Through-scalp deep-brain stimulation in tether-free, naturally-behaving mice with widefield NIR-II illumination

Abstract Neural modulation techniques with electricity, light and other forms of energy have enabled the deconstruction of neural circuitry. One major challenge of existing neural modulation techniques is the invasive brain implants and the permanent skull attachment of an optical fiber for modulating neural activity in the deep brain. Here we report an implant-free and tether-free optical neuromodulation technique in deep-brain regions through the intact scalp with brain-penetrant second near-infrared (NIR-II) illumination. Macromolecular infrared nanotransducers for deep-brain stimulation (MINDS) demonstrate exceptional photothermal conversion efficiency of 71% at 1064 nm, the wavelength that minimizes light attenuation by the brain in the entire 400-1700 nm spectrum. Upon widefield 1064-nm illumination >50 cm above the mouse head at a low incident power density of 10 mW/mm 2 , deep-brain neurons are activated by MINDS-sensitized TRPV1 channels with minimal thermal damage. Our approach could open opportunities for simultaneous neuromodulation of multiple socially interacting animals by remotely irradiating NIR-II light to stimulate each subject individually.