Dynamic Oscillations Evoked by Subcallosal Cingulate Deep Brain Stimulation

Vineet Tiruvadi, Ki Sueng Choi, Robert E Gross, Robert Butera, Viktor Jirsa, Helen Mayberg, Vineet Tiruvadi, Ki Sueng Choi, Robert E Gross, Robert Butera, Viktor Jirsa, Helen Mayberg

Abstract

Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCCwm) alleviates symptoms of depression, but its mechanistic effects on brain dynamics remain unclear. In this study we used novel intracranial recordings (LFP) in n = 6 depressed patients stimulated with DBS around the SCCwm target, observing a novel dynamic oscillation (DOs). We confirm that DOs in the LFP are of neural origin and consistently evoked within certain patients. We then characterize the frequency and dynamics of DOs, observing significant variability in DO behavior across patients. Under the hypothesis that LFP-DOs reflect network engagement, we characterize the white matter tracts associated with LFP-DO observations and report a preliminary observation of DO-like activity measured in a single patient's electroencephalography (dEEG). These results support further study of DOs as an objective signal for mechanistic study and connectomics guided DBS.

Keywords: DBS; cingulate; dynamics; subcallosal; tractography.

Conflict of interest statement

HM report consulting and intellectual licensing fees from Abbott Labs. RG serves as a consultant to and receives research support from Medtronic, and serves as a consultant to Abbott Labs. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Tiruvadi, Choi, Gross, Butera, Jirsa and Mayberg.

Figures

Figure 1
Figure 1
Overview of Dynamic Oscillations (DO) Identification. (A) Local field potentials (LFP) and dense scalp electroencephalography (dEEG) recordings are taken at therapy onset one month after implantation, with no active DBS in the interim. Six patients are included here. (B) DBS is targeted at patient-personalized subcallosal cingulate white matter (SCCwm). Sagittal view here demonstrates fibers being engaged at therapeutic settings. (C) DBS3387 leads are implanted bilaterally such that SCCwm is close to one of the center two electrodes. OnTarget electrode (blue) is the one closest to the SCCwm while OffTarget (green) is the other middle electrode. (D) Spacing between OnTarget and OffTarget is 1.5 mm edge-to-edge. (E) Separate recording sessions are performed for OnTarget and OffTarget DBS targets. LFP, with combined dEEG in n = 3/6 patients, were recorded continuously before and during DBS ON periods. DBS ON recordings are compared to the immediately previous DBS OFF period.
Figure 2
Figure 2
Filtering setup for SCC-LFP. (A) Example spectrogram of raw LFP from PC+S™. 550 to 600 s is before stimulation at 130 Hz and exhibits small artifacts at 105.5 Hz and 60 Hz. (B) Known artifacts in the PC+S™ become evident during stimulation. (C) Low pass filter at 20 Hz removes all artifacts identified in (B) without significantly altering the low-frequency bins where the DO manifests. (D) Visualization of the effect of the LPF on removing artifacts. (E) Time-domain signal after filtering more clearly demarcates the boundaries of the regimes.
Figure 3
Figure 3
Time evolution of DOs in example DOs. (A) Unfiltered recording during active DBS demonstrated emergence of oscillatory activity changing over minutes of stimulation. (B) DOs are observed in four of six patients. (C) Filtered DO demonstrates distinct phases of activity marked by sharp changes in the oscillatory activity. (D) Characteristic spectrogram of DO from (A). Spectrogram demonstrated a fundamental oscillation around 12 Hz with numerous harmonics. The fundamental changes over the course of 3 min of stimulation, mostly smoothly but punctuated by distinct transitions that are burst-like (dotted lines). The periods bounded by these distinct transitions are called regimes.
Figure 4
Figure 4
LFP-DOs are robust when present. Example spectograms from raw recordings in two patients: Left column—Patient 4, Right column—Patient 1. (A) Patient 4 intraoperative BlackRock Microsystems recordings demonstrated LFP-DOs. (B) Patient 4 extraoperative PC+S™ recordings, taken 4 h later demonstrated LFP-DOs with different structure. (C) In Patient 1, extraoperative PC+S™ recordings taken during three different stimulation conditions demonstrate DOs in left and bilateral stimulation. (D) After 24 weeks of therapy the same experiment still demonstrates DOs evoked by left and bilateral stimulation. However, these DOs exhibit changes in several dynamic features.
Figure 5
Figure 5
DOs evoked by bilateral stimulation across cohort. Spectrograms from all bilateral stimulation conditions, both OnTarget and OffTarget, in all six patients. Red squares indicate LFP-DO+ conditions. Black blocks indicate recordings involving a broken channel and unsalvagable recordings under OffTarget stimulation.
Figure 6
Figure 6
Oscillatory changes evoked by DBS. (A) SCC-LFP recordings are taken for 1 min before and 3 min after DBS initiation at a given target. 20 s, non-overlapping windows are analyzed in the frequency domain to observe the changing frequency content over 3 min stimulation. (B) Changes in power spectral densities (PSD) are calculated in different 20 s long time windows, with the label referring to the end point of the window. In Patient 4 as an example, the change in oscillatory content is evident as overt changes in the PSD along 20 s non-overlapping windows. (C) Log-changes in PSD calculated during the initial 20 s of DBS onset demonstrate significant changes from baseline in a subset of patients. (D) A zoom-in to the artifact-free 0 to 30 Hz range demonstrates the frequency-domain activity defining the DO. The PSDs all miss the dynamics that are present over the stimulation period.
Figure 7
Figure 7
Intrahemispheric Dynamics across LFP-DOs in all patients. First row: measured DOs for each patient, with Left-SCC LFP in blue, Right-SCC LFP in red. Second row: SINDy coefficients for cross-terms - blue block shows coefficients for where Right-SCC LFP affects Left-SCC LFP change, red block shows coefficients for where Left-SCC LFP affects Right-SCC LFP change.
Figure 8
Figure 8
LFP-DO Regime Dynamics in Patient 4 LFP-DO timeseries. Timeseries from Figure 4A is regenerated here with regime markers. (A) Distinct regimes are evident in a DO with smoothly changing dynamics. Smoothly changing regimes are interrupted by abrupt changes in fundamental frequency and associated harmonics. (B) With the regime-4 as an example, left (blue) and right (red) SCC-LFP recordings appear coordinated. (C) Each regime was plotted in phase space with Right-SCC vs. Left-SCC voltages, and color-coded time. (D) The regime-4 (black box) empirical trajectory (colors) was used to learn a model (b equation) and identify directional influence between bilateral SCC.
Figure 9
Figure 9
Axial tractography associated with LFP-DO+ across full n=6 patient cohort. Fibers engaged, on average, more with conditions that evoked measurable DOs (LFP-DO+) and conditions that did not evoke measurable DOs (LFP-DO-). Horizontal slice with frontal pole at top. (A) LFP-DO+ conditions exhibited more engagement of left-UF while (B) LFP-DO- exhibited more engagement of right-CB and Fmin. LFP-DO+ demonstrated more posterior engagement of interhemispheric fibers (white dotted line). UF—Uncinate Fasciculus, CB—Cingulum Bundle, Fmin - Forceps Minor.
Figure 10
Figure 10
EEG exhibits transient low-frequency activity at DO regime timings in Patient 4 EEG. (A) Distribution of maximum 2 to 5 Hz power across all EEG channels. Top 10% of channels were identified and (B) marked (red) in sensor space. (C) Filtered OnTarget EEG from Channel 32 (frontal) demonstrates bursts at similar timescales as LFP-DO. (D) Filtered OffTarget LFP from Left SCC. (E) Spectrogram of unfiltered EEG Channel 32 shows 2 to 5 Hz activity. (F) Spectrogram of unfiltered LFP L-SCC, aligned with (E), with guides (dotted line) for LFP-DO phases and corresponding hints of DO in EEG.

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