Neuromelanin sensitive magnetic resonance imaging (NMS-MRI) has been crucial in identifying abnormalities in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) as PD is characterized by loss of dopaminergic neurons in the SNc. Current techniques employ estimation of contrast ratios of the SNc, visualized on NMS-MRI, to discern PD patients from the healthy controls. However, the extraction of these features is time-consuming and laborious and moreover provides lower prediction accuracies. Furthermore, these do not account for patterns of subtle changes in PD in the SNc. To mitigate this, our work establishes a computer-based analysis technique that uses convolutional neural networks (CNNs) to create prognostic and diagnostic biomarkers of PD from NMS-MRI. Our technique not only performs with a superior testing accuracy (80%) as compared to contrast ratio-based classification (56.5% testing accuracy) and radiomics classifier (60.3% testing accuracy), but also supports discriminating PD from atypical parkinsonian syndromes (85.7% test accuracy). Moreover, it has the capability to locate the most discriminative regions on the neuromelanin contrast images. These discriminative activations demonstrate that the left SNc plays a key role in the classification in comparison to the right SNc, and are in agreement with the concept of asymmetry in PD. Overall, the proposed technique has the potential to support radiological diagnosis of PD while facilitating deeper understanding into the abnormalities in SNc.

Objective: The larger sample sizes available from multi-site publicly available neuroimaging data repositories makes machine-learning based diagnostic classification of mental disorders more feasible by alleviating the curse of dimensionality. However, since multi-site data are aggregated post-hoc, i.e. they were acquired from different scanners with different acquisition parameters, non-neural inter-site variability may mask inter-group differences that are at least in part neural in origin. Hence, the advantages gained by the larger sample size in the context of machine-learning based diagnostic classification may not be realized. Methods: We address this issue using harmonization of multi-site neuroimaging data using the ComBat technique, which is based on an empirical Bayes formulation to remove inter-site differences in data distributions, to improve diagnostic classification accuracy. Specifically, we demonstrate this using ABIDE (Autism Brain Imaging Data Exchange) multisite data for classifying individuals with Autism from healthy controls using resting state fMRI-based functional connectivity data. Results: Our results show that higher classification accuracies across multiple classification models can be obtained (especially for models based on artificial neural networks) from multi-site data post harmonization with the ComBat technique as compared to without harmonization, outperforming earlier results from existing studies using ABIDE. Furthermore, our network ablation analysis facilitated important insights into autism spectrum disorder pathology and the connectivity in networks shown to be important for classification covaried with verbal communication impairments in Autism. Conclusion: Multi-site data harmonization using

We propose a CNN based technique that aggregates feature maps from its multiple layers that can localize abnormalities with greater details as well as predict pathology under consideration. Existing class activation mapping (CAM) techniques extract feature maps from either the final layer or a single intermediate layer to create the discriminative maps and then interpolate to upsample to the original image resolution. In this case, the subject specific localization is coarse and is unable to capture subtle abnormalities. To mitigate this, our method builds a novel CNN based discriminative localization model that we call high resolution CAM (HR-CAM), which accounts for layers from each resolution, therefore facilitating a comprehensive map that can delineate the pathology for each subject by combining low-level, intermediate as well as highlevel features from the CNN. Moreover, our model directly provides the discriminative map in the resolution of the original image facilitating finer delineation of abnormalities. We demonstrate the working of our model on a simulated abnormalities data where we illustrate how the model captures finer details in the final discriminative maps as compared to current techniques. We then apply this technique: (1) to classify ependymomas from grade IV glioblastoma on T1weighted contrast enhanced (T1-CE) MRI and (2) to predict Parkinson's disease from neuromelanin sensitive MRI. In all these cases we demonstrate that our model not only predicts pathologies with high accuracies, but also creates clinically interpretable subject specific high resolution discriminative localizations. Overall, the technique can be generalized to any CNN and carries high relevance in a clinical setting.

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Purpose Existing class activation mapping (CAM) techniques extract the feature maps only from a single layer of the convolutional neural net (CNN), generally from the final layer and then interpolate to upsample to the original image resolution to locate the discriminative regions. Consequently these provide a coarse localization that may not be able to capture subtle abnormalities in medical images. To alleviate this, our work proposes a technique called high resolution class activation mapping (HR-CAMs) that can provide enhanced visual explainability to the CNN models. Methods HR-CAMs fuse feature maps by training a network using the input from multiple layers of a trained CNN, thus gaining information from every layer that can localize abnormalities with greater details in original image resolution. The technique is validated qualitatively and quantitatively on a simulated dataset of 8,000 images followed by applications on multiple image analysis tasks that include (1) skin lesion classification (ISIC open dataset—25,331 cases) and (2) predicting bone fractures (MURA open dataset—40,561 images) (3) predicting Parkinson’s disease (PD) from neuromelanin sensitive MRI (small cohort-80 subjects). Results We demonstrate that our model creates clinically interpretable subject specific high resolution discriminative localizations when compared to widely used CAMs and Gradient-CAMs. Conclusion HR-CAMs provide finer delineation of abnormalities thus facilitating superior explainability to CNNs as has been demonstrated from its rigorous validation.