Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate

Abstract

Background: Transcranial magnetic stimulation (TMS) to the left dorsolateral prefrontal cortex (DLPFC) is used clinically for the treatment of depression. However, the antidepressant mechanism remains unknown and its therapeutic efficacy remains limited. Recent data suggest that some left DLPFC targets are more effective than others; however, the reasons for this heterogeneity and how to capitalize on this information remain unclear.

Methods: Intrinsic (resting state) functional magnetic resonance imaging data from 98 normal subjects were used to compute functional connectivity with various left DLPFC TMS targets employed in the literature. Differences in functional connectivity related to differences in previously reported clinical efficacy were identified. This information was translated into a connectivity-based targeting strategy to identify optimized left DLPFC TMS coordinates. Results in normal subjects were tested for reproducibility in an independent cohort of 13 patients with depression.

Results: Differences in functional connectivity were related to previously reported differences in clinical efficacy across a distributed set of cortical and limbic regions. Dorsolateral prefrontal cortex TMS sites with better clinical efficacy were more negatively correlated (anticorrelated) with the subgenual cingulate. Optimum connectivity-based stimulation coordinates were identified in Brodmann area 46. Results were reproducible in patients with depression.

Conclusions: Reported antidepressant efficacy of different left DLPFC TMS sites is related to the anticorrelation of each site with the subgenual cingulate, potentially lending insight into the antidepressant mechanism of TMS and suggesting a role for intrinsically anticorrelated networks in depression. These results can be translated into a connectivity-based targeting strategy for focal brain stimulation that might be used to optimize clinical response.

Figure 1

Different left DLPFC TMS targets show variability in resting state functional connectivity, especially with the subgenual cingulate. The left hand column shows the coordinates and regions of interest for various left DLPFC TMS targets employed in the literature. The middle columns show resting state functional connectivity maps for each DLPFC region of interest. The border of our a-priori defined subgenual region of interest is show for reference in red. The right hand column is the correlation coefficient between the timecourse from each DLPFC region of interest and that of the subgenual cingulate.

Figure 2

Differences in resting state functional connectivity between more effective versus less effective DLPFC stimulation sites. Coordinates are taken from Herbsman et al. 2009 (A–C) and Fitzgerald et al. 2009 (D–F). The top row (A, D) shows the DLPFC regions of interest compared in each study. The middle row (B, E) shows significant differences in resting state functional connectivity between the two sites (more effective – less effective). The border of our a-priori defined subgenual region of interest is show for reference in red. The bottom row (C, F) shows bar graphs of the correlation of each DLPFC site with the subgenual cingulate. In both cases the more effective DLPFC site is significantly more anticorrelated with the subgenual cingulate than the less effective site.

Figure 3

Identification of optimized left DLPFC TMS targets for depression based on functional connectivity. Regional time courses were extracted from our seed region in the subgenual cingulate (A) and our efficacy-based seed map (B) and used to generate resting state functional connectivity maps (C and D respectively). Peak anticorrelations were identified in the left DLPFC that could serve as optimized targets for focal brain stimulation. fMRI time courses from the subgenual region of interest (red) and the anticorrelated left dorsal lateral prefrontal cortex (green) are shown for a representative subject (r = −0.23).

Figure 4

Replication of principal findings in patients with major depressive disorder. Time course correlations are shown between regions of interest in the dorsal lateral prefrontal cortex (DLPFC) and the subgenual seed region (A–C) or the efficacy-based seed map (D–F). Similar to normal subjects, there is an anticorrelation between TMS targets in the DLPFC and the subgenual (A). Paired comparisons of effective versus less effective DLPFC targets show the same trend as normal subjects and a significant difference between the optimized DLPF target identified using the subgenual seed region (SG Target) and the average 5 cm target (B). Also similar to normal subjects, there is a strong relationship between estimated clinical efficacy (using the Herbsman equation) and anticorrelation with the subgenual (C; r² = 0.66, P<0.005). Using the efficacy-based seed map rather than the small subgenual seed region produces similar but more robust results including examination of regional time course correlations (D), paired comparisons (E), and the correlation between functional connectivity and estimated clinical efficacy (F; r² = 0.76, P<0.001). Labels for DLPFC ROIs are as in Figures 1 and 2 with the addition of optimized DLPFC targets identified in normal subjects using the subgenual seed region (SG Target) and the efficacy-based seed map (SM Target). *P<0.05, **P<0.001, ***P<10⁻⁴.