Slaves to the rhythm: coupling of the subthalamic nucleus–globus pallidus network in Parkinsonian oscillations

Abstract

Systems neuroscience approaches to the study of Parkinson's disease seek to understand how the chronic loss of dopamine alters the normal operation of neuronal networks, resulting in the cardinal symptoms (tremor, rigidity, akinesia and bradykinesia). A recurring theme is the combined change in synchronization and oscillation of whole populations of neurons. Both Parkinsonian patients and animal models show enhanced synchrony of firing between neurons within the cortex and the nuclei of the basal ganglia, correlated with a markedly increased oscillation of activity in the beta band (13-30 Hz;Hammond et al. 2007). With mounting evidence that this enhanced beta oscillation is pathological, the priority is to locate its source mechanism(s). Doing so would suggest a locus for targeted chemical, electrical and other interventions for treating Parkinson's disease. A particular focus has been the recurrent connections between the subthalamic nucleus (STN) and globus pallidus (GP) of the basal ganglia. In animal models of Parkinson's disease, both structures show changed firing patterns and increased neural synchrony, corresponding to enhanced beta-band oscillations. As the STN and GP form a negative feedback loop, a classical system for generating oscillations in engineering, many have proposed that this loop is the source of pathological changes in oscillation and synchrony.If only it were that simple. Evidence against this attractively simple hypothesis has come from a recent study showing that GP comprises two populations functionally defined by their phase of correlation with global oscillations in the cortex under general anaesthesia (Mallet et al. 2008). These authors reported a population labelled GP-TA that fire during activation of the cortical electrocorticogram, thus in phase with STN, and a population labelled GP-TI that fire during inactivation of the cortical electrocorticogram, thus out of phase with STN and GP-TA. These data have thrown open the question of how the STN and GP connections are organized and thus raised the broader question, on what should we base our theories of neural dynamics in the Parkinsonian brain?In this issue of The Journal of Physiology, Nevado-Holgado et al. (2014) use computational models to tackle this problem, with the aim of determining the effective connectivity between STN and GP populations in the Parkinsonian brain. They used a dynamic model describing the change of firing rates in the STN, GP-TI and GP-TA populations, driven by oscillatory inputs from cortex, thalamus and striatum (Fig. 1). While many parameters could be fixed from experimental data, the remaining free parameters of the model encode the many unknowns about this system, particularly the effective weights of connections between each population and of the inputs. To solve this problem, Nevado-Holgado et al. (2014) epitomized the modern use of computer power to search the high-dimensional space of possible parameter values and possible models, with the goal of fitting the response of each population to expe...