Neurogenic inflammation in the context of migraine

Despite considerable research into the pathogenesis of idiopathic headaches, such as migraine, the pathophysiological mechanisms underlying them remain poorly understood. Although it is well established that the trigeminal nerve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is that activation of trigeminal sensory fibers leads to a painful neurogenic inflammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimigraine agents such as ergots, triptans, opioids, and valproate inhibit preclinical neurogenic dural extravasation, suggesting that this activity may be a predictor of potential clinical efficacy of novel agents. However, several clinical trials with other agents that inhibit this process preclinically have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory process during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fibers evokes a CGRP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain, a theory that would ultimately be tested by the clinical testing of a CGRP receptor antagonist.     

Functional neuroimaging of memory: implications for cognitive aging

Our understanding of the ways in which changes in specific neural systems mediate adult age differences in memory is rapidly increasing, due in no small part to the advent of functional neuroimaging techniques. This article reviews age-related changes in memory performance obtained with behavioral measures, describes models of the neural mechanisms of memory, and derives predictions from these models regarding age-related changes in brain activation patterns. The neuroimaging findings obtained to date support models emphasizing the role of prefrontal cortex in age-related changes in memory functioning, especially for episodic memory retrieval. In general, neural activation associated with episodic memory encoding is regionally similar for younger and older adults but relatively lower in magnitude for older adults. During retrieval, activation that is restricted to the right prefrontal cortex for younger adults is more likely to be bilateral for older adults. Prefrontal activation exhibits an age-related increase when working memory tasks require simple storage and an age-related decrease when working memory requires higher-level executive processes. Although the evidence is limited, behavioral performance and activation patterns appear to be similar among younger and older adults on tests of semantic (context-independent) and implicit memory. We conclude that several methodological issues, such as defining the relation between brain structure and function, and determining the relationship between performance and activation, are particularly important for understanding age-related changes. Future directions for aging research include further investigation of the relation between encoding and retrieval and the identification of both spared and impaired neural systems.     

Functional neuroanatomy of amnesia: positron emission tomography studies

In this article, we review the principles of, and provide examples for, the new approach of functional neuropsychology in the field of amnesia. In the permanent amnesic syndrome, positron emission tomography (PET) can provide statistical maps of the brain regions with significantly impaired resting metabolism in comparison with control subjects. These regions include not only Papez's circuit but also the left supramarginal gyrus, which may explain in part the retrograde amnesia present in most cases of amnesic syndrome. This approach is also of great interest in transient global amnesia (TGA) because the defect of episodic memory is highly selective and occurs without permanent damage. The few available PET studies in TGA suggest the dysfunction of a distributed network including the hippocampal region and the prefrontal cortex, with a different pattern individually. Further studies will be necessary to better understand the relationships between the precise cognitive deficits in TGA and the pattern of brain hypometabolism. In Alzheimer's disease (AD), the study of the correlations between memory test scores and metabolic values across a sample of subjects provides a map of those brain structures whose synaptic pathology dysfunction underlies the particular neuropsychological alteration. The distribution of the sites of correlations shows striking differences according to each memory system. This approach should open the way for the unravelling of the neurobiological substrates of both cognitive impairment and compensatory mechanisms in neurodegenerative diseases. Over and above their applications in neurological research, such studies in brain-diseased subjects are particularly useful for establishing cognitive and neurobiological models of human memory, because they allow the highlighting of the neural networks that are essential for memory function. From a cognitive neuroscience perspective, the functional neuropsychology of amnesia is, therefore, complementary to the classic activation paradigm in normal subjects, which identifies the cerebral structures that are involved with, but not necessarily indispensable for, the execution of the task.     

正电子发射断层延迟显像在腹部和盆腔的应用

为明确正电子发射断层(PET)延迟显像对常规显像发现的腹部或盆腔可疑病灶的进一步诊断价值,对70例患者在注射18F-脱氧葡萄糖后约3h进行延迟显像,期间通过饮水、进食、排尿或排便等改变胃肠道及泌尿系统的生理状态。通过病理诊断或临床随访,33例诊为恶性肿瘤,37例为生理性摄取或良性病变。以延迟显像中病灶的标准摄取值降低或升高超过10%诊断良性或恶性,则灵敏度、特异性、准确性、阳性预测值和阴性预测值分别为51%(17/33)、62%(23/37)、57%(40/70)、81%(17/21)和85%(23/27)。故PET延迟显像对腹部和盆腔病变具有一定的鉴别诊断价值。但须注意子宫、卵巢生理性摄取可导致假阳性,而胃癌在进食撑开胃部后摄取可能会减低。     

Functional immunohistochemistry of neuropeptides and nitric oxide synthase in the nerve fibers of the supratentorial dura mater in an experimental migraine model

The supratentorial cerebral dura of the albino rat is equipped with a rich sensory innervation both in the connective tissue and around blood vessels, which includes nociceptive axons and their terminals; these display intense calcitonin gene-related peptide (CGRP) immunoreactivity. Stereotactic electrical stimulation of the trigeminal (Gasserian) ganglion, regarded as an experimental migraine model, caused marked increase and disintegration of club-like perivascular CGRP-immunopositive nerve endings in the dura mater and induced an apparent increase in the lengths of CGRP-immunoreactive axons. Intravenous administration of sumatriptan or eletriptan, prior to electrical stimulation, prevented disintegration of perivascular terminals and induced accumulation of CGRP in terminal and preterminal portions of peripheral sensory axons. Consequently, immunopositive terminals and varicosities increased in size; accumulation of axoplasmic organelles resulted in the "hollow" appearence of numerous varicosities. Since triptans exert their anti-migraine effect by virtue of agonist action on 5-HT(1D/B) receptors, we suggest that these drugs prevent the release of CGRP from perivascular nerve terminals in the dura mater by an action at 5-HT(1D/B) receptors. Nitroglycerine (NitroPOHL), given subcutaneously to rats, induces increased beading of nitric oxide synthase (NOS)-immunoreactive nerve fibers in the supratentorial cerebral dura mater, and an apparent increase in the number of NOS-immunoreactive nerve fibers in the dural areas supplied by the anterior and middle meningeal arteries, and the sinus sagittalis superior. Structural alterations of nitroxidergic axons innervating blood vessels of the dura mater support the idea that nitric oxide (NO) is involved in the induction of headache, a well-known side effect of coronary dilator agents.     

PET/MRI多模式分子成像技术新进展

近年来,多模式成像技术飞速发展。PET/MRI作为刚刚走入临床的多模式分子成像技术组合,成为医学分子影像领域的关注焦点,倍受期待。同机融合PET/MRI的出现依赖于PET和MRI系统各自的技术革新,以及基于MRI数据的衰减校正方法的完善。作为解剖、功能、代谢显像的综合体,PET/MRI较传统显像手段和其他成功的多模式成像技术,如PET/CT和SPECT/CT有更多、更新的应用优势,并已积累临床前和初步临床应用的经验。然而,正在走向商品化的PET/MRI仍有很多方面亟待改进和完善,需要通过不断发展、验证才能成为未来辅助临床诊断和指导治疗决策的有力工具。     

一种面向运动解码的 EEG-fNIRS 时频特征融合 与协同分类方法

脑功能成像技术可以反映人体运动时的大脑生理变化,进而解码运动状态,但单模态信号反映的大脑生理信息存在局 限性。 为此,本文提出了一种基于 EEG 和 fNIRS 信号的时频特征融合与协同分类方法,利用脑神经电活动和血氧信息的互补 特性提高运动状态解码精度。 首先,提取 EEG 的小波包能量熵特征,使用双向长短期记忆网络(Bi-LSTM)提取 fNIRS 的时域特 征,将两类特征组合得到包含时频域信息的融合特征,实现 EEG 和 fNIRS 不同层次特征的信息互补。 然后,利用 1DCNN 提取 融合特征深层次信息。 最后,采用全连接神经网络进行任务分类。 将所提方法应用于公开数据集,本文所提的 EEG-fNIRS 信号 协同分类方法准确率为 95. 31% ,较单模态分类高 7. 81% ~ 9. 60% 。 结果表明,该方法充分融合了两互补信号的时频域信息,提 高了对左右手握力运动的分类准确率。     

Activity-related, dynamic neuron-glial interactions in the hypothalamo-neurohypophysial system.

Magnocellular neurons located in the supraoptic nucleus send their principal axons to terminate in the neurohypophysis, where they release vasopressin and oxytocin into the blood circulation. This magnocellular hypothalamo-neurohypophysial system is known to undergo dramatic activity-dependent structural plasticity during chronic physiological stimulation, such as dehydration and lactation. This structural plasticity is accompanied not only by synaptic remodeling, increased direct neuronal membrane apposition, and dendritic bundling in the supraoptic nucleus, but also organization of neurovascular contacts in the neurohypophysis. The adjacent glial cells actively participate in these plastic changes in addition to magnocellular neurons themselves. Many molecules that are possibly concerned with dynamic structural remodeling are highly expressed in the hypothalamo-neurohypophysial system, although they are generally at low expression levels in other regions of adult brains. Interestingly, some of them are highly expressed only in embryonic brains. On the basis of function, these molecules are classified mainly into two categories. Cytoskeletal proteins, such as tubulin, microtubule-associated proteins, and intermediate filament proteins, are responsible for changing both glial and neuronal morphology and location. Cell adhesion molecules, belonging to immunoglobulin superfamily proteins and extracellular matrix glycoproteins, also participate in neuronal-glial, neuronal-neuronal, and glial-glial recognition and guidance. Thus, the hypothalamo-neurohypophysial system is an interesting model for elucidating physiological significance and molecular mechanisms of activity-dependent structural plasticity in adult brains.     

Determining the neuronal connectivity of Golgi-impregnated neurons: ultrastructural assessment of functional aspects.

The combined light and electron microscopic analysis of Golgi-impregnated neural tissue is a potent tool for determining the connectivity of neural networks within the brain. In the experimental paradigms commonly applied in these studies, the Golgi-impregnated neurons are typically examined as the postsynaptic neuronal components. The structural characteristics and the pattern of distribution of their synaptic connections with other groups of identified neurons are analyzed. Due to the high power of resolution of the Golgi-electron microscopic technique, the ultrastructural analysis of Golgi-impregnated neurons can be expanded to elucidate activity-dependent structural alterations in their cytoarchitecture. These structural alterations can then be correlated under different physiological conditions with changes in the functional efficacy of the subcellular neuronal components.     

ProbingNeuronalCommunicationViaNovelMassSpectralStrategies

Neuropeptides make up the largest and the most complex signaling molecules used in intercellular communication. Because of critical roles that these polypeptides play in the regulation of many physiological processes, it is of great interest to characterize these diverse assortments of chemical messengers and determine their functions in the neural circuitry. The simpler and well-characterized crustacean nervous system provides an excellent model system to facilitate analytical method development and to investigate how a rich repertoire of neuropeptides can fine tune a well-defined neural circuit that produces multiple outputs at the cellular and network levels. Using a highly sensitive mass spectrometry-based peptide profiling and de novo sequencing strategy, a large number of novel peptides have been discovered, revealing that even a relatively simple neural network contains an unexpectedly-rich diversity of neuropeptides^[1]. Furthermore, both mass spectrometric imaging techniques^[2] and in vivo microdialysis sampling tools^[3] have been implemented to follow neuropeptide distribution and secretion in unprecedented details. Towards the goal of functional discovery of bioactive neuropeptides, novel quantitative schemes based on isotopic formaldehyde labeling and multiplexed isobaric labeling based on N,N-dimethylated leucine^[4] have been developed to produce differential display of neuropeptidomes under different physiological conditions^[5]. Examples of neuropeptide regulation of feeding behavior and environmental stress will be described in this presentation. Collectively, these combined peptidomic and physiological studies will help to elucidate the functional roles that neuropeptides play in regulating neural network plasticity.     

高精度光声成像技术在脑成像中应用

光声成像技术可以提供深层组织的高分辨率和高对比度的组织断层图像,是进行脑成像的有力潜在工具之一。本文开展此项研究,搭建一套光声成像实验系统,在此基础上,获得10mm的混浊介质深度下的血管模拟样品图像,直径0.07mm的模拟血管能清晰地成像;活体研究中,成功进行活体白鼠脑部的血管分布的成像研究,重建图像中的各血管位置和形状与实际情况很好的吻合。     

Positron emission tomography—a new technique for studies of the central nervous system

Positron emission tomography (PET) has become an important tool to study the central nervous system. Examples of such studies are cerebral blood flow and metabolism and determination of receptor characteristics of the brain. In the following the basic principles and the physics behind PET are given. Different aspects are discussed such as detector design, image reconstructions and data analyses. Since quantification is essential in PET, data have to be corrected for absorption, scatter and random coincidences. These corrections and their influence on image data are discussed. A review of state-of-the-art PET research of the brain is given.     

Microglia-precursor cell interactions in health and in pathology

Until recently, microglia were mainly known as the resident phagocytes of the brain, i.e. the ‘immunological warriors’ of the brain. However, extensive knowledge is being accumulated about the functions of microglia beyond immunity. Nowadays, it is well accepted that microglial cells are highly dynamic and responsive, and that they intervene in a dual manner in many developmental processes that shape the central nervous system, including neurogenesis, gliogenesis, spatial patterning, synaptic formation and elimination, and neural circuit establishment and maturation. The differentiation and the pool of precursor cells were also shown to be under microglia regulation via bidirectional communication. In this concise review, I discuss our recent work in microglia-Pax6⁺ cell interactions in one of the circumventricular organs, the pineal gland. An analogy with the rest of the central nervous system is also presented. In addition, I briefly examine mechanisms of interaction between microglia and non-microglial cells in both health and disease. New avenues are also introduced, which may lead us to better comprehend the impact of microglia in physiological and pathological conditions.     

Development of the choroid plexus

Mammalian choroid plexuses develop at four sites in the roof of the neural tube shortly after its closure, in the order IVth, lateral, and IIIrd ventricles. Bone morphogenetic proteins and tropomyosin are involved in early specification of these sites and in early plexus growth. Four stages of lateral ventricular plexus development have been defined, based on human and sheep fetuses; these depend mainly on the appearance of epithelial cells and presence or absence of glycogen. Other plexuses and other species are probably similar, although marsupials may lack glycogen. Choroid plexuses form one of the blood-brain barrier interfaces that control the brain's internal environment. The mechanisms involved combine a structural diffusion restraint (tight junctions between the plexus epithelial cells) and specific exchange mechanisms. In this review, it is argued that barrier mechanisms in the developing brain are different in important respects from those in the adult brain, but these differences do not necessarily reflect immaturity of the system. Absence of a barrier mechanism or presence of one not found in the adult may be a specialisation that is appropriate for that stage of brain development. Emphasis is placed on determining which mechanisms are present in the immature brain and relating them to brain development. One mechanism unique to the developing brain transfers specific proteins from blood to cerebrospinal fluid (CSF), via tubulocisternal endoplasmic reticulum in plexus epithelial cells. This results in a high concentration of proteins in early CSF. These proteins do not penetrate into brain extracellular space because of "strap" junctions between adjacent neuroependymal cells, which disappear later in development, when the protein concentration in CSF is much lower. Functions of the proteins in early CSF are discussed in terms of generation of a "colloid" osmotic pressure that expands the ventricular system as the brain grows; the proteins may also act as specific carriers and growth factors in their own right. The pathway for low molecular weight compounds, which is much more permeable in the developing choroid plexuses, appears also to be a transcellular one, rather than paracellular via tight junctions. There is thus good evidence to support a novel view of the state of development and functional significance of barrier mechanisms in the immature brain. It grows in an environment that is different from that of the rest of the fetus/neonate and that is also different in some respects from that of the adult. But these differences reflect developmental specialisation rather than immaturity.     

Event-related potential (ERP) studies of memory encoding and retrieval: a selective review

As event-related brain potential (ERP) researchers have increased the number of recording sites, they have gained further insights into the electrical activity in the neural networks underlying explicit memory. A review of the results of such ERP mapping studies suggests that there is good correspondence between ERP results and those from brain imaging studies that map hemodynamic changes. This concordance is important because the combination of the high temporal resolution of ERPs with the high spatial resolution of hemodynamic imaging methods will provide a greatly increased understanding of the spatio-temporal dynamics of the brain networks that encode and retrieve explicit memories.     

Physiology of meningeal innervation: aspects and consequences of chemosensitivity of meningeal nociceptors

Up to now, the cause of most types of headaches is unknown. Why headache starts or why it fades away during hours or a few days is still a mystery. This phenomenon makes headache unique compared to other pain states. For long it has been known that during headache sensory structures in the meninges are activated. But it was not until the last two decades that scientists investigated the physiology of the sensory innervation of the meninges. Animal models and in vitro preparations have been developed to get access to the meninges and to determine the response properties of meningeal afferents. Although animals hardly can tell their pain, blood pressure measurements and observations of behaviour in two models of headache suggest that such animal models are valid and may add remarkable information to our understanding of human headache. Since chemicals and endogenous inflammatory mediators may alter sensory thresholds and responsiveness of neurons, they are putative key molecules in triggering pathophysiological sensory processing. This review briefly summarizes what is known about the chemosensitivity of meningeal innervation.     

Ultrastructural localization of prion proteins: physiological and pathological implications

The transmissible spongiform encephalopathies (TSE) or prion diseases are fatal neurodegenerative disorders in which the central event is the conversion of a normal host-encoded protein (PrP(c)) into an abnormal isoform (PrP(sc)) which accumulates as amyloid in TSE brain. The two PrP(c) and PrP(sc) prion protein isoforms are membrane sialoglycoproteins synthesized in the central nervous system and various peripheral organ tissues. In this review, we describe the ultrastructural localization of prion proteins in human and animal cerebral and non-cerebral tissues whether or not infected by TSE agents. In addition to the plasma membrane of several cells, PrP(c) was found in association with cytoplasmic organelles of central and nerve-muscle synapses, and secretory granules of epithelial cells. Fibrils of amyloid plaques, synaptic structures, and lysosome-like organelles constitute the subcellular sites harboring PrP(sc). These findings have led to discussions on the physiological role of PrP(c) and the pathological mechanisms underlying prion spongiform encephalopathies.