Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression

Abstract

Background: Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for depression. Mechanisms of action are hypothesized to involve modulation of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging was used to model white matter connections within this network to identify those critical for successful antidepressant response.

Methods: Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years.

Results: Whole-brain activation volume tractography demonstrated that all DBS responders at 6 months (n = 6) and 2 years (n = 12) shared bilateral pathways from their activation volumes to 1) medial frontal cortex via forceps minor and uncinate fasciculus; 2) rostral and dorsal cingulate cortex via the cingulum bundle; and 3) subcortical nuclei. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders.

Conclusions: Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.

Keywords: Antidepressant response; bipolar disorder; deep brain stimulation; diffusion tensor imaging; major depressive disorder; subcallosal cingulate; subgenual cingulate; tractography; treatment-resistant depression.

Figure 1

Identification of contact location, A: post-surgical CT image superimposed on the pre-surgical T1 image for one subject. Contacts are numbered inferior to superior, 1 to 4. B: Activation volume using contact 1 and typical parameters for a sample subject (130Hz, 90us, 6mA), C: Probabilistic tractography connections from the calculated activation volume for one subject.

Figure 2

Whole-brain probabilistic tractography of shared fiber tract maps of SCC DBS target. Left: 6-month responders (n=6); Middle: 6-month non-responders (n=10); 2-year responders (n=12). Responders (6-month and 2-years): Blue. Non-responders (6-month): Green. Based on individual activation volume tract maps: All 6-month responders share bilateral pathways via forceps minor and uncinate fasciculus to medial frontal cortex (BA10); via the cingulum bundle to subgenual, rostral and dorsal anterior and mid-cingulate; and descending subcortical fibers to ventral striatum (nucleus accumbens, ventral pallidum), putamen, hypothalamus and anterior thalamus. 6-month non-responders, while similar in some regions, lack connections to both medial frontal and subcortical regions seen in the responder group. All 2-year responders show a pattern that is nearly identical to the 6-month responder tract map. Abbreviations: mF: medial frontal, vSt: ventral Striatum, Th: thalamus, P: putamen, ACC: anterior cingulate cortex, resp: responder

Figure 3

Change in tract maps in individuals that were non-responders at 6-months and who converted to responders by 2 years (n=6). Green: 6-month shared tract map. Blue: 2-year shared tract map. Structural connection differences are seen in both forceps minor and descending subcortical connections. Abbreviations: mF: medial frontal, vSt: ventral Striatum, Th: thalamus, P: putamen, ACC: anterior cingulate cortex.

Figure 4

Anatomical locations in MNI space of the DBS activation volumes for responders (Blue) and non-responders (Red) at six months. No statistical difference in anatomical location between the responder and non-responder groups was identified.

Figure 5

Optimal SCC DBS Fiber Bundle Target Template. Red: Forceps Minor, Blue: Uncinate Fasciculus, Yellow: Cingulate Bundle. Abbreviations: mF10: medial frontal (Brodmann Area 10), Forceps M.: forceps minor, Uncinate F.: uncinate fasciculus, Cingulum B.: cingulum bundle, vSt: ventral Striatum, nAc: nucleus accumbens, Th: thalamus, SCC25: subcallosal cingulate cortex (BA25), Amg: amygdala, ACC: anterior cingulate cortex, MCC: middle cingulate cortex.