TUNING THE NEURAL CIRCUITRY OF AFFECTIVE BIASES IN DEPRESSION

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.

The key methodologies recruited to clarify the reward and punishment circuitry in depression, in order of application throughout the proposed project, are as follows:

1) Computerised tasks will be designed to assess reward and punishment processing circuits. These tasks will use stress of unpredictable electrical shock as novel way to provoke these circuits. One task will assess perception of rewarding and punishing stimuli, whereas the other will assess learning about rewards and punishments under stress and stress no conditions. The speed and accuracy of responding during these tasks will be compared across healthy and depressed individuals.
2) These tasks will then be completed by healthy and depressed individuals in a brain (Magnetic resonance imaging; MRI) scanner so as to examine the neural circuitry involved in reward and punishment processing.
3) Complex statistical analyses (Dynamic causal modelling; DCM) will be completed on the brain imaging data to examine the interactions between brain regions during these tasks.
4) Computational models of reinforcement-learning - which help describe the way that reward and punishment information is processed in the brain -will be used in combination with the brain imaging data to compare the way that healthy and depressed individuals process information.
5) A novel computerised treatment for depression (a 'cognitive vaccine') will be designed for both the healthy and patient populations in an effort to promote the processing of rewards relative to punishments. The effects of this on circuitry will be examined by MRI scanning.
6) Healthy individuals will complete a 3 week selective serotonin reuptake inhibitor (SSRI) antidepressant course (or matched placebo) and the impact of serotonin increases upon these circuits will be examined.
7) New high resolution imaging techniques will be used to examine the impact of SSRIs on processing in small brain regions (e.g. the habenula)

This work will impact:

1) Patients, by providing a clear understanding of the neurobiological processes underlying depression. Importantly, increasing awareness that depression is a treatable "brain circuit" problem has the potential to reduce stigma, which remains a major issue for sufferers of all mental health problems, including depression.

2) A second potential impact for patients is the prospect of a clearer understanding of how treatments work (in the later stages of the project). The novel computerised 'cognitive vaccine' stage of the project may also sow the seeds for new potential treatments of depression. In the longer-term, this would have significant value for patients and their families, reducing the overall burden of mental ill health.

3) The novel computerised 'cognitive vaccine', which will build on prior work using cognitive tasks to promote positive affective bias, may also be a safe intervention for use in individuals at risk for developing depression and could potentially be the first step towards an active resilience promotion strategy in healthy individuals with positive implications for mental capitol and well-being.

4) A more hypothetical and indirect benefit of such a treatment outcome could be a reduction in the overall costs of mental ill health to the economy. Depression costs a lot to treat, but it also prevents people from actively participating in the workforce.

5) The general public will also benefit from this project via increased dialogues proposed for communicating the findings to the public via websites/blogs/twitter. The incorporated social media aspects will allow direct interaction between the researcher and the public.

6) The research assistant will be trained by Dr Robinson, providing training quantitative skills required in the UK workforce whether or not they pursue a career in academia.

7) A final goal of the proposal will be to bring in funding to take the findings to the next stage, including a potential clinical trial of the proposed 'cognitive vaccine'.

8) Such a trial has a potential value for businesses in that a putative 'cognitive vaccine' might be patentable and marketable.