Neural correlates of ‘pessimistic’ attitude
U. Herwig1,2*, A. B. Bru ¨hl1, T. Kaffenberger1,2, T. Baumgartner3,4, H. Boeker1and L. Ja ¨ncke3
1Psychiatric University Hospital Zu ¨rich, Switzerland
2Department of Psychiatry, University of Ulm, Germany
3Department of Neuropsychology, University of Zu ¨rich, Switzerland
4Institute for Empirical Research in Economics, University of Zu ¨rich, Switzerland
Background. Preparing for potentially threatening events in the future is essential for survival. Anticipating the
future to be unpleasant is also a cognitive key feature of depression. We hypothesized that ‘pessimism’-related
emotion processing would characterize brain activity in major depression.
Method. During functional magnetic resonance imaging, depressed patients and a healthy control group were cued
to expect and then perceive pictures of known emotional valences – pleasant, unpleasant and neutral – and stimuli of
unknown valence that could have been either pleasant or unpleasant. Brain activation associated with the ‘unknown’
expectation was compared with the ‘known’ expectation conditions.
Results. While anticipating pictures of unknown valence, activation patterns in depressed patients within the medial
and dorsolateral prefrontal areas, inferior frontal gyrus, insula and medial thalamus were similar to activations
associated with expecting unpleasant pictures, but not with expecting positive pictures. The activity within a majority
of these areas correlated with the depression scores. Differences between healthy and depressed persons were found
particularly for medial and dorsolateral prefrontal and insular activations.
Conclusions. Brain activation in depression during expecting events of unknown emotional valence was comparable
with activation while expecting certainly negative, but not positive events. This neurobiological finding is consistent
with cognitive models supposing that depressed patients develop a ‘pessimistic’ attitude towards events with an
unknown emotional meaning. Thereby, particularly the role of brain areas associated with the processing of cognitive
and executive control and of the internal state is emphasized in contributing to major depression.
Received 12 November 2008; Revised 26 May 2009; Accepted 16 July 2009; First published online 7 September 2009
Key words: Depression, emotion processing, functional neuroimaging, insula, pessimism, prefrontal cortex.
Anticipation is a basic human cognitive function
involving the preparation for future events (Gilbert &
Wilson, 2007). As we do not know what the future
holds, we prepare for expected events in order to deal
with the associated pleasant or unpleasant outcome.
To be able to cope, it makes sense to consider the
worst-case scenario. This appears to be valid also from
an evolutionary perspective, as our antecedents had
a better chance to survive when they were prepared
to cope, for instance, with predators or a hard winter.
Thus, pessimism, meaning to expect the disadvan-
tageous outcome when facing events of unknown
emotional impact, seems to have positive facets
(Nesse, 2000), such as diminishing of risk behaviour
(Gibson & Sanbonmatsu, 2004) and avoidance of dis-
appointment by setting low expectations (Norem &
Cantor, 1986; Shepperd & McNulty, 2002). However,
the overly pronounced expectation that the future will
be unpleasant also represents a key cognitive feature
in major depression (Pyszczynski et al. 1987; Lavender
& Watkins, 2004). This is expressed in the concept of
the cognitive triad which comprises a negative atti-
tude towards oneself, the environment and the future
(Beck, 1967). Recent reports have shown an altered
emotion processing in depression compared with the
healthy state concerning the perception and also the
anticipation of emotional events (e.g. for reviews,
see Drevets, 2001; Davidson et al. 2002; Phillips et al.
2003; Leppanen, 2006; for recent reports, see Keedwell
et al. 2005; Abler et al. 2006; Johnstone et al. 2007;
Langenecker et al. 2007; Lee et al. 2007; Dannlowski
et al. 2008; Fales et al. 2008; Grimm et al. 2008; Knutson
et al. 2008; Mitterschiffthaler et al. 2008). However, the
* Address for correspondence: U. Herwig, M.D., M.A., Psychiatric
University Hospital, University of Zu ¨rich, Lenggstrasse 31, CH – 8032
Zu ¨rich, Switzerland.
Psychological Medicine (2010), 40, 789–800.
f Cambridge University Press 2009
direct comparison of anticipating events of known
positive and negative valence with an unknown
valence as a model of ‘pessimistic’ expectation has
not yet been performed in depressed patients. In a
previous report in healthy subjects, we demonstrated
that in the case of expecting an event of unknown
emotional valence, emotion processing brain areas are
activated in a way that is comparable with the expec-
tation of an event known to be unpleasant but not with
that of an event known to be positive (Herwig et al.
2007b). Further, distinct activations in that study
correlated with individual depressiveness: the more
depressed, the higher the activity. This finding of a
‘pessimistic’ bias towards expected unknown emo-
tional events may be interpreted as a neural correlate
of our propensity to prepare for a negative outcome.
Given this context, we hypothesized that patients with
major depression would show a ‘pessimistic’ bias in
their brain activation as measured with functional
magnetic resonance imaging (fMRI), meaning a higher
activation in key brain regions during the expectation
of events with negative and unknown valence than
when expecting neutral or positive events. Those ac-
tivations also were assumed to be more prominent in
depressed patients compared with healthy subjects.
Apart from the regions found in the healthy subjects to
be related to ‘pessimism’, regions of key interest were
also those known to be affected in depression and
involved in planning and emotion processing, par-
ticularly the amygdala, dorsolateral prefrontal cortex
(DLPFC), medial prefrontal cortex (MPFC) and an-
terior cingulate cortex (ACC) (e.g. Baxter et al. 1989;
Fuster, 2000; Phillips et al. 2003; Paulus et al. 2005;
Vogt, 2005; Abler et al. 2006; Siegle et al. 2007; Knutson
et al. 2008).
A total of 16 in-patients (14-included in analysis) with
a current diagnosis of a major depressive episode
were recruited at the Psychiatric University Hospital
of Zurich, Switzerland (for demographic and psycho-
metric data, see Table 1). A diagnosis of mildly to
moderately severe depressive episode was made
by trained psychiatrists according to ICD-10 and
DSM-IV criteria. Psychiatric Axis I and other co-
morbidities such as neurological disorders and MRI
contraindications were excluded in a semi-structured
interview prior to scanning. After receiving complete
description of the study, all participants gave writ-
ten informed consent. The study was approved by
the local ethics committee. The patients were on
stable antidepressant medication. They had been off
benzodiazepines and neuroleptics for at least four
half-lives, and they were not taking any mood-
on its own and it was additionally compared with
a group of 14 healthy subjects from a previous report
(Table 1; Herwig et al. 2007b).
During fMRI scanning, the patients performed a
cueing task (programmed with PresentationTM, Neuro-
behavioral Systems, USA) consisting of 56 trials with
expectation and presentation of emotional pictures
(Fig. 1). The trials comprised of two main conditions:
‘known’ or ‘unknown’. The ‘known’ condition con-
sisted of three subconditions (negative, positive,
neutral). For each trial of the ‘known’ subconditions a
small cue was presented that depicted either a smiling
‘^‘ (‘positive’ or ‘pleasant’, ps), a non-smiling ‘_‘
(‘negative’ or ‘unpleasant’, ng) or a neutral symbol
‘x‘ (nt) that indicated the emotional valence of the
pictures presented after an anticipation period. In the
‘unknown condition’, ‘j‘ (uk), either pleasant or un-
pleasant pictures appeared randomly. The cues were
of 1/40 of screen height and the pictures filled the
screen. The cues were presented for 1000 ms followed
by an anticipation period of a further 6920 ms [cue and
Table 1. Demographic and psychometric data of included subjects
Mean age, years (S.D.)40.4 (10.7) 27.6 (3.6)
Mean scale scores (S.D.)
S.D., Standard deviation; BDI, Beck Depression
Inventory; HAMD, Hamilton Depression Scale; MADRS,
Montgomery–A˚sberg Depression Rating Scale; SDS,
Self-rating Depression Scale (score<50: not depressed).
aDifference by t test.
790 U. Herwig et al.
anticipation: four times of MR volume repetitions;
repetition time (TR) 1980 ms], during which a blank
screen with a small fixation point was shown. Sub-
sequently, emotional pictures (International Affective
Picture System; Lang, 1995) were presented for
7920 ms (4 TRs). During the following baseline period
of 15840 ms (8 TR) the blood oxygen level-dependent
signal could wear off before the next trial. Altogether,
56 pre-cued pictures were shown, 14 for each ‘known’
trial as positive, negative and neutral, and 14 for ‘un-
known’ (seven ps, seven ng). The different trials ap-
peared in a randomized order. All participants were
instructed to expect the emotional stimuli after the cue
and to be aware of the emotional valence indicated,
and to subsequently look at the following picture. The
stimuli were matched for complexity, content of faces,
scenery, food and nature, and concerning intensity of
positive and negative valence with the same difference
in valence ratings from neutral. Arousal was matched
as far as possible for pleasant and unpleasant stimuli
(Herwig et al. 2007a). All participants rated the pres-
ented pictures after the scanning according to the
subjective valence on a visual analogue scale (1 most
negative, 9 most positive).
fMRI acquisition and data analysis
Imaging was performed with a 1.5 T Siemens Sonata
whole-body scanner (Erlangen, Germany) equipped
with a head coil. T1* weighted anatomical volumes
(1r1r1 mm) were acquired for co-registration with
the fMRI. T2* weighted functional magnetic resonance
images were obtained using echoplanar imaging in an
axial orientation (image size 64r64 pixels, 22 slices
covering the whole brain, field of view of 220 mm, flip
angle 90x, slice thickness 4 mm with 1 mm gap, voxel
size 3.4r3.4r5 mm, repetition time/echo time (TR/
TE) 1980/40 ms, 908 volumes). The subjects watched
the stimuli in a mirror attached to the head coil and
directed to a screen onto which the stimuli were pro-
jected by a video beamer.
fMRI data were analysed using BrainVoyagerTM
QX 1.8.6 (Brain Innovation, The Netherlands). Pre-
processing included motion correction, slice scan
time correction, high-frequency temporal filtering and
removal of linear trends. Functional images were
superimposed on the two-dimensional anatomical
images and incorporated into three-dimensional (3D)
datasets. The individual 3D datasets were transformed
into Talairach space (Talairach & Tournoux, 1988)
resulting in a voxel size of 3r3r3 mm and then
spatially smoothed with an 8 mm Gaussian kernel
for subsequent group analysis. Eight predictors rep-
resenting the expectation (exp) and presentation (pres)
of each valence (ng, uk, ps, nt) were used to build
the design matrix. Expectation period and picture
presentation periods were modelled as epochs using
the standard two-c haemodynamic response function
provided by BrainVoyager (Glover, 1999).
The fMRI data analysis based on the general
linear model (GLM) comprised of the following steps:
Fixed-effects analyses were calculated separately for
each subject for the six contrasts comparing the emo-
tion expectation conditions ‘negative versus neutral’,
‘positive versus neutral’, ‘unknown versus neutral’,
‘unknown versus negative’, ‘unknown versus positive’
and ‘negative versus positive’, resulting in summary
images. The summary images were subjected to
second-level analyses, separately for both the groups
of the depressed patients and of the healthy subjects.
Addressing our main question to evaluate which of
the ‘known’ emotion expectation conditions (ng, ps,
nt) revealed activations similar to those in the ‘un-
known’ expectation condition (uk), we applied con-
junction analyses based on the single contrasts. These
were done with fixed-effects conjunction analyses with
separate subject predictors in order to address the
Fig. 1. Experimental task. Cues, presented for 1000 ms,
indicated the valence of the picture which appeared after a
delay of a further 6920 ms: ‘^‘, prior to a ‘pleasant’ picture;
‘_‘, prior to an ‘unpleasant’ picture; ‘x‘, prior to a
‘neutral’ picture; and ‘j’, prior to a picture of ‘unknown’
valence, either pleasant or unpleasant. The cues have been
enlarged here for presentation purposes.
Neural correlates of ‘pessimism’ in depression791
minimum-t problem (Nichols et al. 2005). We defined
‘unknown’ expectation-related activity in a certain
brain region as being similar to one of the ‘known’
expectation-related activations, when in this region
both activations were significantly different from the
activations associated with both remaining ‘known’
emotion expectation conditions, but were not different
in the corresponding single contrast. For example,
addressing similarity of the ‘unknown’ and the
‘negative’ condition, the ‘unknown’ condition had
to differ significantly from ‘positive’- (contrast exp
uk>ps) and also ‘neutral’ (exp uk>nt)-related ac-
tivity, and ‘negative’ also had to differ from ‘positive’
(exp ng>ps) and ‘neutral’ (exp ng>nt) expectation-
related activity. These contrasts therefore also com-
prised the direct comparisons between the ‘known’
expectation conditions as ‘negative versus positive’.
The revealed brain regions further should not differ in
the direct comparison, for instance when using the
contrast exp ng>uk.
Accordingly, the following conjunctions were ana-
(1) The ‘pessimism-contrast’: expecting unknown
events to be negative should be reflected by ac-
tivity during exp uk resembling the activity during
exp ng, but differ from ps and nt: exp uk>ps and
uk>nt and ng>ps and ng>nt.
(2) The ‘optimism-contrast’: assuming the upcoming
unknown event to be positive, the brain activity
during the exp uk should be similar to the activity
during exp ps: exp uk>ng and uk>nt and ps>ng
(3) The ‘indifference-contrast’: if subjects anticipate
‘unknown’, thus either positive or negative events,
like neutral events, brain activity might be similar
to the ‘neutral’ expectation: exp uk>ng and
uk>ps and nt>ng and nt>ps.
The statistical threshold for these conjunctions was
set at a level of p<0.001 (uncorrected considering the
conjunction approach with the application of four
single contrasts together) with a cluster size of 135
voxels of 1r1r1 mm corresponding to 5 voxels of
3r3r3 mm. The results obtained from the healthy
subjects have been reported previously (Herwig et al.
2007b). For the depressed patients, further explorative
results with lower cluster size are reported when they
complied with the results from the healthy subject
group. An analysis of the presentation period and
main-effect analyses of emotion and expectation were
performed on an exploratory basis not reported here.
Questionnaires and correlation statistics
The patients completed a handedness questionnaire
(Annett, 1967) and a depression self-rating [Beck’s
Depression Inventory (BDI); Beck et al. 1961]. Further,
depressiveness was assessed by the 21-item Hamilton
Depression Scale (HAMD; Hamilton, 1960) and
the Montgomery–A˚sberg Depression Rating Scales
(MADRS; Montgomery & A˚sberg, 1979). Immediately
after scanning, the patients rated the emotional val-
ence of the pictures (presented again as printouts) on
a visual analogue scale. Using Pearson’s correlation,
we correlated the rating score results of the depression
scales with the individual b-weights (mean from all
voxels of the respective activated cluster) of the emo-
tion expectation conditions in those regions resulting
from the conjunction analyses. Thus, within the
regions of interest (ROIs) derived from the conjunc-
tion analyses, we correlated the different individual
b-weights of the emotion conditions in each ROI with
the individual psychometric data. In order to control
for an influence of age, we also correlated the
b-weights with the age in both groups, healthy and
depressed participants, and performed an exploratory
partial correlation analysis with age as the control
Comparison between depressed patients and
Activations in depressed patients and healthy subjects
were compared. Within the activated clusters in the
depressed patients and in the healthy subjects ran-
dom-effects analyses of the ‘emotion versus neutral’
contrasts were performed by using separate subject
predictors and implementing the factor of being de-
pressed or healthy in the GLM. Additionally, we ex-
plored group differences of the single contrasts in the
bilateral insula based on ROIs derived from the con-
trast ps>nt in the depressed patients in order to assess
whether failing to find hypothesized activations in the
‘pessimism’-contrast might be due to an activation
during the positive expectation.
Participants and behavioural data
From the 16 depressed patients, one had to be ex-
cluded because of movement artefacts (>3 mm in at
least one direction) and one patient reported after
scanning that she had not been able to identify the
cues correctly. Thus, 14 depressed patients were en-
tered into the analysis. All were right-handed. They
were also compared with 14 healthy subjects (Herwig
et al. 2007b), who were younger than the patients.
The picture ratings were not different (Table 1).
Medication in the depressed patients included mirta-
zapin (15–45 mg, n=5), venlafaxin (75–150 mg, n=2),
792 U. Herwig et al.
citalopram/escitalopram (60/20 mg,n=2), citalopram/
escitalopram (20–40 mg) plus mirtazapin (30–60 mg)
(n=3), trazodone (100 mg, n=1) and no medication
Conjointly activated areas during ‘unknown’ and
‘known’ emotion expectation
We performed conjunction analyses to discover which
of the ‘known’ emotion expectation conditions re-
vealed activations similar to those in the ‘unknown’
condition. Regarding the comparison ‘negative’ and
‘unknown’ in the depressed patients we found ac-
tivity within the MPFC [Brodmann area (BA) 8], left
DLPFC (BA 9/46), bilateral inferior frontal gyrus (IFG,
BA 45) and insula (BA 13), in a region adjacent to the
anterior thalamus and head of the caudate nucleus
best fitting the area comprising the bed nucleus of
the stria terminalis (BNST; being aware that this
structure is small for the applied fMRI resolution), in
the anterior and medial thalamus, and in the nucleus
ruber (NR; Table 2, Fig. 2). These areas were not
different in the direct contrast exp ng>uk in either
direction. The equivalent analyses of the relation
of ‘unknown’ and ‘positive’ expectation (‘optimism-
contrast’) and of ‘unknown’ and ‘neutral’ expectation
(‘indifference-contrast’) did not deliver any results
even at a level of p<0.01 uncorrected. Other regions
such as the amygdala were active in the single emotion
expectation contrasts not reported here. Results
from the healthy subjects have been reported earlier
(Herwig et al. 2007b). In brief, activated areas in that
group in the ‘pessimism’-contrast were within the
right IFG, insular regions, medial thalamus, BNST re-
gion, NR and temporo-occipital cortex.
Correlation of brain activation with
The assumption was made that subjects with a higher
level of depressiveness may exert stronger activity in
areas associated with ‘unknown’ and ‘negative’ ex-
pectation. We tested this by correlating psychometric
data obtained from the BDI, HAMD and MADRS with
the mean b-weights obtained from the significantly
activated clusters of the conjunction analyses (one BDI
missing). This analysis revealed significant positive
correlations in the MPFC, left DLPFC, IFG/insula
regions and NR during ‘unknown’ and ‘negative’
expectation (Fig. 2, Table 2). We did not find any cor-
relation of the activations with age, neither in the de-
pressed, nor in the healthy group, and the exploratory
correlation analysis controlled for age provided es-
sentially equivalent results as without this control
Comparison between depressed patients and
We compared the activity in the revealed clusters from
the conjunction analysis in the depressed patients with
the activations in healthy subjects (Fig. 3, Table 2).
Compared with the healthy subjects, depressed pa-
tients showed increased activations during both the
negative and unknown conditions in the left DLPFC
and anterior MPFC, and for the unknown conditions
also in the bilateral IFG/insular regions and left BNST.
Concerning regions activated in healthy subjects but
not in the patients, the right BNST (p=0.04) and left
insula (p=0.04) were more strongly activated in the
respective contrasts in the healthy subjects. The ex-
ploratory analysis of group differences in the single
contrasts within the ROIs based on the ps>nt contrast
found a stronger insular activation in the depressed
patients (see Supplementary Fig. 1, available online).
Assuming a ‘pessimistic’ attitude in depression when
expecting upcoming events, our hypothesis was that
patients with major depression would show brain ac-
tivation while expecting events of unknown emotional
valence as if these events are known to be unpleasant.
Further, we assumed that distinct emotion-processing
brain areas known to be affected in depression would
be activated differently compared with healthy sub-
jects. Our main findings were: (i) while anticipating
pictures of unknown emotional valence, the brain ac-
tivity resembled that observed when expecting pic-
tures known to be negative but not when expecting
positive or neutral pictures; (ii) the activity within a
prominent part of the corresponding brain regions,
particularly within the DLPFC, MPFC and insula/IFG
correlated with the grade of depression; and (iii) the
activation in these regions differed significantly from
that in healthy subjects. This supports the assumption
of considering a negative outcome for future scenarios
to form a key cognitive feature of depression with
distinct neural representations.
Brain regions involved in ‘pessimistic’ expectation
Activations within the DLPFC and MPFC were as-
sociated with ‘pessimistic’ expectation in depressed
patients, which was not the case in the healthy sub-
jects. Further, the activity in these areas correlated
with the depression scores: the more depressed, the
higher the activation. Notably, the activation of the
DLPFC differed between the groups in all, and in
the anterior MPFC in most of the contrasts. This pro-
vides evidence that the ‘pessimistic’ expectation in
Neural correlates of ‘pessimism’ in depression793
Table 2. Conjunction analyses of emotion expectation contrasts, correlations of b-weights with rating scores, and comparison of depressed and healthy groups
Depressed patients: uk and ng>ps and nta
Groups: depressed v. healthy, Fig. 3, p
(x, y, z)tmax
DLPFC L46 1021
x39, 31, 294.00.68
2a 0.03 0.0030.002 0.0001
DLPFC/PMC L6/9 2161
x46, 5, 36 4.6 0.110.06 0.080.02
x47, 20, 2 4.32b 0.005 0.040.030.25
IFG/insula R45/13709 41, 24, x2 4.3 0.420.13 0.800.37
x31, 17, x9 4.20.22 0.19 0.0070.03
MPFC ant R/L8 414 0, 32, 413.9 0.35 0.410.040.21
MPFC post R/L8 512 1, 7, 544.30.640.060.320.04
BNST region L 392
x11, 0, 12 4.50.710.110.820.01
45 37 40, 18, 103.72c 0.710.470.24 0.07
1121, x14, 5 3.82d 0.110.67 0.180.23
29 8, x21, x10 3.92e 0.210.96 0.710.46
uk, Unknown expectation; ng, negative expectation; ps, positive expectation; nt, neutral expectation; BA, Brodmann area; BDI, Beck depression inventory; HAMD, Hamilton
depression scale; MADRS, Montgomery–A˚sberg depression rating scale; DLPFC, dorsolateral prefrontal cortex; L, left; PMC, premotor cortex; IFG, inferior frontal gyrus; R, right;
MPFC, medial prefrontal cortex; ant, anterior; post, posterior; BNST, bed nucleus striae terminals.
On the right, results from the random-effects group comparison of activations within the regions of interest from the ‘pessimism’-contrast.
aActivated regions according to the conjunction analysis of expectation ‘unknown’ and ‘negative’ stimuli, both versus expecting ‘positive’ and versus ‘neutral’ stimuli. Indicated are:
the amount of voxels (mm3); Talairach coordinates (x, y, z) of the centre of mass of the activation; and maximal t-values of the voxels within the regions.
bResults from explorative analysis.
U. Herwig et al.
r = 0.73, p=0.003
r = 0.55, p=0.04
r = 0.51, p=0.06
r = 0.57, p=0.035
r = 0.67, p=0.01
0.5 % signal change
0.5 % signal change
0.5 % signal change
0.5 % signal change
0.5 % signal change
Fig. 2. Comparison of ‘known’ and ‘unknown’ expectation. Conjunction analysis of the conditions ‘unknown’ and
‘unpleasant’ expectation versus ‘pleasant’ and versus ‘neutral’ (exp uk>ps and uk>nt and ng>nt and ng>ps). The activated
voxels were co-registered using structural magnetic resonance imaging and colour coded (consider cross-hair, see coloured
version of this figure in Supplementary online material) according to their significance (t-value). Presented are coronal (COR)
slices of (a) the left dorsolateral prefrontal cortex (DLPFC L), (b) the right inferior frontal gyrus (IFG R), (c) the left IFG (IFG L),
(d) the medial thalamus (Med Thal) and (e) the right nucleus ruber (NR R) and cut-outs of the axial slices of the thalamus
and NR R in the lower left of the respective pictures. Further, on the right, the time courses of the activities within the
marked regions of interest are shown in percentage BOLD signal change, indicating the conjoint activity of the ‘unpleasant’
expectation with the ‘unknown’ expectation. The vertical grey bars represent the beginning of the expectation (Expect) and
presentation (Present) periods, comprising each four volumes. When interpreting the time courses, the delayed haemodynamic
response function has to be considered. Further, the correlations of the b-weights of the activity during the ‘unknown’
expectation condition with the Hamilton depression scores (HAMD) are presented.
Neural correlates of ‘pessimism’ in depression 795
depression may be associated with the functional
domains of the DLPFC and MPFC as a final evaluation
of situations, response planning, and cognitive and
executive control (Fuster, 2000; Gross & John, 2003).
The DLPFC has been associated with hypometabolism
in depression (Soares & Mann, 1997), or with hypo-
functionality in cognitive tasks (Siegle et al. 2007),
possibly leading also to compensatory activation
(Harvey et al. 2005). One may assume that DLPFC re-
sources in depression might be absorbed due to a bias
towards depressive cognition by focusing on corre-
sponding situations and stimuli (Grimm et al. 2008),
for instance, due to a negative attitude towards future
events according to the cognitive triad (Beck, 1967).
This may be represented within neural network
concepts by information processing modules in the
DLPFC acting as attractors (Yuste et al. 2005) for de-
pressive cognition. We also found the MPFC to be ac-
tive during unknown and negative expectation, with
the ‘unknown’-related activity being more prominent
in depressed than in healthy subjects. Whereas the
DLPFC is involved in evaluating and preparing action
in the external world (Fuster, 2000), the MPFC was
reported to be involved in the cognitive control of
internal emotional processes (Gross & John, 2003;
Herwig et al. 2007a). It might be recruited in de-
pression in order to exert cognitive control onto sub-
cortical emotion-associated areas, possibly with an
ineffective compensatory over-activation. Basically,
a complex disturbance of the information processing
within and between functional systems for integrating
emotional–cognitive information is assumed (Pessoa,
2008). In this context, one may consider primary
modulating regions on emotion processing such as the
DLPFC or the amygdala working as ‘connector hubs’
for information processing (Sporns et al. 2007).
In our previous study with healthy subjects, we
found the IFG, insular regions and the medial thala-
mus to be associated with ‘pessimistic’ expectation
(Herwig et al. 2007b). This was essentially also the case
in the depressed patients, with the exception that
certain insular regions revealed different activation
patterns. The IFG, in the region of the ventrolateral
prefrontal cortex, was assumed to represent multi-
modal sensory cues with high emotional salience
(Yamasaki et al. 2002) and to be involved in emotional–
cognitive integration (Mayberg, 2003). It may provide
a link between the evaluation of the internal state as-
sociated with an emotional situation and its cognitive
processing, for instance, by propagating ‘internal’ in-
formation to upstream prefrontal areas. Medial thal-
amic regions receive input from viscero-sensitive and
pain-mediating brainstem areas and are considered
to form a relay within the visceroceptive pathway
towards, for example, insular regions (Craig, 2002;
Vogt, 2005). The insula was found to be involved in
the processing of multimodal sensory and emotional
stimuli, supporting views of a general role of the
insula in emotion processing (Damasio et al. 2000;
Calder et al. 2001; Craig, 2002; Critchley et al. 2004;
Paulus & Stein, 2006; Simmons et al. 2008). It was
proposed that the physical sensation of emotional re-
sponses depends on sensations from the viscera re-
presented in the insula (Critchley et al. 2004). In this
context, the insula may be involved in the mediation of
bodily viscero-sensitive signals for decision making
and behavioural planning according to emotional va-
lences. We found activations in the depressed patients
during both the ‘unknown’ and the ‘negative’ expec-
tation as hypothesized, but also increased activation
during the ‘positive’ expectation compared with the
healthy subjects. This may be interpreted as an insular
*0.03 **0.002 **0.005*0.03 0.22**0.0070.35 *0.04
Fig. 3. Comparison of activity in regions of interest (b-weights) in depressed patients ( ) compared with healthy subjects (%).
Values are means, with standard errors represented by vertical bars. For the different regions and conditions, p values are given
for the difference between the depressed and healthy subjects (* p<0.05, ** p<0.01). DLPFC L, left dorsolateral prefrontal cortex;
exp uk, expectation unknown; exp ng, expectation negative; MPFC, medial prefrontal cortex; IFG L, left inferior frontal gyrus;
IFG R, right inferior frontal gyrus.
796U. Herwig et al.
‘unpleasantness’-signal not only during ‘negative’ or
‘unknown’ expectation but also during ‘positive’ ex-
pectation, and may be associated with anhedonia
(Keedwell et al. 2005). Being depressed is often associ-
ated with unpleasant somatic feelings and a negative
self-perception. This may result from a dysregulation
of interoceptive areas such as the insula due to a mis-
interpretation of external cues based on unpleasant
previous experiences, inducing subjective unpleasant-
ness (Davidson et al. 2003). These considerations lead
to further concepts of the insula to be involved in
self-representation and ‘self-awareness’ (Churchland,
2002; Craig, 2002) and to disturbed ‘self’ functions in
depression (Northoff & Bermpohl, 2004).
At the brainstem level, we found, in both the de-
pressed and the healthy group, a region covering the
NR to be associated with ‘negative’ and ‘unknown’
expectation. The NR has been assumed to be involved
in psychomotor modulation and in behavioural at-
tendance (Horn et al. 2002). During expectation, it may
prime or facilitate the readiness for a later motor re-
Two main brain regions hypothesized as being as-
sociated with functional disturbance in depression
were not found to be activated in the ‘pessimism’-
contrast: the amygdala (e.g. Abler et al. 2006; Lee et al.
2007) and the ACC (Bermpohl et al. 2006; Nitschke
et al. 2006). For the amygdala, this might be explained
by the fact that it also showed activation during the
positive expectation condition (Herwig et al. 2007b)
and thus not fulfilling the criteria for the ‘pessimism’-
contrast but being more generally associated with
valence-independent emotional arousal (Anderson
et al. 2003; McClure et al. 2004). However, though
being difficult to distinguish anatomically, a region
covering and best fitting the bed nucleus of the stria
terminalis was activated in the ‘pessimism’-contrast.
This region was considered to form a functional
unit with the ‘extended’ amygdala (Heimer & Van
Hoesen, 2006) and may be a link to further emotion-
processing circuits. The ACC may be activated more in
the context of conflict monitoring between functional
state and perceived new information with potential
affective or motivational consequences (Carter et al.
2000; Vogt, 2005) and not in the specific context of
Principally, one may assume that a circuit for bias-
ing the organism towards potentially disadvantageous
or even dangerous events makes evolutionary sense.
Whenever we may also have an optimistic bias for
certain personal long-term attitudes towards the
future (Sharot et al. 2007), the chances of survival for
our early ancestors who for instance anticipated a
predator when hearing a rustling sound in the vicinity,
and prepared for it appropriately, were conceivably
higher than for those who did not. Hence, one may
speculate that a certain degree of depressiveness may
be of evolutionary advantage (Nesse, 2000; Panksepp,
2006), in that uncertain future events are more likely
to be evaluated as unpleasant and that the person is
better prepared for when negative events actually do
In reflecting on possible limitations, we addressed the
issue of the differing age of both groups. Whenever
the main analysis of this report was based on the
depressed group, we also performed a group com-
parison with the healthy subjects. One may argue
that the higher activation in the depressed patients
might be accounted for by their higher age. This,
however, would be in contrast with findings of atten-
uated emotion processing-related brain activity with
increasing age (Erk et al. 2008). Furthermore, age-
dependence is unlikely in view of the fact that the
activations correlated with depressiveness, but not
with age, which would have been the case if age had
an influence on the activation. The same holds true for
the medication in the depressed patients. The fact of
being medicated does not explain the correlations with
psychopathology, such that depressiveness, not age
or medication, can be accounted for by our results.
Nevertheless, our findings should be interpreted as
applying to medicated patients because any influence
of medication on activations cannot be excluded
Emotional arousal (McClure et al. 2004) or experi-
ence of uncertainty (Simmons et al. 2008) may also
contribute to the revealed activation. However, again,
the correlations with depressiveness point to an as-
sociation of the activation with depression and not to
these factors. Further, valence-independent arousal
would also have occurred through positive expec-
tation and thus would have led to non-fulfilling
the criteria of ‘pessimism’. Nevertheless, uncertainty
and heightened arousal towards unpleasant events
might be inherent factors for ‘pessimistic’ expectation
(Simmons et al. 2008).
The experimental task was designed to focus
on the mental process during expectation. Therefore,
the highly abstract and graphically comparable cues
were intuitively understandable, so that no prominent
working memory component was necessary to estab-
lish their meaning. Further, no motor reaction was re-
quired, the preparation and exertion of which might
have interfered with processes of emotional antici-
pation. However, the task thus did not comprise an
implemented behavioural control. We decided not to
use such a control, for instance by motor reaction, in
Neural correlates of ‘pessimism’ in depression 797
order to avoid interfering and noisy other brain acti-
vation. On the other hand, a behavioural measure im-
plemented in our task demonstrating a ‘pessimistic’
bias also on the level of behavioural outcome could
have further strengthened the assumption of ‘pessi-
mistic’ expectation in depression. However, here we
focused on the neural correlates considering that
neural aspects, and also subjective emotional experi-
ence, must not necessarily be reflected by observable
behaviour. We asked the subjects and patients after-
wards whether if they had been able to attend to the
task and we attempted to verify this by checking ap-
propriate activation in the visual cortex. If the partici-
pants had not attended, one would have expected
noisy data and no specific activations.
In conclusion, the similarity of ‘unknown’ and
‘unpleasant’ expectation-related brain activity may be
attributed to a ‘pessimistic’ bias towards future events
as expressed particularly in depressed patients. This
supports cognitive models of a ‘pessimistic’ attitude
in depression at the neurobiological level. Dorsolateral
and medial prefrontal regions, known to be involved
in executive and cognitive control, and viscero-
sensitive areas such as the insula appear to play a key
role in biasing the organism towards preparation for
the worst-case scenario and to contribute to depres-
The study was performed at the Psychiatric University
Hospital Zu ¨rich in Switzerland. U.H. and L.J. were
funded by the Swiss National Foundation (SNF no.
3200B0-112631). The SNF had no further role in study
design, in collection, analysis or interpretation of
the data, in writing the report and in the decision to
submit the paper for publication. We are grateful to
Dr D. Huber and C. Sauerwald, Hirslanden Clinic,
Zu ¨rich, for providing the fMRI scanning.
Supplementary material accompanies this paper on
the Journal’s website (http:/ /journals.cambridge.org/
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