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The Neural Basis of Mood-Congruent Processing Biases in Depression
Rebecca Elliott, PhD;
Judy S. Rubinsztein, MB ChB, MRCPsych;
Barbara J. Sahakian, PhD, DipClinPsych;
Raymond J. Dolan, MD, PhD
Arch Gen Psychiatry. 2002;59:597-604.
ABSTRACT
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Background Mood-congruent processing biases are among the most robust research
findings in neuropsychological studies of depression. Depressed patients show
preferential processing of negatively toned stimuli across a range of cognitive
tasks. The present study aimed to determine whether these behavioral abnormalities
are associated with specific neural substrates.
Methods Ten depressed patients and 11 healthy control subjects underwent scanning
during performance of an emotional go/no-go task using functional magnetic
resonance imaging. The task allowed comparison among neural response to happy,
sad, and neutral words, in the context of these words as targets (ie, stimuli
to which subjects were required to make a motor response) or distractors (ie,
stimuli to which the motor response was withheld).
Results Depressed patients showed attenuated neural responses to emotional relative
to neutral targets in ventral cingulate and posterior orbitofrontal cortices.
However, patients showed elevated responses specific to sad targets in rostral
anterior cingulate extending to anterior medial prefrontal cortex. Unlike
controls, patients showed differential neural response to emotional, particularly
sad, distractors in the lateral orbitofrontal cortex.
Conclusions These findings suggest a distinct neural substrate for mood-congruent
processing biases in performance. The medial and orbital prefrontal regions
may play a key role in mediating the interaction between mood and cognition
in affective disorder.
INTRODUCTION
A RELIABLE FINDING in neuropsychological studies of depression is a
bias toward processing of mood-congruent information. Depressed patients show
a facilitation of performance when responding to stimuli with a negative emotional
tone. This phenomenon has been observed in various cognitive contexts. Studies
of memory in depressed patients have reported a tendency toward recall of
negatively toned material,1-5
and have argued that these memory biases may be, at least partly, unconscious
and therefore evident when memory is studied implicitly.6
Mood-congruent biases have also been demonstrated in attentional paradigms.4, 7 For example, depression-related words
cause significantly greater interference in Stroop tasks than neutral or happy
words.8-9 A recent study of an
emotional go/no-go task also found a bias toward sad stimuli in depressed
patients10 and demonstrated a contrasting bias
toward positive information in patients with manic-depressive disorder.
Although mood-congruent biases have been reliably demonstrated, their
exact relationship to depressive symptomatology is unclear. The approach of
studying emotional biases has the advantage of explicitly linking mood and
cognition in a manner that can be related to cognitive-behavioral theories
of depression, on which treatment strategies have been based.11
Thus, patients with depressed mood may be differentially sensitive to negatively
toned information and process it more effectively. This finding could reinforce
depressed mood and contribute to the maintenance of the disorder. A key question
in understanding the role of mood-congruent processing biases in depression
concerns the neural basis for this phenomenon. A previous study of an emotional
Stroop paradigm12 suggested that functional
abnormalities of the anterior cingulate cortex are involved in mood-congruent
response biases in depression, and we sought to examine the issue further.
In a recent study,13 we used a version
of the emotional go/no-go task developed by Murphy et al10
in a functional magnetic resonance imaging (MRI) study of control subjects
to assess differential neural responses to the emotional valence of verbal
stimuli. Regions mediating this response to emotional valence included ventral
and medial prefrontal cortex and, specifically, subgenual cingulate cortex,
a region implicated in the pathophysiology of affective disorders.14-15 The aim of the present study was
to determine whether dysfunction within these prefrontal regions mediates
mood-congruent processing biases in depression. We also hypothesized that
abnormalities may be seen in other regions known to mediate emotional aspects
of processing, ie, the limbic system (the amygdala, hippocampus, and hippocampal
and parahippocampal gyri), thalamus, and insula.
SUBJECTS AND METHODS
SUBJECTS
Ten patients with a diagnosis of unipolar recurrent major depression
were recruited from an affective disorders clinic at Addenbrookes Hospital,
Cambridge, England (7 women and 3 men). Nine patients were right-handed and
1 was left-handed. The diagnosis was established using a structured interview
(the Schedule for Affective Disorders and Schizophrenia–Lifetime Version)
and case note review. Patients had to fulfill research diagnostic criteria
and DSM-IV criteria for major depressive disorder
at each episode, and those with a history of neurologic disease or closed
head injury were excluded. Diagnosis was assigned by one of us (J.S.R.). No
patients with current comorbid anxiety disorders, substance abuse or dependence,
or other psychiatric diagnoses based on DSM-IV were
included. None of the patients had bipolar disorder. One patient had a history
of panic disorder and another had a history of bulimia, but neither fulfilled DSM-IV criteria for these disorders at the time of the
study. Patients were also excluded if they were not euthyroid or if they had
histories of other endocrine disorders or unstable medical disorders. Two
patients were receiving treatment for asthma, 1 for Behçet disease,
and 1 for a hiatal hernia, but these conditions were stable at the time of
scanning. One female patient was postmenopausal and was receiving hormone
replacement therapy; no patient was receiving hormonal contraceptives.
Patients were aged 30 to 59 years, with a mean age of 42.2 years (SD,
8.3 years). Severity of depression was assessed using the 17-item Hamilton
Depression Scale16 (mean score, 23.1; SD, 3.9;
range, 17-30) and the Montgomery-Asberg Depression Rating Scale17
(mean score, 31.3; SD, 5.2; range, 28-42). Only 1 patient was currently hospitalized.
The mean time since first diagnosis was 15 years (SD, 3.3 years; range, 8-23
years), and the mean number of depressive episodes was 3.2 (SD, 1.2; range,
2-5). All patients were receiving medication, and had been for 1 to 8 years.
Four patients were receiving tricyclic antidepressants; 4, selective serotonin
reuptake inhibitors; 1, venlafaxine hydrochloride; and 1, nefazadone hydrochloride.
In addition, 3 patients were receiving lithium carbonate; 2, antipsychotics
(100 mg of oral thioridazine hydrochloride daily); and 3, long-term benzodiazepine
therapy. The clinical heterogeneity observed in the syndrome of major depression
was deliberately limited by including only patients with recurrent major depression
and those under the care of a psychiatrist within the secondary health care
system in the United Kingdom. In all cases, despite medication, patients were
clinically depressed.
These patients were compared with 11 right-handed volunteers who were
recruited by means of advertisement in the local community and underwent MRI
scanning in our earlier study12 (8 women and
3 men; aged 24-59 years [mean age, 37.6 years; SD, 9.7 years]). No significant
difference was found in age between control subjects and patients. Controls
underwent screening using a verbal interview, the Beck Depression Inventory,
and the General Health Questionnaire to exclude any current depressive symptomatology,
neurologic or psychiatric history, closed head injury, or substance abuse.
One female control was postmenopausal and was receiving hormone replacement
therapy. Our results were not affected by removing this control and the corresponding
patient from the analysis. Three of the controls were receiving oral contraceptives.
The study was approved by local research ethics committees (Joint Ethics
Committee of National Hospitals and Institute of Neurology, London, England,
and the Addenbrookes Hospital Research Ethics Committee). Informed written
consent was obtained from all subjects.
COGNITIVE ACTIVATION PARADIGM
The cognitive activation paradigm is discussed in detail in Elliott
et al13 and was identical for both subject
groups. Twenty-four task blocks were interspersed with 24 rest blocks. In
each block, subjects performed a variant of a classic go/no-go task. Before
the start of a block, subjects were given an instruction to respond to certain
targets (go) but ignore distractors (no-go). In the main task conditions,
subjects responded to happy, sad, or neutral targets. The words in each category
were matched for imageability, word length, and frequency.18
Representative examples included joyful, success, and confident for happy; gloomy, hopeless, and failure for sad; and range, vary, and directly for neutral. Under control
conditions, all of the words were neutral, and the targets were defined on
the basis of font (italic vs plain text, an orthographic control condition).
Overall, we used the following 8 conditions: (1) happy targets and sad distractors;
(2) happy targets and neutral distractors; (3) sad targets and happy distractors;
(4) sad targets and neutral distractors; (5) neutral targets and happy distractors;
(6) neutral targets and sad distractors; (7) all words neutral, with targets
in italic and distractors in plain text; and (8) all words neutral, with targets
in plain text and distractors in italic.
In conditions 1 through 6, the task involved judging whether word stimuli
were of one or the other emotional valence. For instance, in condition 1,
subjects were instructed to respond with a button press to happy words (targets),
and to withhold the press for sad words (distractors). Thus, conditions 1
through 6 assessed the effects of attending to words of different emotional
tone and allowed differential responses to both target and distractor valence
to be assessed. Conditions 7 and 8 were control conditions in which subjects
were not required to make semantic judgments.
In each block, 10 targets and 10 distractors were presented in a randomized
order. Each word appeared for 300 milliseconds, and an interstimulus interval
of 900 milliseconds allowed subjects to respond (or not). Each 20-word block
was 24 seconds long and was preceded by a 24-second rest block. At 4 seconds
before the end of each rest block, a written instruction for the next task
block appeared on the screen. Subjects responded by pressing a button as quickly
as possible every time they detected a target. Equal numbers of happy and
sad words were seen during scanning, and therefore we did not anticipate any
effect of mood induction on task performance. However, we examined whether
a significant time x condition interaction existed, which would reflect
a systematic mood change.
MRI SCANNING
We acquired MRI data using a 2-T system (Siemens VISION; Siemens AG,
London). We acquired functional images by means of a gradient echo, echo-planar
T2* sequence using blood oxygenation level dependency contrast. We obtained
294 functional images for each subject. Each image constituted a full brain
volume of 48 axial slices at 3-mm separation and with 3 mm in plane resolution,
acquired continuously with a repetition time of 4 seconds. The first 6 volumes
were dummy volumes to allow for T1-weighted equilibration effects, followed
by 6 volumes per block. We also acquired T1-weighted structural images for
each subject.
DATA ANALYSIS
Data were analyzed using statistical parametric mapping (SPM99; Wellcome
Department of Cognitive Neurology, London, England), which was implemented
using MATLAB (The Mathworks Inc, Sherborn, Mass), and run on a SPARC workstation
(Sun Microsystems, Inc, Surrey, England). This approach to the analysis of
functional imaging data has been described in detail elsewhere.19-23
In brief, scans were first realigned, normalized, and spatially smoothed to
correct for subject motion and to facilitate intersubject averaging. A random-effects
statistical model was used to analyze the data, which accounted for intrasubject
variability and allowed population-based inferences to be drawn. For each
subject, 1 mean image per condition was generated, and these were combined
in a series of linear contrasts to assess group effects. These comparisons
generated statistical parametric maps (SPMs) of the t
statistic (SPM{t}), which was transformed to a normal
distribution (SPM{Z}). In line with established functional imaging conventions,
we report neural responses seen at an uncorrected threshold of P<.001 for regions about which we had an a priori hypothesis. These
regions were the ventral and medial prefrontal regions, limbic system, thalamus,
and insula. For descriptive purposes, we also report neural responses at this
threshold in regions for which there was no prior hypothesis. However, we
restrict discussion and interpretation of the regions with no hypothesis to
those that survived the more stringent threshold of P<.05,
corrected for multiple comparisons. The designation of anatomical localizations
are based on the structural MRIs of the group and the atlas of Duvernoy.24
RESULTS
For clarity, the results we report are between-group comparisons rather
than separate main effects within the 2 groups. The results in the control
group alone have been reported by Elliott et al.13
The mean performance data are given in Table 1. The reaction times did not differ significantly for different
emotional valence, although a trend was found toward depressed subjects responding
more slowly to happy words (t19 = 1.79; P<.10). Both subject groups made minimal errors (<2%)
of omission or commission, and no significant differences were found between
groups. We found no correlations between performance and depression severity.
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Table 1. Performance of Subjects on the Emotional Go/No-Go Task*
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ALL SEMANTIC CONDITIONS COMPARED WITH ORTHOGRAPHIC CONTROLS
We compared conditions 1 through 6 with conditions 7 and 8 to control
for effects unrelated to emotional valence. The depressed patients did not
differ significantly from the controls. The depressed patients were not significantly
different from the controls in their overall neural response to verbal go/no-go
performance (conditions 1-8) compared with the rest condition.
ALL EMOTIONAL TARGETS COMPARED WITH NEUTRAL TARGETS
We compared conditions 1 and 3 with conditions 5 and 6. Conditions 1
and 3 match conditions 5 and 6 for distractor valence, but differ in terms
of target valence (happy and sad vs neutral). In several regions, we found
a significant group x condition interaction (Table 2 and Figure 1)
for the comparison of emotional relative to neutral words in patients relative
to controls. These regions included the left inferior frontal gyrus, ventral
cingulate cortex (extremely close to the subgenual region), left middle temporal
gyrus, left precentral gyrus, left postcentral gyrus, and bilateral pulvinar
region of the thalamus. As shown in Figure
1D, neural responses to neutral words in these regions was comparable
for both groups, but an enhanced response under the emotional conditions,
observed in controls, was not seen in patients. The interaction is thus driven
by attenuation of an emotion-specific response in depressed patients. Figure 1B also shows that the emotion-specific
response in controls was more pronounced for happy than for sad words.
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Table 2. Regions Showing Between-Group Differences in Response to Targets*
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Figure 1. Regions where attenuated neural
response to emotional compared with neutral targets was seen in patients (n
= 10) relative to control subjects (n = 11). Significantly attenuated neural
response in the ventral cingulate (A), pulvinar (B), and inferior frontal
gyrus (C) is shown superimposed on a standard structural magnetic resonance
image template. D, Relative adjusted neural response (no units) in ventral
cingulate to different types of targets in patients (n = 10) and controls
(n = 11), with matched distractor types. Error bars represent SEs. Similar
patterns of response are seen in the thalamus, posterior orbitofrontal cortex,
and insula.
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A significant differential group response was also seen in the reverse
contrast, involving an extensive region of the right lateral frontal cortex
(Brodmann area [BA] 9/46; Table 2
and Figure 2). As shown in Figure 2B, this group x condition interaction
was driven by an elevated response to neutral words in controls and by an
elevated response to sad words in depressed patients.
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Figure 2. A, Enhanced neural responses in
right dorsolateral prefrontal cortex to emotional relative to neutral targets
in patients (n = 10) relative to control subjects (n = 11). The enhanced response
is shown superimposed on sagittal and coronal sections of a standard structural
magnetic resonance image template. B, Relative adjusted neural response (no
units) in right dorsolateral prefrontal cortex to different types of targets
in patients (n = 10) and controls (n = 11), with matched distractor types.
Error bars represent SEs.
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HAPPY COMPARED WITH SAD TARGETS
We compared conditions 2 and 4 (matched for distractor valence and differing
only in terms of target valence). A significant interaction between emotional
valence and subject group was seen in a region of medial prefrontal cortex
extending from the rostral anterior cingulate (BA 32/24) anteriorly to the
medial prefrontal cortex (BA 9/10) (Table
2 and Figure 3). This
interaction was driven by a relatively enhanced response to sad targets in
patients and to happy targets in controls. We also found a significant response
in the right anterior temporal lobe (BA 38), left middle temporal gyrus (BA
21), and bilateral medial frontal gyrus (BA 6). Again, these interactions
were driven by a relatively enhanced response to happy targets in controls
and to sad targets in patients.
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Figure 3. A, Regions where neural response
to sad relative to happy targets was greater in patients (n = 10) relative
to control subjects (n = 11). B, Relative adjusted neural response (no units)
in ventral anterior cingulate to happy and sad targets in patients and controls.
Dissociable response to sad targets in patients and happy targets in controls
is seen. Error bars represent SEs.
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No regions were found where controls showed a greater response to sad
targets or depressed patients showed a greater response to happy ones.
EFFECTS OF DISTRACTORS
Relative to controls, depressed patients showed an enhanced neural response
to emotional compared with neutral distractors (Table 3). This contrast represents conditions 1 and 3 compared with
conditions 2 and 4 (matched target valence and different distractor valence).
Regions showing this enhanced response were the bilateral lateral orbitofrontal
cortices (OFC) (BA 11/47) and bilateral anterior temporal lobe (BAs 20 and
38).
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Table 3. Regions Showing Between-Group Differences in Response to Distractors*
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When the different distractor valences were compared (using conditions
5 and 6 to match for target valence), we found a greater response to sad than
to happy distractors in the right lateral OFC (BA 11/47) and the bilateral
anterior temporal lobe (Table 3
and Figure 4) in patients but not
in controls. Enhanced responses in the same regions were seen when sad distractors
were compared with neutral distractors with matched happy targets.
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Figure 4. Neural responses associated with
sad relative to happy distractors, with neutral targets, seen in depressed
patients (n = 10), but not in control subjects (n = 11). Response in the right
lateral orbitofrontal cortex is displayed superimposed on sagittal and axial
sections of a standard structural magnetic resonance image template.
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We found no regions that responded significantly more to happy than
to sad or neutral distractors, with matched neutral and sad targets, respectively.
TIME x CONDITION INTERACTIONS
We found no significant time x condition interactions, suggesting
that neural responses under the different conditions were consistent across
time. This finding fulfills the expectation that no systematic effect of induced
mood and no significant learning effect on this task existed.
CORRELATIONS WITH DEPRESSION SEVERITY
We found no regions where condition-specific neural responses in depressed
patients correlated significantly with depression severity.
COMMENT
The key findings of this study are abnormal neural responses associated
with emotional processing biases in depressed patients in regions including
the medial and ventral prefrontal cortices. Depressed patients showed a general
attenuation of neural responses to emotional words in cortical and subcortical
structures, including a ventral cingulate region adjacent to the subgenual
cingulate. More specifically, we found a double dissociation of valence-specific
response in the rostral anterior cingulate cortex extending to the anterior
medial prefrontal cortex. This region responded more strongly to happy words
in controls and, conversely, to sad words in patients. Finally, we found differential
responses to the emotional valence of distractor words in patients, but not
in controls. A right lateral orbitofrontal response was associated with the
presence of sad distractors.
Attenuated neural responses to emotional targets in depressed patients
were seen in several regions, including a ventral region of anterior cingulate
cortex, close to the subgenual region discussed in seminal studies by Drevets
et al.14-15 Attenuation was more
pronounced for happy than for sad targets. This region is a focus of structural
and functional abnormalities in patients with depression, and the present
finding suggests that a functional abnormality here might mediate emotional
modulation of cognitive processing. A similar pattern of attenuated response
to emotional targets was seen in posterior OFC, insula, and thalamus. The
OFC25 and the insula26-27
have been implicated in representing changes in body state associated with
emotional responses, and in monitoring autonomic responses to emotionally
salient information.28-29 The
thalamus has been extensively linked to attention and arousal mechanisms.30 Attenuated responses in these interconnected regions
of ventral cingulate, posterior OFC, insula, and thalamus may therefore suggest
a failure of normal autonomic emotional arousal mechanisms in depressed patients.
We also found a region of right dorsolateral prefrontal cortex (DLPFC)
where depressed patients showed greater response to emotional targets than
did controls. This finding was due to depressed subjects showing enhanced
response to sad words, whereas controls showed enhanced response to neutral
words. The DLPFC is not considered a classic substrate for emotional aspects
of processing. Rather, it has been implicated in a number of higher cognitive
functions, including working memory,31-32
episodic memory retrieval,33 attentional set
shifting,34-35 planning,36 and monitoring.37-38
Of these processes, monitoring is most obviously involved in the present task,
with subjects required to monitor a stream of input for targets. In controls,
the monitoring processes subserved by right DLPFC may be biased toward neutral
targets; however, for patients, these monitoring processes may be biased toward
mood-congruent (sad) targets. George et al12
also reported enhanced DLPFC response in depressed patients performing an
emotional Stroop task with sad words, although this was left lateralized.
The classic finding of the response bias in the literature is not only
a bias toward sad information in depression, but also a bias toward happy
information in controls.4 This behavioral dissociation
has direct correlates in the neural response of a medial prefrontal region,
extending from the rostral cingulate to the anterior medial prefrontal cortex,
and also the right anterior temporal lobe. These regions respond differentially
to happy targets in controls but to sad targets in depressed patients. A very
similar prefrontal region, spanning the rostral cingulate and anterior medial
prefrontal cortices, was activated in a positron emission tomographic study
of subjective emotional responses.39 The present
finding suggests that this subjective emotional system is biased toward mood-congruent
information in both controls and depressed patients. Like the subgenual cingulate
cortex, this more rostral and anterior region has been critically associated
with the neuropathology of depression. Mayberg et al40
described the overall level of metabolism in this region as a potential predictor
of treatment response. The present results suggest that a functionally abnormal
response in this region may mediate the bias of depressed patients toward
negative information that is considered by cognitive theorists to be crucial
in the maintenance of the disorder.11, 41
A final important finding of this study is that, unlike controls, depressed
patients make differential responses to emotional distractors in bilateral
anterior temporal regions and lateral orbitofrontal regions. In a direct comparison
between sad and happy distractors, we found an enhanced neural response to
sad distractors in the right lateral OFC. This finding suggests that irrelevant
sad material has a greater capacity to capture attention in depressed patients.
We found no performance differences, suggesting that the effect operates at
a neural but not a behavioral level. Right lateral OFC response has been associated
with performance of nonemotional go/no-go tasks.42-43
Arguments have been made44 that this region
critically mediates behavioral inhibition mechanisms and is therefore recruited
when subjects are required to withhold a prepared or prepotent response. The
present findings suggest that in depressed subjects, mood-congruent distractors
place greater demands on these inhibitory processes in the emotional go/no-go
task.
The differential responses to particular emotional conditions observed
herein occurred in the absence of significant performance differences or general
task-related attenuation of neural responses. Thus, this finding obviates
interpretational problems that typically plague neuroimaging studies of psychiatric
disorders. Condition-specific differences in neural response cannot be attributed
to confounds arising from significant performance impairment, since depressed
patients perform as accurately as controls. Also, when all of the active conditions
in the task are compared with rest conditions, or indeed when semantic conditions
are compared with orthographic conditions, no significant differences are
found in neural response for patients relative to controls. The condition-specific
differences, therefore, do not have to be interpreted in the context of generalized
attenuation in response to cognitive challenge.
However, a number of limitations apply to the present study. One potential
confound is possible drug effects. All patients taking part in the study were
receiving medication, but the variety of different medication regimens precluded
any attempt to compare the effects of different drugs. However, there was
an absence of group differences when all the active conditions were compared
with the rest or the lower-level control condition, which is not consistent
with any systematic effect of the drug on cognitive activation. Nevertheless,
all subjects were medication nonresponders and therefore represent a specific
subgroup of patients with depression. Future study with different subgroups,
including medication-free patients, is needed to establish the generalizability
of the effects observed here. The findings reported herein may be generalized
to other tasks assessing processing biases. For example, Whalen and colleagues45 have developed an emotional version of the Stroop
task for functional MRI and, as with our go/no-go task, have reported a crucial
role for the anterior cingulate in healthy subjects. George et al12 have reported anterior cingulate cortex abnormalities
in depressed patients performing the emotional Stroop task during a single-photon
emission computed tomography study. The clear prediction is that this abnormal
anterior cingulate cortex response to emotional words would be seen in functional
MRI findings, reflecting mood-congruent biases. An event-related approach
would also disambiguate the abnormal responses to specific targets and distractors
in response bias paradigms, which are inevitably confounded to some extent
in the blocked approach used in this study.
To our knowledge, this study is one of the first to look at the functional
neuroanatomy of the emotional modulation of cognitive processing in depressed
patients. Previous studies have reported abnormalities in the network subserving
passive viewing of emotional material46-47
that responds to therapeutic intervention.48
However, specific studies of the interface between mood and cognition have
potentially important implications for our understanding of affective disorders.
Distortions of cognitive processing by affective factors are at the core of
many influential theories of depression, and functional neuroimaging studies
provide the means to relate these distortions to neurobiological abnormalites.
The present findings suggest a critical involvement of ventral and medial
prefrontal regions in mediating mood-congruent response biases in depression.
We suggest that distinct regions mediate separable aspects of this effect
and hypothesize a testable theoretical framework.
AUTHOR INFORMATION
Submitted for publication September 21, 2000; final revision received
May 30, 2001; accepted August 13, 2001.
This study was supported by a program grant to Dr Dolan and to T. W.
Robbins, PhD, B. J. Everitt, PhD, A. C. Roberts, PhD, and Dr Sahakian from
Wellcome Trust, London; by the Betty Behrens research fellowship at Clare
Hall, Cambridge (Dr Rubinsztein); and by a Sackler studentship, University
of Cambridge Medical School, Cambridge (Dr Rubinsztein).
Corresponding author and reprints: Rebecca Elliott, PhD, Neuroscience
and Psychiatry Unit, Room G907, Stopford Bldg, University of Manchester, Oxford
Road, Manchester M13 9PT, England (e-mail: rebecca.elliott{at}man.ac.uk).
From the Neuroscience and Psychiatry Unit, University of Manchester,
Manchester (Dr Elliott); Department of Psychiatry (Drs Rubinsztein and Sahakian),
University of Cambridge, Cambridge; and Wellcome Department of Cognitive Neurology,
Institute of Neurology, London (Dr Dolan), England.
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