TUNING THE NEURAL CIRCUITRY OF AFFECTIVE BIASES IN DEPRESSION

Lead Research Organisation: University College London
Department Name: Institute of Cognitive Neuroscience

Abstract

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.

Technical Summary

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)

Planned Impact

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.
 
Description Researcher representative at responsible Research and Innovation workshop at Science Museum (with directors of major European Science Museums)
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description University of Sydney Visiting Researcher Scheme
Amount $8,500 (AUD)
Organisation University of Sydney 
Sector Academic/University
Country Australia, Commonwealth of
Start 02/2017 
End 04/2017
 
Title Avoidance data 
Description Collection of data, and analysis code 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Paper in press at Biological Psychiatry 
URL https://figshare.com/articles/Avoidance_Anxiety_Materials/3860250
 
Title Frontiers stress paper data 
Description Dataset from The impact of threat of shock on the framing effect and temporal discounting: executive functions unperturbed by acute stress? 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Included in a publication 
URL https://figshare.com/articles/Stress_and_executive_function/1423293/1
 
Title IGT stress data 
Description Dataset exploring the impact of threat of shock induced stress on the Iowa Gambling task as a function of depression and anxiety symptoms. 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact This was included in a published paper 
URL https://figshare.com/articles/Stress_IGT_data/1257693/1
 
Title RI lates data 
Description The impact of induced anxiety on affective response inhibition 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Collected as part of a public engagement activity. Paper submitted for publication 
URL https://figshare.com/articles/The_impact_of_induced_anxiety_on_affective_response_inhibition/1609723
 
Description The Orchestra of the Age of the Enlightenment 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Oliver Robinson spoke to The Orchestra of the Age of the Enlightenment as part of a special season at the South Bank Centre London.
Year(s) Of Engagement Activity 2016
URL https://vimeo.com/154332073
 
Description "A level Psychology study day; The Power of the Mind" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Oliver Robinson spoke to high school students at the Training partnership "A level Psychology study day; The Power of the Mind" 24th November 2014
Year(s) Of Engagement Activity 2015
 
Description "Normal? Festival of the Brain" theatre festival at the Folkstone Quarterhouse 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Oliver Robinson participated in "Normal? Festival of the Brain" theatre festival at the Folkstone Quarterhouse, giving a talk on Sat 23rd May 2015 entitled "Anxiety and the Brain" alongside the arts programme
Year(s) Of Engagement Activity 2015
URL https://www.quarterhouse.co.uk/admin/media/get.php?f=/Normal_Festival_web_flyer.pdf
 
Description Columnist for Guardian Newspaper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Guardian asked Oliver Robinson to write a piece about recent work linking IQ to bipolar disorder. published online 21 September 2015
Year(s) Of Engagement Activity 2015
URL http://www.theguardian.com/commentisfree/2015/aug/21/mental-ill-health-creativity-high-iq-genius
 
Description Diagnosing Diagnosis, discussion event at Wellcome Collection 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sell out discussion of the benefits/downsides of psychiatric diagnoses as part of their Bedlam exhibition. I was the neuroscientist discussant
Year(s) Of Engagement Activity 2016
URL https://wellcomecollection.org/events/symposium-diagnosing-diagnosis
 
Description Feeling Emotional Event at the Wellcome Collection 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Thousands of people attended The Feeling Emotional Event at the Wellcome Collection. Members of the lab ran a threat of shock study
Year(s) Of Engagement Activity 2016
URL https://wellcomecollection.org/sites/default/files/Friday%20Late%20Spectacular%20Feeling%20Emotional...
 
Description More or Less BBC World service 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Oliver Robinson was on the show More or Less on the BBC World Service urging caution when trying to link creativity with mental health.
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/programmes/p037klyj
 
Description Piece in the Guardian newspaper asking What is Depression? 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Oliver Robinson was interviewed as part of a long piece in the Guardian newspaper asking What is Depression? published online 15 July 2015
Year(s) Of Engagement Activity 2015
URL http://www.theguardian.com/commentisfree/2015/jul/15/what-is-depression-google-answer
 
Description Podcast for Lancet Psychiatry 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Podcast triggered interest on twitter and personal conversations

A prospective PhD student cited the podcast as a reason she wanted to pursue a PhD
Year(s) Of Engagement Activity 2014
URL http://download.thelancet.com/flatcontentassets/audio/lanpsy/2014/lanpsy_270814.mp3
 
Description Royal Institution Lates event "Questioning Reality" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Oliver Robinson led a team of UCL ICN researchers at the Royal Institution Lates event "Questioning Reality" on Friday 17th April 2015. They discussed work with guests and ran a study called "Shocking Perspective" exploring the effect of anxiety on cognition
Year(s) Of Engagement Activity 2015
URL http://www.rigb.org/docs/questioning_reality_floorplan_web_0.pdf