Adolescents with current major depressive disorder show dissimilar patterns of age-related differences in ACC and thalamus.

OBJECTIVE: There is little understanding of the neural system abnormalities subserving adolescent major depressive disorder (MDD). In a cross-sectional study we compare currently unipolar depressed with healthy adolescents to determine if group differences in grey matter volume (GMV) were influenced by age and illness severity. METHOD: Structural neuroimaging was performed on 109 adolescents with current MDD and 36 healthy controls, matched for age, gender, and handedness. GMV differences were examined within the anterior cingulate cortex (ACC) and across the whole-brain. The effects of age and self-reported depressive symptoms were also examined in regions showing significant main or interaction effects. RESULTS: Whole-brain voxel based morphometry revealed no significant group differences. At the whole-brain level, both groups showed a main effect of age on GMV, although this effect was more pronounced in controls. Significant group-by-age interactions were noted: A significant regional group-by-age interaction was observed in the ACC. GMV in the ACC showed patterns of age-related differences that were dissimilar between adolescents with MDD and healthy controls. GMV in the thalamus showed an opposite pattern of age-related differences in adolescent patients compared to healthy controls. In patients, GMV in the thalamus, but not the ACC, was inversely related with self-reported depressive symptoms. CONCLUSIONS: The depressed adolescent brain shows dissimilar age-related and symptom-sensitive patterns of GMV differences compared with controls. The thalamus and ACC may comprise neural markers for detecting these effects in youth. Further investigations therefore need to take both age and level of current symptoms into account when disaggregating antecedent neural vulnerabilities for MDD from the effects of MDD on the developing brain.This study was funded by the UK Medial Research Council (grant: G0802226), theNational Institute for Health Research (NIHR) (grant: 06/05/01) and the Behavioural and Clinical Neuroscience Institute (BCNI), University of Cambridge. The BCNI is jointly funded by the Medical Research Council and the Wellcome Trust. Additional support was received from the Cambridge Biomedical Research Centre. CCH is supported by a Parke Davis Fellowship from the University of Cambridge and resides at Columbia University.This is the final published version. It first appeared at: http://www.sciencedirect.com/science/article/pii/S2213158214002046#

Aberrant brain responses to emotionally valent words is normalised after cognitive behavioural therapy in female depressed adolescents.

BACKGROUND: Depression in adolescence is debilitating with high recurrence in adulthood, yet its pathophysiological mechanism remains enigmatic. To examine the interaction between emotion, cognition and treatment, functional brain responses to sad and happy distractors in an affective go/no-go task were explored before and after Cognitive Behavioural Therapy (CBT) in depressed female adolescents, and healthy participants. METHODS: Eighty-two Depressed and 24 healthy female adolescents, aged 12-17 years, performed a functional magnetic resonance imaging (fMRI) affective go/no-go task at baseline. Participants were instructed to withhold their responses upon seeing happy or sad words. Among these participants, 13 patients had CBT over approximately 30 weeks. These participants and 20 matched controls then repeated the task. RESULTS: At baseline, increased activation in response to happy relative to neutral distractors was observed in the orbitofrontal cortex in depressed patients which was normalised after CBT. No significant group differences were found behaviourally or in brain activation in response to sad distractors. Improvements in symptoms (mean: 9.31, 95% CI: 5.35-13.27) were related at trend-level to activation changes in orbitofrontal cortex. LIMITATIONS: In the follow-up section, a limited number of post-CBT patients were recruited. CONCLUSIONS: To our knowledge, this is the first fMRI study addressing the effect of CBT in adolescent depression. Although a bias toward negative information is widely accepted as a hallmark of depression, aberrant brain hyperactivity to positive distractors was found and normalised after CBT. Research, assessment and treatment focused on positive stimuli could be a future consideration. Moreover, a pathophysiological mechanism distinct from adult depression may be suggested and awaits further exploration.The study was funded by the Medial Research Council (grant: G0802226). The IMPACT clinical trial was funded by the NHS Health Technology Assessment (HTA) Programme, Central Manchester and Manchester Children's University Hospitals NHS Trust, and the Cambridge and Peterborough Mental Health Trust. Additional support was provided by the jointly funded Medical Research Council/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.jad.2015.09.00

Functional MRI of emotional memory in adolescent depression.

INTRODUCTION: Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide. Mood-congruent biases in memory tasks are frequently reported in MDD patients, with facilitated memory for negative stimuli. Most functional MRI studies to date have examined the neural correlates of these biases in depressed adults, with fewer studies in adolescents with MDD. Investigation of MDD in adolescence may aid greater understanding of the aetiology and development of the disorder. METHODS: Cognitive biases were investigated in 56 MDD patients aged 11-17 years and a matched group of 30 healthy control participants with a self-referential memory task. Behavioural performance and BOLD fMRI data were collected during both encoding and retrieval stages. RESULTS: The neural response to encoding in adolescents with MDD was found to differ significantly from controls. Additionally, neural responses during encoding and retrieval showed differential relationships with age between patient and control groups, specifically in medial, temporal, and prefrontal regions. CONCLUSIONS: These findings suggest that during adolescence neurophysiological activity associated with emotional memory differs in those with depression compared to controls and may be age sensitive.This study was funded by the UK Medical Research Council (MRC) (G0802226) and the Behavioural and Clinical Neuroscience Institute (BCNI) at the University of Cambridge (jointly funded by the MRC and Wellcome Trust). Additional support was given by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. We thank the participants and their families for taking part in the study. We would also like to thank the Cambridge and Peterborough NHS Foundation trust, Child and Adolescent Mental Health services and members of the IMPACT team. We are grateful to Rebecca Eliot for her advice on the analysis design.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.dcn.2015.12.01

Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task

Compared to female major depressive disorder (MDD), male MDD often receives less attention. However, research is warranted since there are significant sex differences in the clinical presentation of MDD and a higher rate of suicide in depressed men. To the best of our knowledge, this is the first functional magnetic resonance imaging (fMRI) study with a large sample addressing putative sex differences in MDD during adolescence, a period when one of the most robust findings in psychiatric epidemiology emerges; that females are twice as likely to suffer from MDD than males. Twenty-four depressed and 10 healthy male adolescents, together with 82 depressed and 24 healthy female adolescents, aged 11–18 years, undertook an affective go/no-go task during fMRI acquisition. In response to sad relative to neutral distractors, significant sex differences (in the supramarginal gyrus) and group-by-sex interactions (in the supramarginal gyrus and the posterior cingulate cortex) were found. Furthermore, in contrast to the healthy male adolescents, depressed male adolescents showed decreased activation in the cerebellum with a significant group-by-age interaction in connectivity. Future research may consider altered developmental trajectories and the possible implications of sex-specific treatment and prevention strategies for MDD

Magnetic resonance imaging of a randomized controlled trial investigating predictors of recovery following psychological treatment in adolescents with moderate to severe unipolar depression: study protocol for Magnetic Resonance - Improving Mood with Psychoanalytic and Cognitive Therapies (MR-IMPACT)

Background Major depressive disorders (MDD) are a debilitating and pervasive group of mental illnesses afflicting many millions of people resulting in the loss of 110 million working days and more than 2,500 suicides per annum. Adolescent MDD patients attending NHS clinics show high rates of recurrence into adult life. A meta-analysis of recent research shows that psychological treatments are not as efficacious as previously thought. Modest treatment outcomes of approximately 65% of cases responding suggest that aetiological and clinical heterogeneity may hamper the better use of existing therapies and discovery of more effective treatments. Information with respect to optimal treatment choice for individuals is lacking, with no validated biomarkers to aid therapeutic decision-making. Methods/Design Magnetic resonance-Improving Mood with Psychoanalytic and Cognitive Therapies, the MR-IMPACT study, plans to identify brain regions implicated in the pathophysiology of depressions and examine whether there are specific behavioural or neural markers predicting remission and/or subsequent relapse in a subsample of depressed adolescents recruited to the IMPACT randomised controlled trial (Registration # ISRCTN83033550). Discussion MR-IMPACT is an investigative biomarker component of the IMPACT pragmatic effectiveness trial. The aim of this investigation is to identify neural markers and regional indicators of the pathophysiology of and treatment response for MDD in adolescents. We anticipate that these data may enable more targeted treatment delivery by identifying those patients who may be optimal candidates for therapeutic response