MRI measures of brain structure and function as predictors of medium-term response to psychotherapy in adolescent MDD

Lead Research Organisation: University of Cambridge
Department Name: Psychiatry

Abstract

Major depressive disorder (MDD) in adolescence is a challenging priority for NHS mental health services as well as being a difficult experience for the patient and their family. The recommended treatment is psychotherapy, which can be combined with antidepressants if there is no immediate response. Unfortunately, there is no way currently to predict which patients are most likely to respond to psychotherapy. This uncertainty stems in part from our incomplete knowledge of how depression is caused by abnormal function of brain circuits important for mood states and their conscious control. One plausible theory we want to investigate is that depressive symptoms result from an overactive response to negative events or stimuli in one part of the brain (the limbic system), which is not effectively controlled by an underactive response in a different but interconnected brain region (the frontal cortex). We predict that this functional imbalance in fronto-limbic brain networks can be normalised following cognitive behavioural therapy, a form of psychotherapy focused on improving conscious control of mood symptoms. We also expect that the extent of structural and functional abnormality measured in fronto-limbic brain networks before treatment begins can predict patients? responses to treatment up to one and a half years later.

To test these predictions, we are proposing to collect magnetic resonance imaging (MRI) measurements of brain structure and function in 120 adolescent patients with MDD and 40 health adolescent volunteers. All of the patients will be scanned once before they are randomly assigned to one of three different kinds of psychological treatment as part of a larger study, already funded to investigate the clinical effectiveness of psychotherapy for young people with depression. Forty of the patients (and the healthy volunteers) will also be scanned on a second occasion 20 weeks later. MRI scanning is a painless and safe method of obtaining detailed information on the structure and function of the human brain. The design and clinical governance of this study has been informed by a careful consideration of the risks and benefits to adolescent patients and volunteers. We consider that it is timely and important to use modern brain scanning techniques to better understand and predict the course of this serious mental illness in young people and that this research proposal will safely and powerfully test key theoretical predictions in a way that could improve the future clinical care of adolescent patients with major depressive disorder.

Technical Summary

Adolescent major depressive disorder (MDD) is a challenging clinical condition associated with considerable morbidity and mortality as well as poor outcome in adult life, and has been relatively under-investigated by neuroimaging studies to date. Symptomatic response to clinically recommended psychological treatments is variable, but little is known about the neurobiological basis of this variability in adolescent patients and there are few tools available to predict therapeutic response. This proposal will evaluate candidate neuroimaging markers and predictors of response to psychological treatment of adolescents with MDD in the context of a larger-scale, NIHR-funded study of symptomatic and social outcomes measured up to 1.5 years after treatment.

Consistent with existing data on adult MDD, we hypothesise i) that depressive disorder in adolescents will be associated with abnormalities of brain function in a fronto-limbic brain system including the amygdala, anterior cingulate cortex and prefrontal cortex; ii) that these abnormalities at baseline assessment will be ?normalized? by cognitive behavioural therapy; and iii) that baseline measures of fronto-limbic brain structure and function will be predictive of medium-term clinical and social response to psychological treatments.

These hypotheses will be tested by acquiring baseline structural and functional MRI data, immediately prior to initiation of treatment, from a cohort of 120 adolescent MDD patients randomised to one of three psychological treatments: cognitive behavioural therapy (CBT), brief psychodynamic psychotherapy or active clinical care, as part of the IMPACT clinical trial. The subset of 40 patients randomised to receive CBT will be scanned on a second occasion 20 weeks later, after completion of psychotherapy. Functional MRI data will be acquired during performance of emotion-processing and emotionally valent executive and memory tasks, as well as while subjects are at rest. Brain structure will be measured by conventional MRI and diffusion tensor imaging. Image analysis will involve innovative approaches to assessment of endogenous dynamics and complex brain networks in addition to well-validated methods for non-parametric inference on more conventional activation and morphometric statistics. These imaging markers measured in patients at baseline and follow-up will be compared to the same markers measured in an age-matched group of healthy volunteers (N=40) to test hypotheses (i) and (ii); baseline markers on all patients will be used to test hypothesis (iii) and validate candidate neuroimaging predictors of treatment response.

Publications

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Fairchild G (2013) Brain structure abnormalities in adolescent girls with conduct disorder. in Journal of child psychology and psychiatry, and allied disciplines

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Graham J (2013) Meta-analytic evidence for neuroimaging models of depression: state or trait? in Journal of affective disorders

 
Description Behavioural and Clinical Neuroscience Institute - imaging supplement
Amount £19,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 03/2014
 
Description Behavioural and Clinical Neuroscience Institute - imaging supplement
Amount £19,160 (GBP)
Funding ID 093875 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 03/2014
 
Description Commercial Funding
Amount £134,016 (GBP)
Funding ID EM115831 
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2011 
End 09/2012
 
Description Isaac Newton Trust Fellowship scheme
Amount £43,482 (GBP)
Organisation University of Cambridge 
Department Isaac Newton Trust
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2013
 
Description NIHR - Efficacy and Mechanism Evaluation Programme
Amount £1,845,642 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 03/2016
 
Description Parke Davis Exchange Fellowship
Amount £45,000 (GBP)
Organisation Pfizer Ltd 
Department Parke Davis
Sector Private
Country Global
Start 06/2013 
End 05/2014
 
Description Research for Patient Benefit (RfPB) Programme
Amount £249,808 (GBP)
Funding ID PB-PG-0711-25160 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2014
 
Description Seed Funding Grant
Amount $100,000 (SGD)
Organisation National University Hospital (NUH) 
Sector Hospitals
Country Singapore
Start 12/2013 
End 11/2015
 
Description Travel award
Amount £400 (GBP)
Organisation European Brain and Behavior Society (EBBS) 
Sector Charity/Non Profit
Country Netherlands
Start 06/2012 
End 07/2012
 
Title RedCAP data capture and archive system 
Description We have developed a data capture, archive and retrieval system for imaging and associated datasets. This system has been adapted for the Neuroscience in Psychiatry Network database (>2000 participants, 900 MRI assessments). 
Type Of Material Biological samples 
Year Produced 2012 
Provided To Others? Yes  
Impact This is an entirely integrated system providing a single-point of entry and exit for data. It has also been coupled to automated reading systems for upload of paper assessments and case report forms. Efficiency is improved and data security greatly enhanced. 
URL http://project-redcap.org/
 
Description Cambridge Family Study of Autism (CFSA) 
Organisation University of Cambridge
Department Autism Research Centre (ARC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Reciprocal arrangement for CFSA and MR-IMPACT recruitment teams for holiday/sickness. Data sharing to create matching control participant cohorts.
Collaborator Contribution Data sharing has allowed sensitivity and, importantly, sensitivity measurements of newly developed algorithms for assessments task-absent functional imaging datasets
Impact Article submitted.
Start Year 2012
 
Description Help Overcome and Prevent the Emergence of Suicide 
Organisation University of Cambridge
Department Cambridge Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Donation of imaging and supporting datasets as well as processing pipelines and derived data. Scientific consultation on merging multi centre datasets
Collaborator Contribution This collaboration brings together an international, multidisciplinary investigative team with extensive experience and expertise in conducting research in youth mental health, including expertise in adolescent suicide. This collaboration will utilize a multimodal approach to identify mechanisms that lead to suicidal thoughts and behaviours in youth. The project has two overall aims: 1. Elucidate transdiagnostic neurobiological, cognitive, and social risk mechanisms associated with STBs in youth. 2. Identify novel suicide risk phenotypes and real-time predictors of STBs in youth.
Impact Funding from MQ Mental Health, April 2017 - April 2021
Start Year 2017
 
Description MRIMPACT - MHRN 
Organisation National Institute for Health Research
Department INVOLVE
Country United Kingdom 
Sector Public 
PI Contribution This study has been adopted by the Mental Health Research Network
Collaborator Contribution Help with recruitment
Impact None yet
Start Year 2010
 
Description NIHR IMPACT Clinical Trial 
Organisation National Institute for Health Research
Department NIHR IMPACT Clinical Trial
Country United Kingdom 
Sector Public 
PI Contribution Data acquired from the MR-IMPACT adjunct study to this clinical trial have been uploaded for formal testing of intervention efficacy. The IMPACT recruitment team supported participant follow-up and assessment day supervision.
Collaborator Contribution The IMPACT has provided funding to complete MRI follow-up assessments. Other adjunct studies to IMPACT are contributing to collaborative science; in particular, measurements of cortisol, and experiential data from participants.
Impact Articles in draft.
Start Year 2010
 
Description Neuroscience in Psychiatry Network (NSPN): Wellcome Trust Strategy Award 
Organisation NSPN (NeuroScience in Psychiatry Network)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Development of neuroimaging hypotheses for adolescent depression to be subsequently tested in a cohort of patients.
Collaborator Contribution Characterisation of normal brain maturation (>900 MRI assessments in an accelerated longitudinal design) as the foundation for understanding aberrant developmental trajectories as the substrate for the emergence of depressive symptoms. Subsequently, a cohort of adolescents with depression will be assessed with the same MRI protocols to initially replicate MR-IMPACT findings, and then combined with clinical and cognitive, redefine the phenotype in terms of its dynamic aetiology.
Impact Preliminary analysis of MR-IMPACT datasets informed the selection of novel MRI acquisitions for NSPN protocols.
Start Year 2012
 
Description Support Vector Classification of Sexual Dimorphism in Adolescent Major Depressive Disorder 
Organisation University of Granada
Country Spain 
Sector Academic/University 
PI Contribution Funding was received for me to spend two weeks in residence at the University of Granada. During that time I have been assisting them with designing and interpreting analytical approaches to medical imaging data as well introducing some of the methodological work undertaken as part of this grant with respect to analysis of task-based functional MRI studies and characterisation of the connectome.
Collaborator Contribution A graduate student from the University of Granada has spent 3 months with us applying their support vector machines technology to imaging data acquired as part of this MRC-funded project. The hypothesis tested is that specific brain regions identified as sexually dimorphic in adults developmentally diverge according to sex during brain maturation and that aberrant development trajectories in these regions result in the emergence of the symptoms of MDD.
Impact The partnership is ongoing - no outputs to date.
Start Year 2014
 
Description School visits (Cambridge/St Ives) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact Presentations to sixth form classes in comprehensive schools on brain imaging techniques applied to cognitive neuroscience. Careers discussion ensued.

Increased interest and participation in a range of ongoing studies.
Year(s) Of Engagement Activity 2011,2012