Pregenual or subgenual anterior cingulate cortex as potential effective region for brain stimulation of depression

Abstract

Background: The dorsolateral prefrontal cortex (DLPFC) is the standard stimulation target for the repetitive transcranial magnetic stimulation (rTMS) treatment of major depression disorder (MDD). A retrospective study by Fox and colleagues found that a more negative resting-state functional magnetic resonance imaging (RS-fMRI) functional connectivity (FC) between left DLPFC and the subgenual anterior cingulate cortex (sgACC) in a large group of healthy participants is associated with a better curative effects of rTMS in MDD, suggesting that the sgACC may be an effective region. However, a recent meta-analysis on RS-fMRI studies found that the pregenual ACC (pgACC), rather than the sgACC, of MDD patients showed increased local activity.

Methods: We used the stimulation coordinates in the left DLPFC analyzed by Fox et al. to perform RS-fMRI FC between the stimulation targets obtained from previous rTMS MDD studies and the potential effective regions (sgACC and pgACC, respectively) on the RS-fMRI data from 88 heathy participants.

Results: (a) Both the pgACC and the sgACC were negatively connected to the left DLPFC; (b) both FCs of sgACC-DLPFC and pgACC-DLPFC were more negative in responders than in nonresponders; and (c) the associations between DLPFC-sgACC functional connectivity and clinical efficacy were clustered around the midline sgACC.

Conclusions: Both the pgACC and the sgACC may be potential effective regions for rTMS on the left DLPFC for treatment of MDD. However, individualized ACC-DLPFC FC-based rTMS on depression should be performed in the future to test the pgACC or the sgACC as effective regions.

Trial registration: ClinicalTrials.gov NCT02144467.

Keywords: depression; functional connectivity; pregenual anterior cingulate cortex; repetitive transcranial magnetic stimulation; subgenual anterior cingulate cortex.

Conflict of interest statement

All authors declare that they have no conflict of interest.

© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Figures

Figure 1

The seed regions of interest (ROI) of the pgACC and the sgACC. The 5‐mm and 10‐mm radius spheres for both the sgACC and the pgACC were generated by centering on the coordinates determined by previous studies (Fox et al., 2012; Zhou et al., 2017). ACC, anterior cingulate cortex; pgACC, pregenual ACC; sgACC, subgenual ACC

Figure 2

The FC patterns of the sgACC and pgACC with different size of seeds (a, b) (FDR correction, q < 0.001, cluster size > 100 voxels, two‐tailed). The warm color indicates positive FC of ACCs, and the cold color indicates negative FC. ACC, anterior cingulate cortex; FC, functional connectivity; pgACC, pregenual ACC; sgACC, subgenual ACC

Figure 3

The differences of ACC‐DLPFC FCs between the responders and nonresponders. The DLPFC stimulation targets were from Herbsman et al. (2009). The colored regions in the brain indicate the ROIs of DLPFC (a). The definition of DLPFC was centered in the mean coordinate of responders and nonresponders with a 20‐mm radius, respectively. ACC, anterior cingulate cortex; DLPFC, dorsal lateral prefrontal cortex; FC, functional connectivity; pgACC, pregenual ACC; SE, standard error; sgACC, subgenual ACC. *p < .05; **p < .01

Figure 4

The differences of ACC‐DLPFC FCs between the more effective target and less effective target. The DLPFC stimulation targets were from Fitzgerald et al. (2009) and Fox et al. (2012). The colored regions in the brain indicate the ROIs of DLPFC (a). The definition of DLPFC was centered in the coordinate of more effective target and less effective target with a 20‐mm radius, respectively. ACC, anterior cingulate cortex; DLPFC, dorsal lateral prefrontal cortex; eff., effective; FC, functional connectivity; pgACC, pregenual ACC; SE, standard error; sgACC, subgenual ACC. *p < .05

Figure 5

Correlation between 27 ACC‐DLPFC targets FCs and clinical efficacy of 27 patients. Every dot represents the mean FC value of ACC‐DLPFC across 88 healthy participants at a certain DLPFC target. The definition of DLPFC was centered in the previously reported TMS target with a 10‐mm radius. ACC, anterior cingulate cortex; DLPFC, dorsal lateral prefrontal cortex; FC, functional connectivity; MADRS, Montgomery Asberg Depression Rating Scale; pgACC, pregenual ACC; sgACC, subgenual ACC; TMS, transcranial magnetic stimulation

Figure 6

Correlation between estimated clinical efficacy of nine different DLPFC coordinates and functional connectivity of the sgACC/pgACC. The nine DLPFC targets were selected from literatures (see Table 3), and the estimated clinical efficacy was derived from an empirical equation reported by Herbsman et al. (2009). ACC, anterior cingulate cortex; DLPFC, dorsal lateral prefrontal cortex; FC, functional connectivity; HDRS, Hamilton Depression Rating Scale; pgACC, pregenual ACC; sgACC, subgenual ACC. *p < .05; **p < .01

Figure 7

The voxel‐wise FC analyses between DLPFC and sgACC in a 20‐mm radius medial sgACC ROI (x = 0, y = 16, and z = −10). The crosshair located in the original sgACC coordinate (x = 6, y = 16, and z = −10) from Fox et al. (2012). The colored regions in a and b represent the differences between two DLPFC TMS targets (better efficacy target vs. less efficacy target). The cold color indicates that better clinical efficacy target showed more negative FC (a and b). The cold color region in c represents negative correlation between DLPFC‐sgACC FC and estimated clinical efficacy scores in nine DLPFC coordinates. All the statistical maps were thresholded at uncorrected p < .05. The red color in d represents overlapping brain region of a, b, and c. DLPFC, dorsal lateral prefrontal cortex; FC, functional connectivity; L, left; R, right; ROI, region of interest; sgACC, subgenual anterior cingulate cortex; TMS, transcranial magnetic stimulation