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.     

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。     

Deep brain stimulation for neurologic and neuropsychiatric disorders

In the 1960s, ablative stereotactic surgery was employed for a variety of movement disorders and psychiatric conditions. Although largely abandoned in the 1970s because of highly effective drugs, such as levodopa for Parkinson's disease (PD), and a reaction against psychosurgery, the field has undergone a virtual renaissance, guided by a better understanding of brain circuitry and the circuit abnormalities underlying movement disorders such as PD and neuropsychiatric conditions, such as obsessive compulsive disorder. High-frequency electrical deep brain stimulation (DBS) of specific targets, introduced in the early 1990s for tremor, has gained widespread acceptance because of its less invasive, reversible, and adjustable features and is now utilized for an increasing number of brain disorders. This review summarizes the rationale behind DBS and the use of this technique for a variety of movement disorders and neuropsychiatric diseases.     

Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat

Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa.     

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...     

What brain signals are suitable for feedback controzl of deep brain stimulation in Parkinson's disease?

Feedback control of deep brain stimulation (DBS) in Parkinson's disease has great potential to improve efficacy, reduce side effects, and decrease the cost of treatment. In this, the timing and intensity of stimulation are titrated according to biomarkers that capture current clinical state. Stimulation may be at standard high frequency or intelligently patterned to directly modify specific pathological rhythms. The search for and validation of appropriate feedback signals are therefore crucial. Signals recorded from the DBS electrode currently appear to be the most promising source of feedback. In particular, beta-frequency band oscillations in the local field potential recorded at the stimulation target may capture variation in bradykinesia and rigidity across patients, but this remains to be confirmed within patients. Biomarkers that reliably reflect other impairments, such as tremor, also need to be established. Finally, whether brain signals are causally important needs to be established before stimulation can be specifically patterned rather than delivered at empirically defined high frequency.     

Stimulating personality: Ethical criteria for deep brain stimulation in psychiatric patients and for enhancement purposes

Within the recent development of brain-machine-interfaces deep brain stimulation (DBS) has become one of the most promising approaches for neuromodulation. After its introduction more than 20 years ago, it has in clinical routine become a successful tool for treating neurological disorders like Parkinson's disease, essential tremor and dystonia. Recent evidence also demonstrates efficacy in improving emotional and cognitive processing in obsessive-compulsive disorder and major depression, thus allowing new treatment options for treatment refractory psychiatric diseases, and even indicating future potential to enhance functioning in healthy subjects. We demonstrate here that DBS is neither intrinsically unethical for psychiatric indications nor for enhancement purposes. To gain normative orientation, the concept of “personality” is not useful – even if a naturalistic notion is employed. As an alternative, the common and widely accepted bioethical criteria of beneficence, non-maleficence, and autonomy allow a clinically applicable, highly differentiated context- and case-sensitive approach. Based on these criteria, an ethical analysis of empirical evidence from both DBS in movement disorders and DBS in psychiatric disease reveals that wide-spread use of DBS for psychiatric indications is currently not legitimated and that the basis for enhancement purposes is even more questionable. Nevertheless, both applications might serve as ethically legitimate, promising purposes in the future.     

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people. There is a need for novel, effective and practical treatment strategies that are validated in animal models. Neuromodulation, including deep brain stimulation (DBS) therapy, refers to the use of electricity to influence pathological neuronal activity and has shown promise for psychiatric disorders, including drug dependence. DBS in clinical practice involves the continuous delivery of stimulation into brain structures using an implantable pacemaker-like system that is programmed externally by a physician to alleviate symptoms. This treatment will be limited in methamphetamine users due to challenging psychosocial situations. Electrical treatments that can be delivered intermittently, non-invasively and remotely from the drug-use setting will be more realistic. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence. Methamphetamine dependence is rapidly developed in rodents using an operant paradigm of intravenous (IV) self-administration that incorporates a period of extended access to drug and demonstrates both escalation of use and high motivation to obtain drug.     

Deep brain stimulation amplitude alters posture shift velocity in Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is now widely used to alleviate symptoms of Parkinson’s disease (PD). The specific aim of this study was to identify posture control measures that may be used to improve selection of DBS parameters in the clinic and this was carried out by changing the DBS stimulation amplitude. A dynamic posture shift paradigm was used to assess posture control in 4 PD STN-DBS subjects. Each subject was tested at 4 stimulation amplitude settings. Movements of the center of pressure and the position of the pelvis were monitored and several quantitative indices were calculated. The presence of any statistically significant changes in several normalized indices due to reduced/no stimulation was tested using the one-sample t test. The peak velocity and the average movement velocity during the initial and mid phases of movement towards the target posture were substantially reduced. These results may be explained in terms of increased akinesia and bradykinesia due to altered stimulation conditions. Thus, the dynamic posture shift paradigm may be an effective tool to quantitatively characterize the effects of DBS on posture control and should be further investigated as a tool for selection of DBS parameters in the clinic.     

Optimal closed-loop deep brain stimulation using multiple independently controlled contacts

Deep brain stimulation (DBS) is a well-established treatment option for a variety of neurological disorders, including Parkinson’s disease and essential tremor. The symptoms of these disorders are known to be associated with pathological synchronous neural activity in the basal ganglia and thalamus. It is hypothesised that DBS acts to desynchronise this activity, leading to an overall reduction in symptoms. Electrodes with multiple independently controllable contacts are a recent development in DBS technology which have the potential to target one or more pathological regions with greater precision, reducing side effects and potentially increasing both the efficacy and efficiency of the treatment. The increased complexity of these systems, however, motivates the need to understand the effects of DBS when applied to multiple regions or neural populations within the brain. On the basis of a theoretical model, our paper addresses the question of how to best apply DBS to multiple neural populations to maximally desynchronise brain activity. Central to this are analytical expressions, which we derive, that predict how the symptom severity should change when stimulation is applied. Using these expressions, we construct a closed-loop DBS strategy describing how stimulation should be delivered to individual contacts using the phases and amplitudes of feedback signals. We simulate our method and compare it against two others found in the literature: coordinated reset and phase-locked stimulation. We also investigate the conditions for which our strategy is expected to yield the most benefit.     

Subthalamic nucleus deep brain stimulation in elderly patients – analysis of outcome and complications

Background  

There is an ongoing discussion about age limits for deep brain stimulation (DBS). Current indications for DBS are tremor-dominant disorders, Parkinson's disease, and dystonia. Electrode implantation for DBS with analgesia and sedation makes surgery more comfortable, especially for elderly patients. However, the value of DBS in terms of benefit-risk ratio in this patient population is still uncertain.     

Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor

Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor-null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.     

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.     

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。     

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson’s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 MΩ was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.     

Anatomical Targets Associated with Abrupt versus Gradual Washout of Subthalamic Deep Brain Stimulation Effects on Bradykinesia

The subthalamic nucleus (STN) is a common anatomical target for deep brain stimulation (DBS) for the treatment of Parkinson’s disease. However, the effects of stimulation may spread beyond the STN. Ongoing research aims to identify nearby anatomical structures where DBS-induced effects could be associated with therapeutic improvement or side effects. We previously found that DBS lead location determines the rate – abrupt vs. gradual – with which therapeutic effect washes out after stimulation is stopped. Those results suggested that electrical current spreads from the electrodes to two spatially distinct stimulation targets associated with different washout rates. In order to identify these targets we used computational models to predict the volumes of tissue activated during DBS in 14 Parkinson’s patients from that study. We then coregistered each patient with a stereotaxic atlas and generated a probabilistic stimulation atlas to obtain a 3-dimensional representation of regions where stimulation was associated with abrupt vs. gradual washout. We found that the therapeutic effect which washed out gradually was associated with stimulation of the zona incerta and fields of Forel, whereas abruptly-disappearing therapeutic effect was associated with stimulation of STN itself. This supports the idea that multiple DBS targets exist and that current spread from one electrode may activate more than one of them in a given patient, producing a combination of effects which vary according to electrode location and stimulation settings.     

Optimal open-loop desynchronization of neural oscillator populations

Deep brain stimulation (DBS) is an increasingly used medical treatment for various neurological disorders. While its mechanisms are not fully understood, experimental evidence suggests that through application of periodic electrical stimulation DBS may act to desynchronize pathologically synchronized populations of neurons resulting desirable changes to a larger brain circuit. However, the underlying mathematical mechanisms by which periodic stimulation can engender desynchronization in a coupled population of neurons is not well understood. In this work, a reduced phase-amplitude reduction framework is used to characterize the desynchronizing influence of periodic stimulation on a population of coupled oscillators. Subsequently, optimal control theory allows for the design of periodic, open-loop stimuli with the capacity to destabilize completely synchronized solutions while simultaneously stabilizing rotating block solutions. This framework exploits system nonlinearities in order to strategically modify unstable Floquet exponents. In the limit of weak neural coupling, it is shown that this method only requires information about the phase response curves of the individual neurons. The effects of noise and heterogeneity are also considered and numerical results are presented. This framework could ultimately be used to inform the design of more efficient deep brain stimulation waveforms for the treatment of neurological disease.

     

非药物干预治疗物质使用障碍

物质使用障碍（substance use disorder,SUD）是一个全球性的卫生和社会问题。针对大多数成瘾性物质，目前还没有有效的治疗药物，普遍还是采用心理治疗和行为矫治。近年来，针刺、深部脑刺激（DBS）、重复经颅磁刺激（rTMS）、经颅直流电刺激（tDCS）和运动等非药物干预手段在治疗神经系统疾病的有效性逐渐得到重视。越来越多的研究也开始关注非药物干预手段在治疗SUD中的应用。本综述在文献检索（如PubMed、Google Scholar等）的基础上总结了针刺、DBS、rTMS、tDCS和运动等非药物干预手段对阿片类药物、精神活性物质、尼古丁、酒精等不同成瘾性物质的心理渴求、戒断时间、使用剂量和成瘾伴随的情绪、认知功能障碍等的影响。研究表明，针刺、DBS、rTMS、tDCS和运动等非药物干预手段可以有效降低成瘾性物质引起的心理渴求、降低物质摄入量、增加戒断时间，同时改善长期使用成瘾性物质引起的认知障碍、焦虑和抑郁样行为等。如果非药物干预手段结合药物、心理等治疗方式，效果更佳。尽管非药物干预方法在现阶段主要作为辅助性治疗手段，未来的研究应注重明确非药物干预手段的神经生物学机制，...