Functional connectivity of the left DLPFC to striatum predicts treatment response of depression to TMS

Abstract

Background: Repetitive transcranial magnetic stimulation (TMS) is a non-invasive, safe, and efficacious treatment for depression. TMS has been shown to normalize abnormal functional connectivity of cortico-cortical circuits in depression and baseline functional connectivity of these circuits predicts treatment response. Less is known about the relationship between functional connectivity of frontostriatal circuits and treatment response.

Objective/hypothesis: We investigated whether baseline functional connectivity of distinct frontostriatal circuits predicted response to TMS.

Methods: Resting-state fMRI (rsfMRI) was acquired in 27 currently depressed subjects with treatment resistant depression and 27 healthy controls. Depressed subjects were treated with 5 weeks of daily TMS over the left dorsolateral prefrontal cortex (DLPFC). The functional connectivity between limbic, executive, rostral motor, and caudal motor regions of frontal cortex and their corresponding striatal targets were determined at baseline using an existing atlas based on diffusion tensor imaging. TMS treatment response was measured by percent reduction in the 24-item Hamilton Depression Rating Scale (HAMD24). In an exploratory analysis, correlations were determined between baseline functional connectivity and TMS treatment response.

Results: Seven cortical clusters belonging to the executive and rostral motor frontostriatal projections had reduced functional connectivity in depression compared to healthy controls. No frontostriatal projections showed increased functional connectivity in depression (voxel-wise p < 0.01, family-wise α < 0.01). Only baseline functional connectivity between the left DLPFC and the striatum predicted TMS response. Higher baseline functional connectivity correlated with greater reductions in HAMD₂₄ (Pearson's R = 0.58, p = 0.002).

Conclusion(s): In an exploratory analysis, higher functional connectivity between the left DLPFC and striatum predicted better treatment response. Our findings suggest that the antidepressant mechanism of action of TMS may require connectivity from cortex proximal to the stimulation site to the striatum.

Keywords: Brain stimulation; Frontostriatal; Functional connectivity; TMS; Treatment resistant depression; fMRI.

Figure 1

Representation of striatal regions of interest or seeds (A and B) and the regions of frontal cortex with which they are most strongly connected (C and D). These regions were determined by a prior study using DTI probabilistic tractography to track white matter pathways from known functionally significant cortical regions to the striatum [25] (caudal motor: green, rostral motor: yellow, executive: red, limbic: blue. A and C: right hemisphere view, B and D: anterior view).

Figure 2

24-item HAMD scores in depressed subjects before and after 5 weeks of open-label TMS. Response is defined as a > 30% reduction in HAMD. Horizontal line = mean. Error bars = SEM. Black-filled circles, responders. There was a statistically significant reduction in HAMD₂₄ after TMS (see text).

Figure 3

Hypoconnectivity of the executive frontostriatal projection in depressed subjects vs. healthy controls. A. In the depressed group, four clusters in the executive cortex had lower functional connectivity to the executive division of the striatum. Clusters shown on 3D cutaway image of the brain represent statistically thresholded difference maps showing the difference in frontostriatal functional connectivity, Z, between depressed subjects and healthy controls in each abnormally connected cluster (family-wise α < 0.01, voxel-wise p < 0.01). Clusters overlap the right DLPFC, left DLPFC, left VMPFC, and left dACC. B. Axial (top row) and sagittal (bottom row) images are 2-dimensional representations of the clusters in A. C. Bar graphs plot functional connectivity of the same clusters in depressed patients (blue) and controls (green).

Figure 4

Hypoconnectivity of the rostral motor frontostriatal projection in depressed subjects vs. healthy controls. A. In the depressed group, three clusters in the rostral motor cortex had lower functional connectivity to the rostral motor division of the striatum. 3D statistical map as in Fig. 3A. These clusters overlap the right Supplementary Motor Area, left Supplementary Motor Area, and right Premotor Cortex. B. Axial and sagittal images as in Figure 3B. C. Bar graphs as in Figure 3C.

Figure 5

Baseline functional connectivity of left DLPFC to the executive region of the striatum predicts treatment response to TMS over the left DLPFC. Percent reduction in HAMD₂₄ is plotted on the vertical axis and baseline functional connectivity of the left DLPFC cluster to striatum on the horizontal axis. The solid black line is the linear regression with dashed lines depicting the 95% confidence interval. Reduction in HAMD₂₄ correlated with higher baseline functional connectivity.