Hyperpolarization of the subthalamic nucleus alleviates hyperkinetic movement disorders

Abstract

Modulation of subthalamic nucleus (STN) firing patterns with injections of depolarizing currents into the STN is an important advance for the treatment of hypokinetic movement disorders, especially Parkinson’s disease (PD). Chorea, ballism and dystonia are prototypical examples of hyperkinetic movement disorders. In our previous study, normal rats without nigro-striatal lesion were rendered hypokinetic with hyperpolarizing currents injected into the STN. Therefore, modulation of the firing pattern by injection of a hyperpolarizing current into the STN could be an effective treatment for hyperkinetic movement disorders. We investigated the effect of injecting a hyperpolarizing current into the STNs of two different types of hyperkinetic animal models and a patient with an otherwise uncontrollable hyperkinetic disorder. The two animal models included levodopa-induced hyperkinetic movement in parkinsonian rats (L-DOPA-induced dyskinesia model) and hyperkinesia induced by an intrastriatal injection of 3-nitropropionic acid (Huntington disease model), covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops. Delivering hyperpolarizing currents into the STN readily alleviated the hyperkinetic behaviors in the two animal models and in the clinical case, with an evident increase in subthalamic burst discharges in electrophysiological recordings. Application of a hyperpolarizing current into the STN via a Deep brain stimulation (DBS) electrode could be an effective general therapy for a wide spectrum of hyperkinetic movement disorders.