High Frequency Stimulation of the Subthalamic Nucleus Eliminates Pathological Thalamic Rhythmicity in a Computational Model

Abstract

Abstract. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has recently been recognized as an important form of intervention for alleviating motor symptoms associated with Parkinson's disease, but the mechanism underlying its effectiveness remains unknown. Using a computational model, this paper considers the hypothesis that DBS works by replacing pathologically rhythmic basal ganglia output with tonic, high frequency firing. In our simulations of parkinsonian conditions, rhythmic inhibition from GPi to the thalamus compromises the ability of thalamocortical relay (TC) cells to respond to depolarizing inputs, such as sensorimotor signals. High frequency stimulation of STN regularizes GPi firing, and this restores TC responsiveness, despite the increased frequency and amplitude of GPi inhibition to thalamus that result. We provide a mathematical phase plane analysis of the mechanisms that determine TC relay capabilities in normal, parkinsonian, and DBS states in a reduced model. This analysis highlights the differences in deinactivation of the low-threshold calcium T -current that we observe in TC cells in these different conditions. Alternative scenarios involving convergence of thalamic signals in the cortex are also discussed, and predictions associated with these results, including the occurrence of rhythmic rebound bursts in certain TC cells in parkinsonian states and their drastic reduction by DBS, are stated. These results demonstrate how DBS could work by increasing firing rates of target cells, rather than shutting them down.

Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

“…According to their simulation the mechanism of DBS may be a replacement of the pathological firing pattern with high frequency firing. Although the results presented are insightful, the model is based on numerous assumptions (Rubin and Terman 2004;Pascual et al 2006). The therapeutic mechanisms that underlie DBS, however, most likely represent a combination of several phenomena (McIntyre et al 2004;Benabid et al 2002).…”

“…9(b), (d), and (f)], which is assumed to cause synaptic failure due to an inability of the stimulated neurons to follow the rapid train of electrical stimuli produced by DBS, resulted in an increase in STN activity. However, according to Rubin and Terman (2004), the STN is capable of following the rapid train of stimuli produced by DBS. According to the model simulations, a direct inhibition of STN cell body firing could also be a possible mechanism of action of DBS, whereas an improvement in PD symptoms by a direct excitation of the STN cell body could not be explained by the firing rate model.…”

“…Rubin and Terman (2004) presented a network model, consisting of single compartment conductance based models of STN, GPe, GPi and thalamus. In this model the thalamus is simplified into a relaying station whose role it is to respond faithfully to incoming sensorimotor signals, while this function is disturbed by rhythmic GPi firing under parkinsonian conditions.…”

“…In this situation the upper limit of the STN firing rate (B Stn,DBS ) is set at 200 spikes per second, since it is known that STN neurons are capable of firing at frequencies beyond their normal frequency range when stimulated at high frequencies (Nakanishi et al 1987;Bevan and Wilson 1999;Rubin and Terman 2004). Mechanism 6 Orthodromic excitation of efferent nuclei (GPi and GPe) by adding input I DBS,exc,eff =20:…”

“…While there is little argument that Deep Brain Stimulation (DBS) of the STN, GPi and thalamus has been an effective tool in the treatment of the various symptoms of Parkinson's disease, there remains considerable debate concerning the methods underlying the beneficial effect of DBS and its mechanisms of action are still unknown (Montgomery and Baker 2000;Benabid et al 2002;McIntyre et al 2004, Rubin andTerman 2004). Therefore, possible mechanisms of DBS based on the firing rate of BG nuclei were investigated.…”