健康与遗传心理学研究室知识库

恐惧是在生物进化过程中演化出来的一种基本情感，是我们非常熟悉的基本情绪之一。在远古时期，它可以帮助我们躲避猛兽，预测天灾。现在它依然可以帮助我们抵御和预防外在危险，保护我们的人身安全，在我们的生活中发挥重要作用。然而，过度的恐惧则会适得其反，导致一系列的精神疾病，比如焦虑障碍(anxiety disorders)、惊恐障碍(panic disorders)、创伤后应激障碍(post-traumatic stress disorder, PTSD)等。近年来随着经济发展速度提升，人们的生活节奏加快，生活压力逐渐增大;自然环境恶化，人与自然的矛盾增加;现代社会的工作分工越来越细致，行业竞争更加激烈，这些因素都对人们的心理健康造成了不良影响，使得恐惧的相关疾病呈现高发的趋势。但是目前恐惧的机制和相关神经环路基础还有待进一步探索，恐惧相关疾病的治疗技术还不够完善和成熟，使得许多恐惧相关的疾病得不到很好的治疗。因此研究恐惧情绪的各个加工过程的神经机制就变得尤为重要。恐惧加工过程包括恐惧记忆的习得、提取、消退等过程，探索恐惧的各个加工过程中涉及的神经机制能够为临床上治疗和预防恐惧相关疾病提供理论依据和切实指导。

大量动物研究表明，恐惧习得和表达依赖于内侧前额叶皮层(medial prefrontal cortex, mPFC)和基底外侧杏仁核(brio-lateral amygdale, BLA)的协调活动，theta振荡支持这种远距离的同步活动。然而，目前尚不清楚这种杏仁核-内侧前额叶的theta环路是否可以推广到人类的恐惧习得过程中。因此，本研究旨在探讨使用人类颅内脑电(intracranial electroencephalography, iEEG)和皮肤电(skin conductance response, SC助记录的内侧前额叶皮层和基底外侧杏仁核在条件性恐惧习得中的作用，并进一步探究腹内侧前额叶皮层(ventral medial prefrontal cortex, dmPFC)与背内侧前额叶(dorsal medial prefrontal cortex, dmPFC)在恐惧习得中的功能是否存在差异。具体来说，我们想要探究以下几占.

(1)基底外侧杏仁核与腹/背内侧前额叶参与恐惧记忆习得过程的具体活动特征。

(2)基底外侧杏仁核与腹/背内侧前额叶的活动在恐惧习得过程中是否存在同步性。

(3)恐惧习得过程中的各个试次之间，各区域活动的时间动态性。

为了探讨这些问题，我们使用了一种恐惧条件反射范式。在研究一中，我们研究了条件刺激(conditioned stimulus, CS)个数和电击概率对恐惧学习过程中的皮肤电反应的影响。这项任务由两个或三个不同颜色的方块作为CS(红、绿、蓝或红、绿)，电刺激作为非条件刺激(unconditioned stimulus ,US)。其中一个或两个CS (CS+)与US在50%或38%的试次中配对，而另一个CS (CS-)不与US配对。在实验期间记录被试的皮肤电反应。共有40名在读大学生参与了这项研究。结果发现，当CS+个数为两个时，把电击概率提高到50%，在组上水平被试能够成功学会其中一个CS+，成功率为43%，而当电击概率为38%时，被试无法学会任意一个CS+，成功率为20%;当CS+个数调整为一个时，被试在组上水平的CS+, CS一的皮肤电反应达到了显著，且成功率从43%提高到了67%。因此，当电击概率增加，CS+个数减少时，被试越容易习得恐惧，表现为CS+与CS一的皮肤电反应差异越大。

在研究二中，我们想要探究在恐惧学习过程中，人类的杏仁核一内侧前额叶环路的神经振荡特征与同步性。实验任务由两个不同颜色的方块作为cs(红、绿)，电刺激作为US。其中一个cs acs+}与US在50%的试次中配对，而另一个CS (CS-)不与US配对。在实验期间同时记录颅内脑电和皮肤电反应。共有13名患有药物难治性癫痈患者(7名男性和6名女性)参与了这项研究，4名被试因为未能成功学会恐惧任务被排除出进一步的分析，因此最终对9名被试(5名男性和4名女性)进行了所有的分析。为了识别特定于恐惧记忆的神经活动，我们比较了CS+和CS一的不同电生理反应。

我们发现，在恐惧获取期间，在CS+呈现时，BLA, vmPFC和dmPFC的theta振荡(4-8Hz增强。且BLA-mPFC环路中的theta振荡同步性增强。我们的研究结果表明，mPFC-BLA的theta振荡环路在人类恐惧习得过程中发挥了重要作用，vmPFC也参与了恐惧习得且可能发挥着与dmPFC不同的关键作用，从而将动物研究的关键发现扩展了到人类领域中。

Fear is a basic emotion that evolved in the biological evolution and is one of the most important emotions we are very familiar with. In ancient times, it helped us to avoid beasts and predict natural disasters. Now it can still help us resist and prevent external dangers, protect our personal safety and play an important role in our lives. However, excessive fear can be counterproductive, leading to a range of mental illnesses such as anxiety disorders, panic disorders, and post-traumatic stress disorders (PTSD). In recent years, along with the rapid development of economy, the quickening pace of life, life pressure has gradually increased; the natural environment has deteriorated, and the contradiction between man and nature has increased; the division of work in modern society has become more and more detailed, and industry competition has become more intense. It has a negative impact on people's mental health, making the related diseases of fear appear to be high incidence. However, the current mechanism of fear and the basis of related neural circuits need to be further explored. The treatment techniques of fear-related diseases are still not perfect and mature, and many fear-related diseases are not well treated. Therefore, exploring the neural mechanism of various processes of fear is becoming more and more important. The neural mechanisms of fear learning and extinction can provide theoretical basis and practical guidance for clinical treatment and prevention of fear-related diseases.

A large number of animal studies have shown that fear acquisition and expression are dependent on coordinated activities of the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), which supports this long-distance synchronized activity. However, it is unclear whether the theta band activity of the amygdala-medial prefrontal cortex can be extended to human fear acquisition. Therefore, this study aimed to investigate the role of mPFC and BLA in conditional fear learning using human intracranial electroencephalography (iEEG) and skin conductance responses (SCR）recording. And we want to further explore the difference function between ventral medial prefrontal cortex (vmPFC) and the dorsal medial prefrontal cortex (dmPFC) in fear learning. Specifically, we want to explore the following:

(1) How do BLA and ventral/dorsal medial prefrontal cortex participating in fear learning?

(2) Is there synchronized activity between BLA and ventral/dorsal medial prefrontal cortex during fear learning?

(3) What the dynamics of activities in three regions in the process of fear learning?

To explore these issues, we used a fear conditioning paradigm. In Study 1，we investigated the effects of conditioned stimulus (CS) numbers and shock probability on SCR during fear learning. This task consists of two or three different colored squares as CS (red, green, blue or red, green) and electrical stimulation as an unconditioned stimulus (US). During fear learning, 2 or 1 conditioned stimulus (CS+) were repeatedly paired with an unconditioned stimulus (US) in 50% or 38% trials while one additional conditioned stimuli (CS一)was never paired with a US. The SCR of the subjects was recorded during the experiment. A total of 40 undergraduate students participated in the study. We found that when the probability of electric shock is increased to 50%, people can successfully learn one of the CS+ on group level, the success rate is 43%, but when the probability of shock is 38%, people can't learn any CS+, and the success rate is 20%. When the number of CS+ is adjusted to one, the SCR of CS+ significantly higher than CS一on group level, and the success rate has increased from 43% to 67%. Therefore, when the probability of electric shock increases and the number of CS+ decreases, the more easily the subject learns the fear, the greater difference in SCR between CS+ and CS-.

In Study 2, we wanted to explore the neural activity of BLA-mPFC in humans during fear learning. The experimental task consisted of two different colors as CS (red, green) and electrical stimulation as US. One CS (CS+) is paired with US in 50% of the trials, while the other CS (CS一)is not paired with US. IEEG and SCR were recorded simultaneously during the experiment. A total of 13 patients with pharmacologically refractory epilepsy (7 males and 6 females) participated in the study, and 4 subjects were excluded from further analysis because they failed to learn the fear. Finally, all analyses were performed on 9 patient (5 males and 4 females). To identify neural activities in fear learning, we compared the different responses of CS+ and CS-.

We found that during the fear learning, theta oscillations (4-8 Hz) of BLA, vmPFC and dmPFC were enhanced at CS+ presentation. And theta oscillation synchronization in the BLA-mPFC is enhanced. Our results suggest that the theta oscillation of mPFC-BLA plays an important role in human fear learning, and vmPFC is also involved in fear learning and may play a key role different from dmPFC, so we can help generalize the insights from animial studies to humans.