity of a venomous animal to physically subdue prey. Centipedes, one of the oldest yet least-studied venomous lineages, appear to defy this rule. Although scutigeromorph centipedes produce less complex venom than those secreted by scolopendrid centipedes, they appear to rely heavily on venom for prey capture. We show that the venom glands are large and well developed in both scutigerid and scolopendrid species, but that scutigerid forcipules lack the adaptations that allow scolopendrids to inflict physical damage on prey and predators. Moreover, we reveal that scolopendrid venom glands have evolved to accommodate a much larger number of secretory cells and, by using imaging mass spectrometry, we demonstrate that toxin production is heterogeneous across these secretory units. We propose that the differences in venom complexity between centipede orders are largely a result of morphological restrictions of the venom gland, and consequently there is a strong correlation between the morphological and biochemical complexity of this unique venom system. The current data add to the growing body of evidence that toxins are not expressed in a spatially homogenous manner within venom glands, and they suggest that the link between ecology and toxin evolution is more complex than previously thought. venom evolution | venom-gland morphology | centipede | mass spectrometry imaging | venom optimization hypothesis

lop-DWI: A Novel Scheme for Pre-Processing of Diffusion-Weighted Images in the Gradient Direction Domain

Frontiers in neurology, 2014

We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion... more We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion-gradient directions for high angular resolution diffusion magnetic resonance imaging. Our pre-processing method incorporates prior knowledge about the acquired diffusion-weighted signal, facilitating noise reduction. Periodic spiral sampling of gradient direction encodings results in an acquired signal in each voxel that is pseudo-periodic with characteristics that allow separation of low-frequency signal from high frequency noise. Consequently, it enhances local reconstruction of the orientation distribution function used to define fiber tracks in the brain. Denoising with periodic spiral sampling was tested using synthetic data and in vivo human brain images. The level of improvement in signal-to-noise ratio and in the accuracy of local reconstruction of fiber tracks was significantly improved using our method.

Toxins, 2013

Although known for their potent venom and ability to prey upon both invertebrate and vertebrate s... more Although known for their potent venom and ability to prey upon both invertebrate and vertebrate species, the Barychelidae spider family has been entirely neglected by toxinologists. In striking contrast, the sister family Theraphosidae (commonly known as tarantulas), which last shared a most recent common ancestor with Barychelidae over 200 million years ago, has received much attention, accounting for 25% of all the described spider toxins while representing only 2% of all spider species. In this study, we evaluated for the first time the venom arsenal of a barychelid spider, Trittame loki, using transcriptomic, proteomic, and bioinformatic methods. The venom was revealed to be dominated by extremely diverse inhibitor cystine knot (ICK)/knottin peptides, accounting for 42 of the 46 full-length toxin precursors recovered in the transcriptomic sequencing. In addition to documenting differential rates of evolution adopted by different ICK/knottin toxin lineages, we discovered homologu...

Microscopic diffusion properties of fixed breast tissue: Preliminary findings

Magnetic Resonance in Medicine, 2014

To investigate the microscopic diffusion properties of formalin-fixed breast tissue. Diffusion mi... more To investigate the microscopic diffusion properties of formalin-fixed breast tissue. Diffusion microimaging was performed at 16.4T with 40-μm isotropic voxels on two normal and two cancer tissue samples from four patients. Results were correlated with histology of the samples. Diffusion-weighted images and mean diffusivity maps demonstrated distinct diffusivity differences between breast tissue components. Mean diffusivity (MD) in normal tissue was 0.59 ± 0.24 μm(2) /ms for gland lobule (voxels containing epithelium and intralobular stroma) and 1.23 ± 0.34 μm(2) /ms for interlobular fibrous stroma. In the cancer samples, MD = 0.45 ± 0.23 μm(2) /ms for invasive ductal carcinoma (voxels contain epithelium and intralobular stroma) and 0.61 ± 0.35 μm(2) /ms for ductal carcinoma in situ. There were significant MD differences between all tissue components (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005), except between gland lobule and ductal carcinoma in situ (P = 0.71). The low diffusivity of epithelium-rich cancer tissue and of normal epithelium relative to its supporting fibrous stroma was similar to that reported for prostate tissue and the esophageal wall. Diffusion microimaging demonstrates distinct diffusivity differences between breast tissue glandular structures. Low diffusivity may be a distinctive feature of mammalian epithelia. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Visualization of mouse barrel cortex using ex-vivo track density imaging

NeuroImage, 2014

We describe the visualization of the barrel cortex of the primary somatosensory area (S1) of ex v... more We describe the visualization of the barrel cortex of the primary somatosensory area (S1) of ex vivo adult mouse brain with short-tracks track density imaging (stTDI). stTDI produced much higher definition of barrel structures than conventional fractional anisotropy (FA), directionally-encoded color FA maps, spin-echo T1- and T2-weighted imaging and gradient echo T1/T2*-weighted imaging. 3D high angular resolution diffusion imaging (HARDI) data were acquired at 48 micron isotropic resolution for a (3mm)(3) block of cortex containing the barrel field and reconstructed using stTDI at 10 micron isotropic resolution. HARDI data were also acquired at 100 micron isotropic resolution to image the whole brain and reconstructed using stTDI at 20 micron isotropic resolution. The 10 micron resolution stTDI maps showed exceptionally clear delineation of barrel structures. Individual barrels could also be distinguished in the 20 micron stTDI maps but the septa separating the individual barrels appeared thicker compared to the 10 micron maps, indicating that the ability of stTDI to produce high quality structural delineation is dependent upon acquisition resolution. Close homology was observed between the barrel structure delineated using stTDI and reconstructed histological data from the same samples. stTDI also detects barrel deletions in the posterior medial barrel sub-field in mice with infraorbital nerve cuts. The results demonstrate that stTDI is a novel imaging technique that enables three-dimensional characterization of complex structures such as the barrels in S1 and provides an important complementary non-invasive imaging tool for studying synaptic connectivity, development and plasticity of the sensory system.

lop-DWI: A Novel Scheme for Pre-Processing of Diffusion-Weighted Images in the Gradient Direction Domain

Frontiers in Neurology, 2015

We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion... more We describe and evaluate a pre-processing method based on a periodic spiral sampling of diffusion-gradient directions for high angular resolution diffusion magnetic resonance imaging. Our pre-processing method incorporates prior knowledge about the acquired diffusion-weighted signal, facilitating noise reduction. Periodic spiral sampling of gradient direction encodings results in an acquired signal in each voxel that is pseudo-periodic with characteristics that allow separation of low-frequency signal from high frequency noise. Consequently, it enhances local reconstruction of the orientation distribution function used to define fiber tracks in the brain. Denoising with periodic spiral sampling was tested using synthetic data and in vivo human brain images. The level of improvement in signal-to-noise ratio and in the accuracy of local reconstruction of fiber tracks was significantly improved using our method.

NeuroImage, 2012

The recently proposed track-density imaging (TDI) technique was introduced as a means to achieve ... more The recently proposed track-density imaging (TDI) technique was introduced as a means to achieve superresolution using diffusion MRI. This technique is able to increase the spatial resolution of the reconstructed images beyond the acquired MRI resolution by incorporating information from whole-brain fibre-tracking results. It not only achieves super-resolution, but also provides very high anatomical contrast with a new MRI contrast mechanism. However, the anatomical information-content of this novel contrast mechanism has not yet been assessed. In this work, we perform such a study using diffusion MRI of ex vivo mouse brains acquired at 16.4T, to compare the results of the super-resolution TDI technique with histological staining (myelin and Nissl stains) in the same brains. Furthermore, a modified version of the directionally-encoded colour TDI map using short-tracks is introduced, which reduces the TDI intensity dynamic range, and therefore enhances the directionality colour-contrast. Good agreement was observed between structures visualised in the superresolution TDI maps and in the histological sections, supporting the anatomical information-content of the images generated using the TDI technique. The results therefore show that the TDI methodology does provide meaningful and rich anatomical contrast, in addition to achieving super-resolution. Furthermore, this study is the first to show the application of TDI to mouse brain imaging: the high-resolution, high-quality images demonstrate the useful complementary information that can be achieved using super-resolution TDI.

NeuroImage, 2011

The hippocampal formation plays an important role in cognition, spatial navigation, learning, and... more The hippocampal formation plays an important role in cognition, spatial navigation, learning, and memory. High resolution magnetic resonance (MR) imaging makes it possible to study in vivo changes in the hippocampus over time and is useful for comparing hippocampal volume and structure in wild type and mutant mice. Such comparisons demand a reliable way to segment the hippocampal formation. We have developed a method for the systematic segmentation of the hippocampal formation using the perfusion-fixed C57BL/6 mouse brain for application in longitudinal and comparative studies. Our aim was to develop a guide for segmenting over 40 structures in an adult mouse brain using 30 μm isotropic resolution images acquired with a 16.4 T MR imaging system and combined using super-resolution reconstruction.

NeuroImage, 2013

This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 7... more This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 70 μm in-plane resolution, 1 mm slice thickness) to evaluate the spatiotemporal development of severe mid-thoracic contusive spinal cord injury (SCI) in mice. In vivo imaging was performed prior to SCI, then again at 2 h, 1 day, 3 days, 7 days, and 30 days post-SCI using a Bruker 16.4 T small animal nuclear magnetic resonance spectrometer. Cross-sectional spinal cord areas were measured in axial slices and various DTI parameters, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ || ) and radial diffusivity (λ ⊥ ), were calculated for the total spared white matter (WM), ventral funiculi (VF), lateral funiculi (LF) and dorsal columns (DCs) and then correlated with histopathology. Cross-sectional area measurements revealed significant atrophy (32% reduction) of the injured spinal cord at the lesion epicentre in the chronic phase of injury. Analysis of diffusion tensor parameters further showed that tissue integrity was most severely affected in the DCs, i.e. the site of immediate impact, which demonstrated a rapid and permanent decrease in FA and λ || . In contrast, DTI parameters for the ventrolateral white matter changed more gradually with time, suggesting that these regions are undergoing more delayed degeneration in a manner that may be amenable to therapeutic intervention. Of all the DTI parameters, λ ⊥ was most closely correlated to myelin content whereas changes in FA and λ || appeared more indicative of axonal integrity, Wallerian degeneration and associated presence of macrophages. We conclude that longitudinal DTI at 16.4 T provides a clinically relevant, objective measure for assessing white matter pathology following contusive SCI in mice that may aid the translation of putative neuroprotective strategies into the clinic.

NeuroImage, 2012

• We present a methodology for systematic delineation of the C57BL/6J mouse cerebellum in MRI. • ... more • We present a methodology for systematic delineation of the C57BL/6J mouse cerebellum in MRI. • We have successfully delineated 38 cerebellar and cerebellar-related structures.

Magnetic Resonance in Medicine, 2012

Diffusion tensor microimaging with 40 µm isotropic voxels at 16.4 T was used to investigate compa... more Diffusion tensor microimaging with 40 µm isotropic voxels at 16.4 T was used to investigate compartmentation of water diffusion and biexponential diffusion decay in formalin fixed prostate tissue. Tissue samples (~28 mm 3 ) were similar in volume to a typical prostate DWI voxel in vivo and were imaged with ~400,000 voxels. The bulk mean diffusivity ('ADC') of epithelial, stromal, and ductal/acinal compartments was estimated by two methods: manual region of interest (ROI) selection; and Gaussian fitting of whole sample voxel diffusivity histograms.

Magnetic Resonance in Medicine, 2012

Diffusion tensor microimaging at 16.4 T with 40 mm isotropic voxels was used to investigate aniso... more Diffusion tensor microimaging at 16.4 T with 40 mm isotropic voxels was used to investigate anisotropic water diffusion in prostate tissue at spatial resolution approaching the cellular scale. Nine normal glandular tissue samples were collected from the peripheral zone of six formalin fixed radical prostatectomy specimens. Fibromuscular stromal tissue exhibited microscopic diffusion anisotropy (mean fractional anisotropy range 0.47-0.66) significantly higher (P < 0.01, Student's t-test) than in epithelium-containing voxels (mean fractional anisotropy range 0.31-0.54) in six of the seven normal tissue samples in which both compartments could be measured. Fiber tracking demonstrated principle stromal fiber directions consistent with myocyte orientation seen on light microscopy of the same sample. Diffusion tensor microimaging may be valuable for investigation of variable results from attempts to measure diffusion anisotropy in the prostate in vivo. Magn Reson Med 000:000-000, 2012. V C 2012 Wiley Periodicals, Inc.

Journal of Neurotrauma, 2013

Blocking the action of inhibitory molecules at sites of central nervous system injury has been pr... more Blocking the action of inhibitory molecules at sites of central nervous system injury has been proposed as a strategy to promote axonal regeneration and functional recovery. We have previously shown that genetic deletion or competitive antagonism of EphA4 receptor activity promotes axonal regeneration and functional recovery in a mouse model of lateral hemisection spinal cord injury. Here we have assessed the effect of blocking EphA4 activation using the competitive antagonist EphA4-Fc in a rat model of thoracic contusive spinal cord injury. Using a ledged tapered balance beam and open-field testing, we observed significant improvements in recovery of locomotor function after EphA4-Fc treatment. Consistent with functional improvement, using high-resolution ex vivo magnetic resonance imaging at 16.4T, we found that rats treated with EphA4-Fc had a significantly increased cross-sectional area of the dorsal funiculus caudal to the injury epicenter compared with controls. Our findings indicate that EphA4-Fc promotes functional recovery following contusive spinal cord injury and provides further support for the therapeutic benefit of treatment with the competitive antagonist in acute cases of spinal cord injury.

Brain Structure and Function, 2014

The complex pathogenesis of temporal lobe epilepsy includes neuronal and glial pathology, synapti... more The complex pathogenesis of temporal lobe epilepsy includes neuronal and glial pathology, synaptic reorganization, and an immune response. However, the spatio-temporal pattern of structural changes in the brain that provide a substrate for seizure generation and modulate the seizure phenotype is yet to be completely elucidated. We used quantitative magnetic resonance imaging (MRI) to study structural changes triggered by status epilepticus (SE) and their association with epileptogenesis and with activation of complement component 3 (C3). SE was induced by injection of pilocarpine in CD1 mice. Quantitative diffusion-weighted imaging and T2 relaxometry was performed using a 16.4-Tesla MRI scanner at 3 h and 1, 2, 7, 14, 28, 35, and 49 days post-SE. Following longitudinal MRI examinations, spontaneous recurrent seizures and interictal spikes were quantified using continuous video-EEG monitoring. Immunohistochemical analysis of C3 expression was performed at 48 h, 7 days, and 4 months post-SE. MRI changes were dynamic, reflecting different outcomes in relation to the development of epilepsy. Apparent diffusion coefficient changes in the hippocampus at 7 days post-SE correlated with the severity of the evolving epilepsy. C3 activation was found in all stages of epileptogenesis within the areas with significant MRI changes and correlated with the severity of epileptic condition.