TUNING THE NEURAL CIRCUITRY OF AFFECTIVE BIASES IN DEPRESSION

抑郁症的患病年数比其他任何疾病都要长。它对患者和他们的家人都是一种毁灭性的疾病，可能是致命的，具有很强的自杀风险。目前的经济低迷导致抑郁症病例显著增加(见BBC新闻，2011年4月7日；“金钱困难‘与抑郁症的上升有关’”)，随着寿命的延长，患上特别恶性形式的抑郁症的几率也增加(见“科学”杂志，“情绪障碍的负担”，2012年10月5日)，这使得这一项目特别及时。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起作用的，也不知道为什么起作用。这个项目试图清楚地了解患有抑郁症和没有抑郁症的人大脑回路的差异，然后关键地探索如何将这些回路调整到健康的功能并改善抑郁情绪。展望未来，它还询问是否有可能安全地调整有抑郁风险的健康人的这些回路，着眼于促进幸福感和智力资本的长期目标。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。抑郁症患者更注重惩罚(例如损失金钱、遭受电击)而不是奖励(例如金钱或食物)；一种消极的情感偏见。因此，抑郁的人倾向于只关注糟糕的经历，这可能会导致螺旋式下降，导致进一步的抑郁情绪。相比之下，在一些健康的人身上可以看到积极的情感偏见；对负面信息的抑制反应可能会预防抑郁症的发生。这个项目询问是否有可能通过将负面偏向调整为积极偏向来治疗抑郁症。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)。该项目试图通过使用一系列新颖而复杂的大脑成像技术来检查皮质-皮质下奖惩回路中较低脑区(称为皮质下)和较高脑区(称为皮质)之间的相互作用，以求纠正这一问题。人脑成像研究表明，杏仁核和纹状体等皮质下结构，以及腹侧和背侧扣带前皮质等皮质结构，在奖惩过程中起着关键作用，并导致情感偏差，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，许多皮质下结构如此之小，以至于神经成像技术直到最近才发展到有可能准确测量它们在人类身上的活动的程度。在描绘了这些回路之后，该项目的关键最后阶段将专注于治疗结果。这一阶段将研究传统抗抑郁药物对奖惩回路的影响，但也将探索使用新型计算机心理干预作为“认知疫苗”的可能性，以促进抑郁症和高危健康个体的积极偏见。有没有可能安全地调整与奖励相关的回路，以及调节与惩罚相关的回路，以减少抑郁症患者的负面偏见？总而言之，总体目标有三个：目标1：澄清负责处理奖励和惩罚的大脑回路。目标2：比较健康和抑郁个体的这一回路，以了解为什么抑郁症患者倾向于更多地关注惩罚而不是奖励。目标3：使用治疗方法(包括新的心理方法和药物治疗)来改变这一回路，使抑郁(和有抑郁风险的健康人)更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.