Reduced NEXI protocol for the quantification of human gray matter microstructure on the Connectome 2.0 scanner

arXiv:2509.09513v2 Announce Type: replace-cross Abstract: Biophysical diffusion MRI models like Neurite Exchange Imaging (NEXI) are essential for probing gray matter microstructure, estimating compartment diffusivities, neurite fraction, and exchange time. However, NEXI's multi-shell, multi-diffusion-time requirements cause prohibitively long acquisitions. Leveraging the Connectome 2.0 ultra-high gradient scanner, we developed a time-efficient protocol using an Explainable AI (XAI) framework. Combining XGBoost, SHAP, and Recursive Feature Elimination trained on synthetic signals, XAI identified an optimal 8-feature subset, cutting scan time from 27 to 14 minutes. Validated in vivo in seven healthy participants, the XAI protocol was benchmarked against the full 15-feature acquisition, a Cram'er-Rao Lower Bound (CRLB) theoretical optimum, and two heuristics ("Mid-Range" and "Corner"). It robustly reproduced parameter estimates and maintained test-retest reproducibility. Remarkably, the XAI selection converged to the CRLB optimum. This validates XAI's optimality while highlighting its main advantage: achieving gold-standard optimization without complex analytical Jacobians, making it easily adaptable to numerical models or complex noise where CRLB is intractable. Furthermore, XAI showed superior in vivo robustness over heuristics: "Mid-Range" sampling yielded biased exchange time estimates from insufficient temporal diversity, while "Corner" sampling gave unstable intra-neurite diffusivity estimates (5-fold higher CV) due to noise sensitivity. Ultimately, this robust 14-minute protocol accelerates exchange-sensitive microstructural mapping, establishing a model-agnostic optimization framework adaptable to future ultra-high gradient systems and existing clinical scanners.