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

Highlights

• First study to investigate STN beta bursts during gait in freely moving PD subjects

• Prolonged movement beta band burst durations were a pathological feature of FOG

• STN DBS shortened pathological burst durations and improved gait in Freezers

• Normal gait parameters, accompanied by shorter bursts, were not modulated by DBS

• Greater difference in burst duration between STNs correlated with more impaired gait

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.

Introduction

Axial motor symptoms of Parkinson's disease (PD) such as freezing of gait (FOG) and postural instability are major reasons for loss of autonomy, falls, institutionalization, and death in patients with PD (Giladi et al., 1992, Giladi et al., 1997; Bloem et al., 2004; Vervoort et al., 2016). FOG frequently manifests as patients attempt to initiate walking, turning, and while navigating obstacles. It results in life-threatening falls or sudden immobility that renders patients helpless in dangerous situations such as crossing a street. The response of FOG to treatment is complex, variable, and has yet to be optimized. Both dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) at low and high frequencies may improve FOG, suggesting that neural mechanisms underlying FOG reside within the sensorimotor networks accessed by both medication and DBS (Moreau et al., 2008; Sidiropoulos et al., 2013; Annic et al., 2014; Khoo et al., 2014; Nantel and Bronte-Stewart, 2014; Vercruysse et al., 2014; Fasano et al., 2015; Xie et al., 2015). However, PD patients may still develop FOG while on medication and/or DBS even while the other cardinal motor signs of PD (tremor, rigidity, and bradykinesia) are well-treated (Lilleeng et al., 2015). Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG make 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 freely-moving subjects and in the lack of gait tasks that reliably elicit FOG. Until recently, subcortical local field potentials (LFPs) could only be recorded in the intra- or peri-operative period, when PD subjects were stationary and attached to cables (Thevathasan et al., 2012; Singh et al., 2013; Toledo et al., 2014). Additionally, there is a lack of knowledge concerning the contribution of each hemisphere to an axial task such as gait. Recent clinical reports demonstrated that unilateral STN DBS can be as efficacious as bilateral DBS for treating gait impairment but the neural mechanism underlying this finding remains unknown (Ricciardi et al., 2015; Lizarraga et al., 2017; Rizzone et al., 2017).

Advances in concurrent sensing and stimulating technology from an implanted sensing neurostimulator (Activa® PC + S, Medtronic Inc.) have made it possible to record synchronized subthalamic neural activity and quantitative kinematic data in freely-moving human PD subjects (Quinn et al., 2015; Blumenfeld et al., 2017; Hell et al., 2018). Using such technology we recently demonstrated that Freezers exhibited increased STN sample entropy during periods of FOG suggesting that temporal fluctuations of STN neural activity may play an important role in FOG (Syrkin-Nikolau et al., 2017). Short fluctuations in beta (13–30 Hz) oscillations (beta bursts) are a physiological feature of normal cortical and subcortical motor circuitry and it has been proposed that short duration beta bursts represent normal signal processing in the sensorimotor network (Murthy and Fetz, 1992, Murthy and Fetz, 1996; Courtemanche et al., 2003; Feingold et al., 2015). This hypothesis has been supported by evidence that longer duration beta bursts in the resting-state, correlated with PD motor disability and were reduced in number by therapeutic doses of dopaminergic medication (Tinkhauser et al., 2017a; Tinkhauser et al., 2017b).

To date no study has investigated the nature of STN beta bursts during gait and freezing of gait in freely moving human subjects with PD, nor whether the nature of dynamic fluctuations in beta activity is different in PD subjects with FOG (Freezers) compared to Non-Freezers. Moreover, whether beta burst properties are modulated by STN low or high frequency DBS, during tasks that elicit FOG, has yet to be explored. To optimize therapies for the treatment of FOG, these gaps need to be addressed. Using synchronized neural and kinematic recordings and concurrent sensing and neurostimulation in freely-moving PD subjects, we demonstrate for the that STN beta burst duration, measured during novel gait tasks that elicited FOG in freely-moving PD subjects, differentiated Freezers from Non-Freezers during gait without freezing and were longer in Freezers during FOG. We also demonstrate that STN DBS, either at 60 Hz or 140 Hz shortened the pathological, longer beta burst durations and improved gait impairment in Freezers but left unchanged the shorter burst durations and normal gait parameters in Non-Freezers.