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论文题名(中文):

 经颅磁声耦合刺激中超声场和耦合电场对神经 电活动复合作用效果研究    

姓名:

 谭如欣    

论文语种:

 chi    

学位:

 博士    

学位类型:

 学术学位    

学校:

 北京协和医学院    

院系:

 北京协和医学院生物医学工程研究所    

专业:

 生物医学工程(工)-生物医学工程    

指导教师姓名:

 刘志朋    

论文完成日期:

 2024-05-24    

论文题名(外文):

 Study on the effect of the compound action of ultrasonic field and coupled electric field on neural electrical activity in transcranial magnetoacoustic coupled stimulation    

关键词(中文):

 经颅磁声耦合刺激 经颅超声刺激 神经调控 神经振荡 神经元 模型 突触可塑性    

关键词(外文):

 transcranial magneto-acoustic stimulation transcranial ultrasound stimulation neuromodulation rhythmic oscillations neuronal model synaptic plasticity    

论文文摘(中文):

神经电活动是大脑正常功能的基础,涉及离子通道的动态变化、突触传递的 精确性、以及神经环路之间的协调配合。神经电活动异常在癫痫、帕金森病、多 发性硬化症、阿尔茨海默病多种脑神经系统疾病中均普遍存在。无创神经调控技 术作为非侵入的神经干预手段,在脑科学研究和脑疾病治疗领域都具备广阔的应 用前景。其中经颅超声刺激(transcranial ultrasound stimulation,TUS)和经颅磁声 耦合刺激(transcranial magneto-acoustic coupling stimulation,TMAS)由于其高穿 透性高空间分辨率的优势引起了浓厚的兴趣,其神经调控效果和潜在的调控机制 被广泛研究。基于磁声耦合效应,TMAS 是包含超声场和耦合电场的复合场刺激, 其调控效果可能比单一超声场的 TUS 更优,但 TMAS 中超声场和耦合电场具体对 神经电活动发挥怎样的调控作用,增加耦合电场在调控海马突触可塑性和神经振 荡中具体有怎样的表现,目前尚未可知。 首先建立了针对 TMAS 超声场和耦合电场共同作用的仿真计算模型,在仿真 模型中探究了超声和耦合电场在细胞尺度上调控神经元电活动的基本机制,以及 这些机制在不同神经元模型中的变化,并对比了不同超声强度,超声基础频率, 占空比和重复频率对调控效果的影响,探究了增加耦合电场对神经元放电模式的 影响。研究结果显示,TUS 和 TMAS 都具有超声剂量依赖性,TMAS 中耦合电场 的加入能够显著降低发放阈值对超声剂量需要,这一现象在不同类型的神经元模 型上均存在。同时,TMAS 中的耦合电场能显著缩短 TUS 作用效果积累的时间, 降低发放电位的潜伏期。 随后将不同强度的 TMAS 和 TUS 聚焦于 C57BL 小鼠的深部脑区海马区,探 索 TMAS 和 TUS 对海马区突触可塑性以及学习记忆能力的调控效果。结果显示, TUS 和 TMAS 都能增强小鼠的短期记忆,两者未表现出明显差异,而在空间学习 记忆中,仅 TMAS 具有明显的增强作用 。进一步比较了 TUS 和 TMAS 在突触水 平上的调节作用,发现在加入耦合电场后,TMAS 组的长时程增强与 sham 组相比 明显增加,反映了突触可塑性的增强,超声刺激和电刺激相结合显示出更好的调 节效果。通过评估突触可塑性相关蛋白的水平,发现 TMAS 对 NMDA 受体的调节 程度以及对突触后致密蛋白 95 和突触体素的调节能力更强,可能是 其增强突触可 塑性的原因。 最后比较了 TMAS 与 TUS 在两种不同超声强度下对海马区神经振荡的调控效 果。TMAS 组 gamma 振荡的相对功率不仅明显高于 sham 组,也高于 TUS 组; TMAS 增强了海马网络在 theta 和 gamma 频段的相位同步和功率同步以及 theta- ii gamma 相位-振幅耦合,对于提高工作记忆的读取和回放能力以及增强空间学习记 忆均有重要意义。TMAS 对 gamma 振荡及其相关同步和跨频耦合的增强效果非常 显著,这可能是由于 TMAS 中额外增加的耦合电场可提高-氨基丁酸受体的表达 水平, TMAS 中的电场和超声场能同时作用于兴奋性神经元和抑制性神经元,从 而促进兴奋-抑制平衡。 本研究从神经元、突触和神经振荡三个层面探究了 TMAS 中耦合电场与超声 场对神经电活动的复合作用效果,并初步探究了可能的机制,结果证明了增加耦 合电场可取得的有益之处,为调控海马区提供了更有效的干预方法,也为 TMAS 在神经调控中的应用提供理论支撑。

论文文摘(外文):

Neuroelectrical activity is fundamental to normal brain function and involves dynamic changes in ion channels, precision of synaptic transmission, and coordination between neural circuits. Abnormalities in neural electrical activity are prevalent in a variety of neurological disorders, including epilepsy, Parkinson's disease, multiple sclerosis, and Alzheimer's disease. Non-invasive neuromodulation techniques, as noninvasive neurological interventions, have broad application prospects in brain science research and brain disease treatment. Among them, transcranial ultrasound stimulation (TUS) and transcranial magneto-acoustic coupling stimulation (TMAS) have aroused great interest due to their advantages of high penetration and high spatial resolution. Their neuromodulatory effects and potential regulatory mechanisms have been widely investigated. Based on the magneto-acoustic coupling effect, TMAS is a composite field stimulation containing both ultrasound field and coupled electric field, and its modulation effect may be superior to that of TUS with a single ultrasound field. However, the specific modulation effects of the ultrasound field and coupled electric field on neuroelectrical activity in TMAS remain unknown, particularly how the additional coupled electric field specifically affects hippocampal synaptic plasticity and neural oscillations. Firstly, a computational simulation model was established for the simultaneous action of ultrasound fields and coupled electric fields within TMAS. This model explored the fundamental mechanisms by which ultrasound and coupled electric fields regulate neuronal electrical activity at the cellular level, and the variations of these mechanisms across different neuronal models. Additionally, the model compared the effects of varying ultrasound intensities, ultrasound fundamental frequencies, duty cycles, and repetition frequencies on modulation effectiveness. The study also investigated the impact of increasing the coupled electric field on neuronal firing patterns. The results indicate that both TUS and TMAS exhibit ultrasound dose-dependency, with the inclusion of the coupled electric field in TMAS significantly lowering the threshold firing levels required for ultrasound dosages. This phenomenon was observed across different types of neuronal models. Concurrently, the coupled electric field in TMAS significantly shortened the time required for the accumulation of TUS effects and decreased the latency of the firing potential. Subsequently, different intensities of TMAS and TUS were focused on the  hippocampus, a deep brain region of C57BL mice, to explore the modulatory effects of TMAS and TUS on synaptic plasticity as well as learning and memory ability in the hippocampus. The results showed that both TUS and TMAS enhanced short-term memory in mice, and there was no difference in their modulatory effects. As for spatial learning and memory, only TMAS had a significant enhancement effect. Further comparing the modulatory effects of TUS and TMAS at the synaptic level, after adding coupled electric fields, the long-term potentiation in the TMAS group was significantly increased compared with that in the sham group, reflecting the enhancement of synaptic plasticity, and the combination of mechanical and electrical stimulation showed a better modulatory effect. By assessing levels of synaptic plasticity-related proteins, it was found that TMAS exerted a stronger regulatory effect on NMDA receptors as well as on postsynaptic density protein 95 and synaptophysin, potentially underlying its enhanced synaptic plasticity effects. Finally, the modulation effects of TMAS and TUS on neural oscillations in the hippocampal region at two different ultrasound intensities were compared. The relative power of gamma oscillations in the TMAS group was not only significantly higher than that in the sham group, but also higher than that in the TUS group. TMAS enhanced both phase and power synchronization in the theta and gamma frequency bands, as well as theta-gamma phase-amplitude coupling within the hippocampal network. These enhancements are critical for improving the abilities of working memory retrieval and replay, as well as enhancing spatial learning and memory. The significant effects of TMAS on gamma oscillations, associated synchronization, and cross-frequency coupling are likely due to the additional coupled electric field, which may elevate γ-aminobutyric acid (GABA) receptor expression levels. The simultaneous impact of electric and ultrasonic fields in TMAS on both excitatory and inhibitory neurons may promote an optimal excitation-inhibition balance. This study explored the effect of the compound action of coupled electric field and ultrasonic field on neural electrical activity in TMAS from the three levels of neurons, synapses and neural oscillations, and preliminarily probed the possible mechanisms. The results proved the benefits that can be achieved by increasing the coupled electric field, which provides a more effective intervention method for modulating hippocampal area, and also provides theoretical support for the application of TMAS in neuromodulation. 

开放日期:

 2024-07-15    

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