Activity Patterns in a Model for the Subthalamopallidal Network of the Basal Ganglia

Abstract

Based on recent experimental data, we have developed a conductance-based computational network model of the subthalamic nucleus and the external segment of the globus pallidus in the indirect pathway of the basal ganglia. Computer simulations and analysis of this model illuminate the roles of the coupling architecture of the network, and associated synaptic conductances, in modulating the activity patterns displayed by this network. Depending on the relationships of these coupling parameters, the network can support three general classes of sustained firing patterns: clustering, propagating waves, and repetitive spiking that may show little regularity or correlation. Each activity pattern can occur continuously or in discrete episodes. We characterize the mechanisms underlying these rhythms, as well as the influence of parameters on details such as spiking frequency and wave speed. These results suggest that the subthalamopallidal circuit is capable both of correlated rhythmic activity and of irregular autonomous patterns of activity that block rhythmicity. Increased striatal input to, and weakened intrapallidal inhibition within, the indirect pathway can switch the behavior of the circuit from irregular to rhythmic. This may be sufficient to explain the emergence of correlated oscillatory activity in the subthalamopallidal circuit after destruction of dopaminergic neurons in Parkinson's disease and in animal models of parkinsonism. Key words: basal ganglia; subthalamic nucleus; globus pallidus; computational models; oscillations; synchrony; Parkinson's diseaseMost current models of the basal ganglia are static models, in that they represent the inputs and outputs of the component nuclei as firing rates. For example, the Albin et al. (1989) model, commonly used to explain the symptoms of Parkinsonism, views the interactions of the direct and indirect pathway as constant in time and explains the symptoms of Parkinson's disease in terms of changes in mean rate of the basal ganglia output (Wichmann and DeLong, 1996). In contrast, recent experimental studies have not strongly confirmed the predicted changes in mean rate in these structures under dopamine depletion, but have instead revealed prominent low-frequency periodicity (4 -30 Hz) of firing and dramatically increased correlations among neurons in the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN) (Bergman et al., 1994;Nini et al., 1995;Magnin et al., 2000;Raz et al., 2000;Brown et al., 2001). It is remarkable that the changes in firing pattern seen in those structures do not appear to be attributable to comparable changes in the firing patterns of striatal output cells, although cholinergic striatal interneurons show changes comparable with those seen in the globus pallidus (Raz et al., 1996). The authors of those studies have proposed that a rate model of the basal ganglia is inadequate to capture the dynamic interaction of the STN and GPe that may generate these pathological changes.In particular, such dynamic interactions ma...

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

“…These studies compare firing before HFS with that after HFS, however; thus, they do not establish how firing changes during HFS. Indeed, it is quite possible that after a period of sustained, high-frequency STN firing, STN activity will be suppressed by the activation of a calcium-gated potassium afterhyperpolarization current (Bevan et al, 1999(Bevan et al, , 2000Terman et al, 2002).…”

“…Several authors have pointed out that the pattern of neuronal activity, not just the rate, may be important (Bergman et al, 1994;Nini et al, 1995;Magnin et al, 2000;Montgomery et al, 2000;Obeso et al, 2000;Raz et al, 2000;Brown et al, 2001;Terman et al, 2001Terman et al, , 2002. In particular, numerous experimental studies have demonstrated that neurons within both the STN and GPi show an increased level of synchrony and bursting activity during parkinsonian states (Bergman et al, 1994;Nini et al, 1995;Magnin et al, 2000;Raz et al, 2000;Brown et al, 2001).…”

“…This model was introduced in Terman et al (2002). We make some parameter adjustments so that the STN cells display firing patterns more similar to those seen in vivo.…”

“…This model was also introduced in Terman et al (2002), and as with the STN model, slight parameter adjustments have been made to reflect in vivo firing patterns. Here, I app is a constant and represents input from the striatum.…”

“…In Terman et al (2002), we describe several different types of activity patterns that may be generated by the isolated model STN/GPe network (but with a constant level I app of striatal inhibition to GPe), along with a detailed description of how the activity patterns depend on parameters. We demonstrate that this network can produce both irregular asynchronous activity and synchronous tremorlike activity as shown in Fig.…”