Closed-Loop Decoding and Intervention of Pain: A Novel BMI Strategy Integrating θ-Band Detection and Mechano-Electro-Biological Coupled Hydrogels.

Neuropathic pain (NP) lacks objective biomarkers and effective therapies. We developed a closed-loop brain-machine interface (BMI) using a novel hydrogel electrode for integrated NP management. Clinically, we identified enhanced prefrontal θ-band (4-8 Hz) activity as a specific NP biomarker. To achieve stable long-term recording, we engineered a PFAPT hydrogel with superior biocompatibility, anti-swelling, and low impedance. In rats, it enabled stable electrocorticography (ECoG) acquisition for 28 d, outperforming screw electrodes, and validated θ-band alterations in NP. Incorporated into a closed-loop BMI, the hydrogel delivered θ-triggered cortical stimulation, which increased pain thresholds and alleviated anxiety- and depression-like behaviors in NP rats. Spatial transcriptomics revealed that stimulation bidirectionally regulated inflammation, central sensitization, and affective pathways. This work presents a hydrogel-based closed-loop BMI as a precise diagnostic and therapeutic platform for NP.