A macaque's brain activity is being scanned moment by moment as it makes decisions, receives feedback, and adjusts its behaviour—all to reveal the neural circuits that go awry in depression and bipolar disorder. The problem is that we know which brain regions—prefrontal and cingulate cortex—are involved in evaluating outcomes and choosing actions, but we do not understand the *mechanisms* by which they do this. Without that mechanistic understanding, we cannot explain why, in illnesses like bipolar depression, behaviour becomes too volatile—overreacting to every minor piece of feedback—or why some people draw odd conclusions about what they are responsible for. This is fundamental science. The researchers are designing precise behavioural tasks, recording fMRI signals in macaques (whose prefrontal cortex closely resembles ours), and making subtle, targeted interventions to test whether specific activity patterns *cause* specific behaviours. If successful, the work will provide a causal, circuit-level account of how the brain attributes feedback to events, how it decides when to change course, and how it makes inferences from partial experience. That mechanistic knowledge could eventually guide more targeted treatments for the cognitive distortions seen in psychological illness.
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Every day we make decisions about what to do next. We do this because we are constantly monitoring and evaluating how well things are going. As a consequence we adjust our behaviour so it is appropriate for the current context or we decide to take one course of action rather than another. Sometimes we are aware of making these evaluations and decisions but often we are not. Nevertheless, however much we take these abilities for granted, it is striking when they are altered in psychological illnesses such as depression. The aim of this proposal is to undertake work to understand what the brain does to enable us to behave in the way that we do. Our focus is on parts of the brain called the prefrontal and cingulate cortex. We already know that these brain regions are especially important for the behaviour we are interested in but what we do not know is how they accomplish the role they play. We want to find out the mechanisms by which they operate and the way in which they interact with the rest of the brain. A key part of the work is designing behavioural tasks to probe cognitive operations in a precise way to reveal their mechanistic basis. A second component is recording brain activity and seeing how it relates to behaviour. We do this by using a magnetic resonance imaging (MRI) scanner, usually by taking what are called functional MRI (fMRI) scans. FMRI scans tell us about blood oxygenation in the brain. This is useful because the blood oxygen level dependent (BOLD) signal tracks the activity of the brain's cells -- neurons -- in a very precise way. It is, for example, possible to estimate changes in distribution of BOLD signal in specific brain areas from moment to moment as a decision is made or as feedback is provided to enable adjustments and changes in behaviour. We conduct the fMRI recording in animals because we also want to examine the consequences of manipulating the activity we record. This is essential for finding out what activity patterns are causally driving behaviours. We can test causation by making precise and circumscribed interventions in the brain. We do this under anaesthesia in the same way that it would be done with human patients. When the animals recover we monitor changes in behaviour. Usually there are no obvious changes in behaviour because the interventions we carry out are subtle. If, however, we have designed our behavioural tasks with care so as to precisely probe specific cognitive processes, then we may be able to pick up equally subtle alterations in behaviour. They can then be measured and quantified. We use macaques because they provide a model of many features of human prefrontal and cingulate cortex. Most other animals lack these features so they cannot be used as models. One of the questions that we are examining concerns how quickly we should change and adjust our behaviour. There is evidence that in some psychological illnesses, such as bipolar depression, our behaviour becomes too responsive to each minor piece of feedback; the behaviour becomes too volatile. We are also interested in how, when we receive feedback for a choice, we attribute that feedback correctly to the event that really caused it. There is evidence that we do not always manage this simple job well and when we are very poor at it we may draw odd conclusions about what we are, and are not, responsible for. Again this may be a feature of psychological illnesses. A third process we are interested in is inference. Often neuroscientists have studied the neural mechanisms that mediate learning about particular events or actions. Once the learning is done a good decision can be made next time the event is encountered or the action is needed. However, often in the real world we make inferences about what to do next on the basis of experience of some situations with some similar component elements. We will attempt to understand how such inferences are made.
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