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.

β-bursts reveal the trial-to-trial dynamics of movement initiation and cancellation

“…To date, most studies of β-band activity in PD are still based on trial-averages. However, recent studies have already used trial-level β-burst measurements in subcortical areas of the basal ganglia to identify gait problems in PD [46] and have investigated the effect of deep-brain stimulation on subcortical β-burst [47]. Future studies may aim to investigate the relationship between abnormal patterns of β-bursting on the scalp and the specific impairments in movement cancellation that are commonly observed in PD [48][49][50].…”

Corticomuscular control of walking in older people and people with Parkinson’s disease

“…Patterns of STN beta oscillations (i.e. duration of beta bursts) were also found to be linked to freezing of gait (Anidi et al 2018). A number of studies that investigated cortical oscillatory activity during upper limb movements reported beta frequencies to be affected by PD (Pollok et al 2012, Heinrichs-Graham et al 2013, Hirschmann et al 2013, Stegemoller et al 2016.…”

Invasive and Noninvasive Brain Stimulation in Parkinson's Disease: Clinical Effects and Future Perspectives

“…However, not all patients with PD have clear beta oscillation in STN, and beta oscillation intensity did not correlate with all cardinal symptoms (e.g., tremors). Besides, STN beta power is reduced during walking compared with rest . If beta oscillation level is used as the control signal for aDBS, this may reduce stimulation intensity when the patient needs higher stimulation intensities when performing activities.…”

“…Besides, STN beta power is reduced during walking compared with rest. 70 If beta oscillation level is used as the control signal for aDBS, this may reduce stimulation intensity when the patient needs higher stimulation intensities when performing activities. Therefore, the utility of other frequency bands, such as the gamma or the low (2-8 Hz) frequency band 52 in the basal ganglia, or information rather than spectrum power alone, such as PAC, should also be explored in the future.…”