光通过多种机制改善认知损伤

认知功能是大脑的重要能力，但在神经病理状况或疾病中受损时易出现认知损伤。目前，针对认知损伤患者的有效治疗和康复措施尚不明确。光疗作为一种无创物理疗法，受到越来越多的关注。本文旨在介绍光疗在与神经精神疾病相关认知损伤中的临床应用现状，特别是在阿尔茨海默病（Alzheimer’s disease,AD）、轻度认知功能损害（mild cognitive impairment, MCI）、脑损伤后认知障碍（post-traumatic cognitive impairment, PTCI）以及精神分裂症相关的认知损伤（cognition impairments associated with schizophrenia,CIAS）方面。光疗影响认知的机制是多方面的，包括调节昼夜节律、神经保护和修复、改善血液循环、调节神经递质、抗炎作用、神经可塑性、减少氧化应激等。此外，光疗还被认为与脑电活动、神经环路、神经营养因子以及神经递质有关。这些机制对于理解光疗如何改善认知损伤具有重要意义。最后，文章将讨论光疗在临床应用中的局限性原因，包括光照参数的标准化和个体差异的影响等。光疗在临床应用中的局限性包括...     

认知控制的一般性/特异性机制:研究逻辑和争论

认知控制是人类主动调控行为的高级认知功能,在冲突加工、工作记忆、决策等心理过程中都具有重要作用。然而,不同冲突的加工过程中是否具有相同的认知控制机制仍有很多争论。已有的认知控制理论往往认为认知控制是一般性的,但这种观点受到了近年来实证研究的挑战。研究一般性/特异性问题采用的逻辑主要包括可迁移性、平行比较、相关性以及认知资源竞争等。目前的一些研究证据分别支持了一般性、特异性以及二者兼有的观点。针对这种争论,未来的研究可以从以下视角展开,比如毕生发展变化、动态的脑网络、综合不同的研究逻辑、脑损伤的因果关系、计算神经建模、认知灵活性和功能连接等。     

氯胺酮诱导细胞自噬的研究进展

氯胺酮是一种N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂,常作为分离性麻醉剂广泛应用于临床和外科手术中,因其具有较强的致幻效应并使人产生欣快感而在众多娱乐场所中被消遣滥用。此外,氯胺酮还是一种起效迅速的抗抑郁药,对中枢神经系统兼有兴奋和抑制作用,但是长期使用氯胺酮会对中枢神经系统产生较强的神经毒性和精神依赖性。自噬是一个溶酶体依赖性降解蛋白质和细胞器以维持内环境稳态的过程。在氯胺酮诱导神经毒性的过程中,自噬具有双向调控的作用,可加重或减轻机体的神经毒性,但其具体的机制尚不清楚。该文主要从氯胺酮诱导细胞自噬的机制、氯胺酮诱导的自噬与神经毒性的关系以及药物对氯胺酮神经毒性的干预作用等方面进行综述,旨在为进一步研究氯胺酮诱导细胞自噬的机制以及自噬在氯胺酮神经毒性中的调控机制提供参考。     

婴幼儿发育期全身麻醉药暴露对认知功能的影响及机制

随着医疗技术的进步,各类先进设备、检测手段不断增加,通过手术或其他有创方式救治的疾病谱不断增加。越来越多的婴幼儿需要接受全身麻醉药(全麻药)麻醉进行临床检查或治疗,而全麻药是否对仍处在发育期的婴幼儿脑结构和功能(如认知)产生影响是一个重要、复杂而又有争议的问题,因而受到神经生物学、麻醉学和儿科学等领域学者的高度关注。人群调查结果证实,发育期短期单次全麻药暴露对认知功能的影响较弱,多次全麻药暴露则会对认知功能造成损伤。基于动物的研究进一步揭示了发育期全麻药暴露的损伤机制。全麻药暴露的时间点较麻醉时长更关键,突触形成高峰期最易受全麻药损伤;在突触形成高峰期,全麻药暴露可诱导胞内钙超载、线粒体损伤、能量代谢失衡,损伤细胞功能;启动细胞凋亡,诱导过度自噬,导致细胞丢失;抑制突触相关蛋白的表达,突触形成受损,干扰突触传递过程及可塑性,影响神经环路和脑区功能活动。因此,细胞损伤、细胞丢失和神经环路功能受损构成发育期全麻药暴露损伤认知功能的重要机制。此外,有研究应用高通量组学技术对全麻药暴露引起的差异表达基因进行了初步筛选,为深入研究全麻药损伤的基因表达及调控机制提供了新思路。本文从整体行为学、神经元网络、细胞损伤、基因表达及调控和脑功能代谢等方面对发育期全麻药暴露影响认知功能及相关机制的研究进展进行综述,希望能为临床婴幼儿全麻方案的制定提供理论依据。     

丙泊酚对认知的损伤及成瘾性研究进展

作为一种临床上常用的静脉麻醉药,丙泊酚主要用于诱导或维持全身麻醉,近年来随着临床实践及实验室研究发现,除了麻醉作用外,丙泊酚还有许多其他非麻醉效应。如在给药期间可导致认知功能的损伤,其机制可能涉及增强抑制性神经元的活性、抑制兴奋性神经元的活性、抑制某些神经递质如一氧化氮的产生等影响记忆的形成;同时该药一经临床使用,就有报道指出其可能存在潜在的成瘾性,而后续多数研究均提示其能够诱导奖赏效应的产生从而导致其成瘾及滥用。为更好的推动对丙泊酚认知功能损伤的机制及保护措施的研究、以及其成瘾机制及戒断方法的研究,本文就近年丙泊酚对认知功能损伤作用及潜在成瘾性的研究进展作一综述。     

肠神经胶质细胞与体外循环致肠损伤相关性的研究进展

近年来,体外循环术后所引起的肠道功能改变及反映肠损伤的相关炎性介质变化越来越受到人们的关注。当肠屏障发生损害时,将会导致肠道内细菌移位、大量毒素及炎性因子释放,产生系统性炎症反应,进而引起脑、肺、肝、肾等多脏器功能衰竭。肠神经胶质细胞(EGCs)作为肠神经系统的重要组成部分,具有保护肠屏障功能及调节肠神经系统活动的作用。基础研究已证实,肠神经胶质细胞可作为肠屏障功能保护的相应靶点,通过激活EGCs的α7n Ach R来减轻肠屏障损伤所致的炎性反应。本文通过对近年体外循环所致肠屏障功能损伤机制和肠神经胶质细胞特点及其相关性的研究进展作一综述,从而为临床寻求防治肠损伤措施提供理论依据。     

神经病理性痛的交感—感觉耦联作用

周围组织和神经受到损伤引起自发性疼痛、触刺激诱发痛和痛觉过敏等慢性痛症状。交感神经系统通过发展异常交感功能,或者通过影响传入神经异常活动参与上述的病理性变化,进而造成神经病理性痛。本文对目前关于交感－感觉耦联作用及其受体、细胞内和神经机制进行综述。     

慢性睡眠剥夺加重APP/PS1/tau小鼠学习记忆能力和病理损伤

睡眠在认知功能和情绪的调节过程中发挥重要作用。近年研究显示,睡眠障碍是阿尔茨海默病(Alzheimer’s disease,AD)重要的危险因素之一,但慢性睡眠剥夺对于AD模型小鼠认知功能的影响及其机制尚不明确。本研究采用改良多平台法对8月龄雄性APP/PS1/tau三转基因AD模型(3xTg-AD)小鼠和野生型(wild type, WT)小鼠(每组8只)进行连续21天、每天20 h的睡眠剥夺。睡眠剥夺结束后,采用旷场、高架十字迷宫、糖水偏好、物体识别、Y迷宫和条件恐惧记忆实验等多种行为学手段观察慢性睡眠剥夺对3xTg-AD小鼠的焦虑和抑郁样行为以及多种认知功能的影响,并通过免疫组织化学染色观察小鼠海马区β淀粉样蛋白(amyloidβprotein, Aβ)斑块沉积、神经原纤维缠结和小胶质细胞的活化程度。结果显示:(1)慢性睡眠剥夺未影响3xTg-AD小鼠的焦虑(P=0.539)和抑郁样行为(P=0.874);(2)慢性睡眠剥夺加重了3xTg-AD小鼠的识别记忆(P 0.001)、工作记忆(P=0.002)和条件恐惧记忆能力(P=0.039)损伤;(3)慢性睡眠剥夺增加了3xTg-AD小鼠海马区Aβ斑块的沉积(P 0.001)和小胶质细胞的过度活化(P 0.001),但并未导致tau蛋白异常磷酸化和神经原纤维缠结出现。以上结果表明,慢性睡眠剥夺加重了3xTg-AD小鼠的识别记忆、工作记忆和条件恐惧记忆能力损伤,且其损伤作用与3xTg-AD小鼠海马区Aβ斑块沉积增加和小胶质细胞过度活化密切相关。     

间歇性θ节律经颅磁刺激改善大鼠工作记忆的海马与前额叶跨脑区神经网络效应研究

目的 间歇性θ节律刺激（iTBS）作为一种新型的经颅磁刺激模式，已经广泛应用于探索大脑认知功能和神经调控等方面，但其电生理调控机制尚不清晰，探索iTBS对大脑认知功能的影响及其电生理机制，对脑疾病的治疗和磁刺激的临床应用具有重要意义。方法 本文利用iTBS制备磁刺激大鼠模型，采集记录大鼠在执行工作记忆（WM）任务过程中腹侧海马（vHPC）和内侧前额叶皮层（mPFC）的局部场电位（LFPs）信号，应用格兰杰因果网络分析方法，研究了iTBS对大鼠WM过程中vHPC与mPFC跨脑区神经网络协同和信息交互的影响。结果 iTBS增强了大鼠的学习记忆能力，使其完成工作记忆任务所需时长减少（2.67±1.63）d（P<0.05），iTBS显著改善了大鼠的行为学表现；同时iTBS增强了大鼠在WM期间vHPC与mPFC脑区的自因果网络连接，增加了网络连接强度、连接密度和全局效率（P<0.05）；并且iTBS增强了vHPC与mPFC脑区的跨脑区网络连接，增加了vHPC-mPFC跨脑区的节点度和因果流向（P<0.05）。结论 iTBS磁刺激对大鼠工作记忆行为学及相关脑区神经网络均有显著的积极作用，iTBS可以促进大鼠认知能力，提高大脑神经网络的信息交互和传递效率，iTBS的神经调控机制可能是通过增强大脑vHPC与mPFC之间的网络连接和信息交互来提高工作记忆能力。     

糖尿病介导的周细胞损伤对脊髓损伤后血脊屏障破坏的作用

糖尿病是一种常见的慢性代谢异常性疾病,可通过血糖异常诱导体内内环境紊乱,引起一系列急性或慢性并发症。慢性高血糖可引起大血管和微血管病变,该过程由错综复杂的分子机制协同调控,例如炎症反应、细胞内应激作用、细胞焦亡和细胞铁死亡等。糖尿病可抑制脊髓损伤后血脊屏障修复,加重神经功能损伤,从而不利于运动功能恢复。周细胞是神经血管单元的重要组成部分,参与调控血管再生、毛细血管血流量以及血脊屏障渗透性。脊髓损伤后,血脊屏障遭到破坏,周细胞覆盖率显著降低,血管正常功能受到巨大影响。糖尿病不仅参与调控周细胞的收缩表型和信号传导,而且改变周细胞分泌基因组谱,影响周细胞正常功能。此外,有研究证实,糖尿病促进脊髓损伤后周细胞丢失。本综述系统阐述了糖尿病对血管系统中周细胞的调控作用,及其介导的周细胞损伤对脊髓损伤后血脊屏障修复影响的研究进展。     

From cognitive to neural models of working memory

Working memory refers to the temporary retention of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment. These internal representations are short-lived, but can be stored for longer periods of time through active maintenance or rehearsal strategies, and can be subjected to various operations that manipulate the information in such a way that makes it useful for goal-directed behaviour. Empirical studies of working memory using neuroscientific techniques, such as neuronal recordings in monkeys or functional neuroimaging in humans, have advanced our knowledge of the underlying neural mechanisms of working memory. This rich dataset can be reconciled with behavioural findings derived from investigating the cognitive mechanisms underlying working memory. In this paper, I review the progress that has been made towards this effort by illustrating how investigations of the neural mechanisms underlying working memory can be influenced by cognitive models and, in turn, how cognitive models can be shaped and modified by neuroscientific data. One conclusion that arises from this research is that working memory can be viewed as neither a unitary nor a dedicated system. A network of brain regions, including the prefrontal cortex (PFC), is critical for the active maintenance of internal representations that are necessary for goal-directed behaviour. Thus, working memory is not localized to a single brain region but probably is an emergent property of the functional interactions between the PFC and the rest of the brain.     

认知地图的神经环路基础

空间记忆是人类认识世界和改造世界的基本认知能力,与我们的生活息息相关.无论是寻找常用的生活物件,如钥匙和手机,还是外出上班、购物和约会,都依赖我们对周围环境的记忆.截止到目前已有大量研究从不同水平探讨大脑如何表征其周围环境,但仍然有很多未解的问题.本文系统综述了基于脑成像和神经电生理技术开展的空间记忆研究进展.通过梳理以往研究中有关生物体在构建认知地图的神经结构和神经活动规律,提出了海马结构和新皮层对空间记忆的编码环路和表征机制,并在此基础上对未来研究进行了展望.     

COMT rs4680 Met is not always the ‘smart allele’: Val allele is associated with better working memory and larger hippocampal volume in healthy Chinese

Catechol‐O‐methyltransferase (COMT) Val158Met (rs4680) polymorphism plays a crucial role in regulating brain dopamine level. Converging evidence from Caucasian samples showed that, compared with rs4680 Val allele, the Met allele was linked to lower COMT activity, which in turn was linked to better cognitive performance such as working memory (WM) and to a larger hippocampus (a brain region important for WM). However, some behavioral studies have shown that the function of rs4680 appears to vary across different ethnic groups, with Chinese subjects showing an opposite pattern as that for Caucasians (i.e. the Val allele is linked to better cognitive functions related to WM in Chinese). Using a sample of healthy Han Chinese college students (ages from 19 to 21 years), this study investigated the association of COMT Val158Met genotype with behavioral data on a two‐back WM task (n = 443, 189M/254F) and T1 MRI data (n = 320, 134M/186F). Results showed that, compared to the Met allele, the Val allele was associated with larger hippocampal volume (the right hippocampus: β = ?0.118, t = ?2.367, P = 0.019, and the left hippocampus: β = ?0.099, t = ?1.949, P = 0.052) and better WM performance (β = ?0.110, t = ?2.315, P = 0.021). These results add to the growing literature on differentiated effects of COMT rs4680 polymorphism on WM across populations and offer a brain structural mechanism for such population‐specific genetic effects.     

An Event-Related fMRI Study of Phonological Verbal Working Memory in Schizophrenia

Background

While much is known about the role of prefrontal cortex (PFC) in working memory (WM) deficits of schizophrenia, the nature of the relationship between cognitive components of WM and brain activation patterns remains unclear. We aimed to elucidate the neural correlates of the maintenance component of verbal WM by examining correct and error trials with event-related fMRI.

Methodology/Findings

Twelve schizophrenia patients (SZ) and thirteen healthy control participants (CO) performed a phonological delayed-matching-to-sample-task in which a memory set of three nonsense words was presented, followed by a 6-seconds delay after which a probe nonsense word appeared. Participants decided whether the probe matched one of the targets, and rated the confidence of their decision. Blood-oxygen-level-dependent (BOLD) activity during WM maintenance was analyzed in relation to performance (correct/error) and confidence ratings. Frontal and parietal regions exhibited increased activation on correct trials for both groups. Correct and error trials were further segregated into true memory, false memory, guess, and true error trials. True memory trials were associated with increased bilateral activation of frontal and parietal regions in both groups but only CO showed deactivation in PFC. There was very little maintenance-related cortical activity during guess trials. False memory was associated with increased left frontal and parietal activation in both groups.

Conclusion

These findings suggest that a wider network of frontal and parietal regions support WM maintenance in correct trials compared with error trials in both groups. Furthermore, a more extensive and dynamic pattern of recruitment of the frontal and parietal networks for true memory was observed in healthy controls compared with schizophrenia patients. These results underscore the value of parsing the sources of memory errors in fMRI studies because of the non-linear nature of the brain-behavior relationship, and suggest that group comparisons need to be interpreted in more specific behavioral contexts.     

Diverse synchrony of firing reflects diverse cell-assembly coding in the prefrontal cortex

In the present paper, we focus on the coding by cell assemblies in the prefrontal cortex (PFC) and discuss the diversity of the coding, which results in stable and dynamic representations and the processing of various information in that higher brain region. The key activity that reflects cell-assembly coding is the synchrony of the firing of multiple neurons when animals are performing cognitive and memory tasks. First, we introduce some studies that have shown task-related synchrony of neuronal firing in the monkey PFC. These studies have reported fixed and several types of dynamic synchronous firing during working memory, long-term visual memory, and goal selection. The results of these studies have indicated that cell assemblies in the PFC can contribute to both the stability and the dynamics of various types of information. Second, we refer to rat studies and introduce the findings of cellular interactions that contribute to synchrony in working memory, learning-induced changes in synchrony in spatial tasks, and interactions of the PFC and hippocampus in dynamic synchrony. These studies have proposed neuronal mechanisms of cell-assembly coding in the PFC and its critical role in the learning of task demands in problematic situations. Based on the monkey and rat studies, we conclude that cell-assembly coding in the PFC is diverse and has various facets, which allow multipotentiality in the higher brain region. Finally, we discuss the problem of the sizes of cell assembly, how diverse the sizes are in the PFC, and the technical problems in their investigation. We introduce a unique spike-sorting method that can detect small and local cell assemblies that consist of closely neighboring neurons. Then, we describe the findings of our study that showed that the monkey PFC has both small and large cell assemblies, which have different roles in information coding in the working brain.     

The impact of anxiety-inducing distraction on cognitive performance: a combined brain imaging and personality investigation

Background

Previous investigations revealed that the impact of task-irrelevant emotional distraction on ongoing goal-oriented cognitive processing is linked to opposite patterns of activation in emotional and perceptual vs. cognitive control/executive brain regions. However, little is known about the role of individual variations in these responses. The present study investigated the effect of trait anxiety on the neural responses mediating the impact of transient anxiety-inducing task-irrelevant distraction on cognitive performance, and on the neural correlates of coping with such distraction. We investigated whether activity in the brain regions sensitive to emotional distraction would show dissociable patterns of co-variation with measures indexing individual variations in trait anxiety and cognitive performance.

Methodology/Principal Findings

Event-related fMRI data, recorded while healthy female participants performed a delayed-response working memory (WM) task with distraction, were investigated in conjunction with behavioural measures that assessed individual variations in both trait anxiety and WM performance. Consistent with increased sensitivity to emotional cues in high anxiety, specific perceptual areas (fusiform gyrus - FG) exhibited increased activity that was positively correlated with trait anxiety and negatively correlated with WM performance, whereas specific executive regions (right lateral prefrontal cortex - PFC) exhibited decreased activity that was negatively correlated with trait anxiety. The study also identified a role of the medial and left lateral PFC in coping with distraction, as opposed to reflecting a detrimental impact of emotional distraction.

Conclusions

These findings provide initial evidence concerning the neural mechanisms sensitive to individual variations in trait anxiety and WM performance, which dissociate the detrimental impact of emotion distraction and the engagement of mechanisms to cope with distracting emotions. Our study sheds light on the neural correlates of emotion-cognition interactions in normal behaviour, which has implications for understanding factors that may influence susceptibility to affective disorders, in general, and to anxiety disorders, in particular.     

Hippocampal-prefrontal connectivity predicts midfrontal oscillations and long-term memory performance

The hippocampus and prefrontal cortex interact to support working memory (WM) and long-term memory [1-3]. Neurophysiologically, WM is thought to be subserved by reverberatory activity of distributed networks within the prefrontal cortex (PFC) [2, 4-8], which become synchronized with reverberatory activity in the hippocampus [1, 4]. This electrophysiological synchronization is difficult to study in humans because noninvasive electroencephalography (EEG) cannot measure hippocampus activity. Here, using a novel integration of EEG and diffusion-weighted imaging, it is shown that individuals with relatively stronger anatomical connectivity linking the hippocampus to the right ventrolateral PFC (ventral Brodmann area 46) exhibited slower frequency neuronal oscillations during a WM task. Furthermore, subjects with stronger hippocampus-PFC connectivity were better able to encode the complex pictures used in the WM task into long-term memory. These findings are consistent with models suggesting that electrophysiological oscillations provide a mechanism of long-range interactions [9] and link hippocampus-PFC structural connectivity to PFC rhythmic electrical dynamics and memory performance. More generally, these results highlight the importance of incorporating individual differences when linking structure and function to cognition.     

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.     

Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette's Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.     

White Matter Integrity Supports BOLD Signal Variability and Cognitive Performance in the Aging Human Brain

Decline in cognitive performance in old age is linked to both suboptimal neural processing in grey matter (GM) and reduced integrity of white matter (WM), but the whole-brain structure-function-cognition associations remain poorly understood. Here we apply a novel measure of GM processing–moment-to-moment variability in the blood oxygenation level-dependent signal (SD_BOLD)—to study the associations between GM function during resting state, performance on four main cognitive domains (i.e., fluid intelligence, perceptual speed, episodic memory, vocabulary), and WM microstructural integrity in 91 healthy older adults (aged 60-80 years). We modeled the relations between whole-GM SD_BOLD with cognitive performance using multivariate partial least squares analysis. We found that greater SD_BOLD was associated with better fluid abilities and memory. Most of regions showing behaviorally relevant SD_BOLD (e.g., precuneus and insula) were localized to inter- or intra-network “hubs” that connect and integrate segregated functional domains in the brain. Our results suggest that optimal dynamic range of neural processing in hub regions may support cognitive operations that specifically rely on the most flexible neural processing and complex cross-talk between different brain networks. Finally, we demonstrated that older adults with greater WM integrity in all major WM tracts had also greater SD_BOLD and better performance on tests of memory and fluid abilities. We conclude that SD_BOLD is a promising functional neural correlate of individual differences in cognition in healthy older adults and is supported by overall WM integrity.