A model of brain morphological changes related to aging and Alzheimer's disease from cross-sectional assessments

In this study we propose a deformation-based framework to jointly model the influence of aging and Alzheimer's disease (AD) on the brain morphological evolution. Our approach combines a spatio-temporal description of both processes into a generative model. A reference morphology is deformed along specific trajectories to match subject specific morphologies. It is used to define two imaging progression markers: 1) a morphological age and 2) a disease score. These markers can be computed locally in any brain region. The approach is evaluated on brain structural magnetic resonance images (MRI) from the ADNI database. The generative model is first estimated on a control population, then, for each subject, the markers are computed for each acquisition. The longitudinal evolution of these markers is then studied in relation with the clinical diagnosis of the subjects and used to generate possible morphological evolution. In the model, the morphological changes associated with normal aging are mainly found around the ventricles, while the Alzheimer's disease specific changes are more located in the temporal lobe and the hippocampal area. The statistical analysis of these markers highlights differences between clinical conditions even though the inter-subject variability is quiet high. In this context, the model can be used to generate plausible morphological trajectories associated with the disease. Our method gives two interpretable scalar imaging biomarkers assessing the effects of aging and disease on brain morphology at the individual and population level. These markers confirm an acceleration of apparent aging for Alzheimer's subjects and can help discriminate clinical conditions even in prodromal stages. More generally, the joint modeling of normal and pathological evolutions shows promising results to describe age-related brain diseases over long time scales.Comment: NeuroImage, Elsevier, In pres

Neuroimaging of structural pathology and connectomics in traumatic brain injury: Toward personalized outcome prediction.

Recent contributions to the body of knowledge on traumatic brain injury (TBI) favor the view that multimodal neuroimaging using structural and functional magnetic resonance imaging (MRI and fMRI, respectively) as well as diffusion tensor imaging (DTI) has excellent potential to identify novel biomarkers and predictors of TBI outcome. This is particularly the case when such methods are appropriately combined with volumetric/morphometric analysis of brain structures and with the exploration of TBI-related changes in brain network properties at the level of the connectome. In this context, our present review summarizes recent developments on the roles of these two techniques in the search for novel structural neuroimaging biomarkers that have TBI outcome prognostication value. The themes being explored cover notable trends in this area of research, including (1) the role of advanced MRI processing methods in the analysis of structural pathology, (2) the use of brain connectomics and network analysis to identify outcome biomarkers, and (3) the application of multivariate statistics to predict outcome using neuroimaging metrics. The goal of the review is to draw the community's attention to these recent advances on TBI outcome prediction methods and to encourage the development of new methodologies whereby structural neuroimaging can be used to identify biomarkers of TBI outcome

DEVELOPING A PREDICTIVE MODEL OF HEART WALL MOTION IN FLUOROSCOPIC IMAGES

Image guided surgery (IGS) is an integral part of minimally invasive surgery. IGS combines pre- and perioperative images acquired from different imaging modalities to give the surgeon a more complete view of the internal organs. These modalities include computed tomography, magnetic resonance imaging, and fluoroscopy, to name a few. Fluoroscopy is also known as video x-ray and is becoming increasingly popular in procedures around the heart. Unfortunately, this increase in fluoroscopy use also brings an increase in exposure to ionizing radiation for the patient and the surgeon. This radiation can lead to increased cancer risk and a number of other problems. Studies show that medical radiation exposure has increased six times from 1992 to 2009. This exposure accounts for approximately half of all radiation exposure that humans receive with background radiation being the only source larger. Of the medical exposure, fluoroscopy accounts for approximately 25%. An increasingly popular trend in IGS is the use of predictive modeling. Davatzikos, et al, presents a framework for predictive modeling of anatomical structures but focuses on simple structures like ovals and circles. We seek to apply this framework to a more complex organ with more complex motions such as the heart. A predictive model of the heart could provide the surgeon with an effective partial replacement to fluoroscopy. This could significantly reduce radiation exposure as well as the risks of associated diseases

Grid simulation services for the medical community

The first part of this paper presents a selection of medical simulation applications, including image reconstruction, near real-time registration for neuro-surgery, enhanced dose distribution calculation for radio-therapy, inhaled drug delivery prediction, plastic surgery planning and cardio-vascular system simulation. The latter two topics are discussed in some detail. In the second part, we show how such services can be made available to the clinical practitioner using Grid technology. We discuss the developments and experience made during the EU project GEMSS, which provides reliable, efficient, secure and lawful medical Grid services

Doctor of Philosophy

dissertationAn important aspect of medical research is the understanding of anatomy and its relation to function in the human body. For instance, identifying changes in the brain associated with cognitive decline helps in understanding the process of aging and age-related neurological disorders. The field of computational anatomy provides a rich mathematical setting for statistical analysis of complex geometrical structures seen in 3D medical images. At its core, computational anatomy is based on the representation of anatomical shape and its variability as elements of nonflat manifold of diffeomorphisms with an associated Riemannian structure. Although such manifolds effectively represent natural biological variability, intrinsic methods of statistical analysis within these spaces remain deficient at large. This dissertation contributes two critical missing pieces for statistics in diffeomorphisms: (1) multivariate regression models for cross-sectional study of shapes, and (2) generalization of classical Euclidean, mixed-effects models to manifolds for longitudinal studies. These models are based on the principle that statistics on manifold-valued information must respect the intrinsic geometry of that space. The multivariate regression methods provide statistical descriptors of the relationships of anatomy with clinical indicators. The novel theory of hierarchical geodesic models (HGMs) is developed as a natural generalization of hierarchical linear models (HLMs) to describe longitudinal data on curved manifolds. Using a hierarchy of geodesics, the HGMs address the challenge of modeling the shape-data with unbalanced designs typically arising as a result of follow-up medical studies. More generally, this research establishes a mathematical foundation to study dynamics of changes in anatomy and the associated clinical progression with time. This dissertation also provides efficient algorithms that utilize state-of-the-art high performance computing architectures to solve models on large-scale, longitudinal imaging data. These manifold-based methods are applied to predictive modeling of neurological disorders such as Alzheimer's disease. Overall, this dissertation enables clinicians and researchers to better utilize the structural information available in medical images

A dual role for prediction error in associative learning

Confronted with a rich sensory environment, the brain must learn statistical regularities across sensory domains to construct causal models of the world. Here, we used functional magnetic resonance imaging and dynamic causal modeling (DCM) to furnish neurophysiological evidence that statistical associations are learnt, even when task-irrelevant. Subjects performed an audio-visual target-detection task while being exposed to distractor stimuli. Unknown to them, auditory distractors predicted the presence or absence of subsequent visual distractors. We modeled incidental learning of these associations using a Rescorla--Wagner (RW) model. Activity in primary visual cortex and putamen reflected learning-dependent surprise: these areas responded progressively more to unpredicted, and progressively less to predicted visual stimuli. Critically, this prediction-error response was observed even when the absence of a visual stimulus was surprising. We investigated the underlying mechanism by embedding the RW model into a DCM to show that auditory to visual connectivity changed significantly over time as a function of prediction error. Thus, consistent with predictive coding models of perception, associative learning is mediated by prediction-error dependent changes in connectivity. These results posit a dual role for prediction-error in encoding surprise and driving associative plasticity

Articular human joint modelling

Copyright @ Cambridge University Press 2009.The work reported in this paper encapsulates the theories and algorithms developed to drive the core analysis modules of the software which has been developed to model a musculoskeletal structure of anatomic joints. Due to local bone surface and contact geometry based joint kinematics, newly developed algorithms make the proposed modeller different from currently available modellers. There are many modellers that are capable of modelling gross human body motion. Nevertheless, none of the available modellers offer complete elements of joint modelling. It appears that joint modelling is an extension of their core analysis capability, which, in every case, appears to be musculoskeletal motion dynamics. It is felt that an analysis framework that is focused on human joints would have significant benefit and potential to be used in many orthopaedic applications. The local mobility of joints has a significant influence in human motion analysis, in understanding of joint loading, tissue behaviour and contact forces. However, in order to develop a bone surface based joint modeller, there are a number of major problems, from tissue idealizations to surface geometry discretization and non-linear motion analysis. This paper presents the following: (a) The physical deformation of biological tissues as linear or non-linear viscoelastic deformation, based on spring-dashpot elements. (b) The linear dynamic multibody modelling, where the linear formulation is established for small motions and is particularly useful for calculating the equilibrium position of the joint. This model can also be used for finding small motion behaviour or loading under static conditions. It also has the potential of quantifying the joint laxity. (c) The non-linear dynamic multibody modelling, where a non-matrix and algorithmic formulation is presented. The approach allows handling complex material and geometrical nonlinearity easily. (d) Shortest path algorithms for calculating soft tissue line of action geometries. The developed algorithms are based on calculating minimum ‘surface mass’ and ‘surface covariance’. An improved version of the ‘surface covariance’ algorithm is described as ‘residual covariance’. The resulting path is used to establish the direction of forces and moments acting on joints. This information is needed for linear or non-linear treatment of the joint motion. (e) The final contribution of the paper is the treatment of the collision. In the virtual world, the difficulty in analysing bodies in motion arises due to body interpenetrations. The collision algorithm proposed in the paper involves finding the shortest projected ray from one body to the other. The projection of the body is determined by the resultant forces acting on it due to soft tissue connections under tension. This enables the calculation of collision condition of non-convex objects accurately. After the initial collision detection, the analysis involves attaching special springs (stiffness only normal to the surfaces) at the ‘potentially colliding points’ and motion of bodies is recalculated. The collision algorithm incorporates the rotation as well as translation. The algorithm continues until the joint equilibrium is achieved. Finally, the results obtained based on the software are compared with experimental results obtained using cadaveric joints

A validated computational framework to evaluate the stiffness of 3D printed ankle foot orthoses

The purpose of this study was to create and validate a standardized framework for the evaluation of the ankle stiffness of two designs of 3D printed ankle foot orthoses (AFOs). The creation of four finite element (FE) models allowed patient-specific quantification of the stiffness and stress distribution over their specific range of motion during the second rocker of the gait. Validation was performed by comparing the model outputs with the results obtained from a dedicated experimental setup, which showed an overall good agreement with a maximum relative error of 10.38% in plantarflexion and 10.66% in dorsiflexion. The combination of advanced computer modelling algorithms and 3D printing techniques clearly shows potential to further improve the manufacturing process of AFOs