BrainRotViT: Transformer-ResNet Hybrid for Explainable Modeling of Brain Aging from 3D sMRI

Abstract

Accurate brain-age estimation from structural MRI provides a valuable biomarker for studying healthy aging and neurodegenerative disease. We propose BrainRotViT (Brain ResNet over trained Vision Transformer), a two-stage, slice-based (2.5D) framework that approximates volumetric context while combining the strengths of CNNs and transformers. A Vision Transformer is pretrained on an auxiliary age-sex composite classification task and subsequently frozen. Its per-slice embeddings are stacked into a 160 x 768 feature matrix and processed as a pseudo-image by a lightweight 2D residual CNN regressor, with subject sex incorporated at the final prediction layer. Trained and validated on 5,108 samples from 11 multi-site datasets and tested on four independent held-out cohorts comprising 948 samples, BrainRotViT achieves a validation mean absolute error (MAE) of 3.43 years (Pearson r = 0.98, $R^2$ = 0.96, Spearman $\rho$ = 0.97) and cross-cohort MAEs of 4.79-5.35 years, outperforming retrained 3D-ResNet, SFCN, 3D-ViT, Global-Local Transformer, Triamese-ViT, and TSAN baselines. After age-bias correction and covariate adjustment, brain-age gap is significantly associated with Alzheimer's disease, mild cognitive impairment, and autism spectrum disorder. An interpretability pipeline combining ViT attention with guided backpropagation, saliency sanity checks, and AAL3-based anatomical localization identifies aging-related regions including the occipital lobe, cerebellum, precentral and postcentral gyri, temporal lobes, and medial superior frontal gyrus. BrainRotViT thus provides an efficient and interpretable bridge between CNN and transformer paradigms, demonstrating cross-cohort generalization while yielding biologically meaningful insights into brain aging.