Hippocampal stimulation reveals causal role of persistent neural activity in human working memory

Working memory (WM) enables the temporary maintenance and manipulation of information, supporting flexible, goal-directed behavior. While converging evidence suggests that the hippocampus contributes to WM storage, its causal role in WM remains unclear. Here, we combined simultaneous intracranial single-neuron recordings in the hippocampus and several cortical areas with focal electrical stimulation in the human hippocampus to test the causal necessity of hippocampal activity for WM. Thirty patients with implanted hybrid depth electrodes performed a WM task with images as memoranda. Electrical stimulation (2 s, 50 Hz, 1 mA) was delivered to the hippocampus during the maintenance period on a subset of trials. Behaviorally, stimulation impaired WM performance, reducing accuracy and increasing response times. Neuronally, stimulation reduced memoranda-selective persistent activity in hippocampus and ventral temporal cortex (VTC), thereby disrupting content-specific neural representations. The extent of neural disruption was correlated trial-by-trial with impaired WM-related behavior, establishing a causal link between disrupted neural activity and impaired WM. At the population level, stimulation shifted neural trajectories farther from attractor states, consistent with degraded mnemonic fidelity. Together, these data provide causal evidence that persistent activity of individual neurons in hippocampus and VTC supports WM maintenance in humans. Our results demonstrate that perturbing hippocampal dynamics disrupts both single-neuron coding and population-level attractor stability, linking cellular mechanisms to behavior and highlighting hippocampal contributions to WM maintenance.