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Dynamic joint analysis as a method to document coordination disabilities associated with Parkinson's disease.

OBJECTIVE: The purpose of the present study was to introduce dynamic joint analysis and subsequent phase partitioning of the movement pattern as a method for investigating the force control deficits associated with Parkinson's disease. DESIGN: Pilot data were collected from four non-impaired individuals and four patients afflicted with Parkinson's disease while performing arm movements of different spatiotemporal features. BACKGROUND: Investigation of motor performance in Parkinson's patients has related the clinically observed symptoms to the ability to control muscular force. METHODS: Experimental movements were filmed using a high speed camera operating at 200 Hz. The mechanical power characteristics of the elbow and shoulder were determined by applying inverse dynamic solutions to the kinematic data. Movement was reflected in a series of goal-directed phases describing the functional role of muscle activity across the joint. RESULTS: The analysis revealed that Parkinson's disease impairs the ability of the muscles to produce the energy required for performing ballistic, segmental movements. Moreover, patients demonstrated greater difficulty in controlling a two-joint task as opposed to a single-joint one; this was reflected by additional phases of activity at the elbow. CONCLUSIONS: Slowness of movement is associated with the inappropriate scaling of the muscle force, as well as with the limited use of motion-dependent forces in accelerating distal segment movement.

Journal Article↗

A phylotypic stage in vertebrate brain development: GABA cell patterns in zebrafish compared with mouse.

A recent comparison of early forebrain gene expression in mouse and zebrafish revealed highly comparable expression patterns of developmentally relevant genes, for example, of proneural (Neurogenin1, NeuroD, Mash1/Zash1a) genes involved in neurogenesis at a particular time window (mouse: embryonic day 12.5/13.5; zebrafish: 3 days). Here we extend this analysis to the description of gamma-aminobutyric acid (GABA) cell patterns in the early postembryonic zebrafish brain (i.e., during early secondary neurogenesis). We find again an astonishing degree of correspondences of GABA cell patterns between zebrafish and mouse during this previously established critical time window, for example, regarding absence of GABA cells in certain forebrain regions (pallium, dorsal thalamus, eminentia thalami) or with respect to the spatiotemporal occurrence of GABA cells (e.g., late cerebellar GABA cells). Furthermore, there is perfect correlation with previously established proneural gene expression patterns (i.e., absence of Mash1/Zash1a gene expression in GABA-cell-free forebrain regions) between mouse and zebrafish. The available information in additional vertebrate species, especially in Xenopus, is also highly consistent with our analysis here and suggests that a "phylotypic stage" of neurogenesis during vertebrate brain development may be present.

Animals↗

Oligodendrocyte and astrocyte development in rodents: an in situ and immunohistological analysis during embryonic development.

Lineally related multipotent neuroepithelial cells (NEP), neuronal restricted precursors (NRP), and glial restricted precursors (GRP) have been identified in the spinal cord. To determine the sequence of differentiation and identify lineage and stage-specific markers, we have examined the spatiotemporal expression of established glial markers during rodent embryonic development and within fetal cell culture. In this report, we show that proliferating stem cells in the developing neural tube do not express any glial markers at E10.5. By E11, however, glial precursors have begun to differentiate and at least two regions of the ventral neural tube containing glial precursor cells can be distinguished, an Nkx2.2/Neurogenin 3 (Ngn3) domain and a platelet-derived growth factor receptor alpha (PDGFRalpha)/Olig2/Sox10 domain. Radial glia, as identified by RC1 immunoreactivity, develop in concert with other glial precursors and can be distinguished by their morphology, spatial distribution, and antigen expression. Astrocytes as assessed by glial fibrillary acidic protein (GFAP) immunoreactivity are first detected at E16. A novel dorsal domain of CD44 immunoreactivity that can be distinguished from the more ventral glial precursor domains can be detected as early as E13.5.

Animals↗

Activation of murine cytomegalovirus immediate-early promoter in cerebral ventricular zone and glial progenitor cells in transgenic mice.

Cytomegalovirus (CMV) is the most common infectious cause of congenital anomalies of the CNS in humans. We recently reported that the murine cytomegalovirus (MCMV) immediate-early (IE) gene promoter directs astrocyte-specific expression in adult transgenic mice. In the present study, we analyzed the activation of the MCMV IE promoter in developing transgenic mouse brains and compared the activation with that of the Musashi 1 (Msi1) gene, which is expressed in neural progenitor cells, including neural stem cells. During the early phase of neurogenesis, the transgene was expressed predominantly in endothelial cells of the vessels, but not in neuroepithelial cells in which Msi1 was expressed. During later stages of gestation, expression of the transgene was largely restricted to the ventricular zone (VZ) in the CNS, similar to the expression of Msi1. In neurosphere cultures from transgenic embryos in the late phase of neurogenesis, the transgene was expressed in some cells of neurospheres expressing Msi1 and nestin. In neural precursor cells induced to differentiate from stem cells, expression of the transgene was detected in glial progenitor cells, expressing GFAP, nestin, and Msi1, but not in cells expressing MAP2 or MAG. In postnatal development, persistent expression of the transgene was observed in astrocyte lineage cells as was Msi1. These spatiotemporal changes of the MCMV IE promoter activity during development of transgenic mice correlated with susceptible sites in congenital HCMV infection. Moreover, this transgenic mouse model may provide useful model for analysis of the regulation of the switching of neuronal and astrocyte differentiation, and the maintenance of the astrocyte lineage.

Animals↗

Upregulation of annexins I, II, and V after traumatic spinal cord injury in adult rats.

The posttraumatic inflammatory reaction contributes to progressive tissue damage after spinal cord injury (SCI). Annexins, a family of structurally related calcium- and phospholipid-binding proteins, have potent anti-inflammatory effects by inhibiting the activity of phospholipase A(2) (PLA(2)), a key enzyme responsible for inflammation and cytotoxicity. We investigated spatiotemporal expression of annexins I, II, and V after a contusive SCI using the New York University impact device (a 10-g rod, height 12.5 mm) in adult rats. Western blot analysis revealed that annexin I expression increased at 3 days after injury, peaked at 7 days (1.75-fold above the baseline level; P < 0.01), started to decline at 14 days, and returned to the baseline level at and beyond 28 days post-injury. The expression of annexin II started to increase at 3 days, reached its maximal level at 14 days (2.73-fold; P < 0.01), remained at a high level up to 28 days, and then declined to the basal level by 56 days after injury. Annexin V expression started at 3 days, reached its maximal level at 7 days (1.61-fold; P < 0.05) and remained at this level until 56 days after injury. RT-PCR results confirmed expression of all three annexins at the mRNA level after SCI. Immunohistochemistry and immunofluorescence double-labeling analyses revealed that increased annexins I, II, and V were localized in neurons and glial cells. The present study thus revealed increased expression of the three annexin isoforms after moderate contusive SCI. The precise role of annexins in posttraumatic inflammation and neuroprotection after SCI remains to be determined.

Animals↗

Magnetic effect for electrochemically driven cellular convection.

Hydrodynamic instability analogous to Rayleigh-Bénard convection is observed in an electrolytic solution between two parallel copper wire electrodes. The laser interferometric technique can reveal the dissipation structure created by the motion of the fluid, which is controlled electrochemically. It is shown that under the presence of horizontal magnetic field the roll cells move horizontally along the electrodes. The electrochemically driven convection is simply controlled and monitored by setting and measuring the electrochemical parameters and forms many kinds of spatiotemporal patterns, especially under the magnetic field. The phenomenon is modeled by considering a Boussinesq fluid under a concentration gradient. The stability of the resulting equations is studied by linear stability analysis. The time dependent nonlinear system is investigated numerically and the main features of the experimental response are reproduced.

Journal Article↗

Nonequilibrium wetting transitions with short range forces.

We analyze within mean-field theory as well as numerically a Kardar-Parisi-Zhang equation that describes nonequilibrium wetting. Both complete and critical wettitng transitions were found and characterized in detail. For one-dimensional substrates the critical weting temperature is depressed by fluctuations. In addition, we have investigated a region in the space of parameters (temperature and chemical potential) where the wet and nonwet phases coexist. Finite-size scaling analysis of the interfacial detaching times indicates that the finite coexistence region survives in the thermodynamic limit. Within this region we have observed (stable or very long lived) structures related to spatiotemporal intermittency in other systems. In the interfacial representation these structures exhibit perfect triangular (pyramidal) patterns in one dimension (two dimensions), which are characterized by their slope and size distribution.

Journal Article↗

Cortical potential distributions and information processing.

The use of sets of spatiotemporal cortical potential distributions (CPDs) as the basis for cognitive information processing results in a very large space of cognitive elements with natural metrics. Results obtained from current source density (CSD) analysis suggest that in the CPD picture, action potentials may make only a relatively minor contribution to the brain's code. In order to establish if two CPDs are close, we consider standard metrics in spaces of continuous functions, and these may be employed to ascertain if two stimuli will be identified as the same. The correspondence between the electrical activity within brain regions, including not only action potentials but all postsynaptic potentials (PSPs), and CPDs is considered. We examine the possibility of using the CSD approach to find potential distributions using the descriptive approach in which precise sets of times are ascribed to the occurrence of action potentials and PSPs. Using metrics in the multidimensional space of paths of collections of point processes, we show that closeness of CPDs is implied by closeness of sets of spike times and PSP times if a certain metric is used but not others. We also set forth a dynamical model consisting of a system of reaction-dif fusion equations for ionic concentrations coupled with nerve membrane potential equations and active transport systems. Making the approximation of a descriptive approach, the correspondence between sets of spike times and PSP times and CPDs is obtained as with the CSD method. However, since it is not possible to ascribe precise times to the occurrence of PSPs and action potentials, the descriptive approach cannot be used to describe the configuration of electrical activity in cortical regions accurately. We also discuss how the CPD framework relates to the binding problem and submillisecond timing.

Algorithms↗

Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs. remote non-ischemic cortex.

Focal brain infarcts are surrounded by extended perilesional zones that comprise the partially ischemic penumbra but also completely non-ischemic cortex of the remote ipsilateral hemisphere. To delineate the impact of lesion-associated vs. remote processes on transcriptional programming after focal ischemia, we used cDNA array analysis, quantitative real-time polymerase chain reaction and immunohistochemistry in the photothrombosis model of circumscribed cortical ischemia in rats. At an early stage of 4 h after ischemia, gene induction occurred to a similar extent in the ischemic infarct and remote non-ischemic cortex of the ipsilateral hemisphere. Among the genes induced in non-ischemic cortex we found the NGF-inducible genes PC3, VGF and Arc, the transcriptional regulators I kappa B-alpha and Stat3, and the beta-chemokine MIP-1 alpha (CCL3). At 3 days, the spatial pattern of gene expression had changed dramatically with brain fatty acid-binding protein as the only gene significantly induced in non-ischemic ipsilateral cortex. In contrast, numerous genes were exclusively regulated at the lesion site, comprising genes involved in cell cycle regulation, proteolysis, apoptosis, lipid homeostasis and anti-inflammatory counter-regulation. Cortical spreading depression was identified as the main mechanism underlying gene induction in remote non-ischemic cortex. Our data demonstrate a dynamic spatiotemporal pattern of gene induction, which may contribute to delayed progression of damage or, alternatively, mediate neuroprotection, tissue remodeling and functional compensation.

AIDS-Related Complex↗

Spatial analysis of 3' phosphoinositide signaling in living fibroblasts, III: influence of cell morphology and morphological Polarity.

Activation of phosphoinositide (PI) 3-kinase is a required signaling pathway in fibroblast migration directed by platelet-derived growth factor. The pattern of 3' PI lipids in the plasma membrane, integrating local PI 3-kinase activity as well as 3' PI diffusion and turnover, influences the spatiotemporal regulation of the cytoskeleton. In fibroblasts stimulated uniformly with platelet-derived growth factor, visualized using total internal reflection fluorescence microscopy, we consistently observed localized regions with significantly higher or lower 3' PI levels than adjacent regions (hot and cold spots, respectively). A typical cell contained multiple hot spots, coinciding with apparent leading edge structures, and at most one cold spot at the rear. Using a framework for finite-element modeling with actual cell contact area geometries, we find that although the 3' PI pattern is affected by irregular contact area shape, cell morphology alone cannot explain the presence of hot or cold spots. Our results and analysis instead suggest that these regions reflect different local 3' PI dynamics, specifically through a combination of mechanisms: enhanced PI 3-kinase activity, reduced 3' PI turnover, and possibly slow/constrained 3' PI diffusion. The morphological polarity of the cell may thus bias 3' PI signaling to promote persistent migration in fibroblasts.

Animals↗

Spatiotemporal continuity implicated in the binding of features and object identity.

This study continues the work of Anes et al. (in preparation) in which manipulation of features incidental to an object elicited robust effects in a dynamic object recognition paradigm. In the current series, the spatiotemporal continuity of identity and feature presentation is increasingly distorted between experiments in an attempt to disrupt a process Triesman (1996) calls "binding" of an object's identity and features. Across three experiments, increasing disruption of spatiotemporal continuity significantly diminished the effect of features on object identification, evidence that spatiotemporal continuity is, in part, responsible for binding features to an object.

Adult↗

Electrotonically mediated oscillatory patterns in neuronal ensembles: an in vitro voltage-dependent dye-imaging study in the inferior olive.

Spatiotemporal profiles of ensemble subthreshold neuronal oscillation were studied in brainstem slices using high-speed voltage-sensitive dye imaging. After local electrical stimuli, the overall voltage profile demonstrated coherent oscillatory waves that spread over the inferior olive (IO). These oscillations were also observed in concurrently obtained intracellular recordings from IO neurons. Over the first few seconds after the stimuli, the optically recorded oscillations clustered into coherent groups comprising hundreds of neurons. Statistical analysis of the spatial profiles of these clusters revealed size fluctuation around stable core regions that were surrounded by a rim the diameter of which varied in time during the oscillation period. The neuronal ensemble oscillations were calcium derived and had an average frequency range of 1-7 Hz. This rhythmic response demonstrated a different spatiotemporal distribution in the presence of picrotoxin, which induced the merging of neuronal clusters into larger areas of coherent activity. The possibility that such clustering is a consequence of intrinsic oscillations in ensembles of coupled neurons was tested using mathematical modeling.

Action Potentials↗

Modulation of theta/alpha frequency profiles of slow auditory-evoked responses in the songbird zebra finch.

Spatiotemporal patterns of forebrain neural activity associated with auditory perception of biologically relevant complex acoustic stimuli can be conveniently studied in the songbird zebra finch. Here we present a time-frequency analysis of averaged slow auditory-evoked potentials (sAEPs) obtained at electrode locations overlying the main song control nucleus, high vocal center. Gabor spectrograms of these sAEPs show a prolonged response time course consisting of unimodal frequency peaks in the theta/alpha range (4-17 Hz). There is a stimulus-dependent modulation of the duration of the response and of the total number of its constituent frequency peaks, an effect that is bilateral in 75% of the birds and lateralized to the left side in the remaining 25%. Since the state of alertness of birds modulates these parameters along a similar continuum, these findings suggest that modulation of sAEP frequency profile may be dependent on attentional mechanisms. The presence and modulation of neurobiologically ubiquitous dominant frequency components also implicate the possible role of induced cerebral neuronal circuit oscillations in songbird auditory perception.

Acoustic Stimulation↗

Cortically coupled computer vision for rapid image search.

We describe a real-time electroencephalography (EEG)-based brain-computer interface system for triaging imagery presented using rapid serial visual presentation. A target image in a sequence of nontarget distractor images elicits in the EEG a stereotypical spatiotemporal response, which can be detected. A pattern classifier uses this response to reprioritize the image sequence, placing detected targets in the front of an image stack. We use single-trial analysis based on linear discrimination to recover spatial components that reflect differences in EEG activity evoked by target versus nontarget images. We find an optimal set of spatial weights for 59 EEG sensors within a sliding 50-ms time window. Using this simple classifier allows us to process EEG in real time. The detection accuracy across five subjects is on average 92%, i.e., in a sequence of 2500 images, resorting images based on detector output results in 92% of target images being moved from a random position in the sequence to one of the first 250 images (first 10% of the sequence). The approach leverages the highly robust and invariant object recognition capabilities of the human visual system, using single-trial EEG analysis to efficiently detect neural signatures correlated with the recognition event.

Algorithms↗

Interactions between cat lateral geniculate neurons.

Action potentials of 31 pairs of cat LGN neurons were recorded on single electrodes. Cross-correlograms, response planes, and a new function, the logical response plane, were calculated. The cross-correlograms between these pairs revealed four interactive classes: 1) a class with a flat cross-correlogram, 2) a class with a peak in the center of the cross-correlogram seen both during spontaneous activity and during driven activity, 3) a class with an inhibitory dip in the center of the cross-correlogram seen only when the cell pairs were driven by a stimulus and predicted by the shift predictor, 4) finally, a class with an inhibitory dip in the center of the cross-correlogram seen both during driven activity and spontaneous activity and not predicted by the shift predictor. Response plane pairs calculated for the unit pairs with flat cross-correlograms showed no predictable relationship. The pairs with a dip in the center of the cross-correlograms always had response planes that were antagonistic (i.e., approximate negative images of each other). When one cell was excited, the second cell was inhibited, and vice versa. More detailed analysis, using the logical response plane, demonstrated that the majority of the antagonistic response planes had either excitatory or inhibitory overlap. That is, the cells were simultaneously excited and/or inhibited at specific spatiotemporal loci on the response plane. These data are consistent with a feed-forward inhibitory circuit in LGN. Furthermore, the data suggest that retinal centers (PE domains) produce LGN excitatory centers (PE domains) and inhibitory centers (PI domains). In turn, retinal excitatory surrounds (SE domains) produce LGN excitatory surrounds (SE domains) and inhibitory surrounds (SI domains).

Action Potentials↗

Significance of serum early pregnancy factor concentrations during pregnancy and embryonic development in Sminthopsis macroura (Spencer) (Marsupialia: Dasyuridae).

Marsupial pregnancy differs from that in eutherians in duration, placentation and hormonal profile so much so that maternal recognition of pregnancy may not occur in polyovular marsupials. However, a comparison of gravid and non-gravid uteri reveals differences indicative of histological and physiological adaptations to pregnancy. In the present study, the hypothesis that embryo-maternal signalling occurs in polyovular marsupials was tested by examining serum from non-pregnant and pregnant Sminthopsis macroura for the presence of early pregnancy factor (EPF), a serum protein secreted by the ovary in response to the presence of a newly fertilized egg in the oviduct. EPF is detectable in the serum of pregnant, but not in non-pregnant, females in all eutherians studied to date. In the present study, EPF was detected in S. macroura serum by the rosette inhibition test during the first 9 days of the 10.7 day gestation period in this marsupial. However, EPF was not detected on day 10, just before parturition, or in non-pregnant or preovulatory animals. Immunohistochemical analysis of ovaries from gravid and non-gravid animals demonstrates that EPF is found in the capillaries, interstitial spaces and secretory cells of the corpus luteum. It is concluded that the spatiotemporal pattern of EPF activity described strongly indicates that maternal recognition of pregnancy in marsupials is mediated, at least in part, by EPF. Because the endocrinological milieu is the same in pregnant and non-pregnant marsupials, the possibility of using marsupials as an experimental system for studying EPF function unconfounded by hormonal effects is presented.

Animals↗

Neural tube is partially dorsalized by overexpression of HrPax-37: the ascidian homologue of Pax-3 and Pax-7.

The origin and elaboration of the central nervous system played an important role in chordate and vertebrate history. All chordates possess a dorsal tubular central nervous system, but elaboration of dorsoventral and segmental pattern is far more pronounced in cephalochordates and vertebrates than in the more basal urochordates. Analysis of the urochordates, therefore, should allow deduction of the neural organization and neuronal patterning mechanisms that predated overt dorsoventral and segmental complexity. Here we report functional studies of the ascidian Pax gene (HrPax-37). The spatiotemporal expression pattern of HrPax-37 has suggested involvement in two distinct developmental processes: specification of dorsal cell fates of ectoderm during neurulation, and regional differentiation of the neural tube in later stages. Here we show that HrPax-37 is descendent from the precursor of the Pax-3 and Pax-7 genes implicated in specification of dorsal fate in the vertebrate neural tube. We also demonstrate that injection of HrPax-37 RNA into fertilized eggs causes ectopic expression of the dorsal neural marker tyrosinase gene in neurulae, confirming a regulatory role in dorsal patterning of the neural tube comparable to its vertebrate homologues. These results suggest that dorsal specification in the neural tube by Pax-3/7 subfamily genes was established in the ancestors of extant chordates during emergence of the dorsal tubular nervous system.

Amino Acid Sequence↗

Integrative analysis of transcriptome and DNA methylome dynamics during caudal fin regeneration in silver pomfret (Pampus argenteus).

Caudal fin regeneration in teleost fish is a complex, multi-stage process involving coordinated molecular and cellular changes. While the role of epigenetic regulation particularly DNA methylation has been studied in model freshwater species such as zebrafish, its contribution to regeneration in marine teleosts remains largely unexplored. In this study, we integrated transcriptomic and DNA methylomic data to characterize the temporal dynamics of gene expression and methylation during caudal fin regeneration in the silver pomfret (Pampus argenteus). Using RNA-sequencing and reduced representation bisulfite sequencing (RRBS) at three biologically critical time points 1, 3, and 7&#xa0;days post-amputation (dpa), we characterized the spatiotemporal molecular landscape of caudal fin regeneration. These time points capture the key transitional phases of wound healing and inflammation (1 dpa), blastema formation and progenitor proliferation (3 dpa), and regenerative outgrowth with tissue remodeling (7 dpa), enabling robust detection of the major molecular programs underlying epimorphic regeneration. Concurrently, CG-methylome analysis identified thousands of dynamically changing differentially methylated regions (DMRs). A strong global inverse correlation was observed between promoter methylation and gene expression. Integrative analysis pinpointed key regeneration genes (fgf20a, msxb, sox9b) whose expression was associated with dynamic methylation changes in their promoters or gene bodies. We conclude that DNA methylation is a dynamic and key regulatory layer that acts in concert with transcriptional reprogramming to coordinate tissue regeneration, providing new insights into the epigenetic mechanisms underlying complex regenerative processes in teleosts.

Animals↗