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This paper describes an activity-dependent intracortical microstimulation (ICMS) system-on-chip (SoC) that converts extracellular neural spikes recorded from one brain region to electrical stimuli delivered to another brain region in real time in vivo. The 10.9-mm2 SoC incorporates two identical 4-channel modules, each comprising an analog recording front-end with total input noise voltage of 3.12 μVrms and noise efficiency factor (NEF) of 2.68, 5.9-μW 10-bit successive approximation register analog-to-digital converters (SAR ADCs), 12.4-μW digital spike discrimination processor, and a programmable constant-current microstimulating back-end that delivers up to 94.5 μA with 6-bit resolution to stimulate the cortical tissue when triggered by neural activity. For autonomous operation, the SoC also integrates biasing and clock generation circuitry, frequency-shift-keyed (FSK) transmitter at 433 MHz, and dc-dc converter that generates a power supply of 5.05 V for the microstimulating back-end from a single 1.5-V battery. Measured results from electrical performance characterization and biological experiments with anesthetized rats are presented from a prototype chip fabricated in AMS 0.35 μm two-poly four-metal (2P/4M) CMOS. A noise analysis for the selected low-noise amplifier (LNA) topology is presented that obtains a minimum NEF of 2.33 for a practical design given the technology parameters and power supply voltage. Future considerations in the SoC design with respect to silicon area and power consumption when increasing the number of channels are also discussed.