高频电刺激改变神经元发放与场电位节律之间的锁相关系
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摘要
临床上,已将深部脑刺激(DBS)技术成功应用于治疗多种脑部疾病。近年的研究推测,DBS技术使用的电脉冲高频刺激(HFS)可以改变神经元动作电位的病理性节律发放,这可能是DBS治疗脑部疾病的重要机制之一,但是这种推测尚需实验数据的证实。本文在已麻醉的大鼠海马CA1区的输入轴突束薛氏侧支(Schaffer collaterals)施加时长为1 min、频率为100 Hz的HFS,并分析刺激下游CA1区的锥体神经元和中间神经元的锋电位,考察两种神经元的节律性动作电位发放的变化情况。结果显示,麻醉大鼠CA1区的场电位存在明显的θ节律,且在顶树突层尤其明显,而神经元锋电位与θ节律存在锁相关系。与此基线记录相比较,在HFS期间,锥体神经元的锋电位与顶树突层θ节律的锁相值从0.36±0.12显著减小至0.06±0.04(P<0.001,配对t检验,N=8);中间神经元锋电位的锁相值也从0.27±0.08减小至0.09±0.05(P<0.01,配对t检验,N=8)。两类神经元与胞体层θ节律的锁相关系也有类似改变。此结果表明,对轴突束施加HFS可以消除下游神经元动作电位发放与场电位θ节律之间的锁相关系,改变神经元的节律性发放模式。这种现象产生的机制可能是HFS诱导的轴突传导障碍,此发现对于深入研究DBS的作用机制具有重要的意义。
Deep brain stimulation(DBS) has been successfully used to treat a variety of brain diseases in clinic.Recent investigations have suggested that high frequency stimulation(HFS) of electrical pulses used by DBS might change pathological rhythms in action potential firing of neurons, which may be one of the important mechanisms of DBS therapy. However, experimental data are required to confirm the hypothesis. In the present study, 1 min of 100 Hz HFS was applied to the Schaffer collaterals of hippocampal CA1 region in anaesthetized rats. The changes of the rhythmic firing of action potentials from pyramidal cells and interneurons were investigated in the downstream CA1 region. The results showed that obvious θ rhythms were present in the field potential of CA1 region of the anesthetized rats. The θ rhythms were especially pronounced in the stratum radiatum. In addition, there was a phase-locking relationship between neuronal spikes and the θ rhythms. However, HFS trains significantly decreased the phase-locking values between the spikes of pyramidal cells and the θ rhythms in stratum radiatum from 0.36 ± 0.12 to 0.06 ± 0.04(P < 0.001, paired t-test, N = 8). The phase-locking values of interneuron spikes were also decreased significantly from 0.27 ± 0.08 to 0.09 ± 0.05(P < 0.01,paired t-test, N = 8). Similar changes were obtained in the phase-locking values between neuronal spikes and the θrhythms in the pyramidal layer. These results suggested that axonal HFS could eliminate the phase-locking relationship between action potentials of neurons and θ rhythms thereby changing the rhythmic firing of downstream neurons. HFS induced conduction block in the axons might be one of the underlying mechanisms. The finding is important for further understanding the mechanisms of DBS.
Deep brain stimulation(DBS) has been successfully used to treat a variety of brain diseases in clinic.Recent investigations have suggested that high frequency stimulation(HFS) of electrical pulses used by DBS might change pathological rhythms in action potential firing of neurons, which may be one of the important mechanisms of DBS therapy. However, experimental data are required to confirm the hypothesis. In the present study, 1 min of 100 Hz HFS was applied to the Schaffer collaterals of hippocampal CA1 region in anaesthetized rats. The changes of the rhythmic firing of action potentials from pyramidal cells and interneurons were investigated in the downstream CA1 region. The results showed that obvious θ rhythms were present in the field potential of CA1 region of the anesthetized rats. The θ rhythms were especially pronounced in the stratum radiatum. In addition, there was a phase-locking relationship between neuronal spikes and the θ rhythms. However, HFS trains significantly decreased the phase-locking values between the spikes of pyramidal cells and the θ rhythms in stratum radiatum from 0.36 ± 0.12 to 0.06 ± 0.04(P < 0.001, paired t-test, N = 8). The phase-locking values of interneuron spikes were also decreased significantly from 0.27 ± 0.08 to 0.09 ± 0.05(P < 0.01,paired t-test, N = 8). Similar changes were obtained in the phase-locking values between neuronal spikes and the θrhythms in the pyramidal layer. These results suggested that axonal HFS could eliminate the phase-locking relationship between action potentials of neurons and θ rhythms thereby changing the rhythmic firing of downstream neurons. HFS induced conduction block in the axons might be one of the underlying mechanisms. The finding is important for further understanding the mechanisms of DBS.
引文
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2Lega B C,Halpern C H,Jaggi J L,et al.Deep brain stimulation in the treatment of refractory epilepsy:update on current data and future directions.Neurobiol Dis,2010,38(3):354-360.
3Mayberg H S,Lozano A M,Voon V,et al.Deep brain stimulation for Treatment-Resistant depression.Neuron,2005,45(5):651-660.
4Birdno M J,Kuncel A M,Dorval A D,et al.Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation.J Neurophysiol,2012,107(1):364-383.
5Chiken S,Nambu A.Mechanism of deep brain stimulation:inhibition,excitation,or disruption?Neuroscientist,2016,22(3):313-322.
6Udupa K,Chen R.The mechanisms of action of deep brain stimulation and ideas for the future development.Prog Neurobiol,2015,133:27-49.
7Alhourani A,Mcdowell M M,Randazzo M J,et al.Network effects of deep brain stimulation.J Neurophysiol,2015,114(4):2105-2117.
8Iremonger K J,Anderson T R,Hu Bin,et al.Cellular mechanisms preventing sustained activation of cortex during subcortical highfrequency stimulation.J Neurophysiol,2006,96(2):613-621.
9Deniau J M,Degos B,Bosch C,et al.Deep brain stimulation mechanisms:beyond the concept of local functional inhibition.Eur J Neurosci,2010,32(7):1080-1091.
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11Rosenbaum R,Zimnik A,ZHENG Fang,et al.Axonal and synaptic failure suppress the transfer of firing rate oscillations,synchrony and information during high frequency deep brain stimulation.Neurobiol Dis,2014,62(2):86-99.
12Feng Zhouyan,Zheng Xiaojing,Yu Ying,et al.Functional disconnection of axonal fibers generated by high frequency stimulation in the hippocampal CA1 region in-vivo.Brain Res,2013,1509(7):32-42.
13Yu Ying,Feng Zhouyan,Cao Jiayue,et al.Modulation of local field potentials by high-frequency stimulation of afferent axons in the hippocampal CA1 region.J Integr Neurosci,2016,15(1):1-17.
14Buzsáki G.Theta oscillations in the hippocampus.Neuron,2002,33(3):325-340.
15Rutishauser U,Ross I B,Mamelak A N,et al.Human memory strength is predicted by theta-frequency phase-locking of single neurons.Nature,2010,464(7290):903-907.
16Kitchigina V,Popova I,Sinelnikova V,et al.Disturbances of septohippocampal theta oscillations in the epileptic brain:reasons and Consequences.Exp Neurol,2013,247(3):314-327.
17Singh A,Mewes K,Gross R E,et al.Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.Proc Natl Acad Sci U S A,2016,113(34):9629-9634.
18Dorval A D,Russo G S,Hashimoto T,et al.Deep brain stimulation reduces neuronal entropy in the MPTP-primate model of Parkinson's disease.J Neurophysiol,2008,100(5):2807-2818.
19Mc Connell G C,So R Q,Grill W M.Failure to suppress lowfrequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.J Neurophysiol,2016,115(6):2791-2802.
20Feng Zhouyan,Wang Zhaoxiang,Guo Zheshan,et al.High frequency stimulation of afferent fibers generates asynchronous firing in the downstream neurons in hippocampus through partial block of axonal conduction.Brain Res,2017,1661:67-78.
21Vargas-Irwin C E,Donoghue J P.Automated spike sorting using density grid contour clustering and subtractive waveform decomposition.J Neurosci Methods,2007,164(1):1-18.
22BarthóP,Hirase H,Monconduit L,et al.Characterization of neocortical principal cells and interneurons by network interactions and extracellular features.J Neurophysiol,2004,92(1):600-608.
23Klausberger T,Márton L F,Baude A,et al.Spike timing of dendrite-targeting bistratified cells during hippocampal network oscillations in vivo.Nat Neurosci,2004,7(1):41-47.
24Berens P.Circ Stat:a MATLAB toolbox for circular statistics.J Stat Softw,2009,31(1):1-21.
25Lowet E,Roberts M J,Bonizzi P,et al.Quantifying neural oscillatory synchronization:a comparison between spectral coherence and Phase-Locking value approaches.PLo S One,2016,11 (1):e0146443.
26Lee M G,Chrobak J J,Sik A,et al.Hippocampal theta activity following selective lesion of the septal cholinergic system.Neuroscience,1994,62(4):1033-1047.
27Kamondi A,Acsády L,Wang X J,et al.Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo:activitydependent phase-precession of action potentials.Hippocampus,1998,8(3):244-261.
28Buzsáki G,Moser E I.Memory,navigation and theta rhythm in the hippocampal-entorhinal system.Nat Neurosci,2013,16(2):130-138.
29Meeks J P,Mennerick S.Selective effects of Potassium elevations on glutamate signaling and action potential conduction in hippocampus.J Neurosci,2004,24(1):197-206.
30Bellinger S C,Miyazawa G,Steinmetz P N.Submyelin Potassiumaccumulation May functionally block subsets of local axons during deep brain stimulation:a modeling study.J Neural Eng,2008,5(3):263-274.
31Ranck J B.Which elements are excited in electrical stimulation of mammalian central nervous system:a review.Brain Res,1975,98(3):417-440.
32Lehnertz K,Bialonski S,Horstmann M T,et al.Synchronization phenomena in human epileptic brain networks.J Neurosci Methods,2009,183(1):42-48.
33Rubchinsky L L,Park C,Worth R M.Intermittent neural synchronization in Parkinson’s disease.Nonlinear Dyn,2012,68(3):329-346.
2Lega B C,Halpern C H,Jaggi J L,et al.Deep brain stimulation in the treatment of refractory epilepsy:update on current data and future directions.Neurobiol Dis,2010,38(3):354-360.
3Mayberg H S,Lozano A M,Voon V,et al.Deep brain stimulation for Treatment-Resistant depression.Neuron,2005,45(5):651-660.
4Birdno M J,Kuncel A M,Dorval A D,et al.Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation.J Neurophysiol,2012,107(1):364-383.
5Chiken S,Nambu A.Mechanism of deep brain stimulation:inhibition,excitation,or disruption?Neuroscientist,2016,22(3):313-322.
6Udupa K,Chen R.The mechanisms of action of deep brain stimulation and ideas for the future development.Prog Neurobiol,2015,133:27-49.
7Alhourani A,Mcdowell M M,Randazzo M J,et al.Network effects of deep brain stimulation.J Neurophysiol,2015,114(4):2105-2117.
8Iremonger K J,Anderson T R,Hu Bin,et al.Cellular mechanisms preventing sustained activation of cortex during subcortical highfrequency stimulation.J Neurophysiol,2006,96(2):613-621.
9Deniau J M,Degos B,Bosch C,et al.Deep brain stimulation mechanisms:beyond the concept of local functional inhibition.Eur J Neurosci,2010,32(7):1080-1091.
10Mc Connell G C,So R Q,Hilliard J D,et al.Effective deep brain stimulation suppresses low-frequency network oscillations in the basal ganglia by regularizing neural firing patterns.J Neurosci,2012,32(45):15657-15668.
11Rosenbaum R,Zimnik A,ZHENG Fang,et al.Axonal and synaptic failure suppress the transfer of firing rate oscillations,synchrony and information during high frequency deep brain stimulation.Neurobiol Dis,2014,62(2):86-99.
12Feng Zhouyan,Zheng Xiaojing,Yu Ying,et al.Functional disconnection of axonal fibers generated by high frequency stimulation in the hippocampal CA1 region in-vivo.Brain Res,2013,1509(7):32-42.
13Yu Ying,Feng Zhouyan,Cao Jiayue,et al.Modulation of local field potentials by high-frequency stimulation of afferent axons in the hippocampal CA1 region.J Integr Neurosci,2016,15(1):1-17.
14Buzsáki G.Theta oscillations in the hippocampus.Neuron,2002,33(3):325-340.
15Rutishauser U,Ross I B,Mamelak A N,et al.Human memory strength is predicted by theta-frequency phase-locking of single neurons.Nature,2010,464(7290):903-907.
16Kitchigina V,Popova I,Sinelnikova V,et al.Disturbances of septohippocampal theta oscillations in the epileptic brain:reasons and Consequences.Exp Neurol,2013,247(3):314-327.
17Singh A,Mewes K,Gross R E,et al.Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.Proc Natl Acad Sci U S A,2016,113(34):9629-9634.
18Dorval A D,Russo G S,Hashimoto T,et al.Deep brain stimulation reduces neuronal entropy in the MPTP-primate model of Parkinson's disease.J Neurophysiol,2008,100(5):2807-2818.
19Mc Connell G C,So R Q,Grill W M.Failure to suppress lowfrequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.J Neurophysiol,2016,115(6):2791-2802.
20Feng Zhouyan,Wang Zhaoxiang,Guo Zheshan,et al.High frequency stimulation of afferent fibers generates asynchronous firing in the downstream neurons in hippocampus through partial block of axonal conduction.Brain Res,2017,1661:67-78.
21Vargas-Irwin C E,Donoghue J P.Automated spike sorting using density grid contour clustering and subtractive waveform decomposition.J Neurosci Methods,2007,164(1):1-18.
22BarthóP,Hirase H,Monconduit L,et al.Characterization of neocortical principal cells and interneurons by network interactions and extracellular features.J Neurophysiol,2004,92(1):600-608.
23Klausberger T,Márton L F,Baude A,et al.Spike timing of dendrite-targeting bistratified cells during hippocampal network oscillations in vivo.Nat Neurosci,2004,7(1):41-47.
24Berens P.Circ Stat:a MATLAB toolbox for circular statistics.J Stat Softw,2009,31(1):1-21.
25Lowet E,Roberts M J,Bonizzi P,et al.Quantifying neural oscillatory synchronization:a comparison between spectral coherence and Phase-Locking value approaches.PLo S One,2016,11 (1):e0146443.
26Lee M G,Chrobak J J,Sik A,et al.Hippocampal theta activity following selective lesion of the septal cholinergic system.Neuroscience,1994,62(4):1033-1047.
27Kamondi A,Acsády L,Wang X J,et al.Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo:activitydependent phase-precession of action potentials.Hippocampus,1998,8(3):244-261.
28Buzsáki G,Moser E I.Memory,navigation and theta rhythm in the hippocampal-entorhinal system.Nat Neurosci,2013,16(2):130-138.
29Meeks J P,Mennerick S.Selective effects of Potassium elevations on glutamate signaling and action potential conduction in hippocampus.J Neurosci,2004,24(1):197-206.
30Bellinger S C,Miyazawa G,Steinmetz P N.Submyelin Potassiumaccumulation May functionally block subsets of local axons during deep brain stimulation:a modeling study.J Neural Eng,2008,5(3):263-274.
31Ranck J B.Which elements are excited in electrical stimulation of mammalian central nervous system:a review.Brain Res,1975,98(3):417-440.
32Lehnertz K,Bialonski S,Horstmann M T,et al.Synchronization phenomena in human epileptic brain networks.J Neurosci Methods,2009,183(1):42-48.
33Rubchinsky L L,Park C,Worth R M.Intermittent neural synchronization in Parkinson’s disease.Nonlinear Dyn,2012,68(3):329-346.