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The Journal of Neuroscience, June 15, 1999, 19(12):5034-5043
Depression Duration But Not Age Predicts Hippocampal Volume Loss
in Medically Healthy Women with Recurrent Major Depression
Yvette I.
Sheline1, 2, 3,
Milan
Sanghavi1,
Mark A.
Mintun1, 2, 3, and
Mokhtar H.
Gado2, 3
Departments of 1 Psychiatry and 2 Radiology
2 and the 3 Mallinckrodt Institute of Radiology,
Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
This study takes advantage of continuing advances in the precision
of magnetic resonance imaging (MRI) to quantify hippocampal volumes in
a series of human subjects with a history of depression compared with
controls. We sought to test the hypothesis that both age and duration
of past depression would be inversely and independently correlated with
hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical
comorbidity, and 24 case-matched controls underwent MRI
scanning. Subjects with a history of depression (post-depressed)
had smaller hippocampal volumes bilaterally than controls.
Post-depressives also had smaller amygdala core nuclei volumes, and
these volumes correlated with hippocampal volumes. In addition,
post-depressives scored lower in verbal memory, a neuropsychological
measure of hippocampal function, suggesting that the volume loss was
related to an aspect of cognitive functioning. In contrast, there was
no difference in overall brain size or general intellectual
performance. Contrary to our initial hypothesis, there was no
significant correlation between hippocampal volume and age in either
post-depressive or control subjects, whereas there was a significant
correlation with total lifetime duration of depression. This suggests
that repeated stress during recurrent depressive episodes may result in
cumulative hippocampal injury as reflected in volume loss.
Key words:
hippocampus; depression; age; amygdala; magnetic
resonance imaging; MRI; glucocorticoids; neurotoxicity; stereology
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INTRODUCTION |
Hippocampal volume loss in humans
has been associated with depression (Sheline et al., 1996 ) and aging
(Jernigan et al., 1991). One explanation for volume loss in depression
might be increased neuronal cell death secondary to glucocorticoid (GC)
neurotoxicity (Sapolsky et al., 1986; McEwen, 1992). The
pathophysiology of major depression involves impairment in negative
feedback control of the hypothalamic-pituitary-adrenal (HPA) axis
(Young et al., 1991), resulting in elevated cortisol levels during
depressive episodes (Carroll et al., 1981). Prolonged exposure to
elevated levels of glucocorticoids reduces hippocampal cell number
(Sapolsky et al., 1985) and can induce cultured neurons to undergo
apoptosis (Reagan and McEwen, 1997). This same effect has been shown in intact animals. Chronic stress or chronic administration of
glucocorticoids to rodents (Watanabe et al., 1992) or nonhuman primates
(Sapolsky et al., 1990) results in the degeneration of vulnerable
hippocampal neurons, especially CA3 pyramidal cells. Animals exposed to
high physiological levels of corticosterone (CORT) exhibited a
persistent depletion of hippocampal CORT receptors and evidence of an
impaired HPA axis (Sapolsky et al., 1983). Furthermore, a recent study (Lupien et al., 1998) has shown that in human aging, higher cortisol levels correlated longitudinally with greater hippocampal volume loss.
In addition to direct neurotoxicity, glucocorticoid exposure may also
enhance neuronal vulnerability to other insults, including hypoxia/ischemia (Tombaugh and Sapolsky, 1992), superoxide radical generators (McIntosh and Sapolsky, 1996), and hypoglycemia (Lawrence and Sapolsky, 1994).
Some studies in rodents have found age-related hippocampal neuronal
loss based on neuron density studies (Landfield et al., 1981; Meaney et
al., 1988; Issa et al., 1990). However, studies using unbiased
stereological techniques have not found age-related loss of neurons in
the CA1-CA3 hippocampal regions in humans, monkeys, or rodents (West,
1993; Rapp and Gallagher, 1996; Rasmussen et al., 1996). Differences in
sampling procedures and counting methods could possibly account for
some of the discrepancies between studies. Aged animals have decreases
in hippocampal CORT receptors and evidence of an impaired HPA axis
(Sapolsky et al., 1983) similar to animals exposed to high
physiological levels of CORT. Although both aging and neurotoxic
exposure produce loss of vulnerable hippocampal neurons, the
combination of neurotoxic exposure and aging may have a synergistic
effect through enhanced vulnerability to cell damage (Sapolsky, 1992).
The analogy between aging and glucocorticoid exposure-induced neuronal
vulnerability raises the question of the nature of the interaction
between glucocorticoids and age. Because neuropathological studies of
cell loss in Alzheimer's disease have been associated with volume loss
in magnetic resonance imaging (MRI) studies, observable volume loss in
MRI studies of depression may also result from cell loss. The present
study was intended to use advances in the precision of MRI of the brain to quantify hippocampal volumes in a series of normal and depressed human subjects in mid and late life. We sought to test the hypothesis that both increasing age and increasing duration of depression would be
independently associated with reductions in hippocampal volume. In
addition we tested whether there would be an interaction between the
two variables to produce synergistic effects in reducing hippocampal volume.
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MATERIALS AND METHODS |
Subjects. Depressed subjects were recruited to the
outpatient psychiatry service at Washington University School of
Medicine (WUSM), primarily from referrals from other psychiatrists who knew the inclusionary and exclusionary criteria (17/24 subjects) and
also from advertisements to the general public (7/24 subjects). Control
subjects were recruited primarily from the Aging and Development Project maintained by the Psychology Department at Washington University (13/24 subjects) and also from notices posted at the medical
center (11/24 subjects). Subjects were recruited over a 4 year period.
Subjects ranged in age from 23 to 86 years (mean = 54; median = 56). Inclusionary criteria were a history of recurrent major
depression, with at least one previous episode requiring psychiatric
treatment, female gender, right-handedness, and no medical illness
potentially affecting the CNS. No subjects with current acute
depression were included in the study to eliminate potential confounds
in MRI volumetric measurements related to state-dependent changes such
as hypercortisolemia. None of the subjects had been acutely depressed
within the past 4 months. Only women were selected to decrease the
incidence of occult cardiovascular disease and to minimize gender-based
brain differences (Aboitiz et al., 1992). A case-control design was
used to match patients with a history of depression (post-depressed)
for age and educational level within 2 years. Groups were matched
post hoc for height, a predictor of general brain size
(Andreason et al., 1994). Potential subjects were screened by one of us
(Y.I.S.) using a questionnaire, medical history, review of medical
records, and physical exam to exclude those with medical problems
potentially affecting the CNS. Exclusionary conditions included a
current or past neurological disorder, head trauma, uncontrolled
hypertension, myocardial infarction or ischemia, diabetes, Cushing's
disease, steroid use, and drug/alcohol abuse. All subjects had
documented normotension. In addition, subjects who had received more
than three courses of electroconvulsive therapy (ECT) were excluded.
Subjects gave written informed consent before inclusion in the study.
Clinical assessment was conducted by a psychiatrist (Y.I.S.)
experienced in the use of the Diagnostic Interview for Genetic Studies
(DIGS). The DIGS is a structured interview with high reliability (Nurnberger et al., 1993) that was used to make the diagnosis of past
episodes of recurrent major depression by Diagnostic and Statistical
Manual of Mental Disorders-IV criteria and to exclude other psychiatric
diagnoses. The DIGS was used to assess both depressed and control
subjects. Current antidepressant status and dosage were determined. To
determine the presence and severity of any current depressive symptoms,
all patients and controls were assessed using the Hamilton Rating Scale
for Depression (HAMD).
Estimation of total time depressed. The number of symptoms
and duration (days) of each episode were determined using the DIGS, as
described above to define episodes of major depression. This was
conducted using the Post Life Charting Method (Post et al., 1988) to
anchor each episode. The total cumulative duration of depression was
then calculated, summing over all episodes. Rigorous diagnostic
criteria were used to establish each episode, and whenever possible,
corroborating information was obtained from family members or treating
psychiatrists, because in depressed populations, self-reporting may
underestimate the duration of earlier episodes. Patients with more
severe histories of depression, such as those in the current study,
have been shown to have greater stability of diagnosis (Rice et al.,
1987).
Neuropsychological testing. To determine the functional
significance of brain volumetric changes, neuropsychological testing was performed. Subjects were administered the following tests: Wechsler
Memory Scale-Revised (WMS-R), Logical Memory I (LMI) and II (LMII)
subtests (Wechsler, 1987); Auditory Verbal Learning Test (AVLT) (Rey,
1964); Trail Making Test, parts A and B; and Weschler Adult
Intelligence Scale-Revised (WAIS-R), Information and Block Design
subtests (Wechsler, 1981). All tests were administered before
administration of the dexamethasone suppression test (see below).
The Logical Memory subtest was administered according to the
standardized protocol outlined in the WMS-R Manual (1987). Two stories
were read aloud to the subject by the examiner. The subject was asked
to repeat the story using as many of the same words as they could
recall from memory after each story. One point was given for each
verbatim or accepted alternate response phrase. After a 30 min delay
the subject was asked to recall each story again. Subjects' responses
were recorded on audiotape and transcribed to ensure accurate scoring.
Scores were tabulated for each story as well as the total score for the
immediate (LMI) and delayed (LMII) trials.
The AVLT was administered using a standard protocol (Lezak, 1995) to
present a 12-word list five times followed each time by recall of as
many words as possible, then a second 12-word list with recall. After a
30 min delay subjects were asked to recall the first list again. One
point was given for each recalled word during each presentation. The
sum of the total number of words recalled in presentations one through
five was also calculated.
Trails A and B were administered in two parts according to a standard
protocol (Lezak, 1995). On part A, subjects were asked to draw a line
to connect consecutively numbered circles as quickly as possible, with
time necessary to complete the task recorded in seconds. On part B,
subjects were asked to draw a line connecting consecutively numbered
and lettered circles as quickly as possible, alternating between
numbers and letters (1 to A, A to 2, 2 to B, etc). Time to completion
was recorded in seconds.
WAIS-R Information was administered according to the WAIS-R Manual
(1981). Twenty-nine questions arranged in order of increasing difficulty were read directly from the manual, and the subjects' responses were recorded. The test was discontinued after five consecutive failures. One point was scored for each correctly answered
question. WAIS-R Block Design also was administered according to the
WAIS-R Manual (1981). Subjects were presented with designs requiring
assembly of four blocks (first five designs) or nine blocks (last four
designs). For each design the subject was shown a card with a picture
of the design. There was a 1 min time limit on the first five designs
and a 2 min time limit on the last four designs. The test was
discontinued after two consecutive failed design constructions.
Subjects were given points according to time needed for completion of
each correctly assembled design, and the total earned points was calculated.
Magnetic resonance imaging. MRI scans were obtained using a
Magnetom SP-4000 1.5T imaging system (Siemens Medical Systems, Iselin,
NJ), and a standard Siemens 30 cm circularly polarized radio frequency
(rf) head coil. Anatomic images consisted of 128 contiguous
1.25-mm-thick sagittal slices and were acquired using magnetization-prepared rapid gradient echo (MPRAGE) acquisition. No
sedation was used during scanning. Specific MPRAGE scanning parameters
were as follows: TR = 10 msec, TE = 4 msec, inversion time = 300 msec, flip angle = 8, matrix = 256 × 256 pixels, voxel size = 1 × 1 × 1.25 mm, slice
thickness = 1.25 mm.
Image preprocessing. A graphics workstation (Sun
Sparcstation 20, Sun Microsystems, Mountain View, CA) was used for
initial image processing using ANALYZE software (Biomedical Imaging
Resource, Mayo Foundation) (Robb, 1990). Images were interpolated to
0.5 mm sections. They were then reoriented to the anterior-posterior commissure plane for standard alignment. To minimize inter-scan variations, MR images underwent gray-scale normalization. Cylindrical regions-of-interest subvolumes inclusive of the amygdala and
hippocampus were generated to aid in tissue classification. These
subvolumes were analyzed using PeakFit software (Jandel Scientific, San
Rafael CA), by the Marquardt-Levenberg algorithm for nonlinear curve fitting (Donald and Marquardt, 1963). The images were then scaled to
create high contrast between gray and white matter in an eight-bit format.
Stereological method and reliability. Two raters (Y.I.S.,
M.S.) measured unilateral hippocampal gray matter volumes after training and assessment standardization with a neuroradiologist (M.H.G.) expert in hippocampal neuroanatomy. Stereological estimation methods, which have been used with precision in microscopy and MR
volume determination (Mayhew, 1992) were used to estimate all hippocampal, amygdala, and whole brain volumes. Sampling parameters and
grid size were set to yield at least 150 "hits" per measurement, a
number that has previously been determined to yield reliable measurements in brain volume determination (Gundersen, 1988). From
three-dimensional MRI cubical subvolumes composed of 0.5 × 0.5 × 0.5 mm voxels, coronal slices were sampled every 1.5 mm for
hippocampus, every 1.0 mm for total amygdala, and every 0.5 mm for
amygdala core nuclei. A rigid grid of points was then superimposed on
the images. Grid points falling within the hippocampal, total amygdala,
or amygdala core nuclei gray matter (see definitions below) were
counted. Measurements were made using MEASURE (courtesy of P. Barta,
Johns Hopkins University) in the coronal orientation, but the program
displays grid points simultaneously in three orthogonal perspectives:
sagittal, axial, and coronal (Fig. 1) to
aid in anatomic localization. Volume estimates were calculated by
MEASURE based on the number of selected grid points. Raters were blind to subject identity and measured left and right volumes separately. Mean volumes were determined from an average of four measurements of
each volume, two measurements each by two independent raters for
hippocampal, amygdala core nuclei, and total cerebral volumes. Means
for total amygdala volumes, left and right, were determined from an
average of two independent measures by the same rater. Intra-rater and
inter-rater reliability were determined using the intraclass R. Intra-rater correlation coefficients were calculated for total (0.94 and 0.95), left (0.90 and 0.95), and right (0.95 and 0.98) hippocampal
volumes, total (0.97 and 0.96), left (0.94 and 0.93), and right (0.92 and 0.90) amygdala core nuclei volumes, total (0.90), left (0.86), and
right (0.88) whole amygdala volumes, and whole brain volumes (0.93 and
0.93). Inter-rater correlation coefficients were calculated for total
(0.95), left (0.90), and right (0.95) hippocampal volumes, total
(0.89), left (0.90), and right (0.82) amygdala core nuclei volumes, and
whole brain volumes (0.92). For hippocampus, 48 pairs of intra-rater
measurements and 48 pairs of inter-rater comparisons were made. For
amygdala, 48 pairs of intra-rater and inter-rater core amygdala
measurements were made, and 48 pairs of intra-rater measurements were
made for whole amygdala by one rater. For whole brain, 48 pairs of intra-rater reliability measurements were made, and 28 pairs of inter-rater reliability measurements were made.
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Figure 1.
Hippocampal volume measurement using stereology.
A, Coronal section through the hippocampus. Points
within the hippocampus highlighted in red were selected
from a randomly placed 5 × 5 mm2 grid
overlying the hippocampus and are simultaneously displayed in
(A) coronal, (B) sagittal,
and (C) horizontal views. Arrow
indicates the caudate (A), and  indicates the
amygdala 171 (B). D, Cubic volumes
containing the hippocampus were sectioned out from the total brain
volume.
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Anatomic definition of the hippocampus. Anatomical
boundaries were defined by specific rules (Duvernoy, 1988; Bartzokis et al., 1993) as follows: every third coronal slice was assessed, beginning with the posterior-most slice in which the hippocampus was
visualized. Orthogonal views were consulted in cases of anatomic uncertainty, although the coronal view retained priority. Posteriorly, the tail of the hippocampus continues as the indusium griseum, a thin
strip of gray matter overlying the surface of the corpus callosum. For
purposes of measurement, the posterior-most slice for inclusion was
defined as the slice where the hippocampus first appeared adjacent to
the trigone of the lateral ventricle. Included tissues were an
elongated gray matter complex bordered superiorly by the fornix-fimbria
white matter junction, inferiorly by parahippocampal gyrus white
matter, medially by the subarachnoid spaces of various cisterns (e.g.,
ambient cistern), and laterally by the CSF-filled lateral ventricle.
The gray matter complex included the cornu ammonis (CA), dentate gyrus,
and subiculum, (i.e., the head and body of the hippocampus were
included). The vertical digitation of the head of the hippocampus,
which curves up and medial to the amygdala in coronal sections, was
included. Excluded tissues were the fornix-fimbria white matter
complex; the alveus, the intraventricular white matter covering of the
hippocampus; the white matter of the parahippocampal gyrus; various
fluid-filled spaces including ventricles, subarachnoid spaces, and
sporadic fluid-density spaces in the hippocampus complex; and the
amygdala proper and the white matter border with it, a thin white
matter line, discernible in high resolution MR images, which separated the hippocampus from the amygdala.
The subiculum extends medially from the cornu ammonis. The superior
component of the CA does not extend medially far enough to aid in
demarcating the border of the hippocampus, and the inferior component
of the CA is in direct continuity with the subiculum. Because no clear
gross anatomic separation exists between the hippocampus, subiculum,
presubiculum, or parasubiculum, we adopted a previous procedure to
include the subiculum in the measured volume of the hippocampus
(Bartzokis et al., 1993).
Anatomic definition of the amygdala core nuclei. As
described (Sheline et al., 1998), these structures were defined by the white matter tracts (longitudinal association bundles) surrounding them. Included were the basal nucleus, accessory basal nucleus, and the
lateral nucleus (medial portions). Excluded structures were the
periamygdaloid areas, the medial nucleus, and the central nucleus.
Anatomic definition of the noncore amygdala. The amygdala
was visualized in three planes simultaneously during measurement, and
some boundaries were better visualized in one plane than in another.
The noncore amygdala was defined by measuring the total amygdala and
subtracting the core amygdala. The anterior boundary of the amygdala,
visualized in coronal section, was the first section in which the
temporal stalk connected to the white matter of the insula. Dorsally,
visualized in coronal section, the border was defined in anterior
sections by the endorhinal sulcus between the basal forebrain and
temporal lobe, and posteriorly in sagittal sections by a horizontal to
the posteroinferior edge of the temporal stem with the temporal horn of
the lateral ventricle. Ventrally, visualized in sagittal section, the
amygdala was bounded by a horizontal line connecting to the
ventral/anterior edge of the hippocampus. Posteriorly, seen in sagittal
section, the amygdala was bounded by its border with the hippocampus.
Medially, seen in coronal section, the amygdala was bounded by
subarachnoid space. Laterally, seen in coronal section, the amygdala
was bounded by white matter. These boundaries defined the total
amygdala. The noncore amygdala was defined as the total amygdala minus
the core amygdala.
Total cerebral volume. All brain tissue of the cerebral
hemispheres, both gray and white matter, was included in the assessment of total cerebral volume. The midbrain superior to the pons was also
included. The superior border of the pons was chosen as the point of
demarcation because it is easily recognizable. This volume measurement
was made using stereological methods as described above.
Cortisol levels. Blood samples were obtained to measure
cortisol concentrations at 8:00 A.M. and 4:00 P.M. on the day before (baseline) and the day after oral administration of 1 mg dexamethasone at 11:00 P.M. (dexamethasone suppression test). Plasma was obtained within 1 hr of obtaining each sample by centrifuging the sample at
 1000 × g for 15 min. All plasma samples were stored
at  20°C until assay by fluorescence polarization immunoassay using
the TDX analyzer and a commercially available kit (Abbott Laboratories).
Data analysis. Two-tailed paired t tests were
used to compare post-depressed and control subjects on all demographic
and MRI measures. The Pearson correlation was used to determine the
significance of correlations among and between MRI measures and total
cumulative duration of depression. Before using the Pearson
correlation, variables were tested to determine whether they met
criteria for normal distribution (Kolmogorov-Smirnov test). Pearson
correlations were used to determine the correlation between age and
hippocampal volumes separately in both the depressed and control
samples, as well as in the total sample. A multiple regression with age and depression duration as independent variables was used to test these
effects on hippocampal volumes. To examine the effect of age on
hippocampal volumes, after removing the effect of depression duration,
a regression analysis was conducted using age versus hippocampal
volumes corrected for depression duration. This correction factor was
derived from the multiple regression analysis with age and depression
duration as independent variables and hippocampal volume as the
dependent variable. In addition, to determine whether there was an
interaction between age and depression status in predicting hippocampal
volumes, these variables were combined into a new variable, and a
multiple regression analysis was run using all three variables.
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RESULTS |
Demographic and cortisol data
Table 1 summarizes demographic and
cortisol data for the 24 post-depressed subjects and their case-matched
controls. The HAMD scores are consistent with the absence of acute
current depression. Post-depressed subjects had a mean of 4.8 lifetime
episodes of major depression (range 1-18) accounting for a lifetime
mean of 1058 d depressed (range 21-3752; median, 624). Five
subjects had received electroconvulsive therapy (ECT) previously during
the course of their treatment and had elapsed times since last ECT treatment of 34, 30, and 14 years, and 7 and 11 months. Sixteen of the
24 post-depressed subjects were currently receiving antidepressants: selective serotonin reuptake inhibitors in four cases; tricyclic antidepressants in five cases; trazodone in two cases; and maprotiline, moclobemide, mirtazapine, nefazodone, and buproprion in one case each.
Two post-depressed patients had previously been treated with
neuroleptics: one with chlorpromazine and one with haloperidol. In both
cases treatment duration was brief, and neither patient was psychotic
at the time of treatment. Cortisol data were obtained from 17 of the
total of 24 subject pairs. There was no difference between
post-depressed and matched controls in either baseline cortisol levels
(p = 0.56) or post-dexamethasone cortisol levels (p = 0.38) (Table 1), as would be expected in
subjects who were not acutely depressed.
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Table 1.
Demographic and clinical characteristics of subjects with a
history of major depression and matched controls
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In this sample, 26 women were postmenopausal and 22 were premenopausal.
Of the 26 postmenopausal women, 14 were from the post-depressed group
and 12 were controls ( 2 p value = 0.67).
In the total sample, 17 women were on hormone replacement therapy. Of
women on hormone replacement therapy, 9/17 were post-depressed and 8/17
were controls (2 p value = 0.85).
Brain volumetric data
Table 2 summarizes brain
volumetric data for post-depressed subjects and matched controls. Mean
total, left, and right hippocampal gray matter volumes were
significantly smaller for post-depressed subjects than for controls. On
average the differences were 9, 10, and 8% for the total, left, and
right volumes, respectively (Fig. 2).
Mean total, left, and right amygdala core nuclei volumes were
significantly smaller in post-depressives than in control subjects; on
average 13, 13, and 12% for total, left, and right volumes,
respectively (Table 2), whereas amygdala noncore volumes, total
amygdala volumes, and total cerebral volumes did not differ. Examining
hormone replacement therapy alone as a predictor of total hippocampal
volume, there was no statistically significant difference in volume
between subjects on hormone replacement therapy (4699 mm3) and those not on therapy (4780 mm3) (p = 0.67).
Postmenopausal status alone did not predict total hippocampal volume
(4845 mm3 premenopausal vs 4620 mm3 postmenopausal; p = 0.23).
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Figure 2.
Left and right hippocampal gray matter volumes.
The lines connect the hippocampal volumes for each
subject pair consisting of subject with a history of major depression
(post-depressed) and the age, gender, education, and height-matched
case control; the mean and the SDs for each group are also shown.
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Correlations between hippocampal gray matter volumes, age,
menopausal status, and total time depressed
In the total sample, the correlation between age and total
hippocampal volume was r = 0.19
(p = 0.20). For post-depressed subjects the
correlation between total hippocampal volume and age was
r = 0.32 (p = 0.13). In
control subjects the correlation between age and total gray matter
hippocampal volume was r = 0.08 (p = 0.71). Analysis of interaction indicated
that there was no interaction between age and depression status
(p = 0.43). In contrast, there was a significant
inverse correlation between total days depressed and total hippocampal
gray matter volume (r = 0.60; p = 0.002) (Fig. 3). This was true for both
left hippocampal gray matter volume (r = 0.57,
p = 0.003) and right hippocampal gray matter volume
(r = 0.55, p = 0.005).
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Figure 3.
Correlation between duration of depression and
hippocampal volume. The Pearson correlation between cumulative lifetime
total days of major depression was derived from the Diagnostic
Interview for Genetic Studies using the Post Life Charting Method (Post
et al., 1988) and the total hippocampal gray matter volumes.
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To correct for a contribution of depression duration to the
relationship between age and hippocampal volume, a regression analysis
was conducted using age versus hippocampal volume corrected for
depression duration. This analysis showed no significant correlation with age (r = 0.17, p = 0.26) (Fig.
4).
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Figure 4.
Correlation between age and total hippocampal gray
matter volumes corrected for depression duration. The correction factor
was derived from a multiple regression ANOVA using age and depression
duration as independent variables and hippocampal gray matter volume as
the dependent variable (see Materials and Methods).
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A multiple regression analysis did not find a significant relationship
(p = 0.61) using hormone replacement therapy,
post-menopausal status, and age as independent variables and total
hippocampal volume as the dependent variable. Examination of left and
right hippocampal volumes separately also did not yield significant relationships.
Correlations between hippocampal gray matter volumes and amygdala
core nuclei volumes
The correlation between total hippocampal gray matter volume and
total amygdala core nuclei volume for post-depressed subjects was
r = 0.68, p = 0.0001 (Fig.
5), and this held for the left (r = 0.65, p = 0.0004) and right sides
(r = 0.58, p = 0.002) as well. In
control subjects these respective correlations were r = 0.50 (p = 0.01), r = 0.54 (p = 0.006), and r = 0.42 (p = 0.04). In contrast, the correlations in
post-depressed subjects between total and both left and right
hippocampal gray matter volumes and total (r = 0.11,
p = 0.63) (Fig. 5), left (r = 0.15, p = 0.49), and right (r = 0.02,
p = 0.93) amygdala noncore nuclei volumes,
respectively, were not significant. The respective correlations in
control subjects (r = 0.46, p = 0.02;
r = 0.45, p = 0.03; and r = 0.42, p = 0.04) with amygdala
noncore nuclei volumes were significant.
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Figure 5.
Correlations between hippocampal and amygdala
volumes. A, The Pearson correlation between total
hippocampal gray matter volume and the total amygdala core nuclei
volume; B, the correlation between total hippocampal
gray matter volume and total amygdala noncore volume in subjects with a
history of major depression.
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Neuropsychological data
As shown in Table 3, scores for list
learning, total recall and list learning, long delay were significantly
decreased in subjects with a history of depression compared with
controls. Paragraph recall scores did not achieve significance.
Trails A, Trails B, and WAIS information subscale scores were
not significantly different between the groups. The WAIS block design
subscale score was significantly less in subjects with a history of
depression than in control subjects.
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Table 3.
Comparison of subjects with a history of major depression
and matched controls on neuropsychological variables
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Effect of removing subjects who had received ECT
The data analyses comparing hippocampal gray matter volumes
between post-depressed and control subjects were rerun after removal of
the five subjects who had received ECT and their matched controls. There was still a significant difference in total (t = 2.1, p = 0.04) and left (t = 2.4,
p = 0.03) hippocampal gray matter volumes and a trend
toward a difference in right (t = 1.8,
p = 0.08) hippocampal volumes between post-depressed
and control subjects. In post-depressed subjects there was also a
significant correlation between days depressed and both left
(r = 0.59, p = 0.005) and right
(r = 0.53, p = 0.01) hippocampal volumes.
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DISCUSSION |
The main findings of this study are the lack of a correlation
between age and hippocampal volume in medically healthy subjects and
the finding of smaller hippocampal volumes in subjects with a history
of depression. These subjects also had evidence of poorer verbal memory
performance, despite being in remission. Extending our pilot study
(Sheline et al., 1996), we report that 24 women with a history of
depression, but no medical comorbidity, had bilaterally smaller
hippocampal volumes than age-matched controls. Findings of decreased
hippocampal volumes have been reported in acutely depressed subjects
(Narayan et al., 1998) and in patients suffering from post-traumatic
stress disorder (Bremner et al., 1995). We show that post-depressed
women exhibited abnormalities on a neuropsychological measure of
hippocampal function, the AVLT, suggesting that their reduced
hippocampal volumes were the result of functionally significant damage.
Furthermore, hippocampal volumes correlated inversely with the
cumulative lifetime duration of depression. In contrast to differences
in hippocampal volumes and AVLT scores, post-depressed patients did not
differ from control subjects in overall brain size or on general
intellectual performance as assessed by the WAIS information subscale.
Given age- and depression-related increases in medical conditions, it
is critical to know whether patients with changes in brain structure
volumes had concurrent physical illnesses that could enhance neuronal
vulnerability. In the present study, unlike most previous studies, we
selected only subjects with no current or past medical or neurological
conditions. An increased incidence of microinfarction has been linked
to both chronic hypertension (Kobayashi et al., 1991) and diabetes
(Aronson, 1973; Desmond et al., 1993). We excluded patients with
any history of substance abuse because alcohol dependence can cause
cerebral atrophy (Charness, 1993). Patients with a history of
myocardial infarction were excluded because it is a cerebrovascular
disease risk factor and produces a large independent increase in the
incidence of depression (Carney et al., 1987).
Contrary to our initial hypothesis, there was not a significant
age-related hippocampal volume loss in either post-depressed or control
subjects. Some previous studies of hippocampal volume in "normal"
aging found a decrease starting at age 50 (Jernigan et al., 1991),
whereas others did not (Lim et al., 1990). Our sample showed slight
(~1% per decade) nonsignificant decreases in hippocampal volumes
with age, more so in the depressed population, although there was no
interaction between age and depression status. It is possible that
aging per se may not lead to neurodegeneration in the hippocampus but
rather may increase vulnerability to other factors causing cell death,
and these factors may have differed across study populations. It is
possible that by selecting subjects without medical comorbidity we may
have created a sample of "supernormals" who do not show a decrease
in brain structure volumes with age.
One confounding variable is ECT. Although there has been no direct
evidence demonstrating ECT-induced structural brain changes (Devanand
et al., 1994), animal electroconvulsive stimulation (ECS) studies
suggest that brief kindled seizures may induce selective hippocampal
neuronal loss (Cavazos et al., 1994). ECS exposure sufficient to induce
kindling, however, far exceeds the human equivalent ECT electrical
doses. We did not exclude ECT-treated patients, because they had
the most severe histories of depression. A post hoc analysis
after removing the five ECT-treated subjects showed a significant
difference in total hippocampal gray matter volume
(p = 0.04) and a correlation between total days
depressed and total hippocampal gray matter volume
(p = 0.004). Another confound was ongoing
antidepressant therapy in most post-depressed subjects, although there
is no known evidence that therapeutic levels are neurotoxic or that
antidepressant exposure reduces brain volumes.
Additional potentially confounding variables, which we examined
post hoc, were menopausal status and hormone replacement
therapy. The effects of estrogen on rat hippocampus dendritic spine
density (Wooley et al., 1997) and on neuropsychological function in
postmenopausal women in some studies (Resnick et al., 1998) make this
an important variable to examine. We did not find any significant
differences between the groups in either postmenopausal or hormone
replacement status, making it unlikely that these factors could account
for differences in brain volumes. When we examined the issue of whether there were differences in hippocampal volume between postmenopausal and
premenopausal subjects and between subjects who had received hormone
replacement therapy versus those who had not, we did not find
significant differences. However, we have a small sample size, and it
would be interesting to examine this question in a larger study
prospectively with concurrent serum hormone level determination.
Our study found significant differences between post-depressed subjects
and controls in a neuropsychological measure of hippocampal function,
AVLT list learning, total score, and delayed score. In subjects with
more severe hippocampal damage caused by mesial temporal sclerosis, the
degree of left hippocampal atrophy in patients with left temporal lobe
epilepsy was correlated with severity of verbal memory deficits as
measured by AVLT total and delayed recall (Kilpatrick et al., 1997). In
addition, in nondemented subjects who developed Alzheimer's disease
during longitudinal followup (Tierney et al., 1996), the single biggest
neuropsychological predictor was the AVLT score. Subjects in both
groups had known hippocampal pathology that correlated with
abnormalities in the AVLT. Our finding of abnormalities in AVLT in
post-depressed subjects who also had hippocampal volume decreases
appears to indicate hippocampal dysfunction. The groups did not differ,
however, in logical memory test performance, another measure of
hippocampal function (Squire, 1992). Depressed subjects did have lower
WAIS block design subscale scores. Bremner et al. (1995) found that post-traumatic stress disorder patients performed more poorly on the
Benton Visual Retention task, a test that reflects spatial memory and
depends on right hippocampal integrity. Another possibility is that
post-depressed subjects performed more poorly on timed tasks. However,
both the WAIS block design and Trails A and B are timed tests; there
was no difference in performance on Trails A and B between
post-depressed and control subjects.
Although further study will be needed to fully elucidate the nature of
the observed association between recurrent depression and volume
reduction, evidence suggests that the link may be causal that sustained depression in humans may cause hippocampal damage, resulting in a reduction of tissue volume and memory function. A limitation of
the current study is that reliability of the Post Life Charting Method in determining retrospective measures of depression
duration has not been established. There is no reason to believe that
the data create a biased relationship between depression duration and
hippocampal volumes, however, because volume data were obtained independently and blindly. The quantitative correlation between depression duration and hippocampal volume is explained most directly by such a causal relationship in that progressively more severe changes
occur in the hippocampus as the length of time depressed, and
presumably the length of time with abnormal GC levels, increases. Furthermore, in animals, repeated episodes of stress have been shown to
damage the hippocampus. This appears to be mediated by GC-induced
neurotoxicity (for review, see Sapolsky et al., 1986; Reagan and
McEwen, 1997). In addition, there is evidence in normal elderly humans
that long-term exposure to GCs predicts hippocampal atrophy and memory
deficits (Lupien et al., 1998).
The relevance to depression of these studies showing that chronically
elevated GC levels damage hippocampal neurons depends, however, on the
assumption that depression is associated with dysregulation of the
glucocorticoid system. Almost 40 years ago, excessive cortisol
secretion during depression was first reported (Gibbons and McHugh,
1962). Hypercortisolism and insensitivity to feedback suppression
during depression have been extensively investigated to determine the
relative contributions of adrenal hypersensitivity to ACTH (Amsterdam
et al., 1989), pituitary resistance to GC feedback (Holsboer et al.,
1987), pituitary hypersensitivity to CRF and other hormones (Gold et
al., 1984), and resistance at the hippocampus (Sapolsky et al., 1991;
Young et al., 1991). Although we do not have cortisol levels from
previous depressive episodes, many of our subjects had histories of
hospitalization, ECT treatment, and multiple episodes, indicating
relatively more severe major depression, a predictor of elevated
cortisol and dexamethasone suppression test nonsuppression (Whiteford
et al., 1987). Taken together, these findings suggest that HPA axis
dysregulation in depression can produce repeated episodes of
hypercortisolemia, which may result in hippocampal neurotoxicity.
The precise mechanisms whereby chronic glucocorticoid exposure leads to
hippocampal cell death are not defined, but enhanced vulnerability to
excitotoxicity may be a main factor (Armanini et al., 1990). We have
shown a reduction in volumes of the core nuclei of the amygdala in
recurrent major depression (Sheline et al., 1998) and now demonstrate a
high correlation between hippocampal and amygdala core nuclei volume
loss. Because glutamatergic pyramidal cells in the core nuclei of the
amygdala are predominant and reciprocally connected with the
hippocampus, it may be that overexcitation in one part of this circuit
produces damage in connected structures. Furthermore, there was no
difference in volumes of noncore amygdala nuclei, which contain
primarily nonglutamatergic cells (Price et al., 1987).
In addition to glucocorticoid-induced neurotoxicity, other mechanisms
consistent with hippocampal volume loss in recurrent depression include
neurotoxic effects of corticotrophin-releasing factor (CRF) and a
decrease in trophic factors such as brain-derived neurotrophic factor
(BDNF). Elevated CRF levels have been described in both depressed
humans (Nemeroff et al., 1984) and animal models of depression and have
neurotoxic effects (Wong et al., 1995). Furthermore, CRF antagonists
are neuroprotective against seizure-induced excitotoxicity (Maecker et
al., 1997). Stress decreases the expression of BDNF (Duman et al.,
1997), and BDNF is neuroprotective (Mamounas et al., 1995). These
mechanismsglucocorticoid toxicity, CRF neurotoxicity, and BDNF loss
resulting in increased neuronal vulnerabilityare not mutually
exclusive and could all be operating to alter the vulnerability of
hippocampal neurons in depression.
In summary, the present study shows an association between depression
and structural changes in the hippocampus. It should be pointed out
that volume changes cannot be equated with neuropathological studies
directly performing cell counts; only the latter would provide direct
evidence for cell loss. This gray matter hippocampal volume loss does
not appear to be related to aging but could be related to factors
commonly associated with aging, such as medical illnesses, which were
not examined in this study. Depression-related volume loss does appear
to be cumulative, suggesting that immediate recognition and treatment
of depressive episodes is important in preventing cumulative damage
that occurs with repeated episodes of depression.
| |
FOOTNOTES |
Received Dec. 3, 1998; revised March 9, 1999; accepted April 6, 1999.
This work was supported by National Institutes of Health Grants MH K07
1370 (Y.I.S.), MH 58444 (Y.I.S.), and MH 54731 (M.A.M), and by the
Washington University General Clinical Research Center National
Institutes of Health Grant 5M01 RR00036. We thank Dr. Rosalind Neuman
for helpful statistical advice.
Correspondence should be addressed to Dr. Yvette I. Sheline, Department
of Psychiatry, Box 8134, Washington University School of Medicine, 4940 Childrens Place, St. Louis, MO 63110.
| |
REFERENCES |
-
Aboitz F,
Scheibel A,
Zaidel E
(1992)
Morphometry of the Sylvian fissure and the corpus callosum, with emphasis on sex differences.
Brain
115:1521-1541[Abstract/Free Full Text].
-
Amsterdam J,
Maislin G,
Berwish N,
Phillips J,
Winokur A
(1989)
Enhanced adrenocortical sensitivity to submaximal doses of cosyntropin in depressed patients.
Arch Gen Psychiatry
46:550-554[Abstract/Free Full Text].
-
Andreasen NC,
Flashman L,
Flaum M,
Arndt S,
Swayzee V,
O'Leary DS,
Ehrhardt JC,
Yuh WTC
(1994)
Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging.
JAMA
272:1763-1769[Abstract/Free Full Text].
-
Armanini MP,
Hutchins C,
Stein BA,
Sapolsky RM
(1990)
Glucocorticoid endangerment of hippocampal neurons is NMDA-receptor dependent.
Brain Res
532:7-12[Web of Science][Medline].
-
Aronson S
(1973)
J. Intracranial vascular lesions in patients with diabetes mellitus.
Neuropathol Exp Neurol
32:183-196[Web of Science][Medline].
-
Bartzokis G,
Mintz J,
Marx P,
Osborn D,
Gutkind D,
Chiang F,
Phelan CK,
Marder SR
(1993)
Reliability of in vivo volume measures of hippocampus and other brain structures using MRI.
Magn Reson Imaging
11:993-1006[Web of Science][Medline].
-
Bremner J,
Randall P,
Scott T,
Bronen R,
Seibyl J,
Southwick S,
Delaney R,
McCarthy G,
Charney D,
Innis R
(1995)
MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder.
Am J Psychiatry
152:973-981[Abstract/Free Full Text].
-
Carney R,
Rich M,
teVelde A
(1987)
Major depressive disorder in coronary artery disease.
Am J Cardiol
60:1273-1275[Web of Science][Medline].
-
Carroll R,
Feinberg M,
Greden J,
Tarika J,
Albala A,
Haskett R,
James M,
Kronfol A,
Lohr N,
Steiner M,
de Vigne J,
Young E
(1981)
A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility.
Arch Gen Psychiatry
38:15-22[Abstract/Free Full Text].
-
Cavazos JE,
Das I,
Sutula TP
(1994)
Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures.
J Neurosci
14:3106-3121[Abstract].
-
Charness ME
(1993)
Brain lesions in alcoholics.
Alcohol Clin Exp Res
17:2-11[Web of Science][Medline].
-
Devanand DP,
Dwork AJ,
Hutchinson ER,
Bolwig TG,
Sackeim HA
(1994)
Does ECT alter brain structure?
Am J Psychiatry
151:957-970[Abstract/Free Full Text].
-
Donald J,
Marquardt W
(1963)
An algorithm for least-square estimation of nonlinear parameters.
J Soc Indust Appl Math
11:431-441.
-
Duman RS,
Heninger GR,
Nestler EJ
(1997)
A molecular and cellular theory of depression.
Arch Gen Psychiatry
54:597-606[Abstract/Free Full Text].
-
Duvernoy HM
(1988)
In: Human hippocampus: an atlas of applied anatomy. Munich: Bergmann Verlag.
-
Gibbons J,
McHugh P
(1962)
Plasma cortisol in depressive illness.
J Psychiatry Res
1:162-171[Web of Science][Medline].
-
Gold P,
Chrousos G,
Kellner C,
Post R,
Roy A,
Avgerinos P,
Schulte H,
Oldfield E,
Loriaux D
(1984)
Psychiatric implications of basic and clinical studies with CRF.
Am J Psychiatry
141:619-627[Abstract/Free Full Text].
-
Gundersen HJG,
Bendtsen TF,
Korbo N
(1988)
Some new, simple and efficient stereological methods and their use in pathological research and diagnosis.
Acta Pathol Microbiol Scand
96:379-394.
-
Holsboer F,
Gerken A,
Stalla G,
Muller O
(1987)
Blunted aldosterone and ACTH release after human CRH administration in depressed patients.
Am J Psychiatry
144:229-231[Abstract/Free Full Text].
-
Issa AM,
Rowe W,
Gauthier S,
Meaney MJ
(1990)
Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats.
J Neurosci
10:3247-3254[Abstract].
-
Jernigan TL,
Archibald SL,
Berhow MT,
Sowell ER,
Foster DS,
Hesselink JR
(1991)
Cerebral structure on MRI, Part I: localization of age-related changes.
Biol Psychiatry
29:55-67[Web of Science][Medline].
-
Kilpatrick C,
Murrie V,
Cook M,
Andrews D,
Desmond P,
Hopper J
(1997)
Degree of left hippocampal atrophy correlates with severity of neuropsychological deficits.
Seizure
6:213-218[Web of Science][Medline].
-
Kobayashi S,
Okada K,
Yamashita K
(1991)
Incidence of silent lacunar lesion in normal adults and its relation to cerebral blood flow and risk factors.
Stroke
22:1379-1383[Abstract/Free Full Text].
-
Landfield PW,
Baskin RK,
Pitler TA
(1981)
Brain aging correlates: retardation by hormonal-pharmacological treatments.
Science
214:581-584[Abstract/Free Full Text].
-
Lawrence MS,
Sapolsky RM
(1994)
Glucocorticoids accelerate ATP loss following metabolic insults in cultured hippocampal neurons.
Brain Res
646:303-306[Web of Science][Medline].
-
Lezak MD
(1995)
In: Neuropsychological assessment, Ed 3. New York: Oxford UP.
-
Lim KO,
Zipursky RB,
Murphy Jr GM,
Pfefferbaum A
(1990)
In vivo quantification of the limbic system using MRI: effects of normal aging.
Psychiatry Res
35:15-26[Web of Science][Medline].
-
Lupien SJ,
de Leon M,
deSanti S,
Convit A,
Tarshish C,
Nair NPV,
Thakur M,
McEwen BS
(1998)
Cortisol levels during human aging predict hippocampal atrophy and memory deficits.
Nat Neurosci
1:69-73.[Web of Science][Medline]
-
Maecker H,
Desai A,
Dash R,
Rivier J,
Vale W,
Sapolsky R
(1997)
Astressin, a novel and potent CRF antagonist, is neuroprotective in the hippocampus when administered after a seizure.
Brain Res
744:166-170[Web of Science][Medline].
-
Mamounas LA,
Blue ME,
Siuciak JA,
Altar C
(1995)
BDNF promotes the survival and sprouting of serotonergic axons in the rat brain.
J Neurosci
15:7929-7939[Abstract].
-
Mayhew TM
(1992)
A review of recent advances in stereology for quantifying neural structure.
J Neurocytol
21:313-328[Web of Science][Medline].
-
McEwen BS
(1992)
Re-examination of the glucocorticoid hypothesis of stress and aging.
In: Progress in brain research (Swaab D,
Hofman M,
Mirmiran M,
Ravid R,
van Leeuwen F,
eds), pp 356-383. New York: Elsevier.
-
McIntosh LJ,
Sapolsky RM
(1996)
Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture.
Exp Neurol
141:201-206[Web of Science][Medline].
-
Meaney MJ,
Aitkin DH,
van Berkel C,
Bhatnagar S,
Sapolsky RM
(1988)
Effect of neonatal handling on age-related impairments associated with the hippocampus.
Science
239:766-768[Abstract/Free Full Text].
-
Narayan M,
Anderson E,
Miller H,
Staib L,
Charney D,
Bremner J
(1998)
Hippocampal volume in MDD. Abstract presented at the annual meeting of the American Psychiatric Association, May 1998, Toronto, Canada
-
Nemeroff CB,
Widerlov E,
Walleus H,
Karlsson I,
Eklund K,
Kilts CD,
Loosen PT,
Vale W
(1984)
Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.
Science
226:1342-1344[Abstract/Free Full Text].
-
Nurnberger J,
Blehar MC,
Kaufmann CA,
York-Cooler C,
Simpson SG,
Harkavy-Friedman J,
Severe JB,
Malaspina D,
Reich T,
collaborators from the NIMH Genetics Initiative
(1993)
Diagnostic interview for genetic studies. Rationale, unique features, and training.
Arch Gen Psychiatry
11:849-859; 863-864.
-
Post RM,
Roy-Byrne PP,
Uhde T
(1988)
Graphic representation of the life course of illness in patients with affective disorder.
Am J Psychiatry
145:844-848[Abstract/Free Full Text].
-
Price J,
Russchen F,
Amaral D
(1987)
The limbic region. II: The amygdaloid complex.
In: Handbook of chemical neuroanatomy, Vol 5 (Bjorkland A,
Hokfelt T,
Swanson L,
eds), pp 279-388. New York: Elsevier.
-
Rapp PR,
Gallagher M
(1996)
Preserved neuron number in the hippocampus of aged rats with spatial learning deficits.
Proc Natl Acad Sci USA
93:9926-9930[Abstract/Free Full Text].
-
Rasmussen T,
Schliemann T,
Sorensen JC,
Zimmer J,
West MJ
(1996)
Memory impaired aged rats: no loss of principal hippocampal and subicular neurons.
Neurobiol Aging
17:143-147[Web of Science][Medline].
-
Reagan LP,
McEwen BS
(1997)
Controversies surrounding glucocorticoid-mediated cell death in the hippocampus.
J Chem Neuroanat
13:149-167[Web of Science][Medline].
-
Resnick S,
Maki K,
Golski S,
Kraut M,
Zonderman A
(1998)
Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance.
Horm Behav
34:171-182[Medline].
-
Rey A
(1964)
In: L'examen clinique en psychologie. Paris: Presses Universitaires de France.
-
Rice J,
Endicott J,
Knesevich M,
Rochberg N
(1987)
The estimation of diagnostic sensitivity using stability data: an application to major depressive disorder.
J Psychiat Res
21:337-345[Web of Science][Medline].
-
Robb RA
(1990)
A software system for interactive and quantitative analysis of biomedical images.
In: 3D imaging in medicine, Vol F (Hohne KH,
Fuchs M,
Pizer SM,
eds), pp 333-361. Nato ISI Series.
-
Sapolsky RM
(1992)
Is this relevant to the human?
In: Stress, the aging brain and the mechanisms of neuron death, pp 305-339. Cambridge, MA: MIT.
-
Sapolsky RM,
Krey LC,
McEwen BS
(1983)
Corticosterone receptors decline in a site-specific manner in the aged rat brain.
Brain Res
289:235-240[Web of Science][Medline].
-
Sapolsky RM,
Krey LC,
McEwen BS
(1985)
Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging.
J Neurosci
5:1222-1227[Abstract].
-
Sapolsky RM,
Krey LC,
McEwen BS
(1986)
The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis.
Endocrinol Rev
7:284-301[Abstract/Free Full Text].
-
Sapolsky RM,
Uno H,
Rebert CS,
Finch CE
(1990)
Hippocampal damage associated with prolonged glucocorticoid exposure in primates.
J Neurosci
10:2897-2902[Abstract].
-
Sapolsky RM,
Zola-Morgan S,
Squire L
(1991)
Inhibition of glucocorticoid secretion by the hippocampal formation in the primate.
J Neurosci
11:3695-3704[Abstract].
-
Sheline YI,
Wang PW,
Gado MH,
Csernansky JG,
Vannier MW
(1996)
Hippocampal atrophy in recurrent major depression.
Proc Natl Acad Sci USA
93:3908-3913[Abstract/Free Full Text].
-
Sheline YI,
Gado M,
Price JL
(1998)
Amygdala core nuclei volumes are decreased in recurrent major depression.
NeuroReport
9:2023-2028[Web of Science][Medline].
-
Squire LR
(1992)
Declarative and nondeclarative memory: multiple brain systems supporting learning and memory.
J Cognit Neurosci
4:232-243[Web of Science].
-
Tierney MC,
Szalai JP,
Snow WG,
Fisher RH,
Nores A,
Nadon G,
Dunn E,
St. George-Hyslop PH
(1996)
Prediction of probable Alzheimer's disease in memory-impaired patients: a prospective longitudinal study.
Neurology
46:661-665[Free Full Text].
-
Tombaugh GC,
Sapolsky RM
(1992)
Corticosterone accelerates hypoxia- and cyanide-induced ATP loss in cultured hippocampal astrocytes.
Brain Res
588:154-158[Web of Science][Medline].
-
Watanabe Y,
Gould E,
McEwen BS
(1992b)
Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons.
Brain Res
588:341-345[Web of Science][Medline].
-
West MJ
(1993)
Regionally specific loss of neurons in the aging human hippocampus.
Neurobiol Aging
14:287-293[Web of Science][Medline].
-
Wechsler D
(1981)
In: WAIS-R manual. New York: The Psychological Corporation.
-
Wechsler D
(1987)
In: Wechsler Memory Scale-Revised Manual. San Antonio, TX: The Psychological Corporation.
-
Whiteford H,
Peabody C,
Csernansky J,
Warner M,
Berger P
(1987)
Elevated baseline and postdexamethasone cortisol levels. A reflection of severity or endogeneity?
J Affective Disord
12:199-202[Web of Science][Medline].
-
Wong M,
Loddick S,
Bongiorno P,
Gold P,
Rothwell N,
Licinio J
(1995)
Focal cerebral ischemia induces CRH mRNA in rat cerebral cortex and amygdala.
NeuroReport
6:1785-1788[Web of Science][Medline].
-
Wooley C,
Weiland N,
McEwen B,
Schwartzkroin P
(1997)
Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density.
J Neurosci
17:1848-1859[Abstract/Free Full Text].
-
Young EA,
Haskett RF,
Murphy-Weinberg V,
Watson SJ,
Akil H
(1991)
Loss of glucocorticoid fast feedback in depression.
Arch Gen Psychiatry
48:693-698[Abstract/Free Full Text].
Copyright © 1999 Society for Neuroscience 0270-6474/99/19125034-10$05.00/0
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C. A. Reyes-Ortiz, I. M. Berges, M. A. Raji, H. G. Koenig, Y.-F. Kuo, and K. S. Markides
Church Attendance Mediates the Association Between Depressive Symptoms and Cognitive Functioning Among Older Mexican Americans
J. Gerontol. A Biol. Sci. Med. Sci.,
May 1, 2008;
63(5):
480 - 486.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-C. Ni, H.-M. Liu, and M. M. Tseng
Electroconvulsive Therapy of a Depressed Patient with Septo-Optic Dysplasia
J Neuropsychiatry Clin Neurosci,
May 1, 2008;
20(2):
242 - 243.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ballmaier, K. L. Narr, A. W. Toga, V. Elderkin-Thompson, P. M. Thompson, L. Hamilton, E. Haroon, D. Pham, A. Heinz, and A. Kumar
Hippocampal Morphology and Distinguishing Late-Onset From Early-Onset Elderly Depression
Am J Psychiatry,
February 1, 2008;
165(2):
229 - 237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. W. Koo and R. S. Duman
IL-1 is an essential mediator of the antineurogenic and anhedonic effects of stress
PNAS,
January 15, 2008;
105(2):
751 - 756.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yamasue, O. Abe, M. Suga, H. Yamada, H. Inoue, M. Tochigi, M. Rogers, S. Aoki, N. Kato, and K. Kasai
Gender-Common and -Specific Neuroanatomical Basis of Human Anxiety-Related Personality Traits
Cereb Cortex,
January 1, 2008;
18(1):
46 - 52.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Kang, D. H. Adams, A. Simen, B. B. Simen, G. Rajkowska, C. A. Stockmeier, J. C. Overholser, H. Y. Meltzer, G. J. Jurjus, L. C. Konick, et al.
Gene Expression Profiling in Postmortem Prefrontal Cortex of Major Depressive Disorder
J. Neurosci.,
November 28, 2007;
27(48):
13329 - 13340.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. H. Novack, O. Cameron, E. Epel, R. Ader, S. R. Waldstein, S. Levenstein, M. H. Antoni, and A. R. Wainer
Psychosomatic Medicine: The Scientific Foundation of the Biopsychosocial Model
Acad Psychiatry,
October 1, 2007;
31(5):
388 - 401.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. S. McEwen
Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain
Physiol Rev,
July 1, 2007;
87(3):
873 - 904.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Janssen, H. E Hulshoff Pol, F.-E. de Leeuw, H. G Schnack, I. K Lampe, R. M Kok, R. S Kahn, and T. J Heeren
Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression
J. Neurol. Neurosurg. Psychiatry,
June 1, 2007;
78(6):
638 - 640.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. D. Perera, J. D. Coplan, S. H. Lisanby, C. M. Lipira, M. Arif, C. Carpio, G. Spitzer, L. Santarelli, B. Scharf, R. Hen, et al.
Antidepressant-Induced Neurogenesis in the Hippocampus of Adult Nonhuman Primates
J. Neurosci.,
May 2, 2007;
27(18):
4894 - 4901.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Frodl, C. Schule, G. Schmitt, C. Born, T. Baghai, P. Zill, R. Bottlender, R. Rupprecht, B. Bondy, M. Reiser, et al.
Association of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism With Reduced Hippocampal Volumes in Major Depression
Arch Gen Psychiatry,
April 1, 2007;
64(4):
410 - 416.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. G. Csernansky, H. Dong, A. M. Fagan, L. Wang, C. Xiong, D. M. Holtzman, and J. C. Morris
Plasma Cortisol and Progression of Dementia in Subjects With Alzheimer-Type Dementia
Am J Psychiatry,
December 1, 2006;
163(12):
2164 - 2169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hajszan and N. J. MacLusky
Neurologic links between epilepsy and depression in women: Is hippocampal neuroplasticity the key?
Neurology,
March 28, 2006;
66(66_suppl_3):
S13 - S22.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Ganguli, Y. Du, H. H. Dodge, G. G. Ratcliff, and C.-C. H. Chang
Depressive Symptoms and Cognitive Decline in Late Life: A Prospective Epidemiological Study
Arch Gen Psychiatry,
February 1, 2006;
63(2):
153 - 160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K Alagiakrishnan, P McCracken, and H Feldman
Treating vascular risk factors and maintaining vascular health: Is this the way towards successful cognitive ageing and preventing cognitive decline?
Postgrad. Med. J.,
February 1, 2006;
82(964):
101 - 105.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. V. Parsey, R. S. Hastings, M. A. Oquendo, Y.-y. Huang, N. Simpson, J. Arcement, Y. Huang, R. T. Ogden, R. L. Van Heertum, V. Arango, et al.
Lower Serotonin Transporter Binding Potential in the Human Brain During Major Depressive Episodes
Am J Psychiatry,
January 1, 2006;
163(1):
52 - 58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Wagner, H. Tennen, G. A. Mansoor, and G. Abbott
History of Major Depressive Disorder and Endothelial Function in Postmenopausal Women
Psychosom Med,
January 1, 2006;
68(1):
80 - 86.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Clark, A. Sarna, and G. M. Goodwin
Impairment of Executive Function But Not Memory in First-Degree Relatives of Patients With Bipolar I Disorder and in Euthymic Patients With Unipolar Depression
Am J Psychiatry,
October 1, 2005;
162(10):
1980 - 1982.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. D. Taylor, D. C. Steffens, M. E. Payne, J. R. MacFall, D. A. Marchuk, I. K. Svenson, and K. R. R. Krishnan
Influence of Serotonin Transporter Promoter Region Polymorphisms on Hippocampal Volumes in Late-Life Depression
Arch Gen Psychiatry,
May 1, 2005;
62(5):
537 - 544.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. N. Abrous, M. Koehl, and M. Le Moal
Adult Neurogenesis: From Precursors to Network and Physiology
Physiol Rev,
April 1, 2005;
85(2):
523 - 569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Bonanno, R. Giambelli, L. Raiteri, E. Tiraboschi, S. Zappettini, L. Musazzi, M. Raiteri, G. Racagni, and M. Popoli
Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus
J. Neurosci.,
March 30, 2005;
25(13):
3270 - 3279.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Hickie, S. Naismith, P. B. Ward, K. Turner, E. Scott, P. Mitchell, K. Wilhelm, and G. Parker
Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression
The British Journal of Psychiatry,
March 1, 2005;
186(3):
197 - 202.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Schatzberg
Recent Studies of the Biology and Treatment of Depression
Focus,
January 1, 2005;
3(1):
14 - 24.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. MacQueen, S. Campbell, B. S. McEwen, K. Macdonald, S. Amano, R. T. Joffe, C. Nahmias, and L. T. Young
Course of Illness, Hippocampal Function, and Hippocampal Volume in Major Depression
Focus,
January 1, 2005;
3(1):
146 - 155.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Winter and E. Irle
Hippocampal Volume in Adult Burn Patients With and Without Posttraumatic Stress Disorder
Am J Psychiatry,
December 1, 2004;
161(12):
2194 - 2200.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Inagaki, Y. Matsuoka, Y. Sugahara, T. Nakano, T. Akechi, M. Fujimori, S. Imoto, K. Murakami, and Y. Uchitomi
Hippocampal Volume and First Major Depressive Episode After Cancer Diagnosis in Breast Cancer Survivors
Am J Psychiatry,
December 1, 2004;
161(12):
2263 - 2270.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Videbech and B. Ravnkilde
Hippocampal Volume and Depression: A Meta-Analysis of MRI Studies
Am J Psychiatry,
November 1, 2004;
161(11):
1957 - 1966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. O'Brien, A. Lloyd, I. McKeith, A. Gholkar, and N. Ferrier
A Longitudinal Study of Hippocampal Volume, Cortisol Levels, and Cognition in Older Depressed Subjects
Am J Psychiatry,
November 1, 2004;
161(11):
2081 - 2090.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Payne and L. Nadel
Sleep, dreams, and memory consolidation: The role of the stress hormone cortisol
Learn. Mem.,
November 1, 2004;
11(6):
671 - 678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Lloyd, I. N. Ferrier, R. Barber, A. Gholkar, A. H. Young, and J. T. O'brien
Hippocampal volume change in depression: late- and early-onset illness compared
The British Journal of Psychiatry,
June 1, 2004;
184(6):
488 - 495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Campbell, M. Marriott, C. Nahmias, and G. M. MacQueen
Lower Hippocampal Volume in Patients Suffering From Depression: A Meta-Analysis
Am J Psychiatry,
April 1, 2004;
161(4):
598 - 607.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Bremner, M. Vythilingam, E. Vermetten, V. Vaccarino, and D. S. Charney
Deficits in Hippocampal and Anterior Cingulate Functioning During Verbal Declarative Memory Encoding in Midlife Major Depression
Am J Psychiatry,
April 1, 2004;
161(4):
637 - 645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. E. Wood, L. T. Young, L. P. Reagan, B. Chen, and B. S. McEwen
Stress-induced structural remodeling in hippocampus: Prevention by lithium treatment
PNAS,
March 16, 2004;
101(11):
3973 - 3978.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. P. Reagan, D. R. Rosell, G. E. Wood, M. Spedding, C. Munoz, J. Rothstein, and B. S. McEwen
Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: Reversal by tianeptine
PNAS,
February 17, 2004;
101(7):
2179 - 2184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Frodl, E. M. Meisenzahl, P. Zill, T. Baghai, D. Rujescu, G. Leinsinger, R. Bottlender, C. Schule, P. Zwanzger, R. R. Engel, et al.
Reduced Hippocampal Volumes Associated With the Long Variant of the Serotonin Transporter Polymorphism in Major Depression
Arch Gen Psychiatry,
February 1, 2004;
61(2):
177 - 183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Jindal, D. J. Buysse, and M. E. Thase
Maintenance Treatment of Insomnia: What Can We Learn From the Depression Literature?
Am J Psychiatry,
January 1, 2004;
161(1):
19 - 24.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. P. Blumberg, J. Kaufman, A. Martin, R. Whiteman, J. H. Zhang, J. C. Gore, D. S. Charney, J. H. Krystal, and B. S. Peterson
Amygdala and Hippocampal Volumes in Adolescents and Adults With Bipolar Disorder
Arch Gen Psychiatry,
December 1, 2003;
60(12):
1201 - 1208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. K. Lampe, H. E. Hulshoff Pol, J. Janssen, H. G. Schnack, R. S. Kahn, and T. J. Heeren
Association of Depression Duration With Reduction of Global Cerebral Gray Matter Volume in Female Patients With Recurrent Major Depressive Disorder
Am J Psychiatry,
November 1, 2003;
160(11):
2052 - 2054.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Rajkowska
Depression: What We can Learn from Postmortem Studies
Neuroscientist,
August 1, 2003;
9(4):
273 - 284.
[Abstract]
[PDF]
|
|
|
|
|
|
|
Y. I. Sheline, M. H. Gado, and H. C. Kraemer
Untreated Depression and Hippocampal Volume Loss
Am J Psychiatry,
August 1, 2003;
160(8):
1516 - 1518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Bremner, M. Vythilingam, C. K. Ng, E. Vermetten, A. Nazeer, D. A. Oren, R. M. Berman, and D. S. Charney
Regional Brain Metabolic Correlates of {alpha}-Methylparatyrosine-Induced Depressive Symptoms: Implications for the Neural Circuitry of Depression
JAMA,
June 18, 2003;
289(23):
3125 - 3134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Keller
Past, Present, and Future Directions for Defining Optimal Treatment Outcome in Depression: Remission and Beyond
JAMA,
June 18, 2003;
289(23):
3152 - 3160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. guzman-marin, N. Suntsova, D. R Stewart, H. Gong, R. Szymusiak, and D. McGinty
Sleep deprivation reduces proliferation of cells in the dentate gyrus of the hippocampus in rats
J. Physiol.,
June 1, 2003;
549(2):
563 - 571.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. P. Merke, J. D. Fields, M. F. Keil, A. C. Vaituzis, G. P. Chrousos, and J. N. Giedd
Children with Classic Congenital Adrenal Hyperplasia Have Decreased Amygdala Volume: Potential Prenatal and Postnatal Hormonal Effects
J. Clin. Endocrinol. Metab.,
April 1, 2003;
88(4):
1760 - 1765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. MacQueen, S. Campbell, B. S. McEwen, K. Macdonald, S. Amano, R. T. Joffe, C. Nahmias, and L. T. Young
Course of illness, hippocampal function, and hippocampal volume in major depression
PNAS,
February 4, 2003;
100(3):
1387 - 1392.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Posener, L. Wang, J. L. Price, M. H. Gado, M. A. Province, M. I. Miller, C. M. Babb, and J. G. Csernansky
High-Dimensional Mapping of the Hippocampus in Depression
Am J Psychiatry,
January 1, 2003;
160(1):
83 - 89.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Vythilingam, C. Heim, J. Newport, A. H. Miller, E. Anderson, R. Bronen, M. Brummer, L. Staib, E. Vermetten, D. S. Charney, et al.
Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression
Am J Psychiatry,
December 1, 2002;
159(12):
2072 - 2080.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Nakano, M. Wenner, M. Inagaki, A. Kugaya, T. Akechi, Y. Matsuoka, Y. Sugahara, S. Imoto, K. Murakami, and Y. Uchitomi
Relationship Between Distressing Cancer-Related Recollections and Hippocampal Volume in Cancer Survivors
Am J Psychiatry,
December 1, 2002;
159(12):
2087 - 2093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Andriamampandry, C. Muller, C. Schmidt-Mutter, S. Gobaille, M. Spedding, D. Aunis, and M. Maitre
Mss4 Gene Is Up-Regulated in Rat Brain after Chronic Treatment with Antidepressant and Down-Regulated When Rats Are Anhedonic
Mol. Pharmacol.,
December 1, 2002;
62(6):
1332 - 1338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bell-McGinty, M. A. Butters, C. C. Meltzer, P. J. Greer, C. F. Reynolds III, and J. T. Becker
Brain Morphometric Abnormalities in Geriatric Depression: Long-Term Neurobiological Effects of Illness Duration
Am J Psychiatry,
August 1, 2002;
159(8):
1424 - 1427.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Schatzberg
Major Depression: Causes or Effects?
Am J Psychiatry,
July 1, 2002;
159(7):
1077 - 1079.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Frodl, E. M. Meisenzahl, T. Zetzsche, C. Born, C. Groll, M. Jager, G. Leinsinger, R. Bottlender, K. Hahn, and H.-J. Moller
Hippocampal Changes in Patients With a First Episode of Major Depression
Am J Psychiatry,
July 1, 2002;
159(7):
1112 - 1118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Fillit, R. N. Butler, A. W. O'Connell, M. S. Albert, J. E. Birren, C. W. Cotman, W. T. Greenough, P. E. Gold, A. F. Kramer, L. H. Kuller, et al.
Achieving and Maintaining Cognitive Vitality With Aging
Mayo Clin. Proc.,
July 1, 2002;
77(7):
681 - 696.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. J. SHAH, M. F. GLABUS, G. M. GOODWIN, and K. P. EBMEIER
Chronic, treatment-resistant depression and right fronto-striatal atrophy
The British Journal of Psychiatry,
May 1, 2002;
180(5):
434 - 440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Shirayama, A. C.-H. Chen, S. Nakagawa, D. S. Russell, and R. S. Duman
Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression
J. Neurosci.,
April 15, 2002;
22(8):
3251 - 3261.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. I. Sheline, M. A. Mintun, S. M. Moerlein, and A. Z. Snyder
Greater Loss of 5-HT2A Receptors in Midlife Than in Late Life
Am J Psychiatry,
March 1, 2002;
159(3):
430 - 435.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Nolan, G. J. Moore, R. Madden, T. Farchione, M. Bartoi, E. Lorch, C. M. Stewart, and D. R. Rosenberg
Prefrontal Cortical Volume in Childhood-Onset Major Depression: Preliminary Findings
Arch Gen Psychiatry,
February 1, 2002;
59(2):
173 - 179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Posener, C. DeBattista, G. H. Williams, and A. F. Schatzberg
Cortisol Feedback During the HPA Quiescent Period in Patients With Major Depression
Am J Psychiatry,
December 1, 2001;
158(12):
2083 - 2085.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Lyons, C. Yang, A. M. Sawyer-Glover, M. E. Moseley, and A. F. Schatzberg
Early Life Stress and Inherited Variation in Monkey Hippocampal Volumes
Arch Gen Psychiatry,
December 1, 2001;
58(12):
1145 - 1151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. S. Duman, J. Malberg, and S. Nakagawa
Regulation of Adult Neurogenesis by Psychotropic Drugs and Stress
J. Pharmacol. Exp. Ther.,
November 1, 2001;
299(2):
401 - 407.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Sapolsky
Depression, antidepressants, and the shrinking hippocampus
PNAS,
October 23, 2001;
98(22):
12320 - 12322.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. Belanoff, M. Kalehzan, B. Sund, S. K. Fleming Ficek, and A. F. Schatzberg
Cortisol Activity and Cognitive Changes in Psychotic Major Depression
Am J Psychiatry,
October 1, 2001;
158(10):
1612 - 1616.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Lucassen, M. B. Muller, F. Holsboer, J. Bauer, A. Holtrop, J. Wouda, W. J. G. Hoogendijk, E. R. De Kloet, and D. F. Swaab
Hippocampal Apoptosis in Major Depression Is a Minor Event and Absent from Subareas at Risk for Glucocorticoid Overexposure
Am. J. Pathol.,
February 1, 2001;
158(2):
453 - 468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Driessen, J. Herrmann, K. Stahl, M. Zwaan, S. Meier, A. Hill, M. Osterheider, and D. Petersen
Magnetic Resonance Imaging Volumes of the Hippocampus and the Amygdala in Women With Borderline Personality Disorder and Early Traumatization
Arch Gen Psychiatry,
December 1, 2000;
57(12):
1115 - 1122.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Lyons, J. M. Lopez, C. Yang, and A. F. Schatzberg
Stress-Level Cortisol Treatment Impairs Inhibitory Control of Behavior in Monkeys
J. Neurosci.,
October 15, 2000;
20(20):
7816 - 7821.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Sapolsky
Glucocorticoids and Hippocampal Atrophy in Neuropsychiatric Disorders
Arch Gen Psychiatry,
October 1, 2000;
57(10):
925 - 935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
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G. Ende, D. F. Braus, S. Walter, W. Weber-Fahr, and F. A. Henn
The Hippocampus in Patients Treated With Electroconvulsive Therapy: A Proton Magnetic Resonance Spectroscopic Imaging Study
Arch Gen Psychiatry,
October 1, 2000;
57(10):
937 - 943.
[Abstract]
[Full Text]
[PDF]
|
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D. FANNON, L. TENNAKOON, S. O'CEALLAIGH, V. DOKU, W. SONI, X. CHITNIS, J. LOWE, A. SUMICH, and T. SHARMA
Third ventricle enlargement and developmental delay in first-episode psychosis: preliminary findings
The British Journal of Psychiatry,
October 1, 2000;
177(4):
354 - 359.
[Abstract]
[Full Text]
[PDF]
|
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M. D. De Bellis, D. B. Clark, S. R. Beers, P. H. Soloff, A. M. Boring, J. Hall, A. Kersh, and M. S. Keshavan
Hippocampal Volume in Adolescent-Onset Alcohol Use Disorders
Am J Psychiatry,
May 1, 2000;
157(5):
737 - 744.
[Abstract]
[Full Text]
|
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|
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Hippocampal Loss Associated with Lifetime Duration of Depression
Journal Watch Psychiatry,
September 1, 1999;
1999(901):
6 - 6.
[Full Text]
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TOP
ABSTRACT
INTRODUCTION
