Neuromodulation targets pathological not physiological beta bursts during gait in Parkinson's disease
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.
Section snippets
Human subjects
Twelve PD subjects (7 male) had bilateral implantation of DBS leads (model 3389, Medtronic, Inc.) in the sensorimotor region of the STN using a standard functional frameless stereotactic technique and multi-pass microelectrode recording (MER) (Bronte-Stewart et al., 2010; Quinn et al., 2015). Dorsal and ventral borders of each STN were determined during MER, and the base of electrode zero was placed at the ventral border of the STN. The two leads were connected to the implanted investigative
Results
Age, disease duration, preoperative off- and on- medication Unified Parkinson's disease Rating Scale III (UPDRS III) scores were not significantly different between Freezers (N = 8) and Non-Freezer groups (N = 4), see Supplementary Table 2 for demographics. UPDRS III was also performed by the same experienced rater for each patient at each research visit, throughout the duration of the study. There was no significant difference in off medication / off stimulation UPDRS III at the time of the
Discussion
For the first time, this study has demonstrated that beta burst duration and power, recorded during freely-moving gait, differentiated PD Freezers from Non-Freezers and was differentially modulated during low and high frequency STN DBS. STN beta burst durations were longer in Freezers compared to Non-Freezers during all gait tasks, in which gait was more impaired in Freezers. Within Freezers, burst durations were longer during periods of FOG compared to during gait without freezing. There was
Conclusion
The study demonstrates that longer duration of beta bursts in the movement band is a defining feature of freezing behavior in freely-moving PD subjects. Our results show that both 60- and 140 Hz STN DBS can improve gait impairment in Freezers and shorten pathological beta burst durations. In contrast to Freezers, Non-Freezers exhibited shorter duration beta bursts and normal gait, which were unchanged on versus off DBS. These results support the hypothesis that in PD, pathological prolonged
Acknowledgements
We thank Varsha Prabhakar, Raumin Neuville, Tom Prieto, Amaris Martinez, Leanel Liwanag, Russell Mendonca, and Talora Martin for their support during the experiments and helpful comments. We would also like to thank our dedicated patient population who contributed their time to participating in our study (ClinicalTrials.gov Identifier: NCT02304848). This study was supported by the Michael J Fox Foundation, the NINDS Grant 5 R21 NS096398-02, the Robert and Ruth Halperin Foundation, the John A.
Declaration of interest
None of the authors have any conflicts of interest.
Funding
This study was supported by the NINDS Grant 5 R21 NS096398-02, the Michael J Fox Foundation, the Robert and Ruth Halperin Foundation, the John A. Blume Foundation, the Helen M. Cahill Award for Research in Parkinson's Disease, and Medtronic Inc., who provided the devices used in this study but no additional financial support.
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