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Deep brain stimulation (DBS) is an established therapy for movement disorders, including tremor, dystonia, and Parkinson's disease, but the mechanisms of action are not well understood. Symptom suppression by DBS typically requires stimulation frequencies ≥100 Hz, but when the frequency is increased above ~2 kHz, the effectiveness in tremor suppression declines (Benabid et al.,  1991 ). We sought to test the hypothesis that the decline in efficacy at high frequencies is associated with desynchronization of the activity generated within a population of stimulated neurons. Regularization of neuronal firing is strongly correlated with tremor suppression by DBS, and desynchronization would disrupt the regularization of neuronal activity. We implemented computational models of CNS axons with either deterministic or stochastic membrane dynamics, and quantified the response of populations of model nerve fibers to extracellular stimulation at different frequencies and amplitudes. As stimulation frequency was increased from 2 to 80 Hz the regularity of neuronal firing increased (as assessed with direct estimates of entropy), in accord with the clinical effects on tremor of increasing stimulation frequency (Kuncel et al.,  2006 ). Further, at frequencies between 80 and 500 Hz, increasing the stimulation amplitude (i.e., the proportion of neurons activated by the stimulus) increased the regularity of neuronal activity across the population, in accord with the clinical effects on tremor of stimulation amplitude (Kuncel et al.,  2007 ). However, at stimulation frequencies above 1 kHz the regularity of neuronal firing declined due to irregular patterns of action potential generation and conduction block. The reductions in neuronal regularity that occurred at high frequencies paralleled the previously reported decline in tremor reduction and may be responsible for the loss of efficacy of DBS at very high frequencies. This analysis provides further support for the hypothesis that effective DBS masks the intrinsic patterns of activity in the stimulated neurons and replaces it with regularized firing.

Kilohertz Frequency Deep Brain Stimulation Is Ineffective at Regularizing the Firing of Model Thalamic Neurons