Background: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson’s disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. Objective: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. Methods: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. Results: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. Conclusion: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.
Intra- and perioperatively recorded local field potential (LFP) activity of the nucleus subthalamicus (STN) has been suggested to guide contact selection in patients undergoing deep brain stimulation (DBS) for Parkinson’s disease (PD). Despite the invention of sensing capacities in chronically implanted devices, a comprehensible algorithm that enables contact selection using such recordings is still lacking. We evaluated a fully automated algorithm that uses the weighted average of bipolar recordings to determine effective monopolar contacts based on elevated activity in the beta band. LFPs from 14 hemispheres in seven PD patients with newly implanted directional DBS leads of the STN were recorded. First, the algorithm determined the stimulation level with the highest beta activity. Based on the prior determined level, the directional contact with the highest beta activity was chosen in the second step. The mean clinical efficacy of the contacts chosen using the algorithm did not statistically differ from the mean clinical efficacy of standard contact selection as performed in clinical routine. All recording sites were projected into MNI standard space to investigate the feasibility of the algorithm with respect to the anatomical boundaries of the STN. We conclude that the proposed algorithm is a first step towards LFP-based contact selection in STN-DBS for PD using chronically implanted devices.
Gait impairments such as freezing of gait (FOG) are among the most common and disabling symptoms of Parkinson's disease (PD). While the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with early or advanced PD has been proven in large randomised controlled trials, its effect on gait impairments is still insufficiently understood. Moreover, there is uncertainty about pathways that need to be modulated to improve gait impairments. In this bi-centric study, we investigated how STN-DBS alters FOG in 47 subjects with PD. We assessed freezing prevalence and severity using the Freezing of Gait Questionnaire and Item 14 of the Unified Parkinson's Disease Rating Scale-II. Using a model of publicly available basal-ganglia pathways we determined a connectivity profile for postoperative changes in FOG. Compared to preoperative baseline, freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. We found that optimal stimulation sites for improving freezing of gait structurally connected to primary and supplementary motor areas, the dorsolateral prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of freezing of gait. Our findings highlight the need for optimal identification and characterisation for network structures that can be implemented in stereotactic planning and can additionally pose a target for postoperative stimulation strategies.
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