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Brief report

Subregional hippocampal deformations in major depressive disorder

James Cole a, Arthur W. Toga b, Cornelius Hojatkashani b, Paul Thompson b, Sergi G. Costafreda a,Anthony J. Cleare a, Steven C.R. Williams a, Edward T. Bullmore c, Jan L. Scott d,Martina T. Mitterschiffthaler a, Nicholas D. Walsh e, Catherine Donaldson a, Mubeena Mirza b,Andre Marquand a, Chiara Nosarti a, Peter McGuffin a, Cynthia H.Y. Fu a,⁎a Institute of Psychiatry, King's College London, De Crespigny Park, London, UKb Laboratory of NeuroImaging, University of California Los Angeles, Los Angeles, USAc Brain Mapping Unit, University of Cambridge, Department of Psychiatry, Addenbrooke's Hospital, Cambridge, UKd University Department of Psychiatry, Royal Victoria Infirmary, Newcastle University, Newcastle upon Tyne, UKe Developmental Psychiatry Section, University of Cambridge, Department of Psychiatry, Cambridge, UK

a r t i c l e i n f o

⁎ Corresponding author. Institute of Psychiatry, 103London SE5 8AF, UK. Tel: +44 207 848 5350; fax: +4

E-mail address: c.fu@iop.kcl.ac.uk (C.H.Y. Fu).

0165-0327/$ – see front matter © 2010 Elsevier B.V.doi:10.1016/j.jad.2010.03.004

Please cite this article as: Cole, J., et al., Su(2010), doi:10.1016/j.jad.2010.03.004

a b s t r a c t

Article history:Received 7 July 2009Received in revised form 5 March 2010Accepted 5 March 2010Available online xxxx

Background: Hippocampal atrophy is a well reported feature of major depressive disorder,although the evidence has been mixed. The present study sought to examine hippocampalvolume and subregional morphology in patients with major depressive disorder, who were allmedication-free and in an acute depressive episode of moderate severity.Methods: Structural magnetic resonance imaging scans were acquired in 37 patients (mean age42 years) and 37 age, gender and IQ-matched healthy individuals. Hippocampal volume andsubregional structural differences were measured by manual tracings and identification ofhomologous surface points to the central core of each hippocampus.Results: Both right (P=0.001) and left (P=0.005) hippocampal volumes were reduced inpatients relative to healthy controls (n=37 patients and n=37 controls), while only the righthippocampus (P=0.016) showed a reduced volume in a subgroup of first-episode depressionpatients (n=13) relative to healthy controls. Shape analysis localised the subregionaldeformations to the subiculum and CA1 subfield extending into the CA2-3 subfieldspredominantly in the tail regions in the right (P=0.017) and left (P=0.011) hippocampi.Limitations: As all patients were in an acute depressive episode, effects associated withdepressive state cannot be distinguished from trait effects.Conclusions: Subregional hippocampal deficits are present early in the course of majordepression. The deformations may reflect structural correlates underlying functional memoryimpairments and distinguish depression from other psychiatric disorders.

© 2010 Elsevier B.V. All rights reserved.

Keywords:DepressionHippocampusMorphologyShapeMRI

1. Introduction

Reduced hippocampal volume is the most consistentlyobserved structural abnormality in major depressive disorder(MDD) (reviewed in: Campbell et al., 2004; Videbech andRavnkilde, 2004; McKinnon et al., 2009), with some

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bregional hippocampal

conflicting reports (Rusch et al., 2001; Posener et al., 2003;Hastings et al., 2004; Vythilingam et al., 2004). Subregionaldeformations though may be discernible in the hippocampus,which are not captured by volumetric measures alone(Posener et al., 2003). Measures of regional brain structuralmorphology quantify the dimensions of the structure in itsentirety as well as subregional features, providing an outputof both the structural volume and morphological shape(Thompson et al., 2004). Analysis of hippocampal morphol-ogy have identified distinct and potentially characteristic

deformations in major depressive disorder, J. Affect. Disord.

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subregional deformations in schizophrenia (Narr et al., 2004),late-life depression (Ballmaier et al., 2008) and adolescentbipolar disorder (Bearden et al., 2008).

In the present study, we sought to examine hippocampalvolume and shape in mid-life depression. We applied manualtracing of each hippocampus for each subject and point-by-point statistical comparisons at each surface location(Thompson et al., 2004). In late-life depression, Ballmaieret al. (2008) observed significant hippocampal atrophy andlocalised deficits to the anterior CA1–CA3 regions andsubiculum bilaterally. However, in mid-life depression,reports of hippocampal atrophy have been mixed (Ruschet al., 2001; Posener et al., 2003; Zou et al., 2010), perhapsreflecting a greater number of episodes or duration of illnessin late-life depression (Campbell et al., 2004; Videbech andRavnkilde, 2004; McKinnon et al., 2009). The present sampleconsisted of mid-life, adult MDD patients with a history of 2or fewer episodes, all were suffering from an acute depressiveepisode and were medication-free (Costafreda et al., 2009).We expected to find similar deformations in the subiculumand adjacent hippocampal subfields, although perhaps lessextensive than that observed in late-life depression.

2. Methods

2.1. Participants

Thirty-seven right-handed patients were recruitedmeetingDSM-IV criteria for major depressive disorder (APA, 1994) bythe Structured Clinical Interview for DSM-IV (SCID) (First et al.,1995) and a clinical interview with a consultant psychiatrist(Costafreda et al., 2009). Inclusion criteria were an acuteepisode of unipolar major depression and a minimum score of18on the17-itemHamiltonRatingScale forDepression (HRSD)(Hamilton, 1960). Exclusion criteria were a history of neuro-logical trauma resulting in loss of consciousness, currentneurological disorder, current co-morbid Axis I disorderincluding bipolar disorder or an anxiety disorder, history ofsubstance abuse within 2 months of study participation, and alifetime history of substance dependence. All patients weremedication-free for a minimum of 2 weeks prior to the scan(4 weeks if the previous treatment had been fluoxetine). Eightpatients had received previous antidepressant medications,which included citalopram, fluoxetine and paroxetine. Thirty-

Table 1Demographic features and hippocampal volumetric data.

Healthy controls Depressed

All patient

Number of subjects 37 37Mean age (years) 42.2 (9.0) 41.9 (8.9)Sex (male/female) 9/28 9/28HRSD 0.2 (0.6) 20.7 (2.2) a

Verbal IQ 114.5 (13.2) 108.7 (17.1L hippocampus 1.98 (0.29) 1.77 (0.26)R hippocampus 2.08 (0.28) 1.86 (0.22)Intracranial volume 1501.57 (137.73) 1459.45 (1

Data presented asmean and standard deviation in parenthesis. Volumemeasures area Indicates data showing a significant difference from healthy controls.

Please cite this article as: Cole, J., et al., Subregional hippocampal(2010), doi:10.1016/j.jad.2010.03.004

seven age, sex, and IQ-matched, right-handed healthy controlswere recruited with no history of psychiatric disorder,neurological disorder, or head injury resulting in a loss ofconsciousness and an HRSD score b7 (Table 1). All subjectswere recruited by advertisement from the local community,and all patients were outpatients. All participants providedwritten informed consent to participate in this study inaccordance with the guidelines of the Institute of Psychiatryand South London and Maudsley NHS Trust Ethics (Research)Committee.

2.2. Image acquisition

Structural MRI brain scans were acquired using a 1.5 T GENV/i Signa system (General Electric, Milwaukee WI, USA) atthe Maudsley Hospital, London. Head movement was limitedby foam padding within the head coil and a restraining bandacross the forehead. 3D spoiled gradient recalled (SPGR) T1-weighted scans were obtained with the acquisition para-meters: TE=8, TR=24ms, flip angle=30º, field of view=25cm×25cm, slice thickness=1.3 mm, number of partitions(slices)=124, image matrix=256×256×124, voxel size=0.97 mm×0.97 mm×1.3 mm. Image requisition parametersare consistent with most MRI acquisition protocols that havebeen used for defining the hippocampus (reviewed in: Konradet al, 2009) and is a standard resolution for many structuralstudies (http://www.loni.ucla.edu/ADNI/Research/Cores/).Image contrast for datasetswas chosenwith the aid of a softwaretool for optimising image contrast (Simmons et al, 1996).

2.3. Image pre-processing and analysis

Pre-processing steps consisted of removal of non-corticaltissue, linear alignment to standard space, and reslicing into theanterior–posterior orientation. Each hippocampus was out-lined manually in MultiTracer (Woods, 2003) by a trainedinvestigator (JC) blind to the diagnosis. Inter and intra-raterreliability (intra-class correlation coefficient=0.91) was cal-culated based on established protocols (Narr et al., 2004;Thompson et al., 2004). Outlines were traced in the coronalorientation, from anterior to posterior along contiguous imageslices, and included all hippocampal grey matter including thedentate gyrus and subiculum. Volumetric measures werecalculated from the centre of the first slice to the centre of the

patients

s First-episode Recurrent

13 2438.1 (7.9) 44.0 (9.4)2/11 7/1721.5 (2.7) a 20.2 (1.7) a

) 103.1 (20.3) 111.6 (15.0)a 1.81 (0.29) 1.75 (0.24) a

a 1.85 (0.21) a 1.84 (0.24) a

25.30) 1464.24 (105.54) 1456.86 (136.91)

inmL units. HRSD=Hamilton Rating Scale for Depression; L= left, R= right

deformations in major depressive disorder, J. Affect. Disord.

.

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last, 1 mmsamplingalong theaxis,with the square root of areasvarying linearly from slice to slice. The sum of these areasgenerated the hippocampal volume. Intracranial volume (ICV)was calculated with the Brain Extraction Tool (BET) (Smith,2002) which removes all non-brain matter from MR images.The original unprocessed images were BET-segmented, thenmanually checked to ensure accurate identification of greymatter, white matter and cerebrospinal fluid. Measures ofvolume, in mm3, were generated from the extracted images.Subgroup analyses of hippocampal volume were also con-ductedwith thepatient group divided into patients in theirfirstepisode of depression (n=13) and those with recurrentepisodes of depression (n=24) (Table 1).

2.4. Morphological analysis

Surface mesh modelling analysis was performed asdescribed in Thompson et al. (2004).

Briefly, parametric surface meshes were computed fromthe manually-derived hippocampal outlines. Surface mesheswere combined to form a mean shape representing eachgroup in three dimensions. In each individual, the medialcore, a central 3D curve threading down the long axis of thestructure, was computed. From each point on the hippocam-pal surface, a radial distance measure was derived to themedial core. As the same surface grid was imposed on allsubjects' hippocampi in the same coordinate space, statisticalcomparisons were made at each hippocampal surface pointbetween the groups to index contrasts on a local scale.Probability values from these statistical comparisons weremapped onto an average hippocampal shape for the entiresample to generate a 3D representation of the structuraldifferences between the groups. Permutation testing wasperformed in order to correct for the 30,000 simultaneouscomparisons made for each hippocampus. Each subject wasrandomly assigned to a diagnostic group 150,000 timeswith astatistical threshold of Pb0.05, and the area of the hippo-campus with suprathreshold statistics in each group com-parisonwas comparedwith its null distribution, thus derivingan overall corrected significance value for the pattern ofeffects for each hippocampus.

3. Results

There was an expected significant difference in HRSDratings between healthy controls and patients (F=1611.34,df=2, 71, Pb0.001), in which post-hoc Tukey's test showed asignificant difference between healthy controls and patientswith recurrent episodes of depression (Pb0.001), healthycontrols and patients in their first episode (Pb0.001), and atrend towards significance between patients with recurrentepisodes and those in their first episode (P=0.055).

There was no significant difference in intracranial volume(ICV) between healthy controls and patients (F=0.95, df=2,71, P=0.39). Left hippocampal volume showed a significantdifference between patients and healthy controls (F=5.64,df=2, 71, P=0.005), and post-hoc Tukey's test revealed asignificant difference between healthy controls and patientswith recurrent episodes of depression (P=0.005), but notbetween healthy controls and patients in their first episode orbetween the patient subgroups. Right hippocampal volume

Please cite this article as: Cole, J., et al., Subregional hippocampal(2010), doi:10.1016/j.jad.2010.03.004

also showed a significant difference between patients andhealthy controls (F=7.58, df=2, 71, P=0.001), and post-hocTukey's test revealed significant differences between healthycontrols and both patient subgroups: patients with recurrentepisodes of depression (P=0.003) and patients in their firstepisode (P=0.016), but there were no differences betweenthe patient subgroups. There were no significant correlationswith right or left hippocampal volume and the number ofprevious episodes, duration of illness, or severity of illness asmeasured by the HRSD score. There were no significantdifferences between males and females in terms of age, IQ,right or left hippocampal volumes, or corrected hippocampalvolumes, all p-valuesN0.3.

Morphological analysis revealed distinct hippocampaldeformations in the subiculum and CA1 extending into theCA2-3 subfields predominantly in the tail regions in both theleft (corrected P=0.011) and right (corrected P=0.017)hippocampi in patients relative to healthy controls (Fig. 1).

4. Discussion

We found significant bilateral hippocampal atrophy inmedication-free patients with major depression of a moderateseverity. Morphological analysis localised the atrophy todistinct subregions within the hippocampi. Marked deforma-tions were evident in the subiculum and CA1 subfieldextending into the CA2-3 subfields largely in the tail regionsof both hippocampi in depressed patients relative to healthycontrols. The findings indicate that subregional hippocampaldeficits are not confined to late-life depression (Ballmaier et al.,2008), but are evident early in the illness.

Thehippocampaldeformationsobserved fromMRI scansaresupportedbyneuropathologicalfindings (Rosoklija et al., 2000).Neumeister et al. (2005) reported decreased hippocampalvolume in its whole and more pronounced in the posteriorregion, and Maller et al. (2007) found localised volumereductions in the most posterior region of the tail of thehippocampus in patients with treatment-resistant depression.Posener et al. (2003) noted specific abnormalities in thesubiculum in patients with similar demographic features tothose in the present study, but half the patient group wasreceiving psychiatric medications. In the present study, allpatients were medication-free, right-handed, and had 2 orfewer episodes of depression. In late-life depression, Ballmaieret al. (2008)observed extensivemorphological abnormalities inthe subiculum and CA1 subregions which extended into theCA2-3 subfields. In the late-life depression group, those patientswith a comparable age of onset to our sample had an average of5 previous episodes of depression at the time of their scan(Ballmaier et al., 2008). Our findings revealed that the mainhippocampal body was relatively intact while deformationswere evidentparticularly in the tail regionwithin the subiculumand CA1 subfield but as well in the CA2-3 subfields. Together,these data suggest that the subregional hippocampal abnor-malities present at early stages in the illness may becomemoreextensive with recurrent episodes, contributing to the hippo-campal atrophy that is particularly evident in recurrent andtreatment-resistant depression (reviewed in: Campbell et al.,2004; Videbech and Ravnkilde, 2004; McKinnon et al., 2009).

The posterior portion of the hippocampus is engaged bymemory retrieval (Lepage et al., 1998), and the subiculum has

deformations in major depressive disorder, J. Affect. Disord.

Fig. 1.Morphological analysis of bilateral hippocampi in major depressive disorder. Top panel presents a schematic figure of the hippocampi in-situ. In the middlepanel, regional subfield deformations are depicted on hippocampal surface maps. Smaller p-values reflect greater medial distance reductions in patients withdepression (n=37) relative to healthy controls (n=37). Reference shapes are presented in the lower panel depicting the hippocampal subfields based on thesubfield definitions used by Bearden et al. (2008). Hippocampi are presented left to right in the following order: right hippocampus, superior view; lefhippocampus, superior view; left hippocampus, inferior view; right hippocampus, inferior view. CA = cornu ammonis.

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been specifically implicated in the retrieval of episodicmemories (Gabrieli et al., 1997; Zeineh et al., 2003; Eldridgeet al., 2005). Memory impairments are associated withhippocampal atrophy in depression (Hickie et al., 2005). Inparticular, deficits in episodic memory are a commonlyreported feature (Golinkoff and Sweeney, 1989; Ilsley et al.,1995), which may be greater in the retrieval, as opposed tothe encoding, aspects of the memory trace (Fossati et al.,2002). These deficits are not evident in the first episode ofdepression, but become more prominent in recurrentdepression (Fossati et al., 2004). A main component ofautobiographical memory is the recall of episodes in one'slife (Brewer, 1986). It is widely recognised that individualswith depression have difficulty in recalling specific autobio-graphical events (Williams and Broadbent, 1986; Williamsand Scott, 1988), instead they tend to produce an over-generalised memory, which may be more pronounced withnegative incidents (Williams and Scott, 1988).

Although we observed a right lateralised deficit in hippo-campal volume in first-episode patients, bilateral hippocampal

Please cite this article as: Cole, J., et al., Subregional hippocampal deformations in major depressive disorder, J. Affect. Disord.(2010), doi:10.1016/j.jad.2010.03.004

t

atrophy has been reported in medication-naïve, first-episodepatients with depression (Zou et al., 2010), in medication-freepatients with recurrent depression (Neumeister et al., 2005),and a recent meta-analysis indicates a 4% aggregate loss inhippocampal volume in depression with no significant later-alisation effects (McKinnon et al., 2009). A left lateralisedreduction in hippocampal volume has been noted in first-episode male patients (Frodl et al., 2002) and in late-lifedepression of a mean age of onset of 35 years (Ballmaier et al.,2008). The reason for the right lateralised effect that we haveobserved is unclear, but we did not find any significantcorrelations with right or left hippocampal volume and thenumber of previous episodes, duration of illness, or severity ofillness.

However, hippocampal atrophy is not specific to depressionas it has been observed in other psychiatric disorders, such asschizophrenia (Sumich et al., 2002), obsessive–compulsivedisorder (Atmaca et al., 2008), and borderline personalitydisorder (Driessen et al., 2000). The present study may help todistinguish between hippocampal abnormalities found in

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depression and other psychiatric disorders. For example, bothdepression and schizophrenia have been associatedwith globalhippocampal volume reductions (Sumich et al., 2002). Mor-phological analysis revealed localised deformations in theanterior regions in schizophrenia (Narr et al., 2004), while wefound greater alterations in posterior tail regions. Furthermore,in schizophrenia the deficits were generally bilateral, moreextensive, and clearly evident in patients in their first episode(Narr et al., 2004). In depression, the hippocampal deforma-tions were more circumscribed in mid-life depression andvolumetric atrophywas only found in the right hippocampus infirst-episode depression. This dissociation between psychiatricdisorders may have important aetiological and diagnosticimplications, and the specificity of the morphological changeswill require further investigation.

A caveat to the interpretation of morphological analysisthough is limited anatomical accuracy. Hence, local deficitsidentified with shape mapping and MRI would be charac-terized with greater precision by neuropathological exam-ination. Furthermore, the present study did not addresspossible causative mechanisms, such as hippocampal apo-ptosis and decreased neurogenesis, which may be driven byhypercortisolemia or diminished neurotrophin levels (Czehand Lucassen, 2007). Posener et al. (2003) examinedhippocampal morphology by delineating the boundaries ofthe hippocampus based on specific landmarks, reporting nodifference in hippocampal volume but deficits in thesubiculum region. The method though consisted of a limitednumber of anatomical landmarks to define hippocampalmorphology which may have minimised gross and localirregularities. Moreover, we did not observe a correlationbetween hippocampal volume and the number of depressiveepisodes. The present group though consisted of patientswith none or few previous episodes of depression, whichmay have limited the observation of any correlations as theymay become evident in a larger sample with a greater rangeof episodes.

In summary, hippocampal deformations localised to thesubiculum and CA1 subregion extending into the CA2-3subregions were observed in patients with major depression.Subregional hippocampal deformations may distinguishdepression from other psychiatric disorders.

Role of funding sourceThis workwas funded by a National Alliance for Research in Schizophrenia

and Depression Young Investigator Award (CF) and the National Institutes ofHealth through the National Center for Research Resources (P41 RR13642) andthe NIH Roadmap for Medical Research, Grant U54 RR021813. Information onthe National Centers for Biomedical Computing can be obtained from http://nihroadmap.nih.gov/bioinformatics. The Funders had no further role in studydesign; in the collection, analysis and interpretationof data; in thewriting of thereport; and in the decision to submit the paper for publication.

Conflict of interestAll authors declare that they have no conflicts of interest.

Acknowledgements

We thank all the patients who participated in the studyand the radiographers for their assistance in data collection.

Please cite this article as: Cole, J., et al., Subregional hippocampal(2010), doi:10.1016/j.jad.2010.03.004

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