No abstract

Current treatments of Parkinson's disease (PD) have limited efficacy in alleviating axial symptoms, such as freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanism underlying this paired stimulation approach is unknown. The hypothetical rationale behind it relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs. However, to date, it is unclear how simultaneous high-frequency DBS in two different interconnected basal ganglia nuclei affect large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare the effects of different stimulation modes on the cortico-subcortical network underlying FoG. We develop a new network-based computational framework to uncover the most effective subcortical DBS target sites and their combinations through exhaustive analysis of the brain attractor dynamics in the healthy, PD and DBS states. We demonstrate the validity of the approach and the superior performance of combined STN+SNr DBS in the normalization of spike propagation flow in the FoG network. The present framework aims to move towards a better mechanistic understanding of the brain network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders.