Initial Unilateral Exposure to Deep Brain Stimulation in Treatment-Resistant Depression Patients Alters Spectral Power in the Subcallosal Cingulate

Otis Smart, Ki S Choi, Patricio Riva-Posse, Vineet Tiruvadi, Justin Rajendra, Allison C Waters, Andrea L Crowell, Johnathan Edwards, Robert E Gross, Helen S Mayberg, Otis Smart, Ki S Choi, Patricio Riva-Posse, Vineet Tiruvadi, Justin Rajendra, Allison C Waters, Andrea L Crowell, Johnathan Edwards, Robert E Gross, Helen S Mayberg

Abstract

Background: High-frequency Deep Brain Stimulation (DBS) of the subcallosal cingulate (SCC) region is an emerging strategy for treatment-resistant depression (TRD). This study examined changes in SCC local field potentials (LFPs). The LFPs were recorded from the DBS leads following transient, unilateral stimulation at the neuroimaging-defined optimal electrode contact. The goal was identifying a putative electrophysiological measure of target engagement during implantation. Methods: Fourteen consecutive patients underwent bilateral SCC DBS lead implantation. LFP recordings were collected from all electrodes during randomized testing of stimulation on each DBS contact (eight total). Analyses evaluated changes in spectral power before and after 3 min of unilateral stimulation at the contacts that later facilitated antidepressant response, as a potential biomarker of optimal contact selection in each hemisphere. Results: Lateralized and asymmetric power spectral density changes were detected in the SCC with acute unilateral SCC stimulation at those contacts subsequently selected for chronic, therapeutic stimulation. Left stimulation induced broadband ipsilateral decreases in theta, alpha, beta and gamma bands. Right stimulation effects were restricted to ipsilateral beta and gamma decreases. These asymmetric effects contrasted with identical white matter stimulation maps used in each hemisphere. More variable ipsilateral decreases were seen with stimulation at the adjacent "suboptimal" contacts, but changes were not statistically different from the "optimal" contact in either hemisphere despite obvious differences in impacted white matter bundles. Change in theta power was, however, most robust and specific with left-sided optimal stimulation, which suggested a putative functional biomarker on the left with no such specificity inferred on the right. Conclusion: Hemisphere-specific oscillatory changes can be detected from the DBS lead with acute intraoperative testing at contacts that later engender antidepressant effects. Our approach defined potential target engagement signals for further investigation, particularly left-sided theta decreases following initial exposure to stimulation. More refined models combining tractography, bilateral SCC LFP, and cortical recordings may further improve the precision and specificity of these putative biomarkers. It may also optimize and standardize the lead implantation procedure and provide input signals for next generation closed-loop therapy and/or monitoring technologies for TRD.

Keywords: DBS; LFP; SCC; VTA/VTR; depression; intraoperative; power spectra; tractography.

Figures

Figure 1
Figure 1
The combined tractography and anatomical images guided a connectomic surgical procedure to implant the subcallosal cingulate DBS leads. (A) connectomic blueprint used for structural connectivity based target selection (intersection of forceps minor, uncinate fasciculus, cingulum bundle, and fronto-striatal fibers), (B) a representative deterministic tractography target selection map from one patient: optimal target location within SCC region with modeled stimulation impacting necessary fiber bundles for effective SCC DBS. FM, Forceps Minor; UF, Uncinate Fasciculus; CB, Cingulum Bundle; F-St, fronto-striatal fibers. (A) adapted from Figure 4 in Riva-Posse et al. (2014).
Figure 2
Figure 2
Intraoperative DBS-Evoked behavioral testing and stimulation protocol. (A) The location of DBS leads within the subcallosal region. (B) Tractography-based verification of the defined effective and ineffective targets with a differential signal recording. (C) Intraoperative stimulation protocol. (D) A 1-min epoch of unfiltered differential signals. (E) The same epoch in (D) but filtered differential signals including artifacts (i.e., high amplitude deflections at the beginning and end of the epoch). (F) The same epoch in (E) after filtration and artifact removal (notice the clipped time interval). (G) Power spectra of the unfiltered (red curves) and filtered (blue curves) epochs. The arrows indicate representative spectral noise in the unfiltered signal not present in the filtered signal. (H) Power spectra of filtered signals for 1-min epochs during sedation (red curves) and no sedation (blue curves). In (D–F), the differential signals are L1–L3, L2–L4, R1–R3, and R2–R4 respectively. E, Effective contact; I, Ineffective contact; U, Upper VTR; L, Lower VTR.
Figure 3
Figure 3
Ipsilateral band-delimited power changes with Effective DBS in Responders (n = 11). Decreased spectral power ipsilateral to site of HFS is demonstrated. Differential patterns are seen following Left-sided and Right-sided DBS. Left-sided HFS with Left SCC recording in Red. Right-sided HFS with Right SCC recordings in Blue. Grouped patient values are represented by the box plots (Responders only). Individual patient values are represented by dots (with non-responders shown in gray). Significant decreases were induced by Left effective stimulation in Theta, alpha, beta and gamma band. More limited decreases were induced by right effective stimulation in beta and gamma bands. Statistically significant changes are marked with an asterisk.
Figure 4
Figure 4
Ipsilateral change pattern contrasting HFS delivered to effective Left (red) and ineffective left (green) contacts (A) and Effective Right (Blue) and ineffective right (green) contacts (B). Decreased spectral power ipsilateral to site of HFS is demonstrated with ineffective contacts. But no significant differences were identified via direct comparison of effective and ineffective contacts, although Left Theta decreases show a trend (p = 0.043) to differentiate effective from ineffective contacts. Statistically significant changes are marked with an asterisk.
Figure 5
Figure 5
Sources of asymmetry. (A) Estimated volume of tissue recorded (VTR: 7.5 mm radius sphere) on the center of the corresponding LFP recording contacts, (B) Left mean response connectivity map of Effective (Red) and Ineffective (Green) contacts, and Right mean response connectivity map of Effective (Blue) and Ineffective (Green) contacts, (C) Pre-stimulation power of left and right effective contacts. (D) Estimated anatomical current sources within VTRs using FreeSurfer cortical parcellation. There are no clear sources of asymmetry between left and right hemisphere in pre-stimulation power, amount of gray/white/CSF within volume of tissue recorded, or impacted white matter bundles. However, there are clear differences in anatomical current sources within the VTRs; left received less input from the ACC compared to the right, and right received less input from the suborbital frontal cortex. ACC, Anterior Cingulate Cortex; Sub. OFC, Suborbital Frontal Cortex; SCC, Subcallosal Cingulate; nAc/Caudate, Nucleus Accumbens/Caudate.

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