J Psychiatry Neurosci 2008;33(3)
Objective: In patients with major depressive disorder (MDD), enhanced activation of the rostral anterior cingulate cortex (rACC) during
conflict resolution has been demonstrated with the use of functional magnetic resonance imaging (fMRI), which suggests dysregulation of
the affective compartment of the ACC associated with error monitoring and cognitive control. Moreover, several previous studies have re-
ported disrupted structural integrity in limbic brain areas and the orbitofrontal cortex in MDD. However, the relation between structural and
functional alterations remains unclear. Therefore, the present study sought to investigate whether structural brain aberrations in terms of
grey matter decreases directly in the medial frontal regions or in anatomically closely connected areas might be related to our previously
reported functional alterations. Methods: A sample of 16 female, drug-free patients with an acute episode of MDD and 16 healthy control
subjects matched for age, sex and education were examined with structural high-resolution T1-weighted MRI; fMRI images were obtained
in the same session. Results: Voxel-based morphometry (VBM) revealed grey matter decreases in the orbitofrontal and subgenual cortex,
in the hippocampus-amygdala complex and in the middle frontal gyrus. The relative hyperactivation of the rACC in terms of inability to de-
activate this region during the Stroop Color-Word Test showed an inverse correlation with grey matter reduction in the orbitofrontal cortex.
Conclusion: The present study provides strong evidence for an association between structural alterations in the orbitofrontal cortex and
disturbed functional activation in the emotional compartment of the ACC in patients with MDD during cognitive control.
Objectif : Chez des patients atteints de trouble dépressif majeur (TDM), on a démontré au moyen de l’imagerie par résonance magné-
tique fonctionnelle (IRMf) une plus grande activité du cortex cingulaire antérieur rostral (CCAr) pendant la résolution des différends, ce
qui indique une dysrégulation du compartiment affectif du CCA associé à la surveillance des erreurs et au contrôle de la cognition. De
plus, plusieurs études antérieures ont signalé une perturbation de l’intégrité structurelle dans des aires limbiques du cerveau et le cortex
orbitofrontal dans les cas de TDM. Le lien entre les altérations structurelles et fonctionnelles demeure toutefois flou. C’est pourquoi
l’étude visait à déterminer si les aberrations structurelles du cerveau en termes de diminutions de la matière grise survenant directement
dans les régions frontales médiales ou dans les régions reliées étroitement sur le plan anatomique pourraient être reliées aux altérations
fonctionnelles signalées antérieurement. Méthodes : On a examiné par IRM structurelle haute résolution à pondération T1un échantillon
composé de 16 femmes ne prenant pas de médicament et ayant un épisode aigu de TDM et de 16 sujets témoins en bonne santé
jumelés en fonction de l’âge, du sexe et de l’éducation. On a obtenu des images IRMf au cours de la même séance. Résultats : La mor-
phométrie Voxel a révélé des diminutions de la matière grise dans le cortex orbitofrontal et subgénual, dans le complexe hippocampe-
amygdales et dans la circonvolution frontale médiane. L’hyperactivation relative du CCAr (incapacité de désactiver cette région au cours du
test de Stroop sur les couleurs et les mots) a révélé une corrélation inverse avec la réduction de la matière grise dans le cortex orbitofrontal.
Conclusion: L’étude démontre solidement l’existence d’un lien entre des altérations structurelles du cortex orbitofrontal et la perturbation de
l’activation fonctionnelle dans le compartiment émotionnel du CCA, au cours du contrôle cognitif chez les patients atteints de TDM.
Article de recherche
Enhanced rostral anterior cingulate cortex activation
during cognitive control is related to orbitofrontal
volume reduction in unipolar depression
Gerd Wagner, PhD; Kathrin Koch, PhD; Claudia Schachtzabel; Jürgen R. Reichenbach, PhD;
Heinrich Sauer, MD; Ralf G.M. Schlösser MD
Wagner, Koch, Schachtzabel, Sauer, Schlösser — Department of Psychiatry; Reichenbach — Institute of Diagnostic and
Interventional Radiology, University of Jena, Germany
Correspondence to: Dr. G. Wagner, Department of Psychiatry, University of Jena, Centre for Neuroimaging, Jahnstr. 3, Ersatztext
Jena, Germany; fax 49 0 3641935280; email@example.com
J Psychiatry Neurosci 2008;33(3):199-208.
Medical subject headings: magnetic resonance imaging; depressive disorder; depression.
Submitted May 21, 2007; Revised Sept. 4, 2007; Accepted Oct. 16, 2007
© 2008 Canadian Medical Association
Aside from depressed mood and anhedonia, patients with
the diagnosis of major depressive disorder (MDD) experience
worries and negative thoughts about themselves and their
future that they perceive as being automatic, persistent and
unintended. This leads to a cycle of depression producing
even more rumination and accompanying emotional arousal.
This subjectively observed inability to suppress negative
thoughts has been supported by objective evidence from the
neuropsychological perspective. Patients with MDD have ex-
hibited not only an attentional bias toward negative emo-
tional stimuli1but also a more general deficit in cognitive
control processes and decision making.2,3Especially in cogni-
tive paradigms with conflicting response alternatives, pa-
tients with depression revealed a lack of inhibitory control of
prepotent stimulus-response contingencies and showed en-
hanced interference sensitivity.4
Converging lines of evidence from cognitive neuroscience
indicate that lateral prefrontal regions, that is, the ventrolat-
eral prefrontal cortex (VLPFC; Brodmann’s area [BA] 44/45)
and dorsolateral PFC (DLFPC; BA 9/46) and the anterior cin-
gulate cortex (ACC; BA 24/32), play a crucial role in flexible
goal-directed behaviour involving cognitive functions such
as the selection and activation of appropriate responses
(VLPFC), the monitoring of conflicts and performance out-
come (ACC) and the cognitive inhibition of task-irrelevant
Neuroimaging studies have provided strong evidence for
dysfunctions in these areas in patients with MDD. Attenuated
resting-state blood flow and glucose metabolism in prefrontal
and anterior cingulate brain areas were reported in resting-
state positron emission tomography studies.6,7Further, func-
tional magnetic resonance imaging (fMRI) studies with cogni-
tive paradigms taxing executive functions reported attenuated
activations in the PFC and ACC when patients showed an im-
paired task performance in comparison with matched healthy
control subjects8and a relative hyperactivity in patients when
they were matched for task performance.9
In our previous study with the Stroop Color-Word Test
(SCWT),10an established neuropsychological test taxing cog-
nitive inhibition processes, we directly tested the hypothesis
of disrupted prefrontal and anterior cingulate functions.11
Our main finding was that patients showed a behavioural
performance and dorsal ACC (dACC) activity comparable to
healthy control subjects but a relative hyperactivity in the
rostral ACC (rACC) and left DLPFC. The rACC activity cor-
related positively with the Stroop interference (more time
spent to inhibit the word reading during the incongruent v.
the congruent condition) and with left DLPFC activity. We
interpreted these results as an inability of patients with MDD
to inhibit cognitive interferences from the emotional state,
which they probably compensate for with stronger cognitive
control exerted by the DLPFC to produce normal behavioural
This view is supported by studies examining the functional
heterogeneity of ACC regions.12,13Whereas the dorsal (“cogni-
tive”) part, through its strong interconnections with parietal,
prefrontal and supplementary motor areas, is mainly acti-
vated in cognitively demanding tasks, the rostral (“affective”)
part is strongly connected to the orbitofrontal cortex (OFC),
amygdala, hippocampus and periaqueductal grey matter
and has been found to be mainly activated in tasks requiring
processing and integration of affect-related information.
Moreover, the affective part has additionally been shown to
correlate with autonomic responses during execution of cog-
nitive tasks (e.g., in the Stroop task).14
An interesting aspect is the reported dynamic interplay be-
tween these subdivisions in healthy subjects, which shows a
relative deactivation in the dACC during emotional para-
digms, and in the rACC during cognitive tasks, in compari-
son with baseline, possibly to allocate resources for effective
cognitive processing.15Moreover, there is strong evidence for
a so-called “default mode” of the brain,16,17a physiological
baseline involving mainly cortical midline areas such as the
dorsomedial PFC (DMPFC) and ventromedial PFC (VMPFC)
as well as the posterior cingulate cortex (PCC), which reveal a
high resting-state activity (e.g., during passive viewing of
simple visual stimuli) but an attenuated activity during goal-
directed behaviour. Although the meaning of this physiologi-
cal baseline is not fully understood, there are suggestions that
this activity in the midline cortical areas can be interpreted in
terms of continuous self-referential processing.18
One prominent area within the default mode brain net-
work is the VMPFC including the rACC; in our previous
fMRI study,11activity relative to baseline was elevated in pa-
tients and decreased in healthy control subjects during the
In the present study, our main purpose was to investigate
why patients suffering from depression are unable to inhibit
conflicting affective responses in terms of deactivation of the
rostral, or affective, part of the ACC. One possible explana-
tion for this observation is that the investigated patients had
structural abnormalities directly in this region or in brain ar-
eas interconnected with the rACC, such as the subgenual cor-
tex, OFC, amygdala or hippocampus.
Structural imaging studies have reported a relatively consis-
tent volume reduction in the hippocampus of patients with
MDD.19In their positron emission tomography study on pa-
tients with familial MDD, Drevets and colleagues20observed
reduced glucose metabolism and cerebral blood flow in the
subgenual PFC in association with a volume reduction in the
subgenual cortex that could also be demonstrated in a post-
mortem neuropathological study.21Further, Bremner and col-
leagues,22in a volumetric MRI study, as well as Rajkowska and
colleagues,23in a postmortem study, were able to demonstrate
reduced volume of the OFC in patients with depression that
was due to decreases in glial cells but also to decreases in neu-
ronal cell density. Additionally, Rajkowska and colleagues23re-
ported a similar reduction in cell density for the DLPFC. De-
spite this evidence of structural alterations in frontolimbic
areas in patients with depression, the relation of these struc-
tural changes to functional aberrations remains unclear.
In light of these findings, to reveal potential structural un-
derpinnings of the reported elevated rACC activity, we per-
formed a voxel-based morphometry (VBM) analysis with
Wagner et al
Rev Psychiatr Neurosci 2008;33(3)
rACC activation and orbitofrontal volume in MDD
J Psychiatry Neurosci 2008;33(3)
T1-weighted images of the same sample of patients and con-
trol subjects as were investigated with the Stroop task in our
previous study. VBM represents a sophisticated and objective
whole brain technique to assess subtle regional grey matter
On the basis of previous study findings and anatomical
considerations, we hypothesized that the abnormal activity
of the rACC in patients with MDD might be directly related
to grey matter reduction occurring mostly in the medial PFC,
such as the subgenual area or OFC.
In an exploratory analysis, we examined the relation be-
tween these regional structural findings and clinical variables
(illness duration, the number of previous depressive episodes
and symptom severity). Further, we investigated the relation
between Stroop performance and grey matter density in pa-
tients with depression.
Additionally, from the fMRI perspective, we explicitly in-
vestigated the hypothesis of the abnormal default mode of
brain activity in patients with MDD by concentrating on de-
activations, relative to baseline, within the frontocingulate
network during Stroop task performance.
Sixteen female patients who met the criteria for MDD accord-
ing to the Structured Clinical Interview for DSM-IV Axis I
Disorders (SCID)24were recruited from the inpatient and out-
patient service of a psychiatric university hospital. Detailed
demographic and clinical characteristics are outlined in
Table 1. None of the patients had a history of lithium admin-
istration or electroconvulsive therapy. All study patients un-
derwent a washout period of at least double the half-life of
their preexisting medications and were free of psychotropic
medication for a week, on average, at the time of the fMRI
Sixteen healthy female control subjects matched for age
and education (Table 1) were recruited through local
newspaper advertisements and screened for psychiatric or
neurologic diseases. The sample composition and the inclu-
sion and exclusion criteria were identical to those in our
previous paper. One patient was excluded from structural
analyses because of movement artifacts during the structural
MRI scanning procedure.
The study protocol was approved by the Ethics Committee
of the University of Jena.
The Stroop task was presented in an event-related design and
consisted of a congruent and an incongruent condition. In the
congruent condition, colour words were presented in the
colour denoted by the corresponding word (e.g., the word
“red” shown in red); in the incongruent condition, colour
words were displayed in one of 3 colors not denoted by the
word (e.g., the word “green” shown in red). This target stim-
ulus was presented in the centre of the display screen. Two
possible answers (colour words in black type) were pre-
sented below it (in the lower visual field) to minimize contex-
tual memory demand. By pressing 1 of 2 buttons (with the in-
dex or middle finger), the subjects had to indicate the Word
Type colour that corresponded spatially to both possible an-
swers. Stroop stimuli were presented for 1500 milliseconds,
with an interstimulus interval of 10.5 seconds, and were
pseudorandomly jittered over the repetition time (TR). Fur-
ther details can be found in our previous paper.
Functional and structural MRI scanning procedure
The functional and structural data were collected at the same
time on a 1.5 T Siemens Magnetom Vision whole-body sys-
tem (Siemens, Erlangen, Germany) equipped with a head
volume coil. Head immobilization was established by head
pads within the head coil. A series of 440 T2-weighted images
were obtained with the use of a gradient-echo planar se-
quence (TR = 2000 ms, echo time [TE] = 60 ms, flip angle =
90°, field of view = 240 mm) with 19 contiguous transversal
slices of 5-mm thickness, in 2 sessions (220 scans in each ses-
sion). Matrix size was 64 × 64 pixels with in-plane resolution
of 3.75 × 3.75 mm.
High-resolution structural T1-weighted volume scans were
obtained in sagittal orientation (TR = 15 ms, TE = 5 ms, flip
angle = 30°, field of view of 256 mm) with a slice thickness of
1 mm and in-plane resolution of 1 × 1 mm.
Functional data analysis
For functional image processing and statistical analyses, we
used the Statistical Parametric Mapping-2 (SPM2) software
(Wellcome Department of Imaging Neuroscience, London,
UK, 2003). We described the several analysis steps in detail in
our previous paper.11
The functional data were corrected for differences in time
acquisition by sinc interpolation, realigned at the first image
of every session, normalized to the Montreal Neurological In-
stitute (MNI) reference brain and smoothed with a Gaussian
kernel (10 mm, full width at half maximum [FWHM]).
Table 1: Demographic and clinical characteristics of the sample
Group; mean (and SD)*
(n = 15†)
(n = 16)
Age at onset, y
Duration of illness
Mean no. of past depressive
episodes (and range)
BDI = Beck Depression Inventory; HAMD = Hamilton Depression Rating Scale;
MDD = major depressive disorder; SD = standard deviation.
*Unless otherwise indicated.
†Of original 16 patients, 1 excluded owing to movement artifacts during structural
magnetic resonance imaging.
The data were subsequently analyzed voxel-wise within
the general linear model to calculate statistical parametric
maps of t statistics for condition-specific effects. Prior to this
analysis, the data were high-pass filtered with a cut-off pe-
riod of 128 seconds and corrected for serial correlations
choosing the AR(1) variable.
We performed a fixed-effect model at a single-subject level
to create images of parameter estimates; they were then en-
tered into a second-level analysis (random-effects analysis)
using the subjects’ individual 1-sample t tests.
To test the default-mode hypothesis, a 1-sample sample
t test was computed within groups for the contrast baseline
greater than incongruent condition. A between-group com-
parison in regard to the incongruent condition, which was
depicted in our previous paper,11is displayed in Figure 1C
and Table 2. According to our previous paper, predefined
image masks of frontocingulate areas were applied as de-
rived from existing literature on the Stroop task. Regions of
interest were defined according to the WFU_Pickatlas
(www.fmri.wfubmc.edu) and included the following regions:
the cingulate gyrus, inferior frontal gyrus, medial frontal
gyrus, middle frontal gyrus and superior frontal gyrus.
All resulting statistics were subject to a significance level of
p < 0.001, with a spatial extent threshold of 20 contiguous
voxels corresponding to the expected number of voxels per
cluster. The reported coordinates were transformed into
Structural data analysis
We applied an optimized VBM protocol as developed and
described by Good and colleagues,25using the VBM-toolbox
(http://dbm.neuro.uni-jena.de/) implemented in the SPM2
package. First, from the images of all patients and control
subjects, we created a study-specific template set consisting
of a mean T1-weighted image and a mean grey matter image.
For this purpose, we applied a 12-parameter affine and non-
linear spatial transformation to spatially normalize images to
the SPM2 T1-weighted template (MNI, Montréal). Then we
segmented them into grey matter, white matter and cere-
brospinal fluid compartments and smoothed them with a
Gaussian kernel of 8 mm FWHM. Last, we averaged the im-
ages to provide study-specific templates with reduced
scanner- and population-specific bias.
Next, we processed the original images of all patients and
control subjects, applying the following operations: First, we
segmented all images, using the study-specific T1template.
Subsequently, we normalized the extracted grey matter im-
ages to the customized grey matter template, applying
12-parameter affine and nonlinear spatial transformation,
which we then reapplied to the original structural images.
Using a modified mixture model cluster analysis, we cor-
rected these normalized images for nonuniformities in signal
intensity and partitioned them into grey and white matter
and cerebrospinal fluid. To improve the segmentation algo-
rithm, we applied the hidden Markov random field model,26
which models spatial dependencies at the tissue-class mem-
bership level and which is implemented in the VBM toolbox.
Finally, the resulting images were smoothed with a Gaussian
kernel of 12 mm FWHM.
We performed voxel-by-voxel 1-way analysis of variance
with these grey matter images to test for differences in regional
grey matter concentration between control subejcts and pa-
tients. To avoid possible edge effects around the border be-
tween grey and white matter, only voxels with absolute grey
matter values above 0.15 were entered into the analysis. All sta-
tistical images were thresholded at p < 0.001 (uncorrected for
multiple comparisons), and only clusters with a minimum of
193 voxels are reported according to expected voxels per cluster
threshold (kE). To investigate an association between demo-
graphic and clinical data, Stroop performance data and altered
grey matter density, we performed a correlational analysis in
the patients, using SPSS 13.1 (SPSS Inc., Chicago, Ill.).
Combined fMRI-VBM analysis
To test the effect of structural brain changes on the blood
Wagner et al
Rev Psychiatr Neurosci 2008;33(3)
Fig. 1: Baseline greater than incongruent Stroop condition (p <
0.001, cluster size > 19). (A) HC subjects showed a relative deacti-
vation in the PCC and in the VMPFC/rACC and DMPFC. (B) MDD
patients revealed relative decreases in BOLD signal in the PCC
and DMPFC. (C) The direct comparison between patients and con-
trol subjects is displayed, revealing mainly a relative hyperactivity
in the rACC in patients during the incongruent Stroop condition.
BOLD = blood oxygen level dependent; DMPFC = dorsomedial
prefrontal cortex; HC = healthy control; MDD = major depressive
disorder; PCC = posterior cingulate cortex; rACC = rostral anterior
cingulate cortex; VMPFC = ventromedial prefrontal cortex.
Table 2: Activation of regions showing significant* blood
oxygenation level dependent signal increase in patients compared
with healthy control subjects in the incongruent Stroop condition
Region of activation R/LBA
Inferior frontal gyrus
Anterior cingulate gyrus
BA = Brodmannís area; L = left; R = right.
*p < 0.001, cluster size > 19.
rACC activation and orbitofrontal volume in MDD
J Psychiatry Neurosci 2008;33(3)
oxygen level dependent (BOLD) signal in the rACC/VMPFC,
we extracted the first eigenvariate (main component of the
PCA) from the resulting clusters of differences in grey matter
density and correlated these according to Pearson’s correla-
tion coefficient with parameter estimates from the fMRI
analysis, using SPSS 13.1. To confirm the significance of this
correlation, we used SPM2 to additionally perform a correla-
tional analysis between the contrast incongruent condition
greater than fixation baseline and the first eigenvariate of the
grey matter values from the OFC cluster in patients. We
masked this correlation with the contrast patients greater
than control subjects with regard to the incongruent condi-
tion (unmasked, p < 0.001) to correlate only voxels that were
statistically different between groups.
Moreover, we tested the hypothesis of decreased grey
matter density directly in the region of the functional activa-
tion difference, that is, in the rACC. For this purpose, we
created a region-of-interest image of the functional rACC
activation difference in patients and used this image as a
mask image in the VBM analysis, performing a small volume
In light of structural differences between patients with de-
pression and control subjects, we tested the significance and
robustness of the relative rACC hyperactivity in patients for
the contrast incongruent greater than fixation baseline while
controlling for the grey matter values from the OFC cluster
by means of analysis of covariance in SPM2.
Differences in grey matter
With regard to global grey matter alterations (in litres), there
were no significant differences between patients (mean 0.666,
standard deviation [SD] 0.062 L) and healthy control subjects
(mean 0.673, SD 0.058 L).
When we tested differences in regional grey matter density
between patients and healthy control subjects (p < 0.001), we
found 4 clusters of regional decreases in grey matter in pa-
tients with MDD, as displayed in Figure 2 and outlined in
Table 3. The largest cluster comprised voxels from the right
amygdala and right hippocampus formation (subiculum).
The second cluster consisted of voxels from the medial OFC,
including the left and right portion of the gyrus rectus
(BA 11). Additionally, we found a reduction of grey matter
volume in the subgenual cortex (BA 25) and in the left mid-
dle frontal gyrus (BA 8/9). Testing the hypothesis of de-
creased grey matter density directly in the rACC, we found
no significant difference between patients and healthy con-
trol subjects (small volume correction).
Relation to fMRI activation data
The detailed results of the functional MRI analysis are pre-
sented in detail elsewhere.11
Fig. 2: Regions of significant grey matter reduction in patients with major depressive disorder compared with
healthy control subjects (p < 0.001, cluster size > 192). Amy = amygdala; Hipp = hippocampal formation; MFG =
medial frontal gyrus; OFC = orbitofrontal cortex; SgC = subgenual cortex.
In Figure 1A and 1B, 1-sample t tests of the contrast fixation
baseline greater than incongruent Stroop condition are illus-
trated separately for patients and control subjects to display
brain areas of relative deactivation during Stroop perfor-
mance. Control subjects revealed a relative deactivation during
the incongruent condition in the PCC (x = 4, y = –54, z = 19;
p< 0.001; k = 870), in the dorsomedial PFC (x = –14, y = 55, z = 32;
p < 0.001; k = 486) and in the ventromedial PFC (x = –8, y = 48,
z = –6; p < 0.001; k = 276) including the rACC. Patients
showed a relative deactivation during the incongruent condi-
tion only in the PCC (x = –10, y = –51, z = 22; p < 0.001; k = 296)
and in the dorsomedial PFC (x = –12, y = –59, z = 30; p < 0.001;
k = 105). In agreement with the results of these 1-sample
t tests, the direct between-groups comparison of the incongru-
ent condition (Fig. 1C) revealed as a main finding a significant
relative hyperactivity in the rACC, as displayed in Table 2
and reported in our previous study.11
Testing our main hypothesis of a relation between this in-
ability of patients with MDD to deactivate the rACC during
the Stroop task and structural brain alterations, we found a
significant negative Pearson’s correlation between parameter
estimates in the rACC from the fMRI analysis and grey matter
values in the medial OFC (r = –0.62, p = 0.013) in patients and
not in healthy control subjects (r = –0.03, p = nonsignificant),
as illustrated in Figure 3. Both correlation coefficients were
significantly different (z = –1.74, p < 0.05). No significant cor-
relations resulted between rACC parameter estimates and
other brain areas of decreased grey matter density in patients.
Using SPM2 for the correlation between OFC grey matter
values and the contrast incongruent Stroop condition greater
than fixation baseline in patients, we observed, in accordance
with the SPSS analysis, a significant negative correlation only
in the rACC (x = –12, y = 45, z = 3; p < 0.05, familywise error
Controlling for the effect of decreased grey matter density
in the OFC, we still observed relative hyperactivity in the
rACC in patients with depression compared with healthy
control subjects with regard to the incongruent Stroop condi-
tion (x = –14, y = 52, z = –6; p < 0.001).
Relation to clinical variables and Stroop test performance
Controlling for the effects of age, we found no significant cor-
relations between illness duration, number of prior episodes
of depression and grey matter values in the regions of signifi-
cantly reduced grey matter in patients with MDD.
Wagner et al
Rev Psychiatr Neurosci 2008;33(3)
r (patients) = –0.62,
p = 0.013
r (controls) = –0.03,
p = n.s.
Parameter estimates in rostral ACC (BOLD signal)
Gray matter values of first eigenvariate from OFC
Fig. 3: The scatterplot depicts the correlation of the parameter estimates extracted from maximum activation in
the rACC and the grey matter values of first eigenvariate from the OFC in patients with depression and control
subjects. On the T1overlay, we mapped the cluster of decreased grey matter density in the OFC in patients and
the functional rACC cluster of relative hyperactivity in patients for the direct group comparison (incongruent
Stroop condition greater than fixation baseline). For better visualization, we used a threshold of p < 0.005 for the
functional overlay. ACC = anterior cingulate cortex; BOLD = blood oxygen level dependent; fMRI = functional
magnetic resonance imaging; OFC = orbitofrontal cortex; rACC = rostral ACC; VBM = voxel-based morphometry.
Table 3: Activation of regions showing significant* grey matter
reduction in patients with unipolar depression compared with
healthy control subjects
Orbitofrontal cortex (gyrus
rectus, BA 11)
Middle frontal gyrus (BA 8/9)
Subgenual cortex (BA 25) /
gyrus rectus (BA 11)
118316 –9–24 4.97
8502 –41 –28 4.43
BA = Brodmann’s area.
*p < 0.001, cluster size > 192.
rACC activation and orbitofrontal volume in MDD
J Psychiatry Neurosci 2008;33(3)
As we already stated in our previous paper,11we found no
significant association between symptom severity as assessed
by the Hamilton Depression Rating Scale (HAMD)27and
BOLD signal in the rACC.
Testing the relation between symptom severity and struc-
tural data, we found a significant negative correlation only
between decreased grey matter in the left middle frontal
gyrus and HAMD total score in patients (r = –0.66, p = 0.008,
adjusted with Bonferroni correction).
Controlling for the effect of BOLD signal in the rACC, we
found no significant correlations between regions of de-
creased grey matter density and Stroop interference score
(adjusted with Bonferroni correction).
The present study aimed to combine hemodynamic and mor-
phometric measurements to investigate whether potential
structural abnormalities in patients with MDD might be re-
lated to specific functional abnormalities in a cingulo-
prefrontal network.11The main result of the previous fMRI
study was that medication-free female patients with acute
depression revealed an absence of activity decrease in the
rACC (resulting in hyperactivation relative to baseline and to
healthy control subjects) that correlated positively with the
interference score in the Stroop task.
As we further investigated in the present paper, healthy
control subjects deactivated this region (in terms of signifi-
cantly lower BOLD signal during the incongruent condition
compared with fixation baseline) as well as the PCC and
DMPFC. These regions were previously shown to be part of
the so-called default-mode network and were consistently re-
ported to reveal a decreased blood flow or negative BOLD
signal during various cognitive tasks.16
Hence, the observed activation difference between patients
and healthy control subjects is not a simple difference in the
amount of activation above fixation baseline but represents,
rather, completely different activation directions. Patients
with depression were not able to suppress task-irrelevant ac-
tivity in the rACC, as was seen in healthy control subjects,
and therefore might have a disruption in the default-mode
Thus the question is, Why are patients unable to suppress
the interfering rACC/VMPFC activity? One potential expla-
nation might be structural changes (e.g., in grey matter in the
region of functional activation difference or in regions closely
connected with the rACC/VMPFC).
As a main finding of the current structural VBM analysis,
we observed significantly reduced regional grey matter den-
sity in several regions in patients with MDD. In addition to
extensive volume reductions in the left amygdala/hippocam-
pus formation, predominantly in the subiculum, left middle
frontal gyrus (BA 8/9) and subgenual cortex (BA 25), we
found a significant grey matter decrease bilaterally in the
gyrus rectus of the medial OFC (BA 11). We did not find a
significant between-groups difference in grey matter density
in the rACC/VMPFC area.
Most important, the combination of fMRI and VBM analy-
ses revealed the hypothesized relation between structural
and functional abnormalities in MDD patients in terms of a
significantly negative correlation only between decreased
grey matter values in the medial OFC and elevated BOLD
signal in the VMPFC/rACC during the Stroop task.
The morphometric findings of our study, which is to our
knowledge the first combined fMRI–VBM study in patients
with MDD, correspond to findings in several previous volu-
metric and postmortem studies: in a postmortem
histopathological analysis of the density and size of pre-
frontal neurons, significant reductions in DLPFC and OFC
regions were detected in MDD patients when compared
with healthy subjects.23
With regard to grey matter decreases in the OFC, an MRI
study by Bremner and colleagues22revealed a 32% volume re-
duction of the OFC (gyrus rectus) in patients with MDD.
Similar findings have been reported by Lacerda and col-
leagues.28Findings show that lesions in the OFC, which is
known to be critically involved in emotional processing (pre-
dominantly its medial parts15), are associated with abnormali-
ties in a wide range of affective behaviours, such as de-
pressed mood, aggression, affective instability, anxiety and
anhedonia. This indicates that volume reductions in this re-
gion might be etiologically related to the disorder of major
Likewise, volume reductions in the subgenual ACC have
been associated with MDD in an MRI volumetric study20and
in postmortem studies that revealed glial reduction in the
corresponding grey matter.21A recent multimodal study by
Pezawas and colleagues31also reported volume reductions in
the subgenual ACC in healthy subjects with a genetically in-
creased risk of depression. Alternatively, Pizzagalli and col-
leagues32did not find any morphometric differences in the
subgenual ACC in melancholic as well as in nonmelancholic
depression subjects relative to healthy control subjects, but
did find a reduced resting-state metabolism and increased
delta activity only in patients with melancholic depression.
Whereas some studies on amygdala volume in MDD patients
revealed glial cell and volume reductions,33,34Frodl and col-
leagues35demonstrated an increased amygdala volume in pa-
tients with a first depressive episode in comparison with pa-
tients with recurrent MDD and healthy control subjects, as
well as no differences between the latter 2 groups.
MRI studies of hippocampal volumes in MDD also lack
consistency. Thus, while several studies found no differences
between patients and healthy control subjects in grey matter
hippocampal volume,36,37several other studies revealed sig-
nificant reductions in grey matter volume in the hippocam-
pus formation in patients with MDD.38,39A meta-analysis by
Videbech and colleagues19reported an average 8% volume
reduction of the left hippocampus and an average 10% reduc-
tion of the right hippocampus in patients with MDD. Major
causes for the heterogeneity of these volumetric findings are
probably differences in scanning protocols (e.g., slice thick-
ness), in tracing procedures and in sample composition (e.g.,
sex and age of subjects).19
The lack of association between grey matter volume and
clinical variables such as illness duration is not surprising
given inconsistencies in earlier studies that investigated the
relation between illness duration or number of previous
episodes and the volume of a region of interest. MacQueen
and colleagues40found a significant logarithmic association
and Sheline and colleagues41a significant linear association
between hippocampus volume and total illness duration.
However, other studies35,38,42did not find any association be-
tween clinical variables and decreased volume in the hip-
pocampus or amygdala. For the OFC, in agreement with our
study, Bremner and colleagues22and Lacerda and colleagues28
reported no significant association between OFC volume de-
crease and clinical variables. Further, the lack of correlation
in our study might be attributable to the comparatively
smaller sample size, which might not be sensitive enough to
detect this kind of association, and a very small variance re-
garding past depressive episodes (range 0–3). The significant
negative correlation between HAMD total score and de-
creased grey matter density in the left middle frontal gyrus
should be interpreted with caution. It is difficult to relate
state-dependent variables such as acute symptoms of depres-
sion to relatively stable, long-term structural changes.
With regard to our focus of investigation, namely, the inte-
gration of structural and functional abnormalities, the corre-
lation between VMPFC/rACC BOLD signal (which was sig-
nificantly increased in patients owing to their inability to
deactivate this brain area during the incongruent Stroop con-
dition) and structural brain alterations yielded a significantly
negative result between VMPFC/rACC BOLD signal and
OFC grey matter values. Thus patients with a strong grey
matter volume reduction revealed a high BOLD signal in the
VMPFC/rACC, whereas patients with less distinct structural
abnormalities seemed to be better able to deactivate the
VMPFC/rACC during cognitive performance.
Given the strong anatomical interconnections between the
rostral part of the ACC and the medial OFC,43this finding
suggests that volumetric abnormalities in the medial OFC
might be a major factor influencing the patients’ reduced abil-
ity to deactivate the VMPFC/rACC and might be associated
with a potentially chronically increased signal in the rACC.
We concluded from our results that local grey matter dif-
ferences directly in the rACC do not lead to differences in
BOLD signal between healthy control subjects and patients
depression. Additionally, after controlling for the effect of de-
creased grey matter in the OFC, we still observed relative
rACC hyperactivity in patients with depression, compared
with healthy control subjects, with regard to the incongruent
Stroop condition, which provides compelling evidence for
functional abnormality in the rACC.
We therefore assume that, for the Stroop task, irrelevant
functional hyperactivity in the rACC of patients with depres-
sion might be explained by potential abnormal functional ac-
tivity in the OFC. Our fMRI sequence was not optimized to
acquire echo planar images with sufficient signal in basal
structures predominantly in the OFC, owing to local suscep-
tibility gradients near the air/tissue interface. Therefore, we
could not test this hypothesis of disrupted functional connec-
tivity and were not able to relate these potential functional
changes in MDD patients to observed local grey matter de-
creases. We can only speculate that grey matter decrease in
the OFC potentially leads to abnormal functional activity in
this region. This in turn may influence rACC activity. It
would be promising to test this hypothesis and to relate grey
matter decreases in these regions to functional activations
with an appropriate paradigm and optimized echo planar
The rACC bordering on the VMPFC constitutes the “affec-
tive” part of the ACC and has frequently been found to show
increased activity in healthy subjects during processing of
pain and affective stimuli (e.g., during experimentally in-
Moreover, the rACC/VMPFC interface constitutes part of
the so-called default network; it has previously been demon-
strated to decrease in activity in healthy subjects during cog-
nitive processing and to be abnormally activated in patients
with MDD during rest.17,31,45,46Our findings strongly suggest
that structural abnormalities might be at least partly respon-
sible for the inability of MDD patients to flexibly up- and
downregulate activation in this symptomatically relevant
area. Other parts of the default-mode network within the
frontocingulate areas (i.e., the DMPFC and PCC) decreased
their activity similarly in patients and healthy control sub-
jects during the incongruent trial, relative to fixation baseline,
indicating a normal functioning of these areas in MDD.
The VMPFC has been detected to play a relevant role in the
context of self-referential processing (e.g., when subjects have
to make judgements about their own abilities and traits).18
Thus our finding of a significantly increased signal in the
VMPFC (or the reduced ability to deactivate the VMPFC) in
patients with MDD seems plausible when it is taken into con-
sideration that increased (and predominantly negative) self-
referenced processing (in the form of automatic and unstop-
pable pondering about one’s own “inabilities” and “defective”
character traits) is a characteristic symptom of the disorder.
Consequently, our data strongly indicate that the reduced
ability of MDD patients to deactivate this medial perigenual
area, which encompasses the rACC and ventromedial pre-
frontal regions, might play a relevant role in the psy-
chopathology of the disorder. Further, the data suggest that
this functional disturbance might be closely related to struc-
tural abnormalities in more inferior regions that are anatomi-
cally closely connected to this region. Our results, moreover,
corroborate previous studies reporting structural abnormali-
ties in several limbic and cortical regions. However, the ques-
tion of whether these abnormalities are a cause or conse-
quence of the disorder remains to be elucidated and requires
Recapitulating our data and considering the substantial
anatomical connection of the medial OFC and VMPFC to lim-
bic structures such as the amygdala, subiculum and entorhinal
cortex,47the present fMRI VBM study revealed structural and
functional aberrations within this reciprocal network that is
mainly engaged in processing and integrating affective infor-
mation. Cognitive aspects of depression, such as rumination
and deficient cognitive control, as well as another accompany-
ing core symptom of depression, such as anhedonia (as a sign
of disturbance in the reward-processing network), may be
Wagner et al
Rev Psychiatr Neurosci 2008;33(3)
rACC activation and orbitofrontal volume in MDD
J Psychiatry Neurosci 2008;33(3)
directly related to disturbed connectivity within the
orbitofrontal-limbic network. Thus the inability to inhibit the
activity of the rACC together with the positive relation be-
tween the level of this activity and the amount of interference
in the Stroop task offer strong evidence for dysbalance of the
orbitofrontal-limbic network in controlling maladaptive affec-
tive and vegetative responses during cognitive processing that
is strongly related to structural lesions within this network.
Some potential limitations of the present study should be
mentioned. We studied only female patients, so our results
cannot be generalized to the whole population of patients
with depression. The rationale for this selection was to re-
duce the potential variance in BOLD signal due to sex effects.
Because male and female patients clearly differ with regard
to their illness characteristics, including illness severity and
concurrent symptoms (for a review, see Marcus and col-
leagues48), there is reason to assume that differences between
male and female patients also exist on the cerebral level.
However, potential sex differences in brain metabolism have
not to date been studied in patients with MDD. Because the
lifetime prevalence rates of depression are about 2 to 3 times
higher for women than men, the results of our study can be
generalized to most patients with depression.
Further, the limitations of the VBM method should be men-
tioned. VBM strongly depends on correct segmentation and
classification of brain tissue types. Moreover, to statistically
compare the grey matter images between groups, they have to
be registered to a common anatomical space. Thus either sys-
tematic tissue classification differences between groups or reg-
istration error may produce between-groups effects that are
not attributable to real differences in grey or white matter.49
Conversely, VBM represents an unbiased, objective and com-
prehensive method for testing differences in local composition
of brain tissue after global shape differences are discounted.
The VBM method is an established tool in morphometry and
was successfully applied in various studies with neurologic or
psychiatric patients.31,50,51The validity of the methods can be
shown (e.g., Keller and colleagues’52comparison of hippocam-
pus volume with VBM and manual segmentation).
Despite these limitations, our results provide strong evi-
dence for an association between functional and structural
abnormalities in patients with MDD. Further studies with a
larger number of patients are needed to further elucidate the
nature of this relation.
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Acknowledgements: We thank all the patients and control subjects
who participated in this study.
This work was supported by an IZKF program grant of the
Friedrich-Schiller-University of Jena (TMWFK B30701-015/-016)
and the Bundesministerium für Bildung und Forschung BMBF
Competing interests: None delcared.
Contributors: Drs. Wagner, Sauer and Schlösser designed the study.
Dr. Wagner and Ms. Schachtzabel acquired the data, which Drs. Wag-
ner, Koch, Reichenbach and Schlösser analyzed. Drs. Wagner, Koch
and Schlösser wrote the article, and Drs. Koch, Reichenbach, Sauer
and Schlösser and Ms. Schachtzabel revised it. All authors gave final
approval for the article to be published.
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