Article

Altered Hippocampal Morphology in Unmedicated Patients with Major Depressive Illness

Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
ASN Neuro (Impact Factor: 4.02). 10/2009; 1(4). DOI: 10.1042/AN20090026
Source: PubMed
ABSTRACT
Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. In the present study we acquired brain MRIs (magnetic resonance images) from 31 unmedicated patients with MDD (major depressive disorder; mean age 39.2+/-11.9 years; 77% female) and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 (cornu ammonis 1) subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend towards larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.

Full-text

Available from: Paolo Brambilla
Altered hippocampal morphology in
unmedicated patients with major
depressive illness
Carrie E Bearden*
1
, Paul M Thompson
{
, Christina Avedissian
{
, Andrea D Klunder
{
, Mark Nicoletti
{
, Nicole Dierschke
1
,
Paolo Brambilla
I
and Jair C Soares
"
*Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, U.S.A.
{
Laboratory of Neuro Imaging, Department of Neurology, University of California, Los Angeles, CA 90095, U.S.A.
{
Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, U.S.A.
1
Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, U.S.A.
I
Scientific Institute IRCCS, E. Medea, and Section of Psychiatry, Department of Pathology and Experimental and Clinical Medicine, University of Udine,
Udine, Italy
"
Department of Psychiatry and Behavioral Sciences, University of Texas at Houston School of Medicine, 1300 Moursund Street, Houston, TX 77030,
U.S.A.
Cite this article as: Bearden CE, Thompson PM, Avedissian C, Klunder AD, Nicoletti M, Dierschke N, Brambilla P and Soares JC (2009) Altered
hippocampal morphology in unmedicated patients with major depressive illness. ASN NEURO 1(4):art:e00020.doi:10.1042/AN20090026
ABSTRACT
Despite converging evidence that major depressive illness is
associated with both memory impairment and hippocam-
pal pathology, findings vary widely across studies and it is
not known whether these changes are regionally specific.
In the present study we acquired brain MRIs (magnetic
resonance images) from 31 unmedicated patients with
MDD (major depressive disorder; mean age 39.2¡11.9
years; 77% female) and 31 demographically comparable
controls. Three-dimensional parametric mesh models were
created to examine localized alterations of hippocampal
morphology. Although global volumes did not differ
between groups, statistical mapping results revealed that
in MDD patients, more severe depressive symptoms were
associated with greater left hippocampal atrophy, particu-
larly in CA1 (cornu ammonis 1) subfields and the
subiculum. However, previous treatment with atypical
antipsychotics was associated with a trend towards larger
left hippocampal volume. Our findings suggest effects of
illness severity on hippocampal size, as well as a possible
effect of past history of atypical antipsychotic treatment,
which may reflect prolonged neuroprotective effects. This
possibility awaits confirmation in longitudinal studies.
Key words: antipsychotic, brain mapping, hippocampus,
mood disorder, neuroimaging, subiculum, unipolar depression.
INTRODUCTION
Memory deficits are one of the most consistently reported
cognitive difficulties in both symptomatic and remitted
patients with major depressive illness (Porter et al., 2003;
Weiland-Fiedler et al., 2004; Bearden et al., 2006). Given the
central role of the hippocampus in the formation and
consolidation of new memories (Eichenbaum and Fortin,
2005), as well as its importance for the regulation of
motivation and emotion (Davidson et al., 2002), hippocampal
pathology is likely to be involved in the pathophysiology of
the illness. Indeed, reduced hippocampal volume has been
reported by many, but not all, neuroimaging studies of MDD
(major depressive disorder) (Campbell and MacQueen, 2004;
Videbech and Ravnkilde, 2004). Results of a recent meta-
analysis indicated that differences in hippocampal volume
were only apparent among MDD patients with a duration of
illness longer than 2 years, or who had more than a single
disease episode, suggesting that hippocampal volume reduc-
tions typically occur after disease onset in MDD patients
(McKinnon et al., 2009).
However, a major limitation in most prior investigations is
that patients were studied while on a variety of medications.
The acute and long-term effects of psychotropic medica-
tions on brain structure are not well understood. There is
recent evidence for neurotrophic or neuroprotective prop-
erties of lithium (Bearden et al., 2008; Yucel et al., 2008a),
1
To whom correspondence should be addressed (email cbearden@mednet.ucla.edu).
Abbreviations: CA, cornu ammonis; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders 4th Edition; HDRS, Hamilton Depression Rating Scales; MDD, major
depressive disorder; MRI, magnetic resonance imaging; SCID, Structured Clinical Interview for DSM-IV.
E 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://
creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is
properly cited.
RESEARCH ARTICLE
ASN NEURO 1(4):art:e00020.doi:10.1042/AN20090026
asnneuro.org / Volume 1 (4) / art:e00020 265
Page 1
atypical antipsychotics (Jones et al., 2009; Thompson et al.,
2009) and antidepressant medications (Sheline et al., 2003).
Also, many patients with mood disorders take multiple
medications, at various doses and with variable consistency
over the course of the illness, and these effects are very
difficult to quantify rigorously.
Finally, the question of regional specificity of hippocampal
abnormalities in MDD has rarely been examined. Only one prior
study, to our knowledge, has applied three-dimensional
mapping methods to examine hippocampal morphology in
depressed patients. In this study of patients with elderly
depression, Ballmaier et al. (2008) found pronounced, localized
surface contractions in patients with late-onset depression,
relative to early-onset depression, although differences in
overall hippocampal volumes were not detectable. Post-
mortem studies have identified neuronal abnormalities in the
subiculum, as well as in specific hippocampal subfields, with
the most pronounced changes in the CA1 (cornu ammonis 1)
region in the brains of depressed individuals (Rosoklija et al.,
2000). The CA1 region sends significant output forward to the
subiculum, which has direct connections to the entorhinal
cortex and the amygdala. It also projects to the ventromedial
prefrontal cortex, thalamus, hypothalamus and striatum,
structures critically involved in mood regulation (Sapolsky,
2004).
To overcome limitations of prior investigations, we studied a
group of relatively young unmedicated patients, diagnosed
with MDD with no comorbidities. We used high-resolution MRI
(magnetic resonance imaging) and a three-dimensional radial
mapping approach to assess subregional structural deforma-
tions in the hippocampus. This technique (Thompson et al.,
2004a) improves upon other methods in that it visualizes the
spatial profile of neuropathological abnormalities, allowing
more refined neuroanatomical localization of regionally
specific alterations in depressed patients. We hypothesized
that unmedicated depressed patients would exhibit localized
alterations in hippocampal structure, relative to healthy
comparison subjects, which would be most pronounced in
the subiculum and CA1 subfields. Secondly, we examined
relationships between hippocampal morphology and clinical
variables (depression severity, family history, prior medication
history and duration of illness). Given prior evidence that
antidepressant and antipsychotic medications affect brain
structure, we also explored the effects of previous treatment
with these medications within the patient sample.
MATERIALS AND METHODS
Subjects
The present study was approved by the University of
Pittsburgh Biomedical Institutional Review Board. All subjects
provided written informed consent, after study procedures
were fully explained. In total 31 unmedicated outpatients
with MDD and 31 demographically matched healthy controls
were studied (see Table 1). Some subjects in the present study
were included in previous reports that focused on other brain
structures (Brambilla et al., 2005; Caetano et al., 2006). At the
time of participation in the study, all patients were off all
psychotropic drugs for at least 2 weeks.
Patients met DSM-IV (Diagnostic and Statistical Manual of
Mental Disorders 4th Edition) diagnostic criteria for unipolar
MDD, as determined by direct interview with the SCID
(Structured Clinical Interview for DSM-IV) (Spitzer et al.,
1994). Exclusion criteria were any DSM-IV axis I comorbidity,
current medical problems, history of neurological illness,
history of head trauma with loss of consciousness, substance
or alcohol abuse within the 6 months preceding the study, or
history of substance or alcohol dependence at any time. The
BRMS (Bech–Rafaelsen Mania Scale) (Bech et al., 1979) and
the HDRS (Hamilton Depression Rating Scales) (Hamilton,
1960) were used to rate clinical symptoms, and were
administered within a week of the MRI scan. At the time of
the MRI scan, 20 subjects (65%) were in a depressed mood
state, whereas 11 (35%) were euthymic. Family history
information was obtained by directly questioning patients
and/or relatives, and by reviewing the medical records. On the
basis of this information, first-degree relatives were con-
sidered positive for mood disorders if there was a past history
of ever having received a diagnosis of unipolar major
depression or bipolar disorder by a physician. Patients with
at least one first-degree relative with a history of mood
disorders were considered familial mood disorder patients.
Healthy controls had no DSM-IV axis I disorders, as
determined by direct interview with the SCID-IV-NP (SCID-
IV non-patient version). They had no current medical
problems and no history of psychiatric disorder among
first-degree relatives. The SCID-IV interviews for patients and
controls were completed by a trained clinical social worker or
a registered nurse at the University of Pittsburgh Outpatient
Mood Disorders Clinic. After completion of the SCID-IV
interview, psychiatric diagnoses were confirmed by a board-
certified study psychiatrist.
MRI procedure
MRI scans were acquired with a 1.5T GE Signa Imaging System
running version Signa 5.4.3 software (General Electric Medical
Systems). A sagittal scout series was first obtained to verify
patient position, image quality and locate a midline sagittal
image. A T1-weighted sagittal scout image was obtained for
graphical prescription of the coronal and axial images. Three-
dimensional gradient echo imaging (Spoiled Gradient Recalled
Acquisition, SPGR) was performed in the coronal plane [TR
(repetition time), 25 ms; TE (echo time), 5 ms; FOV (field of
view), 24 cm; slice thickness, 1.5 mm; NEX (number of
excitations), 1; matrix size, 256 mm6192 mm] to obtain 124
images covering the entire brain. Additionally, a double echo-
spin echo sequence was used to obtain T2-weighted and
CE Bearden and others
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Page 2
proton-density images in the axial plane, to screen for
neuroradiological abnormalities.
Anatomical analysis
Individual brain volumes were reformatted in the axial plane,
corrected for magnetic field inhomogeneities (Sled and Pike,
1998), resampled into 1-mm isotropic voxels and spatially
realigned to the International Consortium for Brain Mapping
non-linear average brain template (ICBM152), using FLIRT
(available at http://www.fmrib.ox.ac.uk/fsl/). At the same time,
image volumes were corrected for head-tilt and alignment
with a three-translation and three-rotation rigid-body trans-
formation (without scaling) (Woods et al., 1998), to ensure that
brain measurements were not influenced by orientation. The
hippocampi from each brain were traced using a software
program (Tracer) (Woods, 2003), available at http://www.
loni.ucla.edu/Software/Software_Detail.jsp?software_id510.
Hippocampi were manually traced bilaterally by a trained
image analyst, who was blinded to all demographic variables,
and had established excellent reliability with ‘gold standard’
ratings on a training set of six pairs of hippocampi (intraclass
correlation coefficient ,0.90). This level of agreement is
comparable with that obtained in prior studies (Becker et al.,
2006; Frisoni et al., 2006). Anatomical segmentation was
performed using a standard neuroanatomical atlas of the
hippocampus (Duvernoy, 1988) according to criteria detailed
in Narr et al. (2004). Hippocampal models were delineated in
contiguous coronal brain sections using standard guidelines
(Pantel et al., 2000), including the hippocampus proper,
dentate gyrus and subiculum [see (Becker et al., 2006; Frisoni
et al., 2006) for further details]. Hippocampal borders were
determined by the temporal horn, choroidal fissure, uncal and
ambient cisterns, and the grey/white junction between the
subiculum and parahippocampal gyrus. Anatomical landmarks
were followed in all three orthogonal viewing planes using
interactive segmentation software. Volumes obtained from
these tracings were retained for statistical analyses.
To identify regional changes in hippocampal morphology,
we used surface-based anatomical mesh modelling methods
that allow for precise matching of anatomy between subjects
and groups at each hippocampal surface point. To do this, a
gridded surface is stretched over the hippocampus, using a
rectilinear mesh of equally spaced three-dimensional points
along the hippocampal axis and across the upper and lower
surfaces. To assess global hippocampal differences, the
volumes of these three-dimensional models were measured
in cubic millimetres. To measure local differences, a three-
dimensional medial curve is defined along the long axis of the
hippocampus and radial distance measures (i.e. the distance
from homologous hippocampal surface points to the central
core of the individual’s hippocampal surface model) are
estimated, as previously described in Becker et al. (2006). This
procedure also allows the averaging of hippocampal surface
morphological features across all individuals belonging to a
group and records the amount of variation between
Table 1 Demographics of patients used in the present study
Values are means¡S.D. or percentages (n).
Demographic
Unmedicated patients with
unipolar depression (
n
531)
Healthy comparison
subjects (
n
531) Between-group differences
Age (years) 39.2¡11.9 36.7¡10.7 F (1,60)50.73
P50.40
Female (n) 77% (24) 77% (24) X
2
50
P51.0
Right-handed (n) 100% (31) 94% (29) X
2
52.07
P50.49
Education level (years) 15.4¡3.4 15.3¡2.7 F (1,60)50.55
P50.40
Race
Caucasian (n) 100% (31) 93% (29) X
2
51.0
P50.60
African-American (n) 0 7% (2)
Other (n) 3% (1) 0
HDRS 11.8¡9.1
Duration of illness (years) 11.42¡10.6
Age at onset (years) 27.9¡11.6
Number of episodes 5.1¡5.9
Current mood state
Depressed (n) 65% (20)
Euthymic (n) 35% (11)
Family history positive (n) 65% (20)
Medication naı
¨
ve (n) 58% (18)
Previous atypical antipsychotic use (n) 16% (5)
Previous antidepressant use (n) 42% (13)
Hippocampal volume (mm
3
)–
Right 1911.1¡280.1 1828.9¡284.2 F (1,59)5 2.03
P50.16
Left 1885.4¡230.8 1851.9¡326.8 F (1,59)5 2.26
P50.14
Hippocampus in unmedicated depressed patients
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267
Page 3
corresponding surface points relative to the group averages.
These methods reveal tissue alterations on the hippocampal
surface, e.g. in regions approximately corresponding to the
underlying CA1–3 subfields and subiculum/presubiculum
(Frisoni et al., 2006; Bearden et al., 2008), and are similar,
in some respects, to the high-dimensional computational
mapping approach developed for local shape analysis of the
hippocampus (Csernansky et al., 2002).
Regressions were performed at each surface point to map
linkages between radial size and covariates (i.e. diagnosis,
age). In addition, we examined hippocampal parameters both
with and without brain size correction in our statistical
analyses, given that relationships between hippocampal size
and brain size may differ across diagnostic groups, and our
goal was to target differences specific to the hippocampus.
Uncorrected two-tailed probability values were mapped on
to the averaged hippocampal surface models for the entire
group and displayed in three dimensions. As statistical tests
were applied at each of the hippocampal surface points, we
conducted permutation-based statistics with a threshold of
P,0.05 to ensure that the overall pattern of effects in the
surface-based maps could not have been observed by chance
alone (Thompson et al., 2004b). For this purpose, subjects were
randomly assigned to either patient or control groups 100 000
times (while keeping the number of subjects in each group the
same), and a new statistical test was performed at each
hippocampal surface point for each random assignment. The
number of significant results from these randomizations was
then compared with the number of significant results in the
true assignment to produce a corrected overall significance
value for the uncorrected statistical maps. Permutation was
conducted both for negative disease effects (control.MDD)
and for positive disease effects (MDD.control).
RESULTS
Overall volumetric differences
The two groups did not differ in total brain volume, total grey
matter volume or total white matter volume [F (1,60)50.11,
P50.74; F (1,60)51.4, P50.24; and F (1,60)50.67, P50.42
respectively]. Hippocampal volumes did not differ signifi-
cantly between controls and MDD subjects [left:
1851.9¡326.8 compared with 1885.4¡230.8 respectively,
F (1,59)5 2.26, P50.14; right: 1828.9¡284.2 compared with
1911.1¡280.1 respectively, F (1,59)52.03, P50.16]. These
results were not substantively different when controlling for
total brain volume [F (1,58)51.98, P50.12].
Three-dimensional hippocampal maps
Statistical three-dimensional maps (Figure 1) indicated local
differences in hippocampal structure between patients with
MDD and control subjects, in terms of percentage difference
and statistical significance. Although global volumes did not
differ, localized increases (shown in purple) were detected in
MDD patients in regions approximately corresponding to the
CA1 subfields and portions of the subiculum bilaterally.
However, these local differences were not significant
following correction for multiple comparisons via permuta-
tion analysis (P50.10).
Effects of clinical variables
In the overall sample, hippocampal volume was inversely
correlated with age (left: r520.27, P50.03; right: r520.32,
P50.01). Within the depressed group alone, age showed a
similar trend-level inverse relationship with hippocampal
volume (r520.35, P50.055). In addition, HDRS scores were
inversely correlated with hippocampal volume within the
depressed group (r520.35, P#0.05), i.e. a greater severity of
depressive symptoms was associated with a lower hippocampal
volume. To further examine the relationship between age,
depression severity and hippocampal volume, we conducted a
multiple regression analysis, using age and HDRS scores as
predictors of hippocampal volume. The overall model was
highly significant [F (1,28)56.31, P50.005], and there were
significant main effects of both age and HDRS score, indicating
that both of these factors made significant independent
contributions to hippocampal size. Categorically, those
patients who were currently in a depressed mood state
(HDRS>12) had significantly smaller hippocampal volumes
than those who were in a remitted state [F (1,29)55.05,
P50.03, eta
2
50.15]. These results remained significant after
controlling for the effects of age (P#0.05).
As age and depression severity were correlated, we
examined linkages between age-adjusted HDRS score and
hippocampal radial distance. Significant inverse correlations,
confirmed by permutation tests, were observed between
HDRS score and hippocampal surface morphology within the
MDD group, such that more severe depression was associated
with greater left hippocampal atrophy, particularly in the
subiculum and CA1 subfields (permutation-corrected P
values: right, P50.29; left, P50.009; Figure 2).
Hippocampal structure was not significantly associated with
duration of illness, the number of prior mood episodes, family
history of mood disorder or past history of antidepressant use
(P.0.10, not significant). However, MDD patients who had
previously been treated with atypical antipsychotics showed a
trend toward larger hippocampi than MDD patients who were
antipsychotic-naı¨ve (permutation-corrected P values: left,
P50.06; right, P50.07; see Supplementary Figure S1 at
http://www.asnneuro.org/an/001/an001e020add.htm).
DISCUSSION
The hippocampal maps in the present study provide novel
findings regarding regional hippocampal alterations in
CE Bearden and others
268 E 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/)
which permits unrestricted non-commerical use, distribution and reproduction in any medium, provided the original work is properly cited.
Page 4
unmedicated patients with major depression. Specifically,
overall hippocampal volume was preserved in unmedicated
depressed patients, concomitant with localized (non-signifi-
cant) increases in CA1 subfields and portions of the
subiculum bilaterally in depressed patients relative to
controls. However, the sample was heterogeneous, and
several clinical variables, particularly severity of depression
and age, made independent contributions to hippocampal
morphology and volume.
The notion that hippocampal volume reduction may be a
consequence of depression has been influential in guiding
recent animal, postmortem and clinical examinations of the
pathophysiological basis of depression (Campbell and
MacQueen, 2004). The findings of the present study support
this, as we find that increased depression severity was
associated with left hippocampal atrophy; however, hippo-
campal reduction did not characterize this sample of
relatively young, currently unmedicated depressed outpati-
ents overall. Indeed, we found a trend toward increased
hippocampal volume in unipolar patients previously treated
with atypical antipsychotics, which may reflect postulated
neuroprotective effects of these agents (Thompson et al.,
2009). Although caution is clearly warranted in interpreting
these findings, given the small number of subjects previously
Figure 1 Three-dimensional hippocampal maps
(A) Topographical correspondence of pathology on blank MRI-based models of the hippocampal formation of normal controls, from
inferior (left) and superior (right) views. Based on Duvernoy (1988), where neuropathological areas are shown in seven equally spaced
coronal slices spanning the entire length of the hippocampus. (B and C) Statistical three-dimensional maps indicate local differences
in hippocampal structure between MDD patients and control subjects, in terms of percentage difference (B) and statistical
significance (C). Purple colours indicate regions of localized increase in MDD patients compared with controls, whereas red colours
indicate relative thinning in MDD patients relative to controls. Although overall volumes did not differ, localized increases (purple
colours) were detected in MDD patients, in regions approximately corresponding to the CA1 subfields and portions of the subiculum/
presubiculum bilaterally.
Hippocampus in unmedicated depressed patients
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269
Page 5
treated with antipsychotics, these findings suggest that not
only current drug treatment status, but past history of
psychotropic medication usage, may be important in asses-
sing structural neuroanatomical differences in patients with
mood disorders.
In a large sample of bipolar patients, Jones et al. (2009)
found that current antipsychotic use was associated with
significantly larger temporal white matter volumes; specif-
ically, bipolar subjects taking antipsychotics had larger white
matter volumes than bipolar subjects not taking antipsycho-
tics or healthy comparison subjects. Sheline et al. (2003)
observed that longer duration of untreated depression was
associated with hippocampal volume reduction, which
provides some tentative evidence that antidepressants may
have a neuroprotective effect. In addition, Frodl et al. (2008)
found a significant left hippocampal volume increase in a
subgroup of depressed patients who took antidepressants
over a 3-year period. In contrast, Yucel et al. (2008b) found
that medication-exposed patients with unipolar major
depression, and those with multiple episodes, had smaller
subgenual prefrontal cortical volumes than patients with no
exposure to medication and healthy controls, suggesting that
illness burden and short-term medication exposure may
mediate brain alterations in anterior cingulate regions. Thus,
although previous studies have observed effects of current
medication use, this is the first study, to our knowledge, to
suggest that prior use of atypical antipsychotics may have a
persistent effect on hippocampal structure. While caution is
clearly warranted in interpreting these trend-level findings,
we felt that their inclusion was important to encourage
investigation of such effects in other studies. To confirm this
suggestive finding, longitudinal studies that assess the same
individuals repeatedly over time are needed.
The results of the present study are generally consistent
with a recent meta-analysis (McKinnon et al., 2009), which
found that studies including young adult patients showed
equivalent hippocampal volumes between MDD patients and
controls, which may be due to reduced burden of illness in
this population. In addition, other studies are consistent with
ours in showing that specific clinical characteristics of the
sample may affect neuroanatomical findings (Frodl et al.,
2002; Ballmaier et al., 2008; MacQueen et al., 2008). Another
recent study of medial temporal structures in major
depressive illness (Keller et al., 2008) found that depressed
patients with psychosis had a significantly smaller mean
amygdala volume relative to depressed patients without
Figure 2 Correlation of hippocampal morphology with depression severity
Three-dimensional statistical maps show significant relationships between age-adjusted HDRS score and regional hippocampal
atrophy within the depressed group (left-hand depicts inferior view of the hippocampus, right-hand depicts superior view). In the
significance maps (bottom panel), red and white colours denote P values #0.05. Greater depression severity was associated with
greater left hippocampal atrophy, particularly in the subiculum and CA1 subfields (left, P
corrected
50.009; right, P
corrected
50.29).
CE Bearden and others
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Page 6
psychosis and healthy comparison subjects, but no differ-
ences between depressed patients without psychosis and
healthy comparison subjects. Similar to our findings, they
observed no group differences in hippocampal volume.
Nevertheless, our findings contrast with those of Alexander
et al. (2005), who studied a comparably sized sample of
unmedicated patients with major depressive illness, and
found smaller posterior (but not anterior) hippocampal
volume in clinically remitted MDD patients as compared
with controls. Notable differences between our samples
include symptomatic status, as Alexander and colleagues
included only clinically remitted patients, whereas 65% of the
patients in the present study were in a depressive episode at
the time of investigation. In addition, although we had a
similar proportion of subjects who were medication-naı¨ve, no
subjects in the Alexander et al. (2005) study had been
previously treated with antipsychotics.
Hippocampal differences may be somewhat localized and
difficult to detect in small, heterogeneous samples using
global measures (McDonald et al., 2004). The identification of
regional alterations in hippocampal structure may thus help
to elucidate the underlying pathophysiological mechanisms
associated with depression, and also indicate functional
systems that may be selectively disturbed in the illness. Our
findings indicated depression-associated atrophy in the left
hippocampus that was particularly pronounced in the
subiculum and CA1 subfields. Using a rigorous measurement
protocol for tracing the hippocampus, Maller et al. (2007)
reported differential volume loss in the tail of the
hippocampus in MDD patients relative to healthy controls.
This region approximately corresponds to the CA1 subfields
that we found to be affected by depression severity. Notably,
MacQueen et al. (2008) also found that, in patients with
recurrent MDD, larger volume in the hippocampal body/tail
(but not the head) was associated with better treatment
response at 8 weeks, suggesting that localized hippocampal
alterations may be associated with clinical response. In a
study of late-onset depression using methods similar to ours,
Ballmaier et al. (2008) found that regional surface contrac-
tions were significantly pronounced in late- relative to early-
onset depression, particularly in the anterior of the subiculum
and lateral posterior of the CA1 subfield in the left
hemisphere. These findings, as well as our own, are consistent
with postmortem studies, which have identified neuronal
abnormalities in the subiculum in the brains of depressed
individuals (Rosoklija et al., 2000), as well as in distinct layers
of hippocampal subfields, with most pronounced changes in
CA1 regions, followed by CA2 and CA3 subfields (Stockmeier
et al., 2004). The CA1 and CA2 subfields may be particularly
vulnerable to vascular damage (Duvernoy, 1988), which is
consistent with findings of local volume reductions in
late-onset depression (Ballmaier et al., 2008) and with the
hypothesis that ischaemic small-vessel disease may be
implicated in the pathogenesis of elderly depression (Lyness,
2002).
Certain limitations of the present study should be noted.
First, only some of the subjects were medication-naı¨ve.
Although samples were small for subgroup analyses, we
nevertheless found a significant association between regional
hippocampal volume reduction and depression severity, as
well as a suggestive relationship between prior treatment
with atypical antipsychotics and hippocampal volume. As our
study was cross-sectional, it cannot be ruled out that the
observed group differences were attributable to other factors.
However, it is tempting to speculate that these suggestive
findings may reflect postulated effects of neuropil increase
related to atypical antipsychotic treatment, manifested as
subtle volumetric increases on MRI. Using the same
methodology for hippocampal mapping in a sample of
patients with bipolar disorder, we previously found that
unmedicated bipolar patients showed localized deficits in the
right hippocampus, in regions corresponding primarily to the
CA1 subfields, as compared with both normal controls and
lithium-treated bipolar patients (Bearden et al., 2008). Finally,
we did not assess neurocognitive function in this sample, so
the functional significance of these hippocampal alterations
remains to be established.
One prior study (Ballmaier et al., 2008) has assessed the
relationship between regional hippocampal morphology and
memory performance in elderly depressed patients, using
the CVLT (California Verbal Learning Test). This study found a
strong correlation between delayed verbal memory and left-
sided regional atrophy in the CA1 subfield and subiculum in
patients with late-onset depression, which may resemble the
patterns found in early Alzheimer’s disease. However, these
elderly depressed patients did not show deficits on memory
measures relative to comparison subjects, suggesting that
regional hippocampal atrophy patterns and their associa-
tions with memory performance could become apparent
before clinical evidence of cognitive decline. Although it is
unknown whether this sample of relatively young, unme-
dicated depressed patients suffered from memory impair-
ment at the time of the present study, the patterns of
localized atrophy we found in relation to depression severity
are highly consistent with the regional findings of Ballmaier
et al. (2008), suggesting that hippocampal CA1 subfields and
the subiculum may be particularly vulnerable to the effects
of depression. Hypercortisolaemia and ischaemia have both
been hypothesized to contribute to hippocampal damage in
major depression (MacQueen et al., 2003; Sheline et al.,
2003). It has also been proposed that impaired neurogenesis
may contribute to mood symptoms in major depression
(Sapolsky, 2004). Although admittedly speculative, this may
be the mechanism underlying our finding of more
pronounced hippocampal deficits associated with increasing
depression severity. However, whether these changes are
reversible with symptomatic improvement is unknown.
Longitudinal studies are clearly needed to better understand
the time course of hippocampal changes in relation to
symptomatic and cognitive changes in major depressive
illness.
Hippocampus in unmedicated depressed patients
E 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/)
which permits unrestricted non-commerical use, distribution and reproduction in any medium, provided the original work is properly cited.
271
Page 7
ACKNOWLEDGEMENTS
We wish to thank the study participants for making this work
possible.
FUNDING
This work was supported by the National Institutes of Health
[grant numbers K23 MH074644-01 (to C.E.B.), MH 01736, MH
30915, RR020571]; the Veterans Administration (VA Merit
Review); and the CAPES (Coordenac¸a˜o de Aperfeic¸oamento de
Pessoal de ´vel Superior) Foundation (Brazil).
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Received 13 May 2009/25 July 2009; accepted 17 August 2009
Published as Immediate Publication 20 October 2009, doi 10.1042/AN20090026
Hippocampus in unmedicated depressed patients
E 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/)
which permits unrestricted non-commerical use, distribution and reproduction in any medium, provided the original work is properly cited.
273
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    • "patients had smaller volumes of the subiculum, cornu ammonis 2– 3, cornu ammonis 4-dentate gyrus compared to female healthy controls. Previous structural MRI studies on human hippocampi using the surface mapping method, reported that subfield volume reduction of MDD patients mainly occurs in the cornu ammonis 1 and subiculum (Ballmaier et al., 2008; Bearden et al., 2009). In the hippocampal subfield volume analysis of Huang et al., the authors found that unmedicated MDD patients had a lower dentate gyrus volume compared to heathy controls and medicated MDD patients, and a lower cornu ammonis 1–3 volume compared to healthy controls (Huang et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Background Hippocampal volume loss is known as the best-replicated finding of structural brain imaging studies on major depressive disorder (MDD). Several evidences suggest localized mechanisms of hippocampal neuroplasticity lead the brain imaging studies on the hippocampus and MDD to perform analyses in the subfield level. The aim of this study was to investigate the differences in total and subfield hippocampal volumes, between medication-naïve female MDD patients and healthy controls, through automated segmentation and volumetric methods. Methods Twenty medication-naïve female patients diagnosed with MDD and 21 age-matched healthy controls, underwent T1-weighted structural magnetic resonance scanning. Total volumes of both hippocampi and subfield regions were calculated by the automated procedure for volumetric measures implemented in FreeSurfer and automated segmentation method by Van Leemput et al. Results We observed patients to have significantly smaller volumes of the left hippocampus, subiculum, cornu ammonis 2–3, cornu ammonis 4-dentate gyrus, and right subiculum compared to healthy controls. There were no significant predictors for these subfield region volumes among the illness burden-related parameters including duration of illness, number of depressive episodes, severity of depressive symptoms and memory performances. Limitations Our findings relied on the data of only female participants. Conclusions We found significant volume reductions in several hippocampal subfield regions in medication-naïve female MDD patients. Our results are consistent with neurobiological evidences on hippocampal neuroplasticity in MDD, and replicate previous findings that suggest morphologic changes of hippocampal subfields in MDD patients.
    Full-text · Article · Apr 2016 · Journal of Affective Disorders
    • "Also, the MLTCITAL combination regulated different events of the neurogenic process in the hippocampus. Depression is a neuropsychiatric disorder that courses with neurochemical, morphological, and behavioral altera- tions [62, 63] . In addition, several attempts have been proposed to counteract the negative impact of stress, which acts as a key player in precipitating depression [59]. "
    [Show abstract] [Hide abstract] ABSTRACT: Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison to control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of doublecortin-associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.This article is protected by copyright. All rights reserved.
    No preview · Article · Mar 2014 · Journal of Pineal Research
    • "This factor (mood state) may also significantly confound results; two recent reports found an effect of acute depression on cortical structure (Brooks et al. 2009; Nery et al. 2009). Findings of amygdala structure in bipolar disorder from our laboratory (Foland-Ross et al. in press), as well as a study of the hippocampus in major depression (Bearden et al. 2009) have similarly found effects of depressed mood on subcortical gray matter. Additional studies, therefore, that control for the possible effects of lithium status and mood state are needed to elucidate structural differences in the medial temporal brain region between adults with bipolar disorder and healthy controls. "
    [Show abstract] [Hide abstract] ABSTRACT: Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.
    No preview · Article · Nov 2012
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