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PubMed1992

Stimulus configuration, classical conditioning, and hippocampal function.

Hippocampal participation in classical conditioning is described in terms of a multilayer network that portrays stimulus configuration. The network (a) describes behavior in real time, (b) incorporates a layer of "hidden" units positioned between input and output units, (c) includes inputs that are connected to the output directly as well as indirectly through the hidden-unit layer, and (d) uses a biologically plausible backpropagation procedure to train the hidden-unit layer. Nodes and connections in the neural network are mapped onto regional cerebellar, cortical, and hippocampal circuits, and the effect of lesions of different brain regions is formally studied. Computer simulations of the following classical conditioning paradigms are presented: acquisition of delay and trace conditioning, extinction, acquisition-extinction series of delay conditioning, blocking, over-shadowing, discrimination acquisition, discrimination reversal, feature-positive discrimination, conditioned inhibition, negative patterning, positive patterning, and generalization. The model correctly describes the effect of hippocampal and cortical lesions in many of these paradigms, as well as neural activity in hippocampus and medial septum during classical conditioning. Some of these results might be extended to the description of anterograde amnesia in human patients.

Animals↗
PubMed2004

Role of serotonin in the pathophysiology of the irritable bowel syndrome.

The irritable bowel syndrome (IBS) is a complex disorder that is associated with altered gastrointestinal motility, secretion, and sensation. Serotonin (5-HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal tract. 5-HT release from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. The enteric nervous system (ENS) comprises a semiautonomous effector system that is connected to the central autonomic network. Parasympathetic and sympathetic nerves modulate the ENS via afferent and efferent communications. Ongoing, bidirectional brain-gut interactions involving 5-HT pathways occur that significantly influence the effector systems. Altered 5-HT signalling may lead to both intestinal and extraintestinal symptoms in IBS. 5-HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. 5-HT modulates sensation and perception of visceral stimulation at peripheral and central sites. Therapeutic agents targeting altered 5-HT signalling may provide new, effective treatments for patients with IBS.

Animals↗
PubMed2003

Executive functions and their disorders.

The term executive function defines complex cognitive processing requiring the co-ordination of several subprocesses to achieve a particular goal. Neuropsychological evidence suggests that executive processing is intimately connected with the intact function of the frontal cortices. Executive dysfunction has been associated with a range of disorders, and is generally attributed to structural or functional frontal pathology. Neuroimaging, with PET and fMRI, has confirmed the relationship; however, attempts to link specific aspects of executive functioning to discrete prefrontal foci have been inconclusive. Instead, the emerging view suggests that executive function is mediated by dynamic and flexible networks, that can be characterised using functional integration and effective connectivity analyses. This view is compatible with the clinical presentation of executive dysfunction associated with a range of pathologies, and also with evidence that recovery of executive function can occur after traumatic brain injury, perhaps due to functional reorganisation within executive networks.

Brain Injuries↗
PubMed1997

Modifiable neuronal connections: an overview for psychiatrists.

Synaptic plasticity is currently the target of much neurobiological research, because it is thought to play an important role in brain function (particularly memory formation). However, it has attracted little attention from psychiatrists to date despite accumulating evidence that links it to various clinical syndromes, including amnesia and possibly psychosis. The purpose of this article is to present an overview of the two major arms of synaptic plasticity research-theoretical (the field of neural network modeling) and neurobiological (long-term potentiation). Artificial neural networks are a class of theoretical model that has been developed with the aim of understanding how information could, in principle, be represented by large numbers of interconnected and relatively simple units. Over the past few decades, several theoretical accounts of information-processing mechanisms have been developed, and these are briefly reviewed. The principle common to representation formation in nearly all neural networks is that of "associability"-the idea that streams of information are combined by forming, strengthening, or pruning connections between them to form new representations that can later be retrieved. Associability also lies at the heart of psychological theories of information storage in the brain. Research into associability has directed the attention of many experimenters toward the possible biological correlates of such mechanisms. Of particular interest is the recent discovery that some neurons appear to possess connections of modifiable strength. The implications of this finding for psychiatry are discussed in relation to representational disorders such as delusions and amnesia.

Amnesia↗
PubMed1997

The evolutionary origin of the language areas in the human brain. A neuroanatomical perspective.

The capacity to learn syntactic rules is a hallmark of the human species, but whether this has been acquired by the process of natural selection has been the subject of controversy. Furthermore, the cortical localization of linguistic capacities has prompted some authors to suggest a modular representation of language in the brain. In this paper, we rather propose that the neural device involved in language is embedded into a large-scale neurocognitive network comprising widespread connections between the temporal, parietal and frontal (especially prefrontal) cortices. This network is involved in the temporal organization of behavior and motor sequences, and in working (active) memory, a sort of short-term memory that participates in immediate cognitive processing. In human evolution, a precondition for language was the establishment of strong cortico-cortical interactions in the postrolandic cortex that enabled the development of multimodal associations. Wernicke's area originated as a converging place in which such associations (concepts) acquired a phonological correlate. We postulate that these phonological representations projected into inferoparietal areas, which were connected to the incipient Broca's area, thus forming a working memory circuit for processing and learning complex vocalizations. As a result of selective pressure for learning capacity and memory storage, this device yielded a sophisticated system able to generate complicated utterances (precursors of syntax) as it became increasingly connected with other brain regions, especially in the prefrontal cortex. This view argues for a gradual origin of the neural substrate for language as required by natural selection.

Animals↗
PubMed2001

Ocular motor system: anatomy and functional magnetic resonance imaging.

This article reviews current positron emission tomography and functional MR imaging (fMRI) studies of brain activation and indicates some of the insights they provide into the neuronal network mediating motion-perception and ocular motor control. The complexity of the network and the activation of the entire system seemingly independent of the specific ocular motor task performed makes functional interpretation extremely difficult. At the same time, however, the complexity illustrates the dilemma of associating a particular locus with one specific function. Caution is required to differentiate specific from nonspecific effects, to identify activations and deactivations, and to distinguish which of the systems has been activated inadvertently through poor stimulus control. The next step required for meaningful correlations of structure with function is for fMRI studies to test neurologic patients with distinct and separate lesions of the network. Such a comparison must evaluate the effect of the ocular motor deficit on the lesion site and the connected network in the acute stage and then following functional recovery caused by plasticity and neuronal repair.

Brain↗
PubMed1990

Lead poisoning and brain cell function.

Exposure to excessive amounts of inorganic lead during the toddler years may produce lasting adverse effects upon brain function. Maximal ingestion of lead occurs at an age when major changes are occurring in the density of brain synaptic connections. The developmental reorganization of synapses is, in part, mediated by protein kinases, and these enzymes are particularly sensitive to stimulation by lead. By inappropriately activating specific protein kinases, lead poisoning may disrupt the development of neural networks without producing overt pathological alterations. The blood-brain barrier is another potential vulnerable site for the neurotoxic action of lead. Protein kinases appear to regulate the development of brain capillaries and the expression of the blood-brain barrier properties. Stimulation of protein kinase by lead may disrupt barrier development and alter the precise regulation of the neuronal environment that is required for normal brain function. Together, these findings suggest that the sensitivity of protein kinases to lead may in part underlie the brain dysfunction observed in children poisoned by this toxicant.

Blood-Brain Barrier↗
PubMed2003

Sleep networks and the anatomic and physiologic connections with respiratory control.

A central neuronal network regulates airway functions from the nares to the bronchioles and is an integral component of a regulatory system for brain control of breathing and airway patency during wakefulness and sleep. This network, components of which include sleep generating sites and monoaminergic neurons in particular, is characterized by reciprocal interconnections, parallel organization, and state-dependent activity patterns, which can be influenced by both genes and environment. Sleep generating neurons are interconnected with the monoaminergic containing cells to the extent that sleep-related changes in upper and lower airway patency could be due to inhibitory influences of sleep-activated neurons on serotonergic and noradrenergic producing cells. Neurochemical studies and physiologic experiments show that serotonergic and noradrenergic producing cells can make parallel pathways, directly innervating the hypoglossal motor cells regulating upper airway dilating muscles, and vagal preganglionic neurons providing cholinergic outflow to the airways. Activation of serotonergic and noradrenergic cell groups preferentially increases activity of the genioglossus muscle, but diminishes cholinergic outflow to the airways. Hence, inhibition of monoaminergic neurons during sleep may lead to a decrease in upper airway dilating forces and an elevation of cholinergic outflow to the airways. Qualitatively different responses of hypoglossal and airway-related vagal preganglionic neurons (AVPNs) occur in response to endogenously released serotonin or norepinephrine and could be related to its simultaneous action on different serotonin or norepinephrine receptor subtypes. Dysfunction of monaminergic cell groups during sleep may predispose to upper airway occlusion as well as bronchoconstriction. Pharmacological corrections of alterations of these transmitter specific converging systems might be an avenue for treatment of sleep related airway disorders such as sleep apnea and worsening of asthma.

Animals↗
PubMed2003

Combined functional MRI and tractography to demonstrate the connectivity of the human primary motor cortex in vivo.

In this study, we combined advanced MR techniques to explore primary motor cortex (M1) connectivity in the human brain. We matched functional and anatomical information using motor functional MRI (fMRI) and white matter tractography inferred from diffusion tensor imaging (DTI). We performed coregistered DTI and motor task fMRI in 8 right-handed healthy subjects and in 1 right-handed patient presenting with a left precentral tumour. We used the fast-marching tractography (FMT) algorithm to define 3D connectivity maps within the whole brain, from seed points selected in the white matter adjacent to the location of the maximum of fMRI activation. Connectivity maps were then anatomically normalised and analysed using statistical parametric mapping software (SPM99) allowing group comparisons (left versus right hemisphere in control subjects and patient versus control subjects). The results demonstrated, in all control subjects, strong connections from M1 to the pyramidal tracts, premotor areas, parietal cortices, thalamus, and cerebellum. M1 connectivity was asymmetric, being more extensive in the dominant hemisphere. The patient had differences in M1 connectivity from the control group. Thus, fMRI-correlated DTI-FMT is a promising tool to study the structural basis of functional networks in the human brain in vivo.

Adult↗
PubMed2004

Effects of brain-derived neurotrophic factor on cell survival, differentiation and patterning of neuronal connections and Müller glia cells in the developing retina.

The aim of the present study was to determine the influence of brain-derived neurotrophic factor (BDNF) on survival, phenotype differentiation and network formation of retinal neurons and glia cells. To achieve a defined concentration and constant level of BDNF over several days, experiments were performed in an organotypic culture of the developing rat retina. After 6 days in vitro, apoptosis in the different cell layers was determined by TUNEL staining and cell-type-specific antibodies were used to identify distinct neuronal cell types and Müller cells. Cultured retinas treated with BDNF (100 ng BDNF/mL medium) were compared with untreated as well as with age-matched in vivo retinas. Quantitative morphometry was carried out using confocal microscopy. BDNF promoted the in vitro development and differentiation of the retina in general, i.e. the number of cells in the nuclear layers and the thickness of the plexiform layers were increased. For all neurons, the number of cells and the complexity of arborizations in the synaptic layers were clearly up-regulated by BDNF. In control cultures, the synaptic stratification of cone bipolar cells within the On- and Off-layer of the inner plexiform layer was disturbed and a strong reactivity of Müller cell glia was observed. These effects were not present in BDNF-treated cultures. Our data show that BDNF promotes the survival of retinal interneurons and plays an important role in establishing the phenotypes and the synaptic connections of a large number of neuronal types in the developing retina. Moreover, we show an effect of BDNF on Müller glia cells.

Age Factors↗
PubMed2002

Visualizing selective neural pathways with WGA transgene: combination of neuroanatomy with gene technology.

Functional logic employed by the nervous system for information processing resides mainly in the wiring patterns among specific types of neurons. Therefore, detailed knowledge on neuronal networks is essential for understanding a wide range of brain functions. A powerful and long-awaited method for analyzing the neuronal connectivity patterns would be to deliver tracers selectively to specific types of neurons and at the same time to label transsynaptically their axonal target neurons. For this purpose, we took advantage of a unique property of plant lectin, wheat germ agglutinin (WGA), which has been used as a transsynaptic tracer in classical neuroanatomical studies. We developed a novel genetic strategy that employs WGA cDNA as a transgene, for the visualization of selective and functional neural pathways in the nervous system. In this article, I will introduce several examples of neural pathways visualized with the WGA transgene and discuss about its further refinement and applications.

Animals↗
PubMed1995

The cranial venous system in the rat: anatomical pattern and ontogenetic development. II. Dorsal drainage.

The precise anatomical pattern and the developmental sequences of the dorsal cranial sinuses are described with special reference to the petrosquamosal sinus. The pattern of the dorsal cranial venous system of the rat is quite similar to that of man, although there are certain important differences. In rats, the transverse sinus bifurcates into the small dorsally directed sigmoid sinus and the large laterally directed petrosquamosal sinus. The latter emerges through the wide petrosquamosal fissure and joins the maxillary and posterior facial veins, sending two roots to each. The superior sagittal sinus anastomoses ventrally with the interperioptic sinus. This pattern is already established at an early developmental stage and is obvious by gestational day E 19. The anlages of the transverse and the sigmoid sinuses are formed from anastomoses between the three dural stems which drain the blood from the brain vesicles via the primary head vein into the anterior cardinal veins. The middle dural stem is connected by a rich capillary network to both the developing maxillary vein and the external jugular venous system before day E 16, thus establishing the anlage of the petrosquamosal sinus. Its definitive pattern is already discernible on day E 18. The external jugular vein becomes the main cranial venous outflow in the postnatal rat.

Aging↗
PubMed2006

Jacques Benoit Lecture. Information processing in the hypothalamus: peptides and analogue computation.

Peptides in the hypothalamus are not like conventional neurotransmitters; their release is not particularly associated with synapses, and their long half-lives mean that they can diffuse to distant targets. Peptides can act on their cells of origin to facilitate the development of patterned electrical activity, they can act on their neighbours to bind the collective activity of a neural population into a coherent signalling entity, and the co-ordinated population output can transmit waves of peptide secretion that act as a patterned hormonal analogue signal within the brain. At their distant targets, peptides can re-programme neural networks, by effects on gene expression, synaptogenesis, and by functionally rewiring connections by priming activity-dependent release.

Animals↗
PubMed1997

Neuronal circuits are subdivided by differential expression of type-II classic cadherins in postnatal mouse brains.

A number of type-II classic cadherin cell-cell adhesion molecules are expressed in the brain. To investigate their roles in brain morphogenesis, we selected three type-II cadherins, cadherin-6 (cad6), -8 (cad8) and -11 (cad11), and mapped their expressions in the forebrain and other restricted regions of postnatal mouse brains. In the cerebral cortex, each cortical area previously defined was delineated by a specific combinatorial expression of these cadherins. The thalamus and other subcortical regions of the forebrain were also subdivided by differential expression of the three cadherins; e.g., the medial geniculate body expressed only cad6; the ventral posterior thalamic nucleus, cad6/cad11; and the anteroventral thalamic nucleus, cad6/cad8. Likewise, in the olivocerebellar system, each subdivision of the inferior olive expressed a unique set of the three cadherins, and the cerebellar cortex had parasagittal stripes of cad8/cad11 expressions. Close analysis of these cadherin expression patterns revealed that they are correlated with neuronal connection patterns. Examples of these correlations include that cad6 delineates the auditory projection system, cad6/cad8/ cad11 are expressed by part of the Papez circuit, and cad6/cad8 are expressed by subdivisions of the olivo-nuclear circuit. Together with the recent finding that the cadherin adhesion system is localized in synaptic junctions, our findings support the notion that cadherin-mediated cell-cell adhesion plays a role in selective interneuronal connections during neural network formation.

Animals↗
PubMed2004

Model-free functional MRI analysis based on unsupervised clustering.

Conventional model-based or statistical analysis methods for functional MRI (fMRI) are easy to implement, and are effective in analyzing data with simple paradigms. However, they are not applicable in situations in which patterns of neural response are complicated and when fMRI response is unknown. In this paper the "neural gas" network is adapted and rigourosly studied for analyzing fMRI data. The algorithm supports spatial connectivity aiding in the identification of activation sites in functional brain imaging. A comparison of this new method with Kohonen's self-organizing map and with a fuzzy clustering scheme based on deterministic annealing is done in a systematic fMRI study showing comparative quantitative evaluations. The most important findings in this paper are: (1) both "neural gas" and the fuzzy clustering technique outperform Kohonen's map in terms of identifying signal components with high correlation to the fMRI stimulus, (2) the "neural gas" outperforms the two other methods with respect to the quantization error, and (3) Kohonen's map outperforms the two other methods in terms of computational expense. The applicability of the new algorithm is demonstrated on experimental data.

Adult↗
PubMed2007

Detecting functional nodes in large-scale cortical networks with functional magnetic resonance imaging: a principal component analysis of the human visual system.

This study aimed to demonstrate how a regional variant of principal component analysis (PCA) can be used to delineate the known functional subdivisions of the human visual system. Unlike conventional eigenimage analysis, PCA was carried out as a second-level analysis subsequent to model-based General Linear Model (GLM)-type functional activation mapping. Functional homogeneity of the functional magnetic resonance imaging (fMRI) time series within and between clusters was examined on several levels of the visual network, starting from the level of individual clusters up to the network level comprising two or more distinct visual regions. On each level, the number of significant components was identified and compared with the number of clusters in the data set. Eigenimages were used to examine the regional distribution of the extracted components. It was shown that voxels within individual clusters and voxels located in bilateral homologue visual regions can be represented by a single component, constituting the characteristic functional specialization of the cluster(s). If, however, PCA was applied to time series of voxels located in functionally distinct visual regions, more than one component was observed with each component being dominated by voxels in one of the investigated regions. The model of functional connections derived by PCA was in accordance with the well-known functional anatomy and anatomical connectivity of the visual system. PCA in combination with conventional activation mapping might therefore be used to identify the number of functionally distinct nodes in an fMRI data set in order to generate a model of functional connectivity within a neuroanatomical network.

Adult↗
PubMed2000

Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections.

Cross-correlation of low-frequency temporal fluctuations (<0.08 Hz) was used to correlate widely separated anatomic regions during continuous performance of a spatial working memory task. The regions of highest correlation to right-hemisphere dorsolateral prefrontal cortex correspond to the regions of largest baseline signal change in a conventional block-style functional MRI paradigm. Additionally, it is shown that the correlations between elements of the functional network increase during performance of a task that activates the network when compared to a task that does not directly stimulate the functionally connected network.

Attention↗
PubMed2006

An intimate connection: Oliver Zangwill and the emergence of neuropsychology in Britain.

In this article, the author argues that a number of conditions conspired to place the Cambridge psychologist Oliver Zangwill in a pivotal position for pursuing and promoting neuropsychology in Britain after World War II. In broad terms, these were the background and experience of Zangwill himself, the practical engagement of psychologists with patients with brain damage, neurologists, and psychiatrists, the introduction of medical reform including the establishment of a National Health Service, rekindled interest in cortical localization, and the elite social networks that existed in medicine and university life in postwar Britain. The author claims that the career of Zangwill reveals rather than obscures the importance of these wider conditions and demonstrates an unusually close connection between an individual and the emergence of a subdiscipline.

Brain Injuries↗