Quantitation in MRI : application to ageing and epilepsy

Multi-atlas propagation and label fusion techniques have recently been developed for segmenting the human brain into multiple anatomical regions. In this thesis, I investigate possible adaptations of these current state-of-the-art methods. The aim is to study ageing on the one hand, and on the other hand temporal lobe epilepsy as an example for a neurological disease. Overall effects are a confounding factor in such anatomical analyses. Intracranial volume (ICV) is often preferred to normalize for global effects as it allows to normalize for estimated maximum brain size and is hence independent of global brain volume loss, as seen in ageing and disease. I describe systematic differences in ICV measures obtained at 1.5T versus 3T, and present an automated method of measuring intracranial volume, Reverse MNI Brain Masking (RBM), based on tissue probability maps in MNI standard space. I show that this is comparable to manual measurements and robust against field strength differences. Correct and robust segmentation of target brains which show gross abnormalities, such as ventriculomegaly, is important for the study of ageing and disease. We achieved this with incorporating tissue classification information into the image registration process. The best results in elderly subjects, patients with TLE and healthy controls were achieved using a new approach using multi-atlas propagation with enhanced registration (MAPER). I then applied MAPER to the problem of automatically distinguishing patients with TLE with (TLE-HA) and without (TLE-N) hippocampal atrophy on MRI from controls, and determine the side of seizure onset. MAPER-derived structural volumes were used for a classification step consisting of selecting a set of discriminatory structures and applying support vector machine on the structural volumes as well as morphological similarity information such as volume difference obtained with spectral analysis. Acccuracies were 91-100 %, indicating that the method might be clinically useful. Finally, I used the methods developed in the previous chapters to investigate brain regional volume changes across the human lifespan in over 500 healthy subjects between 20 to 90 years of age, using data from three different scanners (2x 1.5T, 1x 3T), using the IXI database. We were able to confirm several known changes, indicating the veracity of the method. In addition, we describe the first multi-region, whole-brain database of normal ageing

Doctor of Philosophy

dissertationThe gold standard for evaluation of arterial disease using MR continues to be contrast-enhanced MR angiography (MRA) with gadolinium-based contrast agents (Gd-MRA). There has been a recent resurgence in interest in methods that do not rely on gadolinium for enhancement of blood vessels due to associations Gd-MRA has with nephrogenic systemic fibrosis (NSF) in patients with impaired renal function. The risk due to NSF has been shown to be minimized when selecting the appropriate contrast type and dose. Even though the risk of NSF has been shown to be minimized, demand for noncontrast MRA has continued to rise to reduce examination cost, and improve patient comfort and ability to repeat scans. Several methods have been proposed and used to perform angiography of the aorta and peripheral arteries without the use of gadolinium. These techniques have had limitations in transmit radiofrequency field (B1+) inhomogeneities, acquisition time, and specific hardware requirements, which have stunted the utility of noncontrast enhanced MRA. In this work feasibility of noncontrast (NC) MRA at 3T of the femoral arteries using dielectric padding, and using 3D radial stack of stars and compressed sensing to accelerate acquisitions in the abdomen and thorax were tested. Imaging was performed on 13 subjects in the pelvis and thighs using high permittivity padding, and 11 in the abdomen and 19 in the thorax using 3D radial stack of stars with tiny golden angle using gold standards or previously published techniques. Qualitative scores for each study were determined by radiologists who were blinded to acquisition type. Vessel conspicuity in the thigh and pelvis showed significant increase when high permittivity padding was used in the acquisition. No significant difference in image quality was observed in the abdomen and thorax when using undersampling, except for the descending aorta in thoracic imaging. All image quality scores were determined to be of diagnostic quality. In this work it is shown that NC-MRA can be improved through the use of high permittivity dielectric padding and acquisition time can be decreased through the use of 3D radial stack of stars acquisitions

Normative data for subcortical regional volumes over the lifetime of the adult human brain

Normative data for volumetric estimates of brain structures are necessary to adequately assess brain volume alterations in individuals with suspected neurological or psychiatric conditions. Although many studies have described age and sex effects in healthy individuals for brain morphometry assessed via magnetic resonance imaging, proper normative values allowing to quantify potential brain abnormalities are needed. We developed norms for volumetric estimates of subcortical brain regions based on cross-sectional magnetic resonance scans from 2790 healthy individuals aged 18 to 94 years using 23 samples provided by 21 independent research groups. The segmentation was conducted using FreeSurfer, a widely used and freely available automated segmentation software. Models predicting subcortical regional volumes of each hemisphere were produced including age, sex, estimated total intracranial volume (eTIV), scanner manufacturer, magnetic field strength, and interactions as predictors. The mean explained variance by the models was 48%. For most regions, age, sex and eTIV predicted most of the explained variance while manufacturer, magnetic field strength and interactions predicted a limited amount. Estimates of the expected volumes of an individual based on its characteristics and the scanner characteristics can be obtained using derived formulas. For a new individual, significance test for volume abnormality, effect size and estimated percentage of the normative population with a smaller volume can be obtained. Normative values were validated in independent samples of healthy adults and in adults with Alzheimer's disease and schizophrenia

Translation of quantitative MRI analysis tools for clinical neuroradiology application

Quantification of imaging features can assist radiologists by reducing subjectivity, aiding detection of subtle pathology, and increasing reporting consistency. Translation of quantitative image analysis techniques to clinical use is currently uncommon and challenging. This thesis explores translation of quantitative imaging support tools for clinical neuroradiology use. I have proposed a translational framework for development of quantitative imaging tools, using dementia as an exemplar application. This framework emphasises the importance of clinical validation, which is not currently prioritised. Aspects of the framework were then applied to four disease areas: hippocampal sclerosis (HS) as a cause of epilepsy; dementia; multiple sclerosis (MS) and gliomas. A clinical validation study for an HS quantitative report showed that when image interpreters used the report, they were more accurate and confident in their assessments, particularly for challenging bilateral cases. A similar clinical validation study for a dementia reporting tool found improved sensitivity for all image interpreters and increased assessment accuracy for consultant radiologists. These studies indicated benefits from quantitative reports that contextualise a patient’s results with appropriate normative reference data. For MS, I addressed a technical translational challenge by applying lesion and brain quantification tools to standard clinical image acquisitions which do not include a conventional T1-weighted sequence. Results were consistent with those from conventional sequence inputs and therefore I pursued this concept to establish a clinically applicable normative reference dataset for development of a quantitative reporting tool for clinical use. I focused on current radiology reporting of gliomas to establish which features are commonly missed and may be important for clinical management decisions. This informs both the potential utility of a quantitative report for gliomas and its design and content. I have identified numerous translational challenges for quantitative reporting and explored aspects of how to address these for several applications across clinical neuroradiology

Classification and Lateralization of Temporal Lobe Epilepsies with and without Hippocampal Atrophy Based on Whole-Brain Automatic MRI Segmentation

Brain images contain information suitable for automatically sorting subjects into categories such as healthy controls and patients. We sought to identify morphometric criteria for distinguishing controls (n = 28) from patients with unilateral temporal lobe epilepsy (TLE), 60 with and 20 without hippocampal atrophy (TLE-HA and TLE-N, respectively), and for determining the presumed side of seizure onset. The framework employs multi-atlas segmentation to estimate the volumes of 83 brain structures. A kernel-based separability criterion was then used to identify structures whose volumes discriminate between the groups. Next, we applied support vector machines (SVM) to the selected set for classification on the basis of volumes. We also computed pairwise similarities between all subjects and used spectral analysis to convert these into per-subject features. SVM was again applied to these feature data. After training on a subgroup, all TLE-HA patients were correctly distinguished from controls, achieving an accuracy of 96 ± 2% in both classification schemes. For TLE-N patients, the accuracy was 86 ± 2% based on structural volumes and 91 ± 3% using spectral analysis. Structures discriminating between patients and controls were mainly localized ipsilaterally to the presumed seizure focus. For the TLE-HA group, they were mainly in the temporal lobe; for the TLE-N group they included orbitofrontal regions, as well as the ipsilateral substantia nigra. Correct lateralization of the presumed seizure onset zone was achieved using hippocampi and parahippocampal gyri in all TLE-HA patients using either classification scheme; in the TLE-N patients, lateralization was accurate based on structural volumes in 86 ± 4%, and in 94 ± 4% with the spectral analysis approach. Unilateral TLE has imaging features that can be identified automatically, even when they are invisible to human experts. Such morphometric image features may serve as classification and lateralization criteria. The technique also detects unsuspected distinguishing features like the substantia nigra, warranting further study

Optimized Targeting in Deep Brain Stimulation for Movement Disorders.

Deep brain stimulation (DBS) is the dominant surgical therapy for medically-refractory Parkinson’s Disease (PD) and Essential Tremor (ET). Despite its success in treating the physical symptoms of many movement disorders, optimal targeting protocols are unknown. The success of the surgery is highly dependent upon proper placement of the electrode in the brain. However, the anatomical targets for PD and ET DBS—the subthalamic nucleus (STN) and ventral intermediate (Vim) nucleus of the thalamus, respectively—are not distinguishable on conventional magnetic resonance imaging. Neurosurgeons typically locate these structures using imprecise atlas-based indirect targeting methods requiring several attempts, increasing the risk of intracranial hemorrhage. The purpose of this work was to optimize targeting in DBS for PD and ET. First, we evaluated the most common indirect STN targeting methods with our validated 3-Tesla MRI protocol optimized for STN visualization. We calculated indirect targets as prescribed by midcommissural point (MCP) -based and red nucleus-based (RN) methods, and compared those coordinates to the position of the STN. We found that RN-based targeting is statistically superior to MCP-based targeting and should be routinely used in the absence of direct STN visualization. In our next study, we investigated the volume of tissue activated (VTA) in thalamic DBS. First, we developed a k-means clustering algorithm that operates on diffusion tensor imaging data to segment the thalamus into its functionally-distinct nuclei. We segmented individual patient thalami and an atlas thalamus in an existing VTA model, and created an individualized VTA model by utilizing each patient’s own anatomy and tissue conductivity. We measured stimulation overlaps with relevant nuclei for clinically efficacious stimulation settings. Our preliminary results indicated that individualized VTA modeling may provide more precise modeling results than existing atlas-based VTA modeling. Next, we investigated the ability of atlas-based and individualized VTA modeling methods to explain common side effects from thalamic DBS. We found that individualized VTA modeling is superior to atlas-based modeling in the prediction of side effects. The results of this work advance the understanding of proper DBS targeting for movement disorders, and our VTA modeling system represents the most individualized approach for ET DBS surgical planning.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111402/1/hlayla_1.pd

Reproducibility of hippocampal atrophy rates measured with manual, FreeSurfer, AdaBoost, FSL/FIRST and the MAPS-HBSI methods in Alzheimer's disease

The purpose of this study is to assess the reproducibility of hippocampal atrophy rate measurements of commonly used fully-automated algorithms in Alzheimer disease (AD). The reproducibility of hippocampal atrophy rate for FSL/FIRST, AdaBoost, FreeSurfer, MAPS independently and MAPS combined with the boundary shift integral (MAPS-HBSI) were calculated. Back-to-back (BTB) 3D T1-weighted MPRAGE MRI from the Alzheimer's Disease Neuroimaging Initiative (ADNI1) study at baseline and year one were used. Analysis on 3 groups of subjects was performed – 562 subjects at 1.5 T, a 75 subject group that also had manual segmentation and 111 subjects at 3 T. A simple and novel statistical test based on the binomial distribution was used that handled outlying data points robustly. Median hippocampal atrophy rates were −1.1%/year for healthy controls, −3.0%/year for mildly cognitively impaired and −5.1%/year for AD subjects. The best reproducibility was observed for MAPS-HBSI (1.3%), while the other methods tested had reproducibilities at least 50% higher at 1.5 T and 3 T which was statistically significant. For a clinical trial, MAPS-HBSI should require less than half the subjects of the other methods tested. All methods had good accuracy versus manual segmentation. The MAPS-HBSI method has substantially better reproducibility than the other methods considered