Showing papers by "David C. Reutens published in 2018"

The 2018 correlative microscopy techniques roadmap.

Abstract: Developments in microscopy have been instrumental to progress in the life sciences, and many new techniques have been introduced and led to new discoveries throughout the last century. A wide and diverse range of methodologies is now available, including electron microscopy, atomic force microscopy, magnetic resonance imaging, small-angle x-ray scattering and multiple super-resolution fluorescence techniques, and each of these methods provides valuable read-outs to meet the demands set by the samples under study. Yet, the investigation of cell development requires a multi-parametric approach to address both the structure and spatio-temporal organization of organelles, and also the transduction of chemical signals and forces involved in cell-cell interactions. Although the microscopy technologies for observing each of these characteristics are well developed, none of them can offer read-out of all characteristics simultaneously, which limits the information content of a measurement. For example, while electron microscopy is able to disclose the structural layout of cells and the macromolecular arrangement of proteins, it cannot directly follow dynamics in living cells. The latter can be achieved with fluorescence microscopy which, however, requires labelling and lacks spatial resolution. A remedy is to combine and correlate different readouts from the same specimen, which opens new avenues to understand structure-function relations in biomedical research. At the same time, such correlative approaches pose new challenges concerning sample preparation, instrument stability, region of interest retrieval, and data analysis. Because the field of correlative microscopy is relatively young, the capabilities of the various approaches have yet to be fully explored, and uncertainties remain when considering the best choice of strategy and workflow for the correlative experiment. With this in mind, the Journal of Physics D: Applied Physics presents a special roadmap on the correlative microscopy techniques, giving a comprehensive overview from various leading scientists in this field, via a collection of multiple short viewpoints.

Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning.

Abstract: The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance.

Presurgical language fMRI: Technical practices in epilepsy surgical planning.

Abstract: Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, image acquisition, analysis and interpretation, and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4, or 5 tasks with a modal run duration of 5 min. Variants of over 15 protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols was used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, and brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.

The challenge of bias-free coil combination for quantitative susceptibility mapping at ultra-high field.

Abstract: Purpose Quantitative susceptibility mapping is a technique to estimate the magnetic property of tissue with particularly high sensitivity at ultra-high field. However, a key challenge at ultra-high field is the combination of phase data acquired using phased array receive coils. Several methods for combining phase data have been proposed, but the influence of coil combination choices on susceptibility quantitation has not been studied systematically. Methods We combined phase data using COMPOSER (COMbining Phase data using a Short Echo-time Reference scan) and a reference-free channel-by-channel method. We investigated the effect of the chosen combination method on susceptibility results in a group of 28 participants at 7 Tesla. Results Our results show that reference scans can bias susceptibility values. Although the proposed reference-free channel-by-channel method cannot remove transmit field phase, it shows comparable results to the COMPOSER method in which a high-resolution ultrashort echo-time reference scan was used. Conclusions We conclude that ultrashort echo-time reference scans reduce quantitation bias and remove the transmit field phase when using COMPOSER to combine phase data, and not combining the phase data before susceptibility processing avoids this bias, resulting in comparable results. Magn Reson Med 79:97–107, 2018. © 2017 InternationalSociety for Magnetic Resonance in Medicine.

Utility of gradient recalled echo magnetic resonance imaging for the study of myelination in cuprizone mice treated with fingolimod.

Abstract: The availability of high-field-strength magnetic resonance imaging (MRI) systems has brought about the development of techniques that aim to map myelination via the exploitation of various contrast mechanisms. Myelin mapping techniques have the potential to provide tools for the diagnosis and treatment of diseases, such as multiple sclerosis. In this study, we evaluated the sensitivity of T2 *, frequency shift and susceptibility measures to myelin levels in a cuprizone mouse model of demyelination. The model was supplemented with two different dosages of fingolimod, a drug known to positively affect demyelination. A decrease in grey-white matter contrast with the cuprizone diet was observed for T2 *, frequency shift and susceptibility measures, together with myelin basic protein antibody findings. These results indicate that T2 *, frequency shift and susceptibility measures have the potential to act as biomarkers for myelination. Susceptibility was found to be the most sensitive measure to changes in grey-white matter contrast. In addition, fingolimod treatment was found to reduce the level of demyelination, with a larger dosage exhibiting a greater reduction in demyelination for the in vivo MRI results. Overall, susceptibility mapping appears to be a more promising tool than T2 * or frequency shift mapping for the early diagnosis and treatment of diseases in which myelination is implicated.

Memory dysfunction in school-aged children exposed prenatally to antiepileptic drugs.

Abstract: Prenatal exposure to antiepileptic drugs (AEDs) and in particular valproate (VPA) has been shown to impair intellectual and language development in children, but the impact on memory functioning has not been thoroughly investigated. This study aimed to evaluate memory skills in school-age children who were exposed to AEDs prenatally. The sample comprised of 105 children aged 6 to 8 years. Information on AED exposure, maternal epilepsy, pregnancy, and medical history was prospectively obtained. Children completed a neuropsychological assessment including measures of verbal and nonverbal memory. Children exposed to VPA performed lower than expected on list learning, story recall, and figure recall tasks. Those exposed to VPA in a polytherapy regime achieved poorer verbal memory scores compared with other drug exposure groups. VPA dose was negatively correlated with both verbal and nonverbal memory measures. Language ability predicted performance on all verbal memory measures and VPA dose was an additional predictor of retroactive interference on the list learning task. Performance on figure recall was predicted by exposure to VPA in polytherapy. Children exposed to carbamazepine (CBZ) also showed a higher rate of impairment on nonverbal memory measures. Both verbal and nonverbal memory skills are at risk in children exposed prenatally to VPA, particularly in those exposed to higher VPA doses. There may also be a selective vulnerability of the medial temporal lobe to VPA exposure. Our data highlight the possibility that nonverbal memory may also be affected in children exposed to CBZ. These findings have significant implications for the provision of cognitive and educational strategies to children exposed to AEDs in utero. (PsycINFO Database Record

Whole-Volume Clustering of Time Series Data from Zebrafish Brain Calcium Images via Mixture Modeling.

Abstract: Calcium is a ubiquitous messenger in neural signaling events. An increasing number of techniques are enabling visualization of neurological activity in animal models via luminescent proteins that bind to calcium ions. These techniques generate large volumes of spatially correlated time series. A model-based functional data analysis methodology via Gaussian mixtures is suggested for the clustering of data from such visualizations is proposed. The methodology is theoretically justified and a computationally efficient approach to estimation is suggested. An example analysis of a zebrafish imaging experiment is presented.

Building a high-resolution in vivo minimum deformation average model of the human hippocampus

Abstract: Objective: Minimum deformation averaging (MDA) procedures exploit the information contained in inter-individual variations to generate high-resolution, high-contrast models through iterative model building. However, MDA models built from different image contrasts reside in disparate spaces and their complementary information cannot be utilized easily. The aim of this work was to develop an algorithm for the non-linear alignment of two MDA models with different contrasts to create a high-resolution in vivo model of the human hippocampus with a spatial resolution of 300 μm. Methods: A Turbo Spin Echo MDA model covering the hippocampus was contrast matched to a whole-brain MP2RAGE MDA model and aligned using cross-correlation and non-linear transformation. The contrast matching algorithm followed a global voxel location-based approach to estimate the relationship between intensity values of the two models. The performance of the algorithm was evaluated by comparing it to a non-linear registration obtained using mutual information without contrast matching. The complimentary information from both contrasts was then utilized in an automated hippocampal subfield segmentation pipeline. Results: The contrast of the Turbo Spin Echo MDA model could successfully be matched to the MP2RAGE MDA model. Registration using cross correlation provided more accurate alignment of the models compared to a mutual information based approach. The segmentation using ASHS resulted in hippocampal subfield delineations that resembled the tissue boundaries observed in the Turbo Spin Echo MDA model. Conclusion: The developed contrast matching algorithm facilitated the creation of a high-resolution multi-modal in vivo MDA model of the human hippocampus. This model can be used to improve algorithms for hippocampal subfield segmentation and could potentially support the early detection of neurodegenerative diseases.

Postural change in convulsive seizures: a retrospective review of video-electroencephalographic recordings.

Abstract: Objectives Prone position has been identified as an important risk factor for Sudden Unexpected Death in Epilepsy (SUDEP) raising the possibility of avoidance of this posture in sleep as a preventative measure. To evaluate the potential utility of such postural measures, we studied patterns of postural change during generalised tonic clonic seizures (GTCSs). Methods Video electroencephalographic (video-EEG) recordings for patients undergoing investigations at the Royal Brisbane and Women's Hospital between 2005 and 2013 were reviewed independently by two raters. Head and truncal positions (left and right lateral, supine, sitting, prone) at seizure onset and offset, before and after nurse interventions were recorded. Post-ictal postural changes and evidence of stertorous respirations were also recorded. Results Thirty-one seizures from 27 patients were included in the study. One seizure began with the patient asleep in the prone position. One patient became prone during a seizure, having previously been asleep in the left lateral position. Nine patients changed position during a seizure. Seven of these patients were sitting or in a lateral position at the time of seizure onset, two patients were supine at seizure onset. No patient rolled by more than 90 degrees during a seizure. Post-ictal stertorous respirations were observed in 14 patients, one of whom was prone. Conclusion The incidence of patients attaining a prone position during a seizure was low. Given that no patient rolled more than 90 degrees, patients are least likely to attain a prone position if they are supine at the beginning of a seizure.

Presurgical language fMRI: Current technical practices in epilepsy surgical planning

Abstract: Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, imaging acquisition, analysis and interpretation and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4 or 5 tasks with a modal run duration of five minutes. Variants of over fifteen protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols were used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.

Comparison of biodistribution following subcutaneous and intravenous administration of a novel Zirconium-89 labelled anti-CD20 antibody using imaging

Abstract: Objective: To investigate subcutaneous administration of a novel Zirconium-89 ( 89 Zr) labeled anti-CD20 antibody, and to compare imaging and biodistribution data with that of intravenous administration in control mice. Background: Anti-CD20 therapies have shown clinical efficacy in multiple sclerosis by acting on lymph node resident B-cells which are, for example, antigen-presenting cells that facilitate autoimmune activation. Design/Methods: Biodistribution of 89 Zr-labeled anti-CD20 antibody was examined in healthy mice, following either intravenous tail vein injection or subcutaneous right lower flank injection. Biodistribution was assessed using positron emission tomography/computed tomography (PET-CT) and gamma counting of excised organs at early (4–24 hours) and later (72 hours through to 7–10 days) time points. Results: PET-CT data demonstrated that the proportion of 89 Zr-anti-CD20 antibody remaining in the whole body at 7 days following intravenous injection (63±5%) is comparable to the proportion remaining following subcutaneous injection (55±4%). In gamma counting experiments at early time points following intravenous injection, highest levels of 89 Zr-anti-CD20 antibody were found in the circulation and in highly perfused organs, while following subcutaneous injection, highest levels were found in inguinal lymph nodes and circulating blood. Lymph node accumulation showed a peak uptake at 72 hours with >11% ID/g (injected dose per gram) after intravenous injection and >47% ID/g following subcutaneous injection. Levels of 89 Zr-anti-CD20 antibody in liver were 10.2% ID/g after intravenous and 19.9% ID/g after subcutaneous injection compared to spleen (intravenous: 28.8%; subcutaneous: 21.3%) and lymph nodes (intravenous: 8.3%; subcutaneous: 26.8%) at 7 days post injection. Conclusions: The route of administration affects the distribution of 89 Zr-anti-CD20 antibody. Subcutaneous administration of 89 Zr-anti-CD20 antibody results in effective absorption from the injection site and subsequent distribution preferentially to lymph nodes and to a lesser extent to the spleen as compared to the distribution following intravenous injection. Study Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Migotto has received research support from This research is funded through a collaborative research agreement between the University of Queensland and Novartis Pharma AG. Dr. Bhalla has received research support from This study was supported by: Novartis pharma AG, Basel, Switzerland. Dr. Mardon has received research support from This study was supported by: Novartis pharma AG, Basel, Switzerland. Dr. Orian has received personal compensation in an editorial capacity for Associate Editor — Emerging and Evolving Topics in Multiple Sclerosis Pathogenesis and Treatments. Current Topics in Behavioral Neurosciences, Vol 26, Springer De. Dr. Orian has received research support from Novartis. Dr. Weckbecker has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Kneuer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis. Dr. Reutens has received research support from Research support from Novartis, BGI, Innate.

Optimal-margin evolutionary classifier.

Abstract: We introduce a novel approach for discriminative classification using evolutionary algorithms. We first propose an algorithm to optimize the total loss value using a modified 0-1 loss function in a one-dimensional space for classification. We then extend this algorithm for multi-dimensional classification using an evolutionary algorithm. The proposed evolutionary algorithm aims to find a hyperplane which best classifies instances while minimizes the classification risk. We test particle swarm optimization, evolutionary strategy, and covariance matrix adaptation evolutionary strategy for optimization purpose. Finally, we compare our results with well-established and state-of-the-art classification algorithms, for both binary and multi-class classification, on 19 benchmark classification problems, with and without noise and outliers. Results show that the performance of the proposed algorithm is significantly (t-test) better than all other methods in almost all problems tested. We also show that the proposed algorithm is significantly more robust against noise and outliers comparing to other methods. The running time of the algorithm is within a reasonable range for the solution of real-world classification problems.

Monopole Antenna Array with Individual Shields for Ultra High Field Magnetic Resonance Imaging

Abstract: Magnetic resonance imaging (MRI) requires the use of radio frequency (RF) coils for transmission and signal reception. In ultra-high field MRI, i.e., operating at 298 MHz and above, the design and development of RF coils becomes challenging due to a relatively short wavelength, inhomogeneity in the transmit RF field, and interference and coupling between coil elements. Designs which can overcome existing limitations can potentially lead to an improvement in magnetic resonance image quality, due to a stronger and more homogeneous signal across the image. We investigated the potential utility of a shielded monopole antenna array tuned to 298 MHz for 7 T MRI head imaging. We aimed to develop a 298 MHz monopole antenna array with four monopole elements. We considered a number of different shielding arrangements, included single and three sided designs. Using COMSOL simulations, we examined how mutual decoupling can be minimised whilst maximising array sensitivity and RF field homogeneity. We fabricated an unshielded and a shielded prototype four element monopole array and performed bench testing to validate simulation findings and also to empirically evaluate frequency of operation, shielding performance and array sensitivity. The use of shielding monopole array elements was able to improve field homogeneity. Without the use of shielding as much as 10.75% increase in field variability was observed when the field-of-view extended across the entire brain, however when monopole elements were shielded the increase in variation reduced to 0.86%. Shielding also improved the decoupling between individual monopole array elements (−11.72 dB versus −22.38 dB). Field intensity increased on average by 33.77% using the optimised three sided shields on each monopole. Based on our findings, appropriately shielded monopole antenna arrays can potentially produce RF coil sensitivity and field uniformity above the benchmark required for ultra-high field MRI applications. Such arrays may find use in head imaging applications, wherein RF coil insensitivity and field inhomogeneity hinder image interpretation.