Nsp022 313.327

SCAN (2009) 4, 313–327 Medial cortex activity, self-reflection anddepression Marcia K. Johnson, Susan Nolen-Hoeksema, Karen J. Mitchell, and Yael LevinDepartment of Psychology, Yale University, PO Box 208205, New Haven, CT 06520-8205, USA Using functional magnetic resonance imaging, we investigated neural activity associated with self-reflection in depressed[current major depressive episode (MDE)] and healthy control participants, focusing on medial cortex areas previously shownto be associated with self-reflection. Both the MDE and healthy control groups showed greater activity in anterior medial cortex(medial frontal gyrus, anterior cingulate gyrus) when cued to think about hopes and aspirations compared with duties andobligations, and greater activity in posterior medial cortex (precuneus, posterior cingulate) when cued to think about dutiesand obligations (Experiment 1). However, the MDE group showed less activity than controls in the same area of medial frontalcortex when self-referential cues were more ambiguous with respect to valence (Experiment 2), and less deactivation in a non-self-referential condition in both experiments. Furthermore, individual differences in rumination were positively correlated withactivity in both anterior and posterior medial cortex during non-self-referential conditions. These results provide convergingevidence for a dissociation of anterior and posterior medial cortex depending on the focus of self-relevant thought. They alsoprovide neural evidence consistent with behavioral findings that depression is associated with disruption of positively valencedthoughts in response to ambiguous cues, and difficulty disengaging from self-reflection when it is appropriate to do so.
Keywords: self-reflection; medial frontal cortex; posterior medial cortex; rumination; depression Anterior medial cortex (e.g., medial frontal gyrus, anterior In addition, individual differences in chronic promotion cingulate cortex) and posterior medial cortex (e.g., posterior orientation (i.e. a focus towards approach goals; Higgins, cingulate cortex, precuneus) show increased activity during 1997, 1998) were positively correlated with activity in self-referential processing (Johnson et al., 2002; Fossati et al., medial prefrontal cortex (PFC) during hopes/aspirations 2003; Macrae et al., 2004; Ochsner et al., 2005; Vogt and trials. Similarly, in a medial frontal area near the location Laureys, 2005; Amodio and Frith, 2006; Johnson et al., that Johnson et al. (2006) found correlated with promotion 2006; Northoff et al., 2006). Furthermore, activity in these focus, Sharot et al. (2007) found that more optimistic people two areas may be associated with different types of self- showed greater activity when thinking about positive events, referential processing. Based on the idea that different relative to negative events. Together, these findings suggest types of self-relevant agendas (e.g. goals; Johnson and that anterior medial PFC may be recruited during positive, Reeder, 1997) are an important part of one's self-definition approach-oriented self-relevant thought (see also, Mitchell and play a key role in determining one's emotions and reg- et al., 2009).
ulating interactions with others (Markus and Nurius, 1986; Differences in medial cortex activity have been observed in Cantor and Kihlstrom, 1987; Higgins, 1997), Johnson et al.
comparisons of depressed individuals with healthy controls, (2006) investigated two broad classes of agendashopes and both in resting state and active tasks (Mayberg et al., 1999; aspirations, and duties and obligations. Replicating others, Drevets, 2000; Charney and Manji, 2004; see Drevets et al., they observed greater activity in anterior and posterior 2008; Gotlib and Hamilton, 2008, for reviews). In addition, medial areas for self-referential than for non-self-referential depression is associated with rumination about negative self- processing [e.g. thinking about concrete things such as polar relevant information (Nolen-Hoeksema et al., 2008), and the bears fishing (Nolen-Hoeksema, 2004)]. They also found a tendency to ruminate may be related to differences in ante- dissociation: there was greater activity in anterior medial rior medial cortex activity (e.g. Ray et al., 2005; Greicius et al., 2007). However, the specific factors (e.g. types of aspirations, but greater activity in posterior medial areas self-focus) that affect whether depressed individuals show when participants thought about duties and obligations.
elevated or reduced activity in medial cortical regions (andin which subregions) remain to be specified (Drevets, 2000; Received 19 June 2008; Accepted 21 June 2009 Davidson et al., 2002; Mayberg, 2003a; Phillips et al., 2003; Advance Access publication 20 July 2009 These studies were funded by National Institutes of Health (AG09253). We thank MR technologists Hedy Mayberg et al., 2005).
Sarofin and Cheryl McMurray for assistance in collecting the MR data; Kathleen Muller for help The present experiments begin to address this issue by with figures and scoring of the participants' post-scan reports; and Anna Swan for help with report scoring.
comparing medial cortex activity of individuals experiencing Correspondence should be addressed to Marcia K. Johnson, Department of Psychology, Yale University, PO Box 208205, New Haven, CT 06520-8205, USA. E-mail: [email protected].
a major depressive episode (MDE) and control participants ß The Author (2009). Published by Oxford University Press. For Permissions, please email: [email protected] M. K. Johnson et al.
as they engaged in different types of self-reflective thought disorder, and normal, or corrected to normal, vision. Beck compared with non-self-reflective thought. On self-reflection Depression Inventory (BDI-II; Beck et al., 1996) scores were trials in Experiment 1, we cued participants either to think obtained on the day of the scan. Control participants [n ¼ 24 about hopes and aspirations or duties and obligations, con- (11 females)] had BDI scores 8 (M ¼ 4.04, s.d. ¼ 2.65); ditions shown previously to differentially engage anterior and MDE participants [n ¼ 20 (9 females)] had BDI scores 21 posterior medial cortex in healthy controls. In Experiment 2, (M ¼ 27.85, s.d. ¼ 6.23). All MDE participants met full we cued participants either to engage in self-evaluation or to criteria for a current MDE according to the Structured think about their current state, activities that previously have Clinical Interview for DSM-IV (SCID; First et al., 1998), been shown to differentially induce rumination in depressed administered at the end of the scan session. None of the participants. Thus, Experiment 1 assessed whether depressed participants in the control group met the criteria for either participants differed from controls in engagement of anterior current or past MDE. Inter-rater reliability on the SCID was medial cortex associated with positive thoughts such as good ( ¼ 0.67, P < 0.0001). The groups did not differ on age hopes and aspirations when specifically cued to do so; [Mcontrol ¼ 20.6 and Experiment 2 assessed whether depressed participants (s.d. ¼ 2.9 years); P > 0.05] or education [reported in years; differed from controls in the engagement of this area under Mcontrol ¼ 14.4 (s.d. ¼ 1.9 years), MMDE ¼ 15.3 (s.d. ¼ 2.2 conditions that did not specifically cue positive thoughts.
years); P > 0.10]. Four of the MDE participants self-reportedtaking psychotropic medications (lamictal, effexor, zyprexa, zoloft). Because the pattern of findings remained the same Emotional distress (depression and anxiety) has been asso- when participants taking medications were removed, we ciated with reductions in promotion or approach goals and report the data with these participants included. The increases in avoidance goals (Gray, 1982; Fowles, 1988; Davidson, 1998; Dickson and MacLeod, 2006). Building on Medical School approved the protocol, and consent was the finding that anterior medial PFC is especially associated obtained according to the Declaration of Helsinki (1991, with thinking about promotion or approach goals (e.g.
Br Med J, 302, 1194). All participants were paid.
hopes and aspirations; Johnson et al., 2006), we predicted Design and procedure.
The study was a mixed 2 that, when asked to think about hopes and aspirations, indi- (group: control, MDE)  3 (condition: hopes, duties, dis- viduals experiencing a MDE would show less activity in traction) design. Participants saw short phrases and were anterior medial cortex than controls. The prediction was instructed to ‘focus on the idea expressed by the phrase less clear about the relative activity in the two groups in and use your imagination to visualize or think about the posterior medial cortex in the hopes and aspirations vs idea . .'. They were asked to press a button when they had duties and obligations conditions. Activity in this region ‘formed a really clear thought, or idea, or image' and to keep was not found to correlate with either promotion or preven- thinking about the idea until a cross-hair appeared. There tion orientation (Johnson et al., 2006) or with optimism were six practice trials outside the scanner. During the scan, (Sharot et al., 2007). In addition, although duties and obli- participants saw the cue ‘hopes and aspirations' 12 times gations may be associated with avoidance goals (Higgins, (‘hopes' condition), the cue ‘duties and obligations' 12 1998), such thoughts are not necessarily negatively valenced.
times (‘duties' condition) and 12 different concrete ‘distrac- Depression can be associated with difficulty disengaging tion' cues (e.g. pattern on oriental rug, shape of USA; from self-focus, particularly from negative self-relevant Nolen-Hoeksema, 2004). Cue types were pseudo-randomly thoughts, when the task demands it. For example, people intermixed in 3 runs of 12 trials each (four trials per condi- who tend to ruminate when distressed (i.e. who passively tion). Each trial was 18 s, with the cue shown for 14 s and focus on feelings of distress and their meanings and conse- a cross-hair shown for 4 s.
quences; Nolen-Hoeksema, 1991) show greater difficulty Post-scan reports.
Immediately after the scan session compared with non-ruminators in disengaging attention (which included Experiment 2, described later), participants from or inhibiting irrelevant information (Siegle et al., moved to another room where they were asked to write a 2002; Joormann, 2004, 2005, 2006; Donaldson et al., 2007).
paragraph or two describing what they thought about during Thus, we predicted that individuals experiencing a MDE, the scan when they saw the phrases ‘hopes and aspirations' and individuals prone to ruminate, would show greater and ‘duties and obligations', with order of reports counter- neural activity (i.e. less deactivation) in either or both ante- balanced. Two research assistants, blind to the participants' rior and posterior medial areas associated with self-reflection MDE status, coded each report for both positivity and nega- when directed to focus on non-self-relevant thoughts during tivity (1 ¼ not at all to 4 ¼ very). Inter-rater reliability was the distraction trials.
good ( ¼ 0.83, P < 0.0001), and each participant wasassigned the average of the scores of the two raters. One rater counted the words in each report and also gave each Participants self-reported being in good phy- a global detail rating on a scale from 1 (no detail, very vague) sical health, with no history of cardiovascular or neurological to 5 (extremely detailed).
Medial cortex, self-reflection and depression Visual analog scale of mood.
Participants' current 1995), or a group (control, MDE)  condition  time inter- mood was measured using a 14-item visual analog scale at action with a minimum of six contiguous voxels, each being three points in the procedure: before going into the scanner, significant at P < 0.001 (Forman et al., 1995). For the regions between Experiments 1 and 2 and again after the post-scan thus identified, subsequent analyses were conducted on report. Adjectives appeared one-at-a-time on the screen and percent signal change (from Time 1) for the region at participants indicated for each item how much it described Times 4–7, which is the period during which event-related how they were currently feeling on a scale from 0% (not at hemodynamic responses tended to peak in this task. Here, all) to 100% (very much). The scale was in 10% intervals, we focus on the medial areas identified and, for these areas, and participants pressed a button to indicate their response we report results of planned group  condition contrasts in for each item. There were six relatively negative items percent signal change when each self-focus condition was (anxious, guilty, hopeless, irritable, sad and worthless), separately compared with distraction. We also conducted four positive items (calm, energetic, happy and mellow) planned contrasts between conditions within each group, and four filler items that we considered to be relatively neu- and between the groups for each condition. These contrasts tral in this context (bored, hungry, talkative and tired) pre- were performed on regions initially identified using sented in a different pseudorandom order each time.
the stringent criteria described above, and had specific Individual difference measures.
After the scan, parti- directional predictions (P < 0.05, one-tailed); therefore, cipants filled out questionnaires that assessed depressive we note all two-tailed effects significant at P < 0.10.
symptoms (BDI-II; Beck et al., 1996) and tendency to rumi- Conditions for Experiment 2 will be described in the nate (Treynor et al., 2003). Participants were also adminis- ‘Methods' section, but the analysis strategy was identical to tered the mood module of the SCID (First et al., 1998).
that used in Experiment 1. For completeness, Tables 1 and 2 fMRI procedure.
Anatomical images were acquired report all areas identified in Experiments 1 and 2, using a 1.5T Siemens Sonata scanner at the Magnetic Resonance Research Center at Yale University. Functional In addition, for each region in Figures 1–3, the mean scans were acquired with a single-shot echoplanar gradi- percent change scores (Times 5–8 or 6–9) for each partici- ent-echo pulse sequence [repetition time (TR) ¼ 2000 ms, pant for each condition were correlated with their scores on echo time (TE) ¼ 35 ms, flip angle ¼ 808 and field of view the post-scan rumination questionnaire. We used slightly (FOV) ¼ 24]. The 24 oblique axial slices (3.8 mm thick with later time frames than used to assess peak activations in an in-plane resolution of 3.75  3.75 mm) were aligned with the main analysis (Times 4–7) because it seems likely that the anterior commissure-posterior commissure (AC-PC) ruminative tendencies would be more related to differences line. Each run began with 12 blank seconds to achieve seen later in trials. Scatter plots are provided for all signifi- steady state magnetization, and was followed by a 1-min cant correlations in the areas shown in Figures 1–3.
rest interval. One volume was collected every 2 s, or ninefull brain images for each trial (108 images per participant Results and discussion per condition).
Figure 1A (see also Table 1) shows an area of medial frontal fMRI analyses.
After reconstruction, time series were gyrus and anterior cingulate [Brodmann areas (BA) 10, 32] shifted by sinc interpolation to correct for slice acquisition identified in our initial whole brain analysis (see ‘Methods' times. Data were motion-corrected using a six parameter section). Subsequent planned comparisons between distrac- automated algorithm (AIR; Woods et al., 1992). A 12 para- tion and each of the two self-referential conditions showed meter AIR algorithm was used to co-register participants' that the difference in activity between hopes and distraction images to a common reference brain. Data were mean-nor- (F ¼ 5.42, P ¼ 0.025) and between duties and distraction malized across time and participant and spatially smoothed (F ¼ 6.56, P ¼ 0.014) was greater for control than MDE par- (3D, 8 mm FWHM gaussian kernel). The data were analyzed ticipants. These interactions largely arose because the MDE using NeuroImaging Software (http://kraepelin.wpic.pitt group showed less deactivation in the distraction condition .edu/nis/). We used voxel-based analysis of variance than the controls (F ¼ 4.65, P ¼ 0.04), and the groups did (ANOVA) with participant as a random factor and all not differ in the other conditions (both P's > 0.10). Within other factors fixed. F-maps were transformed to Talairach the control group in this area, activity in the hopes condition space using Analysis of Functional NeuroImages (AFNI) was greater than (>) the activity in the distraction condition (Cox, 1996), and areas of activation were localized using (F ¼ 75.71, P < 0.001), duties > distraction (F ¼ 50.12, AFNI and Talairach Daemon software (Lancaster et al., P < 0.001) and hopes > duties (F ¼ 4.28, P ¼ 0.05). Within 1997) and manually checked against atlases (Talairach and the MDE group in this area, hopes > distraction (F ¼ 36.38, Tournoux, 1988; Duvernoy, 1999).
P < 0.001), duties > distraction (F ¼ 8.20, P ¼ 0.01) and hopes > duties (F ¼ 8.23, P ¼ 0.01).
(hopes, duties, distraction)  time within trial (images Figure 1B shows an area of superior frontal gyrus, medial 1–9) interaction with a minimum of six contiguous voxels, frontal gyrus (BA 10) somewhat superior to the region in each being significant at P < 1.0  1021 (Forman et al., Figure 1A. In subsequent comparisons of activity in this area, M. K. Johnson et al.
Table 1 Regions of activation in Experiment 1 Hopes > duties > distraction Medial frontal gyrus, anterior cingulate (Figure 1A) Duties > hopes > distraction Precuneus, posterior cingulate, cuneus (Figure 1C) Duties > hopes ¼ distraction Cuneus, lingual gyrus (Figure 1D) Hopes ¼ duties > distraction Superior, medial frontal gyri (Figure 1B) Middle temporal gyrus, angular gyrus Distraction > hopes ¼ duties Middle, inferior frontal gyri Inferior frontal gyrus, precentral gyrus Inferior frontal gyrus (inferior precentral gyrus) Inferior temporal gyrus, fusiform gyrus, middle temporal gyrus Inferior, middle temporal gyri Inferior parietal lobule Inferior parietal lobule Superior/middle occipital gyrus Areas were identified via either a condition  time interaction (with a minimum of six contiguous voxels each significant at P < 1  1021; Forman et al., 1995) or a group condition  time (six contiguous voxels, P < 0.001) in an initial whole-brain ANOVA. Talairach coordinates (X, Y, Z) are shown for the voxel with the maximum F-value in eacharea of activation. For identified areas, planned contrasts were performed on percent signal change from Time 1 at Times 4, 5, 6 and 7 (see ‘Methods' section). Headings refer topatterns for Controls. Major anatomical regions and BA numbers are listed in descending order of approximate size, with areas of approximately equal size indicated by a slash(parentheses indicate a small extent relative to other areas listed). Different patterns for MDE group: aDiscussed in text; bDistraction > hopes > duties. H, hemisphere; L, left; M,medial; R, right; BA, Brodmann area.
the difference between duties and distraction conditions was hopes > distraction (F ¼ 134.22, P < 0.001), duties > distrac- greater for the controls than the MDE group (F ¼ 5.06, tion (F ¼ 161.66, P < 0.001) and duties > hopes (F ¼ 6.09, P ¼ 0.030). The difference in this region between hopes P ¼ 0.018). For the control group, hopes > distraction and distraction did not differ between groups (P > 0.10), (F ¼ 56.51, P < 0.001), duties > distraction (F ¼ 82.88, and the difference between groups was not significant for and duties > hopes any of the conditions (all P > 0.10). Within the control Similarly, within the MDE group, hopes > distraction group, hopes > distraction (F ¼ 18.41, P < 0.001) and (F ¼ 94.39, P < 0.001), duties > distraction (F ¼ 83.08, duties > distraction (F ¼ 18.15, P < 0.001), but hopes and P < 0.001) and duties > hopes (F ¼ 3.17, P ¼ 0.09).
duties did not differ significantly (P > 0.10). In the MDE An additional posterior medial area [cuneus, lingual group, hopes > distraction (F ¼ 10.03, P ¼ 0.005) and gyrus, BA 18 (19); Figure 1D] showed an interesting pattern: hopes > duties (F ¼ 3.94, P ¼ 0.062), while duties and dis- greater difference in activity between the hopes and distrac- traction did not differ (P > 0.10).
tion conditions for the MDE group than for controls Thus, both groups showed a more inferior area of anterior (F ¼ 5.33, P ¼ 0.026). The groups did not differ when medial PFC where activity was greater on hopes than duties duties and distraction were compared (P > 0.10). The MDE trials and a more superior area of anterior medial PFC in group showed greater activity than the controls in the hopes which activity in the two self-referential conditions did not condition (F ¼ 4.53, P ¼ 0.039), but the groups did not differ differ, replicating and extending Johnson et al. (2006) to in the other two conditions (both P's > 0.10). For controls, MDE participants. Contrary to our expectations, MDE par- hopes did not differ significantly from distraction (P > 0.10), ticipants did not show less activity than controls during the while duties > distraction (F ¼ 11.71, P ¼ 0.002) and duties hopes trials. However, as expected, the MDE group did show > hopes (F ¼ 9.11, P ¼ 0.006). For the MDE group, hopes > less deactivation than controls during distraction trials distraction (F ¼ 8.47, P ¼ 0.009) and duties > distraction (Figure 1A).
(F ¼ 7.09, P ¼ 0.015), while hopes and duties did not differ Figure 1C shows an area of precuneus, posterior cingulate, (P > 0.10).
cuneus (BAs 7, 31, 23, 19) where the difference between Thus, as in Johnson et al. (2006), both groups showed an each of the two self-focus conditions and distraction area (Figure 1C) of posterior medial cortex where activity did not differ between groups (both P's > 0.10), and the was greater in the duties than hopes condition. In addition, difference between groups was not significant in any of the in this area, MDE and control groups looked very similar. In three conditions (all P > 0.10). Collapsed across groups, a more inferior and posterior area (Figure 1D), controls Medial cortex, self-reflection and depression Table 2 Regions of activation in Experiment 2 Analytical > experiential > distraction Medial frontal gyrus, anterior cingulate (Figure 2A) Medial, superior frontal gyri (Figure 2B) Medial, superior frontal gyri (anterior cingulate) (Figure 2C) Precuneus, cuneus, cingulate gyrus (Figure 3A) Experiential > analytical > distraction Cingulate gyrus (Figure 3B) Analytical ¼ experiential > distraction Inferior frontal gyrus (precentral gyrus) Inferior frontal gyrus Middle, superior temporal gyri Superior temporal, supramarginal, angular gyrus Analytical ¼ experiential ¼ distractionLingual gyrus Distraction > experiential ¼ analytical Parahippocampal gyrus (hippocampus) Parahippocampus (hippocampus), fusiform gyrus Distraction > experiential > analytical Middle, inferior frontal gyri Middle frontal gyrus Precentral gyrus, inferior frontal gyrus Inferior, middle temporal gyri, middle occipital gyrus Inferior, middle temporal gyri Middle temporal gyrus Inferior parietal lobule Superior parietal lobule Precuneus, superior parietal lobule Superior occipital gyrus Superior occipital gyrus Areas were identified via either a condition  time interaction (with a minimum of six contiguous voxels each significant at P < 1  1021; Forman et al., 1995) or a group condition  time (six contiguous voxels, P < 0.001) in an initial whole-brain ANOVA. For identified areas, planned contrasts were performed on percent signal change from Time1 at Times 4, 5, 6 and 7 (see ‘Methods' section). Headings refer to patterns for controls. Major anatomical regions and BA numbers are listed in descending order of approximatesize, with areas of approximately equal size indicated by a slash (parentheses indicate a small extent relative to other areas listed). Different patterns for MDE group: aDiscussed intext; bA > E ¼ D; cD > E ¼ A; dD ¼ E > A; eD ¼ E ¼ A. H, hemisphere; L, left; M, medial; R, right.
again showed greater activity for duties than hopes, but the offered a career in intelligence. For duties trials, topics MDE group showed equal activity for these two self-refer- included: keep[ing] parents and friends at home updated ential conditions.
on my life, studying for finals, [attending] family reunions, Individual differences in rumination.
Higher trait rumi- accepting and seeing people for their best, helping my nation scores were associated with less activity in anterior younger sister, volunteering, [thinking of] friends who medial cortex during hopes trials (r ¼ 0.28, P ¼ 0.07, expect me to be there and how I find it very difficult, Figure 1A) and with more activity in posterior medial [owing] bills, and [being married] and the level of commit- ment one must have-even during the rocky times. There Figure 1B). During duties trials, rumination scores did not were no significant group or condition differences in correlate with activity in any of the areas identified in number of words (M ¼ 100.5; all P > 0.10) or amount of detail (M ¼ 3.20; all P > 0.10) in the post-scan reports.
Post-scan reports.
Participants reported thinking of a With respect to valence ratings, there was a valence  wide range of topics in response to the self-relevant cues. For report type interaction (F ¼ 108.79, P < 0.001). As might be hopes cues, topics included: help[ing] developing and poor expected, for the hopes reports positivity ratings (M ¼ 3.02) countries, finding the cure for cancer, writing a screenplay, were higher than negativity ratings (M ¼ 1.20), while for the owning a large house, helping my uncle's business grow, duties reports, negativity ratings (M ¼ 1.85) were higher winning scholarships, being worry-free about money/debt, than positivity ratings (M ¼ 1.29). A group main effect be[ing] able to say intelligent things and hav[ing] people (MMDE ¼ 1.97, Mcontrols ¼ 1.71; F ¼ 6.19, P < 0.05) was listen and respect me, find[ing] a research mentor for this qualified by a group  valence interaction (F ¼ 4.43, summer, meet[ing] a woman my mother will like, and being P < 0.05) because the MDE participants' (M ¼ 1.79) reports

M. K. Johnson et al.
Fig. 1 Experiment 1. Bar graphs show the mean percent change in bold signal value for control (left) and MDE (right) groups and scatter plots show significant correlationswithin conditions (distraction and hopes) between mean percent signal change and rumination score (see text). See Table 1 for details regarding coordinates, BA and maximum Ffor the region. (A) Area of anterior medial cortex showing hopes > duties > distraction for both groups, and MDE > controls in the distraction condition. (B) A more superiorarea of anterior medial cortex showing hopes ¼ duties > distraction for both groups, with no significant condition differences between the groups. (C) Area of posterior medialcortex showing duties > hopes > distraction for both groups, with no significant condition differences between the groups. (D) Area of posterior medial cortex showing duties >hopes and duties >distraction, but hopes ¼ distraction for controls; duties ¼ hopes > distraction for the MDE group, and MDE > controls in the hopes condition.
Fig. 2 Experiment 2. Bar graphs show the mean percent change in bold signal value for control (left) and MDE (right) groups and scatter plots show significant correlationswithin conditions (distraction and hopes) between mean percent signal change and rumination score (see text). See Table 2 for details regarding coordinates, BA and maximum Ffor the region. (A and B) Areas of anterior medial cortex showing control > MDE in the analytical condition and MDE > control in the distraction condition, with no difference inthe experiential condition. (C) Area of anterior medial cortex showing MDE > control in the distraction condition only.

Medial cortex, self-reflection and depression interpretation. However, the means were in the expecteddirection of less activity in medial PFC during hopes trialsin the MDE group (Figure 1A), and rumination scores werenegatively correlated (P < 0.07) with activity in medial PFCduring hopes trials. In addition, post-scan reports of MDEparticipants were rated as significantly more negative thanthose of controls. Taken together, these findings suggest thatunder the right cuing conditions, we might observe a sig-nificant reduction in medial PFC activity associated withdepression. Specifically, we might expect larger differencesin medial PFC activity between groups to emerge when par-ticipants are cued to think about themselves, but are notspecifically cued to think about positively valenced topicssuch as hopes and aspirations. This hypothesis was testedin Experiment 2.
When depressed participants are given emotionally neutralself-focused cues, they tend to ruminate about negative per-sonal experiences more than non-depressed participants do Fig. 3 Experiment 2. Bar graphs show the mean percent change in bold signal value (Lyubomirsky et al., 1999). Watkins (2008) distinguished for control (left) and MDE (right) groups and scatter plots show significant correla- between two types of self-focused rumination cues: ‘analy- tions within conditions (distraction and hopes) between mean percent signal change tical cues', which focus participants' attention on self-evalua- and rumination score (see text). See Table 2 for details regarding coordinates, BA and tions (e.g. who you strive to be, why things turn out as they maximum F for the region. (A) Area of posterior medial cortex showing MDE > do), and ‘experiential cues', which focus participants' atten- controls in the distraction condition, with no other condition differences between thegroups. (B) Area of posterior medial cortex showing no differences between MDE and tion on their current state (e.g. current physical sensations, controls for any of the conditions.
how alert you feel). Both types of cues direct participants'attention to the self, but not specifically to positive or nega-tive aspects (Lyubomirsky and Nolen-Hoeksema, 1993).
were rated as more negative than the control participants' Watkins and Teasdale (2001; also Rimes and Watkins, (M ¼ 1.26) for both types of reports, with no difference in 2005) found that for depressed individuals, both types of positive ratings (MMDE ¼ 2.15, Mcontrols ¼ 2.16).
cues maintain depressed mood, but analytical cues are espe- In short, in Experiment 1, for control participants, we cially likely to result in negative self-referential thought. That replicated two findings reported by Johnson et al. (2006): is, for depressed but not control participants, analytical cues (i) a double dissociation where activity was greater in ante- result in self-focus that is evaluative, perseverative and nega- rior medial cortex when participants thought about hopes tive. In addition, such cues prompt depressed individuals to than duties and greater in posterior medial cortex when retrieve more negative autobiographical memories, give participants thought about duties than hopes, and (ii) a more negative interpretations of current personal events dissociation within anterior medial PFC where a more infer- and make more negative predictions about their future ior area showed hopes > duties and a more superior area than control participants (Nolen-Hoeksema et al., 2008; showed hopes ¼ duties. We expected that the MDE group Watkins, 2008).
would show less activity in anterior medial cortex during These behavioral findings, in combination with the fMRI hopes trials and less deactivation in this region during dis- findings from Experiment 1, suggest that analytical cues, but traction trials. While the second prediction was confirmed, perhaps not experiential cues, would result in less activity in the first was not (Figure 1A and B). These findings suggest medial PFC in MDE participants compared with controls.
that MDE participants were relatively successful in engaging This is because MDE participants should be less likely to positive self-referential processing when cued to do so, but spontaneously generate positive self-focused thoughts in were less successful in disengaging from self-referential pro- thinking about self-evaluations, and more likely to turn to cessing in the distraction task. Thus, when MDE participants negative rumination. We also expected to replicate and were specifically cued to think about hopes and aspirations extend the results from Experiment 1 showing less deactiva- and duties and obligations, the activity in anterior and pos- tion in anterior medial cortex when MDE participants are terior medial cortex suggests that they were doing so. The given distraction cues. This would indicate that these parti- fact that MDE and control participants' post-scan reports cipants have more difficulty disengaging from self-focused did not differ in positivity ratings is consistent with this M. K. Johnson et al.
Participants were the same as in Experiment 1 (Experiment 2 P ¼ 0.027), but the groups did not differ in the other condi- followed Experiment 1 in the same scanning session). The tions (both P's > 0.10). Within the control group, analytical study was a mixed 2 (group: control, MDE)  3 (condition: > distraction (F ¼ 60.18, P < 0.001), experiential > distrac- analytical self-focus, experiential self-focus, distraction) tion (F ¼ 18.91, P < 0.001) and analytical > experiential design. Twelve of each cue type were randomly intermixed (F ¼ 28.49, P < 0.001). Within the MDE group, analytical > as in Experiment 1: new distraction cues (e.g. truckload of distraction (F ¼ 16.16, P < 0.001), experiential did not differ watermelons, shape of Italy), analytical cues (e.g. who you from distraction (P > 0.10) and analytical > experiential strive to be, why things turn out as they do, what your (F ¼ 13.62, P ¼ 0.002).
feelings mean, quality of your friendships) and experiential In short, relative to controls, for MDE participants, sub- cues (e.g. current physical sensations, how alert you feel, how regions of anterior medial PFC were less engaged during the motivated you feel, how decisive you feel). The procedure, analytical condition (Figure 1A and B) and less likely to be fMRI acquisition and analyses paralleled Experiment 1.
disengaged (i.e. deactivate) during the distraction condition(Figure 1A–C). The groups did not differ in any of these Results and discussion areas in the experiential condition.
Two areas of posterior medial cortex were also identified Three areas of anterior medial cortex were identified (Figure 3, Table 2). An area of precuneus and cuneus, (Figure 2 and Table 2). An area of medial frontal gyrusand anterior cingulate (BAs 10 and 32) is shown in extending into cingulate gyrus (BAs 7, 31, 23), is shown in Figure 2A. Comparisons of each self-referential condition Figure 3A. Comparisons of each self-referential condition with distraction resulted in group with distraction found no significant group  condition  condition interactions (analytical, F ¼ 12.16, P ¼ 0.001; experiential, F ¼ 13.22, interaction for the analytical condition (P > 0.10), but there P ¼ 0.001). As predicted, the MDE group showed less activ- was an interaction for the experiential condition (F ¼ 3.38, ity in this area than controls during the analytical condition P ¼ 0.073). The MDE group showed greater activity than (F ¼ 2.99, P ¼ 0.091) and more activity during the distrac- tion condition (F ¼ 14.43, P ¼ 0.001); they did not differ in P ¼ 0.042), but the groups did not differ in the other condi- the experiential condition (P > 0.10). Within the control tions (both P's > 0.10). Within the control group, analytical group, analytical > distraction (F ¼ 31.76, P < 0.001), experi- > distraction (F ¼ 35.64, P < 0.001), experiential > distrac- ential > distraction (F ¼ 7.18, P ¼ 0.013) and analytical > tion (F ¼ 28.18, P < 0.001) and analytical > experiential experiential (F ¼ 38.54, P < 0.001). In contrast, in the MDE (F ¼ 3.22, P ¼ 0.086). Within the MDE group, analytical > group, the analytical and distraction conditions did not distraction (F ¼ 18.89, P < 0.001) and experiential > distrac- differ in this area (P > 0.10), but distraction > experiential tion (F ¼ 25.12, P < 0.001), but analytical did not differ from (F ¼ 6.22, P ¼ 0.022) and analytical > experiential (F ¼ 5.85, experiential (P > 0.10).
P ¼ 0.026).
An area of cingulate gyrus (BAs 23/24) is shown in In an area of medial, superior frontal gyrus (BAs 9, 10) Figure 3B. Comparisons of each self-referential condition represented in Figure 2B, comparisons of each self-referential with distraction resulted in no significant group  condition condition with distraction also resulted in group  condi- interactions (both P's > 0.10), and there were no group tion interactions for analytical (F ¼ 13.18, P ¼ 0.001) and differences for the individual conditions (all P > 0.10).
experiential (F ¼ 10.83, P ¼ 0.002) conditions. As with the Within the control group, however, analytical > distraction region in Figure 2A, the MDE group showed less activity (F ¼ 17.35, P < 0.001), experiential > distraction (F ¼ 36.40, than controls during the analytical condition (F ¼ 3.78, P < 0.001) and experiential > analytical (F ¼ 3.33, P ¼ 0.081).
P ¼ 0.059) and more activity than controls during the dis- Within the MDE group, analytical > distraction (F ¼ 33.75, traction condition (F ¼ 10.76, P ¼ 0.002) in this area; the groups did not differ in the experiential condition (P > 0.10). Within the control group, analytical > distraction experiential (P > 0.10).
(F ¼ 56.49, P < 0.001), experiential > distraction (F ¼ 12.30, Overall, in posterior medial cortex, the only difference between the control and MDE groups was less deactivation P < 0.001). Within the MDE group, neither analytical nor during distraction in the precuneus, cuneus area as shown in experiential differed from distraction (both P's > 0.10), but Figure 3A. In contrast to the pattern in anterior medial analytical > experiential (F ¼ 7.05, P ¼ 0.016).
cortex, in posterior medial cortex there was little difference A region of medial, superior frontal gyrus, extending into in activity between the two self-referential conditions or anterior cingulate [BAs 9, 10 (32)] is shown in Figure 2C.
between groups in the self-referential conditions.
Comparisons of each self-referential condition with dis- Individual differences in rumination.
As expected, higher traction resulted in a group  condition interaction for rumination scores were associated with less activity in ante- analytical (F ¼ 3.31, P ¼ 0.076) and experiential (F ¼ 6.39, rior medial cortex during analytical trials (r ¼ 0.30, P ¼ 0.015). The MDE group showed more activity than P ¼ 0.046, Figure 2B). In addition, higher rumination Medial cortex, self-reflection and depression scores were associated with more activity during distraction Table 3 Mean mood ratings (s.e. of the cell mean) for three time points trials in anterior medial cortex (r ¼ 0.45, P < 0.001, P ¼ 0.072, Figure 2C), and in posterior medial cortex Experiments 1 and 2 Figure 3B). Rumination scores were not significantly corre- lated with activity in regions shown in Figures 2 and 3 during experiential trials (P > 0.10).
Visual analog mood scale results.
scores obtained pre-scan (Time 1), between Experiments 1 and 2 (Time 2) and post-scan (Time 3) are presented in Table 3 (n ¼ 18 in the MDE group because two participants were each missing one measure and thus were excluded fromanalysis). A 2 (group: control, MDE)  3 (valence: negative,neutral, positive)  3 (Time: 1, 2, 3) ANOVA on the moodscale scores showed a three-way interaction (F ¼ 3.06, group gave higher ratings to the filler items than did the P ¼ 0.018). As might be expected, compared with controls, control group at Time 1 (t ¼ 2.23, P ¼ 0.032) and Time 3 the ratings of the MDE group were significantly more nega- (t ¼ 2.47, P ¼ 0.02), suggesting that they may have been tive for the negative items, and significantly less positive for more sensitive to their bodily feelings than were the control the positive items, at all three time points (all P's < 0.001).
participants before and after the scan session, but not However, the full pattern of mood data argues against an interpretation that the current fMRI findings are based In sum, as predicted, when participants were induced to merely on a task-induced worsening of mood during the think about themselves and their life with cues that did not scans in the MDE group. Specifically, the MDE group's rat- explicitly direct them toward thoughts with a particular ings for negative items became less negative over time: from valence, MDE participants showed less activity in anterior Time 1 to 2, the ratings decreased 3.15% (P > 0.10) and from medial cortex than did controls. That this pattern was Time 2 to 3, they decreased 6.39% (t ¼ 3.81, P ¼ 0.001).
observed during analytical but not experiential trials is con- Hence from Time 1 to 3, the MDE group's ratings on nega- sistent with previous behavioral findings suggesting that ana- tive items decreased on average 9.54% (t ¼ 2.69, P ¼ 0.015).
lytical cues are more likely than experiential cues to induce For control participants, the decrease from Time 1 to 3 was rumination (Watkins, 2008). Rumination scores were also only 3.38%, which, although a reliable change (t ¼ 2.48, negatively correlated with activity in anterior medial cortex P < 0.02), was marginally less than that of the MDE group during analytical trials and positively correlated with activity (t ¼ 1.79, P ¼ 0.081). The MDE group showed no changes in in both anterior and posterior medial cortex during distrac- their ratings of the positive items (all P's > 0.10). The control tion trials. Thus, the results of Experiment 2 demonstrate group showed a 7.5% decrease on the positive items from that, when responding to valence-neutral cues that induce Time 1 to 2 (t ¼ 3.60, P ¼ 0.002), but a small increase (3.9%) self-evaluative thought, depression is associated with from Time 2 to 3 (t ¼ 3.89, P ¼ 0.079); thus, the change from reduced likelihood of engaging regions of anterior medial Time 1 to 3 was not significant (P > 0.10).1 Finally, although cortex that have been shown to be associated with positive there was not much change in ratings of the filler items (e.g.
thoughts about one's hopes and aspirations. The findings hungry, tired, bored) over time in either group, the MDE also indicate that depression is associated with less deactiva-tion of medial regions associated with self-referentialthought, suggesting difficulties disengaging from self-focusedthought when the task demands (Siegle et al., 2002; Joorman, As noted in the introduction to Experiment 2, we knew from existing behavioral literature (Watkins and 2004, 2005).
Teasdale, 2001; also Rimes and Watkins, 2005) that the self-reflection manipulations used in Experiment 2 Finally, the relative absence of activity associated with self- were likely to induce rumination in the MDE group. We thus tested everyone first in Experiment 1 to minimizepotential carryover effects that might have attenuated MDE participants' likelihood of recruiting medial cortex reflection in posterior medial cortex in both groups in areas when specifically prompted with cues that we knew would recruit these areas in controls. Of course, Experiment 2, especially in the experiential condition, pro- there could have been carryover effects of the Experiment 1 manipulation on the nature of participants' self- vides further evidence that this region is not simply a ‘self' reflection in Experiment 2, as well. For example, if MDE participants failed to come up with compelling hopesin Experiment 1, or failed to feel hopeful about the ones they did generate, they may have had more negative area. Rather it may be involved in more specific functions, thoughts in the analytical condition in Experiment 2 than they otherwise would have. If so, this would be such as the revival of episodic memories (Hassabis et al., consistent with findings that depression leads to a cycle of negative thinking that pervades even ostensibly 2007), that may occur more as one thinks about self-relevant neutral situations. However, the significant rise in mood scores in the MDE group suggests that priming ofpositive ideas might have worked against our predictions for Experiment 2. That is, being prompted to come agendas such as hopes and duties (Experiment 1; Johnson up with specific hopes in Experiment 1 may have attenuated differences between groups in Experiment 2 by et al., 2006) than less concrete issues associated with self- priming positive thoughts for MDE participants that would not otherwise have been accessed. Thus, the group evaluation (e.g. analytic cues such as considering the nature difference we found in medial PFC in Experiment 2 actually might have underestimated the true (unprimed)difference in these groups in the nature of their spontaneous self-reflection.
of one's relationships).
M. K. Johnson et al.
GENERAL DISCUSSION thought (Johnson et al., 2006; see also Moran et al., 2006).
To our knowledge, these are the first fMRI studies to com- Converging evidence for the hypothesis that inferior pare medial cortex activity of MDE and control individuals medial PFC is associated with positively valenced thoughts contrasting self-focused cues about two types of personally (Johnson et al., 2006; Sharot et al., 2007) was reported by relevant agendas (hopes, duties; Experiment 1) and contrast- D'Argembeau et al. (2008), who cued participants to think of ing self-referential cues that have been shown to differen- positive and negative future events (generated by the same tially induce rumination in depressed individuals (analytic, participants in a previous session) and found positive > experiential; Experiment 2).
negative in an area of inferior medial PFC close to the area In Experiment 1, activity in an inferior area of anterior we found in both experiments (0, 51, 4, compare with medial cortex (Figure 1A) was greater in response to cues to current Figures 1A and 2A). Nonetheless, the areas of ante- think about hopes and aspirations than cues to think about rior medial cortex associated with valence do vary some across self-referential studies (Gutchess et al., 2007; (Johnson et al., 2006). Furthermore, activity in this region Yoshimura et al., 2009). Thus, differentiating functional did not differ significantly between control and MDE parti- sub-regions of anterior medial cortex with respect to valence cipants. These findings suggest that MDE participants were and the interaction between valence and self-reference able to recruit this area when explicitly given cues to engage remains a challenge.
the sorts of self-reflective processing previously shown to Investigators have also begun to identify sub-regions of activate this region in control participants, and are consis- anterior medial cortex that appear to be involved in other tent with behavioral studies showing that depressed indivi- duals can generate positive memories and thoughts when Cunningham (in press) investigated whether greater medial guided to do so (Wenzlaff et al., 1988). However, behavioral PFC activity for hopes than duties might be related to the studies also indicate that depressed individuals have diffi- more distant time frame that is likely to be considered for culty generating positive memories and thoughts on their hopes than for duties. They cued participants to the time own (Wenzlaff et al., 1988), and findings from Experiment frame to consider (e.g. this week, next year, 10 years from 2 provide neural evidence consistent with these behavioral now) and found hopes > duties in an area (6, 46, 1) very close to the inferior medial PFC area as shown in In Experiment 2, a similar area of anterior medial PFC Figures 1A and 2A. In addition, this area was not sensitive (Figure 2A) was more engaged in response to analytical self- to time frame. Rather, both Packer and Cunningham (in focus cues (e.g. ‘why things turn out as they do') than experi- press) and D'Argembeau et al. (2008) reported evidence ential cues (e.g. ‘current physical sensations'), consistent that an even more inferior PFC region (BA 11: 0, 28, 19; with findings from Experiment 1 that this region is not and 3, 45, 19, respectively) than found in the present simply a self-focus region, but rather is especially sensitive study is differentially active when participants think about to certain types of self-focus (see also Johnson et al., 2006; distant compared with near events. Packer and Cunningham Mitchell et al., 2009). Further, control participants showed also found an area of more superior medial PFC (3, 49, 29) greater activation in medial PFC compared with MDE near the areas in Figures 1B (4, 60, 21) and 2B (4, 57, 21), participants in the analytical cue condition. This pattern of which they associated with more domain general processes activation would be expected if this sub-region of medial invoked when the task was more difficult (in their experi- PFC is associated with positively valenced self-focus ment near hopes and far duties were more difficult than far (Johnson et al, 2006; Sharot et al., 2007) and if analytical hopes and near duties). (Where published papers reported self-focus led to negative self-thought (rumination) in MNI coordinates, to facilitate comparison, we converted to susceptible individuals (Watkins, 2008). That is, depressed Talairach using BioImage Suite http://www.bioimagesuite individuals may show reduced medial PFC activity, com- pared with those without depression, because they are less It is notable that across five studies comparing hopes and likely or able to generate positive ideas in response to duties conditions (Johnson et al., 2006, Experiments 1 and 2; analytical cues, because the positive thoughts they do Mitchell et al., 2009; Packer and Cunningham, in press, generate feel less positive, and/or negative thoughts offset and the present Experiment 1), the z coordinates of local the impact of positive thoughts.
maxima in anterior medial regions showing hopes > duties The present findings provide additional evidence for dif- (in young/control participants) ranged from 7 to 16 and ferent functional sub-regions of medial PFC (Ochsner et al., the z coordinates of anterior medial regions showing hopes 2004; Mitchell et al., 2005; Amodio & Frith, 2006; Northoff ¼ duties ranged from 21 to 32. This pattern is consistent et al., 2006). In particular, these results provide converging with suggestions of a ventral/dorsal division of functions in support for the conclusion that an area of inferior medial medial PFC with respect to more/less valenced self- PFC is associated with more positive thought, while a more processing (Ochsner et al., 2005; Johnson et al., 2006; superior medial PFC area is associated with either more Moran et al., 2006) and, more generally, similar to the general self-focus or with less-affective aspects of self-focused ventral/dorsal division of anterior cingulate cortex into Medial cortex, self-reflection and depression more/less emotional processing areas (Bush et al., 2000).
the MDE and control groups in length or rated detail.
Thus, the relatively reduced recruitment of the two areas Thus, the difference in anterior medial cortex activity of medial PFC found in Experiment 2 for the MDE group in the analytical condition in Experiment 2, coupled with likely reflects a combination of more goal-specific factors no under-recruitment of posterior medial cortex in the (e.g. affective content, Figure 2A) and more general factors MDE group in either experiments, suggests a difference (e.g. the type or complexity of reflective processes engaged, between groups not in ‘how much' participants were think- Figure 2B), but not differences in the time frames considered ing, but in ‘what' they were thinking, i.e. a difference in by the two groups.
specific content and/or valence. Further studies will be Posterior medial cortex has also been found to be active needed to dissociate the impact of the amount of detail in during self-referential processing (Johnson et al., 2002; Vogt what is thought from the valence, specificity or other features and Laureys, 2005; Northoff et al., 2006), and more so when of what is thought. Nevertheless, the fact that the MDE people are cued to think about their duties and obligations group did not show reduced activity relative to controls in than their hopes and aspirations (Johnson et al., 2006). We posterior medial cortex during self-reflection in a range of replicated this latter finding in both control and MDE par- cuing conditions represented in the two experiments argues ticipants in Experiment 1 (Figure 1C). Control participants for a relatively specific reduction in anterior medial cortex also showed greater activity on duties trials than hopes trials activity associated with depression.
in a more inferior and posterior area, whereas MDE partici- In short, the overall pattern across these two experiments pants did not (Figure 1D). The similar activity in hopes and suggests that a primary difference between MDE and control duties trials in the posterior medial area in Figure 1D in the individuals when engaging in self-reflection is an under- MDE group suggests that the thoughts of MDE participants recruitment in MDE participants of anterior medial areas in response to cues meant to elicit hopes and aspirations associated with positively valenced thoughts (e.g. hopes were in some way more similar to those meant to elicit and aspirations) when cues are ambiguous in terms of duties and obligations than was the case for controls.
valence and do not specifically elicit such thoughts.
Activity in the posterior medial cortex is associated with This fits with models of depression suggesting it is charac- autobiographical retrieval (Cavanna and Trimble, 2006; terized by an underactive approach system, leading to Hassabis et al., 2007), and thinking about duties may gen- low motivation and a failure to experience positive effect erate more episodic recall of past events (e.g. specific com- (Gray, 1982; Fowles, 1988; Davidson, 1998; Schaefer et al., mitments made to others) than thinking about hopes (Johnson et al., 2006). Thus, one hypothesis is that the pat- When Johnson et al. (2006) originally reported a double tern seen in the area of posterior medial cortex shown in dissociation between the nature of self-relevant agendas Figure 1D may reflect a greater tendency of MDE partici- (hopes vs duties) and the medial regions that are most pants to think back to past episodes during attempts to think active (anterior vs posterior medial cortex, respectively), of future-oriented hopes. However, the area in Figure 1D is they suggested a number of potential factors to explore more posterior and inferior to those (such as the area in that could contribute to this finding: (i) differences in con- Figure 1C) typically associated with self-referential proces- tent; (ii) differences in the component processes engaged sing and with episodic memory. Thus, this interesting pat- (e.g. generating/discovering new relations vs retrieving epi- tern needs to be replicated using more systematic sodic information); (iii) differences in affective/motivational manipulations in order to isolate its role in self-referential significance; (iv) differences in subjective experience of self (e.g. instrumental control vs experience of awareness); and Anterior, as well as posterior, medial cortex has been asso- (v) differences in social/contextual factors (e.g. duties may be ciated with autobiographical memory and with imagining more likely to involve others; differences in perspective future events (Addis et al., 2007; Hassabis et al., 2007; taking). Of course, these are not entirely orthogonal factors.
D'Argembeau et al., 2008). Given that depression is not For example, differences in the subjective experience of self only associated with less positive thinking, but also with should be related to differences in the component processes less specific, more general thoughts, both for autobiographi- engaged (Johnson and Reeder, 1997). The present results add cal memories and for imagining future events, particularly to other recent findings (e.g. Vogt and Laureys, 2005; when depression involves analytical rumination (Williams Cavanna and Trimble, 2006; Johnson et al., 2006; Hassabis et al., 1996; Williams et al., 2000; Dickson and Bates, 2006; et al., 2007; Sharot et al., 2007; D'Argembeau et al., 2008; Watkins, 2008), the reduced activity in the MDE group in Packer and Cunningham, in press) that together suggest that anterior medial cortex in the analytical condition of specific sub-regions of medial cortex are differentially asso- Experiment 2 might reflect more impoverished thoughts.
ciated with factors such as type of processing engaged, type However, it is of note that we found no evidence of reduced of goal, valence and time-frame considered. Such factors activity associated with depression in posterior medial cortex would be expected to show important group and individual in either experiment. Recall also that the post-scan reports differences and thus should be promising targets for further about what participants were thinking did not differ for M. K. Johnson et al.
It is also important to note that regions in anterior and Our findings provide strong support for the idea that indi- posterior medial cortex are part of a network that has come viduals with depression engage in self-focused thought even to be called the ‘default network' because activity is found in when the task is to engage in non-self-relevant processing these regions when people do not have any particular cog- (see also, e.g. Sheline et al., 2009, for a similar suggestion).
nitive task to do (Gusnard et al., 2001). Commonly, in fMRI These findings are in line with behavioral data that depressed studies, these areas are active at rest and ‘deactivate' during individuals have difficulty withdrawing attention from self- performance of a cognitive task. In both Experiments 1 and relevant information when it would be appropriate to do so 2, the MDE group showed less deactivation than did the (Joormann, 2004, 2006; Donaldson et al., 2007). If deactiva- control group in medial cortex during distraction trials, sug- tion of medial cortex is necessary for the activation of other gesting that they may be disengaging these default areas less areas in response to certain cognitive task demands (e.g.
than controls when presented with a non-self-referential, attention and memory tasks, Grady et al., 2006), then cognitive task. In individuals with major depression, the depression would be expected to disrupt cognitive perfor- medial cortex regions associated with the default network, mance, and there is behavioral evidence that it does so especially more inferior anterior regions including subgenual (Strack et al., 1985; Hertel, 1998; Nolen-Hoeksema et al., cingulate cortex, show hypermetabolism (e.g. Drevets et al., 2002; Mayberg, 2003b) and increased functional connectivity Together, the findings discussed may help explain why, (e.g. Greicius et al., 2007) during the resting state (see across studies of depression, the specific patterns of findings Drevets et al., 2008; Gotlib and Hamilton, 2008, for recent in medial cortex are mixed. For example, in medial PFC, reviews). These areas also demonstrate less deactivation studies sometimes show hypofrontality and sometimes during cognitive or emotion processing tasks in depressed, hyperfrontality (Mayberg, 2003a; Phillips et al., 2003; compared with control, participants (e.g. Vasic et al., 2008; Drevets et al., 2008; Gotlib and Hamilton, 2008 for reviews Grimm et al., 2009; Sheline et al., 2009; see also, Drevets and discussion). Our results are generally consistent with et al., 2008; Gotlib and Hamilton, 2008, for recent reviews).
earlier neuroimaging studies finding reduced task-related Moreover, such differences correlate with depressive symp- activity in medial PFC associated with depression (Bench toms. For example, amount of subgenual cingulate cortex et al., 1993; Drevets, 2000; Charney and Manji, 2004), and connectivity within the default network correlates with the consistent with the idea that depression involves dysfunction duration of current episode of depression (Grecius et al., in the ability to self-regulate emotion via the recruitment 2007), and less deactivation during the processing of (nega- and maintenance of approach-related self-relevant agendas tive) emotional pictures in ventromedial PFC correlates with (as in Joormann and Siemer, 2004; Wenzlaff et al., 1988).
subjective ratings of hopelessness and less deactivation in But, our results also suggest that some variability in findings posterior cingulate cortex correlates with level of depression with depressed individuals across studies may in part reflect (i.e. scores on the Hamilton Depression Scale) (Grimm et al., differences in the nature of the spontaneous thoughts engaged by participants during, for example, resting periods Because fMRI data are correlational, the present findings or baseline assessments.
alone cannot differentiate whether: (i) the observed group Our results also suggest that some variability in findings differences in medial cortex activity signal differences in with depressed individuals may depend in part on whether what is motivationally significant or salient during self- and what kind of self-reflective processing is relevant to the relevant thinking in individuals with depression, so that task at hand, and how well cues engage that specific proces- changes in focus or content lead to changes in medial sing. For example, if self-relevant processing of positive cortex activity; or (ii) changes in the functioning of medial information such as hopes and aspirations is specifically cortex in depression promote differences in the content or cued, based on our findings, we would expect less difference focus of self-relevant thinking. However, based on a range between controls and depressed participants in medial PFC of neurophysiological evidence, including developmental activity than in tasks that put fewer constraints on the nature trajectories, it has been suggested that default network con- of self-referential thinking. Group differences should be most nectivity is sculpted by experience (Sheline et al., 2009).
likely in the unconstrained case because depressed partici- Thus, it may be that long-term self-focused, negative rumi- pants are less likely to spontaneously generate positive native thinking, such as that engaged by many depressed thoughts and more likely to spontaneously generate negative individuals, strengthens connectivity of certain medial thoughts (Wenzlaff et al., 1988). If self-relevant processing areas of the default network (Greicius et al., 2007), making (positively or negatively valenced) is not appropriate to the it more difficult to disengage when appropriate (e.g. during task at all (as in many cognitive tasks), we would expect to distraction tasks).
find more medial PFC activity (i.e. less deactivation) asso- In any event, differences in activity within specific areas of ciated with depression (Siegle et al., 2002), consistent with a the ‘default network' may provide an index of the extent and failure to disengage from self-relevant processing when it is type of self-focused thought that is spontaneously engaged, not appropriate. In other words, increases in activity in and these may differ systematically between populations.
medial PFC associated with depression, relative to controls, Medial cortex, self-reflection and depression would be expected if depressed participants are less able to and aspirations when the cues to self-reflection are ambig- disengage self-focused thought and engage processes uous. Furthermore, a tendency to ruminate is correlated required for other tasks.
with greater activation in anterior and posterior medial Depression is a heterogeneous disorder. Studies of dys- cortex during tasks where these regions typically deactivate, phoric and MDD/MDE participants along the lines of the suggesting a persisting self-focus when it may not be appro- present study, that manipulate the specific nature of both priate. Exploring differential engagement and disengagement self-relevant and non-self-relevant processing, would help of specific regions in anterior and posterior medial cortex in distinguish between individual differences in dysfunction different populations under different circumstances should of the self-relevant and self-regulatory processing networks help clarify the role that these regions normally play in self- that involve anterior and posterior medial cortex regions and reflection and emotion regulation and in the interaction could clarify individual differences in the circumstances between motivation, emotion and cognition more generally.
under which these areas are engaged, which could be clini-cally useful. For example, in subclinical dysphoric popula- Conflict of Interest tions, the extent to which medial PFC is engaged under None declared.
specific instructions to think about hopes and aspirationsor the extent to which engagement is predicted by rumina-tion scores may provide an early biomarker of susceptibility to develop clinically significant depression. In clinically Addis, D.R., Wong, A.T., Schacter, D.L. (2007). Remembering the past and depressed patients, such responses may predict response to imagining the future: common and distinct neural substrates duringevent construction and elaboration. Neuropsychologia, 45, 1363–77.
treatment. Alternatively, measures of spontaneous activity Amodio, D.M., Frith, C.D. (2006). Meeting of the minds: the medial frontal during ambiguous cues or during rest may provide better cortex and social cognition. Nature Reviews. Neuroscience, 7, 268–77.
biomarkers of susceptibility and/or responsiveness to treat- Beck, A.T., Steer, R.A., Brown, G.K. (1996). Manual for the Beck Depression ment. Such possibilities warrant further exploration. In addi- Inventory-II. San Antonio, TX: The Psychological Corporation.
tion, depression frequently co-occurs with other disorders Bench, C.J., Friston, K.J., Brown, R.G., Frackowiak, R.S. J., Dolan, R.J.
(1993). Regional cerebral blood flow in depression measured by positron (Davidson et al., 2002) that also involve emotional dysregu- emission tomography: the relationship with clinical dimensions.
lation or non-constructive self-reflection (e.g. anxiety disor- Psychological Medicine, 23, 579–90.
ders, borderline personality disorder, post-traumatic stress Bush, G., Luu, P., Posner, M.I. (2000). Cognitive and emotional influences disorder; Gross and Munoz, 1995; Nolen-Hoeksema et al., in anterior cingulate cortex. Trends in Cognitive Sciences, 4, 215–22.
Cantor, N., Kihlstrom, J.F. (1987). Personality and Social Intelligence.
2008). Our understanding would be advanced by systemati- Englewood Cliffs, NJ: Prentice-Hall.
cally investigating these co-occurring disorders to establish Cavanna, A.E., Trimble, M.R. (2006). The precuneus: a review of its func- whether the current findings are specific to depression or are tional anatomy and behavioural correlates. Brain, 129, 564–83.
present in other forms of psychopatholgy as well.
Charney, D.S., Manji, H.K. (2004). Life stress, genes, and depression: Finally, we note that although discussions of depression Multiple pathways lead to increased risk and new opportunities for inter-vention. Science's STKE (Electronic Resource: Signal Transduction tend to focus on areas, such as subgenual anterior cingulate, Knowledge Environment), 225, re5.
that are somewhat inferior to our most inferior area Cox, R.W. (1996). AFNI: software for analysis and visualization of func- (Figures 1A and 2A), other anterior medial areas clearly tional magnetic resonance neuroimages. Computers and Biomedical show disruption in depression (besides the current studies, Research, 29, 162–73.
see also, e.g. Vasic et al., 2008; Grimm et al., 2009; Sheline D'Argembeau, A., Xue, G., Lu, Z.-L., Van der Linden, M., Bechara, A.
(2008). Neural correlates of envisioning emotional events in the near et al., 2009). As we begin to discover more about the func- and far future. NeuroImage, 40, 398–407.
tional specificity of sub-regions of anterior medial cortex Davidson, R.J. (1998). Affective style and affective disorders: perspectives (e.g. Johnson et al., 2006; D'Argembeau et al., 2008; Packer from affective neuroscience. Cognition and Emotion, 12, 307–30.
and Cunningham, in press; current experiments), the differ- Davidson, R.J., Pizzagalli, D., Nitschke, J.B., Putnam, K. (2002). Depression: ences in the sub-regions of medial cortex found to be perspectives from affective neuroscience. Annual Review of Psychology, 53,545–74.
affected in depression under different conditions should pro- Dickson, J.M., Bates, G.W. (2006). Autobiographical memories and views of vide information about both this disorder and the functions the future: in relation to dysphoria. International Journal of Psychology, of these regions. For example, it may be that the more infer- 41, 107–16.
ior, subgenual region of medial PFC, which appears to be Dickson, J.M., MacLeod, A.K. (2006). Dysphoric adolescents' causal expla- nations and expectations for approach and avoidance goals. Journal of hyperactive in treatment-resistant depression and which Adolescence, 29, 177–91.
responds to deep brain stimulation, plays a specific role in Donaldson, C., Lam, D., Mathews, A. (2007). Rumination and attention in maintaining negative mood (Mayberg et al., 2005), whereas major depression. Behaviour Research and Therapy, 45, 2664–78.
the regions of slightly more superior medial PFC observed in Drevets, W.C. (2000). Neuroimaging studies of mood disorders. Biological the present studies play a role in maintaining positive mood.
Psychiatry, 48, 813–29.
Drevets, W.C., Bogers, W., Raichle, M.E. (2002). Functional anatomical In conclusion, our findings suggest that depression is asso- correlates of antidepressant drug treatment assessed using PET measures ciated with lower probability of engaging regions of anterior of regional glucose metabolism. European Neuropsychopharmacology, 12, medial PFC associated with positive thoughts such as hopes M. K. Johnson et al.
Drevets, W.C., Price, J.L., Furey, M. L. (2008). Brain structural and Joormann, J. (2005). Inhibition, rumination, and mood regulation in depression. In: Engle, R.W., Sedek, G., Hecker, U.V., McIntosh, D.N., neurocircuitry models of depression. Brain Structure and Function, 213, editors. Cognitive Limitations in Aging and Psychopathology. New York: Cambridge University Press, pp. 275–312.
Duvernoy, H.M. (1999). The Human Brain: Surface, Three-dimensional Joormann, J. (2006). Differential effects of rumination and dysphoria on the Sectional Anatomy with MRI, and Blood Supply, 2nd edn. New York: inhibition of irrelevant emotional material: evidence from a negative priming task. Cognitive Therapy and Research, 30, 149–60.
First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W. (1998). Structured Joormann, J., Siemer, M. (2004). Memory accessibility, mood regulation, Clinical Interview for DSM-IV Axis I Disorders – Patient Edition (Version and dysphoria: difficulties in repairing sad mood with happy memories? 2.0). New York: Biometrics Research Department.
Journal of Abnormal Psychology, 113, 179–88.
Forman, S.D., Cohen, J.D., Fitzgerald, M., Eddy, W.F., Mintun, M.A., Lancaster, J.L., Summerlin, J.L., Rainey, L., Freitas, C.S., Fox, P.T. (1997).
Noll, D.C. (1995). Improved assessment of significant activation in func- The Talairach daemon, a database server for Talairach atlas labels.
tional magnetic resonance imaging (fMRI): use of a cluster-size threshold.
NeuroImage, 5, S633.
Magnetic Resonance in Medicine, 33, 636–47.
Lyubomirsky, S., Nolen-Hoeksema, S. (1993). Self-perpetuating properties Fossati, P., Hevenor, S.J., Graham, S.J., et al. (2003). In search of the emo- of dysphoric rumination. Journal of Personality and Social Psychology, 65, tional self: an fMRI study using positive and negative emotional words.
American Journal of Psychiatry, 160, 1938–45.
Lyubomirsky, S., Tucker, K.L., Caldwell, N. D., Berg, K. (1999). Why Fowles, D.C. (1988). Psychophysiology and psychopathology: a motiva- ruminators are poor problem solvers: clues from the phenomenology tional approach. Psychophysiology, 25, 373–91.
of dysphoric rumination. Journal of Personality and Social Psychology, Gotlib, I.H., Hamilton, J.P. (2008). Neuroimaging and depression: current 77, 1041–60.
status and unresolved issues. Current Directions in Psychological Science, Macrae, C.N., Moran, J.M., Heatherton, T.F., Banfield, J.F., Kelley, W.M.
17, 159–63.
(2004). Medial prefrontal activity predicts memory for self. Cerebral Grady, C.L., Springer, M.V., Hongwanishkul, D., McIntosh, A.R., Cortex, 14, 647–54.
Winocur, G. (2006). Age-related changes in brain activity across the Markus, H., Nurius, P. (1986). Possible selves. American Psychologist, 41, adult lifespan. Journal of Cognitive Neuroscience, 18, 227–41.
Gray, J. (1982). The Neuropsychology of Anxiety: An Enquiry into the Mayberg, H.S. (2003a). Modulating dysfunctional limbic-cortical circuits in Functions of the Septo-Hippocampal System. Oxford: Oxford University depression: towards development of brain-based algorithms for diagnosis and optimised treatment. British Medical Bulletin, 65, 193–207.
Greicius, M.D., Flores, B.H., Menon, V., et al. (2007). Resting-state func- Mayberg, H.S. (2003b). Positron emission tomography imaging in depres- tional connectivity in major depression: abnormally increased contribu- sion: a neural systems perspective. Neuroimaging Clinics of North America, tions from subgenual cingulate cortex and thalamus. Biological Psychiatry, 13, 805–15.
62, 429–37.
Mayberg, H.S., Liotti, M., Brannan, S.K., et al. (1999). Reciprocal limbic- Grimm, S., Boesiger, P., Beck, J., et al. (2009). Altered negative BOLD cortical function and negative mood: converging PET findings in depres- responses in the default-mode network during emotion processing in sion and normal sadness. American Journal of Psychiatry, 156, 675–82.
depressed subjects. Neuropsychopharmacology, 34, 932–43.
Mayberg, H.S., Lozano, A.M., Voon, V., et al. (2005). Deep brain stimula- Gross, J.J., Munoz, R.F. (1995). Emotion regulation and mental health.
tion for treatment-resistant depression. Neuron, 45, 651–60.
Clinical Psychology: Science and Practice, 2, 151–64.
Mitchell, J.P., Banaji, M.R., Macrae, C.N. (2005). The link between social Gusnard, D.A., Akbudak, E., Shulman, G.L., Raichle, M.E. (2001). Medial cognition and self-referential thought in medial prefrontal cortex. Journal prefrontal cortex and self-referential mental activity: relation to a default of Cognitive Neuroscience, 17, 1306–15.
mode of brain function. Proceedings of the National Academy of Sciences, Mitchell, K.J., Raye, C.L., Ebner, N.C., Tubridy, S.M., Frankel, H., USA, 98, 4259–64.
Johnson, M.K. (2009). Age-group differences in medial cortex activity Gutchess, A. H., Kensinger, E.A., Schacter, D.L. (2007). Aging, self- associated with thinking about self-relevant agendas. Psychology and referencing, and medial prefrontal cortex. Social Neuroscience, 2, Aging, 24, 438–449.
Moran, J.M., Macrae, C.N., Heatherton, T.F., Wyland, C.L., Kelley, W.M.
Hassabis, D., Kumaran, D., Maguire, E.A. (2007). Using imagination to (2006). Neuroanatomical evidence for distinct cognitive and affective understand the neural basis of episodic memory. The Journal of components of self. Journal of Cognitive Neuroscience, 18, 1586–94.
Neuroscience, 27, 14365–74.
Nolen-Hoeksema, S. (1991). Responses to depression and their effects on Hertel, P.T. (1998). Relation between rumination and impaired memory in the duration of depressive episodes. Journal of Abnormal Psychology, 100, dysphoric moods. Journal of Abnormal Psychology, 107, 166–72.
Higgins, E.T. (1997). Beyond pleasure and pain. American Psychologist, 52, Nolen-Hoeksema, S. (2004). The response style theory. In: Papageorgiou, C., Wells, A., editors. Depressive Rumination: Nature, Theory, and Treatment.
Higgins, E.T. (1998). Promotion and prevention: Regulatory focus New York: Wiley, pp. 107–23.
Nolen-Hoeksema, S., Wisco, B.E., Lyubomirsky, S. (2008). Rethinking Psychology, 30, 1–46.
rumination. Perspectives on Psychological Science, 3, 400–24.
Johnson, M.K., Reeder, J.A. (1997). Consciousness as meta-processing.
Northoff, G., Heinzel, A., de Greck, M., Bermpohl, F., Dobrowolny, H., In: Cohen, J.D., Schooler, J.W., editors. Scientific Approaches to Panksepp, J. (2006). Self-referential processing in our brain – a meta- Consciousness. Mahwah, NJ: Erlbaum, pp. 261–93.
analysis of imaging studies on the self. NeuroImage, 31, 440–57.
Johnson, S. C., Baxter, L. C., Wilder, L. S., Pipe, J. G., Heiserman, J. E., Ochsner, K.N., Beer, J.S., Robertson, E.R., et al. (2005). The neural Prigatano, G. P. (2002). Neural correlates of self-reflection. Brain, 125, correlates of direct and reflected self-knowledge. NeuroImage, 28, Johnson, M.K., Raye, C.L., Mitchell, K.J., Touryan, S.R., Greene, E.J., Ochsner, K.N., Knierim, K., Ludlow, D.H., et al. (2004). Reflecting upon Nolen-Hoeksema, S. (2006). Dissociating medial frontal and posterior feelings: an fMRI study of neural systems supporting the attribution of cingulate activity during self-reflection. Social Cognitive and Affective emotion to self and other. Journal of Cognitive Neuroscience, 16, 1748–1772.
Neuroscience, 1, 56–64.
Packer, D.J., Cunningham, W.A. (in press). Neural correlates of reflection Joormann, J. (2004). Attentional bias in dysphoria: the role of inhibitory on goal states: The role of regulatory focus and temporal distance. Social processes. Cognition and Emotion, 18, 125–47.
Medial cortex, self-reflection and depression Phillips, M. L., Drevets, W.C., Rauch, S.L., Lane, R. (2003). Neurobiology of Vasic, N., Walter, H., Sambataro, F., Wolf, R.C. (2008). Aberrant functional emotion perception II: implications for major psychiatric disorders.
connectivity of dorsolateral prefrontal and cingulate networks in patients Biological Psychiatry, 54, 515–28.
with major depression during working memory processing. Published Ray, R.D., Ochsner, K.N., Cooper, J.C., Robertson, E.R., Gabrieli, J.D.E., online by Cambridge University Press, 10 October 2008, doi:10.1017/ Gross, J.J. (2005). Individual differences in trait rumination and the neural systems supporting cognitive reappraisal. Cognitive, Affective, & Vogt, B.A., Laureys, S. (2005). Posterior cingulate, precuneal and retrosple- Behavioral Neuroscience, 5, 156–68.
nial cortices: cytology and components of the neural network correlates of Rimes, K.A., Watkins, E. (2005). The effects of self-focused rumination on consciousness. In: Laureys, S., editor. Progress in Brain Research, Vol. 150.
global negative self-judgments in depression. Behaviour Research and The Netherlands: Elsevier, pp. 205–17.
Therapy, 43, 1673–81.
Watkins, E.R. (2008). Constructive and unconstructive repetitive thought.
Schaefer, H.S., Putnam, K.M., Benca, R.M., Davidson, R.J. (2006). Event- Psychological Bulletin, 134, 163–206.
related functional magnetic resonance imaging measures of neural reac- Watkins, E., Teasdale, J.D. (2001). Rumination and overgeneral memory in tivity to positive social stimuli in pre and post-treatment depression.
depression: effects of self-focus and analytic thinking. Journal of Abnormal Biological Psychiatry, 60, 974–86.
Psychology, 110, 353–7.
Sharot, T., Riccardi, A.M., Raio, C.M., Phelps, E.A. (2007). Neural mechan- Wenzlaff, R.M., Wegner, D.M., Roper, D.W. (1988). Depression and mental isms mediating optimism bias. Nature, 450, 102–5.
control: the resurgence of unwanted negative thoughts. Journal of Sheline, Y.I., Barch, D.M., Price, J.L., et al. (2009). The default mode Personality and Social Psychology, 55, 882–2.
network and self-referential processes in depression. Proceedings for the Williams, J.M.G., Ellis, N.C., Tyers, C., Healy, H., Rose, G., MacLeod, A.K.
National Academy of Sciences of the United States of America, 106, 1942–7.
(1996). The specificity of autobiographical memory and imageability of Siegle, G.J., Steinhauer, S.R., Thase, M.E., Stenger, V.A., Carter, C.S. (2002).
the future. Memory & Cognition, 24, 116–25.
Can't shake that feeling: event-related fMRI assessment of sustained Williams, J.M.G., Teasdale, J.D., Segal, Z.V., Soulsby, J. (2000).
amygdala activity in response to emotional information in depressed Mindfulness-based cognitive therapy reduces overgeneral autobiographi- individuals. Biological Psychiatry, 51, 693–707.
cal memory in formerly depressed patients. Journal of Abnormal Strack, S., Blaney, P.H., Ganellen, R.J., Coyne, J.C. (1985). Pessimistic self- Psychology, 109, 150–5.
performance deficits, and depression. Journal of Woods, R.P., Cherry, S.R., Mazziotta, J.C. (1992). Rapid automated algo- Personality and Social Psychology, 49, 1076–85.
rithm for aligning and reslicing PET images. Journal of Computer Assisted Talairach, J., Tournoux, P. (1988). Co-Planar Stereotaxic Atlas of the Human Tomography, 16, 620–33.
Brain- 3-Dimensional Proportional System: An Approach to Cerebral Yoshimura, S., Ueda, K., Suzuki, S.-I., Onoda, K., Okamoto, Y., Imaging. New York: Thieme.
Yamawaki, S. (2009). Self-referential processing of negative stimuli Treynor, W., Gonzalez, R., Nolen-Hoeksema, S. (2003). Rumination recon- within the ventral anterior cingulate gyrus and right amygdala. Brain sidered: a psychometric analysis. Cognitive Therapy and Research, 27, and Cognition, 69, 218–25.

Source: http://memlab.yale.edu/sites/default/files/files/2009_Johnson_Nolen-Hoeksema_Mitchell_Levin_SCAN.pdf