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

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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).