Mapping the neural circuit of credit assignment for a new targeted intervention in addiction

想象一下，你不能穿着你的幸运袜子去参加即将到来的考试。如果失败了，你会责怪自己没穿衣服还是准备不足？识别哪些操作导致特定事件发生的能力称为“信用分配”。这种能力使个人能够正确地做出决定并从错误中吸取教训。学分分配的问题与各种心理健康状况有关，如成瘾和强迫症--个人继续相信自己的吸毒或仪式会带来积极的结果[1]。然而，临床医生倾向于根据他们的临床症状来定义和诊断精神疾病，而不是根据他们潜在的心理特征或生物异常[2]。还没有人研究大脑的变化如何导致精神障碍中出现的信用分配问题。解开这个谜题将帮助我们理解人类如何计算出因果关系，以及当他们失去这种能力时会发生什么。我与这一奖学金的计划是：i)从大型数据库中提取描述一个人的能力或缺乏能力的临床相关特征，ii)将它们映射到大脑机制上，iii)恢复已识别的电路功能障碍，从而减少成瘾患者的相关适应不良行为。为了做到这一点，我将在第一阶段从一项在线研究中收集大规模数据集(“大数据”)，参与者将把功劳分配给预测各种事件的不同刺激。计算学习模型将被用来解释这个庞大的数据集，梳理出信用分配的隐藏的注意和学习特征[3-5]，并将它们与不同的精神病学维度联系起来。然后，这些数据将与神经数据(在参与者执行相同的信用分配任务时通过功能磁共振获得)进行对比。这将有助于绘制出涉及信用分配的完整神经回路，并将其与精神健康问题的表型联系起来。在团契的第二阶段，我计划使用一种名为超声波神经刺激的尖端技术，针对导致病理性信用分配和过度依赖习惯的大脑不同部分。超声波神经刺激是一种早期的非侵入性治疗技术，通过以毫米级的精度刺激脑组织，有可能改善数百万精神健康患者的生活[6]。我之前的研究最近表明，超声波可以安全地调节猕猴大脑深层区域的活动，从而引发精确的行为变化[7]。重要的是，它在人类身上的安全使用也已经确定[8-9]。综上所述，超声神经刺激将被用来恢复参与信用分配的大脑区域，并缓解患者相应的负面症状。这一方法有可能通过设计有效恢复大脑功能的新刺激范式，帮助近200万患有适应不良成瘾行为模式的患者。此外，除了成瘾障碍外，超声波脑疗法还可以用来恢复与焦虑、情绪障碍和强迫症有关的大脑回路的正常功能，这些疾病迫切需要有效的治疗方法。纳特诺。8,1481-1489(2005)。[2]Hyman&al.NatRevNeuro。8725-732(2007)。[3]Fouragnan&al.NatComm。68107(2015)。[4]Fouragnan&al.本刊记者。7,4762(2017)。[5]Queirazza，Fouragnan等人。即将在科学进步(2019年)上展出。[6]Aubry JoAcoustSocAm.143,1731-1731(2018)。[7]Fouragnan&al.纳特诺。22,797-808(2019)。[8]Fomeko等人。BrainStime。11,1209-1217(2018)。[9]Tsai等人。MedHypo。84,381-383(2015)。

Imagine that you cannot wear your lucky socks for an upcoming test. In the event of failure, will you blame your absent clothing or your lack of preparation? The ability to identify which actions cause a particular event to occur is called "credit assignment". This ability allows individuals to properly make decisions and learn from their mistakes.Problems with credit assignment are linked to various mental health conditions, like addiction and obsessive-compulsive-disorders where individuals continue to believe that their drug-taking or rituals will lead to positive outcomes [1]. However, clinicians tend to define and diagnose mental illnesses in terms of their clinical symptoms, not by their underlying psychological traits or biological abnormalities [2]. No-one has yet studied how changes in the brain lead to the problems of credit assignment that are seen in psychiatric disorders. Solving this riddle will help us understand how humans can work out cause and effect, as well as what happens when they lose this ability.My plan with this fellowship is to i) extract clinically-relevant traits that describe a person's ability - or lack thereof - for credit assignment from a large database, ii) map them onto brain mechanisms, and iii) restore the identified circuit dysfunction and therefore reduce the related maladaptive behaviours in patients suffering from addiction. To do so, I will, in a first stage, collect a large-scale dataset ("big-data") from an online study where participants will assign credit to distinct stimuli that predict a variety of events. Computational learning models will be used to explain this large dataset by teasing apart the hidden attentional and learning features of credit assignment [3-5] and relate them to various psychiatric dimensions. These will then be contrasted against neural data (acquired with fMRI while participants carry out the same credit assignment task). This will help map out the full neural circuitry involved in credit assignment and relate it to the phenotype of mental health issues. In the second stage of the fellowship, I plan to use a cutting-edge technique called ultrasound neurostimulation to target the different parts of the brain that cause pathological credit assignment and over-reliance on habits. Ultrasound neurostimulation is an early-stage, non-invasive therapeutic technology that has the potential to improve the lives of millions of patients with mental health conditions by stimulating brain tissues with millimetre accuracy [6]. My previous research has recently shown that ultrasound can safely modulate activity in deep brain areas in macaques to elicit precise behavioural changes [7]. Importantly, its safe use in humans has also been established [8-9]. In sum, ultrasound neurostimulation will be used to restore the brain regions involved in credit assignment and alleviate the corresponding negative symptoms in patients.This approach has the potential to help the nearly two million patients suffering from maladaptive addictive behavioural patterns by designing new stimulation paradigms that effectively restore brain function. Moreover, besides addictive disorders, ultrasound brain therapy could also be used to restore normal functioning of brain circuits involved in anxiety, mood disorders, and obsessive-compulsive disorders for which effective therapies are desperately needed.[1] Everitt &al. NatNeuro. 8,1481-1489(2005). [2] Hyman &al. NatRevNeuro. 8,725-732(2007). [3] Fouragnan &al. NatComm. 6,8107(2015). [4] Fouragnan &al. SciRep. 7,4762(2017). [5] Queirazza, Fouragnan &al. forthcoming at Science Advances (2019). [6] Aubry JoAcoustSocAm. 143,1731-1731 (2018). [7] Fouragnan &al. NatNeuro. 22,797-808(2019). [8] Fomenko &al. BrainStim. 11,1209-1217(2018). [9] Tsai &al. MedHypo. 84,381-383 (2015).