Grad-CAM helps interpret the deep learning models trained to classify multiple sclerosis types using clinical brain magnetic resonance imaging

Deep learning using convolutional neural networks (CNNs) has shown great promise in advancing neuroscience research. However, the ability to interpret the CNNs lags far behind, confounding their clinical translation. We interrogated 3 heatmap-generating techniques that have increasing generalizability for CNN interpretation: class activation mapping (CAM), gradient (Grad)-CAM, and Grad-CAM++. To investigate the impact of CNNs on heatmap generation, we also examined 6 different models trained to classify brain magnetic resonance imaging into 3 types: relapsing-remitting multiple sclerosis (RRMS), secondary progressive MS (SPMS), and control. Further, we designed novel methods to visualize and quantify the heatmaps to improve interpretability. Grad-CAM showed the best heatmap localizing ability, and CNNs with a global average pooling layer and pretrained weights had the best classification performance. Based on the best-performing CNN model, called VGG19, the 95th percentile values of Grad-CAM in SPMS were significantly higher than RRMS, indicating greater heterogeneity. Further, voxel-wise analysis of the thresholded Grad-CAM confirmed the difference identified visually between RRMS and SPMS in discriminative brain regions: occipital versus frontal and occipital, or temporal/parietal. No study has examined the CAM methods together using clinical images. There is also lack of study on the impact of CNN architecture on heatmap outcomes, and of technologies to quantify heatmap patterns in clinical settings. Grad-CAM outperforms CAM and Grad-CAM++. Integrating Grad-CAM, novel heatmap quantification approaches, and robust CNN models may be an effective strategy in identifying the most crucial brain areas underlying disease development in MS.