A probabilistic atlas of the human thalamic nuclei combining ex vivo MRI and histology

The human thalamus is a brain structure that comprises numerous, highly specific nuclei. Since these nuclei are known to have different functions and to be connected to different areas of the cerebral cortex, it is of great interest for the neuroimaging community to study their volume, shape and connectivity in vivo with MRI. In this study, we present a probabilistic atlas of the thalamic nuclei built using ex vivo brain MRI scans and histological data, as well as the application of the atlas to in vivo MRI segmentation. The atlas was built using manual delineation of 26 thalamic nuclei on the serial histology of 12 whole thalami from six autopsy samples, combined with manual segmentations of the whole thalamus and surrounding structures (caudate, putamen, hippocampus, etc.) made on in vivo brain MR data from 39 subjects. The 3D structure of the histological data and corresponding manual segmentations was recovered using the ex vivo MRI as reference frame, and stacks of blockface photographs acquired during the sectioning as intermediate target. The atlas, which was encoded as an adaptive tetrahedral mesh, shows a good agreement with previous histological studies of the thalamus in terms of volumes of representative nuclei. When applied to segmentation of in vivo scans using Bayesian inference, the atlas shows excellent test-retest reliability, robustness to changes in input MRI contrast, and ability to detect differential thalamic effects in subjects with Alzheimer's disease. The probabilistic atlas and companion segmentation tool are publicly available as part of the neuroimaging package FreeSurfer.The authors would like to thank Professor Karla Miller (Oxford) for her help with the design of the ex vivo MRI acquisition; Ms. Mercedes I~niguez de Onzo~no and Mr. Francisco Romero (UCLM) for their careful technical laboratory help; and Mr. Gonzalo Artacho (UCLM) for his help with the digitization and curation of his organization of histological data. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska- Curie grant agreement No 654911 (project “THALAMODEL”) and by the European Research Council (ERC) Starting Grant agreement No 677697 (“BUNGEE-TOOLS”). It was also funded by the Spanish Ministry of Economy and Competitiveness(MINECO TEC-2014-51882-P, RYC- 2014-15440, PSI2015-65696, and SEV-2015-0490), the Basque Government (PI2016-12), and UCLM Internal Research Groups grants. Support for this research was also provided in part by the National Institute of Biomedical Imaging and Bioengineering (P41EB015896, 1R01EB023281, R01EB006758, R21EB018907, R01EB019956), the National Institute on Aging (5R01AG008122, R01AG016495), the National Institute of Diabetes and Digestive and Kidney Diseases (1-R21-DK- 108277-01), the National Institute of Neurological Disorders and Stroke (R01NS0525851, R21NS072652, R01NS070963, R01NS083534, 5U01NS086625), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S- 10RR023043. Additional support was provided by the NIH Blueprint for Neuroscience Research (5U01-MH093765), part of the multiinstitutional Human Connectome Project. In addition, B.F. has a financial interest in CorticoMetrics, a company whose medical pursuits focus on brain imaging and measurement technologies. B.F.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health Grant U01 AG024904) and DOD ADNI (DOD award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimers Association; Alzheimers Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimers Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California

Systematic comparison of different techniques to measure hippocampal subfield volumes in ADNI2

OBJECTIVE: Subfield-specific measurements provide superior information in the early stages of neurodegenerative diseases compared to global hippocampal measurements. The overall goal was to systematically compare the performance of five representative manual and automated T1 and T2 based subfield labeling techniques in a sub-set of the ADNI2 population. METHODS: The high resolution T2 weighted hippocampal images (T2-HighRes) and the corresponding T1 images from 106 ADNI2 subjects (41 controls, 57 MCI, 8 AD) were processed as follows. A. T1-based: 1. Freesurfer + Large-Diffeomorphic-Metric-Mapping in combination with shape analysis. 2. FreeSurfer 5.1 subfields using in-vivo atlas. B. T2-HighRes: 1. Model-based subfield segmentation using ex-vivo atlas (FreeSurfer 6.0). 2. T2-based automated multi-atlas segmentation combined with similarity-weighted voting (ASHS). 3. Manual subfield parcellation. Multiple regression analyses were used to calculate effect sizes (ES) for group, amyloid positivity in controls, and associations with cognitive/memory performance for each approach. RESULTS: Subfield volumetry was better than whole hippocampal volumetry for the detection of the mild atrophy differences between controls and MCI (ES: 0.27 vs 0.11). T2-HighRes approaches outperformed T1 approaches for the detection of early stage atrophy (ES: 0.27 vs.0.10), amyloid positivity (ES: 0.11 vs 0.04), and cognitive associations (ES: 0.22 vs 0.19). CONCLUSIONS: T2-HighRes subfield approaches outperformed whole hippocampus and T1 subfield approaches. None of the different T2-HghRes methods tested had a clear advantage over the other methods. Each has strengths and weaknesses that need to be taken into account when deciding which one to use to get the best results from subfield volumetry

Bayesian segmentation of brainstem structures in MRI

VK: Lampinen, J.In this paper we present a method to segment four brainstem structures (midbrain, pons, medulla oblongata and superior cerebellar peduncle) from 3D brain MRI scans. The segmentation method relies on a probabilistic atlas of the brainstem and its neighboring brain structures. To build the atlas, we combined a dataset of 39 scans with already existing manual delineations of the whole brainstem and a dataset of 10 scans in which the brainstem structures were manually labeled with a protocol that was specifically designed for this study. The resulting atlas can be used in a Bayesian framework to segment the brainstem structures in novel scans. Thanks to the generative nature of the scheme, the segmentation method is robust to changes in MRI contrast or acquisition hardware. Using cross validation, we show that the algorithm can segment the structures in previously unseen T1 and FLAIR scans with great accuracy (mean error under 1 mm) and robustness (no failures in 383 scans including 168 AD cases). We also indirectly evaluate the algorithm with a experiment in which we study the atrophy of the brainstem in aging. The results show that, when used simultaneously, the volumes of the midbrain, pons and medulla are significantly more predictive of age than the volume of the entire brainstem, estimated as their sum. The results also demonstrate that the method can detect atrophy patterns in the brainstem structures that have been previously described in the literature. Finally, we demonstrate that the proposed algorithm is able to detect differential effects of AD on the brainstem structures. The method will be implemented as part of the popular neuroimaging package FreeSurfer.Peer reviewe

Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

SEGMA: an automatic SEGMentation Approach for human brain MRI using sliding window and random forests

Quantitative volumes from brain magnetic resonance imaging (MRI) acquired across the life course may be useful for investigating long term effects of risk and resilience factors for brain development and healthy aging, and for understanding early life determinants of adult brain structure. Therefore, there is an increasing need for automated segmentation tools that can be applied to images acquired at different life stages. We developed an automatic segmentation method for human brain MRI, where a sliding window approach and a multi-class random forest classifier were applied to high-dimensional feature vectors for accurate segmentation. The method performed well on brain MRI data acquired from 179 individuals, analyzed in three age groups: newborns (38–42 weeks gestational age), children and adolescents (4–17 years) and adults (35–71 years). As the method can learn from partially labeled datasets, it can be used to segment large-scale datasets efficiently. It could also be applied to different populations and imaging modalities across the life course

A probabilistic atlas of the human thalamic nuclei combining ex vivo MRI and histology

The human thalamus is a brain structure that comprises numerous, highly specific nuclei. Since these nuclei are known to have different functions and to be connected to different areas of the cerebral cortex, it is of great interest for the neuroimaging community to study their volume, shape and connectivity in vivo with MRI. In this study, we present a probabilistic atlas of the thalamic nuclei built using ex vivo brain MRI scans and histological data, as well as the application of the atlas to in vivo MRI segmentation. The atlas was built using manual delineation of 26 thalamic nuclei on the serial histology of 12 whole thalami from six autopsy samples, combined with manual segmentations of the whole thalamus and surrounding structures (caudate, putamen, hippocampus, etc.) made on in vivo brain MR data from 39 subjects. The 3D structure of the histological data and corresponding manual segmentations was recovered using the ex vivo MRI as reference frame, and stacks of blockface photographs acquired during the sectioning as intermediate target. The atlas, which was encoded as an adaptive tetrahedral mesh, shows a good agreement with with previous histological studies of the thalamus in terms of volumes of representative nuclei. When applied to segmentation of in vivo scans using Bayesian inference, the atlas shows excellent test-retest reliability, robustness to changes in input MRI contrast, and ability to detect differential thalamic effects in subjects with Alzheimer's disease. The probabilistic atlas and companion segmentation tool are publicly available as part of the neuroimaging package FreeSurfer

Heritability and reliability of automatically segmented human hippocampal formation subregions

The human hippocampal formation can be divided into a set of cytoarchitecturally and functionally distinct subregions, involved in different aspects of memory formation. Neuroanatomical disruptions within these subregions are associated with several debilitating brain disorders including Alzheimer's disease, major depression, schizophrenia, and bipolar disorder. Multi-center brain imaging consortia, such as the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, are interested in studying disease effects on these subregions, and in the genetic factors that affect them. For large-scale studies, automated extraction and subsequent genomic association studies of these hippocampal subregion measures may provide additional insight. Here, we evaluated the test-retest reliability and transplatform reliability (1.5 T versus 3 T) of the subregion segmentation module in the FreeSurfer software package using three independent cohorts of healthy adults, one young (Queensland Twins Imaging Study, N=39), another elderly (Alzheimer's Disease Neuroimaging Initiative, ADNI-2, N=163) and another mixed cohort of healthy and depressed participants (Max Planck Institute, MPIP, N=598). We also investigated agreement between the most recent version of this algorithm (v6.0) and an older version (v5.3), again using the ADNI-2 and MPIP cohorts in addition to a sample from the Netherlands Study for Depression and Anxiety (NESDA) (N=221). Finally, we estimated the heritability (h(2)) of the segmented subregion volumes using the full sample of young, healthy QTIM twins (N=728). Test-retest reliability was high for all twelve subregions in the 3 T ADNI-2 sample (intraclass correlation coefficient (ICC)=0.70-0.97) and moderate-to-high in the 4 TQTIM sample (ICC=0.5-0.89). Transplatform reliability was strong for eleven of the twelve subregions (ICC=0.66-0.96); however, the hippocampal fissure was not consistently reconstructed across 1.5 T and 3 T field strengths (ICC=0.47-0.57). Between-version agreement was moderate for the hippocampal tail, subiculum and presubiculum (ICC=0.78-0.84; Dice Similarity Coefficient (DSC)=0.55-0.70), and poor for all other subregions (ICC=0.34-0.81; DSC=0.28-0.51). All hippocampal subregion volumes were highly heritable (h(2)=0.67-0.91). Our findings indicate that eleven of the twelve human hippocampal subregions segmented using FreeSurfer version 6.0 may serve as reliable and informative quantitative phenotypes for future multi-site imaging genetics initiatives such as those of the ENIGMA consortium. (C) 2016 The Authors. Published by Elsevier Inc

A generative probability model of joint label fusion for multi-atlas based brain segmentation

Automated labeling of anatomical structures in medical images is very important in many neuroscience studies. Recently, patch-based labeling has been widely investigated to alleviate the possible mis-alignment when registering atlases to the target image. However, the weights used for label fusion from the registered atlases are generally computed independently and thus lack the capability of preventing the ambiguous atlas patches from contributing to the label fusion. More critically, these weights are often calculated based only on the simple patch similarity, thus not necessarily providing optimal solution for label fusion. To address these limitations, we propose a generative probability model to describe the procedure of label fusion in a multi-atlas scenario, for the goal of labeling each point in the target image by the best representative atlas patches that also have the largest labeling unanimity in labeling the underlying point correctly. Specifically, sparsity constraint is imposed upon label fusion weights, in order to select a small number of atlas patches that best represent the underlying target patch, thus reducing the risks of including the misleading atlas patches. The labeling unanimity among atlas patches is achieved by exploring their dependencies, where we model these dependencies as the joint probability of each pair of atlas patches in correctly predicting the labels, by analyzing the correlation of their morphological error patterns and also the labeling consensus among atlases. The patch dependencies will be further recursively updated based on the latest labeling results to correct the possible labeling errors, which falls to the Expectation Maximization (EM) framework. To demonstrate the labeling performance, we have comprehensively evaluated our patch-based labeling method on the whole brain parcellation and hippocampus segmentation. Promising labeling results have been achieved with comparison to the conventional patch-based labeling method, indicating the potential application of the proposed method in the future clinical studies

Content based retrieval of PET neurological images

Medical image management has posed challenges to many researchers, especially when the images have to be indexed and retrieved using their visual content that is meaningful to clinicians. In this study, an image retrieval system has been developed for 3D brain PET (Position emission tomography) images. It has been found that PET neurological images can be retrieved based upon their diagnostic status using only data pertaining to their content, and predominantly the visual content. During the study PET scans are spatially normalized, using existing techniques, and their visual data is quantified. The mid-sagittal-plane of each individual 3D PET scan is found and then utilized in the detection of abnormal asymmetries, such as tumours or physical injuries. All the asymmetries detected are referenced to the Talairarch and Tournoux anatomical atlas. The Cartesian co- ordinates in Talairarch space, of detected lesion, are employed along with the associated anatomical structure(s) as the indices within the content based image retrieval system. The anatomical atlas is then also utilized to isolate distinct anatomical areas that are related to a number of neurodegenerative disorders. After segmentation of the anatomical regions of interest algorithms are applied to characterize the texture of brain intensity using Gabor filters and to elucidate the mean index ratio of activation levels. These measurements are combined to produce a single feature vector that is incorporated into the content based image retrieval system. Experimental results on images with known diagnoses show that physical lesions such as head injuries and tumours can be, to a certain extent, detected correctly. Images with correctly detected and measured lesion are then retrieved from the database of images when a query pertains to the measured locale. Images with neurodegenerative disorder patterns have been indexed and retrieved via texture-based features. Retrieval accuracy is increased, for images from patients diagnosed with dementia, by combining the texture feature and mean index ratio value