Toward therapeutic electrophysiology: beta-band suppression as a biomarker in chronic local field potential recordings

Abstract

Adaptive deep brain stimulation (aDBS) is a promising concept for feedback-based neurostimulation, with the potential of clinical implementation with the sensing-enabled Percept neurostimulator. We aim to characterize chronic electrophysiological activity during stimulation and to validate beta-band activity as a biomarker for bradykinesia. Subthalamic activity was recorded during stepwise stimulation amplitude increase OFF medication in 10 Parkinson's patients during rest and finger tapping. Offline analysis of wavelet-transformed beta-band activity and assessment of inter-variable relationships in linear mixed effects models were implemented. There was a stepwise suppression of low-beta activity with increasing stimulation intensity (p = 0.002). Low-beta power was negatively correlated with movement speed and predictive for velocity improvements (p < 0.001), stimulation amplitude for beta suppression (p < 0.001). Here, we characterize beta-band modulation as a chronic biomarker for motor performance. Our investigations support the use of electrophysiology in therapy optimization, providing evidence for the use of biomarker analysis for clinical aDBS.

Fig. 1. Stepwise stimulation increase is mirrored in the stepwise suppression of beta frequency band activity and stepwise improvement of motor performance.

a Stimulation amplitude layered as a red line on the time–frequency plot of a representative recording session in a PD patient during monopolar review b Averaged power spectra for 30 sec mean resting state power per stimulation step across bradykinetic patients (10 STN), (mean beta-band activity [% total sum] by stimulation step: OFF: 4.31 ± 1.2%, 0.5 mA: 4.09 ± 1.06%, 1 mA: 2.27 ± 0.83%, 1.5 mA: 1.53 ± 0.54%, 2 mA: 1.17 ± 0.41%, 2.5 mA: 1.12 ± 0.41%, OFF post-DBS: 4.64 ± 2.22%) c: Mean velocity improvement in bradykinetic patients (mean velocitiy relative to baseline 0.5 mA = 1.24±0.63; 1 mA = 1.44 ± 0.6; 1.5 mA=1.76 ± 0.69; 2 mA = 2.15 ± 1.06; 2.5 mA = 2.1 ± 1.2, OFF post-DBS: 1.24 ± 0.61, central mark in the boxplot is the median, edges are 25th/75th percentile), with paired permutation testing.

Fig. 2. Beta frequency band suppression during stimulation corresponds to bradykinesia improvement.

Representative example of analyzed data per stimulation level. Columns represent steps of increasing stimulation amplitude: stimOFF–1 mA stimON–2 mA stimON–stimOFF. Upper trace shows smoothed velocity traces of finger tapping. Resting state LFP-recordings from contact pair 1–3 are shown as (i) filtered LFP (5–48/52–98 Hz), (ii) beta filtered LFP (13–35 Hz), (iii) theta band filtered LFP (5–8 Hz) as control frequency, and iv) time-frequency representation; left: DBS localization and VTA reconstruction for 1 and 2 mA, visualized as previously described.

Fig. 3. Chronic DBS suppresses beta frequency band activity.

a Mean power spectra are grouped according to clinical effect of stimulation as measured by finger tapping showing that effective stimulation suppresses beta-band activity. b Peak beta-band amplitude is suppressed during effective DBS and spectral peaks are shifted towards lower frequencies (mean peak frequency OFF: 16 ± 2.5 Hz; mean peak frequency ON: 13.7 ± 2.16 Hz, mean peak frequency post-DBS: 16 Hz ± 2.5 Hz), with no significant differences). c Stimulation modulates mean power spectra in a frequency-specific manner with significant suppression of low and high-beta-band power but not alpha or theta band activity. Boxplots with median as the central mark, 25th/75th percentile as edges. Low-beta-band (13–20 Hz) and high-beta-band activity (20–35 Hz) was significantly suppressed through DBS at the stimulation intensity for best clinical effect (low-beta OFF-DBS: 8.43±3.14 [% total sum]/best clinical effect: 2.11 ± 0.85 [% total sum]; p = 0.002; mean high-beta OFF-DBS: 2.32 ± 1.3 [% total sum], mean high-beta best clinical effect: 0.66 ± 0.25 [% total sum], p = 0.002), no significant modulation in the theta (5–8 Hz) and alpha (8–12 Hz) band activity (OFF/best clinical effect, mean theta OFF-DBS: 2.04 ± 0.71 Power [% total sum], mean theta best clinical effect: 2.24 ± 0.96 Power [% total sum]; p = 0.26, mean alpha OFF-DBS: 4.65 ± 3.6 Power [% total sum], mean alpha best clinical effect: 3.79 ± 1.43 Power [% total sum]; p = 0.475).

Fig. 4. Suppression of low-beta activity corresponds with motor improvement.

a Scatter plot summarizing interrelation between motor performance, beta suppression and stimulation intensity for the patient cohort, stimulation is presented in % of maximal stimulation, which was the maximum tolerable intensity. b Linear mixed effects model shows that low-beta-band activity is a strong predictor for velocity improvement, while the relationship between stimulation intensity and beta suppression follows a logarithmic relation (c).