Structural Connectivity of Subthalamic Nucleus Stimulation for Improving Freezing of Gait

Abstract

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.

Freezing of gait depends on cortico-subthalamic network recruitment following STN-DBS in PD patients

“…Conversely, lower FOG severity was related to a higher connectivity of the VAT with sensorimotor cortices (mainly BA 1, 2, 3, 4, 6 and 8), which have been widely demonstrated to be activated in the preparation and execution phases of movement, including gait [29]. This result is in accordance with the recent report of a significant link between FOG improvement after STN-DBS and a higher connectivity with motor and premotor cortico-subthalamic fibres [14], as also reported for other parkinsonian motor signs, such as rigidity or akinesia [10]. In PD patients with STN-DBS, PET imaging also suggested that FOG severity improvement was associated with metabolic activity changes in sensory associative cortices [30].…”

“…In a large retrospective cohort study, we found that the sweet spot for improving FOG was located more anteriorly within the STN, roughly corresponding to its centre, just beyond the posterior sensorimotor part of the nucleus [4]. In a recent retrospective study performed on a cohort of 47 PD patients with STN-DBS, a significant correlation between FOG improvement and the recruitment of premotor, motor and prefrontal dorsolateral corticosubthalamic fibres was also reported [14], suggesting a possible influence of cortico-subthalamic fibres recruitment in post-operative FOG improvement. Taken together, these data suggest that the effects of STN-DBS can be explained by both the modulation of the target site inside the STN and the fibres recruited within the VAT, especially the fibres belonging to the hyperdirect cortico-subthalamic pathway [15].…”

“…However, our DWI technique does not allow to study the influence of other basal ganglia-mesencephalic locomotor networks with high reliability mainly because of the large number of fibres crossing towards the STN and the GPe, pedunculopontine (PPN) and cuneiform nuclei. It is also possible that STN-DBS altered or alleviated the functioning of other pathways involved in gait control such as PPN-STN fibres, known to be altered in PD with dopa-resistant FOG [31], or lenticular fasciculus fibres as recently suggested in a retrospective study [14]. Lastly, the effects of STN-DBS could also be related to the abnormal STN neuronal activity patterns observed in PD patients with increased beta band activity previously found in freezers PD patients at rest or during arrests of stepping movements [32].…”

“…Moreover, the use of normative tractograms could improve the signal to noise ratio for the connectivity assessment, but conversely it could smooth small individual differences. We also did not examine other fiber tracts that could be involved in gait control such as the GPe-STN, STN-GPi or STN-PPN [14], or functional connectivity profile [11]. Even though we used multi-shell diffusion data to improve diffusion signal modelling, these networks are difficult to isolate with high reliability due to the high numbers of crossing fibres.…”

Wireless Stimulation of the Subthalamic Nucleus with Nanoparticles Modulates Key Monoaminergic Systems Similar to Contemporary Deep Brain Stimulation

“…On the other hand, an optogenetic study has demonstrated that gait improvement in STN-stimulated animals was related to the modulation of upstream connections between the STN and frontal cortices [56]. Likewise, a recent structural connectivity study has attributed the beneficial motor effects of STN stimulation in PD patients to the modulation of fiber tracts between the STN and motor cortex [57], suggesting that STN-DBS does not activate the PPN cholinergic neurons. Similarly, in our study we found no indication that magnetic stimulation in the STN influenced PPN cholinergic neurons.…”