Demographic data
As shown in Table 1, there was no statistical difference between BD patients and healthy controls for age, gender, educational level, and mania scores. Handedness laterality was also matched, with 2 left-handed in the BD group and 3 in the HC group. However, euthymic BD patients scored significantly higher on depression (MADRS, p < 0.05) and anxiety measures (STAI-S, p < 0.01; STAI-T, p < 0.001), and they showed higher tendency to ruminate (RRS, p < 0.05).
Behavioral data
Response times in the two word-judgment tasks are shown in Fig. 1b. A 2 × 2 × 2 ANOVA showed a marginal group effect (p = 0.07, F = 3.4) and interaction (focus*switch*group, p = 0.055, F = 3.9). Patients were generally slower than controls. Despite the borderline interaction, and given our specific hypothesis concerning the different task conditions, we performed a further analysis of RTs examining internal and external trials separately. A two-way ANOVA (group × switch) on trials from the external focus task testing for the impact of switching from the other (internal) task or repeating it showed no group effect (p = 0.18, F = 1.8) but a significant effect of switch (p < 0.05, F = 5.38), and no interaction (p = 0.28, F = 1.18). However, planned comparisons with Bonferroni-corrected t-tests revealed a significant difference between switch and repeat trials in BD patients only (p < 0.05), whereas this difference did not reach significance in HC (p > 0.05). On the other hand, a two-way ANOVA on trials from the internal focus task only showed a marginal group difference (p = 0.05, F = 3.9), with patients being slower than healthy controls, but no other effect. Bonferroni-corrected t test comparisons revealed a significant difference of switch vs repeat in HC (p < 0.05) but not in patients, while the difference between groups was significant for repetition trials only (p < 0.05) but not switch trials (p > 0.0.05). Thus, overall, BD patients tended to have more difficulties with the external focus task when it was preceded by internal focus, unlike controls who showed an opposite effect with slower switching from external to internal focus.
fMRI data
Distinct networks activated during internal and external focus
A contrast between all internal vs all external trials (including the instruction and stimulus event periods) across the two groups, at a threshold of p = 0.05 FWE corrected, revealed differential recruitment of widespread brain networks in these two task conditions (see Additional file 1: Figure S1A). In brief, the internal-focus network comprised several midline brain areas usually associated with self-referential processing, including the medial prefrontal cortex, precuneus, and PCC, as well as the lateral orbitofrontal cortex, angular gyrus, middle temporal gyrus, and postero-lateral cerebellum (for detailed coordinates and clusters information see Additional file 1: Table S1A). The external-focus network comprised visual and dorsolateral fronto-parietal areas usually implicated in visuo-spatial attention, as well as the insula cortex and cerebellum vermis (Additional file 1: Table S1B). These results confirm the validity of our task manipulation and its effectiveness in both groups.
Main effect of patients vs healthy controls
A direct group comparison across all conditions (BD > HC, p = 0.05 FWE corrected) revealed highly significant increases in the patients for medial brain areas including sgACC (T = 8.08, x = 3, y = 29, z = − 11), vmPFC (T = 9.95, x = − 6, y = 41, z = − 23, T = 8.25, x = − 12, y = 41, z = − 8), and PCC (T = 6.95, x = − 6, y = − 34, z = 46), as well as in the inferior parietal cortex (L: T = 9.10, x = − 45, y = − 61, z = 37, R: T = 8.96, x = 60, y = − 55, z = 28), and superior occipital gyrus (R: T = 13.59, x = 24, y = − 88, z = 34), as shown in Fig. 2a (in red).
To further assess these group differences as a function of task conditions, we computed a group × attention interaction over the whole brain (BD > HC *internal > external, p = 0.001 uncorrected) that revealed higher activity for patients in regions associated with self-referential processing (Fig. 2a, in yellow). These included peaks in the PCC/precuneus (T = 5.19, x = − 3, y = − 61, z = 25), left vmPFC (T = 3.56, x = − 3, y = 44, z = − 11) and dmPFC (T = 3.88, x = − 6, y = 62, z = 16), plus the left middle frontal gyrus (T = 4.95, x = − 30, y = 26, z = 49) and left inferior parietal cortex (T = 4.99, x = − 45, y = − 67, z = 40). These data accord with our hypothesis of differential engagement of self-related processes in patients.
Switching from internal to external attention
The main effect of switching attentional focus (switch > repetition trials, p = 0.05 FWE, across both groups) showed activity in posterior medial parietal areas, including PCC (T = 8.04, x = 0, y = − 28, z = 28) and precuneus (T = 7.81, x = − 6, y = − 73, z = 40) (Additional file 1: Table S1C), in line with previous research on task switching (Piguet et al. 2016; Yin et al. 2015). Switching from internal to external focus revealed increases in several limbic structures such as amygdala, hippocampus, and striatum across groups, suggesting a delayed deactivation of these areas after a self-reference state (Additional file 1: Table S1D). The reverse contrast showed no effect, i.e., no such inertia of activity in external-focus network.
To test our second hypothesis that patients may have selective difficulties disengaging from internal focus on self-related information, we then compared brain activity between groups on trials that required switching from internal to external focus (int.ext condition) as compared to repeated external focus trials (ext.ext condition; Fig. 2b, in red). Remarkably, patients (vs controls) showed significantly higher activity in the left entorhinal cortex (T = 4.16, x = − 24, y = − 1, z = − 29), an area that has been previously related to rumination tendency in healthy subjects (Piguet et al. 2014). A further analysis separated trials according to the valence of the preceding word meaning (see “Methods”), in order to compare switching from a negative internal trial vs switching from a positive internal trial in patients vs controls (interaction of group × valence on int.ext trials). Results (Fig. 2b, in yellow) confirmed higher activity in the entorhinal cortex (T = 2.75, x = − 21, y = − 4, z = − 29) in this condition. No such effects were observed when switching from an external to internal attentional focus (i.e., ext.int trials) or when repeating the internal focus condition (i.e., int.int trials).
Rumination-related activity in patients
Next, we performed a whole brain multiple regression analysis using the RRS scores from each individual as a regressor in order to identify areas whose activity increased as a function of ruminative tendencies. Significant clusters (p = 0.001 unc., cluster size > 5) were found during repetition trials specifically for the internal focus condition with negative valence for the patients only. Higher rumination trait was associated with higher activity in this condition in the sgACC (x = 3, y = 29, z = − 11), vmPFC (x = 0, y = 35, z = − 20), pgACC (x = − 6, y = 44, z = 1), bilateral anterior insula (L: x = − 42, y = 17, z = − 2, R: x = 33, y = 17, z = 1), middle/posterior cingulate (x = 3, y = − 25, z = 34), and angular gyrus in parietal cortex (x = − 51, y = − 67, z = 40), as shown in Fig. 3. No significant correlation was found during the external focus repetition or the internal switch condition.
An additional correlation analysis of activity (betas) in clusters that were found more active in BD patients vs HC (i.e. Fig. 2a) was also performed (see Additional file 1: Table S2) and confirmed the specificity of this correlation during negative internal repetition trials. No correlation was observed in any condition in healthy controls. Trait rumination thus appears related to activity in brain areas classically implicated in self-referential processing and self-monitoring, in the condition with the most loading on internal focus.
Task-specific modulation of functional connectivity of ACC
Finally, we compared functional connectivity of sgACC (x = 3, y = 29, z = − 11) during the internal vs external focus condition in patients using a PPI analysis, since this region is among those hypothesized as central in rumination processes (Hamilton et al. 2015) and depressive state (Mayberg et al. 2005) and was found overactive in our patients as compared to controls. This analysis revealed significantly increased connectivity (p = 0.05 FWE) of sgACC with pgACC (x = − 3, y = 38, z = − 8), medial superior frontal gyrus (x = 0, y = 32, z = 43), and bilateral anterior insula (left: x = − 36, y = 8, z = − 11, right: x = 39, y = 17, z = − 11) (Fig. 4 in blue). A similar analysis also compared connectivity of pgACC when switching away from internal to external focus (vs repetition of external trials) and again found significant increases in patients (p = 0.001 unc, cluster size > 15) centered on the entorhinal cortex (x = − 27, y = − 1, z = − 26) (Fig. 4 in red). Using the same two seeds, no other significant connectivity pattern was found in patients or controls in other conditions. These connectivity results demonstrate increased engagement of self-processing networks in patients, specifically during internal focus, and lingering effects of brain activity related to internal focus when switching to the external focus task.
Entorhinal cortex activity predicts rumination scores via pgACC activity
A mediation analysis was next conducted, to assess the mediation effect via the pgACC activity of the ability to switch from an internal focus (entorhinal cortex hyperactivity) on rumination trait (RRS scores). In this analysis we defined as “path a” the link between entorhinal cortex and pgACC, as “path b” the link between pgACC and rumination and as “path c” the link between entorhinal cortex and rumination. Mediation analysis from the bootstrap analysis showed a significant indirect effect (M = 3.5, SE = 1.4), with a 95% bias corrected confidence interval excluding zero (1.04, 6.69) and a mediation effect at 69.4%, indicating that the association between the entorhinal cortex activity and rumination passes through pgACC activity. The direct effect and the other coefficient paths of the model were also significant (see Fig. 5 for paths coefficients and p values).