Hippocampal volume changes in healthy subjects at risk of unipolar depression

doi:10.1016/j.jpsychires.2009.12.009

Journal of Psychiatric Research

Volume 44, Issue 10, July 2010, Pages 655-662

https://doi.org/10.1016/j.jpsychires.2009.12.009 Get rights and content

Abstract

Unipolar depression is moderately heritable. It is unclear whether structural brain changes associated with unipolar depression are present in healthy persons at risk of the disorder. Here we investigated whether a genetic predisposition to unipolar depression is associated with structural brain changes. A priori, hippocampal volume reductions were hypothesized. Using a high-risk study design, magnetic resonance imaging brain scans were obtained from 59 healthy high-risk subjects having a co-twin with unipolar depression, and 53 healthy low-risk subjects without a first-degree family history of major psychiatric disorder. High-risk twins had smaller hippocampal volumes than low-risk twins (p < 0.04). The finding was most pronounced in DZ twins. Groups did not differ on global brain tissue volumes or regional tissue volumes assessed in exploratory voxel-wise whole cerebrum analyses. In conclusion, hippocampal volume reduction may index a predisposition to develop depression and thus may be predictive of future onset of the disorder. Further studies are needed to elucidate the role of (shared) environmental and genetic factors.

Introduction

Unipolar depression is heritable with concordance rates from 0.23 to 0.67 for monozygotic (MZ) twins and from 0.14 to 0.43 for dizygotic (DZ) twins (Sullivan et al., 2000). Structural brain imaging studies in unipolar depression have reported increased prevalence of white matter hyperintensities and volume decreases/changes in hippocampus, amygdala, caudate, putamen and frontal cortex (for reviews see Sheline, 2003, Lorenzetti et al., 2009, Koolschijn et al., 2009). The presence of hippocampal volume reduction in patients with unipolar depression is underscored in recent meta-analyses (Videbech and Ravnkilde, 2004, Koolschijn et al., 2009). Familial major depressive disorder has been associated with subgenual frontal volume reduction (Drevets et al., 1997). Moreover, a recent study of young psychotropic-naive patients with familial major depressive disorder, showed that the 22 included patients had significantly smaller left and right hippocampal volumes than the 35 matched controls (MacMaster et al., 2008). It is at present unclear whether structural brain changes associated with unipolar depression can also be observed in healthy persons at risk of the disorder.

In the present study we examined healthy individuals who never experienced depressive episodes to look for neuroanatomical correlates of a genetic predisposition to unipolar depressive disorder. Identification of high and low-risk individuals was accomplished by linking records of the Danish Psychiatric Central Research Register and the Danish Twin Registry. High resolution magnetic resonance (MR) scans of the brain were obtained in healthy MZ and DZ twins with a co-twin diagnosed with unipolar depression, and healthy MZ and DZ twins with a co-twin never diagnosed with an affective disorder. That is, the present study is a high-risk study, not a “classical” twin study, as it was not possible to investigate the (ill) co-twins. A priori we hypothesized that high-risk twins would have smaller hippocampal volumes than low-risk twins. Additionally, we performed exploratory voxel-wise whole cerebrum analyses.

Section snippets

Participants

In the present study 112 participants were included (Table 1): 59 healthy twins at risk of unipolar depression (high-risk – HR – twins) and 53 healthy twins without known personal or co-twin history of hospital contact with affective disorder (low-risk – LR – twins). The healthy high-risk and low-risk twins were identified through record linkage between the Danish Twin Registry, the Danish Psychiatric Research Register and the Danish Civil Register (the registers are described in more detail in

Demographics and clinical data

Groups did not differ on sex, zygosity, height, weight, or handedness (Table 1). However, groups did differ significantly in age and education, with the high-risk twins being somewhat older and having received less years of education. The education effect remained significant after controlling for age.

High-risk twins scored significantly higher on the HAM-D and number of adverse life events in the past 12 months than low-risk twins. Moreover, there was a trend for high-risk twins to score higher

Discussion

Consistent with our hypothesis, after correcting for supratentorial ICV, age, sex, and education, healthy high-risk subjects had smaller hippocampal volumes than healthy low-risk subjects. This effect remained significant after controlling for possible non-linear age effects, group differences on years of education, HAM-D scores and number of adverse life events in the past 12 months. However, excluding subjects with minor depression/anxiety related disorders reduced the Risk effect to trend

Contributors

Lars Vedel Kessing and Maj Vinberg designed the overall study and wrote the protocol. William F.C. Baaré, Terry L. Jernigan, Gitte M. Knudsen and Olaf B. Paulson designed the MR acquisition as well as image analysis part of the study. William F.C. Baaré and Annika R. Langkilde performed the MR image analyses. William F.C. Baaré and Maj Vinberg performed the literature searches and statistical analyses and wrote the first draft of the article. All authors contributed to and have approved the

Role of funding source

The Lundbeck Foundation provided most of the funding for the study. Additional funding came from the Foundation of A.P. Moeller and Chastine Mc-Kinney Moeller, the Foundation of Eli Larsen and Egon Larsen, and the Foundation of Einar Geert-Joergensen and wife Ellen Geert-Joergensen. The 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

None declared.

Acknowledgements

We are grateful to the participants. The Lundbeck Foundation provided most of the funding for the study. Additional funding came from the Foundation of A.P. Moeller and Chastine Mc-Kinney Moeller, the Foundation of Eli Larsen and Egon Larsen, and the Foundation of Einar Geert-Joergensen and wife Ellen Geert-Joergensen. Thanks to the Department of Psychiatric Demography, University of Aarhus, Psychiatric Hospital, Riskov, Denmark, and to the Danish Twin Registry for cooperation in the study.

References (46)

J. Ashburner
A fast diffeomorphic image registration algorithm
Neuroimage
(2007)
J. Ashburner et al.
Voxel-based morphometry – the methods
Neuroimage
(2000)
J. Ashburner et al.
Unified segmentation
Neuroimage
(2005)
L. Bergouignan et al.
Can voxel based morphometry, manual segmentation and automated segmentation equally detect hippocampal volume differences in acute depression?
Neuroimage
(2009)
M.V. Christensen et al.
Subclinical psychopathology and socio-economic status in unaffected twins discordant for affective disorder
Journal of Psychiatry Research
(2007)
C. Davatzikos et al.
Voxel-based morphometry using the RAVENS maps: methods and validation using simulated longitudinal atrophy
Neuroimage
(2001)
E.J. de Geus et al.
Intrapair differences in hippocampal volume in monozygotic twins discordant for the risk for anxiety and depression
Biological Psychiatry
(2007)
C.R. Genovese et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002)
S. Hayasaka et al.
Nonstationary cluster-size inference with random field and permutation methods
Neuroimage
(2004)
J. Jovicich et al.
Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data
Neuroimage
(2006)

L.V. Kessing

Validity of diagnoses and other clinical register data in patients with affective disorder

European Psychiatry

(1998)

K.T. Kronmuller et al.

Hippocampal volume in first episode and recurrent depression

Psychiatry Research

(2009)

V. Lorenzetti et al.

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

Journal of Affective Disorders

(2009)

F.P. MacMaster et al.

Amygdala and hippocampal volumes in familial early onset major depressive disorder

Biological Psychiatry

(2008)

J. Savitz et al.

Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide

Neuroscience and Biobehavioral Reviews

(2009)

Y.I. Sheline

Neuroimaging studies of mood disorder effects on the brain

Biological Psychiatry

(2003)

M.A. Yassa et al.

A quantitative evaluation of cross-participant registration techniques for MRI studies of the medial temporal lobe

Neuroimage

(2009)

A.T. Beck et al.

An inventory for measuring depression

Archives of General Psychiatry

(1961)

A.T. Beck et al.

An inventory for measuring clinical anxiety: psychometric properties

Journal of Consulting and Clinical Psychology

(1988)

L. Christiansen et al.

Age- and sex-differences in the validity of questionnaire-based zygosity in twins

Twin Research

(2003)

M.B. Cuadra et al.

Comparison and validation of tissue modelization and statistical classification methods in T1-weighted MR brain images

IEEE Transactions on Medical Imaging

(2005)

W.C. Drevets et al.

Subgenual prefrontal cortex abnormalities in mood disorders

Nature

(1997)

Ebdrup BH, Glenthoj BY, Rasmussen H, Aggernaes B, Langkilde AM, Paulson OB, et al. Hippocampal and caudate volume...

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Other studies have found smaller hippocampal volumes in (unaffected) high-risk adults and children (42–46). Healthy twin siblings of persons with depression also had smaller hippocampal volumes than twin siblings of persons without depression (82). However, some familial risk studies found no changes (47–49).
Offspring of individuals with major depressive disorder (MDD) are at increased risk for developing MDD themselves. Altered hippocampal, and specifically dentate gyrus (DG), structure and function may be involved in depression development. However, hippocampal abnormalities could also be a consequence of the disease. For the first time, we tested whether abnormal DG micro- and macrostructure were present in offspring of individuals with MDD and whether these abnormalities predicted future symptomatology.
We measured the mean diffusivity of gray matter, a measure of microstructure, via diffusion tensor imaging and volume of the DG via structural magnetic resonance imaging in 102 generation 2 and generation 3 offspring at high and low risk for depression, defined by the presence or absence, respectively, of moderate to severe MDD in generation 1. Prior, current, and future depressive symptoms were tested for association with hippocampal structure.
DG mean diffusivity was higher in individuals at high risk for depression, regardless of a lifetime history of MDD. While DG mean diffusivity was not associated with past or current depressive symptoms, higher mean diffusivity predicted higher symptom scores 8 years later. DG microstructure partially mediated the association between risk and future symptoms. DG volume was smaller in high-risk generation 2 but not in high-risk generation 3.
Together, these findings suggest that the DG has a role in the development of depression. Furthermore, DG microstructure, more than macrostructure, is a sensitive risk marker for depression and partially mediates future depressive symptoms.
Orbitofrontal cortex grey matter volume is related to children's depressive symptoms
2020, NeuroImage: Clinical
Adults with a history of depression show distinct patterns of grey matter volume (GMV) in frontal cortical (e.g., prefrontal cortex, orbitofrontal cortex) and limbic (e.g., anterior cingulate, amygdala, hippocampus, dorsal striatum) structures, regions relevant to the processing and regulation of reward, which is impaired in the context of depression. However, it is unclear whether these GMV associations with depression precede depressive disorder onset or whether GMV is related to early emerging symptoms or familial depression. To address these questions, we used voxel-based morphometry (VBM) to examine GMV in 85 community-dwelling children (M = 11.12 years, SD = 0.63 years) screened for current and lifetime depression. Associations between children’s depressive symptoms (self- and mother-report of children’s symptoms), children’s maternal depression history, and GMV were examined. Although maternal depression history was unrelated to children’s GMV, child GMV in the orbitofrontal cortex (OFC) was negatively related to children’s self-reported depressive symptoms, using both a priori ROI and whole-brain analyses. Moderated regression analyses indicated that girls’ GMV was negatively related to girls’ depressive symptoms (as indexed by both self- and mother-report of girls’ symptoms), whereas boys’ symptoms were positively related to GMV. Our findings suggest that brain morphology in the OFC, a region with functional roles in processes relevant to depressive symptoms (i.e., reward-based learning and reward processing), is associated with early depressive symptoms prior to the development of clinically significant depression.
Disease-discordant twin structural MRI studies on affective disorders
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Magnetic resonance imaging (MRI) studies have identified neural structures implicated in the pathophysiology of mood disorders, especially bipolar disorder (BD) and major depressive disorder (MDD). However, the role of genetic and environmental influences on such brain deficits is still unclear. In this context, the present review summarizes the current evidence from structural MRI and Diffusion Tensor Imaging (DTI) studies on twin samples concordant or discordant for BD or MDD, with the aim of clarifying the role of genetic and environmental risk factors on brain alterations. Although the results showed a complex interplay between gene and environment in affective disorders, the evidence seem to underline that both genetic and environmental risk factors have an impact on brain areas and vulnerability to MDD and BD. However, the precise mechanism of action and the interaction between these factors still needs to be unveiled. Therefore, future larger studies on concordant or discordant twins should be encouraged, because this population provides a unique opportunity to probe separately genetic and environmental markers of disease vulnerability.
The role of genes and environment on brain alterations in Major Depressive Disorder: A review of twin studies: Special Section on “Translational and Neuroscience Studies in Affective Disorders”. Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders
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Citation Excerpt :
GM reduction, however, resulted exclusively in the intra-pair comparison of MZ twins discordant for MDD, suggesting the possibility of a specific environmental contribution to hippocampal alterations linked to depression. Finally, Baaré et al. (2010) replicated these findings by showing that high-risk twins had smaller hippocampal volumes compared to low-risk twins, on a sample composed by both MZ and DZ twins. However, the authors suggested that the volume reduction seemed to be more pronounced in DZ twins, underlining a more complex gene-by-environment interaction, probably affected by shared environment.
Although it has been consistently reported the important role of genetic and environmental risk factors on structural and functional alterations in Major Depressive Disorder (MDD), the mechanism and the magnitude of the interactions between specific genetic and/or environmental risk factors on brain structures in this disabling disorder are still elusive. Therefore, in the last two decades an increased interest has been devoted to neuroimaging investigations on monozygotic and dizygotic twin samples mainly because their intrinsic characteristics may help to separate the effects of genetic and environmental risk factors on clinical phenotypes, including MDD.
In this context, the present review summarizes results from structural and functional Magnetic Resonance Imaging studies that investigated twin samples in correlation with MDD.
Overall the results confirmed that a) MDD is characterized by significant alterations in selective brain areas presiding over emotion recognition and evaluation, including amygdala, insula and prefrontal cortices, and b) both genetic and environmental risk factors play a key role in the pathophysiology of this disorder.
Few MRI studies exploring MDD in twin samples.
The specific contribution of both aspects is still not fully elucidated especially because genes and environment have an impact on the same brain areas, which are particularly vulnerable in MDD. Expansion of the current twin sample sizes would help to clearly establish the potential relationship between risk factors and the development of MDD.

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Hippocampal volume changes in healthy subjects at risk of unipolar depression

Abstract

Introduction

Section snippets

Participants

Demographics and clinical data

Discussion

Contributors

Role of funding source

Conflict of interest

Acknowledgements

Neuroimage

Neuroimage

Neuroimage

Neuroimage

Journal of Psychiatry Research

Neuroimage

Biological Psychiatry

Neuroimage

Neuroimage

Neuroimage

European Psychiatry

Psychiatry Research

Journal of Affective Disorders

Biological Psychiatry

Neuroscience and Biobehavioral Reviews

Biological Psychiatry

Neuroimage

An inventory for measuring depression

Archives of General Psychiatry

An inventory for measuring clinical anxiety: psychometric properties

Journal of Consulting and Clinical Psychology

Age- and sex-differences in the validity of questionnaire-based zygosity in twins

Twin Research

Comparison and validation of tissue modelization and statistical classification methods in T1-weighted MR brain images

IEEE Transactions on Medical Imaging

Subgenual prefrontal cortex abnormalities in mood disorders

Nature