Abstract
Recent studies suggest that subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) may exert at least part of its therapeutic effect through the antidromic suppression of pathological oscillations in the cortex in 6-OHDA treated rats and in parkinsonian patients. STN-DBS may also activate STN neurons by initiating action potential propagation in the orthodromic direction, similarly resulting in suppression of pathological oscillations in the STN. While experimental studies have provided strong evidence in support of antidromic stimulation of cortical neurons, it is difficult to separate relative contributions of antidromic and orthodromic effects of STN-DBS. The aim of this computational study was to examine the effects of antidromic and orthodromic activation on neural firing patterns and beta-band (13-30 Hz) oscillations in the STN and cortex during DBS of STN afferent axons projecting from the cortex. High frequency antidromic stimulation alone effectively suppressed simulated beta activity in both the cortex and STN-globus pallidus externa (GPe) network. High frequency orthodromic stimulation similarly suppressed beta activity within the STN and GPe through the direct stimulation of STN neurons driven by DBS at the same frequency as the stimulus. The combined effect of both antidromic and orthodromic stimulation modulated cortical activity antidromically while simultaneously orthodromically driving STN neurons. While high frequency DBS reduced STN beta-band power, low frequency stimulation resulted in resonant effects, increasing beta-band activity, consistent with previous experimental observations. The simulation results indicate effective suppression of simulated oscillatory activity through both antidromic stimulation of cortical neurons and direct orthodromic stimulation of STN neurons. The results of the study agree with experimental recordings of STN and cortical neurons in rats and support the therapeutic potential of stimulation of cortical neurons.
Highlights
Deep brain stimulation (DBS) is an established surgical therapy for treating the symptoms of medically refractory Parkinson’s disease
Consistent with previous experimental and modeling studies, high frequency DBS was observed to disrupt beta oscillatory activity in the subthalamic nucleus (STN) neurons, with all neurons firing in response to each DBS input stimulus and periodic oscillatory activity of the STN neurons suppressed, Figure 5A
The results of a new computational model presented here, indicate that high frequency DBS applied to STN afferents originating from the cortex modulates the behavior of both cortical and STN neurons, resulting in suppression of oscillatory beta-band neural activity in parkinsonian conditions
Summary
Deep brain stimulation (DBS) is an established surgical therapy for treating the symptoms of medically refractory Parkinson’s disease. The mechanisms by which DBS exerts its therapeutic influence, at both the cellular and system level, remain unclear. Synchronized neural activity throughout the cortico-basal ganglia network is a characteristic hallmark of Parkinson’s disease (Eusebio et al, 2008). It has been shown that beta-band power in the STN is largely attenuated during and immediately following STN-DBS (Kühn et al, 2008; Bronte-Stewart et al, 2009; Eusebio et al, 2011) and abolished following administration of levodopa (Kühn et al, 2006), supporting the hypothesis that DBS exerts at least part of its therapeutic influence by disrupting synchronous oscillations among neural circuits in the brain. The exact mechanisms by which DBS suppresses abnormal neural activity in the cortico-basal ganglia network, remain unknown
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