用于行走功能恢复的硬膜外脊髓电刺激系统研究
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摘要
脊髓损伤是指由于外界直接或间接因素导致的对脊髓任意部位的损伤或者在脊髓椎管内脊神经的损伤，在损害的相应节段出现各种运动、感觉和括约肌功能障碍，肌张力异常及病理反射等相应病变。脊髓损伤后的行走功能恢复是众多脊髓损伤患者的美好愿望，但目前尚无有效疗法能够恢复脊髓损伤导致的运动及感觉缺陷，许多脊髓损伤患者只能在轮椅上度过下半辈子，这给病人及家庭都带来灾难性的后果。
近年来，部分临床研究证实对于与行走功能相关的腰骶段脊髓神经元回路依然完好的脊髓损伤(Spinal Cord Injury, SCI)患者，使用硬膜外脊髓电刺激（EpiduralSpinal Cord Stimulation, ESCS）和减重疗法（Partial Weight Bearing Therapy, PWBT）相结合的方法能够促进患者行走功能的改善。但这些临床研究仅对少数SCI患者进行，该疗法中合理的刺激参数(频率、脉宽、强度、位置等)、疗法的有效性及作用机理还需要通过长期的动物实验进行研究。而目前用于此研究的动物实验用植入式硬膜外脊髓刺激装置尚未见报道，亟待开发。
脑―机接口(Brain―Computer Interface，BCI)可以建立起人脑与计算机或其他电子设备间的直接的交流和控制通道，能帮助患者恢复一定的自主生活能力。而使用头皮脑电(electroencephalograph, EEG)信号的BCI，由于具有无创性及信号易提取，引起了人们广泛的研究。从EEG信号中可以提取出运动意图，此运动意图可以转换成控制命令，控制ESCS的开始或停止，以及控制ESCS的刺激模式。通过将BCI与ESCS相结合，脊髓损伤后瘫痪患者便有可能通过运动想象产生不同的下肢动作，如站立或行走等，这给脊髓损伤患者带来了新的希望。这种全新的BCI控制ESCS的运功神经重建系统是否可行，很大程度上取决于EEG信号的特征提取与分类算法。
本论文不仅对基于EEG的BCI的特征提取与分类方法进行了研究，而且研制了可用于动物实验的植入式ESCS系统，并建立了大鼠ESCS的有限元模型。最后采用研制的植入式ESCS装置进行了动物实验研究，得出了不同刺激参数对后肢运动功能的作用。主要的工作及结果包括以下方面：
(1)研究了基于EEG信号的BCI的特征提取与分类方法。采用离散小波变换提取μ节律与β节律附近频带的特征信号，并使用支持向量机(SVM)方法进行分类；此外，还应用了模糊支持向量机(FSVM)方法对EEG信号进行分类，均实现了较高的分类准确率与互信息率。
(2)研制了可用于动物实验的植入式ESCS系统，该系统可用于ESCS的行走功能作用研究，由植入式脉冲发生器、刺激电极、磁铁、外部控制器、上位机组成。采用固形胶及硅胶的封装方法，使刺激器具有生物兼容性，并能较好抵抗体液的侵蚀。针对大鼠脊髓解剖学结构，设计了具有3触点的镀金柔性电路板电极。封装后的植入式脉冲发生器体积为33mm×24mm×8mm,质量约12.6g，满足了外科植入要求。植入体采用了基于2.4GHz载波频率的体内外无线通讯方案，有效通讯距离可达1米。此外，还结合干簧管，设计了植入体的低功耗工作方案，刺激器平时工作在休眠状态，休眠电流仅40μA。使用单个普通3V纽扣电池时，刺激器能在体内工作2周左右。
(3)建立了大鼠脊髓电刺激的场—神经元模型，研究了脉宽对后根、前根、背柱神经纤维激活效果的影响，并讨论了脊髓电刺激作用下募集的神经元结构。该模型可用于指导大鼠脊髓电刺激实验。
(4)使用研制的植入式ESCS刺激器对大鼠进行脊髓电刺激的实验，研究了不同刺激参数对大鼠后肢运动功能的作用。首先，大鼠脊髓腰骶段为有效刺激节段。然后，对于运动阈下的刺激，大鼠胫骨前肌没有明显EMG响应；而当实施运动阈上刺激时，胫骨前肌的平均EMG峰峰值随着刺激强度增加而增强。随着刺激频率的增加，胫骨前肌的平均EMG峰峰值出现了下降趋势。最后，当刺激脉宽增加时，诱发平均EMG峰峰值逐渐上升。
Spinal cord injuries (SCI) disrupt both axonal pathways and segmental spinal cordcircuitry, producing severe impairments of motor, sensory, and autonomic function at andbelow the level of the injury. The recovery of walking function is one of the main goals ofpatients after spinal cord injury. However, there is no treatment available that restores theinjury-induced loss of function. Most people who experience SCI are destined to spend theremainder of their life in a wheelchair. The consequences of SCI are devastatingphysically and socially.
Recent progress in clinic has shown epidural spinal cord stimulation (ESCS) combinedwith partial weight bearing training can facilitate standing and locomotion in patients withalmost intact neural circuits in the lumbar-sacral segment after spinal cord injuries.However, only a few spinal cord injured subjects were participated in these clinical trials.It is desirable to conduct further research in animals to decipher the potential mechanismsfor the exploration of optimal protocols and stimulating parameters to guide furtherclinical application of this promising treatment for motor function recovery after severeneural injury. There are no previous reports of the development of implantable ESCSdevice for animal research yet.
The final option for restoring function to those with motor impairments is to provide thebrain with a new, non-muscular communication and control channel, a directbrain-computer interface (BCI) for conveying messages and commands to the externalword. Electroencephalography (EEG) based BCI can function in most environments,require relatively simple and inexpensive equipment, and non-invasive, offer thepossibility of a practical BCI. BCI technique makes it possible for paralyzed SCI patientsto control the ESCS device by their motor intention. The feasibility of this novel motorneural system reconstruction method largely depends on the techniques of personal motorintention acquisition and the signal processing.
The research work has been done in this dissertation includes the following aspects:
(1) The dissertation has investigated the feature extraction and the classificationmethods of EEG based BCI. Discrete wavelet transformation has been used for theextraction of features from sub-bands D2(16-32Hz) and D3(8-16Hz). The proposedfuzzy vector machine (FSVM) classifier and support vector machine (SVM) classifier onthe presented feature extraction methods achieve the high classification accuracy and largemutual information rate.
(2) The dissertation presents the development of a fully implantable voltage-regulatedstimulator with bi-directional wireless communication for investigating underlying neuralmechanisms of ESCS facilitating motor function improvement. The stimulation systemconsists of a computer, an external controller, an implantable pulse generator (IPG), amagnet, the extension leads and a stimulation electrode. The IPG is coated with conformalcoating and silicone elastomer to keep tightness and biological compatibility. Thestimulation electrode is manufactured with flexible circuit board technique, and has threeround electrode contacts to target rat spinal cord structure. The contacts are separated with8mm center-to-center distance. The telemetry transmission between the IPG and theexternal controller is achieved by a commercially available transceiver chip with2.4GHzcarrier band. The magnet is used to activate the IPG only when necessary to minimize thepower consumption. The encapsulated IPG measures33mm×24mm×8mm, with a totalmass of~12.6g. The IPG supplied by a primary3V button battery can enable the chronicstimulation of spinal cord for about two weeks in the pilot study.
(3) We develop a computer based integrated field-neuron model to study the influenceof pulse duration on the threshold of dorsal column fibers, dorsal root fibers and ventralroot fibers. Furthermore, the recruited neural structures under spinal cord stimulationcondition are discussed.
(4) Animal experiments are conducted in Sprague-Dawley rats to validate the functionof the stimulator, and to investigate the relationship between ESCS parameters andhindlimb electromyography (EMG) responses. In our experiments, ESCS at lumbar-sacrallevel were effective for inducing hindlimb extension movements in normal anesthetizedrats. Stimulation under motor threshold did not induce observable changes in EMGresponse. However, when the stimulation amplitude was above motor threshold, the EMGresponses of the tibialis anterior (TA) muscle showed a progressive increase in thepeak-to-peak amplitude with increased stimulation amplitude. There was a progressivedecrease in the mean peak-to-peak amplitude with increasing frequency of stimulation. Incontrast, there was a progressive increase in the EMG amplitude with an increase instimulation pulse duration.
近年来，部分临床研究证实对于与行走功能相关的腰骶段脊髓神经元回路依然完好的脊髓损伤(Spinal Cord Injury, SCI)患者，使用硬膜外脊髓电刺激（EpiduralSpinal Cord Stimulation, ESCS）和减重疗法（Partial Weight Bearing Therapy, PWBT）相结合的方法能够促进患者行走功能的改善。但这些临床研究仅对少数SCI患者进行，该疗法中合理的刺激参数(频率、脉宽、强度、位置等)、疗法的有效性及作用机理还需要通过长期的动物实验进行研究。而目前用于此研究的动物实验用植入式硬膜外脊髓刺激装置尚未见报道，亟待开发。
脑―机接口(Brain―Computer Interface，BCI)可以建立起人脑与计算机或其他电子设备间的直接的交流和控制通道，能帮助患者恢复一定的自主生活能力。而使用头皮脑电(electroencephalograph, EEG)信号的BCI，由于具有无创性及信号易提取，引起了人们广泛的研究。从EEG信号中可以提取出运动意图，此运动意图可以转换成控制命令，控制ESCS的开始或停止，以及控制ESCS的刺激模式。通过将BCI与ESCS相结合，脊髓损伤后瘫痪患者便有可能通过运动想象产生不同的下肢动作，如站立或行走等，这给脊髓损伤患者带来了新的希望。这种全新的BCI控制ESCS的运功神经重建系统是否可行，很大程度上取决于EEG信号的特征提取与分类算法。
本论文不仅对基于EEG的BCI的特征提取与分类方法进行了研究，而且研制了可用于动物实验的植入式ESCS系统，并建立了大鼠ESCS的有限元模型。最后采用研制的植入式ESCS装置进行了动物实验研究，得出了不同刺激参数对后肢运动功能的作用。主要的工作及结果包括以下方面：
(1)研究了基于EEG信号的BCI的特征提取与分类方法。采用离散小波变换提取μ节律与β节律附近频带的特征信号，并使用支持向量机(SVM)方法进行分类；此外，还应用了模糊支持向量机(FSVM)方法对EEG信号进行分类，均实现了较高的分类准确率与互信息率。
(2)研制了可用于动物实验的植入式ESCS系统，该系统可用于ESCS的行走功能作用研究，由植入式脉冲发生器、刺激电极、磁铁、外部控制器、上位机组成。采用固形胶及硅胶的封装方法，使刺激器具有生物兼容性，并能较好抵抗体液的侵蚀。针对大鼠脊髓解剖学结构，设计了具有3触点的镀金柔性电路板电极。封装后的植入式脉冲发生器体积为33mm×24mm×8mm,质量约12.6g，满足了外科植入要求。植入体采用了基于2.4GHz载波频率的体内外无线通讯方案，有效通讯距离可达1米。此外，还结合干簧管，设计了植入体的低功耗工作方案，刺激器平时工作在休眠状态，休眠电流仅40μA。使用单个普通3V纽扣电池时，刺激器能在体内工作2周左右。
(3)建立了大鼠脊髓电刺激的场—神经元模型，研究了脉宽对后根、前根、背柱神经纤维激活效果的影响，并讨论了脊髓电刺激作用下募集的神经元结构。该模型可用于指导大鼠脊髓电刺激实验。
(4)使用研制的植入式ESCS刺激器对大鼠进行脊髓电刺激的实验，研究了不同刺激参数对大鼠后肢运动功能的作用。首先，大鼠脊髓腰骶段为有效刺激节段。然后，对于运动阈下的刺激，大鼠胫骨前肌没有明显EMG响应；而当实施运动阈上刺激时，胫骨前肌的平均EMG峰峰值随着刺激强度增加而增强。随着刺激频率的增加，胫骨前肌的平均EMG峰峰值出现了下降趋势。最后，当刺激脉宽增加时，诱发平均EMG峰峰值逐渐上升。
Spinal cord injuries (SCI) disrupt both axonal pathways and segmental spinal cordcircuitry, producing severe impairments of motor, sensory, and autonomic function at andbelow the level of the injury. The recovery of walking function is one of the main goals ofpatients after spinal cord injury. However, there is no treatment available that restores theinjury-induced loss of function. Most people who experience SCI are destined to spend theremainder of their life in a wheelchair. The consequences of SCI are devastatingphysically and socially.
Recent progress in clinic has shown epidural spinal cord stimulation (ESCS) combinedwith partial weight bearing training can facilitate standing and locomotion in patients withalmost intact neural circuits in the lumbar-sacral segment after spinal cord injuries.However, only a few spinal cord injured subjects were participated in these clinical trials.It is desirable to conduct further research in animals to decipher the potential mechanismsfor the exploration of optimal protocols and stimulating parameters to guide furtherclinical application of this promising treatment for motor function recovery after severeneural injury. There are no previous reports of the development of implantable ESCSdevice for animal research yet.
The final option for restoring function to those with motor impairments is to provide thebrain with a new, non-muscular communication and control channel, a directbrain-computer interface (BCI) for conveying messages and commands to the externalword. Electroencephalography (EEG) based BCI can function in most environments,require relatively simple and inexpensive equipment, and non-invasive, offer thepossibility of a practical BCI. BCI technique makes it possible for paralyzed SCI patientsto control the ESCS device by their motor intention. The feasibility of this novel motorneural system reconstruction method largely depends on the techniques of personal motorintention acquisition and the signal processing.
The research work has been done in this dissertation includes the following aspects:
(1) The dissertation has investigated the feature extraction and the classificationmethods of EEG based BCI. Discrete wavelet transformation has been used for theextraction of features from sub-bands D2(16-32Hz) and D3(8-16Hz). The proposedfuzzy vector machine (FSVM) classifier and support vector machine (SVM) classifier onthe presented feature extraction methods achieve the high classification accuracy and largemutual information rate.
(2) The dissertation presents the development of a fully implantable voltage-regulatedstimulator with bi-directional wireless communication for investigating underlying neuralmechanisms of ESCS facilitating motor function improvement. The stimulation systemconsists of a computer, an external controller, an implantable pulse generator (IPG), amagnet, the extension leads and a stimulation electrode. The IPG is coated with conformalcoating and silicone elastomer to keep tightness and biological compatibility. Thestimulation electrode is manufactured with flexible circuit board technique, and has threeround electrode contacts to target rat spinal cord structure. The contacts are separated with8mm center-to-center distance. The telemetry transmission between the IPG and theexternal controller is achieved by a commercially available transceiver chip with2.4GHzcarrier band. The magnet is used to activate the IPG only when necessary to minimize thepower consumption. The encapsulated IPG measures33mm×24mm×8mm, with a totalmass of~12.6g. The IPG supplied by a primary3V button battery can enable the chronicstimulation of spinal cord for about two weeks in the pilot study.
(3) We develop a computer based integrated field-neuron model to study the influenceof pulse duration on the threshold of dorsal column fibers, dorsal root fibers and ventralroot fibers. Furthermore, the recruited neural structures under spinal cord stimulationcondition are discussed.
(4) Animal experiments are conducted in Sprague-Dawley rats to validate the functionof the stimulator, and to investigate the relationship between ESCS parameters andhindlimb electromyography (EMG) responses. In our experiments, ESCS at lumbar-sacrallevel were effective for inducing hindlimb extension movements in normal anesthetizedrats. Stimulation under motor threshold did not induce observable changes in EMGresponse. However, when the stimulation amplitude was above motor threshold, the EMGresponses of the tibialis anterior (TA) muscle showed a progressive increase in thepeak-to-peak amplitude with increased stimulation amplitude. There was a progressivedecrease in the mean peak-to-peak amplitude with increasing frequency of stimulation. Incontrast, there was a progressive increase in the EMG amplitude with an increase instimulation pulse duration.
引文
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