Daume Jonathan, Yebra Mar, Reed Chrystal M, Skelin Ivan, Salimpour Yousef, Kamiński Jan, Marin Andre Cornejo, Anderson William S, Valiante Taufik A, Mamelak Adam N, Rutishauser Ueli
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA.
bioRxiv. 2025 Aug 21:2025.08.20.671301. doi: 10.1101/2025.08.20.671301.
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.
工作记忆（WM）能够对信息进行临时维持和操控，支持灵活的、目标导向行为。虽然越来越多的证据表明海马体有助于工作记忆存储，但其在工作记忆中的因果作用仍不明确。在此，我们将海马体和几个皮质区域的同步颅内单神经元记录与人类海马体的局灶性电刺激相结合，以测试海马体活动对工作记忆的因果必要性。30名植入混合深度电极的患者以图像作为记忆内容执行一项工作记忆任务。在一部分试验的维持期内，对海马体进行电刺激（2秒，50赫兹，1毫安）。在行为层面，刺激损害了工作记忆表现，降低了准确性并延长了反应时间。在神经元层面，刺激减少了海马体和腹侧颞叶皮质（VTC）中记忆内容选择性的持续活动，从而破坏了特定内容的神经表征。神经破坏的程度在逐次试验中与受损的工作记忆相关行为相关，建立了神经活动破坏与工作记忆受损之间的因果联系。在群体水平上，刺激使神经轨迹更远离吸引子状态，这与记忆保真度下降一致。总之，这些数据提供了因果证据，表明海马体和VTC中单个神经元的持续活动支持人类的工作记忆维持。我们的结果表明，干扰海马体动力学既破坏了单神经元编码，也破坏了群体水平的吸引子稳定性，将细胞机制与行为联系起来，并突出了海马体对工作记忆维持的贡献。
