Pulkit Khandelwal

Sadhana Ravikumar, Ranjit Ittyerah, Sydney Lim et al.

When developing tools for automated cortical segmentation, the ability to produce topologically correct segmentations is important in order to compute geometrically valid morphometry measures. In practice, accurate cortical segmentation is challenged by image artifacts and the highly convoluted anatomy of the cortex itself. To address this, we propose a novel deep learning-based cortical segmentation method in which prior knowledge about the geometry of the cortex is incorporated into the network during the training process. We design a loss function which uses the theory of Laplace's equation applied to the cortex to locally penalize unresolved boundaries between tightly folded sulci. Using an ex vivo MRI dataset of human medial temporal lobe specimens, we demonstrate that our approach outperforms baseline segmentation networks, both quantitatively and qualitatively.

Pulkit Khandelwal, Michael Tran Duong, Shokufeh Sadaghiani et al.

Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high resolution of 135 postmortem human brain tissue specimens imaged at 0.3 mm$^{3}$ isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We then segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter. We show generalizing capabilities across whole brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm^3 and 0.16 mm^3 isotropic T2*w FLASH sequence at 7T. We then compute localized cortical thickness and volumetric measurements across key regions, and link them with semi-quantitative neuropathological ratings. Our code, Jupyter notebooks, and the containerized executables are publicly available at: https://pulkit-khandelwal.github.io/exvivo-brain-upenn

Pulkit Khandelwal, Michael Tran Duong, Lisa Levorse et al.

Magnetic resonance imaging (MRI) is the standard modality to understand human brain structure and function in vivo (antemortem). Decades of research in human neuroimaging has led to the widespread development of methods and tools to provide automated volume-based segmentations and surface-based parcellations which help localize brain functions to specialized anatomical regions. Recently ex vivo (postmortem) imaging of the brain has opened-up avenues to study brain structure at sub-millimeter ultra high-resolution revealing details not possible to observe with in vivo MRI. Unfortunately, there has been limited methodological development in ex vivo MRI primarily due to lack of datasets and limited centers with such imaging resources. Therefore, in this work, we present one-of-its-kind dataset of 82 ex vivo T2w whole brain hemispheres MRI at 0.3 mm isotropic resolution spanning Alzheimer's disease and related dementias. We adapted and developed a fast and easy-to-use automated surface-based pipeline to parcellate, for the first time, ultra high-resolution ex vivo brain tissue at the native subject space resolution using the Desikan-Killiany-Tourville (DKT) brain atlas. This allows us to perform vertex-wise analysis in the template space and thereby link morphometry measures with pathology measurements derived from histology. We will open-source our dataset docker container, Jupyter notebooks for ready-to-use out-of-the-box set of tools and command line options to advance ex vivo MRI clinical brain imaging research on the project webpage.

Pulkit Khandelwal, Shokufeh Sadaghiani, Michael Tran Duong et al.

Ex vivo MRI of the brain provides remarkable advantages over in vivo MRI for visualizing and characterizing detailed neuroanatomy. However, automated cortical segmentation methods in ex vivo MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high resolution 7 Tesla dataset of 32 ex vivo human brain specimens. We benchmark the cortical mantle segmentation performance of nine neural network architectures, trained and evaluated using manually-segmented 3D patches sampled from specific cortical regions, and show excellent generalizing capabilities across whole brain hemispheres in different specimens, and also on unseen images acquired at different magnetic field strength and imaging sequences. Finally, we provide cortical thickness measurements across key regions in 3D ex vivo human brain images. Our code and processed datasets are publicly available at https://github.com/Pulkit-Khandelwal/picsl-ex-vivo-segmentation.

Yue Li, Pulkit Khandelwal, Long Xie et al.

The medial temporal lobe (MTL) is a region impacted extensively and non-uniformly in early stages of Alzheimer's disease (AD). Regional MTL morphometric measures extracted from magnetic resonance imaging (MRI) are supportive features for the diagnosis of AD and related disorders (ADRD). Different MRI modalities have distinct advantages for MTL morphometry. Anisotropic T2-weighted (T2w) MRI is preferred for hippocampal subfields due to its higher contrast between hippocampal layers. Isotropic T1-weighted (T1w) MRI is beneficial for thickness calculation of extra-hippocampal subregions due to its stable image quality and isotropic resolution. We propose a multi-modality MTL segmentation algorithm that bridges the T1w and T2w modalities by bringing both to a nearly isotropic voxel space. Guided by high-resolution ex vivo 9.4T MRI, an upsampling model was designed for the ground truth segmentations. Combined with non-local means upsampling, this model was used to construct a nearly iso-tropic T1w and T2w MTL subregion segmentation training set, which was used to train a nnUNet model. Morphometric biomarkers extracted by this model were compared to those extracted using conventional models operating in anisotropic spaces on downstream tasks. Biomarkers extracted using the proposed model had greater ability to discriminate between individuals with mild cognitive impairment and cognitively unimpaired; and had great-er longitudinal stability. These findings suggest that the biomarkers derived from T1w and T2w MRI unsampled to nearly isotropic resolution have sig-nificant potential for improving disease diagnosis and monitoring disease progression in ADRD.

Yue Li, Pulkit Khandelwal, Rohit Jena et al.

Imaging biomarkers in magnetic resonance imaging (MRI) are important tools for diagnosing and tracking Alzheimer's disease (AD). As medial temporal lobe (MTL) is the earliest region to show AD-related hallmarks, brain atrophy caused by AD can first be observed in the MTL. Accurate segmentation of MTL subregions and extraction of imaging biomarkers from them are important. However, due to imaging limitations, the resolution of T2-weighted (T2w) MRI is anisotropic, which makes it difficult to accurately extract the thickness of cortical subregions in the MTL. In this study, we used an implicit neural representation method to combine the resolution advantages of T1-weighted and T2w MRI to accurately upsample an MTL subregion atlas set from anisotropic space to isotropic space, establishing a multi-modality, high-resolution atlas set. Based on this atlas, we developed an isotropic MTL subregion segmentation model. In an independent test set, the cortical subregion thickness extracted using this isotropic model showed higher significance than an anisotropic method in distinguishing between participants with mild cognitive impairment and cognitively unimpaired (CU) participants. In longitudinal analysis, the biomarkers extracted using isotropic method showed greater stability in CU participants. This study improved the accuracy of AD imaging biomarkers without increasing the amount of atlas annotation work, which may help to more accurately quantify the relationship between AD and brain atrophy and provide more accurate measures for disease tracking.

Pulkit Khandelwal, Paul Yushkevich

Deep learning models perform best when tested on target (test) data domains whose distribution is similar to the set of source (train) domains. However, model generalization can be hindered when there is significant difference in the underlying statistics between the target and source domains. In this work, we adapt a domain generalization method based on a model-agnostic meta-learning framework to biomedical imaging. The method learns a domain-agnostic feature representation to improve generalization of models to the unseen test distribution. The method can be used for any imaging task, as it does not depend on the underlying model architecture. We validate the approach through a computed tomography (CT) vertebrae segmentation task across healthy and pathological cases on three datasets. Next, we employ few-shot learning, i.e. training the generalized model using very few examples from the unseen domain, to quickly adapt the model to new unseen data distribution. Our results suggest that the method could help generalize models across different medical centers, image acquisition protocols, anatomies, different regions in a given scan, healthy and diseased populations across varied imaging modalities.