The authors have declared that no competing interests exist.
Conceived and designed the experiments: MS LP NR PK. Performed the experiments: MS LP NR PK. Analyzed the data: MS LP NR PK. Wrote the paper: MS LP NR GR PK.
Pervasive negative thoughts about the self are central to the experience of depression. Brain imaging studies in the general population have localised self-related cognitive processing to areas of the medial pre-frontal cortex.
To use fMRI to compare the neural correlates of self-referential processing in depressed and non-depressed participants.
Cross-sectional comparison of regional activation using Blood Oxygen Level Dependent (BOLD) fMRI in 13 non-medicated participants with major depressive episode and 14 comparison participants, whilst carrying out a self-referential cognitive task.
Both groups showed significant activation of the dorsomedial pre-frontal cortex and posterior cingulate cortex in the ‘self-referent’ condition. The depressed group showed significantly greater activation in the medial superior frontal cortex during the self-referent task. No difference was observed between groups in the ‘other-referent’ condition.
Major depressive episode is associated with specific neurofunctional changes related to self-referential processing.
Both psychological therapy and medication are commonly used in the treatment of major depressive episodes, and have been found to be roughly equally effective
Psychologically, major depressive episodes are associated with widespread and pervasive information-processing and cognitive biases in the functioning of self-related attentional, memory and attribution systems
In several treatment outcome studies, the cortical areas showing functional changes on remission of depressive episode following both pharmacological and psychological treatment have included the posterior cingulate, anterior cingulate gyrus, orbitofrontal and medial prefrontal areas or the dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex
The present study therefore aimed to extend the evidence-base concerning the neural characteristics of self versus other-referential processing in depression, comparing the pattern of processing in the general population and in unmedicated people experiencing major depressive episodes. Given the increased attentional bias to negative self-related information in depression, it was hypothesised that participants currently experiencing a depressive episode would show increased regional brain activity during a self-referential task compared to an other-referential task and in comparison with a never-depressed control group. Given the potentially confounding effects of antidepressant medication on CMS functioning
Functional-MRI, using the Blood Oxygen Level Dependent (BOLD) technique, allows regional brain activity during a target cognitive task to be compared with a baseline condition. Differential BOLD response between the two conditions is localised throughout the brain, allowing the observation of specific anatomical areas of neuronal activity associated with the cognitive task being investigated. Using a well established study design
The study was conducted in a specialist neuroimaging laboratory in the University of Liverpool, UK, with participants recruited from local mental health services and the local community.
This research was approved by Liverpool NHS PCT Local Research Ethics Committee (ref 05/Q1505/10), and was conducted according to the principles expressed in the Declaration of Helsinki, including fully informed, written, consent. All clinical participants were interviewed by a mental health professional involved in their care, who ensured that they had capacity to understand the ethical issues, and nurses experienced in the ethical procedures involved in neuroimaging performed a similar assessment in the case of control participants.
Following ethical approval, participants with a current diagnosis of major depressive episode (Depressed group) were recruited through advertisements in GP surgeries within Central and South Liverpool Primary Care Trusts. Participants with no history of mental health difficulties were recruited via advertisements in the local media (Control group). Age of the depressed group was (mean ± SD) 32.7±7.6 years. Age of the control group was 26.4±9.5 years. There was no significant difference between the age of the groups (p = 0.1, 2-sample t-test). Mean number of years of education was 15 years in both groups ± 2.6 in the depressed group and ± 3.0 in the control group. Inclusion criteria were a Beck Depression Inventory II (BDI-II)
Participants received a physical examination from MRI nurses to confirm that there were no contraindications for brain imaging. This included pulse and blood pressure check, Romberg’s test of cerebellar function, Edinburgh Handedness Inventory, and weight and height check. Participants then completed a Structured Clinical Interview for DSM-IV (SCID)
All scanning was performed on a 3-Tesla Siemens whole-body Trio system. An 8-channel phased array head coil was used to receive the MRI signal. For the fMRI scanning, a standard single-shot echo-planar imaging (EPI) sequence was used with the following acquisition parameters: repetition time 2s, echo time 35ms, matrix size 64 x 64 with a field of view of 224 mm to give in-plane pixel resolution of 3.5 mm. Twenty eight slices with a slice thickness of 3.5 mm and a 10% gap allowed full coverage of the cerebral cortex. Prospective motion correction
Functional brain imaging methodologies for investigating self-referential processing are well established
The methodology used by Kelley and colleagues
Stimulus words were chosen from within Anderson’s list of 555 personality descriptors
The visual stimuli were controlled via Presentation software (Neurobehavioural Systems Inc.)
a = self condition, neutral stimulus word; b = other condition, positive stimulus word; c = case condition, negative stimulus word; d = Rest Interval.
The stimuli were back-projected onto a screen at the rear of the scanner bore and were viewed via a head-coil mirror. Participants were first given a two minute practice run (using target words not appearing in the full stimulus list) inside the scanner. The three functional runs and an 8 minute structural image were then collected.
Mean positive responses (percentage of responses answered ‘yes’) and response times were calculated for each condition for each participant. Mean positive responses and response times that were more than 3 x SD from the global mean (control and depressed participants taken together) were discarded (0.5% of data). A ‘positivity measure’ was defined as: % response ‘yes’ to positive valence words - % response ‘yes’ to negative valence words. Comparisons between groups were made using two-sample t-tests for all 9 conditions. In addition, difference in response time for (self – queen) and (self – case) and the ‘positivity measure’ for self and queen were compared between groups to test for specific differences in self-referential processing. For the response times, a 3-way ANOVA with group (control or depressed), category (queen, self or case) and valence (positive, negative or neutral) was performed in Matlab (The Mathworks, Inc, Massachusetts, USA). Linear regression between (self – queen) response time and the ‘positivity measure’ were made with the BDI II and Rosenberg scores to determine if these measures related to depressive symptoms.
All images were analysed using BrainVoyager software (Brain Innovation, Maastricht). Pre-processing comprised motion correction, slice time correction, spatial smoothing (6 mm FWHM 3D Gaussian filter) and temporal filtering (linear trend removal and 0.02 Hz high pass filtering). The fMRI images were co-registered onto the structural images and transformed into Talairach space.
A general linear model was constructed for each fMRI run of each subject with 9 regressors: 3 valences of word (positive, negative and neutral) x 3 categories of presentation (self, queen and case). A random effects analysis was performed on both the depressed group of 13 subjects and the control group of 14 subjects separately. The contrast (self – queen) was considered collapsed across all 3 word valences. Results pertaining to individual valences were not considered as there would be too few trials of each condition to provide reliable results. Results were thresholded at p<0.005 uncorrected with a cluster threshold set to 8 voxels (voxel here refers to the original size in the fMRI data, one voxel = 47 mm3). This cluster-size method to correct for multiple comparisons avoids the potential over-correction of more conservative tests such as Bonferroni. A fairly lenient statistical threshold was chosen to avoid type II errors at the risk of type I errors. The large cluster size (approximately 400 mm3) effectively guards against type I errors, as any ‘activation’ arising by chance would be expected to be scattered through the brain. This is perhaps at the expense of missing very small regions of true activation. This choice of cluster threshold is supported by the simulation work of Lieberman and Cunningham
In a separate analysis, the difference in activation (self - queen) between the two groups was compared in a random effects analysis. A two-stage procedure was used for this where a first-level fixed effect analysis was used to determine the effect size (self-queen) in each subject. A second-level random effects analysis then compared this effect size between the two groups across the brain. Results were again thresholded at p<0.005 uncorrected with a cluster threshold of 8 voxels. Talairach coordinates were recorded and the BOLD signal amplitude of each of the groups in the active grey matter regions and the significance of any difference was recorded. Linear regression between the BOLD amplitude and the BDI and Rosenberg scores were performed. ‘Self-case’ and ‘queen-case’ contrasts were also analysed, using the same procedure as for ‘self-queen’ above.
Depressed participants scored a mean of 29.1±12.9 on the BDI-II (a score of 20 or above on the BDI-II is indicative of at least moderate depression) and a mean of 10.9±4.6 on the Rosenberg self-esteem inventory (a score of 10 or below on the Rosenberg is indicative of clinically significant low self-esteem). The control group scored a mean of 3.3±2.5 on the BDI-II and 24.8±4.0 on the Rosenberg. Both the BDI-II and Rosenberg scores differed significantly between the two groups at p<0.001 (t(26) = 7.34 for BDI-II scores, t(26) = 8.47 for Rosenberg scores.
In order to examine possible demand characteristics, the behavioural responses of participants to the stimulus questions were analysed. Overall participants recorded a response (i.e either a ‘yes’ or a ‘no’ response) on 98.7% of occasions. There was no significant difference between the number of depressed and control participants’ responses. Both groups responded swiftly to the stimuli materials, with the control group responding significantly faster (1.4±0.2 seconds) overall than the depressed group (1.8±0.2 seconds) (t (26) = 3.23, p<.0005). A summary of response times and endorsement rates, along with results of 2-sample t-tests between the control and depressed groups are presented in
Category | Valence | Control | Depressed | Cont vs Clin |
Mean ± SD (ms) | Mean ± SD (ms) | p-value | ||
Self | Positive | 1317±276 | 1779±205 | <0.0001 |
Neutral | 1565±137 | 1921±192 | 0.03 | |
Negative | 1344±251 | 1859±166 | 0.007 | |
Queen | Positive | 1624±281 | 1824±195 | 0.0006 |
Neutral | 1720±216 | 1966±238 | <0.0001 | |
Negative | 1520±301 | 1783±178 | 0.007 | |
Case | Positive | 1260±208 | 1583±350 | <0.0001 |
Neutral | 1248±189 | 1616±295 | 0.007 | |
Negative | 1245±265 | 1573±327 | 0.006 | |
Self - Queen | All | −213±108 | −5±115 | <0.0001 |
Self - Case | All | 158±128 | 310±166 | 0.01 |
Self | Neg – Pos | 62±93 | 80±167 | 0.7 |
Category | Valence | Control | Depressed | Cont vs Clin |
Mean ± SD (ms) | Mean ± SD (ms) | p-value | ||
Self | Positive | 93±12 | 77±16 | 0.01 |
Neutral | 37±17 | 56±12 | 0.004 | |
Negative | 6±7 | 41±22 | 0.001 | |
Queen | Positive | 63±29 | 76±22 | 0.2 |
Neutral | 29±12 | 33±10 | 0.4 | |
Negative | 21±24 | 17±17 | 0.6 | |
Case | Positive | 49±3 | 51±8 | 0.4 |
Neutral | 50±3 | 52±5 | 0.2 | |
Negative | 52±6 | 53±4 | 0.8 | |
Self | Pos – Neg | 87±16 | 36±36 | 0.0004 |
Queen | Pos - Neg | 34±30 | 43±24 | 0.4 |
A 3-way ANOVA of response times revealed main effects of all factors (group F = 131 p<0.0001; category F = 40 p<0.0001; valence F = 6.5 p = 0.002). There was also a significant interaction between group and category (F = 5.3, p = 0.005) but not between group and valence. The results show that the depressed group were significantly slower than controls in their response to all stimuli (
Significant correlations were found between the (self – queen) response times and the BDI II scores (r2 = 0.38, p = 0.002) and Rosenberg scores (r2 = 0.36, p = 0.002) across the cohort. However, these were not significant within the depressed group alone (BDI II: r2 = 0.01, p = 0.8; Rosenberg: r2 = 0.02, p = 0.6). Similarly, the ‘positivity measure’ for the self condition showed significant correlations with BDI II scores (r2 = 0.65, p<0.0001) and Rosenberg scores (r2 = 0.56, p = 0.0001), but again not within the depressed group alone (BDI II: r2 = 0.25, p = 0.1; Rosenberg: r2 = 0.31, p = 0.1). The strength of these correlations however, suggests that the ‘positivity measure’ may be related to depressive symptoms and the lack of significance may be due to the small sample size.
Areas in red represent regions of increased BOLD activity in the ‘self’ as opposed to ‘queen’ condition.
Region | Talairach coordinates x y z | Volume mm3 | BOLD signal (se) |
T-value of region | p value of region |
Medial superior frontal gyrus | −1 31 40 | 2366 | 1.45 (0.12) | 11.8 | <.000001 |
Medial frontal cortex & anterior cingulated | −4 36 11 | 3870 | 1.25 (0.11) | 11.6 | <.000001 |
Left inferior frontal gyrus | −42 29 7 | 1064 | 0.74 (0.11) | 6.9 | <.000001 |
Significant at the p = 0.005, uncorrected significance level with a cluster threshold of 8 voxels.
The BOLD signal amplitude for the (self – queen) condition is given, taken from the beta weights of the general linear model fit. ‘se’ is the standard error over all participants.
Region | Talairach coordinates x y z | Volume mm3 | BOLD signal (se) |
T-value of region | p value of region |
Medial frontal cortex & anterior cingulated | −6 33 14 | 5369 | 1.1 (0.1) | 10.4 | <.000001 |
Cingulate gyrus (central and posterior) | 21 −15 24 | 3037 | 0.8 (0.1) | 7.7 | <.000001 |
−7 −33 35 | 2506 | 00.78 (0.1) | 77.5 | <.000001 | |
−16 0 27 | 552 | 0.7 (0.1) | 76.7 | <.000001 | |
Right superior temporal gyrus | 50 −31 4 | 2723 | 0.67 (0.1) | 6.4 | <.000001 |
Caudate body | 0 −8 12 | 711 | 0.81 (0.1) | 7.7 | <.000001 |
Bilateral thalamus | 7 −32 3 | 641 | 0.58 (0.1) | 5.6 | <.000001 |
Left parahippocampal gyrus | −42 −27 −8 | 639 | 0.62 (0.1) | 5.9 | <.000001 |
Precuneus | −2 −44 47 | 455 | 0.53 (0.1) | 5.1 | <.000001 |
Left superior frontal gyrus | −21 31 46 | 519 | 0.75 (0.1) | 7.2 | <.000001 |
Left cerebellum | −30 −49 −15 | 627 | 0.4 (0.1) | 3.9 | .0001 |
−38 −65 −18 | 942 | 0.58 (0.1) | 5.8 | <.000001 | |
Right brainstem | 6 −26 −18 | 551 | 0.44 (0.1) | 4.2 | 0.0002 |
Significant at the p = 0.005, uncorrected significance level with a cluster threshold of 8 voxels.
The BOLD signal amplitude for the (self – queen) condition is given, taken from the beta weights of the general linear model fit. ‘se’ is the standard error over all participants.
As can be seen from
The pattern of activation revealed by the ‘self – queen’ contrast was compared between the two participant groups.
(d) represents the statistical distribution of the BOLD signal change in the highlighted area. The areas in red represent areas where the depressed participants showed significantly greater BOLD signal change for the contrast ‘self – queen’ than the control group.
BOLD signal (se) |
BOLD signal (se) |
|||||
Region | Talairach coordinates x y z | Volume mm3 | Clinicals (n = 13) | Controls (n = 14) | T value of region | p value of region |
Medial superior frontal cortex | −1 21 48 | 528 | 0.72 (0.2) | −0.06 (0.12) | 3.6 | 0.001 |
Significant at the p = 0.005, uncorrected significance level with a cluster threshold of 8 voxels.
The BOLD signal amplitude for the (self – queen) condition is given, taken from the beta weights of the general linear model fit. ‘se’ is the standard error over all participants.
Task adherence analysis was conducted by comparing BOLD signal change in the ‘self’ and ‘queen’ tasks with the simple case-judgement task. Both self-case and queen-case comparisons revealed patterns of differential activation that were not statistically different between the two participant groups, providing confirmation that both the depressed and control participants adhered to the demands of each randomly presented task. The lack of activation for self-case and queen-case comparisons gives confidence that the statistical threshold is appropriate to avoid type I errors.
This investigation compared BOLD signal change in depressed and non-depressed participants while performing a well-controlled self-referential task. The ‘experimental’ task – the self-referent decision “does this word describe me?” – has good face validity as a stimulus for the investigation of altered self-related cognitions that are implicated in psychological models of depression
Across the two participant groups, the contrast of the ‘self’ versus ‘queen’ tasks revealed activation associated with self-referential processing in the medial superior frontal gyrus, medial frontal cortex and anterior cingulate. Thus far, therefore, the findings of the present investigation are largely consistent with previous findings regarding the nature of self-referential processing in depressed
As predicted, there was an increased level of activation in the CMS during self-referent tasks in the depressed group, when contrasting BOLD signal change associated with self-referent processing between the participant groups. When depressed participants made evaluative decisions about themselves, there was significantly greater activation of the medial superior frontal cortex than in the control participants. These findings support and may help to explain several other research studies that have reported higher activation (e.g. blood-glucose metabolism) in specific areas of the orbito, superior and medial prefrontal cortex, and in the anterior cingulate cortex associated with depression, and showed more normalised brain activation after remission following treatment with either medication or psychological therapy
Behavioural data in the present investigation showed a distinctly different endorsement profile between the two participant groups. Depressed participants endorsed significantly fewer positive words and significantly more neutral and negative words in the ‘self’ condition as compared with control participants, whereas no significant differences were found in endorsement rates for the ‘other’ or ‘case’ conditions. The ‘positivity measure’ also showed significant correlations between both BDI-II scores and Rosenberg scores. This provides important contextualising information for the BOLD results discussed above. Psychological models predict that depressed individuals will display distinct information-processing and attentional biases in self-related cognition
Given that participants in the present study were free from antidepressant medication, it is of interest that there were no significant differences in left dorsolateral cortex activation in response to self-referential processing tasks. This contrasts with neurofunctional changes in response to self-referential processing reported in association with the use of antidepressant medication
Recent models of mental disorder
The lack of observed differences in regional brain activity between the two groups when engaged in non self-related tasks (the ‘Queen’ and ‘case’ conditions) is also interesting from research design and interpretation perspectives. The findings indicate a clear neurofunctional correlate of altered cognitive processing about the self, but are suggestive of a high level of specificity in this altered functioning. In the present study, there was a specific difference in regional brain activity; which fits with psychological models of depression
This study reported cross-sectional data on a group of people currently suffering from major depressive episode and a group of healthy control participants, and as such provides a ‘snapshot’ of the effects of depression on self-referential processing. Whilst there already is some evidence of specific neurofunctional changes following use of antidepressant medication
All work was carried out at the Division of Clinical Psychology and at the Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool, Brownlow Hill, Liverpool, United Kingdom. L69 3GB. Discussions and pilot work with Dr Debbie Watson, Dr Bruce Moore, Professor Richard Morriss and Professor Krish Singh while developing the fMRI paradigm are gratefully acknowledged.