BACKGROUND Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging-navigated transcranial magnetic stimulation (TMS). METHODS Subjects (N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear. RESULTS During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear. CONCLUSIONS The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large-scale networks for targeting in future studies.

中文翻译：

---

前额叶皮层刺激增强人类的恐惧消退记忆

背景 动物恐惧条件反射研究阐明了感官刺激和恐惧反应之间习得关联的神经元机制。在大鼠中，边缘下皮层的短暂电刺激已被证明可以减少消退记忆回忆期间的条件性冻结。在这里，我们通过磁共振成像导航经颅磁刺激 (TMS) 将这一发现转化为人类。方法受试者（N = 28）厌恶地适应两种不同的线索（第1天）。在灭绝学习期间（第 2 天），TMS 与条件线索之一配对，但不与另一个配对。TMS 参数与大鼠边缘下皮层中使用的参数相似：提示开始后 100 毫秒开始的短暂脉冲序列（20 赫兹时为 300 毫秒），总共四列（28 个 TMS 脉冲）。TMS 应用于左额叶皮层的两个目标之一，一个与腹内侧前额叶皮层下边缘皮层的人类同源物功能连接（目标 1），另一个未连接（目标 2，控制）。皮肤电导反应被用作条件恐惧的指标。结果 在灭绝回忆期间（第 3 天），与 TMS 配对的提示与目标 1 显示皮肤电导反应显着降低，而 TMS 对目标 2 没有影响。此外，我们构建了组级地图，用恐惧水平加权 TMS 诱导的电场和扩散磁共振成像连接估计。这些地图显示了不同的皮质区域和与恐惧减少和增加相关的大规模网络。