Multiscale Mechanisms of Human Memory Modulation by Deep Brain Stimulation

The highly variable effects of deep brain stimulation (DBS) on cognition highlight a fundamental gap in our understanding of how external perturbations interface with the brain’s ongoing, task-engaged state. The current study addressed this challenge by combining intracranial EEG recordings with hippocampal DBS stimulation in human participants during spatial sequence memory task. We found 50 Hz stimulation targeting hippocampal white matter enhanced memory performance, whereas 5 Hz stimulation targeting hippocampal gray matter impaired memory. These opposing behavioral outcomes were both governed by two dissociated mechanisms: a region-specific modulation of theta rhythms in an engagement-dependent fashion, and a global modulation of the fidelity of memory representations across the cortex. Our results suggest targeted stimulation can concurrently fine-tune specialized circuits and govern the brain’s global state, which not only offers a novel roadmap for understanding how external inputs shape human cognition, but also helps to design precise, state-dependent neuromodulation therapies.