An Instructive Neural Interface for Layer-Specific Cortical Repair with Human Brain Organoids

While human brain organoids (hBOs) provide a promising cell source, their therapeutic potential is limited by disorganized integration. Here, we demonstrated that targeted neuromodulation, steered by endogenous narrowband gamma (NBG) rhythms, could instruct the structural and functional integration of hBOs grafts in the injured adult mouse visual cortex.

Using a neural interface system, we first promoted general graft-host coupling and then delivered NBG-rhythmic stimulation to specific functional clusters during a critical period of plasticity. This two-phase strategy guided the emergence of layer 4-appropriate molecular and functional properties within the grafts, established bidirectional connectivity with the host visual pathway, and supported the development of advanced visual processing, including direction selectivity in hBOs neurons.