Learning Biophysical Models of Large-Scale Multineuronal Data To Enable Precise Neurostimulation

Multi-compartment Hodgkin–Huxley (HH) models provide a principled framework for predicting neural dynamics and responses to electrical stimulation. However, fitting HH biophysical parameters typically requires intracellular recordings, which are invasive and low-throughput, limiting the ability to capture the geometry and cell-specific properties of many neurons in a given neural circuit. Multi-electrode arrays (MEAs) offer a scalable alternative—high-density extracellular measurements from full neural populations—but HH model complexity has so far precluded reliable biophysical inference from extracellular data alone. Here, we introduce a framework that rapidly infers HH parameters from designed features of extracellular MEA measurements by leveraging differentiable biophysical simulation and simulation-based inference, unlocking a wide range of downstream applications. In this work, we focus on a central goal of translational neuroengineering: predicting neural spiking responses to candidate neurostimulation patterns that would take hours to measure clinically. To validate our approach, we collected hundreds of hours of stimulation and recording data from isolated macaque retina with a 30 µm-pitch 512-electrode array. Our framework predicted previously unseen multi-electrode stimulation responses with 90.4\% accuracy using HH models fit from only a few minutes of recording, replacing hours of stimulus testing.