Objective: We test the hypothesis of modulating subthalamic neuronal firing pattern via injection of hyperpolarizing current as an effective treatment for hyperkinetic movement disorders.

Background: Modulation of the subthalamic nucleus (STN) firing pattern with injection of depolarizing currents into STN is an important advance for the treatment of hypokinetic movement disorder, namely Parkinson’s disease (PD). STN holds an important position in both hyperdirect and indirect pathways and thus might be closely related to the pathophysiology of hyperkinetic movement, namely chorea, ballism and dystonia. Moreover, it is of note that normal animals can be rendered hypokinetic with hyperpolarizing currents injected into STN.

Method: We investigated the effect of injection of hyperpolarizing current into STN of two different types of hyperkinetic animal models. The two animal models include levodopa-induced hyperkinesia in parkinsonian rats and intra-striatal injection of 3-nitropropionic acid-induced hyperkinesia, covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops.  Both behavioral and electrophysiological data were documented.

Results: We examined the effect of injecting hyperpolarizing currents into STN on the hyperkinetic behaviors in the two animal models. Delivery of constant positive current into STN decreased the sum of the global AIMs scores in L-dopa-induced dyskinesia parkinsonian rats and also increased STN burst firing number significantly. Injection of constant positive current into bilateral STN of intrastriatal 3-NP injection-induced hyperkinetic rats decreased abnormal rats locomotor activity and increased burst counts in STN.

Conclusion: Application of hyperpolarizing current into STN via DBS electrode could be an effective therapy in general for a wide spectrum of hyperkinetic movement disorders.

References: 1. Tai CH, Yang YC, Pan MK, Huang CS, Kuo CC. Modulation of subthalamic T-type Ca(2+) channels remedies locomotor deficits in a rat model of Parkinson disease. J Clin Invest 2011; 121: 3289–305. 2. Tai CH, Pan MK, Lin JJ, Huang CS, Yang YC, Kuo CC. Subthalamic discharges as a causal determinant of parkinsonian motor deficits. Ann Neurol 2012; 72: 464–76. 3. Pan MK, Tai CH, Liu WC, Pei JC, Lai WS, Kuo CC. Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits. J Clin Invest 2014; 124: 4629–41 4. Yang YC, Tai CH, Pan MK, Kuo CC. The T-type calcium channel as a new therapeutic target for Parkinson’s disease. Pflugers Arch 2014; 466: 747–55. 5. Pan MK, Kuo SH, Tai CH, Liou JY, Pei JC, Chang CY, Wang YM, Liu WC, Wang TR,Lai WS, Kuo CC. Neuronal firing patterns outweigh circuitry oscillations inparkinsonian motor control. J Clin Invest. 2016 Dec 1;126(12):4516-4526.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hyperpolarization-of-the-subthalamic-nucleus-alleviates-hyperkinetic-movement-disorders/