Mortality and histopathology in sheepshead minnow (Cyprinodon variegatus) larvae exposed to pectenotoxin-2 and Dinophysis acuminata.

Toxic species of the dinoflagellate genus Dinophysis can produce diarrheic toxins including okadaic acid (OA) and dinophysistoxins (DTXs), and the non-diarrheic pectenotoxins (PTXs). Okadaic acid and DTXs cause diarrheic shellfish poisoning (DSP) in human consumers, and also cause cytotoxic, immunotoxic and genotoxic effects in a variety of mollusks and fishes at different life stages in vitro. The possible effects of co-produced PTXs or live cells of Dinophysis to aquatic organisms, however, are less understood. Effects on an early life stage of sheepshead minnow (Cyprinodon variegatus), a common finfish in eastern USA estuaries, were evaluated using a 96-h toxicity bioassay. Three-week old larvae were exposed to PTX2 concentrations from 50 to 4000 nM, live Dinophysis acuminata culture (strain DAVA01), live cells resuspended in clean medium or culture filtrate. This D. acuminata strain produced mainly intracellular PTX2 (≈ 21 pg cell-1), with much lower levels of OA and dinophysistoxin-1. No mortality or gill damages were observed in larvae exposed to D. acuminata (from 5 to 5500 cells mL-1), resuspended cells and culture filtrate. However, exposure to purified PTX2 at intermediate to high concentrations (from 250 to 4000 nM) resulted in 8 to 100% mortality after 96 h (24-h LC50 of 1231 nM). Histopathology and transmission electron microscopy of fish exposed to intermediate to high PTX2 concentrations revealed important gill damage, including intercellular edema, necrosis and sloughing of gill respiratory epithelia, and damage to the osmoregulatory epithelium, including hypertrophy, proliferation, redistribution and necrosis of chloride cells. Tissue damage in gills is likely caused by the interaction of PTX2 with the actin cytoskeleton of the affected gill epithelia. Overall, the severe gill pathology observed following the PTX2 exposure suggested death was due to loss of respiratory and osmoregulatory functions in C. variegatus larvae.

Optimal electrode diameter in relation to volume of the cochlea.

The volume of the cochlea is a key parameter for electrode-array design. Indeed, it constrains the diameter of the electrode-array for low-traumatic positioning in the scala timpani. The present report shows a model of scala timpani volume extraction from temporal bones images in order to estimate a maximum diameter of an electrode-array. Nine temporal bones were used, and passed to high-resolution computed tomography scan. Using image-processing techniques, scala timpani were extracted from images, and cross-section areas were estimated along cochlear turns. Cochlear implant electrode-array was fitted in these cross-sections. Results show that the electrode-array diameter is small enough to fit in the scala timpani, however the diameter is restricted at the apical part.

Medical Imaging Informatics: Towards a Personalized Computational Patient.

Medical Imaging Informatics has become a fast evolving discipline at the crossing of Informatics, Computational Sciences, and Medicine that is profoundly changing medical practices, for the patients' benefit.

Regional flux analysis for discovering and quantifying anatomical changes: An application to the brain morphometry in Alzheimer's disease.

In this study we introduce the regional flux analysis, a novel approach to deformation based morphometry based on the Helmholtz decomposition of deformations parameterized by stationary velocity fields. We use the scalar pressure map associated to the irrotational component of the deformation to discover the critical regions of volume change. These regions are used to consistently quantify the associated measure of volume change by the probabilistic integration of the flux of the longitudinal deformations across the boundaries. The presented framework unifies voxel-based and regional approaches, and robustly describes the volume changes at both group-wise and subject-specific level as a spatial process governed by consistently defined regions. Our experiments on the large cohorts of the ADNI dataset show that the regional flux analysis is a powerful and flexible instrument for the study of Alzheimer's disease in a wide range of scenarios: cross-sectional deformation based morphometry, longitudinal discovery and quantification of group-wise volume changes, and statistically powered and robust quantification of hippocampal and ventricular atrophy.

Expert-validated CSF segmentation of MNI atlas enhances accuracy of virtual glioma growth patterns.

Biomathematical modeling of glioma growth has been developed to optimize treatments delivery and to evaluate their efficacy. Simulations currently make use of anatomical knowledge from standard MRI atlases. For example, cerebrospinal fluid (CSF) spaces are obtained by automatic thresholding of the MNI atlas, leading to an approximate representation of real anatomy. To correct such inaccuracies, an expert-revised CSF segmentation map of the MNI atlas was built. Several virtual glioma growth patterns of different locations were generated, with and without using the expert-revised version of the MNI atlas. The adequacy between virtual and radiologically observed growth patterns was clearly higher when simulations were based on the expert-revised atlas. This work emphasizes the need for close collaboration between clinicians and researchers in the field of brain tumor modeling.

Toward a comprehensive framework for the spatiotemporal statistical analysis of longitudinal shape data.

This paper proposes an original approach for the statistical analysis of longitudinal shape data. The proposed method allows the characterization of typical growth patterns and subject-specific shape changes in repeated time-series observations of several subjects. This can be seen as the extension of usual longitudinal statistics of scalar measurements to high-dimensional shape or image data. The method is based on the estimation of continuous subject-specific growth trajectories and the comparison of such temporal shape changes across subjects. Differences between growth trajectories are decomposed into morphological deformations, which account for shape changes independent of the time, and time warps, which account for different rates of shape changes over time. Given a longitudinal shape data set, we estimate a mean growth scenario representative of the population, and the variations of this scenario both in terms of shape changes and in terms of change in growth speed. Then, intrinsic statistics are derived in the space of spatiotemporal deformations, which characterize the typical variations in shape and in growth speed within the studied population. They can be used to detect systematic developmental delays across subjects. In the context of neuroscience, we apply this method to analyze the differences in the growth of the hippocampus in children diagnosed with autism, developmental delays and in controls. Result suggest that group differences may be better characterized by a different speed of maturation rather than shape differences at a given age. In the context of anthropology, we assess the differences in the typical growth of the endocranium between chimpanzees and bonobos. We take advantage of this study to show the robustness of the method with respect to change of parameters and perturbation of the age estimates.

LCC-Demons: a robust and accurate symmetric diffeomorphic registration algorithm.

Non-linear registration is a key instrument for computational anatomy to study the morphology of organs and tissues. However, in order to be an effective instrument for the clinical practice, registration algorithms must be computationally efficient, accurate and most importantly robust to the multiple biases affecting medical images. In this work we propose a fast and robust registration framework based on the log-Demons diffeomorphic registration algorithm. The transformation is parameterized by stationary velocity fields (SVFs), and the similarity metric implements a symmetric local correlation coefficient (LCC). Moreover, we show how the SVF setting provides a stable and consistent numerical scheme for the computation of the Jacobian determinant and the flux of the deformation across the boundaries of a given region. Thus, it provides a robust evaluation of spatial changes. We tested the LCC-Demons in the inter-subject registration setting, by comparing with state-of-the-art registration algorithms on public available datasets, and in the intra-subject longitudinal registration problem, for the statistically powered measurements of the longitudinal atrophy in Alzheimer's disease. Experimental results show that LCC-Demons is a generic, flexible, efficient and robust algorithm for the accurate non-linear registration of images, which can find several applications in the field of medical imaging. Without any additional optimization, it solves equally well intra & inter-subject registration problems, and compares favorably to state-of-the-art methods.

Personalization of a cardiac electromechanical model using reduced order unscented Kalman filtering from regional volumes.

Patient-specific cardiac modeling can help in understanding pathophysiology and therapy planning. However it requires to combine functional and anatomical data in order to build accurate models and to personalize the model geometry, kinematics, electrophysiology and mechanics. Personalizing the electromechanical coupling from medical images is a challenging task. We use the Bestel-Clément-Sorine (BCS) electromechanical model of the heart, which provides reasonable accuracy with a reasonable number of parameters (14 for each ventricle) compared to the available clinical data at the organ level. We propose a personalization strategy from cine MRI data in two steps. We first estimate global parameters with an automatic calibration algorithm based on the Unscented Transform which allows to initialize the parameters while matching the volume and pressure curves. In a second step we locally personalize the contractilities of all AHA (American Heart Association) zones of the left ventricle using the reduced order unscented Kalman filtering on Regional Volumes. This personalization strategy was validated synthetically and tested successfully on eight healthy and three pathological cases.

Preliminary specificity study of the Bestel-Clément-Sorine electromechanical model of the heart using parameter calibration from medical images.

Patient-specific cardiac modelling can help in understanding pathophysiology and predict therapy effects. This requires the personalization of the geometry, kinematics, electrophysiology and mechanics. We use the Bestel-Clément-Sorine (BCS) electromechanical model of the heart, which provides reasonable accuracy with a reduced parameter number compared to the available clinical data at the organ level. We propose a preliminary specificity study to determine the relevant global parameters able to differentiate the pathological cases from the healthy controls. To this end, a calibration algorithm on global measurements is developed. This calibration method was tested successfully on 6 volunteers and 2 heart failure cases and enabled to tune up to 7 out of the 14 necessary parameters of the BCS model, from the volume and pressure curves. This specificity study confirmed domain-knowledge that the relaxation rate is impaired in post-myocardial infarction heart failure and the myocardial stiffness is increased in dilated cardiomyopathy heart failures.

Understanding the mechanisms amenable to CRT response: from pre-operative multimodal image data to patient-specific computational models.

This manuscript describes our recent developments towards better understanding of the mechanisms amenable to cardiac resynchronization therapy response. We report the results from a full multimodal dataset corresponding to eight patients from the euHeart project. The datasets include echocardiography, MRI and electrophysiological studies. We investigate two aspects. The first one focuses on pre-operative multimodal image data. From 2D echocardiography and 3D tagged MRI images, we compute atlas based dyssynchrony indices. We complement these indices with presence and extent of scar tissue and correlate them with CRT response. The second one focuses on computational models. We use pre-operative imaging to generate a patient-specific computational model. We show results of a fully automatic personalized electromechanical simulation. By case-per-case discussion of the results, we highlight the potential and key issues of this multimodal pipeline for the understanding of the mechanisms of CRT response and a better patient selection.

Patient-specific electromechanical models of the heart for the prediction of pacing acute effects in CRT: a preliminary clinical validation.

Cardiac resynchronisation therapy (CRT) is an effective treatment for patients with congestive heart failure and a wide QRS complex. However, up to 30% of patients are non-responders to therapy in terms of exercise capacity or left ventricular reverse remodelling. A number of controversies still remain surrounding patient selection, targeted lead implantation and optimisation of this important treatment. The development of biophysical models to predict the response to CRT represents a potential strategy to address these issues. In this article, we present how the personalisation of an electromechanical model of the myocardium can predict the acute haemodynamic changes associated with CRT. In order to introduce such an approach as a clinical application, we needed to design models that can be individualised from images and electrophysiological mapping of the left ventricle. In this paper the personalisation of the anatomy, the electrophysiology, the kinematics and the mechanics are described. The acute effects of pacing on pressure development were predicted with the in silico model for several pacing conditions on two patients, achieving good agreement with invasive haemodynamic measurements: the mean error on dP/dt(max) is 47.5±35mmHgs(-1), less than 5% error. These promising results demonstrate the potential of physiological models personalised from images and electrophysiology signals to improve patient selection and plan CRT.

A statistical model for quantification and prediction of cardiac remodelling: application to tetralogy of Fallot.

Cardiac remodelling plays a crucial role in heart diseases. Analyzing how the heart grows and remodels over time can provide precious insights into pathological mechanisms, eventually resulting in quantitative metrics for disease evaluation and therapy planning. This study aims to quantify the regional impacts of valve regurgitation and heart growth upon the end-diastolic right ventricle (RV) in patients with tetralogy of Fallot, a severe congenital heart defect. The ultimate goal is to determine, among clinical variables, predictors for the RV shape from which a statistical model that predicts RV remodelling is built. Our approach relies on a forward model based on currents and a diffeomorphic surface registration algorithm to estimate an unbiased template. Local effects of RV regurgitation upon the RV shape were assessed with Principal Component Analysis (PCA) and cross-sectional multivariate design. A generative 3-D model of RV growth was then estimated using partial least squares (PLS) and canonical correlation analysis (CCA). Applied on a retrospective population of 49 patients, cross-effects between growth and pathology could be identified. Qualitatively, the statistical findings were found realistic by cardiologists. 10-fold cross-validation demonstrated a promising generalization and stability of the growth model. Compared to PCA regression, PLS was more compact, more precise and provided better predictions.

Inter-model consistency and complementarity: learning from ex-vivo imaging and electrophysiological data towards an integrated understanding of cardiac physiology.

Computational models of the heart at various scales and levels of complexity have been independently developed, parameterised and validated using a wide range of experimental data for over four decades. However, despite remarkable progress, the lack of coordinated efforts to compare and combine these computational models has limited their impact on the numerous open questions in cardiac physiology. To address this issue, a comprehensive dataset has previously been made available to the community that contains the cardiac anatomy and fibre orientations from magnetic resonance imaging as well as epicardial transmembrane potentials from optical mapping measured on a perfused ex-vivo porcine heart. This data was used to develop and customize four models of cardiac electrophysiology with different level of details, including a personalized fast conduction Purkinje system, a maximum a posteriori estimation of the 3D distribution of transmembrane potential, the personalization of a simplified reaction-diffusion model, and a detailed biophysical model with generic conduction parameters. This study proposes the integration of these four models into a single modelling and simulation pipeline, after analyzing their common features and discrepancies. The proposed integrated pipeline demonstrates an increase prediction power of depolarization isochrones in different pacing conditions.

Coupled personalisation of electrophysiology models for simulation of induced ischemic ventricular tachycardia.

Despite recent efforts in cardiac electrophysiology modelling, there is still a strong need to make macroscopic models usable in planning and assistance of the clinical procedures. This requires model personalisation i.e. estimation of patient-specific model parameters and computations compatible with clinical constraints. Fast macroscopic models allow a quick estimation of the tissue conductivity, but are often unreliable in prediction of arrhythmias. On the other side, complex biophysical models are quite expensive for the tissue conductivity estimation, but are well suited for arrhythmia predictions. Here we present a coupled personalisation framework, which combines the benefits of the two models. A fast Eikonal (EK) model is used to estimate the conductivity parameters, which are then used to set the parameters of a biophysical model, the Mitchell-Schaeffer (MS) model. Additional parameters related to Action Potential Duration (APD) and APD restitution curves for the tissue are estimated for the MS model. This framework is applied to a clinical dataset provided with an hybrid X-Ray/MR imaging on an ischemic patient. This personalised MS Model is then used for in silico simulation of clinical Ventricular Tachycardia (VT) stimulation protocol to predict the induction of VT. This proof of concept opens up possibilities of using VT induction modelling directly in the intervention room, in order to plan the radio-frequency ablation lines.

LogDemons revisited: consistent regularisation and incompressibility constraint for soft tissue tracking in medical images.

Non-linear image registration is a standard approach to track soft tissues in medical images. By estimating spatial transformations between images, visible structures can be followed over time. For clinical applications the model of transformation must be consistent with the properties of the biological tissue, such as incompressibility. LogDemons is a fast non-linear registration algorithm that provides diffusion-like diffeomorphic transformations parameterised by stationary velocity fields. Yet, its use for tissue tracking has been limited because of the ad-hoc Gaussian regularisation that prevents implementing other transformation models. In this paper, we propose a mathematical formulation of demons regularisation that fits into LogDemons framework. This formulation enables to ensure volume-preserving deformations by minimising the energy functional directly under the linear divergence-free constraint, yielding little computational overhead. Tests on synthetic incompressible fields showed that our approach outperforms the original logDemons in terms of incompressible deformation recovery. The algorithm showed promising results on one patient for the automatic recovery of myocardium strain from cardiac anatomical and 3D tagged MRI.

Combined diffusion imaging and MR spectroscopy in the diagnosis of human prion diseases.

BACKGROUND AND PURPOSE: The physiopathologic bases underlying the signal intensity changes and reduced diffusibility observed in prion diseases (TSEs) are still poorly understood. We evaluated the interest of MRS combined with DWI both as a diagnostic tool and a way to understand the mechanism underlying signal intensity and ADC changes in this setting. MATERIALS AND METHODS: We designed a prospective study of multimodal MR imaging in patients with suspected TSEs. Forty-five patients with a suspicion of TSE and 11 age-matched healthy volunteers were included. The MR imaging protocol included T1, FLAIR, and DWI sequences. MRS was performed on the cerebellum, pulvinar, right lenticular nucleus, and frontal cortex. MR images were assessed visually, and ADC values were calculated. RESULTS: Among the 45 suspected cases, 31 fulfilled the criteria for probable or definite TSEs (19 sCJDs, 3 iCJDs, 2 vCJDs, and 7 genetic TSEs); and 14 were classified as AltDs. High signals in the cortex and/or basal ganglia were observed in 26/31 patients with TSEs on FLAIR and 29/31 patients on DWI. In the basal ganglia, high DWI signals corresponded to a decreased ADC. Metabolic alterations, increased mIns, and decreased NAA were observed in all patients with TSEs. ADC values and metabolic changes were not correlated; this finding suggests that neuronal stress (vacuolization), neuronal loss, and astrogliosis do not alone explain the decrease of ADC. CONCLUSIONS: MRS combined with other MR imaging is of interest in the diagnosis of TSE and provides useful information for understanding physiopathologic processes underlying prion diseases.

Computation of a probabilistic statistical shape model in a maximum-a-posteriori framework.

OBJECTIVES: When analyzing shapes and shape variabilities, the first step is bringing those shapes into correspondence. This is a fundamental problem even when solved by manually determining exact correspondences such as landmarks. We developed a method to represent a mean shape and a variability model for a training data set based on probabilistic correspondence computed between the observations. METHODS: First, the observations are matched on each other with an affine transformation found by the Expectation-Maximization Iterative-Closest-Points (EM-ICP) registration. We then propose a maximum-a-posteriori (MAP) framework in order to compute the statistical shape model (SSM) parameters which result in an optimal adaptation of the model to the observations. The optimization of the MAP explanation is realized with respect to the observation parameters and the generative model parameters in a global criterion and leads to very efficient and closed-form solutions for (almost) all parameters. RESULTS: We compared our probabilistic SSM to a SSM based on one-to-one correspondences and the PCA (classical SSM). Experiments on synthetic data served to test the performances on non-convex shapes (15 training shapes) which have proved difficult in terms of proper correspondence determination. We then computed the SSMs for real putamen data (21 training shapes). The evaluation was done by measuring the generalization ability as well as the specificity of both SSMs and showed that especially shape detail differences are better modeled by the probabilistic SSM (Hausdorff distance in generalization ability Re approximately 25% smaller). CONCLUSIONS: The experimental outcome shows the efficiency and advantages of the new approach as the probabilistic SSM performs better in modeling shape details and differences.

An augmented reality system for liver thermal ablation: design and evaluation on clinical cases.

We present in this paper an augmented reality guidance system for liver thermal ablation in interventional radiology. To show the relevance of our methodology, the system is incrementally evaluated on an abdominal phantom and then on patients in the operating room. The system registers in a common coordinate system a preoperative image of the patient and the position of the needle that the practitioner manipulates. The breathing motion uncertainty is taken into account with a respiratory gating technique: the preoperative image and the guidance step are synchronized on expiratory phases. In order to fulfil the real-time constraints, we have developed and validated algorithms that automatically process and extract feature points. Since the guidance interface is also a major component of the system effectiveness, we validate the overall targeting accuracy on an abdominal phantom. This experiment showed that a practitioner can reach a predefined target with an accuracy of 2mm with an insertion time below one minute. Finally, we propose a passive evaluation protocol of the overall system in the operating room during five interventions on patients. These experiments show that the system can provide a guidance information during expiratory phases with an error below 5mm.