NeuronSifter: An Agent-in-Twin for Prioritizing Central Nervous System Interventions with World Action Models

Haowei Xu, Wanyi Fu, Hongbin Han, Zhaoheng Xie

Effective central nervous system (CNS) intervention requires more than predicting biological responses: a scientific system must determine which intervention, observation, or additional evidence can improve a decision under uncertainty. However, in partially observed neuronal microenvironments, identical predicted outcomes may correspond to different exposure states, biological mechanisms, and intervention risks. We propose NeuronSifter, a decision-centric Agent-in-Twin framework, where an AI agent operates with an evolving biological digital twin rather than a fixed predictive model. NeuronSifter compiles interventions into state-conditional target-occupancy representations, propagates them through a mechanism-grounded World Action Model (WAM), and selects informative measurements based on their expected reduction in decision uncertainty. A shared probabilistic belief state couples intervention simulation, observation selection, and outcome assimilation, enabling the digital twin to continuously refine its decision-relevant representations through externally verified evidence. We evaluate NeuronSifter in Alzheimer's disease intervention scenarios using mechanistic neuronal…