丘脑底核脑深部电刺激治疗帕金森病的临床分析

目的:通过丘脑底核脑深部电刺激术治疗帕金森病,观察其肌肉僵直、静止性震颤、运动迟缓等症状的改善情况。方法:选取以丘脑底核为刺激靶点收治的帕金森病患者8例,对比手术前后患者肌强直、静止性震颤、运动迟缓等症状的改善情况,并进行UPDRS评分。结果:接受丘脑底核脑深部电刺激术治疗帕金森病6个月后,患者肌肉僵直、静止性震颤、运动迟缓等临床主症的改善上效果良好;与手术前相比,患者术后UPDRS评分均有所降低,差异具有统计学意义(P0.05);患者术后美多巴服用量显著减少,差异具有统计学意义(P0.05);患者术后没有产生永久性的并发症以及较明显的临床症状;但对大量油脂性渗出及典型面具性面容的治疗上未见明显疗效。结论:丘脑底核脑深部电刺激术治疗帕金森氏病,可以使帕金森病主要临床症状肌肉僵直、静止震颤及运动迟缓得到明显改善,显著减少美多巴服药量,具有安全可靠的疗效,对临床具有指导意义,值得临床推广应用。     

丘脑底核-深部脑刺激术术后淡漠的研究进展

帕金森病(Parkinson's disease,PD)是一种由于中脑黑质以及其他核团结构的多巴胺能神经元变性所致的以进行性运动功能障碍为主要表现的疾病。近年来,双侧高频刺激的丘脑底核-深部脑刺激术(STN-DBS)治疗PD效果确切,疗效较好,但其出现了术后淡漠等类似副作用,严重影响了PD治疗效果和患者的生活质量,引起了临床医生的高度重视。本文对STN-DBS术后淡漠发病情况、表现及治疗进行综述,为临床诊治提供思路。     

深部脑刺激作用机制的探讨

深部脑刺激器（deep brain stimulator）,也经常被称为脑起搏器,是可植入人体设备,并连续不断地传送刺激脉冲到深部脑组织的特定区域,即所谓的深部脑刺激（deep brain stimulation,DBS）.迄今为止,深部脑刺激是治疗严重顽固抗药性运动障碍疾病（如帕金森病,原发性震颤及肌张力异常等）的最有效的外科治疗手段之一.此外,广大的科研工作者也不断地探索应用DBS治疗其他神经及精神异常（如,癫痫和强迫症）的新的临床应用.尽管应用DBS治疗运动障碍非常有效,并也迅速被探索性地应用到其他神经障碍治疗中,但其作用机制仍然不是十分清楚,成为学者们争论的热点.DBS治疗效果的作用机制通常有两种基本的观点：高频刺激抑制学说及高频刺激兴奋学说.基于最近发表的关于中枢神经系统内的高频刺激效应的资料、数据及相关评论,两种机制共存并发挥作用的DBS作用假说被提出,认为DBS通过施加高频刺激干扰并控制了核团病理性紊乱随机活动,同时施加兴奋性刺激到其他基底节的网络,以实现对帕金森病的治疗.     

深部脑刺激对大鼠丘脑底核神经活动的影响

为了探求高频电刺激对受刺激核团的影响,在高频刺激丘脑底核的同时,同步记录了大鼠丘脑底核神经元活动．针对同步记录中刺激伪迹的难题,研究并应用了高效的刺激伪迹滤出算法,恢复了被掩盖的神经响应,且失真小．研究了刺激幅度、频率与神经元神经响应类型的关系,以及在临床治疗有效刺激参数下,高频刺激对神经元平均放电率的影响．研究结果显示,放电率的变化可能与帕金森症病理状态无直接关系,爆发式放电增多更可能是帕金森发病潜在的电生理基础,而受刺激核团的自发放电的抑制、放电率的降低及爆发式放电的减少则有可能是深部脑刺激作用机制的一部分．     

脑深部电刺激的临床应用

脑深部电刺激(deep brain stimulation,DBS)是近20年来神经外科领域发展最迅猛的技术。DBS是通过刺激发生器发出的高频电脉冲信号刺激脑神经核团或神经传导束来调节异常的神经环路。DBS已经成为治疗特发性震颤、帕金森病、肌张力障碍等运动障碍病的常规手术方法。自1997年深部脑刺激通过美国FDA认证用于治疗特发性震颤以来,已有超过数万名运动障碍患者接受该疗法,而国内脑深部电刺激最早在1999年应用于帕金森病临床治疗,迄今也有数千例患者接受了植入手术。近年,脑起搏器的临床适应症不断扩大,从最初的运动障碍病逐渐发展到治疗其他神经和精神疾病,如抽动秽语综合征、强迫症、抑郁症、神经性厌食症、难治性疼痛、癫痫、植物状态和阿尔茨海默病等,虽然DBS的治疗机理还不很清楚,但可以预见未来DBS将成为众多神经和精神疾病的重要治疗方法。     

脑起搏器

脑起搏器在医学术语上称“脑深部刺激系统(DBS)”,其外形及工作原理与心脏起搏器类同。DBS由植入脑内的刺激电极、埋在胸部皮下的脉冲发生器和皮下导线组成。脑内电极质地柔软,直径1.2mm,电极头端有4个刺激触点,供刺激选用。脉冲发生器大小为6×6×0.5cm,为整个系统的核心部分,持续发出高频脉冲电刺激,通过皮下导线传递到脑内电极,抑制不正常的脑核团放电,消除帕金森病症状。整个刺激系统均埋在皮下,不影响日常工作和生活。可根据病情选择不同的刺激触点、频率、强度及脉宽等参数,通过体外电脑程控调节,以达到最佳刺激效果,调节时病人无…     

丘脑底核高频和低频电刺激治疗帕金森病的临床效果评价

目的:观察和比较丘脑底核高频电刺激与低频电刺激治疗帕金森病(PD)的临床效果。方法:对入选的31名PD患者行双侧丘脑底核电刺激手术,术后1个月,在高频刺激条件下,进行UPDRS运动评分,同时对震颤、强直、运动迟缓、中轴症状进行评分;术后6个月,在关闭刺激、高频刺激和低频刺激三种刺激条件,同样进行相关评分。结果:术后1个月和术后6个月,除中轴症状外,UPDRS运动评分和震颤、强直、运动迟缓评分均较术前明显降低(P0.05)。术后6个月,HFS、LFS刺激条件下,UPDRS运动评分和震颤、强直、运动迟缓评分均较OFF降低(P0.05),但中轴症状评分无明显降低(P0.05)。术后6个月,LFS较HFS,各项评分均无明显差异。结论:丘脑底核高频和低频电刺激均能改善PD的运动功能,对震颤、强直和运动迟缓疗效明显,但对中轴症状均无明显治疗效果。     

脑深部电刺激自身给药大鼠伏隔核区△FosB的表达

目的:对吗啡依赖大鼠实施双侧伏隔核脑深部电刺激(NAc-DBS),分析NAc区△FosB的表达变化,为NAc-DBS治疗药物依赖提供分子生物学证据.方法:18只大鼠随机分为三组,包括DBS组(n=6,实施颈静脉插管和电板植入手术,吗啡给药,DBS),Sham组(n=6,实施颈静脉插管和电极植入手术,吗啡给药),Control组(n=6,实施颈静脉插管和电极植入手术,给予生理盐水),观察DBS组大鼠在高频电烈激期(160 Hz,1 h/d,7d)的觅药行为变化,然后进行取脑,切片,免疫组化染色,观察伏隔核区△FosB的表达.结果:成瘾大鼠在高频电刺激期,觅药行为明显减少;免疫组化染色后观察到DBS组大鼠NAc区△FosB的表达相对于Sham和Control组明显减少.结论:双侧NAc-DBS抑制吗啡成瘾大鼠的觅药行为以及NAc区△FosB的表达,证实△FosB可能是慢性成瘾转换机制的关键分子的观点.     

基于MSP430的植入式脑起搏器的研制

介绍了一种微型化的植入式脑起搏器;以MSP430单片机为核心处理器,充分利用高性能的外围芯片,例如nRF905、TPS76030、MG-12232等,并结合单片机内部资源;从而使该系统具有精度高、性能好、体积小和功耗低等特点,满足了帕金森病患者的需求。     

微弱电刺激对失眠者睡眠状况及睡眠脑电影响的初步研究

根据睡眠是由脑内亿万神经元同步振荡所刻划的观点［１］,及各种电刺激对动物睡眠影响的实验［２,３］,设计了用特定θ频率的正弦波微弱电流,刺激失眠病人颈部安眠２穴,以观察其对受试者脑电频率的客观影响。其结果是刺激后失眠病人由醒到２期的脑电记录中,θ波逐渐增加,增加了病人的总睡眠时间。这启示我们这种脑部的特殊频率微弱电流刺激,可能有引起脑部神经元群的共振现象,改变了受试者脑电中频率成分的分布特征,从而有助于失眠的治疗。这一现象是值得进一步研究的。     

Deep Brain Stimulation Imposes Complex Informational Lesions

Deep brain stimulation (DBS) therapy has become an essential tool for treating a range of brain disorders. In the resting state, DBS is known to regularize spike activity in and downstream of the stimulated brain target, which in turn has been hypothesized to create informational lesions. Here, we specifically test this hypothesis using repetitive joint articulations in two non-human Primates while recording single-unit activity in the sensorimotor globus pallidus and motor thalamus before, during, and after DBS in the globus pallidus (GP) GP-DBS resulted in: (1) stimulus-entrained firing patterns in globus pallidus, (2) a monophasic stimulus-entrained firing pattern in motor thalamus, and (3) a complete or partial loss of responsiveness to joint position, velocity, or acceleration in globus pallidus (75%, 12/16 cells) and in the pallidal receiving area of motor thalamus (ventralis lateralis pars oralis, VLo) (38%, 21/55 cells). Despite loss of kinematic tuning, cells in the globus pallidus (63%, 10/16 cells) and VLo (84%, 46/55 cells) still responded to one or more aspects of joint movement during GP-DBS. Further, modulated kinematic tuning did not always necessitate modulation in firing patterns (2/12 cells in globus pallidus; 13/23 cells in VLo), and regularized firing patterns did not always correspond to altered responses to joint articulation (3/4 cells in globus pallidus, 11/33 cells in VLo). In this context, DBS therapy appears to function as an amalgam of network modulating and network lesioning therapies.     

Clustered Desynchronization from High-Frequency Deep Brain Stimulation

While high-frequency deep brain stimulation is a well established treatment for Parkinson’s disease, its underlying mechanisms remain elusive. Here, we show that two competing hypotheses, desynchronization and entrainment in a population of model neurons, may not be mutually exclusive. We find that in a noisy group of phase oscillators, high frequency perturbations can separate the population into multiple clusters, each with a nearly identical proportion of the overall population. This phenomenon can be understood by studying maps of the underlying deterministic system and is guaranteed to be observed for small noise strengths. When we apply this framework to populations of Type I and Type II neurons, we observe clustered desynchronization at many pulsing frequencies.     

新型深部脑刺激模式的开发及研究进展

深部脑刺激(deep brain stimulation,DBS)已成为治疗帕金森病等运动障碍疾病的常规方法之一,并且在许多其他神经和精神疾病的治疗中也具有良好的应用前景.但是,目前常规DBS采用单通道恒定脉冲间隔的高频刺激(high frequency stimulation,HFS),刺激模式缺少多样化,限制了DBS在临床上的推广应用.为了开发更多DBS刺激模式,用于改善疗效、拓展应用范围、并节省刺激器的电能,近年来研究人员基于去同步调控机制,在脉冲序列的时间模式和空间排布两方面开发了DBS新模式.主要包括:变频序列(包括规则变频和随机变频)、不同空间位点上的多通道异步刺激以及变频和多通道两者的结合.这些新刺激模式能够提高DBS的临床疗效、降低刺激能耗,在帕金森病以及癫痫、强迫症和微意识障碍等其他脑疾病的治疗中都展现了良好的应用前景.更值得关注的是,多通道异步刺激不仅在刺激期间具有更好的即时疗效,而且刺激结束后还能长时间保持疗效,具有刺激后效应.这个特性突破了常规DBS主要为即时效应的局限性,展现了DBS新前景.本文在概述常规DBS模式及其去同步调控机制的基础上,综述变频脉冲刺激和...     

The Gold-Plated Leucotomy Standard and Deep Brain Stimulation

Walter Freeman, the self styled neurosurgeon, became famous (or infamous) for psychosurgery. The operation of frontal leucotomy swept through the world (with Freeman himself performing something like 18,000 cases) but it has tainted the whole idea of psychosurgery down to the present era. Modes of psychosurgery such as Deep Brain Stimulation and other highly selective neurosurgical procedures for neurological and psychiatric conditions are in ever-increasing use in current practice. The new, more exciting techniques are based in a widely held philosophical position on the relationship between the mind, brain and soul, which is the key to ethical debates in this area. Psychosurgery has always posed questions of responsibility, personality, character, identity, spirit, relationship, integrity, and human flourishing and they do not go away when we enter the brave new world of neuroethics and Deep Brain Stimulation.     

Deep Brain Stimulation with Simultaneous fMRI in Rodents

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to image rodents with simultaneous DBS. DBS fMRI presents a number of technical challenges, including accuracy of electrode implantation, MR artifacts created by the electrode, choice of anesthesia and paralytic to minimize any neuronal effects while simultaneously eliminating animal motion, and maintenance of physiological parameters, deviation from which can confound the BOLD signal. Our laboratory has developed a set of procedures that are capable of overcoming most of these possible issues. For electrical stimulation, a homemade tungsten bipolar microelectrode is used, inserted stereotactically at the stimulation site in the anesthetized subject. In preparation for imaging, rodents are fixed on a plastic headpiece and transferred to the magnet bore. For sedation and paralysis during scanning, a cocktail of dexmedetomidine and pancuronium is continuously infused, along with a minimal dose of isoflurane; this preparation minimizes the BOLD ceiling effect of volatile anesthetics. In this example experiment, stimulation of the subthalamic nucleus (STN) produces BOLD responses which are observed primarily in ipsilateral cortical regions, centered in motor cortex. Simultaneous DBS and fMRI allows the unambiguous modulation of neural circuits dependent on stimulation location and stimulation parameters, and permits observation of neuronal modulations free of regional bias. This technique may be used to explore the downstream effects of modulating neural circuitry at nearly any brain region, with implications for both experimental and clinical DBS.     

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson''s disease by optimizing stimulation in real time according to fluctuating disease and medication state. In the present realization of adaptive DBS we record and stimulate from the DBS electrodes implanted in the subthalamic nucleus of patients with Parkinson''s disease in the early post-operative period. Local field potentials are analogue filtered between 3 and 47 Hz before being passed to a data acquisition unit where they are digitally filtered again around the patient specific beta peak, rectified and smoothed to give an online reading of the beta amplitude. A threshold for beta amplitude is set heuristically, which, if crossed, passes a trigger signal to the stimulator. The stimulator then ramps up stimulation to a pre-determined clinically effective voltage over 250 msec and continues to stimulate until the beta amplitude again falls down below threshold. Stimulation continues in this manner with brief episodes of ramped DBS during periods of heightened beta power.Clinical efficacy is assessed after a minimum period of stabilization (5 min) through the unblinded and blinded video assessment of motor function using a selection of scores from the Unified Parkinson''s Rating Scale (UPDRS). Recent work has demonstrated a reduction in power consumption with aDBS as well as an improvement in clinical scores compared to conventional DBS. Chronic aDBS could now be trialed in Parkinsonism.     

深部脑刺激作用机制的研究进展

深部脑刺激(deep brain stimulation,DBS)已在临床上广泛用于治疗帕金森病等疾病引起的运动障碍,它在难治性癫痫、顽固性强迫症等其他脑中枢神经系统疾病的治疗上也展现出良好的应用前景.经过30多年的临床应用、动物实验和计算模型仿真等多方面的研究,DBS的机制也逐渐明朗.虽然尚无定论,但已取得许多重要进展.本文从电生理角度分析和总结了有关DBS机制的发展历程.从早期的抑制论和兴奋论到目前主导的调控论;从关注刺激位点的神经元活动,到发现神经元胞体与轴突活动的去耦合,再到高频刺激诱导的间歇性轴突阻滞,以及由此轴突活动可能导致的投射区神经元群体的去同步活动.这一系列研究进展表明DBS具有复杂的神经网络调控机制.了解DBS的作用机制对于提高其疗效、开发新刺激模式以及扩大临床应用的范围都具有重要意义.     

Repeated BOLD-fMRI Imaging of Deep Brain Stimulation Responses in Rats

Functional magnetic resonance imaging (fMRI) provides a picture of the global spatial activation pattern of the brain. Interest is growing regarding the application of fMRI to rodent models to investigate adult brain plasticity. To date, most rodent studies used an electrical forepaw stimulation model to acquire fMRI data, with α-chloralose as the anesthetic. However, α-chloralose is harmful to animals, and not suitable for longitudinal studies. Moreover, peripheral stimulation models enable only a limited number of brain regions to be studied. Processing between peripheral regions and the brain is multisynaptic, and renders interpretation difficult and uncertain. In the present study, we combined the medetomidine-based fMRI protocol (a noninvasive rodent fMRI protocol) with chronic implantation of an MRI-compatible stimulation electrode in the ventroposterior (VP) thalamus to repetitively sample thalamocortical responses in the rat brain. Using this model, we scanned the forebrain responses evoked by the VP stimulation repeatedly of individual rats over 1 week. Cortical BOLD responses were compared between the 2 profiles obtained at day1 and day8. We discovered reproducible frequency- and amplitude-dependent BOLD responses in the ipsilateral somatosensory cortex (S1). The S1 BOLD responses during the 2 sessions were conserved in maximal response amplitude, area size (size ratio from 0.88 to 0.91), and location (overlap ratio from 0.61 to 0.67). The present study provides a long-term chronic brain stimulation protocol for studying the plasticity of specific neural circuits in the rodent brain by BOLD-fMRI.