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PubMed1979

Innervation of hippocampal explants by central catecholaminergic neurons in co-cultured fetal mouse brain stem explants.

The ability of central catecholaminergic neurons to grow into and establish functional connections with the hippocampus in vitro was studied using organotypic tissue culture. Brain stem explanted from the region of the locus coeruleus and hippocampal explants, from 18-day fetal mice, were maintained as co-cultures and were also grown separately. After 1-4 weeks these tissues were analyzed by glyoxylic acid-induced histofluorescence, by light and electron microscopic radioautography after incubation with [3H]norepinephrine, and by electrophysiology. Brain stem explants exhibited specifically fluorescent catecholaminergic cell bodies and varicose fibers after 2-4 weeks in culture. In contrast, no fluorescent cells or neurites could be seen in isolated hippocampal cultures grown for 2-3 weeks in vitro. When hippocampal explants were grown near brain stem explants, catecholaminergic fibers grew out of the brain stem and entered the hippocampus. In additional experiments, co-cultures of brain stem and hippocampus were incubated with [3H]norepinephrine (0.5 micron) and the monoamine oxidase inhibitor nialamide (100 micron). Radioautographic analyses revealed that brain stem neurites which entered the hippocampus took up norepinephrine, whereas neurites in the isolated hippocampal explants did not. Electron microscopic studies of the hippocampus showed varicose axon terminals within the hippocampus to be preferentially labeled. Although close relationships could be seen between labeled axons and dendrites, junctions exhibiting the membranous modifications associated with synapses were never seen. Electrophysiological studies suggested that the catecholaminergic neurites within the hippocampus were functional. Complex synaptically mediated slow wave discharges could be evoked by electrical stimuli in isolated hippocampal explants. Introduction of the beta adrenergic antagonist propranolol (0.4-4.3 micron) did not alter, or slightly depressed, these hippocampal discharges. On the other hand, in hippocampus-brain stem co-cultures, these concentrations of propranolol enhanced the complex hippocampal responses to brain stem or hippocampal stimuli. Similar enhancement of hippocampal responses by propranolol also occurred in these cocultures after acute surgical extirpation of the brain stem explant. The data suggest, therefore, that the action of propranol was probably to block adrenergic inhibitory connections with hippocampal synaptic networks. These experiments provide morphological and electrophysiological evidence that catecholaminergic neurons from fetal mouse brain stem maintained in organotypic tissue culture can grow into and functionally innervate the hippocampus.

Animals↗
PubMed2002

Fast computation with spikes in a recurrent neural network.

Neural networks with recurrent connections are sometimes regarded as too slow at computation to serve as models of the brain. Here we analytically study a counterexample, a network consisting of N integrate-and-fire neurons with self excitation, all-to-all inhibition, instantaneous synaptic coupling, and constant external driving inputs. When the inhibition and/or excitation are large enough, the network performs a winner-take-all computation for all possible external inputs and initial states of the network. The computation is done very quickly: As soon as the winner spikes once, the computation is completed since no other neurons will spike. For some initial states, the winner is the first neuron to spike, and the computation is done at the first spike of the network. In general, there are M potential winners, corresponding to the top M external inputs. When the external inputs are close in magnitude, M tends to be larger. If M>1, the selection of the actual winner is strongly influenced by the initial states. If a special relation between the excitation and inhibition is satisfied, the network always selects the neuron with the maximum external input as the winner.

Journal Article↗
PubMed1995

The protective effects of education on simulated brain injury.

Disturbed intellectual function is an important determinant of long-term recovery after head injury. Residual behavioral disability depends largely upon which hemisphere is damaged and the site of injury within the hemisphere. Resulting neurobehavioral syndromes vary with the pattern of brain insult. While this correlation is important, it is still not well understood how damage to single neurons translates into abnormal behavior. In addition, no currently available technology permits in vivo evaluation of such cells in normal or injured states. While research into brain trauma traditionally emphasize single cell pathology, this level of study is insufficient to clarify how individual cell activity contributes to higher cognition. In contrast, neural network simulations may partially fill this void by predicting biological function. Here, we present data generated by a three-layer neural network that employs the ALOPEX algorithm, capable of learning 10 words. The addition of Gaussian distributed noise into connection weights strengths damaged the network's function; interestingly, the rate and extent of network impairment depended upon the level of learning that occurred during the training period, in agreement with human studies that demonstrate a protective effect of education on subsequent brain injury. Damage to input signals resulted in similar effects on network function. Accordingly, such simulations offer powerful evidence that human behavior may be considered in terms of neuronal cell populations and efforts to preserve brain function at the time of injury should emphasize maintaining neural connections.

Algorithms↗
PubMed1993

The connectional organization of neural systems in the cat cerebral cortex.

BACKGROUND: The mammalian brain consists of the cerebral cortical sheet, which is composed of many distinct areas, the cerebellar cortex, and many non-cortical nuclei. Powerful neuroanatomical techniques have revealed a large number of connections between these structures. The large number of brain structures and the very many connections between them form a strikingly complex network. The complexity of this network has made it difficult to understand how the central nervous system is organized. Recently, however, optimization analysis of an important subset of central nervous connections that occur between the different areas of the cerebral cortex has produced understandable and quantitative representations of the organization of cortical systems of the primate brain. RESULTS: Here we briefly report the extension of this approach to the cortical systems of the cat. There were four connectional clusters of cortical areas in the cat. These clusters of areas corresponded to the visual, auditory, and somato-motor systems, and to the frontal and limbic areas, which we call the fronto-limbic complex. All the major sensory systems were hierarchically organized, and their 'higher' stations were more closely associated with the fronto-limbic complex than were their 'lower' stations. CONCLUSIONS: Features of the organization of the cat brain, together with earlier primate results, suggest that there may be a common cortical plan in mammals. We suggest that this common plan may involve relatively discrete, hierarchically organized, cortical sensory systems and a topologically central fronto-limbic complex. Specific variations on this wiring plan may relate to evolutionary history and selection for particular ecological niches.

Journal Article↗
PubMed2006

Modular neuropile organization in the Drosophila larval brain facilitates identification and mapping of central neurons.

Elucidating how neuronal networks process information requires identification of critical individual neurons and their connectivity patterns. For this purpose, we used the third-instar Drosophila larval brain and applied reverse-genetic tools, immunolabeling procedures, and 3D digital reconstruction software. Consistent topological definition of neuropile compartments in the larval brain can be obtained through simple fluorescence-immunolabeling methods. The modular neuropiles can be used as a fiducial framework for mapping the projection patterns of individual neurons labeled with green fluorescent protein (GFP). GFP-labeled neurons often exhibit dendrite-like arbors as well as clustered varicose terminals on neurite branches that innervate identifiable neuropile compartments. We identified candidate cholinergic interneurons in genetic mosaic brains that overlap with the larval optic nerve terminus. By using the neuropile framework, we demonstrate that the candidate visual interneurons are not a subset of the previously identified circadian pacemaker neurons that also contact the larval optic nerve terminus; they may represent parallel pathways in the processing of visual inputs. Thus, in the Drosophila larval brain, modular neuropiles can be used as a framework for systematically identifying, mapping, and classifying interneurons; understanding their roles in behavior can then be pursued further.

Animals↗
PubMed1992

Connectivity and condensation in dreaming.

Converging developments in the cognitive- and neurosciences have brought Freud's hope of a bridge between psychoanalysis and psychophysiology nearer to hand. This paper concerns the relation between dream construction and memory in terms of these new developments. The neural network architecture of memory structures in the brain is described and illustrated with simple examples. We see how a network is connected and how connection weights vary with experience. The distributed representation stored by the network and its crucial properties for mental functioning are discussed. These concepts are used to explain how particular memories of past events are selected for inclusion in the dream. The properties of the neural network suggest that images of distinct past events are conflated at times during the selection process. The appearance of these conflated images may complicate the matching of day residues with representations of past events in the dream itself. Some likely implications for psychoanalytic theory are explored.

Dreams↗
PubMed1999

Computational differences between asymmetrical and symmetrical networks.

Symmetrically connected recurrent networks have recently been used as models of a host of neural computations. However, biological neural networks have asymmetrical connections, at the very least because of the separation between excitatory and inhibitory neurons in the brain. We study characteristic differences between asymmetrical networks and their symmetrical counterparts in cases for which they act as selective amplifiers for particular classes of input patterns. We show that the dramatically different dynamical behaviours to which they have access, often make the asymmetrical networks computationally superior. We illustrate our results in networks that selectively amplify oriented bars and smooth contours in visual inputs.

Animals↗
PubMed2000

On imputing function to structure from the behavioural effects of brain lesions.

What is the link, if any, between the patterns of connections in the brain and the behavioural effects of localized brain lesions? We explored this question in four related ways. First, we investigated the distribution of activity decrements that followed simulated damage to elements of the thalamocortical network, using integrative mechanisms that have recently been used to successfully relate connection data to information on the spread of activation, and to account simultaneously for a variety of lesion effects. Second, we examined the consequences of the patterns of decrement seen in the simulation for each type of inference that has been employed to impute function to structure on the basis of the effects of brain lesions. Every variety of conventional inference, including double dissociation, readily misattributed function to structure. Third, we tried to derive a more reliable framework of inference for imputing function to structure, by clarifying concepts of function, and exploring a more formal framework, in which knowledge of connectivity is necessary but insufficient, based on concepts capable of mathematical specification. Fourth, we applied this framework to inferences about function relating to a simple network that reproduces intact, lesioned and paradoxically restored orientating behaviour. Lesion effects could be used to recover detailed and reliable information on which structures contributed to particular functions in this simple network. Finally, we explored how the effects of brain lesions and this formal approach could be used in conjunction with information from multiple neuroscience methodologies to develop a practical and reliable approach to inferring the functional roles of brain structures.

Behavior↗
PubMed2005

Exuberance in the development of cortical networks.

The cerebral cortex is the largest and most intricately connected part of the mammalian brain. Its size and complexity has increased during the course of evolution, allowing improvements in old functions and causing the emergence of new ones, such as language. This has expanded the behavioural and cognitive repertoire of different species and has determined their competitive success. To allow the relatively rapid emergence of large evolutionary changes in a structure of such importance and complexity, the mechanisms by which cortical circuitry develops must be flexible and yet robust against changes that could disrupt the normal functions of the networks.

Animals↗
PubMed1999

Acute regulation and long-term modulation of presynaptic serotonin output.

This contribution summarizes the present knowledge about the mechanisms involved in the regulation of presynaptic serotonin release. Under conditions of a permanently altered environmental, (psychosocial, drug-induced, nutritional etc.) input, each one of these mechanisms may be adaptively adjusted to the novel use-dependent requirements. Examples of such long-term alterations of the 5-HT-output pattern in distant projection fields of the raphe-neurons are the downregulation of cortical serotonin-transporters after long-term food restriction, the loss of serotonergic nerve terminals caused by substituted amphetamines, the serotonergic hyperinnervation of the frontal cortex seen after olfactory bulbectomy in rats, or the long lasting changes in the levels of tryptophanhydroxylase, of serotonin-transporter depression or in the density of serotonergic nerve terminals in distant projection fields caused by long-term antidepressant treatments. All these long-lasting alterations and imbalances of a previously established serotonin-output-pattern will not only affect the impact of individual regional networks on whole brain information processing but also the established synaptic connectivity in distant projection fields of the central serotonergic system.

Animals↗
PubMed2002

Towards an integrative theory of cognition.

A framework is outlined for connecting brain imaging activity with the underlying biophysical properties of neural networks, and their mechanisms of action and organizing principles. The main thrust of the framework is a dynamic theory of semantics based on functional integration of biophysical neural networks. It asserts that higher-brain function arises from both synaptic and extrasynaptic integration in the neuropil where information on environmental changes are represented dynamically through a discourse of semantics. Consequently, integrative neural modeling is shown to be an important methodology for analyzing the response activities of functional imaging studies in elucidating the relationship between brain and structure, function and behavior.

Biophysical Phenomena↗
PubMed2005

Specific language impairment is not specific to language: the procedural deficit hypothesis.

Specific Language Impairment (SLI) has been explained by two broad classes of hypotheses, which posit either a deficit specific to grammar, or a non-linguistic processing impairment. Here we advance an alternative perspective. According to the Procedural Deficit Hypothesis (PDH), SLI can be largely explained by the abnormal development of brain structures that constitute the procedural memory system. This system, which is composed of a network of inter-connected structures rooted in frontal/basal-ganglia circuits, subserves the learning and execution of motor and cognitive skills. Crucially, recent evidence also implicates this system in important aspects of grammar. The PDH posits that a significant proportion of individuals with SLI suffer from abnormalities of this brain network, leading to impairments of the linguistic and non-linguistic functions that depend on it. In contrast, functions such as lexical and declarative memory, which depend on other brain structures, are expected to remain largely spared. Evidence from an in-depth retrospective examination of the literature is presented. It is argued that the data support the predictions of the PDH, and particularly implicate Broca's area within frontal cortex, and the caudate nucleus within the basal ganglia. Finally, broader implications are discussed, and predictions for future research are presented. It is argued that the PDH forms the basis of a novel and potentially productive perspective on SLI.

Basal Ganglia↗
PubMed2000

Corticothalamic resonance, states of vigilance and mentation.

During various states of vigilance, brain oscillations are grouped together through reciprocal connections between the neocortex and thalamus. The coherent activity in corticothalamic networks, under the control of brainstem and forebrain modulatory systems, requires investigations in intact-brain animals. During behavioral states associated with brain disconnection from the external world, the large-scale synchronization of low-frequency oscillations is accompanied by the inhibition of synaptic transmission through thalamocortical neurons. Despite the coherent oscillatory activity, on the functional side there is dissociation between the thalamus and neocortex during slow-wave sleep. While dorsal thalamic neurons undergo inhibitory processes due to the prolonged spike-bursts of thalamic reticular neurons, the cortex displays, periodically, a rich spontaneous activity and preserves the capacity to process internally generated signals that dominate the state of sleep. In vivo experiments using simultaneous intracellular recordings from thalamic and cortical neurons show that short-term plasticity processes occur after prolonged and rhythmic spike-bursts fired by thalamic and cortical neurons during slow-wave sleep oscillations. This may serve to support resonant phenomena and reorganize corticothalamic circuitry, determine which synaptic modifications, formed during the waking state, are to be consolidated and generate a peculiar kind of dreaming mentation. In contrast to the long-range coherent oscillations that occur at low frequencies during slow-wave sleep, the sustained fast oscillations that characterize alert states are synchronized over restricted territories and are associated with discrete and differentiated patterns of conscious events.

Animals↗
PubMed2006

Changes in neuronal connectivity after stroke in rats as studied by serial manganese-enhanced MRI.

Loss of function and subsequent spontaneous recovery after stroke have been associated with physiological and anatomical alterations in neuronal networks in the brain. However, the spatiotemporal pattern of such changes has been incompletely characterized. Manganese-enhanced MRI (MEMRI) provides a unique tool for in vivo investigation of neuronal connectivity. In this study, we measured manganese-induced changes in longitudinal relaxation rate, R(1), to assess the spatiotemporal pattern of manganese distribution after focal injection into the intact sensorimotor cortex in control rats (n=10), and in rats at 2 weeks after 90-min unilateral occlusion of the middle cerebral artery (n=10). MEMRI data were compared with results from conventional tract tracing with wheat-germ agglutinin horseradish peroxidase (WGA-HRP). Distinct areas of the sensorimotor pathway were clearly visualized with MEMRI. At 2 weeks after stroke, manganese-induced changes in R(1) were significantly delayed and diminished in the ipsilateral caudate putamen, thalamus and substantia nigra. Loss of connectivity between areas of the sensorimotor network was also identified from reduced WGA-HRP staining in these areas on post-mortem brain sections. This study demonstrates that MEMRI enables in vivo assessment of spatiotemporal alterations in neuronal connectivity after stroke, which may lead to improved insights in mechanisms underlying functional loss and recovery after stroke.

Animals↗
PubMed1994

Network analysis of cortical visual pathways mapped with PET.

Brain metabolic mapping techniques, such as positron emission tomography (PET), can provide information about the functional interactions within entire neural systems. With the large quantity of data that can accumulate from a mapping study, a network analysis, which makes sense of the complex interactions among neural elements, is necessary. A network analysis was performed on data obtained from a PET study that examined both the changes in regional cerebral blood flow (rCBF) and interregional correlations among human cortical areas during performance of an object vision (face matching) and spatial vision (dot-location matching) task. Brain areas for the network were selected based on regions showing significant rCBF or interregional correlations between tasks. Anterior temporal and frontal lobe regions were added to the network using a principal components analysis. Interactions among selected regions were quantified with structural equation modeling. In the structural equation models, connections between brain areas were based on known neuroanatomy and the interregional correlations were used to calculate path coefficients representing the magnitude of the influence of each directional path. The combination of the anatomical network and interregional correlations created a functional network for each task. The functional network for the right hemisphere showed that in the object vision task, dominant path influences were among occipitotemporal areas, while in the spatial vision task, occipitoparietal interactions were stronger. The network for the spatial vision task also had a strong feedback path from area 46 to occipital cortex, an effect that was absent in the object vision task. There were strong interactions between dorsal and ventral pathways in both networks. Functional networks for the left hemisphere did not differ between tasks. Networks for the interhemispheric interactions showed that the dominant pathway in the right hemisphere also had stronger effects on homologous left hemisphere areas and are consistent with a hypothesis that intrahemispheric interactions were greater in the right hemisphere in both tasks, and that these influences were transmitted callosally to the left hemisphere.

Adult↗
PubMed2005

Advancing the boundaries of high-connectivity network simulation with distributed computing.

The availability of efficient and reliable simulation tools is one of the mission-critical technologies in the fast-moving field of computational neuroscience. Research indicates that higher brain functions emerge from large and complex cortical networks and their interactions. The large number of elements (neurons) combined with the high connectivity (synapses) of the biological network and the specific type of interactions impose severe constraints on the explorable system size that previously have been hard to overcome. Here we present a collection of new techniques combined to a coherent simulation tool removing the fundamental obstacle in the computational study of biological neural networks: the enormous number of synaptic contacts per neuron. Distributing an individual simulation over multiple computers enables the investigation of networks orders of magnitude larger than previously possible. The software scales excellently on a wide range of tested hardware, so it can be used in an interactive and iterative fashion for the development of ideas, and results can be produced quickly even for very large networks. In contrast to earlier approaches, a wide class of neuron models and synaptic dynamics can be represented.

Action Potentials↗
PubMed2006

Functional connectivity of the fusiform gyrus during a face-matching task in subjects with mild cognitive impairment.

Cognitive function requires a high level of functional interaction between regions of a network supporting cognition. Assuming that brain activation changes denote an advanced state of disease progression, changes in functional connectivity may precede changes in brain activation. The objective of this study was to investigate changes in functional connectivity of the right middle fusiform gyrus (FG) in subjects with mild cognitive impairment (MCI) during performance of a face-matching task. The right middle FG is a key area for processing face stimuli. Brain activity was measured using functional MRI. There were 16 MCI subjects and 19 age-matched healthy controls. The linear correlation coefficient was utilized as a measure of functional connectivity between the right middle FG and all other voxels in the brain. There were no statistical differences found in task performance or activation between groups. The right middle FG of the healthy control and MCI groups showed strong bilateral positive linear correlation with the visual cortex, inferior and superior parietal lobules, dorsolateral prefrontal cortex (DLPFC) and anterior cingulate. The healthy controls showed higher positive linear correlation of the right middle FG to the visual cortex, parietal lobes and right DLPFC than the MCI group, whereas the latter had higher positive linear correlation in the left cuneus. In the healthy controls, the right middle FG had negative linear correlation with right medial frontal gyrus and superior temporal gyrus and with left inferior parietal lobule (IPL), angular gyrus, superior frontal gyrus and anterior cingulate gyrus, but the MCI group had negative linear correlation with the left IPL, angular gyrus, precuneus, anterior cingulate, and to right middle temporal gyrus and posterior cingulate gyrus. In the negatively linearly correlated regions, the MCI group had reduced functional connectivity to the frontal areas, right superior temporal gyrus and left IPL. Different regions of the cuneus and IPL had increased functional connectivity in either group. The putative presence of Alzheimer's disease neuropathology in MCI affects functional connectivity from the right middle FG to the visual areas and medial frontal areas. In addition, higher linear correlation in the MCI group in the parietal lobe may indicate the initial appearance of compensatory processes. The results demonstrate that functional connectivity can be an effective marker for the detection of changes in brain function in MCI subjects.

Aged↗