Program in Neuroscience, Stony Brook University, Stony Brook, New York 11794, Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York 10032, Department of Biomedical Engineering, Stony Brook University School of Medicine, Stony Brook, New York 11794, Department of Psychology, Northern Michigan University, Marquette, Michigan 49855, Department of Psychology, Stony Brook University, Stony Brook, New York 11794, and Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
J Neurosci. 2014 Apr 23;34(17):5855-60. doi: 10.1523/JNEUROSCI.4868-13.2014.
The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.
腹侧被盖区（VTA）主要与奖励动机行为有关。最近，异常的多巴胺能 VTA 信号也与动物模型中的焦虑样行为有关。然而，这些发现尚未扩展到人类的焦虑症。在这里，我们假设临床焦虑与人类在威胁处理过程中中边缘系统回路的功能障碍有关；具体来说，中边缘系统厌恶回路的过度或失调活动可能与区分威胁与安全线索的错误有关，也称为“恐惧过度泛化”。为了验证这一点，我们招募了 32 名患有广泛性焦虑症的女性和 25 名年龄匹配的健康对照组女性。当参与者进行由宽度系统变化的矩形组成的恐惧泛化任务时，我们使用 fMRI 测量了大脑活动。一个中等大小的矩形作为条件刺激（CS；50%的电击概率），而宽度为 CS ±20%、±40%和±60%的矩形作为泛化刺激（GS；从未与电击配对）。健康对照组显示 VTA 反应与线索对 CS（威胁）的感知相似性成正比。相比之下，广泛性焦虑症患者对 GS 的 VTA 反应性增强且缺乏辨别力，这一特征与特质焦虑呈正相关，并且中皮质和中海马回的耦合减少。我们的研究结果表明，人类 VTA 和中边缘系统在威胁处理中起着至关重要的作用，而该系统的异常与临床焦虑中的适应不良威胁处理有关。
