深部脑刺激期间神经元动态活动的光栅图描述方法
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摘要
深部脑刺激(DBS)中常用的电脉冲高频刺激(HFS)已在多种脑疾病的治疗中取得良好疗效。研究HFS期间刺激下游神经元动作电位发放及其与刺激脉冲之间关系的动态变化,对于揭示DBS的作用机制、开发闭环刺激等新型刺激模式都具有重要意义。为了直观地展示HFS期间(尤其在HFS起始阶段)神经元活动的动态变化,本文设计了一种二维光栅图,将HFS期间神经元的动态活动图示化,并研究了光栅图分辨率的变化对图示化效果的影响。研究发现,利用该光栅图研究大鼠海马CA1区轴突HFS的作用,能够直观地展现周期性脉冲刺激期间单个神经元动作电位(即锋电位)的锁相性和潜伏期等指标随时间的动态变化。并且,还可以直观地比较刺激启动前、后的锋电位发放变化,清晰地显示紧随HFS结束后的锋电位发放静息期等其他信息。此外,通过调整分辨率,该光栅图可以适应发放强度不同的神经元活动的图示化。与常规光栅图相比,新设计的光栅图提供的信息更多,图像更清晰,为研究高频脑刺激过程中神经元的活动提供了一种新工具。
Deep brain stimulation(DBS), which usually utilizes high frequency stimulation(HFS) of electrical pulses, is effective for treating many brain disorders in clinic. Studying the dynamic response of downstream neurons to HFS and its time relationship with stimulus pulses can reveal important mechanisms of DBS and advance the development of new stimulation modes(e.g., closed-loop DBS). To exhibit the dynamic neuronal firing and its relationship with stimuli, we designed a two-dimensional raster plot to visualize neuronal activity during HFS(especially in the initial stage of HFS). Additionally, the influence of plot resolution on the visualization effect was investigated. The method was then validated by investigating the neuronal responses to the axonal HFS in the hippocampal CA1 region of rats. Results show that the new design of raster plot is able to illustrate the dynamics of indexes(such as phase-locked relationship and latency) of single unit activity(i.e., spikes) during periodic pulse stimulations. Furthermore, the plots can intuitively show changes of neuronal firing from the baseline before stimulation to the onset dynamics during stimulation,as well as other information including the silent period of spikes immediately following the end of HFS. In addition, by adjusting resolution, the raster plot can be adapted to a large range of firing rates for clear illustration of neuronal activity.The new raster plot can illustrate more information with a clearer image than a regular raster plot, and thereby provides a useful tool for studying neuronal behaviors during high-frequency stimulations in brain.
Deep brain stimulation(DBS), which usually utilizes high frequency stimulation(HFS) of electrical pulses, is effective for treating many brain disorders in clinic. Studying the dynamic response of downstream neurons to HFS and its time relationship with stimulus pulses can reveal important mechanisms of DBS and advance the development of new stimulation modes(e.g., closed-loop DBS). To exhibit the dynamic neuronal firing and its relationship with stimuli, we designed a two-dimensional raster plot to visualize neuronal activity during HFS(especially in the initial stage of HFS). Additionally, the influence of plot resolution on the visualization effect was investigated. The method was then validated by investigating the neuronal responses to the axonal HFS in the hippocampal CA1 region of rats. Results show that the new design of raster plot is able to illustrate the dynamics of indexes(such as phase-locked relationship and latency) of single unit activity(i.e., spikes) during periodic pulse stimulations. Furthermore, the plots can intuitively show changes of neuronal firing from the baseline before stimulation to the onset dynamics during stimulation,as well as other information including the silent period of spikes immediately following the end of HFS. In addition, by adjusting resolution, the raster plot can be adapted to a large range of firing rates for clear illustration of neuronal activity.The new raster plot can illustrate more information with a clearer image than a regular raster plot, and thereby provides a useful tool for studying neuronal behaviors during high-frequency stimulations in brain.
引文
1Wichmann T, Delong M R. Deep brain stimulation for movement disorders of basal ganglia origin:restoring function or functionality?. Neurotherapeutics, 2016, 13(2):264-283.
2Udupa K, Chen R. The mechanisms of action of deep brain stimulation and ideas for the future development. Prog Neurobiol,2015, 133:27-49.
3Florence G, Sameshima K, Fonoff E T, et al. Deep brain stimulation:more complex than the inhibition of cells and excitation of fibers. Neuroscientist, 2016, 22(4):332-345.
4Nowak L G, Bullier J A. But not cell bodies, are activated by electrical stimulation in cortical gray matter.Ⅱ. Evidence from selective inactivation of cell bodies and axon initial segments. Exp Brain Res, 1998, 118(4):489-500.
5 Mcintyre C C, Grill W M, Sherman D L, et al. Cellular effects of deep brain stimulation:model-based analysis of activation and inhibition. J Neurophysiol, 2004, 91(4):1457-1469.
6Moran A, Stein E, Tischler H, et al. Dynamic stereotypic responses of basal ganglia neurons to subthalamic nucleus high-frequency stimulation in the parkinsonian primate. Front Syst Neurosci,2011, 5:21.
7Erez Y, Czitron H, McCairn K, et al. Short-term depression of synaptic transmission during stimulation in the globus pallidus of1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. J Neurosci, 2009, 29(24):7797-7802.
8Kuncel A M, Birdno M J, Swan B D, et al. Tremor reduction and modeled neural activity during cycling thalamic deep brain stimulation. Clin Neurophysiol, 2012, 123(5):1044-1052.
9Chiken S, Nambu A. Mechanism of deep brain stimulation:inhibition, excitation, or disruption?. Neuroscientist, 2016, 22(3):313-322.
10Rosenbaum 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, 62:86-99.
11Agnesi F, Connolly A T, Baker K B, et al. Deep brain stimulation imposes complex informational lesions. PLoS One, 2013, 8(8):e74462.
12Leblois A, Reese R, Labarre D, et al. Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster. Neurobiol Dis, 2010, 38(2):288-298.
13McConnell 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.
14Agnesi F, Muralidharan A, Baker K B, et al. Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS. J Neurophysiol, 2015, 114(2):825-834.
15Feng 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, 1509:32-42.
16Wallisch P, Lusignan M E, Benayoun M D, et al. MATLAB for neuroscientists:an introduction to scientific computing in MATLAB. 2nd ed. London:Elsevier, 2014:550.
17朱玉芳,封洲燕,王兆祥,等.高频电刺激改变神经元锋电位的波形.生物化学与生物物理进展, 2016, 43(8):787-795.
18Feng 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.
19Vinogradova O S, Brazhnik E S, Kitchigina V F, et al.Acetylcholine, theta-rhythm and activity of hippocampal neurons in the rabbit—Ⅳ. Sensory stimulation. Neuroscience, 1993, 53(4):993-1007.
20 Bellistri E, Aguilar J, Brotons-Mas J R, et al. Basic properties of somatosensory-evoked responses in the dorsal hippocampus of the rat. J Physiol, 2013, 591(10):2667-2686.
2Udupa K, Chen R. The mechanisms of action of deep brain stimulation and ideas for the future development. Prog Neurobiol,2015, 133:27-49.
3Florence G, Sameshima K, Fonoff E T, et al. Deep brain stimulation:more complex than the inhibition of cells and excitation of fibers. Neuroscientist, 2016, 22(4):332-345.
4Nowak L G, Bullier J A. But not cell bodies, are activated by electrical stimulation in cortical gray matter.Ⅱ. Evidence from selective inactivation of cell bodies and axon initial segments. Exp Brain Res, 1998, 118(4):489-500.
5 Mcintyre C C, Grill W M, Sherman D L, et al. Cellular effects of deep brain stimulation:model-based analysis of activation and inhibition. J Neurophysiol, 2004, 91(4):1457-1469.
6Moran A, Stein E, Tischler H, et al. Dynamic stereotypic responses of basal ganglia neurons to subthalamic nucleus high-frequency stimulation in the parkinsonian primate. Front Syst Neurosci,2011, 5:21.
7Erez Y, Czitron H, McCairn K, et al. Short-term depression of synaptic transmission during stimulation in the globus pallidus of1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. J Neurosci, 2009, 29(24):7797-7802.
8Kuncel A M, Birdno M J, Swan B D, et al. Tremor reduction and modeled neural activity during cycling thalamic deep brain stimulation. Clin Neurophysiol, 2012, 123(5):1044-1052.
9Chiken S, Nambu A. Mechanism of deep brain stimulation:inhibition, excitation, or disruption?. Neuroscientist, 2016, 22(3):313-322.
10Rosenbaum 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, 62:86-99.
11Agnesi F, Connolly A T, Baker K B, et al. Deep brain stimulation imposes complex informational lesions. PLoS One, 2013, 8(8):e74462.
12Leblois A, Reese R, Labarre D, et al. Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster. Neurobiol Dis, 2010, 38(2):288-298.
13McConnell 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.
14Agnesi F, Muralidharan A, Baker K B, et al. Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS. J Neurophysiol, 2015, 114(2):825-834.
15Feng 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, 1509:32-42.
16Wallisch P, Lusignan M E, Benayoun M D, et al. MATLAB for neuroscientists:an introduction to scientific computing in MATLAB. 2nd ed. London:Elsevier, 2014:550.
17朱玉芳,封洲燕,王兆祥,等.高频电刺激改变神经元锋电位的波形.生物化学与生物物理进展, 2016, 43(8):787-795.
18Feng 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.
19Vinogradova O S, Brazhnik E S, Kitchigina V F, et al.Acetylcholine, theta-rhythm and activity of hippocampal neurons in the rabbit—Ⅳ. Sensory stimulation. Neuroscience, 1993, 53(4):993-1007.
20 Bellistri E, Aguilar J, Brotons-Mas J R, et al. Basic properties of somatosensory-evoked responses in the dorsal hippocampus of the rat. J Physiol, 2013, 591(10):2667-2686.