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PubMed1997

A functional magnetic resonance imaging study of episodic memory.

We have used whole brain fMRI and canonical variate analysis to investigate the anatomical location of brain activity subserving episodic memory encoding and recognition. Recognition of previously presented words did not specifically activate right prefrontal areas although right-sided activations were seen during transitions between the target and reference phases of the paradigm. Encoding was associated with left sided prefrontal activation, but this was within Broca's area rather than dorsolateral prefrontal cortex. The temporal resolution of fMRI, combined with analysis of the apparent functional connectivity of activations observed, revealed activity within complex networks each functionally specialized for the demands of particular aspects of a cognitive task.

Adult↗

PubMed2004

Molecular functions of BRCA1 in the DNA damage response.

Ten years ago, a concerted effort from several labs resulted in the cloning of BRCA1, the first of two major hereditary breast/ovarian cancer predisposition genes. Since that time, BRCA1 has been linked to several key nuclear functions connected with the prevention of genomic instability. In particular, BRCA1 functions in concert with Rad51, BRCA2 and other genes to control double strand break repair (DSBR) and homologous recombination. Here, we reassess the role of BRCA1 and its associated proteins in this process.

Breast Neoplasms↗

PubMed2004

Functional neuroimaging in mental disorders.

Recent advances in functional neuroimaging allow us to map neural activity in the living human brain with precise spatial and temporal resolution and provide an unprecedented opportunity to examine the neurocognitive components of mental disorders. In this article we aim to summarize the main functional neuroimaging findings in the major psychiatric disorders and the different methodological approaches that have been used to study them. We will discuss studies of the resting state and of activation during the performance of cognitive tasks, and studies focused on specific psychiatric symptoms. We will also review work on functional connectivity, discuss future directions in the field and consider how functional neuroimaging may contribute to clinical practice.

Journal Article↗

PubMed2006

Analyzing and shaping human attentional networks.

In this paper we outline a conception of attentional networks arising from imaging studies as connections between activated brain areas carrying out localized mental operations. We consider both the areas of functional activation (nodes) and the structural (DTI) and functional connections (DCM) between them in real time (EEG, frequency analysis) as important tools in analyzing the network. The efficiency of network function involves the time course of activation of nodes and their connectivity to other areas of the network. We outline landmarks in the development of brain networks underlying executive attention from infancy and childhood. We use individual differences in network efficiency to examine genetic alleles that are related to performance. We consider how animal studies might be used to determine the genes that influence network development. Finally we indicate how training may aid in enhancing attentional networks. Our goal is to show the wide range of methods that can be used to suggest and analyze models of network function in the study of attention.

Attention↗

PubMed2006

The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.

To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project.

Alzheimer Disease↗

PubMed1984

Chemical and electrotonic connections between Aplysia neurons in primary culture.

Dissociated Aplysia neurons will regenerate neurites and form functional connections in primary cell cultures. The specificity of intercellular connectivity in these cultures was investigated by coculturing neurosecretory bag cells with neurons dissociated from the buccal ganglion. It was found that bag-bag and buccal-buccal electrotonic synapses form with high frequency, consistent with previous findings in pure bag and buccal cultures. There is specificity in the formation of these connections, since no bag-buccal electrotonic synapses were observed. Chemical interactions, on the other hand, are present between bag and buccal neurons. In a buccal-bag pair, injection of sufficient depolarizing current into the buccal cell to elicit a train of action potentials leads to a slow hyperpolarizing response in the bag cell. The bag cell hyperpolarization is accompanied by an increase in the cell's input conductance. This connection appears to be unidirectional, produces a voltage shift in the bag cell which is opposite in sign to that in the buccal cell, and is blocked by the removal of Ca2+ from the extracellular medium, indicating that it is mediated by a chemical neurotransmitter. The selective formation of electrotonic synapses in these mixed bag-buccal cultures, together with the presence of chemically mediated interactions, make this system particularly useful for investigating the establishment of intercellular connectivity.

Animals↗

PubMed2001

Neural transplantation: restoring complex circuitry in the striatum.

During the last 30 years, the promise of neural transplantation as a therapeutic strategy for neurodegenerative disease has been slowly recognised. Across the world, clinical transplants of embryonic primary dopamine neurones have been shown to ameliorate some of the motor deficits in Parkinson s disease (PD) patients, and more recently, systematic clinical trials have been initiated for the replacement of striatal projection neurones lost in Huntington's disease (HD). Clinical transplantation as a prospective therapy for HD poses a particular set of difficulties. The hallmarks of this neurodegenerative disease include extensive loss of medium spiny long-distance projection neurones of the caudate and putamen, affecting downstream target nuclei, the globus pallidus and substantia nigra, leading to dysregulation of motor control. In addition, extensive loss of cortical neurones that form the afferent systems to the basal ganglia leads to widespread cognitive decline. If transplantation therapy is to succeed in replacing degenerating neurones in HD and reinstating controlled function of complex basal gan-glia circuitry, the new neurones must be able to develop specific long-distance projections that can form accurate and functional connections with neurones in precise target regions. Our ongoing studies are aimed at addressing how we can improve the function of striatal transplants, in particular to optimise the reformation of precise long-distance connections and to re-establish normal motor and cognitive function. In particular, we have investigated optimal requirements for embryonic primary tissue to achieve these aims, and also the potential of other cell sources to provide long-distance projection neurones and reconnect complex circuitry. This review describes current progress of experiments to optimise the reconstruction of neuronal circuitry using primary embryonic tissue transplants, as well as our current initiatives to use neural stem cells or precursors to replace long distance projection neurones in the degenerating basal ganglia.

Animals↗

PubMed2005

Saccharomyces cerevisiaeTSC11/AVO3 participates in regulating cell integrity and functionally interacts with components of the Tor2 complex.

Saccharomyces cerevisiae TSC11/AVO3 is an essential gene encoding one component of TORC2, a multi-protein complex of yeast Tor2p that also contains Lst8p, Avo1p, and Avo2p. Despite the proven physical association among TORC2 components, little is known about the functional linkage or cellular pathways these proteins act in. Here, we present genetic data linking the function of TSC11 to the regulation of cell integrity. Mutants carrying temperature-sensitive (ts) alleles in different regions of TSC11 displayed cell wall defects, evidenced by characteristic osmotic stabilizer-remediable cell lysis, susceptibility to trypan blue staining, and sensitivity to cell wall-digesting enzymes. Dosage suppression analysis identified different groups of genes in rescuing phenotypes of different tsc11(ts) mutants. AVO1 suppressed one class of mutants, whereas active PKC1, AVO2, and SLM1 partially rescued another. Our findings demonstrate functional connections among TORC2 components and we speculate that Tsc11p exerts its function via a Pkc1p-independent mechanism mediated through Avo1p, and a Pkc1p-dependent mechanism mediated through Avo2p and Slm1p.

Actins↗

PubMed2005

Neurogeometry and potential synaptic connectivity.

The advent of high-quality 3D reconstructions of neuronal arbors has revived the hope of inferring synaptic connectivity from the geometric shapes of axons and dendrites, or 'neurogeometry'. A quantitative description of connectivity must be built on a sound theoretical framework. Here, we review recent developments in neurogeometry that can provide such a framework. We base the geometric description of connectivity on the concept of a 'potential synapse'--the close apposition between axons and dendrites necessary to form an actual synapse. In addition to describing potential synaptic connectivity in neuronal circuits, neurogeometry provides insight into basic features of functional connectivity, such as specificity and plasticity.

Animals↗

PubMed1991

Cerebrocerebellar relationship during behavioral activation: a PET study.

The effect of behavioral activation on cerebral and cerebellar glucose metabolism was studied in normal subjects when performing either a verbal memory task or a tactile somatosensory task. Each subject was also studied in a resting state control condition, either 1 h earlier or later than the activation task. Compared to the resting state, both tasks produced asymmetrical metabolic activation, which was opposite in direction within the cerebral and cerebellar hemispheres. In both tasks, the difference of activation of CMRglc in the right and left hemispheres in the cerebellum was negatively correlated with that in the sensory-motor region. This apparently coupled metabolic activation of one cerebellum and areas within the opposite cerebral hemisphere represents the inverse of the crossed cerebellar diaschisis phenomenon commonly observed when a vascular lesion affects one cerebral hemisphere and hypometabolism occurs in the opposite cerebellum. Because these correlations were selective and concordant with known anatomical connections, and were found in two different tasks, they suggest strong functional connections between these specific brain regions.

Aged↗

PubMed2003

Actin assembly and endocytosis: from yeast to mammals.

Internalization of receptors, lipids, pathogens, and other cargo at the plasma membrane involves several different pathways and requires coordinated interactions between a variety of protein and lipid molecules. The actin cytoskeleton is an integral part of the cell cortex, and there is growing evidence that F-actin plays a direct role in these endocytic events. Genetic studies in yeast have firmly established a functional connection between actin and endocytosis. Identification of several proteins that may function at the interface between actin and the endocytic machinery has provided further evidence for this association in both yeast and mammalian cells. Several of these proteins are directly involved in regulating actin assembly and could thus harness forces produced during actin polymerization to facilitate specific steps in the endocytic process. Recent microscopy studies in mammalian cells provide powerful evidence that localized recruitment and polymerization of actin occurs at endocytic sites. In this review, we focus on progress made in elucidating the functions of the actin cytoskeleton in endocytosis.

Actin Cytoskeleton↗

PubMed1996

Experimental surgery in spinal cord lesions by connecting upper motoneurons directly to peripheral targets.

This research was aimed at assessing the possibility to connect central motoneurons with skeletal muscles through PNS segments bypassing a lesion of the spinal cord. The investigation was performed in 20 non-human primates (Macaca fascicularis). The surgical paradigm consisted of anastomosing the lateral bundle of the spinal cord directly with the sciatic nerve of the right hindlimb, using the peroneal nerve as a graft. The animals were followed-up clinically for 18 months; at the end of this observation period, they underwent electrophysiological examinations before being killed. Specimens were taken from the spinal cord, graft, sciatic nerve and potentially reinnervated muscles, and processed for routine light microscopy and immunohistochemistry. Postoperative mortality was fairly high (six monkeys), yet the overall outcome was regarded as very good because the animals were neither restrained nor intensively cared for. Five of the surviving monkeys showed clinical, electrophysiological and histological evidence of successful reinnervation. This research demonstrated that upper CNS motoneurons are potentially capable of elongating neuritic processes into the endoneural tubes of a connecting graft, up to reaching a peripheral nerve (sciatic), and restoring functional connections with the relevant skeletal muscles.

Animals↗

PubMed2000

The sensitivity of tussiphonography for assessing the effectiveness of treatment.

Our previous studies have demonstrated that tussiphonogram is suitable not only for the detection of pathological condition in the respiratory tract but also for treatment effectiveness assessment. The purpose of this study was to evaluate the possibilities of tussiphonography in detection of already little pathological changes in the airways and lungs. Therefore the changes of voluntary cough sound indexes were compared with pulmonary function tests in selected group of asthmatics before and after a pulsatile electromagnetic therapy in which the effect of therapy on pulmonary function tests was minimal. After magnetotherapy in 18 patients with increased expiratory forced lung capacity by 7.3% and increased peak inspiratory flow by 31.7% in average the voluntary cough sound intensity decreased by 37.8%, the sound duration shortened by 11% and the sound pattern showed the tendency to normalization. The improvement of mentioned cough indexes was absent in 17 patients who were treated by magnetotherapy too, but at the same time suffered from respiratory viral infection and in 22 patients treated only with climatotherapy and antiasthmatics. Changes of flow-volume loops in patients were not in the close relation to other followed indices. The correlation analysis showed a functional connection in relative differences of cough sound indices and some pulmonary function tests. The results confirmed the suitability of tussiphonography to indicate even mild pathological changes in respiratory tract. (Fig. 4, Ref. 21.)

Adult↗

PubMed1992

Differentiated reaction of different types of antheridial cells in Chara vulgaris to the changes in light conditions during 24 hours.

Circadian rhythm of activity of 3H-leucine incorporation into antheridial cells of Chara vulgaris, in natural photoperiod was compared with changes in mitotic activity of antheridial filament cells which form spermatozoids. Three types of cells functionally connected with each other i.e. manubria, capitular cells and antheridial filaments indicate high amplitude (80-90%) changes in circadian translational activity and some similarities in their course. The shield cells are characterized by small circadian changes in translational activity in the range of 15-30% and their different rhythm. Manubria, which are the secretive cells indicated the highest dependence of the dynamic of translational activity on the time of day. Their high activity overlaps light phase, low activity--dark phase. The reaction of capitular cells to day/night change is delayed in comparison with the reaction of manubria, and that of antheridial filaments is delayed in comparison with the capitular cells reaction. The assumption was set forth that manubria play the role of oscillators (starttercells) which induce the wave of changes translocating to the other cells functionally and spatialy connected with them. The course of the wave of antheridial filaments mitotic activity suggests that a distinct drop in MI in the morning may be the result of the lack of the factors necessary for initiation of the mitosis, dependent on light-induced high translational activity of antheridial cells.

Cell Division↗

PubMed2003

Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution.

The analysis of functional magnetic resonance imaging (fMRI) time-series data can provide information not only about task-related activity, but also about the connectivity (functional or effective) among regions and the influences of behavioral or physiologic states on that connectivity. Similar analyses have been performed in other imaging modalities, such as positron emission tomography. However, fMRI is unique because the information about the underlying neuronal activity is filtered or convolved with a hemodynamic response function. Previous studies of regional connectivity in fMRI have overlooked this convolution and have assumed that the observed hemodynamic response approximates the neuronal response. In this article, this assumption is revisited using estimates of underlying neuronal activity. These estimates use a parametric empirical Bayes formulation for hemodynamic deconvolution.

Bayes Theorem↗

PubMed2004

Differential effects of testosterone on neuronal populations and their connections in a sensorimotor brain nucleus controlling song production in songbirds: a manganese enhanced-magnetic resonance imaging study.

Nucleus HVC (formerly called high vocal center) of songbirds contains two types of projecting neurons connecting HVC respectively to the nucleus robustus archistriatalis, RA, or to area X. These two neuron classes exhibit multiple neurochemical differences and are differentially replaced by new neurons during adult life: high rates of neuronal replacement are observed in RA-projecting neurons only. The activity of these two types of neurons may also be modulated differentially by steroids. We analyzed by magnetic resonance imaging the effect of testosterone on the volume of RA and area X and on the dynamics of Mn(2+) accumulation in RA and area X of female starlings that had been injected with MnCl(2) through a permanent cannula implanted in HVC. Repeated visualization 6 weeks apart (before and after testosterone treatment) identified a volume increase of both nuclei in testosterone-treated birds associated with a concomitant decrease in controls. Following testosterone treatment, the total amount of Mn(2+) transported to RA and area X increased but the dynamics of accumulation, reflecting in part the activity of HVC neurons, was specifically altered in area X but not in RA. These data indicate that testosterone differentially affects the RA- and area X-projecting neurons in HVC. Manganese-enhanced magnetic resonance imaging (ME-MRI) thus provides repeated measures of connected brain areas and demonstrates testosterone-dependent regionally specific changes in brain activity and functional connectivity. The slow time scales investigated by this technique (compared to functional MRI) appear ideally suited for characterizing slow processes such as those involved in brain plasticity and learning.

Animals↗

PubMed1994

Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula.

While one of the original underpinnings of the dopamine theory of schizophrenia was the paranoid psychosis which often develops during the binges or speed runs of chronic amphetamine addicts (and, more recently, in cocaine addicts), neurochemical studies of such drug abusers or from animals given continuous stimulants in an effort to model stimulant psychoses have not played a major role in the further evolution of this theory. One clear persisting alteration produced by continuous amphetamine is a neurotoxicity to dopaminergic innervations in caudate. Yet continuous cocaine administration apparently does not induce a similar neurotoxicity and this makes this effect a poor candidate for an underpinning of stimulant psychoses. However, it has recently been found that both continuous amphetamine and cocaine induce a strong pattern of degeneration which is highly confined to the lateral habenula and its principal output pathway, fasciculus retroflexus. This finding has led to a reconsideration of the role of these structures in psychoses. The habenula, as the chief relay nucleus of the descending dorsal diencephalic system (consisting of stria medullaris, habenula and fasciculus retroflexus), is an important link between limbic and striatal forebrain and lower diencephalic and mesencephalic centers. Studies of glucose utilization have consistently shown the habenula to be highly sensitive to dopamine agonists and antagonists. Lesions of habenula produce a wide variety of behavioral alterations. The dorsal diencephalic system has major and predominantly inhibitory connections onto dopamine-containing cells and it mediates part of the negative feedback from dopamine receptors onto dopamine cell bodies. It represents one of the major inputs in brain to the raphe nuclei and has anatomical and functional connections to modulate important functions such as sensory gating through thalamus, pain gating through central gray and raphe and motor stereotypies and reward mechanisms through substantia nigra and the ventral tegmental area. It is argued that alterations in these pathways are ideal candidates for producing the behaviors which occur during psychosis and that future considerations of the circuitry underlying psychoses need to include this highly important but relatively neglected system.

Animals↗

PubMed1992

Specificity of VIIIth nerve regeneration in lower vertebrates.

From the initial studies of Sperry (Am. J. Physiol, 144:735-741, 1945) to more recent investigations, the regenerative capacity of the VIIIth cranial nerve in nonmammalian vertebrates has been noted for its robust and accurate recovery of functional connections after transection. The VIIIth cranial nerve contains nerve fibers that link functionally distinct sensory epithelial to various areas within the central nervous system (CNS), yet after transection these multiple components of the nerve navigate back to their original central target areas, without innervating inappropriate nuclei. A number of factors may be required to establish and direct VIIIth nerve regeneration. Cellular interactions appear to be necessary for the initiation of outgrowth and the maintenance of neural connections. The release of chemotropic substances from target cells has been postulated as the most likely mechanism guiding the reinnervation of central targets. Furthermore, the growth characteristics of these neurons in tissue culture, without target cells present, indicates that intrinsically regulated growth features may also contribute to the process of VIIIth nerve regeneration.

Animals↗