Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

Abstract

Background Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCC) is an evolving investigational treatment for major 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 (DTI) was used to model white matter connections within this network to identify those critical for successful antidepressant response to SCC DBS. Methods Pre-operative high-resolution MRI data, including DTI, were acquired in 16 patients with treatment-resistant depression who then received SCC DBS. Computerized tomography was used post-operatively to locate DBS contacts. The activation volume around the active contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts that traveled 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 (AVT) demonstrated that all DBS responders at six 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. Non-responders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from non-responders. Conclusions Patient-specific AVT modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.

Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases

“…In these cases, we found convergence between anatomical connectivity measured with diffusion tractography and positive correlations measured with rs-fcMRI ( Fig. S4) (77)(78)(79)(80)(81)(82)104). Perhaps surprising are the rs-fcMRI correlations between the fornix, a white matter structure, and distant memory regions including the hippocampus and retrosplenial cortex (Fig.…”

“…S3). Finally, because activation of specific white matter tracks has been shown to be important for DBS effects in the subgenual cingulate (77)(78)(79), the VIM nucleus of the thalamus (80)(81)(82), and the fornix (5, 83), we explored anatomical connectivity with these sites using diffusion tractography and compared those results with the present findings with rs-fcMRI (Fig. S4).…”

Target-specific deep brain stimulation of the ventral capsule/ventral striatum for the treatment of neuropsychiatric disease

“…Fibers of passage rather than a gray matter target such as the subthalamic nucleus (STN) may mediate the therapeutic effects of DBS. Pre-operative diffusion tensor imaging data were acquired in a cohort with TRD to produce patient-specific white matter tractography maps (26). Post-operative field modeling analysis based on diffusion tensor imaging has shown that the DBS activation volumes of all responders to SCC DBS affect a particular combination of fiber bundles.…”

Neuroplasticity and the brain connectome: what can Jean Talairach’s reflections bring to modern psychosurgery?

“…31 Regarding depression, DBS targeting the subgenual cortex/subcallosal cingulate cortex (which is currently the most effective target) is mediated by its impact on white matter rather than by direct cortical activations. 62,72 This target appears to be an important triple functional node by connecting the right and left prefrontal cortex through the anterior part of the corpus callosum, medial frontal cortex to the cingulate system through the cingulum, and linking the subcallosal cingulate cortex to the mesial frontal cortex, subcortical structures, and anterior thalamus through the uncinate fasciculus. Moreover, a recent pilot study used individual tractography maps to determine targets in a patient-specific way, opening up the use of individual connectome mapping to guide therapeutic intervention.…”