ABSTRACT
The mechanism of high-frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high-frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K(+)](e) to 18 mm, in vitro. In this study, we assessed whether elevated K(+) can elicit DBS-like therapeutic effects in hemiparkinsonian rats by employing the limb-use asymmetry test and the self-adjusting stepping test. We then identified how these effects were meditated with in-vivo and in-vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta-frequency (12-30 Hz) oscillations after K(+) treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K(+) injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K(+) may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD.
Subject(s)
Deep Brain Stimulation , Parkinson Disease, Secondary/therapy , Potassium/pharmacology , Animals , Beta Rhythm/drug effects , Forelimb , Hypokinesia/drug therapy , Male , Motor Activity/drug effects , Oxidopamine/toxicity , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/physiopathology , Potassium/therapeutic use , Potassium Chloride/therapeutic use , Rats , Rats, Sprague-Dawley , Substantia Nigra/physiopathology , Subthalamic Nucleus/physiopathologyABSTRACT
Deep brain stimulation (DBS) employing high-frequency stimulation (HFS) is commonly used in the globus pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with Parkinson's disease (PD). Although DBS improves motor function in most PD patients, disease progression and stimulation-induced nonmotor complications limit DBS in these areas. In this study, we assessed whether stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use asymmetry tests. After SNr-HFS (150 Hz), rats touched equally with both forepaws, similar to naive and sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 to 18 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr neuronal activity. We demonstrate improvement of forelimb akinesia with SNr-HFS and suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased SNr beta oscillations, and increased activity of VM thalamic neurons, suggesting that the SNr may be a plausible DBS target for treating motor symptoms of DBS.
