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PubMed2003

The origin of brain asymmetry and its psychotic reversal.

Ontogenetic brain-asymmetry and its reversal in schizophrenia constitute special cases of a more fundamental principle of sensory-motor integration. Transmitted through an immature optical system, asymmetric inputs from the left visual field induce the infant's right hemispheric preference for lower spatial frequencies during early mother-child interaction. The emerging classical features of hemispheric specialisation later in life can be accounted for by a transformation law of the neuronal reference frames based on relativistic non-linear information processing. Accordingly, the asymmetric distributions of the cannabinoid receptor CB1 in the right basal ganglia and the left area of Wernicke reflect the preferences for lateralised posture, positioning, and speech. Epigenetic development of brain asymmetry thus unifies the different aspects related to cradling and breast-feeding, speech- and visuospatial processing, the dimensional conversion of spatiotemporal information and, in the case of a dysbalanced cannabinoid system, its psychotic reversal. The predicted right hemispheric shift and the inverse relationship between Kolmogorov entropy and its dimensional embedding (Shannon entropy) has ultimately been confirmed by non-linear EEG analysis of a fluoro-methyl-anadamide induced model psychosis splitting conscious from unconscious mental processes.

Brain↗
PubMed1996

Comprehensive gait analysis in posterior-stabilized knee arthroplasty.

Sixteen patients implanted with a posterior-stabilized prosthesis (Insall-Burstein PS II, Zimmer, Warsaw, IN) and 32 age-matched control subjects were evaluated by isokinetic muscle testing and comprehensive gait analysis at a mean 46 months following the index arthroplasty. The contralateral knee was normal in 13 patients and an asymptomatic total knee arthroplasty in 3 patients. No significant differences (P > .05) were found between the study and control groups in spatiotemporal gait parameters nor were there isokinetic strength deficits. A prolonged firing of the vastus medialis was observed in some patients. Knee range of motion during level walking and stair descent was decreased significantly (P < .05) in the study group. There was no significant difference for knee range of motion between the study and control groups during stair ascent. Spatiotemporal gait parameters in the total knee arthroplasty patients show no significant differences from the control subject at nearly 4 years after surgery. However, other gait abnormalities are present and cannot be accounted for on the basis of muscle weakness, abnormal phasic muscle activity, or inadequate knee range of motion. With reference to historic control subjects, the persistent gait abnormalities of patients implanted with posterior-stabilized prostheses (posterior cruciate substituting) are comparable to those of patients implanted with cruciate-retaining prostheses and superior to cruciate-sacrificing prostheses.

Adult↗
PubMed2003

MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum.

Matrix metalloproteinases (MMPs) are responsible for the extensive extracellular proteolysis that plays a central role in regulating the pericellular environment, contributing to morphogenesis and developmental remodeling. In the CNS, there is increasing in vitro evidence for the involvement of MMPs in neurite elongation and axonal guidance. Here, we show that expression of MMP-9 is spatiotemporally related to cerebellar granule cell migration during postnatal development. Using cerebellar explant cultures, we demonstrated that a specific MMP-9-blocking antibody affects granular cell axonal outgrowth and migration in a dose-dependent manner. In addition, the in vivo analysis of MMP-9-deficient mice revealed abnormal accumulation of granular precursors (GPs) in the external granular layer (EGL) at a time when migration is normally extensive. Furthermore, GP migration was delayed and their programmed cell death was reduced in MMP-9-deficient mice, suggesting that MMP-9 is involved in the control of granule cell migration and apoptosis. These results provide direct evidence for a physiological role of MMP-9 in neuronal precursor migration and apoptosis in the developing cerebellum, and emphasize the importance of MMP-9 in the temporal regulation of the cerebellar microenvironment.

Animals↗
PubMed2003

The dynamic expression of tenascin-C and tenascin-X during early heart development in the mouse.

One of a family of extracellular matrix proteins, tenascin-C (TNC) is expressed in a spatiotemporally restricted pattern associated with tissue remodeling during embryonic development, wound healing, cancer invasion and tissue regeneration. Another form, tenascin-X (TNX), is found in most tissues but most predominantly in heart and muscle, often complementarily to TNC. The present analysis demonstrated their expression during early heart development, using mouse lines containing the lacZ gene targeted to the TNC locus, by RT-PCR, immunohistochemistry, and in situ hybridization. TNC was transiently expressed at important steps during heart development: (1) precardiac mesodermal cells differentiating to cardiomyocytes and endocardial cells at E 7.5 - 8.5; (2) cardiomyocytes in the outflow tract at E 8.5 - 12; (3) endocardial cells forming cushion tissue at E 9.5 - 13; and (4) mesenchymal cells in the proepicardial organ (PEO), the precursors of coronary vessels, at E 9.5. When PEO cells were transferred onto the heart surface, the expression of TNC was downregulated, while TNX was upregulated at E 11. Initially, epicardial cells around the AV groove and atrium started to express TNX. TNX-positive cells then gradually spread all over the entire surface of the heart and invaded and formed primitive vascular channels in the myocardium. Despite restricted expression at important sites and steps during cardiogenesis, the hearts of TNC deficient mice developed normally. No difference in the expression pattern of TNX were observed in TNC knockout and wild mice. These results suggest; (1) TNC could play important roles in the differentiation of cardiomyocytes and the early morphogenesis of the heart; (2) TNX could be involved in coronary vasculogenesis; (3) TNX does not compensate for the loss of TNC.

Animals↗
PubMed2002

Modeling and estimation problems in the turtle visual cortex.

The goal of this paper is to verify that position and velocity of a spot of light incident on the retina of a turtle are encoded by the spatiotemporal dynamics of the cortical waves they generate. This conjecture is examined using a biophysically realistic large-scale computational model of the visual cortex implemented with the software package, GENESIS. The cortical waves are recorded and analyzed using principal components analysis and the position and velocity information from visual space is mapped onto an abstract B-space, to be described, using the coefficients of the principal components expansion. The likely values of the position/velocity are estimated using standard statistical detection methods.

Algorithms↗
PubMed2006

Effect of hiatal hernia on proximal oesophageal acid clearance in gastro-oesophageal reflux disease patients.

BACKGROUND: Proximal acid reflux is common in gastro-oesophageal reflux disease and is a determinant of symptoms. Patients with hiatal hernia complain of more symptoms than those without and are less responsive to proton-pump inhibitors. AIM: To evaluate the role of hiatal hernia on spatiotemporal characteristics of acid reflux. METHODS: Thirty seven consecutive gastro-oesophageal reflux disease patients underwent endoscopy, videofluoroscopy, manometry and multichannel 24-h pH test. Data were compared with those of 15 asymptomatic controls. Multivariate linear regression was used for statistical analysis. RESULTS: At videofluoroscopy, hiatal hernia was found in 16 of 37 patients. The mean size of hiatal hernia was 3.4 cm. Patients showed significantly prolonged acid clearance time, both at proximal and distal oesophagus, compared with controls. Hiatal hernia patients showed a significantly delayed acid clearance, along the oesophageal body, compared with non-hiatal hernia patients. The prolonged acid exposure was maintained during upright and supine position. The presence of hiatal hernia significantly predicted acid clearance delay in the distal and proximal oesophagus [at 10 cm below upper oesophageal sphincter: Delta + 2.5 min (95% confidence interval: 0.4-4.5); P < 0.02]. CONCLUSIONS: The presence of hiatal hernia is a strong predictor of more prolonged proximal oesophageal acid exposure and clearance. Hiatal hernia is likely to play a role in the pathophysiology of gastro-oesophageal reflux disease symptoms, and should be taken into greater consideration in the treatment strategies of the disease.

Adult↗
PubMed2000

A novel color M-mode Doppler echocardiographic index for left ventricular relaxation: depth of the maximal velocity point of left ventricular inflow in early diastole.

Color M-mode Doppler echocardiography (CMD) has been utilized in assessing left ventricular (LV) filling dynamics. We tested a novel CMD index, the depth of the spatiotemporal maximum of early diastolic inflow (D-maxV) in the left ventricle, to clarify its significance in assessing LV diastolic function. In 26 normal subjects and 32 patients with ischemic heart disease, D-maxV was determined with CMD as the distance from the mitral valve opening point to the center of the aliasing area in early diastole. Transmitral flow velocity was measured with pulsed Doppler. During routine catheterization, high-fidelity LV pressure measurements yielded diastolic variables in patients. D-maxV was significantly lower in the patients than the normals (13.0+/-7.0 vs 23.4+/-6.8 mm, P < 0.0001). D-maxV exhibited significant linear correlations with the minimal first derivative of LV pressure (r = 0.72, P < 0.01), the time constant of isovolumic relaxation (r = -0.67, P < 0.01), and LV minimal pressure (r = -0.53, P < 0.02) in the patients with wide ranges of peak early to late inflow velocity ratio (0.43-3.9) and deceleration time of early filling (79-293 ms). D-maxV showed an inverse correlation with LV end-diastolic pressure (r = -0.53, P < 0.02) and no significant correlation with mean pulmonary capillary wedge pressure. Moreover, Kaplan-Meier analysis focusing on the patients with myocardial infarction revealed that the group with D-maxV < 10.4 mm (n = 13) exhibited a lower cumulative cardiac event-free rate than that with D-maxV > or = 10.4mm (n = 14) (49.4% vs 92.9% at 5 years, P < 0.05). The depth of the spatiotemporal maximum of early diastolic LV inflow velocity reflects LV relaxation and is free of pseudonormalization. Evaluation of the LV relaxation separately from preload may have a prognostic value for myocardial infarction.

Adult↗
PubMed1999

A hot/cool-system analysis of delay of gratification: dynamics of willpower.

A 2-system framework is proposed for understanding the processes that enable--and undermine--self-control or "willpower" as exemplified in the delay of gratification paradigm. A cool, cognitive "know" system and a hot, emotional "go" system are postulated. The cool system is cognitive, emotionally neutral, contemplative, flexible, integrated, coherent, spatiotemporal, slow, episodic, and strategic. It is the seat of self-regulation and self-control. The hot system is the basis of emotionality, fears as well as passions--impulsive and reflexive--initially controlled by innate releasing stimuli (and, thus, literally under "stimulus control"): it is fundamental for emotional (classical) conditioning and undermines efforts at self-control. The balance between the hot and cool systems is determined by stress, developmental level, and the individual's self-regulatory dynamics. The interactions between these systems allow explanation of findings on willpower from 3 decades of research.

Disruptive, Impulse Control, and Conduct Disorders↗
PubMed2006

Oscillations, period doublings, and chaos in CO oxidation and catalytic mufflers.

Early experimental observations of chaotic behavior arising via the period-doubling route for the CO catalytic oxidation both on Pt(110) and Ptgamma-Al(2)O(3) porous catalyst were reported more than 15 years ago. Recently, a detailed kinetic reaction scheme including over 20 reaction steps was proposed for the catalytic CO oxidation, NO(x) reduction, and hydrocarbon oxidation taking place in a three-way catalyst (TWC) converter, the most common reactor for detoxification of automobile exhaust gases. This reactor is typically operated with periodic variation of inlet oxygen concentration. For an unforced lumped model, we report results of the stoichiometric network analysis of a CO reaction subnetwork determining feedback loops, which cause the oscillations within certain regions of parameters in bifurcation diagrams constructed by numerical continuation techniques. For a forced system, numerical simulations of the CO oxidation reveal the existence of a period-doubling route to chaos. The dependence of the rotation number on the amplitude and period of forcing shows a typical bifurcation structure of Arnold tongues ordered according to Farey sequences, and positive Lyapunov exponents for sufficiently large forcing amplitudes indicate the presence of chaotic dynamics. Multiple periodic and aperiodic time courses of outlet concentrations were also found in simulations using the lumped model with the full TWC kinetics. Numerical solutions of the distributed model in two geometric coordinates with the CO oxidation subnetwork consisting of several tens of nonlinear partial differential equations show oscillations of the outlet reactor concentrations and, in the presence of forcing, multiple periodic and aperiodic oscillations. Spatiotemporal concentration patterns illustrate the complexity of processes within the reactor.

Carbon Monoxide↗
PubMed1983

Basic aspects of development and maturation of the brain: embryological contributions to neuroendocrinology.

The interpretation of studies on the development of neuroendocrine function presupposes a thorough knowledge of the complementary phenomena of morphogenesis and histogenesis of the brain. A short analysis of the morphogenesis of the diencephalic floor is given. The pituitary Anlage can be identified early in the neural plate stage. The hypophysis cerebri appears to be a key structure in the morphogenesis of both the head and the brain. The spatiotemporal pattern of histogenesis within the brain can be analysed by a study of the proliferative activity of the neuroepithelial matrix cell layer; a heterochrony of matrix (ventricular) layer mitotic activity and of mantle (intermediate) layer differentiation can be demonstrated. The process of neuron differentiation shows an articulate sequence of phenomena, among them migration, axon growth, dendrite growth, synapse formation and myelination. Dendritogenesis and the development of synapses in a particular area are strongly influenced by the ingrowth of axon nerve terminals from elsewhere. A number of structures observed in the developing central nervous system are only temporary phenomena that go into regression during subsequent stages; dendrites and synapses especially show a high degree of plasticity. Cell death occurs as a normal concomitant of development. Monoaminergic neuron systems originate early and show a positive histofluorescence shortly afterwards; their target areas are retarded as far as differentiation is concerned. The development of these target regions probably is influenced by the monoaminergic cells. The monoaminergic neurons are not subject to feedback regulation for some time, because of the typical late development of the dendritic receptive apparatus in these cells. Steroid receptors may play a role in the development of intersexual dimorphism of the brain. Probably a modulation of neurotransmitter synthesis is the intermediate between steroid receptor stimulation and a change in synaptogenesis in the target area of the neuron. Neuropeptide systems appear to possess a distribution beyond the limits of the hypophysiotropic area. The early presence of some of the neuropeptides within the embryonic brain suggests a role in histogenesis that is different from the usually presumed neurotransmitter or neuromodulator function of the neuropeptides.

Animals↗
PubMed1997

Targeted gene disruption: applications in neurobiology.

In classical gene inactivation approaches by homologous recombination in embryonic stem cells, the resulting knockout mice are genotypically homogeneous. The inactivation of a gene in the complete organism may sometimes lead to early embryonic lethality. The observation that bacterial recombinases can drive site-specific recombination in mammalian cells has allowed for spatiotemporally controlled genetic modifications. Thus, conditional gene inactivation can be achieved in a specific subset of cells, leaving the rest of the organism genotypically unchanged. Another application of bacterial recombinases is the generation of exon-specific knockout mice, allowing for the analysis of the role of tissue-specific splice variants. A combination of the above-mentioned bacterial recombinase technique with inducible promoter systems permits the investigator to choose precisely the onset of recombination. An extension of the above-mentioned techniques is the combination of the bacterial recombinase technique with adenovirus-based technology, which would open vast possibilities of tissue-specific genetic modifications in a controlled time frame.

Animals↗
PubMed2026

Decoding spatiotemporal fibrotic and cellular immunosuppression of therapeutic T cells in live pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is profoundly immunosuppressive. To help define this behavior, we present integrated experimental and computational frameworks to elucidate therapeutic T cell dynamics. Through the development of TME-CARTographer (TME-CART), a computational pipeline integrating high-dimensional data, graph theory, behavior analysis, and deep learning (DL), we present quantitative insights on 4D T cell-TME interactions in live PDA tumors. Mapping physical immunosuppression demonstrates that collagen fiber architectures direct migration while concomitantly limiting off-axis movement, creating immune exclusion zones. Expanding these findings, we establish that the collagen matrix harbors and spatially organizes immunosuppressive myeloid cells to serve as cooperative co-modulators of T cell behaviors, including migration, sampling, repulsion, and sequestration. Consistent with these findings, DL defines both linear and nonlinear collagen matrix and cellular neighborhood interactions as drivers of T cell behavior. The TME-CART DL framework also accurately predicts shifts in immunosuppression following depletion of myeloid cells. Overall, we identify synergistic barriers impeding anti-tumor T cell behaviors and present TME-CART as a discovery platform for interpreting complex 4D data to enhance the understanding and design of immunotherapies.

Journal Article↗
PubMed2000

In search of the elusive zonal flow using cross-bicoherence analysis

We show that the modulational instability growth rate of zonal flows is determined directly from the quasilinear wave kinetic equation. We also demonstrate the relation between zonal-flow growth and the cross bispectrum of the high-frequency drift-wave-driven Reynolds stress and the low-frequency plasma potential by explicit calculation. Experimental measurements of the spatiotemporal evolution of the spectrum integrated bicoherence at the L-->H transition near the edge shear layer indicate a modification in the nonlinear phase coupling, which might be linked to the generation of sheared ExB flows.

Journal Article↗
PubMed2001

Modeling of transcellular Ca transport in rat duodenum points to coexistence of two mechanisms of apical entry.

Employing realistic parameters, we have demonstrated that a relatively simple mathematical model can reproduce key features of steady-state Ca2+ transport with the assumption of two mechanisms of Ca2+ entry: a channel-like flux and a carrier-mediated transport. At low luminal [Ca2+] (1-5 mM), facilitated entry dominates and saturates with Km = 0.4 mM. At luminal [Ca2+] of tens of millimolar, apical permeability is dominated by the channel flux that in turn is regulated by cytosolic Ca2+. The model reproduces the linear relationship between maximum Ca2+ transport rate and intestinal calbindin D9K (CaBP) content. At luminal [Ca2+] > 50 mM, local sensitivity analysis shows transcellular transport to be most sensitive to variations in CaBP. At low luminal [Ca2+], transport becomes sensitive to apical entry regulation. The simulations have been run within the Virtual Cell modeling environment, yielding the time course of external Ca2+ and spatiotemporal distributions of both intracellular Ca2+ and CaBP. Coexistence of two apical entry mechanisms accords with the properties of the duodenal Ca2+ transport protein CaT1 and the epithelial Ca2+ channel ECaC.

Animals↗
PubMedDate not supplied

Limitations and significance of thermal washout data obtained during microwave and ultrasound hyperthermia.

It is common in clinical hyperthermia to calculate an 'effective blood flow' by neglecting tissue thermal conduction and fitting thermal washout data to a simple, perfusion-dominated exponential model. We have applied this approach to characterize thermal dissipative mechanisms in patients treated at the Harvard-MIT Hyperthermia Center, by analysing thermal washout curves which were obtained during treatment sessions by momentarily interrupting the applied heating. Unfortunately, these measurements of 'effective blood flow' in patient sessions have given inconsistent results. These inconsistencies arise from uncertainties inherent in the clinical situation: the actual thermal boundary conditions and the spatiotemporal characteristics of the heating field. To quantify these observations a Green's function solution to the tissue bioheat equation has been derived, to enable temperature fields produced by various heating geometries to be easily calculated. This has been applied to the analysis of temperature decay curves following local energy deposition representative of ultrasound and microwave hyperthermia therapy devices. These results show that thermal washout data are as dependent on patient- and session-specific parameters as on tissue properties and perfusion. For measurements of effective blood flow following ultrasonic heating, errors are dependent on the measurement position within the heated volume, heating geometry, and duration of heating prior to the decay; for microwave heating, results are dependent on the position of the measurement point within the heated field, the heating frequency, and the surface boundary conditions, whether heated, cooled, or insulated. Thus, any effective tissue property calculated without correctly modelling the heating geometry, boundary conditions and initial conditions will be of a qualitative rather than quantitative nature, and may lead to erroneous and misleading conclusions concerning tissue and tumour response.

Biophysical Phenomena↗
PubMed1996

Spatiotemporal properties of short-term plasticity sensorimotor thalamocortical pathways of the rat.

Each region of neocortex receives synaptic input from several thalamic nuclei, but the response properties of thalamocortical pathways may differ. We have studied the frontoparietal (motor and somatosensory) neocortex of the rat and have examined the responses induced by stimulating two convergent thalamocortical projections originating in the ventrolateral (VL) nucleus and ventroposterior lateral (VPL) nucleus. Depth recordings and current-source density (CSD) analysis revealed two primary responses with different laminar and temporal patterns when VL and VPL were stimulated. Single shocks to VL produced a characteristic small current sink in layer V, which strongly enhanced in response to a second pulse delivered within a 50-200 msec interval (i.e., the augmenting response). In contrast, a shock to VPL evoked a large current sink that originated in layer IV, spread strongly into the supragranular layers, and was almost abolished in response to a second pulse at intervals of <200 msec (i.e., the decremental response). Control experiments determined that these responses could not be attributed to the antidromic firing of corticothalamic cells, intrathalamic mechanisms, or anesthesia. Topographic response maps were obtained from a grid of 30 sites across frontoparietal cortex. One shock to VL excited a very limited cortical region, but an augmenting response evoked 50-200 msec later spread at approximately 1 m/sec to synchronize the activity across an area up to 25 times larger. In contrast, a single shock to VPL activated a relatively large area, but the area activated by a second shock delivered within 200 msec was much smaller. We conclude that overlapping thalamocortical projections, originating in different thalamic nuclei, have distinct spatiotemporal response characteristics that may serve the functional specializations of these pathways.

Animals↗
PubMed2001

Synapse-specific contribution of the variation of transmitter concentration to the decay of inhibitory postsynaptic currents.

Synaptic transmission is characterized by a remarkable trial-to-trial variability in the postsynaptic response, influencing the way in which information is processed in neuronal networks. This variability may originate from the probabilistic nature of quantal transmitter release, from the stochastic behavior of the receptors, or from the fluctuation of the transmitter concentration in the cleft. We combined nonstationary noise analysis and modeling techniques to estimate the contribution of transmitter fluctuation to miniature inhibitory postsynaptic current (mIPSC) variability. A substantial variability (approximately 30%) in mIPSC decay was found in all cell types studied (neocortical layer2/3 pyramidal cells, granule cells of the olfactory bulb, and interneurons of the cerebellar molecular layer). This large variability was not solely the consequence of the expression of multiple types of GABA(A) receptors, as a similar mIPSC decay variability was observed in cerebellar interneurons that express only a single type (alpha(1)beta(2)gamma(2)) of GABA(A) receptor. At large synapses on these cells, all variance in mIPSC decay could be accounted for by the stochastic behavior of approximately 36 pS channels, consistent with the conductance of alpha(1)beta(2)gamma(2) GABA(A) receptors at physiological temperatures. In contrast, at small synapses, a significant amount of variability in the synaptic cleft GABA transient had to be present to account for the additional variance in IPSC decay over that produced by stochastic channel openings. Thus, our results suggest a synapse-specific contribution of the variation of the spatiotemporal profile of GABA to the decay of IPSCs.

Animals↗