Review
Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies

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Abstract

Background

While there is evidence to suggest that major depressive disorder (MDD) is associated with structural brain abnormalities, the precise nature of these abnormalities remains unclear.

Aims

To review recent structural magnetic resonance imaging (MRI) research findings in MDD while considering the potential influence of key clinical and demographic variables.

Method

A selective review of all T1-weighted structural MRI studies published between 2000 and 2007 in adult samples of MDD patients.

Results

Volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC are consistently found in MDD patients, with more persistent forms of MDD (e.g., multiple episodes or repeated relapses, longer illness duration) being associated with greater impact on regional brain volumes. Gender, medication, stage of illness, and family history all affect the nature of the findings in a regionally specific manner.

Limitations

Overall, differences between the samples in factors such as illness severity, medication, gender and family history of mental illness makes difficult to identify their confounding effects on the observed neuroanatomical changes. Also, the tracing protocols used for particular brain regions were different amongst the reviewed studies, making difficult to compare their findings.

Conclusions

The data support the notion that MDD involves pathological alterations of limbic and cortical structures, and that they are generally more apparent in patients with more severe or persistent forms of the illness.

Introduction

Major Depressive Disorder (MDD) has been identified as a leading cause of disability worldwide, and will represent an increasing health, social and economic problem in the forthcoming years (Murray and Lopez, 1996, Murray and Lopez, 1997). For these reasons, it is critical to understand the relevant causal mechanisms in order to develop effective intervention strategies to prevent these illnesses and/or ameliorate their effects. From a neurobiological perspective, we are only beginning to understand the critical processes and brain regions that are associated with MDD. Nonetheless, the application of Magnetic Resonance Imaging (MRI) has fuelled increasingly sophisticated efforts to identify the disorder's pathophysiological mechanisms.

A large body of neuroimaging research in MDD has now been published, identifying several neuroanatomical changes in affected patients. However, findings can vary significantly across studies. Given the heterogeneity of depression, it is likely that one important issue is investigating the influence of key clinical and demographic characteristics (e.g., treatment status, stage of illness, gender) on the findings across different brain regions. Most neuroimaging studies still lack the power to examine the influence of these clinical and demographic differences on structural brain abnormalities within depressive samples, therefore systematic reviews of the literature can play a critical role in examining these effects across studies, and thus can direct future research efforts. To date, several reviews of this work have already been published (Beyer and Krishnan, 2002, Brambilla et al., 2002a, Campbell and Mac Queen, 2006, Drevets et al., 1998, Soares and Mann, 1997, Steffens and Krishnan, 1998, Videbeck and Ravnkilde, 2004), but they have often been quite broad. Indeed, several reviews focussed on how brain changes in MDD relate to those seen in other disorders, thus preventing detailed consideration of how the findings relate to the pathophysiology of MDD specifically. Also, other reviews have considered studies of adolescent or elderly samples in addition to adult patient groups, which may be limited in what their observations cannot disentangle disease-related changes from neurodevelopmental and/or age-related effects (Raz et al., 2005, Raz et al., 2007, Raz et al., 2004, Resnick et al., 2003). Alternatively, various reviews have maintained a narrow focus, restricting their discussion to one or a few specific brain regions. In fact, since 2000, only one systematic review of imaging research in MDD has been reported (Campbell and Mac Queen, 2006), but it only considered research published between 2004 and 2005. As such, the studies and findings were restricted to a very specific time period.

This paper presents a selective review of studies that investigated the more “trait like” neurobiological underpinning of MDD by using T1-weighted structural MRI, in contrast to other MRI measures such as functional Magnetic Resonance Imaging or even Magnetic Resonance Spectroscopy, as it provides a relatively stable brain measure that minimizes state related processes associated with the stage of illness, recovery and outcome. We selected the studies which have been published between 2000 and 2007, that investigated adult samples of patients (age 19–50 years) with a diagnosis of MDD, with specific attention being paid to the influence of clinical and demographic factors on the putative neuroanatomical phenotype of the disorder.

Section snippets

Methods

We followed the QUORUM (Moher et al., 1999) and AMSTAR (Shea et al., 2007) guidelines to perform the review. First, we searched the databases PubMed, MEDLINE, and PsycINFO using the terms “unipolar depression AND MRI”. We then restricted the search criteria in order to include only studies conducted on adult human beings, published between 2000 and 2007 and other criteria (i.e., described in Fig. 1). All the studies that investigated psychopathology/medical conditions other than MDD were

Method

In accordance with the QUORUM and AMSTAR guidelines there are a few study characteristics that should be noted. Firstly, most of the reviewed studies have matched the clinical and the control groups on cognitive and socio-demographical variables. A few studies did not explicitly match their groups (Brambilla et al., 2002b, Monkul et al., 2007, Saylam et al., 2006, Vythilingam et al., 2002, Vythilingam et al., 2004) but did not differ in these variables (e.g., IQ, education, gender, handedness

Discussion

The evidence to date supports the contention that neuroanatomical alterations in limbic and cortical structures are observable in adult MDD patients with a longer course or a more severe illness, as previously suggested (Pattern, 2006). Specifically, we have noted that volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC tend to be consistent in the reviewed literature. Interestingly, amygdala volume changes appear to be dynamic throughout the course of illness, being

Conclusions

This review of structural MRI findings in adults with MDD suggests that changes in temporal (e.g., STG, hippocampus, amygdala) and frontal (e.g., ACC and OFC) brain regions are associated with the disorder, and that they are generally more apparent in patients with more severe or persistent forms of the illness. While gender and medication appear to influence the precise nature of the findings, further work is necessary to better understand these effects. Together, the data support the notion

Role of the funding source

Funding for this study was provided by grants from the Australian Research Council (I.D. DP0557663); NHMRC Program Grant (I.D. 350241), the Colonial Foundation; J.N. Peters Fellowship; Faculty of Psychology scholarship of The University of Bologna. All the aforementioned funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

All the authors declare that they have no conflict of interest.

Acknowledgements

This research was supported by grants from the Australian Research Council (I.D. DP0557663) Dr Yücel is supported by a NHMRC Program Grant (I.D. 350241) and the Colonial Foundation. Dr Fornito is supported by a J.N. Peters Fellowship and by a NHMRC CJ Martin Fellowship (ID: 454797). Valentina Lorenzetti is supported by a scholarship of the Faculty of Psychology, The University of Bologna; by the International Postgraduate Research Scholarship, and by the Melbourne International Research

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