McIntyre Cameron C, Grill Warren M, Sherman David L, Thakor Nitish V
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21218, USA.
J Neurophysiol. 2004 Apr;91(4):1457-69. doi: 10.1152/jn.00989.2003. Epub 2003 Dec 10.
Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.
深部脑刺激（DBS）是治疗药物难治性运动障碍的一种有效疗法。然而，关于DBS对电极周围神经元的影响仍存在一些基本问题。实验研究得出了明显相互矛盾的结果，显示受刺激核团的活动受到抑制，但投射核团的输入增加。我们推测，细胞体放电不能准确反映高频细胞外脉冲刺激的神经元的传出输出，而体细胞和轴突活动的这种解耦解释了矛盾的实验结果。我们结合临床DBS电极的有限元模型和丘脑皮质（TC）中继神经元的多节段电缆模型研究了刺激。电极产生的电势以及突触前终末刺激诱导的兴奋性和抑制性跨突触输入的分布都应用于TC中继神经元。神经元对DBS的反应主要取决于轴突相对于电极的位置和方向以及刺激参数。低于直接激活TC中继神经元阈值的刺激在刺激串期间通过突触前终末的激活介导抑制内在放电（紧张性或爆发性）活动。高于阈值的刺激导致体细胞中的内在放电受到抑制，但在轴突中以刺激频率产生传出输出。细胞体和轴突放电的这种独立性解决了关于DBS作用的明显相互矛盾的实验结果。反过来，本研究结果支持刺激诱导的病理网络活动调制作为DBS治疗机制的假设。
