A Human Depression Circuit Derived From Focal Brain Lesions

Abstract

Background: Focal brain lesions can lend insight into the causal neuroanatomical substrate of depression in the human brain. However, studies of lesion location have led to inconsistent results.

Methods: Five independent datasets with different lesion etiologies and measures of postlesion depression were collated (N = 461). Each 3-dimensional lesion location was mapped to a common brain atlas. We used voxel lesion symptom mapping to test for associations between depression and lesion locations. Next, we computed the network of regions functionally connected to each lesion location using a large normative connectome dataset (N = 1000). We used these lesion network maps to test for associations between depression and connected brain circuits. Reproducibility was assessed using a rigorous leave-one-dataset-out validation. Finally, we tested whether lesion locations associated with depression fell within the same circuit as brain stimulation sites that were effective for improving poststroke depression.

Results: Lesion locations associated with depression were highly heterogeneous, and no single brain region was consistently implicated. However, these same lesion locations mapped to a connected brain circuit, centered on the left dorsolateral prefrontal cortex. Results were robust to leave-one-dataset-out cross-validation. Finally, our depression circuit derived from brain lesions aligned with brain stimulation sites that were effective for improving poststroke depression.

Conclusions: Lesion locations associated with depression fail to map to a specific brain region but do map to a specific brain circuit. This circuit may have prognostic utility in identifying patients at risk for poststroke depression and therapeutic utility in refining brain stimulation targets.

Keywords: Depression; Functional MRI; Functional connectivity; Imaging; Lesion; Network; Stroke.

Conflict of interest statement

Disclosures: The authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:

Lesions from depressed and non-depressed subjects from each of our five datasets demonstrate heterogeneity in lesion location: Dataset 1: Naidech et al, 2016 (intracerebral hemorrhage); Dataset 2: Corbetta et al, 2015 (stroke); Dataset 3: Egorova et al, 2018 (stroke); Dataset 4: Gozzi et al, 2004 (stroke); Dataset 5: Koenigs et al, 2008 (penetrating traumatic brain injury).

Figure 2:

Lesion locations associated with depression intersect a connected brain circuit, not an individual brain region. (A) A sample lesion from a depressed subject and a non-depressed subject are depicted in green. Standard voxel-based lesion-symptom mapping identified no lesioned voxels significantly associated with depression. (B) Functional connectivity of each lesion location to the rest of the brain was computed using resting state functional connectivity data from 1000 healthy controls. A focal region in the left dorsolateral prefrontal cortex showed greater functional connectivity to lesions of depressed subjects than to lesions of non-depressed subjects (depicted in red; voxel-level family-wise error [FWE] corrected p

Figure 3.

Lesion locations associated with depression intersect a brain circuit derived from independent lesion datasets. (A) The analysis shown in figure 2B was repeated five times, each time leaving out one of the five datasets. In all five analyses, a similar region in the left dorsolateral prefrontal cortex was significantly more connected to lesions of depressed subjects than to lesions of non-depressed subjects (depicted in red; voxel-level family-wise error [FWE] corrected p

Figure 4.

Network damage score is associated with depression severity and prevalence. (A) All subjects were divided into three risk categories based on their network damage score. Mean depression score significantly differed across the risk categories and was highest in the high-risk group. (B) Prevalence of depression significantly differed across the risk categories and was highest in the high-risk group.

Figure 5.

Our lesion-based depression circuit aligns with TMS sites used to treat post-stroke depression. Spheres indicate the stimulation locations used by prior transcranial magnetic stimulation studies that have successfully treated post-stroke depression. Our depression circuit is displayed on the cortical surface and thresholded at T = ±5 for ease of visualization (actual network is unthresholded).