Subthalamic discharges as a causal determinant of parkinsonian motor deficits

Objective: We have reported that intrinsic membrane properties, especially T-type Ca2+ channels, play a key role in the genesis of burst discharges in the subthalamic nucleus (STN) and parkinsonian locomotor symptoms. Whether deep brain stimulation (DBS) exerts its clinical benefits on Parkinson disease (PD) with changes in T currents or other conductances, however, remains elusive. Methods: Different stimulation protocols, including constant currents of opposite polarity, were applied to STN in vivo or in vitro, and the electrophysiological and behavioral effects were documented in normal and parkinsonian rodents. The effect of correlatively adjusted DBS protocols was also explored in 3 PD patients. Results: Delivery of negative constant current into STN dramatically ameliorated locomotor deficits in parkinsonian rats. It also depolarized STN neurons and decreased T-channel availability as well as burst discharges. In contrast, delivery of positive constant currents to STN induced PD-like locomotor deficits and increased STN burst discharges in normal rats. In addition, the therapeutic effect of DBS was greatly improved in 3 PD patients simply by increasing the pulse width from 60 to 240 microseconds, even at a lower stimulation frequency of 60Hz. Interpretation: The increased tendency of STN burst discharges may by itself serve as a direct cause of parkinsonian locomotor deficits, even in the absence of deranged dopaminergic innervation. Effective DBS therapy in PD very likely relies on adequate depolarization, and consequent modification of the relevant ionic currents and discharge patterns, of STN neurons. ANN NEUROL 2012;72:464-476. Copyright ? 2012 American Neurological Association.