Neuromodulation targets pathological not physiological beta bursts during gait in Parkinson's disease

Abstract

Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG render this symptom one of the unsolved challenges in the treatment of PD. Subcortical neural mechanisms of gait impairment and FOG in PD are largely unknown due to the challenge of accessing deep brain circuitry and measuring neural signals in real time in freely-moving subjects. Additionally, there is a lack of gait tasks that reliably elicit FOG. Since FOG is episodic, we hypothesized that dynamic features of subthalamic (STN) beta oscillations, or beta bursts, may contribute to the Freezer phenotype in PD during gait tasks that elicit FOG. We also investigated whether STN DBS at 60 Hz or 140 Hz affected beta burst dynamics and gait impairment differently in Freezers and Non-Freezers. Synchronized STN local field potentials, from an implanted, sensing neurostimulator (Activa® PC + S, Medtronic, Inc.), and gait kinematics were recorded in 12 PD subjects, off-medication during forward walking and stepping-in-place tasks under the following randomly presented conditions: NO, 60 Hz, and 140 Hz DBS. Prolonged movement band beta burst durations differentiated Freezers from Non-Freezers, were a pathological neural feature of FOG and were shortened during DBS which improved gait. Normal gait parameters, accompanied by shorter bursts in Non-Freezers, were unchanged during DBS. The difference between the mean burst duration between hemispheres (STNs) of all individuals strongly correlated with the difference in stride time between their legs but there was no correlation between mean burst duration of each STN and stride time of the contralateral leg, suggesting an interaction between hemispheres influences gait. These results suggest that prolonged STN beta burst durations measured during gait is an important biomarker for FOG and that STN DBS modulated long not short burst durations, thereby acting to restore physiological sensorimotor information processing, while improving gait.

Keywords: Beta bursts; Deep brain stimulation; Freezing of gait; Parkinson's disease; Subthalamic nucleus.

Figure 1:

Beta burst determination process (A) Raw local field potential was band pass filtered around the STN specific frequency band of interest during 30 seconds of the movement state. (B) The filtered local field potential signal was squared and, an envelope, denoted in red, connected consecutive peaks from the squared signal. (C) The envelope of the filtered squared signal; green dots indicate the identified troughs of the envelope signal. The baseline of the envelope power, represented by the green line, was determined by taking two times the median of the trough power.

Figure 2:

State-dependent beta band profiles. Time frequency spectrograms and synchronized kinematic traces (A, D) and power spectral density (PSD) diagrams (E, F) from a representative subject during resting and movement states of the stepping in place (SIP) (A–C) and forward walking (FW) (D–F) tasks. Kinematics from the right and left foot of the subject are represented by the red and blue traces, respectively. Shaded blue region in PSD (B–C, E–F) diagram indicates movement band chosen for each STN.

Figure 3:

Distribution of envelope power, burst duration and mean burst power with kinematics for Freezer and Non-Freezer. Beta burst distribution of a Non-Freezer and Freezer performing stepping in place (SIP) during no DBS. Envelope power of the squared LFP signal of a representative STN, with the green line indicating the baseline of the signal, is used to determine each individual beta bursts (represented by solid black circles) throughout the task (A, B). The distribution of burst duration (C, D) and relative burst power (E, F) is plotted along with synchronized kinematics (G, H).

Figure 4:

Three-dimensional spectrogram and kinematics during no DBS. Synchronized kinematics and three-dimensional spectrogram plotting time, frequency, and local field potential power for a representative Non-Freezer (A) and Freezer (B) throughout the duration of the stepping in place task during no DBS.

Figure 5:

Bilateral beta burst duration distribution. Synchronized beta burst durations in the LSTN (MA) (A) and RSTN (LA) (B) with kinematics of the stepping in place task. The horizontal green lines represent the mean group burst duration for Non-Freezers ± two standard deviations.

Figure 6:

Stepping-in-place kinematics during no, 60 Hz, and 140 Hz STN DBS. Force plate traces from the stepping in place (SIP) task from a representative Freezer during the three stimulation conditions: (A) no DBS, (B) 60 Hz, and (C) 140 Hz DBS.