Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 µm) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson’s disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1–100 Hz, 100 µA, 0.3 ms, 50–60 pulses). Subthalamic firing attenuated with ≥20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with ≥3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At ≥30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse ratios calculated at the beginning of the train revealed that 20 Hz (P < 0.05) was the minimum frequency required to induce synaptic depression. Lastly, the average amplitude of evoked field potentials during 1 Hz pulses showed significant inhibitory synaptic potentiation after long-train high frequency stimulation (P < 0.001) and these increases were coupled with increased durations of neuronal inhibition (P < 0.01). The subthalamic nucleus exhibited a higher frequency threshold for stimulation-induced inhibition than the substantia nigra pars reticulata likely due to differing ratios of GABA:glutamate terminals on the soma and/or the nature of their GABAergic inputs (pallidal versus striatal). We suggest that enhancement of inhibitory synaptic plasticity, and frequency-dependent potentiation and depression are putative mechanisms of deep brain stimulation. Furthermore, we foresee that future closed-loop deep brain stimulation systems (with more frequent off stimulation periods) may benefit from inhibitory synaptic potentiation that occurs after high frequency stimulation.

中文翻译：

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帕金森氏病的基底神经节神经元的神经元抑制和突触可塑性

丘脑底核的深部脑刺激是治疗帕金森氏病症状的有效方法。深度脑刺激的治疗益处是频率依赖性的，但潜在的生理机制仍不清楚。为了推进深部脑刺激疗法，对基本机制的理解至关重要。这项研究的目的是（i）比较频率依赖性对丘脑底核和黑质网状细胞射击的影响；（ii）量化频率对黑质网状组织短期可塑性的影响；（iii）研究连续的长期高频刺激（与传统的深部脑刺激相比）对突触可塑性的影响。将两个间距很小的（600 µm）微电极推进到丘脑下核（n = 27）和22例因帕金森氏病接受了深部脑刺激手术的患者的黑质网状组织（n = 14）。在相邻频率的一系列频率（1–100 Hz，100 µA，0.3 ms，50–60脉冲）的刺激序列中，用一个微电极记录了细胞放电和诱发的场电势。丘脑下烧成衰减与≥20赫兹（P < 0.01）的刺激（在100赫兹沉默），而黑质网状与≥3赫兹（降低P <0.05）（在50 Hz时静音）。黑质黑质网状体在刺激后的瞬时静默期也表现出更显着的增加。丘脑底核内100 Hz刺激后沉默期较长的患者在深部脑刺激后往往具有更好的临床效果。在≥30 Hz时，网状黑质中刺激序列的第一个诱发场电位被增强（P < 0.05）；然而，随后电位的平均幅度迅速衰减（P < 0.01）。这提示突触促进，然后快速抑郁。在列车开始时计算的成对脉冲比率显示出20 Hz（P <0.05）是诱导突触抑制所需的最低频率。最后，在长频率高频刺激后，在1 Hz脉冲期间诱发的场电位的平均幅度显示出显着的抑制性突触增强作用（P < 0.001），这些增加与神经元抑制作用持续时间的增加（P <0.01）。丘脑下核比黑质网显示出更高的刺激诱导抑制频率阈值，这可能是由于体细胞中GABA：谷氨酸末端比例不同和/或它们的GABA能量输入性质（苍白与纹状体）所致。我们建议增强抑制性突触可塑性，以及频率依赖性增强和抑制是深部脑刺激的推定机制。此外，我们预见到，未来的闭环深部脑刺激系统（更频繁的关闭刺激时间）可能会受益于高频刺激后发生的抑制性突触增强。