非药物干预治疗神经精神疾病作用及机制研究

<正>近年来，随着非药物干预技术和方法的更新，其在治疗神经精神疾病中的作用及相关的机制也引起了广泛的关注。非药物干预包括运动、认知、经颅磁刺激、经颅电刺激，声光感觉刺激等^[1-4]。非药物干预在早期预防、减少药物副作用等方面存在优势。多项研究表明，非药物干预在预防和治疗脑缺血、阿尔茨海默病(Alzheimer’s disease,AD)、帕金森病、神经性疼痛、共情缺陷、意识障碍、物质使用障碍等神经精神疾病都有较好效果^[5-24]。     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

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。     

非药物疗法在慢性疼痛干预中的应用和治疗机制

疼痛是一种由身体组织的真实或潜在损伤引起的不舒服感觉，慢性疼痛为持续时间超过3个月以上的疼痛。慢性疼痛可以由多种疾病引起，发病率高。然而应用药物治疗慢性疼痛存在一定的局限性。非阿片类药物对部分类型的慢性痛，如神经病理性疼痛，疗效不佳。而阿片类镇痛药物则因成瘾和易诱发胃肠道副作用而受限，因此非药物干预治疗逐渐受到关注。目前临床上对于治疗慢性疼痛常用的非药物疗法包括脉冲射频（pulsed radiofrequency,PRF）、脊髓电刺激（spinal cordstimulation, SCS）、光生物调节（photobiomodulation, PBM）和重复经颅磁刺激（repetitive transcranial magnetic stimulation,rTMS）。最新研究揭示了光照和声音的中枢镇痛机制，提示光疗和声疗在临床转化上的潜力。鉴于光照和声音都属于非侵入性治疗，因此这两者在临床应用上具有广阔的前景。本文通过梳理以上非药物镇痛手段的干预方法、优缺点以及镇痛机制，希望为深入理解慢性痛的发病机制提供依据，为优化疼痛的非药物干预手段提供新的思路。     

针刺治疗药物成瘾的研究进展

近35年来,针刺治疗物质依赖的研究引起了越来越多的国内外相关学者和临床医生的关注.该领域内的研究进展大致可以分为三个主要阶段:(一)香港的温祥来医师于1973年首次报道,采用电针(两对体针和一对耳针连接电刺激)可以减轻阿片成瘾者的戒断症状(身体依赖);(二)纽约M.Smith医师(1985)领导的美国国家针刺脱毒协会(NADA)确定,仅采用耳针,不加电刺激,治疗药物依赖(身体依赖);(三)北京大学神经科学研究所(PKU NRI)韩济生教授及其同事(1992-)用特定频率的躯体穴位电刺激缓解海洛因成瘾者的戒断症状(身体依赖),并可抑制患者脱毒后对毒品的心理渴求(精神依赖)以预防复吸.本文将综述针刺干预药物依赖的临床疗效、实验研究及初步作用机制.     

精准定位脑刺激对运动功能调控研究进展

脑刺激是神经科学研究的重要手段,传统的经颅磁刺激和经颅电刺激等脑刺激方法尽管能调控运动功能(包括减轻运动性障碍疾病的运动障碍、提高运动能力等),但存在空间分辨率低且无法刺激深部脑组织的局限性.近年来迅速发展的深部脑刺激(deep brain stimulation,DBS)、光遗传学、经颅超声刺激(transcranial ultrasound stimulation,TUS)、时间干涉(temporal interference,TI)等精准定位脑刺激方法,具有空间分辨率高、可聚焦深部脑组织等优点.本文综述了上述几种脑刺激方法的原理、特点,对运动功能调控的研究进展,以及面临的挑战和发展前景,从而为神经科学研究提供更好的研究工具,为临床实践提供更多的干预治疗手段.     

重复经颅磁刺激改善帕金森病运动症状的脑功能网络分析

目的 重复经颅磁刺激（rTMS）技术已广泛应用在临床中，实现对神经、精神类疾病的治疗，特别在抑郁症、强迫症中取得较好的临床治疗效果。近年来越来越多的研究将其应用于帕金森病（PD）的辅助、康复治疗，以期缓解患者的运动症状改善运动功能。目前临床中多以PD统一量表、运动任务评估rTMS对运动症状的辅助治疗效果，缺乏对高频rTMS刺激调控作用机制的探究。方法 本研究采用10 Hz rTMS刺激肢体症状始发侧对侧初级运动皮层（M1），对比分析刺激前后各脑区神经元活动及其连接性的变化，研究高频rTMS刺激初级运动皮层对PD患者大脑神经元活动的调节作用。结果 运动皮层beta振荡增加、gamma振荡降低（P<0.05），额、顶叶脑区间连接性减弱（P<0.05）。结论 10 Hz rTMS主要改变了PD患者beta、gamma振荡，其中运动皮层beta、gamma神经振荡的变化可能与磁刺激对运动功能的改善作用有关，而前额叶gamma振荡的变化可能是磁刺激抑制神经元异常放电活动调节患者运动控制功能。     

康复运动训练联合经颅直流电刺激对帕金森病患者步行功能、平衡功能和认知功能的影响

摘要 目的：探讨康复运动训练联合经颅直流电刺激（tDCS）对帕金森病（PD）患者步行功能、平衡功能和认知功能的影响。方法：选择2018年5月至2021年5月期间我院收治的PD患者60例,根据计算机生成数据随机分为对照组和研究组各30例。对照组患者接受康复运动训练,研究组患者接受康复运动训练联合tDCS,两组均治疗两周。对比两组步行功能、平衡功能、肢体功能、认知功能和生活自理能力的变化。结果：研究组治疗后步速、步频、步宽高于对照组（P<0.05）。研究组治疗后Berg平衡量表（BBS）评分高于对照组（P<0.05）。研究组治疗后蒙特利尔认知评估量表（MoCA）各项评分及总分高于对照组（P<0.05）。研究组治疗后统一帕金森病评价量表第三部分（UPDRS-Ⅲ）评分低于对照组,改良Barthel指数（MBI）评分高于对照组（P<0.05）。结论：PD患者经康复运动训练联合tDCS治疗,运动和非运动障碍均可得到显著改善,生活自理能力提高,临床应用价值较高。     

创伤后应激障碍的经颅磁刺激研究进展

创伤后应激障碍会损伤记忆、注意和执行等认知功能,引起异常的脑活动及脑区间功能连接.尽管药物治疗和心理干预能够取得一定的治疗效果,但存在药物副作用和起效延迟等问题.经颅磁刺激作为新的创伤后应激障碍干预手段受到越来越多的关注.本文通过综述经颅磁刺激干预创伤后应激障碍以及调控认知功能和脑活动的相关研究,系统探讨了创伤后应激障碍干预中经颅磁刺激模式、刺激靶点和疗效评估等问题,并提出未来借助更有效的技术手段进行定位、建立全面有效的评估体系和结合新的记忆理论探索具有长期临床改善效果的干预方案.     

慢性吗啡给予、戒断及再给药过程中大鼠海马感觉门控的动态变化

药物成瘾被认为是药物长期作用于脑而产生的一种慢性复吸性脑疾病,长期反复的药物（如吗啡）滥用会导致一系列严重后果,如药物依赖、药物耐受、强迫性药物寻求等。本实验利用条件化位置偏好（conditioned place preference,CPP）模型来检测大鼠对吗啡依赖和心理渴求等过程;采用双声刺激听觉诱发电位来研究大鼠在慢性吗啡给予、戒断以及再给药过程中海马感觉门控（N40）的动态变化。吗啡组大鼠注射吗啡（10mg／kg,i．p．）12d,经历第一次戒断12d,再次注射吗啡（2．5mg／kg,i．P．）1d,之后经历第二次戒断2d;对照组大鼠注射同体积生理盐水,其余实验条件与吗啡组相同。CPP实验表明,这种药物给予方法促使大鼠对吗啡产生药物依赖和心理渴求。双声刺激诱发电位实验表明,吗啡组大鼠在吗啡给予期间海马感觉门控受到损伤;第一次戒断期的第1～2天海马感觉门控能力减弱,第3天增强,第4～12天逐渐恢复到正常水平;再次给予吗啡后海马感觉门控能力与对照组相比显著降低,并且随后2d的戒断期内海马感觉门控能力也一直保持较低水平,表明再次给药使大鼠海马感觉门控对吗啡更加敏感化。结果提示,长期反复的吗啡给予及再给药干扰了海马的感觉门控能力,吗啡成瘾对大脑可能产生长期影响。     

重复经颅磁刺激对创伤性颅脑损伤患者脑脊液中兴奋性氨基酸含量的影响

目的：探讨重复经颅磁刺激（rTMS）对急性颅脑损伤患者脑脊液中兴奋性氨基酸（EAA）含量的影响。方法：30例创伤性颅脑损伤（TBI）病人按格拉斯哥昏迷评分分为轻型组（rTMS3）、中型组（rTMS2）、重型组（rTMS1）,每组10例,各组病人分别随机分为rTMS对照亚组（A组）及治疗亚组（B组）,每亚组5例。于TBI后第15天行腰椎穿刺采集脑脊液,采用高效液相色谱法测定脑脊液中谷氨酸（ASP）及门冬氨酸（GLU）含量。结果：脑脊液ASP和GLU水平随着脑损伤程度的加重而升高,各rTMS治疗组与相应各对照组的EAA相比,rTMS治疗组EAA的水平均低于相应对照组。结论：rTMS可通过降低TBI后脑脊液EAA水平发挥脑保护作用。脑脊液EAA的含量变化可作为TBI严重程度的生化指标。     

非侵入性脑刺激应用于创伤后应激障碍和物质滥用障碍的记忆干预

记忆是进行思维、想象等高级心理活动的基础，是累积经验、促进个体生存的重要功能。然而，创伤后应激障碍和物质滥用障碍具有某种非适应性记忆过强的特征，不利于个体生存。因此，以病理性改变的记忆为靶点，通过削弱或更新非适应性记忆，可以达到缓解症状甚至治愈的目的。记忆并非是对经验的刻板记录，而是对经验不断更新整合的过程，因此记忆有被干预的可能。记忆的再次激活可能会诱发记忆消退和再巩固，这为记忆相关精神疾病的干预提供了思路和启发。非侵入性脑刺激（noninvasive brain stimulation,NIBS）技术作为一种时间、空间分辨率较高的无创神经调控技术，近年来开始被结合运用到记忆干预研究中。不同刺激参数的NIBS （如频率、极性，以及受刺激区域的初始神经激活状态）应用于特定大脑皮质区域，可以调节神经可塑性，增强或降低靶点脑区的兴奋性，从而削弱或增强行为表现，实现记忆消退增强或在再巩固时间窗内干预记忆。本文首先介绍了记忆相关的脑功能基础研究与局部脑区干预方案的理论联系，继而回顾了近年来NIBS与记忆干预相结合应用于创伤或物质滥用相关障碍的临床干预研究，为精神疾病临床诊疗提供理论依据和启发。     

Behavioral effects of transcranial Direct Current Stimulation (tDCS) induced dorsolateral prefrontal cortex plasticity in alcohol dependence

Transcranial Direct Current Stimulation (tDCS) has been shown to reduce acute substance craving in drug addicts, and improve cognition in neuropsychiatric patients. Here we aimed to explore further tDCS induced behavioral and neurophysiological modulation including assessment of relapse rate over a prolonged time course in alcoholism. We examined the effects of repeated anodal tDCS (2 mA, 35 cm², 20 min) over the left dorsolateral prefrontal cortex (DLPFC) on relapse to the use of alcohol in alcoholics from outpatient services, who received additional routine clinical treatment. Furthermore, event related potentials (ERPs), cognitive and frontal executive processes, craving, depressive and anxiety symptoms were obtained before and after treatment. From thirteen alcoholic subjects, seven were randomized to sham-tDCS and six to real tDCS treatment (once a week for five consecutive weeks). Depressive symptoms and craving were reduced to a larger extent in the tDCS group compared to the sham group (p = 0.005 and p = 0.015, respectively). On the other hand, active tDCS was able to block the increase in neural activation triggered by alcohol related and neutral cues in prefrontal cortex (PFC) as indexed by ERP as seen in the sham-tDCS group. Finally, there was a trend for increased change in executive function in the tDCS group compared to the sham-tDCS group (p = 0.082), and, similarly, a trend for more relapses in the tDCS group compared to sham tDCS (four alcoholic subjects (66.7%) vs. one (14.3%), p = 0.053).These results confirm the previous findings of tDCS effects on craving in alcoholism and also extend these findings as we showed also tDCS-related mood improvement. However, potential increase in relapse is possible; thus the clinical value of an increase in craving and improvement in depression and executive function needs to be carefully assessed in further studies; including investigation of optimal parameters of stimulation.     

Speech facilitation by left inferior frontal cortex stimulation

Electrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting [1], polarity-dependent [2] changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3-8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9-13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Broca's area. Our data support the importance of Broca's area within the normal naming network and as such indicate that Broca's area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region.     

Polarity-Dependent Misperception of Subjective Visual Vertical during and after Transcranial Direct Current Stimulation (tDCS)

Pathologic tilt of subjective visual vertical (SVV) frequently has adverse functional consequences for patients with stroke and vestibular disorders. Repetitive transcranial magnetic stimulation (rTMS) of the supramarginal gyrus can produce a transitory tilt on SVV in healthy subjects. However, the effect of transcranial direct current stimulation (tDCS) on SVV has never been systematically studied. We investigated whether bilateral tDCS over the temporal-parietal region could result in both online and offline SVV misperception in healthy subjects. In a randomized, sham-controlled, single-blind crossover pilot study, thirteen healthy subjects performed tests of SVV before, during and after the tDCS applied over the temporal-parietal region in three conditions used on different days: right anode/left cathode; right cathode/left anode; and sham. Subjects were blind to the tDCS conditions. Montage-specific current flow patterns were investigated using computational models. SVV was significantly displaced towards the anode during both active stimulation conditions when compared to sham condition. Immediately after both active conditions, there were rebound effects. Longer lasting after-effects towards the anode occurred only in the right cathode/left anode condition. Current flow models predicted the stimulation of temporal-parietal regions under the electrodes and deep clusters in the posterior limb of the internal capsule. The present findings indicate that tDCS over the temporal-parietal region can significantly alter human SVV perception. This tDCS approach may be a potential clinical tool for the treatment of SVV misperception in neurological patients.     

Kinase interest you in treating incubated cocaine‐craving? A hypothetical model for treatment intervention during protracted withdrawal from cocaine

A diagnostic criterion for drug addiction, persistent drug‐craving continues to be the most treatment‐resistant aspect of addiction that maintains the chronic, relapsing, nature of this disease. Despite the high prevalence of psychomotor stimulant addiction, there currently exists no FDA‐approved medication for craving reduction. In good part, this reflects our lack of understanding of the neurobiological underpinnings of drug‐craving. In humans, cue‐elicited drug‐craving is associated with the hyperexcitability of prefrontal cortical regions. Rodent models of cocaine addiction indicate that a history of excessive cocaine‐taking impacts excitatory glutamate signaling within the prefrontal cortex to drive drug‐seeking behavior during protracted withdrawal. This review summarizes evidence that the capacity of cocaine‐associated cues to augment craving in highly drug‐experienced rats relates to a withdrawal‐dependent incubation of glutamate release within prelimbic cortex. We discuss how stimulation of mGlu1/5 receptors increases the activational state of both canonical and noncanonical intracellular signaling pathways and present a theoretical molecular model in which the activation of several kinase effectors, including protein kinase C, extracellular signal‐regulated kinase and phosphoinositide 3‐kinase (PI3K) might lead to receptor desensitization to account for persistent cocaine‐craving during protracted withdrawal. Finally, this review discusses the potential for existing, FDA‐approved, pharmacotherapeutic agents that target kinase function as a novel approach to craving intervention in cocaine addiction.     

Multi-Session Transcranial Direct Current Stimulation (tDCS) Elicits Inflammatory and Regenerative Processes in the Rat Brain

Transcranial direct current stimulation (tDCS) is increasingly being used in human studies as an adjuvant tool to promote recovery of function after stroke. However, its neurobiological effects are still largely unknown. Electric fields are known to influence the migration of various cell types in vitro, but effects in vivo remain to be shown. Hypothesizing that tDCS might elicit the recruitment of cells to the cortex, we here studied the effects of tDCS in the rat brain in vivo. Adult Wistar rats (n = 16) were randomized to either anodal or cathodal stimulation for either 5 or 10 consecutive days (500 µA, 15 min). Bromodeoxyuridine (BrdU) was given systemically to label dividing cells throughout the experiment. Immunohistochemical analyses ex vivo included stainings for activated microglia and endogenous neural stem cells (NSC). Multi-session tDCS with the chosen parameters did not cause a cortical lesion. An innate immune response with early upregulation of Iba1-positive activated microglia occurred after both cathodal and anodal tDCS. The involvement of adaptive immunity as assessed by ICAM1-immunoreactivity was less pronounced. Most interestingly, only cathodal tDCS increased the number of endogenous NSC in the stimulated cortex. After 10 days of cathodal stimulation, proliferating NSC increased by ∼60%, with a significant effect of both polarity and number of tDCS sessions on the recruitment of NSC. We demonstrate a pro-inflammatory effect of both cathodal and anodal tDCS, and a polarity-specific migratory effect on endogenous NSC in vivo. Our data suggest that tDCS in human stroke patients might also elicit NSC activation and modulate neuroinflammation.     

Deep brain stimulation of the accumbens increases dopamine,serotonin, and noradrenaline in the prefrontal cortex

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is effective in treatment‐refractory obsessive‐compulsive disorder and major depressive disorder. However, little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. One of the hypotheses is that DBS modulates activity of monoamine neurotransmitters. In this study, we evaluated the effects of DBS in the NAc core on the extracellular concentration of monoaminergic neurotransmitters in the medial (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated in the NAc core for 2 h while dopamine, serotonin, and noradrenaline were measured using in vivo microdialysis in the mPFC and the OFC. We report rapid increases in the release of dopamine and serotonin to a maximum of 177% and 127% in the mPFC and an increase up to 171% and 166% for dopamine and noradrenaline in the OFC after onset of stimulation in the NAc core. These results provide further evidence for the distal effects of DBS and corroborate previous clinical and pre‐clinical findings of altered neuronal activity in prefrontal areas.     

A general method for evaluating incubation of sucrose craving in rats

For someone on a food-restricted diet, food craving in response to food-paired cues may serve as a key behavioral transition point between abstinence and relapse to food taking. Food craving conceptualized in this way is akin to drug craving in response to drug-paired cues. A rich literature has been developed around understanding the behavioral and neurobiological determinants of drug craving; we and others have been focusing recently on translating techniques from basic addiction research to better understand addiction-like behaviors related to food. As done in previous studies of drug craving, we examine sucrose craving behavior by utilizing a rat model of relapse. In this model, rats self-administer either drug or food in sessions over several days. In a session, lever responding delivers the reward along with a tone+light stimulus. Craving behavior is then operationally defined as responding in a subsequent session where the reward is not available. Rats will reliably respond for the tone+light stimulus, likely due to its acquired conditioned reinforcing properties. This behavior is sometimes referred to as sucrose seeking or cue reactivity. In the present discussion we will use the term "sucrose craving" to subsume both of these constructs. In the past decade, we have focused on how the length of time following reward self-administration influences reward craving. Interestingly, rats increase responding for the reward-paired cue over the course of several weeks of a period of forced-abstinence. This "incubation of craving" is observed in rats that have self-administered either food or drugs of abuse. This time-dependent increase in craving we have identified in the animal model may have great potential relevance to human drug and food addiction behaviors. Here we present a protocol for assessing incubation of sucrose craving in rats. Variants of the procedure will be indicated where craving is assessed as responding for a discrete sucrose-paired cue following extinction of lever pressing within the sucrose self-administration context (Extinction without cues) or as responding for sucrose-paired cues in a general extinction context (Extinction with cues).     

Self-Administered Domiciliary tDCS Treatment for Tinnitus: A Double-Blind Sham-Controlled Study

Transcranial direct current stimulation (tDCS) has shown potential for providing tinnitus relief, although positive effects have usually been observed only during a short time period after treatment. In recent studies the focus has turned from one-session experiments towards multi-session treatment studies investigating long-term outcomes with double-blinded and sham-controlled study designs. Traditionally, tDCS has been administered in a clinical setting by a healthcare professional but in studies involving multiple treatment sessions, often a trade-off has to be made between sample size and the amount of labor needed to run the trial. Also, as the number of required visits to the clinic increases, the dropout rate is likely to rise proportionally.The aim of the current study was to find out if tDCS treatment for tinnitus could be patient-administered in a domiciliary setting and whether the results would be comparable to those from in-hospital treatment studies. Forty-three patients with chronic (> 6 months) tinnitus were involved in the study, and data on 35 out of these patients were included in final analysis. Patients received 20 minutes of left temporal area anodal (LTA) or bifrontal tDCS stimulation (2 mA) or sham stimulation (0.3 mA) for ten consecutive days. An overall reduction in the main outcome measure, Tinnitus Handicap Inventory (THI), was found (mean change −5.0 points, p < 0.05), but there was no significant difference between active and sham treatment outcomes. Patients found the tDCS treatment easy to administer and they all tolerated it well. In conclusion, self-administered domiciliary tDCS treatment for tinnitus was found safe and feasible and gave outcome results similar to recent randomized controlled long-term treatment trials. The results suggest better overall treatment response—as measured by THI—with domiciliary treatment than with in-hospital treatment, but this advantage is not related to the tDCS variant. The study protocol demonstrated in the current study is not restricted to tinnitus only.