Regmentation: A New View of Image Segmentation and Registration

Image segmentation and registration have been the two major areas of research in the medical imaging community for decades and still are. In the context of radiation oncology, segmentation and registration methods are widely used for target structure definition such as prostate or head and neck lymph node areas. In the past two years, 45% of all articles published in the most important medical imaging journals and conferences have presented either segmentation or registration methods. In the literature, both categories are treated rather separately even though they have much in common. Registration techniques are used to solve segmentation tasks (e.g. atlas based methods) and vice versa (e.g. segmentation of structures used in a landmark based registration). This article reviews the literature on image segmentation methods by introducing a novel taxonomy based on the amount of shape knowledge being incorporated in the segmentation process. Based on that, we argue that all global shape prior segmentation methods are identical to image registration methods and that such methods thus cannot be characterized as either image segmentation or registration methods. Therefore we propose a new class of methods that are able solve both segmentation and registration tasks. We call it regmentation. Quantified on a survey of the current state of the art medical imaging literature, it turns out that 25% of the methods are pure registration methods, 46% are pure segmentation methods and 29% are regmentation methods. The new view on image segmentation and registration provides a consistent taxonomy in this context and emphasizes the importance of regmentation in current medical image processing research and radiation oncology image-guided applications

A New Mouse Model Of Metastatic Gastric Cancer And E-Cadherin Primary Tumor Suppression

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide. The majority of patients with gastric cancer are diagnosed with disseminated disease and even patients diagnosed with early stage disease have high rates of recurrence. The utility of current mouse models of gastric cancer is limited by slow development of gastric tumors and lack of metastasis. Here I describe a new mouse model of gastric cancer driven by p53 loss, Cdh1 loss, and oncogenic Kras expression in gastric parietal cells (referred to as ACKPY mice). I generated these mice to investigate the contribution of oncogenic Kras to the progression of gastric cancer given the high rate of mutation and amplification of the RTK/Ras pathway identified in gastric cancer patients. These mice develop mixed-type gastric adenocarcinomas with metastases to lymph nodes, lung, and liver. Oncogenic Kras and loss of Trp53 is sufficient to drive rapid carcinogenesis in a variety of models. Therefore, I tested if loss of E-cadherin was necessary for the onset of gastric adenocarcinoma in gastric parietal cells by generating ACKPY mice with one or two alleles of wild-type Cdh1 (E-cadherin). E-cadherin expression significantly increased survival and the limited number of mice with gastric tumors have tumors that were focal in nature, suggesting an additional event was necessary for gastric tumorigenesis. Loss of E-cadherin expression was observed in some of these tumors, suggesting that its loss may be necessary for gastric tumorigenesis in this model. I show that loss of E-cadherin in our model increases β-catenin signaling and that inhibition of β-catenin signaling prolonged survival of ACKPY mice. Microarray data comparing gene expression in stomachs harvested from Cdh1fl/fl and Cdh1fl/+ mice showed a correlation between E-cadherin loss and upregulation of oncogenic Kras signaling. Gene sets regulated by each of the main Kras effector pathways were overrepresented in our microarray data. Examination of ERK phosphorylation revealed that E-cadherin likely does not regulate MAPK activity in our model. The upregulation of oncogenic Kras target genes that result from the loss of E-cadherin may alternatively be explained by E-cadherin regulation of other Kras effector pathways

Autoimmune Diseases

Autoimmune disease represents a group of more than 60 different chronic autoimmune diseases that affect approximately 6% of the population. Autoimmune diseases arise when ones immune system actively targets and destroys self tissue resulting in clinical disease with prime examples such as Lupus and Type 1 diabetes. The immune system is designed to protect us from foreign pathogens such as viruses and bacteria. However, during the process of generating immune cells for this purpose, as a negative consequence, self-reactive immune cells are also generated. This book aims to present the latest knowledge and insights regarding the different contributing factors and their interplay, discussions on several autoimmune diseases and their case studies, and therapeutic treatments, including stem cell, for autoimmune diseases

The hearing hippocampus

The hippocampus has a well-established role in spatial and episodic memory but a broader function has been proposed including aspects of perception and relational processing. Neural bases of sound analysis have been described in the pathway to auditory cortex, but wider networks supporting auditory cognition are still being established. We review what is known about the role of the hippocampus in processing auditory information, and how the hippocampus itself is shaped by sound. In examining imaging, recording, and lesion studies in species from rodents to humans, we uncover a hierarchy of hippocampal responses to sound including during passive exposure, active listening, and the learning of associations between sounds and other stimuli. We describe how the hippocampus' connectivity and computational architecture allow it to track and manipulate auditory information – whether in the form of speech, music, or environmental, emotional, or phantom sounds. Functional and structural correlates of auditory experience are also identified. The extent of auditory-hippocampal interactions is consistent with the view that the hippocampus makes broad contributions to perception and cognition, beyond spatial and episodic memory. More deeply understanding these interactions may unlock applications including entraining hippocampal rhythms to support cognition, and intervening in links between hearing loss and dementia

Microcircuit remodeling processes underlying learning in the adult

One of the most intriguing discoveries in neuroscience of the past decades has been showing that experience is able to induce structural modifications in cortical microcircuit that might underlie the formation of memories upon learning (for a review, see Caroni, Donato and Muller 2012). Hence, learning induces phases of synapse formation and elimination that are strictly regulated by a variety of mechanisms, which impact on cortical microcircuits affecting both excitatory and inhibitory neurons. Nevertheless, the extent to which specific configurations might be implemented to support specific phases of learning, as well as the impact of experience-induced structural modifications on further learning, is still largely unknown. Here, I explore how the remodeling of identified microcircuits in the mouse hippocampus and neocortex supports learning in the adult. In the first part, I identifiy a microcircuit module engaging VIP and Parvalbumin (PV) positive interneurons to regulate the state of the PV+ network upon experience. This defines states of enhanced or reduced structural plasticity and learning based on the distribution of PV intensity in the network. In the second part, I demonstrate how specific hippocampal subdivisions are exploited to learn subtasks of trial-and-errors forms of learning via the deployment of increasingly precise searching strategies, and sequential recruitment of ventral, intermediate, and dorsal hippocampus. In the third part, I highlight the existence of genetically matched subpopulations of principal cells in the hippocampus, which achieve selective connectivity across hippocampal subdivisions via matched windows of neurogenesis and synaptogenesis during development. In the fourth part, I investigate the maturation of microcircuits mediating feedforward inhibition in the hippocampus, and highlight windows during development for the establishment of the proper baseline configuration in the adult. Moreover, I identify a critical window for cognitive enhancement during hippocampal development. In the fifth part, I study how ageing affects the PV network in hippocampal CA3, providing evidence for which age related neuronal loss correlates to reduced incidental learning performances in old mice. Therefore, by manipulating the PV network early during life, I provide strategies to modulate cognitive decline

Recognizing deviations from normalcy for brain tumor segmentation

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2003.Includes bibliographical references (p. 180-189).A framework is proposed for the segmentation of brain tumors from MRI. Instead of training on pathology, the proposed method trains exclusively on healthy tissue. The algorithm attempts to recognize deviations from normalcy in order to compute a fitness map over the image associated with the presence of pathology. The resulting fitness map may then be used by conventional image segmentation techniques for honing in on boundary delineation. Such an approach is applicable to structures that are too irregular, in both shape and texture, to permit construction of comprehensive training sets. We develop the method of diagonalized nearest neighbor pattern recognition, and we use it to demonstrate that recognizing deviations from normalcy requires a rich understanding of context. Therefore, we propose a framework for a Contextual Dependency Network (CDN) that incorporates context at multiple levels: voxel intensities, neighborhood coherence, intra-structure properties, inter-structure relationships, and user input. Information flows bi-directionally between the layers via multi-level Markov random fields or iterated Bayesian classification. A simple instantiation of the framework has been implemented to perform preliminary experiments on synthetic and MRI data.by David Thomas Gering.Ph.D

Development of a high-throughput drug screening platform for oligodendrocyte myelination (for progressive multiple sclerosis)

Aim As part of the broad strategy in Edinburgh and beyond to discover new treatments for progressive Multiple Sclerosis (MS), the aims for my PhD project were: (1) to address the lack of an in vitro phenotypic drug screening platform that is able to fully recapitulate myelin sheath formation, with the long-term goal being to enhance the discovery of pro remyelination therapies in progressive MS, and target the poor drug discovery rates in brain disorders which is partially due to poor disease modelling, and (2) the exploration of non linear optical imaging microscopy techniques that targets both the resolution and speed to study myelination. Background In multiple sclerosis, an inflammatory autoimmune process destroys the oligodendrocytes that provide neuronal support by forming multi-layered compact myelin sheaths around axons, leading to neurodegeneration. Although there are drugs available to suppress the inflammatory attack to limit the formation of demyelinated lesions, no treatments currently exist to promote the regeneration of these myelin sheaths once the damage has occurred. Cell based screens have formed an important part of the strategy used to discover such regenerative drugs. The majority of published cell-based phenotypic drug screens to target repair have focused on the differentiation of oligodendrocyte precursor cells into oligodendrocytes rather than their ability to form mature protective myelin sheaths. However, in many MS lesions, pre-myelinating oligodendrocytes are present, and studies on oligodendrocyte biology show that differentiation and myelination are regulated by distinct mechanisms. There is therefore a need for novel drug screens that target the later myelinating stages of oligodendrocyte development. Results Using a 3D microfibre system for in vitro myelin sheath formation (described by Bechler, Byrne and ffrench-Constant (2015)), I first asked whether compounds that had been v identified as increasing differentiation in conventional 2D culture systems enhanced myelination in the 3D cultures. While Benztropine and Clemastine showed an increase in the number of MBP+ (differentiated) oligodendrocytes in the 2D system, consistent with previous publications, no increase in myelin sheath formation was seen with any of the drugs in the 3D system, highlighting the potentially important differences between differentiation and myelin sheath formation for drug discovery. Next I developed a multiwell plate based assay to allow 3D myelination assays to be used for drug screening. Using electrospinning to produce PLA microfibres, I was able to develop and optimise a technique to insert and suspend the fibres across the bottom of a 96-well plate that can be incorporated into an automated pipeline for high-throughput drug screening. The 3D myelin sheaths could be imaged using the Leica SP8 confocal system with the MatrixScreener extension and the Opera Phenix high-content screening system. Finally, I addressed the problem of imaging myelin in such screens. CARS was shown to be able to preferentially detect myelin sheaths in fixed and live slices in regions and time-points of varying myelin densities. As the development of new myelin sheaths requires the formation of lipid and therefore the incorporation of hydrogen, the consumption of D2O (heavy water) with a 2H atom allowed the non-invasive labelling and detection of myelin sheaths using SRS. Future experiments will allow us to confirm whether this deuterium detection is preferential and/or specific to new myelin sheaths. Significance With only about 10% of drugs that enter Phase I trials successfully launching into clinics, there is an important need for more effective drug screens that better model disease-relevant processes and so reduce late-stage failures. The high-throughput-compatible 96-well plate with suspended PLA microfibres that combines the recent progresses in 3D cellular model systems with bioengineering and the recent advances in high content imaging systems may give us the opportunity to more accurately model these disease-relevant structures in vitro, and therefore improve drug discovery for regenerative therapies in multiple sclerosis and other myelin diseases. The research on Raman-based label-free imaging of myelin sheaths is not only applicable for imaging myelin sheaths in the context of drug validation, but could be important for live imaging of brain slices and detection of newly-formed myelin sheaths without the need for complex and expensive transgenic animals

Injury induced neuroplasticity and cell specific targeting of the lumbar enlargement for gene therapy.

This dissertation is an examination of spinal cord injury induced neuroplasticity and tests whether noninvasive gene therapy can successfully target neurons in the lumbar spinal cord. It begins with an overview of neural control of locomotion and a brief summary of therapeutics that are used and/or in development for treating spinal anatomically characterize s subset of neurons in the spinal cord, long ascending propriospinal neurons, that are involved in interlimb coordination. Characterization of these neurons allows for subsequent evaluation of their potential involvement in injury induced neuroplasticity. This dissertation is divided into five chapters, covering spinal cord injury and therapeutics. Chapter One gives background on locomotor control, propriospinal neurons, spinal cord injury, and therapeutics. Chapter Two develops and characterizes viral tracing methods for spinal cord anatomy. Chapter Three then uses these methods to characterize long ascending propriospinal neurons and evaluate their involvement in injury induced plasticity. Chapter Four then focuses on the development of noninvasive delivery of gene transfer to the lumbar enlargement. This involves optimizing focused ultrasound and intravenous microbubble delivery to focally and transiently permeabilize the blood spinal cord barrier of the lumbar spinal cord. This optimization then allows for successful gene transfer in neurons in the lumbar spinal cord following intravenous delivery of viral vector. Lasty, Chapter Five discusses the implications for all of these findings and how these findings have contributed to our understanding spinal cord anatomy and injury, and how the proof-of-concept in Chapter 4 provides a promising new avenue for spinal cord injury therapeutics