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.     

Using Virtual Reality to Study Alcohol Intoxication Effects on the Neural Correlates of Simulated Driving

The use of virtual reality in the form of simulated tasks can provide a realistic environment in which to study complex naturalistic behaviors. Many of the behavioral effects of alcohol intoxication are well known, but there is relatively little imaging evidence examining how alcohol exposure might transiently modulate brain function, especially in the context of task performance. In this review, we provide a brief synopsis of previous work using functional magnetic resonance imaging (fMRI) to study the neural correlates of alcohol intoxication. We describe in detail two studies from our published work, the first involving a visual perception paradigm, and the second involving virtual reality through a naturalistic behavior; simulated driving. Participants received single-blind individualized doses of beverage alcohol designed to produce blood alcohol content (BAC) of 0.04 and 0.08 or placebo. Subjects were fMRI scanned after training to asymptote performance. In both studies we found specific circuits that were differentially modulated by alcohol, we revealed both global and local effects of alcohol, and we examined relationships between behavior, brain function, and alcohol blood levels.     

fMRI Validation of fNIRS Measurements During a Naturalistic Task

We present a method to compare brain activity recorded with near-infrared spectroscopy (fNIRS) in a dance video game task to that recorded in a reduced version of the task using fMRI (functional magnetic resonance imaging). Recently, it has been shown that fNIRS can accurately record functional brain activities equivalent to those concurrently recorded with functional magnetic resonance imaging for classic psychophysical tasks and simple finger tapping paradigms. However, an often quoted benefit of fNIRS is that the technique allows for studying neural mechanisms of complex, naturalistic behaviors that are not possible using the constrained environment of fMRI. Our goal was to extend the findings of previous studies that have shown high correlation between concurrently recorded fNIRS and fMRI signals to compare neural recordings obtained in fMRI procedures to those separately obtained in naturalistic fNIRS experiments. Specifically, we developed a modified version of the dance video game Dance Dance Revolution (DDR) to be compatible with both fMRI and fNIRS imaging procedures. In this methodology we explain the modifications to the software and hardware for compatibility with each technique as well as the scanning and calibration procedures used to obtain representative results. The results of the study show a task-related increase in oxyhemoglobin in both modalities and demonstrate that it is possible to replicate the findings of fMRI using fNIRS in a naturalistic task. This technique represents a methodology to compare fMRI imaging paradigms which utilize a reduced-world environment to fNIRS in closer approximation to naturalistic, full-body activities and behaviors. Further development of this technique may apply to neurodegenerative diseases, such as Parkinson’s disease, late states of dementia, or those with magnetic susceptibility which are contraindicated for fMRI scanning.     

Non-Scanning Fiber-Optic Near-Infrared Beam Led to Two-Photon Optogenetic Stimulation In-Vivo

Stimulation of specific neurons expressing opsins in a targeted region to manipulate brain function has proved to be a powerful tool in neuroscience. However, the use of visible light for optogenetic stimulation is invasive due to low penetration depth and tissue damage owing to larger absorption and scattering. Here, we report, for the first time, in-depth non-scanning fiber-optic two-photon optogenetic stimulation (FO-TPOS) of neurons in-vivo in transgenic mouse models. In order to optimize the deep-brain stimulation strategy, we characterized two-photon activation efficacy at different near-infrared laser parameters. The significantly-enhanced in-depth stimulation efficiency of FO-TPOS as compared to conventional single-photon beam was demonstrated both by experiments and Monte Carlo simulation. The non-scanning FO-TPOS technology will lead to better understanding of the in-vivo neural circuitry because this technology permits more precise and less invasive anatomical delivery of stimulation.     

Neural and social correlates of attitudinal brokerage: using the complete social networks of two entire villages

To avoid polarization and maintain small-worldness in society, people who act as attitudinal brokers are critical. These people maintain social ties with people who have dissimilar and even incompatible attitudes. Based on resting-state functional magnetic resonance imaging (n = 139) and the complete social networks from two Korean villages (n = 1508), we investigated the individual-level neural capacity and social-level structural opportunity for attitudinal brokerage regarding gender role attitudes. First, using a connectome-based predictive model, we successfully identified the brain functional connectivity that predicts attitudinal diversity of respondents'' social network members. Brain regions that contributed most to the prediction included mentalizing regions known to be recruited in reading and understanding others’ belief states. This result was corroborated by leave-one-out cross-validation, fivefold cross-validation and external validation where the brain connectivity identified in one village was used to predict the attitudinal diversity in another independent village. Second, the association between functional connectivity and attitudinal diversity of social network members was contingent on a specific position in a social network, namely, the structural brokerage position where people have ties with two people who are not otherwise connected.     

功能磁共振和脑电神经成像技术与大脑刺激相结合的研究进展

随着对神经机制问题阐述水平的迅速提高,所应用的神经成像技术、方法及各种工具的复杂程度也在不断提高．一方面是神经成像技术本身的不断发展,另一方面则是大脑直接刺激与神经成像技术同步记录方法的发展．经颅磁刺激-功能磁共振成像同步技术(TMS-fMRI)和经颅磁刺激-脑电技术(TMS-EEG)能为研究大脑网络的功能和有效连通性提供技术手段,该技术在多种认知领域的发展和应用,为神经科学、认知心理学、神经信息学等学科的研究者对人脑的研究开启了多条通道,更加有利于深入地理解人类大脑的工作机制．     

上转换纳米颗粒介导的无线光遗传学技术的研究进展

光遗传学技术是结合基因工程和光学技术对生物体特定细胞进行精确调控的新兴生物技术,该技术可以特异性地兴奋或抑制靶神经元,成为解析介导特定行为神经环路的强有力的工具.传统技术依赖光纤,对脑组织有损伤且限制了动物的自由活动.新一代上转换纳米颗粒介导的无线光遗传学技术,借助近红外光组织穿透相对深的特性,能够对啮齿类动物脑组织深层核团进行无线调控,克服了传统技术中埋置光纤存在的缺陷.本文总结了上转换纳米颗粒介导的无线光遗传学技术的发展历程及现状,比较分析了这类无线光遗传学技术的优缺点,最后对该技术面临的挑战及未来前景进行了分析和展望.     

Precise spatiotemporal control of optogenetic activation using an acousto-optic device

Light activation and inactivation of neurons by optogenetic techniques has emerged as an important tool for studying neural circuit function. To achieve a high resolution, new methods are being developed to selectively manipulate the activity of individual neurons. Here, we report that the combination of an acousto-optic device (AOD) and single-photon laser was used to achieve rapid and precise spatiotemporal control of light stimulation at multiple points in a neural circuit with millisecond time resolution. The performance of this system in activating ChIEF expressed on HEK 293 cells as well as cultured neurons was first evaluated, and the laser stimulation patterns were optimized. Next, the spatiotemporally selective manipulation of multiple neurons was achieved in a precise manner. Finally, we demonstrated the versatility of this high-resolution method in dissecting neural circuits both in the mouse cortical slice and the Drosophila brain in vivo. Taken together, our results show that the combination of AOD-assisted laser stimulation and optogenetic tools provides a flexible solution for manipulating neuronal activity at high efficiency and with high temporal precision.     

基于fMRI的脑功能整合数据分析方法综述

脑功能成像在人脑信息处理和认知活动的神经关联中发挥了不可轻视的作用.从大脑功能整合出发,可以将脑功能成像数据分析方法分为探测大脑功能整合的功能连接和有效连接两方面,功能连接探究空间远离的两个脑区之间的连接,有效连接研究一个脑区对另一个脑区作用的大小.根据这两个概念,相应地可以将功能磁共振数据分析方法分为两大类.本文着重...     

人脑对不同频率穴位电刺激反应的功能性磁共振成像

利用功能性磁共振方法研究人脑对不同频率穴位体表电刺激（transcutaneous electric nerve stimulation,TENS)的反应。实验对11名志愿得进行了22次脑部功能性磁共振成像。成像过程中,每名志愿者分别接受了2和100HzTENS刺激,刺激部位为左腿足三里和三阴交穴,结果为不同频率TENS都激活了初级和次级躯体感觉区,频率特异性的激活信号出现在与运动相关的区域、丘脑、边缘系统和联络皮层。结果显示,在相同穴位给予不同频率的TENS要以在大脑引起不同的反应,提示2和100HzTENS可能激活了不同的神经通路,这些神经通路分别在中枢神经系统起着不同的作用。     

功能性脑成像的多维模式分析方法

利用非侵入式的功能性脑成像记录大脑活动极大地提升了我们对人类认知功能的理解.与此同时,分析成像数据的手段也逐渐从传统的一元方式向更加有效的多元分析转变.在本综述中,特别针对在认知神经科学领域占主导地位的功能性磁共振成像技术,介绍其多元数据分析方法的发展以及这种分析方法的生理学基础和未来发展方向.     

研究报告: 大鼠感觉运动系统静息态脑网络研究

为了理解啮齿类动物的脑功能连接,本文利用9.4T fMRI获得轻度麻醉状态下大鼠静息状态及刺激激活的数据,通过互相关分析构建节点之间的相关系数矩阵并计算相应的网络参数．结果发现：给予前爪电刺激时,刺激对侧初级感觉皮层(S1)、丘脑(Tha)有较强的正激活,双侧尾状壳核(CPu)有较强的负激活．静息状态时大鼠感觉/运动皮层内部、丘脑内部的连接性较强,而感觉/运动皮层与丘脑之间的连接较弱,双侧感觉运动系统之间存在较强的同步低频振荡,感觉运动系统在静息态时的脑网络具有小世界属性．结果提示,啮齿类动物在大脑信息处理中的功能分离和整合可能与人类存在某些相似性,支持哺乳动物中枢神经系统的基本功能存在遗传保守性的观点．     

Functional MRI detection of activation in the primary gustatory cortices in humans

Magnetoencephalography (MEG) has recently revealed that the transitions between the parietal operculum (Pop) and the insula (area G) and the ventral end of the central sulcus (cs) were activated with the shortest latency by instrumental gustatory stimulation, which suggests that the location of the primary gustatory area is in these two regions. However, studies using other noninvasive brain-imaging methods such as positron-emission tomography or functional magnetic resonance imaging (fMRI) with manual application of tastants into the mouth have been unable to confirm this. The present study examined cortical activation by repetitive stimulation of the tongue tip with 1 M NaCl with a computer-controlled stimulator and used fMRI to detect it. In individual brains, activations were detected with multiple comparisons (false discovery rate) across the whole brain corrected (threshold at P < 0.05) at both area G and frontal operculum (Fop) in 8 of 11 subjects and at the rolandic operculum (Rop) in 7 subjects. Activations were also found at the ventral end of the cs (n = 3). Group analysis with random-effect models (multiple comparison using familywise error in regions of interest, P < 0.02) revealed activation at area G in both hemispheres and in the Fop, Rop, and ventral end of the cs on the left side. The present study revealed no activation on the gyrus of the external cerebral surface except for the Rop. Taking MEG findings into consideration, the present findings strongly indicate that the primary gustatory area is present at both the transition between the Pop and insula and the Rop including the gray matter within a ventral part of the cs.     

脑科学和脑功能MR成像

目的：在对大脑认知功能进行脑功能成像研究之中,随着磁共振成像技术的发展,人们现在可以对脑的认知功能,如视觉、运动、语言和记忆等功能中枢进行成像。本文首先介绍了脑科学的发展历程,并从脑功能MR成像的方法出发,分析了其成像机理,探讨了用脑功能MR成像为手段对脑科学—认知科学进行的方法研究,最后对脑功能MR成像应用于脑科学的研究作了展望。     

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.     

Optogenetic investigation of neural circuits in vivo

The recent development of light-activated optogenetic probes allows for the identification and manipulation of specific neural populations and their connections in awake animals with unprecedented spatial and temporal precision. This review describes the use of optogenetic tools to investigate neurons and neural circuits in vivo. We describe the current panel of optogenetic probes, methods of targeting these probes to specific cell types in the nervous system, and strategies of photostimulating cells in awake, behaving animals. Finally, we survey the application of optogenetic tools to studying functional neuroanatomy, behavior and the etiology and treatment of various neurological disorders.     

Insights into new techniques for high resolution functional MRI

Non-invasive functional magnetic resonance imaging (fMRI) has opened a unique window into human and animal brain function, with a spatial resolution of a few millimeters and a temporal resolution of a few seconds. To further improve the current technical limitations of fMRI, various post-processing and data acquisition schemes were developed. Improved fMRI methods include variations of a conventional fMRI technique, mapping a single physiological parameter such as cerebral blood flow or cerebral blood volume, and direct mapping of neural activity. Advances in fMRI techniques allow scientists to map submillimeter columnar and laminar functional structures and to detect tens of millisecond neural activity in certain specific tasks.     

Regional variation in neurovascular coupling and why we still lack a Rosetta Stone

Functional magnetic resonance imaging (fMRI) is the dominant tool in cognitive neuroscience although its relation to underlying neural activity, particularly in the human brain, remains largely unknown. A major research goal, therefore, has been to uncover a ‘Rosetta Stone’ providing direct translation between the blood oxygen level-dependent (BOLD) signal, the local field potential and single-neuron activity. Here, I evaluate the proposal that BOLD signal changes equate to changes in gamma-band activity, which in turn may partially relate to the spiking activity of neurons. While there is some support for this idea in sensory cortices, findings in deeper brain structures like the hippocampus instead suggest both regional and frequency-wise differences. Relatedly, I consider four important factors in linking fMRI to neural activity: interpretation of correlations between these signals, regional variability in local vasculature, distributed neural coding schemes and varying fMRI signal quality. Novel analytic fMRI techniques, such as multivariate pattern analysis (MVPA), employ the distributed patterns of voxels across a brain region to make inferences about information content rather than whether a small number of voxels go up or down relative to baseline in response to a stimulus. Although unlikely to provide a Rosetta Stone, MVPA, therefore, may represent one possible means forward for better linking BOLD signal changes to the information coded by underlying neural activity.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.     

Inside the Syntactic Box: The Neural Correlates of the Functional and Positional Level in Covert Sentence Production

The aim of the present fMRI study was to investigate the neural circuits of two stages of grammatical encoding in sentence production. Participants covertly produced sentences on the basis of three words (one verb and two nouns). In the functional level condition both nouns were animate and so were potential competitors for the grammatical function of subject. In the positional level condition the first noun was animate whereas the second was inanimate. We found activation of Broca''s and adjacent areas, previously indicated as responsible for syntactic processing. Additionally, a later onset of the activation in three brain areas in the functional level condition suggests that there is indeed a competition for assignment of subjecthood. The results constrain theories of grammatical encoding, which differ in whether they assume two separate processing levels or only one.