Neurocognitive Endophenotypes of Stimulant Drug Dependence

Lead Research Organisation: University of Cambridge
Department Name: Psychiatry

Abstract

We know that about 15% of people who try cocaine will become dependent on it within 10 years of their first use. The likelihood of developing cocaine dependence is further increased for people who have a family history of substance use disorders. Thus the addictive potential of cocaine is magnified by genetic risk factors but we currently know little about how the risks for drug dependence are inherited.

We aim to discover more about the genetic basis for cocaine dependence, by using brain imaging and cognitive testing to assess people with a clinical diagnosis of cocaine dependence and their non-dependent first degree relatives, as well as healthy normal volunteers. In this way, we aim to identify heritable traits or endophenotypes in brain organization and cognitive processing that may mediate the genetic predisposition to develop drug addiction.

Identification of such endophenotypes would make an important contribution to understanding of drug addiction, by clarifying the distinction between those brain and cognitive abnormalities that are the effects of long-term drug abuse, versus those that represent predisposing causes of drug abuse. Delineating the neurobiological causes and effects of stimulant drug dependence will be fundamental to future development of more effective therapeutic and preventative interventions.

Technical Summary

This project aims to define neurocognitive endophenotypes of drug addiction by examining two key aspects of brain function, reward sensitivity and inhibitory control, in currently stimulant-dependent individuals, their non-drug using siblings, and unrelated healthy controls (n=40 per group). The groups will be characterized in terms of psychopathology, cognitive function, and MRI-based measurements of brain structure and function; the fMRI paradigms are chosen to activate cortico-subcortical circuits implicated in inhibitory and reward processing. By comparing behavioural and imaging measurements between drug-dependent individuals and healthy volunteers, we will be able to test the hypothesis that reward sensitivity, inhibitory control, and the brain circuits subserving these functions, are abnormal in drug dependence. Moreover, the inclusion of a non-dependent sibling group will additionally allow us to test the hypothesis, supported by the high heritability of drug dependence syndromes, that there will be abnormalities of inhibitory and/or reward processing in first degree relatives of dependent individuals. In other words, the study is designed to test the candidacy of cognitive and imaging markers of inhibitory and reward processing as intermediate phenotypes or endophenotypes that mediate genetic risk for stimulant-dependence. The identification of such neurocognitive endophenotypes would immediately make an important contribution to biological understanding of drug-dependence syndromes by segregating those abnormalities expected in dependent individuals compared to healthy controls which are effects of long-term stimulant drug abuse (and therefore not seen in non-dependent relatives) from those which are predisposing causes of drug abuse (and therefore also seen to some extent in relatives). Clarification of this distinction between neurocognitive causes and effects of stimulant drug dependence has been difficult to achieve in clinical studies yet is fundamental to rational development of future therapeutic and preventative interventions.
 
Description Creature of Habit Questionnaire: Measuring individual proneness to habit
Amount £10,000 (GBP)
Organisation The British Academy 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2019
 
Description Functional networks underpinning drug addiction vulnerability and resilience
Amount £80,000 (GBP)
Funding ID 105602/Z/14/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 09/2017
 
Description MHRN Resarch and Capability Funding
Amount £14,922 (GBP)
Funding ID RG66986 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 06/2012 
End 12/2012
 
Description NHIR Flexibility and Sustainability Funding
Amount £2,725 (GBP)
Funding ID RG65249 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2011 
End 03/2012
 
Description West Anglia CLRN Research Capability Funding
Amount £12,450 (GBP)
Funding ID RG68442 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 10/2012 
End 03/2013
 
Title Drug-related Locus of Control Questionnaire 
Description The DR-LOC is a new instrument for assessing a person's belief of 'being in control' in situations involving drug abuse. It consists of 16 item pairs presented in a forced-choice format, based on the conceptual model outlined by Rotter. 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact The DR-LOC characterizes the extent to which a person believes that the additive behavior and recovery from addiction is under their personal control (internal Locus of Control) or under the influence of external circumstances (external Locus of Control). 
 
Description ICCAM New drugs for addiction 
Organisation Global Medical Excellence Cluster (GMEC)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution The addiction endophenotype study provided valulabe pilot data and experience for the set up of the collaborative ICCAM project.
Impact The ICCAM study is still ongoing, so it is a bit too early for the reporting of results.
Start Year 2009
 
Description "NHS Engagement in Research" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Regional Research Event 2012, which focuses on
NHS engagement in research. It took place in Wyboston Lakes, Wyboston, Bedfordshire, MK44 3BA on 05 July 2012.

My talk was on "Addiction Endophenotypes: A Study into the Causes and Effects of Stimulant Dependence"

After the talk I was approach by health care professionals working in the field of addiction, requesting advice and expressing the wish to get involved in research.
Year(s) Of Engagement Activity 2012
 
Description BBC 10'o clock News 
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 Media (as a channel to the public)
Results and Impact My article in Science this year on the findings of the MRC-funded study on Neurocognitive Endopenotypes raised a lot of media interest. I gave interviews to the media around the world and the BBC showed a video clip on the Ten'o clock News program.

Several NHS Mental Health Trusts and Charities providing care for drug-dependent individuals asked me to give talks or to write about the findings in their local newsletter.
Year(s) Of Engagement Activity 2012
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Unfortunately, I don't have any records of numbers of people who attended this lecture.

The University of Cambridge Office for External Affairs and Communications stated in their Cambridge Scine Festival report that this lecure was extremely popular and received many positive comments.
Year(s) Of Engagement Activity 2011
 
Description European College of Neuropsychopharmacology Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact I presented data on the role of personality traits on addiction vulnerability.

scientific discussion
Year(s) Of Engagement Activity 2013
 
Description Gordon Research Conference (2017) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I presented new data at the Gordon Research Conference on the Neurobiology of Drug Addiction "Mechanistic and Translational Breakthroughs in Drug Addiction Research".
Year(s) Of Engagement Activity 2017
URL https://www.grc.org/neurobiology-of-drug-addiction-conference/
 
Description Mental Health and Learning Disability Research Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact About 50 health care professionals attended the mental health research conference

I gave a talk on addiction vulnerability and made contact with health care professionals working in the field of addicition.
Year(s) Of Engagement Activity 2014
 
Description Pint of Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Pint of Science is a festival that aims to make science accessible and fun by bringing current scientific research to the welcoming atmosphere of the pub.

outreach
Year(s) Of Engagement Activity 2013
URL http://www.pintofscience.com/
 
Description Rustat Converence on Drugs, Science and Social Realities: A Fresh Debate 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact The conference is prompted by the continuing crisis posed by substance abuse and dependency, their far-reaching consequences, and an awareness of the need for further debate and new policy initiatives. I added the findings of my MRC-funded work on the addiction vulnerability to this debate.

outreach
Year(s) Of Engagement Activity 2013
 
Description Society event organised by the European Bioinformatics Institute and held at the Cambridge Union Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact From habit to addiction: A slippery slope is a Science and Society event organised by the European Bioinformatics Institute and held at the Cambridge Union Society.

outreach activity
Year(s) Of Engagement Activity 2013
URL http://www.ebi.ac.uk/training/public/addiction
 
Description Spring School Dresden 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I contributed to the University of Dresden Spring School on Cognitive Control in Volition and Cognition.
Year(s) Of Engagement Activity 2018
URL https://www.sfb940.de/index.html
 
Description The Naked Scientist Radio Show 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Interview regarding the relationship between cocaine and food.

outreach activity
Year(s) Of Engagement Activity 2013
 
Description The Science Show - Cambridge 105 (Radio) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Dr Karen Ersche tells about her research into cocaine addiction. The work investigates the finding that cocaine addiction affects some people and not others. Also, unlike other addictions, there are no substitute chemicals that can be used instead of cocaine. However Karen Ersche's research is looking at a possible candidate. The Science Show's Roger Frost asks about the use of terms such as addiction; habit and compulsive behaviour.

outreach activity
Year(s) Of Engagement Activity 2013
 
Description The science of drug addiction - an introduction to T2 Trainspotting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Introduction to drug addiction at the Cambridge Ats Picturehouse premier of the film 'T2 Trainspotting'.
Year(s) Of Engagement Activity 2017