TUNING THE NEURAL CIRCUITRY OF AFFECTIVE BIASES IN DEPRESSION

抑郁症比其他任何疾病造成的“患病时间”都要长。对患者及其家属来说，这是一种毁灭性的疾病，可能是致命的，有很强的自杀风险。当前的经济衰退导致抑郁症病例显著上升（参见BBC新闻，2011年4月7日；“金钱困境与抑郁症上升有关”），随着寿命的延长，发展为特别恶性的抑郁症的机会也在增加（参见科学“情绪障碍的负担”，2012年10月5日），因此这个项目特别及时。人们对抑郁症的起因知之甚少。许多最常见的抗抑郁药都是偶然发现的，我们不知道它们是如何或为什么起作用的。这个项目试图清楚地了解抑郁症患者和非抑郁症患者大脑回路的差异，然后，关键的是，探索如何调整这些回路，使其恢复健康功能，并解除抑郁情绪。展望未来，该研究还提出了一个问题，即是否有可能在有抑郁症风险的健康人身上安全地调整这些神经回路，以实现促进健康和精神资本的长期目标。使用的主要研究工具是简单的计算机任务和大脑成像，以检查参与处理好或坏经历的大脑回路。抑郁症患者更关注惩罚（如失去金钱，受到电击）而不是奖励（如金钱或食物）；消极的情感偏见。因此，抑郁的人倾向于只关注糟糕的经历，这可能会导致恶性循环，进一步陷入抑郁情绪。相比之下，在一些健康个体中可以看到积极的情感偏见；对负面信息的抑制反应可以防止抑郁的发生。这个项目询问是否有可能通过将消极偏见转变为积极偏见来治疗抑郁症。然而，在抑郁症的这种处理过程中，“缺乏关于高度动态病理通路的神经基础的知识”（科学，2012年10月5日）。这个项目试图通过使用一系列新颖和复杂的脑成像技术来检查皮层-皮层下奖惩回路中大脑下部区域（称为皮层下）和大脑上部区域（称为皮层）之间的相互作用来纠正这一问题。人脑成像研究表明，杏仁核和纹状体等皮层下结构，以及腹侧和背侧前扣带皮层等皮层结构，在奖惩处理过程中至关重要，并导致情感偏见，但尽管我们知道这些区域分别与抑郁有关，但我们不知道它们是如何作为回路相互作用的。此外，许多皮层下结构是如此之小，以至于神经成像技术直到最近才发展到可以精确测量它们在人体中的活动的程度。在描述了这些回路之后，这个项目的关键最后阶段将集中在治疗结果上。这一阶段将检查传统抗抑郁药对奖惩回路的影响，但也将探索使用新型计算机化心理干预作为“认知疫苗”的可能性，以促进抑郁和有风险的健康个体的积极偏见。是否有可能安全地调节与奖励相关的回路，并调节与惩罚相关的回路，以减少抑郁症患者的负面偏见？总之，有三个总体目标：目标1：阐明负责处理奖励和惩罚的大脑回路。目标2：比较健康人与抑郁症患者的神经回路，看看为什么抑郁症患者更倾向于关注惩罚而不是奖励。目标3：使用治疗方法（包括新颖的心理学方法和药物治疗）来改变这种回路，使抑郁症患者（以及有抑郁风险的健康人）更多地关注奖励而不是惩罚。

Depression accounts for more 'years lived with disease' than any other illness. It is a devastating disease for both patients and their families and can be fatal, carrying a strong risk of suicide. The current economic downturn has lead to a significant uptick in cases of depression (see e.g. BBC news, 7 April 2011; "Money woes 'linked to rise in depression'"), and as life-spans increase, so do the chances of developing particularly malignant forms of depression (see e.g. Science "The Burden of Mood Disorders", 5 Oct 2012), making this project especially timely.The causes of depression are poorly understood. Many of the most common antidepressants were discovered by accident, and we do not know how or why they work. This project attempts to clearly understand the differences in brain-circuits in people with and without depression and then, critically, explore how to tune these circuits back to healthy function and lift the depressed mood. Looking to the future, it also asks whether it is possible safely tune these circuits in healthy people at risk of depression with an eye towards a longer-term goal of promoting well-being and mental capital.The main research tools used are simple computer tasks alongside brain imaging to examine the brain circuits involved in the processing of good or bad experiences. People with depression focus more on punishments (e.g. losing money, getting an electrical shock) than rewards (e.g. money or food); a negative affective bias. As such, depressed individuals tend to focus solely on bad experiences which can lead to a downward spiral into further depressed mood. By contrast, positive affective biases are seen in some healthy individuals; a dampened response to negative information that may protect against the onset of depression. This project asks if it is possible treat depression by tuning a negative bias into a positive bias. However, there is a "lack of knowledge regarding the neural underpinnings of the highly dynamic pathological pathways" underlying such processing in depression (Science, 5 Oct 2012). This project seeks to rectify this by using a range of novel and complex brain imaging techniques to examine the interactions between lower brain regions (called subcortical) and higher brain regions (called cortical) in cortical-subcortical reward and punishment circuits. Human brain imaging studies have shown that subcortical structures like the amygdala and striatum, as well as cortical structures like the ventral and dorsal anterior cingulate cortex are critical in reward and punishment processing and contribute to affective bias, but although we know these regions are separately involved in depression, we do not know how they interact as circuits. Furthermore, many subcortical structures are so small that neuroimaging technology has only recently advanced to the point that it is possible to accurately measure their activity in humans.Having delineated these circuits, the critical final stage of this project will focus on treatment outcomes.This phase will examine the impact of conventional antidepressants on reward and punishment circuitry, but will also explore the possibility of using novel computerized psychological interventions as 'cognitive vaccines' to promote positive biases in depressed and at-risk healthy individuals. Is it possible to safely tune-up reward-related circuits, and tune-down punishment-related circuits to reduce negative bias in depressed individuals? In sum, there are three overall aims:Aim 1: Clarify the brain circuitry that is responsible for processing rewards and punishment.Aim 2: Compare this circuitry across healthy and depressed individuals to see why depressed individuals tend to focus more on punishments than rewards.Aim 3: Use treatments (both both novel psychological approaches and drug treatments) to change this circuitry so that depressed (and healthy people at risk of depression) focus more on rewards than punishments.