Field potential 1/ f activity in the subcallosal cingulate region as a candidate signal for monitoring deep brain stimulation for treatment-resistant depression

Abstract

Subcallosal cingulate cortex deep brain stimulation (SCC-DBS) is an experimental therapy for treatment-resistant depression (TRD). Refinement and optimization of SCC-DBS will benefit from increased study of SCC electrophysiology in context of ongoing high-frequency SCC-DBS therapy. The study objective was a 7-mo observation of frequency-domain 1/f slope in off-stimulation local field potentials (SCC-LFPs) alongside standardized measurements of depression severity in 4 patients undergoing SCC-DBS. SCC was implanted bilaterally with a combined neurostimulation-LFP recording system. Following a 1-mo off-stimulation postoperative phase with multiple daily recordings, patients received bilateral SCC-DBS therapy (130 Hz, 90 μs) and weekly resting-state SCC-LFP recordings over a 6-mo treatment phase. 1/f slopes for each time point were estimated via linear regression of log-transformed Welch periodograms. General linear mixed-effects models were constructed to estimate pretreatment sources of 1/f slope variance, and 95% bootstrap confidence intervals were constructed to estimate treatment phase 1/f slope association with treatment response (50% decrease in preimplantation symptom severity). Results show the time of recording was a prominent source of pretreatment 1/f slope variance bilaterally, with increased 1/f slope magnitude observed during night hours (2300-0659). Increase in right 1/f slope was observed in the setting of treatment response, with bootstrap analysis supporting this observation in 3 of 4 subjects. We conclude that 1/f slope can be measured longitudinally in a combined SCC-DBS/LFP recording system and likely conforms to known 1/f circadian variability. The preliminary evidence of 1/f slope increase during treatment response suggests a potential utility as a candidate biomarker for ongoing development of adaptive TRD-neuromodulation strategies.NEW & NOTEWORTHY In four patients with treatment-resistant depression undergoing therapeutic deep brain stimulation (DBS), we present the first longitudinal observations of local field potentials (LFP) from the subcallosal cingulate region outside the postoperative period. Specifically, our results demonstrate that frequency-domain 1/f activity is measurable in a combined DBS-LFP recording system and that right hemisphere recordings appear sensitive to mood state, thus suggesting a potential readout suitable for consideration in ongoing efforts to develop adaptive DBS delivery systems.

Trial registration: ClinicalTrials.gov NCT01984710.

Keywords: 1/; BA25; LFP; SCC; deep brain stimulation; depression.

Conflict of interest statement

H. S. Mayberg has a consulting agreement with St. Jude Medical (now Abbott), which has licensed her intellectual property to develop SCC DBS for the treatment of severe depression (US 2005/0033379A1). The terms of this arrangement have been approved by Emory University in accordance with policies to manage conflict of interest. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

Figures

Fig. 1.

A: in all subjects, the subcallosal cingulate cortex (SCC) was implanted bilaterally with Medtronic model 3387 electrodes (E) connected to the Activa PC+S combined neural stimulator and local field potential (LFP) recorder with a differential “bipolar” recording configuration (red spheres). Estimated volumes of tissue recorded [VTR; see Lempka and McIntyre (2013) for justification of VTR size] include surrounding anatomical gray matter regions. B: off-stimulation SCC-LFP 1/f slope (green dashed line) was estimated from the log-transformed Welch power spectral density (PSD) over 2–48 Hz [frequency range indicated by vertical lines at log10(2) and log10(48)]. Notably, this range omits peaks present in PC+S saline bath recordings (provided by Medtronic in a personal communication), as well as the low-frequency attenuation from a hardware 0.5-Hz high-pass filter.

Fig. 2.

Boxplot descriptions of pre-treatment sources of 1/f slope variation, with negativity on the y-axis (increasing 1/f slope magnitude) indicating 1/f slope steepness. A: pretreatment slopes for all subjects (n = 4), left and right hemisphere, indicating consistently negative 1/f slope values. B: cohort-level pretreatment 1/f slope magnitude appears to be increased during night hours (2300–0659), as suggested by generalized linear mixed-effect models (DF = 1,1220, left 1/f slope: F = 111.98, P < 0.0001, right 1/f Slope: F = 180.34, P < 0.0001). C: pretreatment within-subject right 1/f slope by pretreatment Montgomery-Åsburg Depression Rating Scale (MADRS) score.

Fig. 3.

Trajectory of %baseline-corrected mean weekly left and right off-stimulation subcallosal cingulate cortex local field potential (SCC-LFP) 1/f slope (left hemisphere, open circles; right hemisphere, black diamonds) and Montgomery-Åsburg Depression Rating Scale (MADRS; magenta squares) in 6-mo treatment responders (n = 3 subjects). MADRS scores below the dashed line (−50 on y-axis) indicate a 50% baseline decrease indicative of treatment response. Error bars indicate SE. 1/f slopes were corrected to treatment phase week 1, and MADRS data to preimplantation scores (Table 1).

Fig. 4.

Subject-wise description of treatment phase left-hemisphere off-stimulation subcallosal cingulate cortex local field potential (SCC-LFP) 1/f slope between treatment response states. Within-subject treatment response vs. non-response 1/f slope changes are described using bootstrap 95% confidence intervals (see methods). Asterisks indicate bootstrap 95% confidence intervals that do not include 0. Mean power spectral density (PSD) and 1/f slope plots demonstrate inconsistent left-hemisphere SCC-LFP 1/f slope magnitude differences between subjects. PSD error bars indicate the within-frequency SE.

Fig. 5.

Subject-wise description of treatment phase right-hemisphere off-stimulation subcallosal cingulate cortex local field potential (SCC-LFP) 1/f slope between treatment response states. Within-subject treatment response vs. non-response 1/f slope changes are described using bootstrap 95% confidence intervals (see methods). Asterisks indicate bootstrap 95% confidence intervals that do not include 0. Mean power spectral density (PSD) and 1/f slope plots demonstrate increased right-hemisphere SCC-LFP 1/f slope magnitudes in recordings obtained during periods of treatment response (blue) in 3 of 4 subjects. Increased 1/f slope magnitude is qualitatively observable as a steeper 1/f slope. PSD error bars indicate the within-frequency SE.

Fig. 6.

Right subcallosal cingulate cortex local field potential (SCC-LFP) 1/f slope magnitude is observed to be increased during weeks where Montgomery-Åsburg Depression Rating Scale (MADRS) scores meet treatment response criteria. A: cohort (n = 4 subjects) bootstrap 95% confidence intervals estimate an observed mean increase of right-hemisphere off-stimulation SCC-LFP 1/f slope of 0.17. Horizontal line indicates response vs. nonresponse 1/f slope change of 0. B: time-activity curve of subject 1 weekly %baseline-corrected right-hemisphere off-stimulation SCC-LFP 1/f slope (black circles) and MADRS (magenta squares). MADRS %change of −50 or greater indicates the treatment response threshold. Right 1/f slope association with treatment response (Fig. 3) appears maintained in subject 1 in setting of unstable response trajectory.

Fig. 7.

Within-subject scatterplot comparisons of baseline-corrected 1/f slope and Montgomery-Åsburg Depression Rating Scale (MADRS) scores. Depression severity increases along the x-axis and 1/f slope magnitude increases along the y-axis (Δ, change in values). Vertical line indicates a 50% decline in MADRS, which defines the point of treatment response. Matching the pattern observed following a comparison of 1/f slope values between response and nonresponse states (Fig. 5), right 1/f slope magnitude increase is observed in 2 of 3 responders as well as in a nonresponder case (subject 1), as indicated by bootstrap 95% confidence intervals of the β1 term. R2 values are consistently low in each case.