Rev Psiquiatr Salud Ment (Barc.). 2012;5(1):5---7

www.elsevier.es/saludmental

EDITORIAL

Imaging evidence for depression: Is there biologyin the bibliography?�

Evidencia sobre la depresión con técnicas de imagen:¿hay biología en la bibliografía?

John Suckling

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Introduction

Medical imaging has undoubtedly had a profound influenceon clinical practice. Although this technology has been suc-cessfully translated to imaging the brain−neuroimaging−there has been disappointingly little impact on the manage-ment of individual patients presenting at psychiatry clinics.Neuroimaging, or to be more precise its interpretation, hasbeen derided as merely a new phrenology, but it remains acentral pillar of an evolving evidence base putting psychia-try on a convergent course with other disciplines, as medicalpractice becomes medical science.

Major depressive disorder (MDD) is the fourth leadingcause of disease burden worldwide, and is associated withchronic physical illnesses placing it to become second onlyto heart disease in terms of disease burden.1 The aetiologyof MDD is far from a complete understanding, although itmight be hoped that its biological loci could be describedwith some precision by the wide range of structural andfunctional imaging techniques at our disposal. The physicalprinciples that underpin these techniques and the corre-sponding measurements they make are varied and distinct.What unites them is that when distinguishing pathologicalchanges in anatomy and physiology, the observed effect sizes

are small. Consequently, even for such a prevalent disorder,the prospects for imaging as a diagnostic or prognostic testlook unlikely in the foreseeable future.

� Please cite this article as: Suckling J. Evidencia sobre la depre-sión con técnicas de imagen: ¿ hay biología en la bibliografía? RevPsiquiatr Salud Ment (Barc.). 2012;5:5---7.

E-mail address: js369@cam.ac.uk

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2173-5050/$ – see front matter © 2011 SEP y SEPB. Published by Elsevier

uilding, Cambridge, United Kingdom

Notwithstanding this gloomy analysis, much has beenearnt about the neurobiological basis of MDD from imag-ng and other techniques. Indeed, it is now clear fromhese direct observations that there is a neurobiologicalasis for the disorder favouring the unitarian model codi-ed in DSM-III. Much of the convincing evidence for this hasome the synthesis of published work as meta-analyses, aechnique recently reframed for imaging studies.2 However,hether the brain differences associated with MDD repre-

ent a cogent model requires careful examination. Here weee if pieces really do fall into place.

he hypothalamus---pituitary---adrenal axis

PA axis hyperactivity, leading to prolonged hypercorti-olemia is a potentially powerful model of MDD that predictsellular changes of brain areas that have a high concentra-ion of glucocorticoid receptors such as the hippocampus,mygdala and cingulate cortex; areas of the limbic systemnvolved in mood regulation.

The mainstay of studies of the HPA axis has beentructural MRI using manual tracing of regions with hypoth-sised involvement. Perhaps surprisingly, the eponymousegions of the model have been the least-well studied,ith a recent attempt at a meta-analysis being describeds ‘‘futile’’.3 In contrast, meta-analyses have confirmed

highly significant reduction in the volume of the hip-ocampus and anterior cingulate associated with MDD4 thats not replicated in combined volume measurements of

he amygdale.4---6 The hippocampus is also sensitive to pro-onged illness, with longer durations associated with smallerolumes.7 At the cellular level, neurogensis in the hippocam-us mediated by selective serotonin reuptake inhibitor

España, S.L. All rights reserved.

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SSRI) treatment8,9 has been shown to arise through accel-rated maturation of immature granule cells.10 However,bserving the predictions of these animal model data ofncreased hippocampal volumes in medicated patients isestricted by the small quantity of source data, althoughreater volume loss with moderate rather than severe dura-ion of illness may indicate a restorative effect by chronicreatment.7

The amygdala has a similarly uneven (although dis-inct) pattern of volume change. Several meta-analyses haveailed to find overall differences4---6 and no relationship haseen found with chronicity.5 However, stratifying accordingo medication status reveals a decrease in amgydala vol-me in drug naive patients. Conversely, treated patientsave an increase in volume paralleling increased activityhat accompanies acute administration of SSRI in a dose-esponsive manner.11 Furthermore, chronicity is stronglyonfounded with medication history, potentially masking itsffect.

The overall picture therefore is of differential sensitivi-ies of the components of the HPA axis to hypercortisolemianduced by depressive episodes. It is interesting to notehat when studies looking at the entire cortex (rather thanust a few regions) are combined, the only area that sig-ificantly characterises MDD is the anterior cingulated,12

uggesting small effects and/or variable results acrosstudies. The down-regulation activity by SSRI treatment13

as analogous heterogeneity across the HPA axis. Whetherolume reductions predate clinical symptoms remainsnknown. Meta-analysis of children with MDD provideso evidence either way,7 although an article publishedubsequently14 found that morphologic changes mighte evident initially and that genetic differences mayncrease vulnerability to early-life stress, and thus the riskf MDD.

he fronto-limbic model

simple but influential systems-level model for depressions that enhanced ‘‘bottom-up’’ limbic activation by negativetimuli, in the absence of effective ‘‘top-down’’ inhibitoryontrol by prefrontal cortex, may predispose to rumina-ive amplification of negatively valenced events, attentionalias to negative stimuli, and reduced capacity to recon-truct negative cognitions, leading to the emergence ofepressive symptoms.15 This cognitive model predicts over-ctivation of the (para)limbic system (particularly amygdaland anterior cingulate cortex) by negative emotional stimulin conjunction with under-activation of prefrontal corticalreas that are reciprocally connected to limbic structuresnd are thought to play an important role in mood regula-ion.

Meta-analyses of cross-sectional functional MRI studies ofatients with MDD generally support the predicted patternsf increased limbic and decrease prefrontal activity. How-ver, there is limited overlap of significant effects betweentudies.16,17 It would be easy to dismiss this as a result of dif-erences in methodologies, however a lack of consistency

n the location of activation may in fact be a marker ofDD.17 Effective pharmacotherapy with SSRI is associatedith ‘‘normalization’’ of initial over-activation of limbic

egions and the opposite trend, toward increased activation

J. Suckling

ollowing treatment, in regions of prefrontal and cingulateortex.18

An observation arising from the meta-analyses is themergence of other regions outside of the fronto-limbicystem with reduced activation in patients.16 Whilst inter-sting, this is not unexpected given that most studies arexplorative and thus report effects from across the entireortex. These additional regions include the posterior cin-ulate and other components of the so-called default modeetwork, frequently linked to self-monitoring.19 Abnormalctivation in these regions can easily be envisaged as playing

key role in ruminative behavior. Meta analyses of restingerebral blood flow with positron emission tomography haslso demonstrated the sensitivity of these regions to SSRIreatment.16

In this brief overview of the current evidence for aeurobiology substrate to MDD we have necessarily hado narrow our focus to just two models. Summarizing thendings takes us in two apparently contradictory routes.n the one hand, there is good support for the consistent

nvolvement of HPA axis and fronto-limbic brain systemsn MDD; a significant achievement compared to our knowl-dge only a decade ago. On the other hand, there arelearly additional complexities in the data that are notdequately accounted for by the existing models as theyre described. In short, it looks unlikely that a reduction-st approach will lead to a sufficient or useful descriptionf MDD. Indeed, this is the case more generally acrosshe inventory of mental health disorders. Compartmentalodels in which areas are imbued with specific functions

nd sensitivities do not acknowledge the distributed andntegrative nature of the brain function. As the techniqueso measure the brain mature, an evolution is also neededn our conceptualization of its organization, function andsyfunction.

onflict of interest

he author has no conflict of interest to declare.

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