经颅电刺激镇痛研究的现状及展望

经颅电刺激技术是一种非侵入性神经调控方法,因其具有卓越的安全性、良好的患者依从性以及高度便携性等特点,被视为一种潜在的非药物镇痛手段。然而,目前对于经颅电刺激镇痛效果的研究结果不一致且镇痛机制尚未完全阐明。本文通过系统归纳总结3种主要的经颅电刺激技术——经颅直流电刺激、经颅交流电刺激和经颅随机噪声刺激——在镇痛领域的研究进展,评估了这些技术对短时、急性和慢性疼痛的镇痛效果,并深入剖析了其潜在的镇痛机制。同时,本文系统讨论了既往研究的局限性,并对未来研究提出了一系列切实可行的建议,如借助电场模拟技术实现个性化刺激以克服不同个体头部解剖结构差异的影响、应用多位点刺激和深部脑刺激技术来拓展刺激脑区、搭建经颅电刺激技术同步神经影像平台以制定个体特异性的刺激方案并深入揭示其镇痛机制、探索与其他治疗技术的联合应用以提高疗效等。这些建议的实施将有助于解决当前研究中存在的问题,充分发挥经颅电刺激在疼痛治疗中的临床价值,最终实现患者疼痛的缓解。     

应激导致抑郁症与单胺类递质系统稳态

当机体受到各种应激刺激时,机体会产生一系列特异性和非特异性反应,使机体的生理功能维持在新的稳态。如果应激持续时间过长,或者程度过于强烈,超过了机体稳态调节的范围,应激刺激就会对机体生理功能的稳态产生破坏。与应激相关的精神障碍不仅抑郁症一种,应激影响单胺类递质系统造成抑郁症可能主要是影响了5-HT递质系统的功能,而对NE递质系统或DA递质系统造成的影响不是导致抑郁症发病的主要原因。应激除了改变神经系统,还会影响机体内分泌系统,免疫系统,使抑郁症病人的发病和临床症状极为复杂。主要综述应激,特别是长期的、慢性的应激引起单胺能神经递质系统改变,进而导致抑郁症的神经生物学机制研究进展。     

综述: 无创穿颅电刺激对人脑神经活动和认知功能的调控

穿颅电刺激被认为可以无创调节大脑的神经活动,为研究特定脑区与某一认知功能间的因果关系提供了可能.近些年,对穿颅电刺激作用机制和其对认知、运动功能调控的研究方面取得了很多重要进展.在这篇综述中,我们总结了以往关于穿颅直流电刺激、穿颅交流电刺激和穿颅随机噪声电刺激三种刺激方式的发展历史及其作用机制,同时总结了其对感知觉(主要是视觉知觉)、注意和记忆等认知功能的调控,并对未来的研究方向进行了展望.     

灵孢多糖辅助治疗抑郁症的作用及机制

目的:建立大鼠抑郁模型,研究和探讨灵孢多糖注射液辅助治疗抑郁症的作用及机制。方法:将48只SD大鼠随机分为正常组、抑郁组、生理盐水组及灵孢多糖(低剂量、中剂量、高剂量)治疗组各8只。应用慢性应激刺激的方法诱导抑郁组、生理盐水组、灵孢多糖治疗组大鼠抑郁,通过行为学指标评估建模是否成功。建模成功后,在生理盐水组中注射生理盐水;在灵孢多糖治疗组中分别注射低、中、高剂量灵孢多糖注射液,比较各组间的疗效差异。采用免疫组化的方法测定大鼠脑内多巴胺、去甲肾上腺素、5-羟色胺、酪氨酸羟化酶等单胺类神经递质含量的表达情况。结果:成功的建立了大鼠抑郁模型,抑郁组中大鼠各项行为学指标与正常组相比均明显减少,差异有统计学意义(P0.05);灵孢多糖治疗组大鼠脑内的多巴胺、去甲肾上腺素、5-羟色胺、酪氨酸羟化酶与抑郁组、生理盐水组大鼠脑内的含量均明显升高,差异有统计学意义(P0.05)。结论:灵孢多糖注射液对改善抑郁症状有良好的疗效,具有辅助治疗抑郁症的作用。     

灵孢多糖辅助治疗抑郁症的作用及机制

目的：建立大鼠抑郁模型,研究和探讨灵孢多糖注射液辅助治疗抑郁症的作用及机制。方法：将48只SD大鼠随机分为正常组、抑郁组、生理盐水组及灵孢多糖（低剂量、中剂量、高剂量）治疗组各8只。应用慢性应激刺激的方法诱导抑郁组、生理盐水组、灵孢多糖治疗组大鼠抑郁,通过行为学指标评估建模是否成功。建模成功后,在生理盐水组中注射生理盐水;在灵孢多糖治疗组中分别注射低、中、高剂量灵孢多糖注射液,比较各组间的疗效差异。采用免疫组化的方法测定大鼠脑内多巴胺、去甲肾上腺素、5-羟色胺、酪氨酸羟化酶等单胺类神经递质含量的表达情况。结果：成功的建立了大鼠抑郁模型,抑郁组中大鼠各项行为学指标与正常组相比均明显减少,差异有统计学意义（P〈0．05）;灵孢多糖治疗组大鼠脑内的多巴胺、去甲肾上腺素、5一羟色胺、酪氨酸羟化酶与抑郁组、生理盐水组大鼠脑内的含量均明显升高,差异有统计学意义（P〈0．05）。结论：灵孢多糖注射液对改善抑郁症状有良好的疗效,具有辅助治疗抑郁症的作用。     

抑郁症单胺类递质受体研究进展

目前认为,抑郁症的发病主要与单胺类递质有关,单胺类递质受体系统在抑郁症的发病及治疗过程中会发生明显变化,本文综述了5-羟色胺受体,肾上腺素受体和多巴胺受体在抑郁症发病机制中所起作用的研究进展。     

经颅磁刺激对癫痫病灶脑电相关维数的影响

利用脑功能指标——大鼠病灶区脑电的相关维数,研究低频经颅磁刺激对慢性颞叶癫痫大鼠脑功能改善的作用。对一组颞叶癫痫大鼠施予频率为0．5Hz、强度为0．4T、20次／日、连续一周的低频重复性经颅磁刺激(rTMS)．在rTMS前后,分别测取颞叶癫痫大鼠责任病灶区皮层和海马区的脑电,重构时间延迟吸引子,用G-P算法估算反映对应脑区功能状态的相关维数。研究结果显示：施予适量的rTMS(0.4T、20次／日、连续一周),使颞叶癫痫大鼠海马和相应皮层脑电的相关维数比刺激前明显升高。研究表明适量的rTMS有抑制癫痫的作用。     

综述与专论: 重复经颅磁刺激对卒中后抑郁的治疗效果及机制探索

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病,发病率高,预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术,是临床上治疗PSD的一种重要非药物治疗方法,可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案,并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段,探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加,提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平,进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整,可能是rTMS治疗PSD的重要机制之一。     

经颅电刺激改善阿尔茨海默病的神经分子机制

阿尔茨海默病（Alzheimer’s disease, AD）是常见且严重的痴呆症之一,严重危害患者的身心健康和生活质量,同时给社会带来沉重的负担。近年来,经颅电刺激（transcranial electrical stimulation,t ES）在改善AD认知功能方面表现出巨大的潜力,主要包括经颅直流电刺激（transcranial direct current stimulation,t DCS）和经颅交流电刺激（transcranial alternating current stimulation,t ACS）两种类型。本文综述了t DCS和t ACS改善AD的神经分子机制,其共性主要体现在发挥神经保护作用、通过增加脑血流量来改善神经血管障碍、影响神经胶质细胞的状态和功能、减少Aβ和p-tau蛋白、影响神经可塑性。值得注意的是,t DCS在优化神经血管单元、改善血脑屏障（blood brain barrier,BBB）方面展现出独特的积极影响。此外,在非AD啮齿类动物的研究中,t ES在神经保护、神经胶质细胞、神经可塑性方面还表现出在AD研究中尚未探讨的、更为具体的神经分子机制。这些发现为深入理解t ES的作用原理、AD的病理机制,以及探索治疗其他具有相似病理特征疾病的新途径提供了理论基础。     

经颅电刺激对睡眠剥夺后双侧后扣带回皮质功能连接紊乱干预作用的初步研究

目的:探讨经颅电刺激对睡眠剥夺后双侧后扣带回皮质功能连接紊乱的干预作用。方法:研究采用自身前后对照的试验设计。16名受试者均接受2次24 h睡眠剥夺,2次睡眠剥夺间隔3周,受试者分别于第1次正常睡眠后、24 h睡眠剥夺后、经颅电刺激(真或假刺激)干预后(真、假刺激电流大小均为1 mA,电流作用时间分别为20 min、2 s,干预实验均持续20 min)及第2次经颅电刺激(假或真刺激)干预后采集静息态磁共振成像数据。以睡眠剥夺前收集静息态功能磁共振数据作为基线,选取双侧后扣带回皮质作为种子点进行全脑功能连接分析,观察睡眠剥夺前后及经颅电刺激真、假刺激后大脑的功能连接变化。结果:与正常睡眠后相比,24 h睡眠剥夺后双侧后扣带回皮质与双侧丘脑间的功能连接上升(P<0.01),与右侧楔前叶、海马旁回以及双侧岛叶间的功能下降(P<0.01)。与假刺激相比,给予真刺激后左侧后扣带回皮质与右侧楔前叶功能连接上升(P<0.01);与双侧丘脑、岛叶及右侧大脑皮质功能连接下降(P<0.01)。右侧后扣带回皮质与全脑的功能连接在双侧丘脑、右侧岛叶及大脑皮层间也存在下降(P<0....     

Effect of transcranial electrical stimulation on sleep in rats

Transcranial electrical stimulation with high frequency intermittent current (Limoge's current) was delivered to normal rats and to PCPA-treated rats with impaired sleep. Electrocorticogram was continuously recorded for quantifying the stage of the sleep-waking cycle. The current did not affect the sleep pattern of normal rats whereas the number of paradoxical sleep episodes increased in insomniac animals. The increased duration of paradoxical sleep in PCPA-treated rats favored the recovery of sleep in this group. The stimulation increased the brain serotonin turnover, which could possibly contribute to its hypnogenic action.     

Time-dependent effects of neuromuscular electrical stimulation on changes in spinal excitability are dependent on stimulation frequency: A preliminary study in healthy adults

Neuromuscular electrical stimulation (NMES) can be used as treatment for spasticity. The present study examined differences in time-dependent effects of NMES depending on stimulation frequency. Forty healthy subjects were separated into four groups (no-stim, NMES of 50, 100, and 200?Hz). The un-conditioned H-reflex amplitude and the H-reflex conditioning-test paradigm were used to measure the effectiveness on monosynaptic Ia excitation of motoneurons in the soleus (SOL) muscle, disynaptic reciprocal Ia inhibition from tibialis anterior (TA) to SOL, and presynaptic inhibition of SOL Ia afferents. Each trial consisted of a 30-min period of NMES applied to the deep peroneal nerve followed by a 30-min period with no stimulation to measure prolonged effects. Measurements were performed periodically. Stimulation applied at all frequencies produced a significant reduction in monosynaptic Ia excitation of motoneurons in the SOL muscle, however, only stimulation with 50?Hz showed prolonged reduction after NMES. NMES frequency did not affect the amount of disynaptic reciprocal Ia inhibition and presynaptic inhibition of Ia afferents. The results show a frequency-dependent effect of NMES on the monosynaptic Ia excitation of motoneurons. This result has implications for selecting the optimal NMES frequency for treatment in patients with spasticity.     

电刺激大鼠脚内核对脚桥核神经元放电的影响

目的:观察电刺激大鼠脚内核(EP)对大鼠脚桥核(PPN)神经元自发放电的影响,进一步探讨脑内电刺激治疗帕金森病(PD)的机制。方法:应用细胞外记录的方法观察不同频率电刺激(强度0.6 mA,波宽0.06 ms,时程5 s,频率5 Hz、10Hz、20Hz、50Hz、100Hz、150Hz、200Hz)大鼠EP对PPN神经元放电的影响。结果:实验记录了大鼠33个神经元的自发放电,其放电频率在3.6~52.2Hz之间,平均为(15.95±8.56)Hz;当刺激频率为100Hz时,抑制效应最显著(P<0.05)。结论:高频电刺激大鼠EP对PPN神经元自发放电的影响主要为抑制作用,提示高频刺激EP可通过抑制PPN神经元活动参与PD的治疗。     

电刺激大鼠束旁核对底丘脑核和丘脑腹内侧核神经元的影响

本工作旨在探讨电刺激束旁核（parafascicular nucleus,PF）对帕金森病模型（Parkinson’s disease,PD）大鼠神经行为的改善作用及其机制。成年雄性Sprague—Dawley大鼠黑质致密部注射6一羟基多巴胺建立PD大鼠模型。采用行为学方法观察电刺激PF对阿朴吗啡诱发的大鼠旋转行为的作用,并应用在体细胞外记录法观察电刺激PF对大鼠底丘脑核（subthalamic nucleus,STN）及丘脑腹内侧核（ventromedial nucleus,VM）神经元放电的影响。结果发现,高频电刺激（130Hz,0．4mA,5s）PF一周,明显改善PD大鼠旋转行为。细胞外放电记录显示,高频电刺激PF使PD大鼠STN神经元自发放电减少,且该作用具有频率依赖性。另外,高频电刺激PF可使VM神经元兴奋,该作用也是频率依赖性的。我们在实验中同时观察到微电泳谷氨酸（glutamicacid,Glu）受体拮抗剂MK-801使STN神经元放电频率减少或完全抑制,微电泳t氨基丁酸（T-amino butyricacid,GABA）受体拮抗剂印防己毒素（picrotoxin,Pic）则使神经元放电频率增加。以上结果表明,GABA能和GIu能传入纤维可会聚于同-STN神经元,并对后者有紧张性作用。高频刺激PF,使该核团到STN神经元的Glu能兴奋性输出减少,导致STN的失活。这一作用通过基底神经节的间接通路,最终释放了丘脑运动核团VM的活性。高频刺激PF经PF,STN和VM的神经通路而改善PD大鼠神经行为。     

电刺激大鼠脊神经皮支对远距离机械感受单位电活动的影响

实验采用分离神经细束的方法,观察逆行电刺激大鼠脊神经背侧皮支后,在相距较远的神经细束上记录到的Aδ和C类机械感受单位电活动的变化。刺激T9脊神经背侧皮支,在T12神经细束上记录到59.3%（16/27）的Aδ和71.2%(37/52）的C类单位在刺激后90～120s放电显著增加。刺激T8脊神经背侧皮支,在T12神经细束上记录到47.8%(11/23）的Aδ单位和36.6%(15/41）的C类单位在刺激后120～150s放电显著增加。大多数单位（18/23）的机械感受阈值在电刺激远距离脊神经背侧皮支后降低。结果表明,逆行电刺激外周感觉神经,可以使相距较远的Aδ和C类机械感受单位致敏,其传入放电增加。     

Pulsed subcutaneous electrical stimulation in spinal cord injury: preliminary results

The treatment of long-term, stable para- and quadriplegics with pulsed electrical stimulation for pain control resulted in, anecdotally, a significant number of these individuals showing increased motor function as well as sensory awareness. This small pilot study was conducted in order to assess the hypothesis that pulsed electrical fields can effect diseased neurological function. Thirteen para- and quadriplegic subjects with 18 months of stable neurological signs and symptoms were exposed daily to pulsed electrical stimulation for a 6-month period and assessed for any improvement in motor function or sensory perception. The hypothesis is that pulsed electromagnetic fields can normalize viable but dysfunctional neuronal structures. Results were encouraging.     

Advances in functional electrical stimulation (FES)

This review discusses the advancements that are needed to enhance the effects of electrical stimulation for restoring or assisting movement in humans with an injury/disease of the central nervous system. A complex model of the effects of electrical stimulation of peripheral systems is presented. The model indicates that both the motor and sensory systems are activated by electrical stimulation. We propose that a hierarchical hybrid controller may be suitable for functional electrical stimulation (FES) because this type of controller acts as a structural mimetic of its biological counterpart. Specific attention is given to the neural systems at the periphery with respect to the required electrodes and stimulators. Furthermore, we note that FES with surface electrodes is preferred for the therapy, although there is a definite advantage associated with implantable technology for life-long use. The last section of the review discusses the potential need to combine FES and robotic systems to provide assistance in some cases.     

Sleep deprivation in depression stabilizing antidepressant effects by repetitive transcranial magnetic stimulation

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep - is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p < 0.001) the antidepressant effect of PSD up to 4 days. This finding indicates that rTMS is an efficacious method to prevent relapse after PSD.     

Greater osteoblast proliferation on anodized nanotubular titanium upon electrical stimulation

Currently used orthopedic implants composed of titanium have a limited functional lifetime of only 10–15 years. One of the reasons for this persistent problem is the poor prolonged ability of titanium to remain bonded to juxtaposed bone. It has been proposed to modify titanium through anodization to create a novel nanotubular topography in order to improve cytocompatibility properties necessary for the prolonged attachment of orthopedic implants to surrounding bone. Additionally, electrical stimulation has been used in orthopedics to heal bone non-unions and fractures in anatomically difficult to operate sites (such as the spine). In this study, these two approaches were combined as the efficacy of electrical stimulation to promote osteoblast (bone forming cell) density on anodized titanium was investigated. To do this, osteoblast proliferation experiments lasting up to 5 days were conducted as cells were stimulated with constant bipolar pulses at a frequency of 20 Hz and a pulse duration of 0.4 ms each day for 1 hour. The stimulation voltages were 1 V, 5 V, 10 V, and 15 V. Results showed for the first time that under electrical stimulation, osteoblast proliferation on anodized titanium was enhanced at lower voltages compared to what was observed on conventional (nonanodized) titanium. In addition, compared to nonstimulated conventional titanium, osteoblast proliferation was enhanced 72% after 5 days of culture on anodized nanotubular titanium at 15 V of electrical stimulation. Thus, results of this study suggest that coupling the positive influences of electrical stimulation and nanotubular features on anodized titanium may improve osteoblast responses necessary for enhanced orthopedic implant efficacy.     

Optimizing neuromuscular electrical stimulation for hand opening

Aim: To investigate the effect of introducing an interphase interval to a biphasic pulse on force production and muscle fatigue, during stimulation of the wrist and finger extensors and to determine whether the IPI effect on force is dependent on electrode position.

Methods: Electrically-induced contraction forces of the wrist and finger extensors were measured in 15 healthy subjects undergoing stimulation. These forces were assessed with interphase interval settings at 0, 100, and 200μs, with both electrodes located just distal to common extensor origin (proximal placement) or with the distal electrode placed over the extensor and abductor policies longus muscles (distal placement). The degree of discomfort related to stimulation sensation was evaluated using a numeric rating scale. Muscle fatigue was measured during proximal placement.

Results: Under both electrode locations, introduction of 100 or 200?μs interphase interval enhanced force production; yet, only the 100μs interphase interval increased force without increasing discomfort. Additionally, stimulation sensation was more comfortable with proximal placement. Introducing interphase interval significantly increased the muscle force output during a repetitive stimulation fatigue protocol.

Conclusions: When using neuromuscular electrical stimulation to activate the wrist and finger extensors, clinicians should consider locating both stimulating electrodes proximally over the extensor surface of the forearm and apply a 100?µs interphase interval to a biphasic pulse. Future research that should establish these findings in individuals with various pathologies, especially in patients with residual hand spasticity.