Extracellular excitation of central neurons: implications for the mechanisms of deep brain stimulation

Abstract

High-frequency electrical stimulation (deep brain stimulation (DBS)) of the thalamus and basal ganglia (subthalamic nucleus, internal segment of the globus pallidus) is used to treat motor disorders arising in Parkinson’s disease, multiple sclerosis, and essential tremor. Although clinically effective, the mechanisms of action of DBS are unknown. A number of plausible hypotheses have been offered, however, until the effects of the applied current on the surrounding neurons are understood, it will prove difficult to determine the underlying mechanisms. Computational models of central neurons were used to determine what neural elements are activated by extracellular stimulation. Thresholds for activation of local cells and axons of passage were similar with conventional stimuli. With electrodes positioned over the cell body, action potential initiation invariably occurred in the axon. As a result, activity generated by extracellular stimulation could vary between the soma and axon of the same neuron. Additionally, extracellular chronaxie times were insensitive to the neural element (cell versus axon) that was stimulated. The non-specific activation that occurs with conventional stimuli complicates the determination of the mechanisms of action and may contribute to side effects. Novel asymmetrical stimuli were developed that enable selective stimulation of different populations of neural elements. Understanding the effects of extracellular stimulation on central neurons will limit the plausible hypotheses to explain the effects of DBS, and lead to new stimulation technologies that will improve clinical efficacy.