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Functional connectivity as revealed by spatial independent component analysis of fMRI measurements during rest.

Cortical functional connectivity, as indicated by the concurrent spontaneous activity of spatially segregated regions, is being studied increasingly because it may determine the reaction of the brain to external stimuli and task requirements and it is reportedly altered in many neurological and psychiatric disorders. In functional magnetic resonance imaging (fMRI), such functional connectivity is investigated commonly by correlating the time course of a chosen "seed voxel" with the remaining voxel time courses in a voxel-by-voxel manner. This approach is biased by the actual choice of the seed voxel, however, because it only shows functional connectivity for the chosen brain region while ignoring other potentially interesting patterns of coactivation. We used spatial independent component analysis (sICA) to assess cortical functional connectivity maps from resting state data. SICA does not depend on any chosen temporal profile of local brain activity. We hypothesized that sICA would be able to find functionally connected brain regions within sensory and motor regions in the absence of task-related brain activity. We also investigated functional connectivity patterns of several parietal regions including the superior parietal cortex and the posterior cingulate gyrus. The components of interest were selected in an automated fashion using predefined anatomical volumes of interest. SICA yielded connectivity maps of bilateral auditory, motor and visual cortices. Moreover, it showed that prefrontal and parietal areas are also functionally connected within and between hemispheres during the resting state. These connectivity maps showed an extremely high degree of consistency in spatial, temporal, and frequency parameters within and between subjects. These results are discussed in the context of the recent debate on the functional relevance of fluctuations of neural activity in the resting state.

Adult↗

[Landscape ecological assessment and planning in the watershed of Erlong Mountain reservoir in Heilongjiang Province].

Based on the theories of landscape ecology, the landscape eco-environment in the watershed of Erlong Mountain reservoir in Heilongjiang Province was analyzed and assessed using GIS technique and statistical model of principal component analysis and spatial cluster analysis. It was found that 100.08 km2 (36%) of total area was in good state, 85.73 km2 (31%) was in general state, and 47.26 km2 (17%) and 15.48 km2 (16%) was in relative poor and ideal states, respectively. According to the landscape ecological structure, three landscape functional areas were designed as agricultural area, the developmental direction of which was eco-agriculture, tour agriculture and high-benefit agriculture; eco-environment protection area, the development direction of which was develop soil and water conservation forest; and area for increasing vegetation cover, the developmental direction of which was rational cut and utilization of forest resources, spatial optimization disposal of forest type, and protection of wildwood.

Conservation of Natural Resources↗

Childhood leukaemia in Sweden: using GIS and a spatial scan statistic for cluster detection.

The study of disease clustering is becoming increasingly common in the field of medical epidemiology. There is great public concern and numerous reports on perceived clusters of various diseases, and with cancers, and especially leukaemia, being the most commonly studied. We present a population based study on acute childhood leukaemia in Sweden 1973-1993, illustrating the possibility of a system for full-scale spatial epidemiological study design. The aim of the study is to test a large set of childhood leukaemia cases for the presence of geographical clusters. Necessary prerequisites, in the form of extensive population and disease data, a tool for geographical spatial analysis and a proper statistical method were fulfilled. No significant clusters were found.

Acute Disease↗

Exploring spatio-temporal patterns of mortality using mixed effects models.

A linear mixed effects (LME) model previously used for a spatial analysis of mortality data for a single time period is extended to include time trends and spatio-temporal interactions. This model includes functions of age and time period that can account for increasing and decreasing death rates over time and age, and a change-point of rates at a predetermined age. A geographic hierarchy is included that provides both regional and small area age-specific rate estimates, stabilizing rates based on small numbers of deaths by sharing information within a region. The proposed log-linear analysis of rates allows the use of commercially available software for parameter estimation, and provides an estimator of overdispersion directly as the residual variance. Because of concerns about the accuracy of small area rate estimates when there are many instances of no observed deaths, we consider potential sources of error, focusing particularly on the similarity of likelihood inferences using the LME model for rates as compared to an exact Poisson-normal mixed effects model for counts. The proposed LME model is applied to breast cancer deaths which occurred among white women during 1979-1996. For this example, application of diagnostics for multiparameter likelihood comparisons suggests a restriction of age to a minimum of either 25 or 35, depending on whether small area rate estimates are required. Investigation into a convergence problem led to the discovery that the changes in breast cancer geographic patterns over time are related more to urbanization than to region, as previously thought. Published in 2000 by John Wiley & Sons, Ltd.

Adolescent↗

New dendrimer-peptide host-guest complexes: towards dendrimers as peptide carriers.

Adamantyl urea and adamantyl thiourea modified poly(propylene imine) dendrimers act as hosts for N-terminal tert-butoxycarbonyl (Boc)-protected peptides and form chloroform-soluble complexes. Investigations with NMR spectroscopy show that the peptide is bound to the dendrimer by ionic interactions between the dendrimer outer shell tertiary amines and the C-terminal carboxylic acid of the peptide, and also through host-urea to peptide-amide hydrogen bonding. The hydrogen-bonding nature of the peptide-dendrimer interactions was further confirmed by using Fourier transform IR spectroscopy, for which the NH- and CO-stretch signals of the peptide amide moieties shift towards lower wavenumbers upon complexation with the dendrimer. Spatial analysis of the complexes with NOESY spectroscopy generally shows close proximity of the N-terminal Boc group of the peptide to the peripheral adamantyl groups on the dendrimer host. The influence of side-chain motif on interactions with the host is analyzed by using seven different N-Boc-protected tripeptides as guests for the dendrimer. Downfield shifts of up to 1.3 ppm were observed for the guest amide NH-proton signals. These shifts decreased with increasing 'bulkiness' of the amino acid side chains. Despite this, the dendrimer was capable of making multiple peptide-dendrimer complexes when presented with a library of seven peptides. The different peptides were all present in the host, which did not show specific preferences, and could be released under mild acidic conditions. These results show the general nature of the peptide-dendrimer interactions in the formation of either single- or multiple-peptide-dendrimer complexes.

Amines↗

Development of GABA-immunoreactive neuron patterning in the spinal cord.

In the frog Xenopus laevis, gamma-aminobutyric acid (GABA)-immunoreactive spinal cord neurons (Kolmer-Agduhr cells) formed a dispersed pattern within two columns on either side of the midline. The cellular pattern became established during embryonic and larval development. The GABA-immunoreactive cells are cerebrospinal fluid (CSF)-contacting neurons that began to appear by 1.2 days (st 26) of development. This stage occurred shortly after neural tube closure (0.9 days, st 21) and followed the appearance of ultrastructural characteristics of CSF-contacting neurons. The pattern of GABA-immunoreactive cells emerged during embryogenesis, as their density increased. Each longitudinal column was heterogeneous, containing cells with and without GABA immunoreactivity. Spatial analysis at several embryonic and larval stages showed that the cells in each column formed a nonrandom, dispersed pattern even at early stages of differentiation. This one-dimensional pattern resembled that of dopamine-immunoreactive neurons, which are also located in the ventral spinal cord. The patterning of both cell types followed a different time course, but the ultimate spacing of the neurons remained comparable. These results suggested that the mechanism patterning the two cell types within the same region was similar but not identical and may involve related molecular mechanisms.

Aging↗

Noradrenergic and serotoninergic innervation of cortical, thalamic, and tectal visual structures in Old and New World monkeys.

Antisera directed against human dopamine-beta-hydroxylase and against serotonin were used to characterize the noradrenergic (NA) and serotoninergic (5-HT) innervation of several cortical and subcortical visual areas in squirrel monkey (Saimiri sciureus) and cynomolgus monkey (Macaca fascicularis). Few species differences were observed for either monoamine. Cortical areas 17 and 18, as well as visual areas in the temporal and parietal lobe were found to exhibit regional specialization of both 5-HT and NA innervation. Precisely at the border between areas 17 and 18, the laminar innervation patterns and density characteristic of NA fibers in area 17 (Morrison et al., '82a; Kosofsky et al., '84) shift so that layer IV of area 18 contains more fibers than layer IV of area 17, and the overall density of fibers in area 18 is higher. For 5-HT, the highly laminated patterns characteristic of area 17 (Morrison et al., '82a; Kosofsky et al., '84) also observe this cytoarchitectonic boundary. Fibers in area 18 are more evenly distributed across laminae, and the overall density of fibers decreases. The visual region of the inferotemporal cortex was found to be very lightly innervated by NA fibers and very densely innervated by 5-HT fibers. Area 7 of the parietal lobule was more densely innervated by NA fibers, and less densely innervated by 5-HT fibers, than any other visual cortical region examined. The visual thalamic nuclei exhibited even greater regional differences in the density of NA innervation. The lateral geniculate nucleus was found to be virtually devoid of NA fibers, while the pulvinar-lateral posterior complex was densely innervated. The density of 5-HT fibers was more uniform across thalamic visual nuclei. The lateral geniculate, pulvinar, and lateral posterior nuclei all exhibit a moderate to high density of immunoreactive fibers. In the mesencephalon, the superficial layers of the superior colliculus were found to be densely innervated by NA fibers, whereas 5-HT fibers were most dense in the intermediate layers. These patterns of innervation indicate that, in these primate species, functionally related visual regions share common and distinguishable densities of NA innervation. Specifically, tecto-pulvinar-juxtastriate structures are more densely innervated than geniculo-striate and inferotemporal structures. These relationships suggest that, within the visual system, NA fibers preferentially innervate the regions involved in spatial analysis and visuomotor response rather than those involved in feature extraction and pattern analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

A nonrandom interneuronal pattern in the developing frog spinal cord.

In the developing spinal cord of the frog, Xenopus laevis, a population of interneurons assumes a pattern that represents a previously undescribed level of organization. Glyoxylic acid treatment and immunocytochemistry show that the neurons contain catecholamines and their synthetic enzyme, tyrosine hydroxylase. Cells are located within the ependymal layer of the floor plate region of the larval spinal cord. The cells have several processes including a long one that projects toward the brain without fasciculating with other labeled processes. In addition, the cytoplasm of the catecholaminergic cells extends into the central canal, showing that they are a population of cerebrospinal fluid-contacting neurons. The spatial domain of catecholaminergic neurons starts abruptly at the boundary between the hindbrain and spinal cord and continues to the tip of the tail. The neurons occupy two longitudinal columns within the sheet of floor plate cells, which includes cells that do not exhibit the catecholaminergic phenotype. Unlabeled cells are intercalated between catecholaminergic cells in each column, giving the labeled cells the appearance of being spaced along the length of the spinal cord. This general arrangement is evident at the time of hatching. Spatial analysis showed that the position of cells along a column is not random. The nonrandom behavior is due to cells being excluded from the area immediately surrounding other catecholaminergic cells. Further analysis showed that the cellular pattern lacks segmental or other periodic repeats. Ultimately, the location of a cell within a column depends upon the position of its closest catecholaminergic neighbor.

Animals↗

Pak1 and its T212 phosphorylated form accumulate in neurones and epithelial cells of the developing rodent.

The serine/threonine kinase Pak1 is a target of the RhoGTPases Rac and Cdc42 and an important regulator of cell morphology and migration. Recent work from several laboratories has indicated that Pak1 controls microtubule dynamics as well as the organisation of F-actin microfilaments. Pak1 is phosphorylated on T212 by the p35/Cdk5 or cyclin B1/Cdc2 kinase in postmitotic neurones and mitotic cells, respectively. To understand its function during development, we have carried out a detailed temporal and spatial analysis of Pak1 expression and phosphorylation on T212. In the embryonic forebrain, Pak1 and Pak1T212(PO4) were seen to accumulate in the corpus callosum, intermediate zone, lateral olfactory tracts, and anterior commissures. Epithelial cells of the mouse embryo lung, kidney, intestine, and skin also exhibited high levels of Pak1 and Pak1T212(PO4), suggesting a previously unsuspected role in epithelial differentiation. Pak1T212(PO4) was undetectable in all adult tissues. Together, these data indicate a specific, developmentally regulated role of the Pak1 kinase.

Animals↗

AKAP12 Regulates Perivascular OPC Accumulation in the Corpus Callosum During Cerebral Hypoperfusion.

Oligodendrocyte precursor cells (OPCs) have been reported to interact with cerebral microvessels, but the extent and spatiotemporal regulation of this relationship across maturation and hypoperfusion-induced stress remain incompletely defined. Here, we quantified OPC-vessel relationships in the mouse corpus callosum using PDGFR-α/OLIG2/CD31 immunohistochemistry and distance-based spatial analysis, classifying OPCs within 10 μm of CD31+ vessels as perivascular OPCs. We show that while total OPC density decreases from development to adulthood, the proportion of perivascular OPCs increases in the mature brain. Under cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS), OPC density and the enrichment of perivascular OPCs were increased by Day 7 and remained elevated through Days 14-28. Proliferative OPCs (Ki67-positive OPCs) were preferentially observed within the vessel-proximal domain, indicating that the perivascular compartment functions as a stress-responsive proliferative niche. To identify regulators of this response, we focused on A-kinase anchoring protein 12 (AKAP12), a scaffolding protein expressed in vascular cells. In middle-aged Akap12 global knockout mice subjected to BCAS, hypoperfusion-induced OPC increase was preserved, but perivascular accumulation was reduced. This defect was accompanied by increased IgG leakage without a corresponding reduction in vascular area density, suggesting that AKAP12 supports the integrity of the perivascular microenvironment required for OPC niche remodeling. Together, these findings reveal the perivascular niche as a hypoperfusion-responsive compartment for OPC activation and suggest that AKAP12-dependent vascular barrier integrity contributes to the maintenance of this oligovascular niche.

Animals↗

Human brain oscillatory activity phase-locked to painful electrical stimulations: a multi-channel EEG study.

The main aims of this study were 1) a fine spatial analysis of electroencephalographic (EEG) oscillations after galvanic painful stimulation (nonpainful stimulation as a reference) and 2) a comparative evaluation of phase- and nonphase-locked component of these EEG oscillations. Preliminary surface Laplacian transformation of EEG data (31 channels) reduced head volume conductor effects. EEG phase values were computed by FFT analysis and the statistical evaluation of these values was performed by Rayleigh test (P < 0.05). About 50% of the EEG single trials presented statistically the same FFT phase value of the evoked EEG oscillations (phase-locked single trials), indicating a preponderant phase-locked compared to nonphase-locked component. The remaining single trials showed random FFT phase values (nonphase-locked single trials), indicating a preponderant nonphase-locked compared to phase-locked component. Compared to nonpainful stimulation, painful stimulation increased phase-locked theta to gamma band responses in the contralateral hemisphere and decreased the phase-locked beta band response in the ipsilateral hemisphere. Furthermore, nonphase-locked alpha band response decreased in the ipsilateral fronto-central area. In conclusion, both decreased and increased EEG oscillatory responses to galvanic painful stimulation would occur in parallel in different cortical regions and in the phase- and nonphase-locked EEG data sets. This enriches the actual debate on the mapping of event-related oscillatory activity of human brain.

Afferent Pathways↗

Using DRGs in developing referral policies for coronary care within a local health district.

This paper presents the results of a study into some specific aspects of the management of coronary heart disease within one district health authority. In particular, it is concerned with the appropriate balance of inpatient coronary care between the district general hospital and community hospitals in the light of current and potential changes in the clinical management of coronary cases. The study is an example of a multidisciplinary approach to local health planning which is beginning to emerge within the Exeter Health District, the methodology of which may be applicable to client groups within the medical specialties other than coronary cases, such as strokes or respiratory disorders. It also illustrates the use of spatial analysis and diagnosis-related groups in local planning.

Coronary Care Units↗

Spatial and acoustic pressure dependence of microbubble-mediated gene delivery targeted using focused ultrasound.

BACKGROUND: Ultrasound/microbubble-mediated gene delivery has the potential to be targeted to tissue deep in the body by directing the ultrasound beam following vector administration. Application of this technology would be minimally invasive and benefit from the widespread clinical experience of using ultrasound and microbubble contrast agents. In this study we evaluate the targeting ability and spatial distribution of gene delivery using focused ultrasound. METHODS: Using a custom-built exposure tank, Chinese hamster ovary cells in the presence of SonoVue microbubbles and plasmid encoding beta-galactosidase were exposed to ultrasound in the focal plane of a 1 MHz transducer. Gene delivery and cell viability were subsequently assessed. Characterisation of the acoustic field and high-resolution spatial analysis of transfection were used to examine the relationship between gene delivery efficiency and acoustic pressure. RESULTS: In contrast to that seen in the homogeneous field close to the transducer face, gene delivery in the focal plane was concentrated on the ultrasound beam axis. Above a minimum peak-to-peak value of 0.1 MPa, transfection efficiency increased as acoustic pressure increased towards the focus, reaching a maximum above 1 MPa. Delivery was microbubble-dependent and cell viability was maintained. CONCLUSIONS: Gene delivery can be targeted using focused ultrasound and microbubbles. Since delivery is dependent on acoustic pressure, the degree of targeting can be determined by appropriate transducer design to modify the ultrasound field. In contrast to other physical gene delivery approaches, the non-invasive targeting ability of ultrasound makes this technology an attractive option for clinical gene therapy.

Acoustics↗

Downregulation of apoptosis-related genes in keloid tissues.

BACKGROUND: Physiologically programmed cell death or apoptosis occurs during the natural balance between cellular proliferation and demise. MATERIALS AND METHODS: We compared the expression of 64 apoptosis-related genes in keloids and normal scars to investigate the potential role of apoptosis in keloid formation. Two sets of mRNA were isolated from keloids excised from four previously untreated patients and four normal scar patients separately. Human cDNA arrayed hybridization was performed to compare the apoptosis-related gene expression between these two groups. In addition, TUNEL assays were performed to evaluate the percentage of apoptotic cells in keloids (center and periphery) versus normal scars. RESULTS: Eight of the sixty-four apoptosis-related genes studied were significantly underexpressed in keloid tissue. The underexpressed genes and their relative expression compared with normal scar were defender against cell death 1 (DAD-1) (34.1% of normal scar); nucleoside diphosphate kinase B (c-myc transcription factor) (24.7%); glutathione S-transferase (17.9%); glutathione S-transferase microsomal (28.1%); glutathione peroxidase (47.2%); tumor necrosis factor receptor 1-associated protein (TRADD) (51.0%); 19-kDa interacting protein 3 (NIP3) (36.0%); and cytoplasmic dynein light chain 1 (HDLC1) (47.7%). Spatial analysis of apoptosis using TUNEL assays revealed apoptosis indices of 0.83 for keloid periphery and 0.63 for keloid center. CONCLUSIONS: In this study we demonstrated underexpression of apoptosis-related genes in human keloid tissue and decreased apoptotic activity in fibroblasts derived from keloids versus normal scars. We hypothesized that keloid fibroblasts fail to undergo physiologically programmed cell death and, thus, continue to produce and secrete connective tissue beyond the period expected in normal scar formation, accounting for the progressive and hypertrophic nature of keloids. This mechanism leads to new possibilities for treatment of keloids through induction of apoptosis.

Adolescent↗

A robust assessment of the NoGo-anteriorisation of P300 microstates in a cued Continuous Performance Test.

The Continuous Performance Test (CPT) is successfully applied in clinical routine to evaluate attentional performance. The aim of the present study was to investigate the features of the ERPs related to the conditions of a cued CPT, in particular the Go- and the NoGo-condition demanding either the execution or the inhibition of a prepared motor response. For that purpose, 21-channel-ERPs of ten healthy subjects elicited by the Go, NoGo, primer and distractor cues were analyzed with reference-independent methods. The P300 microstates were identified by means of a data-driven segmentation of the ERPs based on the individual peaks of the Global Field Power (GFP). The topographical assessment of the P300 fields yielded an extraordinarily robust result consisting of a more anterior location of the positive centroid in the NoGo compared to the Go condition in every single subject. In conclusion, this result is an impressive validation of the applied reference-independent spatial analysis which reveals the rapid changes of the brain electrical field configurations related to the execution/inhibition paradigm within the cued CPT. Because of the stability of the NoGo anteriorisation we propose to use this parameter as a topographical standard index, analogous to the amplitude effect between oddball targets and nontargets which defines the classical P300.

Adult↗

Biomechanics of the hip: forces exerted during walking.

Since the work of Pauwels, the forces exerted on the coxofemoral joint during walking have been studied either in different spatial planes (frontal, sagittal and horizontal) or by three-dimensional spatial analysis. Starting from the findings of our own studies, our aim was to compare the two methods of analysis (two-dimensional and three-dimensional) in order to provide a better understanding of the benefits and limitations of each method. In pursuit of this aim, we studied the pressure forces exerted on the coxofemoral joint, using a geometric plane technique following a method similar to that of Pauwels [20], and with a three-dimensional modelling technique using the finite element method. The material, taken from the published literature, was the same in both our studies. The results are expressed in terms of the size and orientation of the pressure force exerted on the coxofemoral joint during the monopodal weightbearing phase of walking. A comparison of these two methods of analysis clearly demonstrates the simplicity of two-dimensional analysis (which must incorporate as a minimum the frontal plane and the sagittal plane) and the richness of the three-dimensional analysis. The latter method, by appropriate manipulation of the information obtained, provides a starting point for computer simulations performed with the aim of testing a biomechanical or therapeutic hypothesis.

Biomechanical Phenomena↗

Role of dopaminoreactive systems of the cortex and the neostriatum in the organization of situational conditioned reflexes.

The results of experiments on dogs with dysfunction of the dopaminoreactive system of the brain suggest the nonidenticality of its different divisions (cortical, striatal, mesencephalic) in the organization of situational conditioned reflexes. It was demonstrated that the nigrostriatal system is involved to a greater degree in the spatial analysis of signals, while the mesocortical system is more involved in the analysis of their biological significance. The dopaminoreactive system of the caudate nucleus is associated to a greater degree with the realization of cognitive, while that of the putamen is associated with the realization of motor programs of situational conditioned reflexes. The thesis of the necessity of the coordinated functioning of the DA-reactive systems for the organization of goal-directed behavior is substantiated.

Acoustic Stimulation↗

Laser tomography of heterogeneous scattering media using spatial and temporal resolution.

Time-resolved tomography is performed in transillumination by using 527 nm picosecond pulses from a passively mode-locked doubled Nd/glass laser and a streak camera to select photons according to their flight time. This work reports on the increase in contrast of a time-resolved profile of a 2 mm radius opaque object embedded in a scattering medium, constituted of diluted milk in a 30 mm thick cell. For spatial analysis, the emerging photons are detected through a 6 mm slit at the outlet face of the cell. Transmission profiles obtained as a function of time show that the contrast is enhanced for the shortest flight times, while the 'shadow' of the object is no longer detected after about 100 ps. Moreover, improvements in contrast are studied for different configurations of the model, to analyse separately the role of collimated and scattered photons. It is expected that such a tomographic method based on time-resolved absorption could be applied to imaging for more complex biological structures in the red and near-infra-red range.

Humans↗