Biomedical subjects

Stephen R Williams

Publications and source records attributed to Stephen R Williams.

17 recordsLinked to original sources

PubMed2006

Dynamical signatures of freezing: stable fluids, metastable fluids, and crystals.

Mean squared displacements and velocity auto correlation functions are calculated using molecular dynamics for hard spheres under a range of conditions (i) for the equilibrium fluid below freezing; (ii) for the metastable fluid above freezing; and (iii) for the hard sphere crystal, both in the metastable region between freezing and melting, and in the stable region above melting. In addition, simulations are carried out for a metastable Lennard-Jones system. The results confirm recent studies that indicated the disappearance of the classical Alder long-time tail, and show that they apply to systems other than the metastable hard sphere fluid. The implications of these results for our understanding of crystallization and the glass transition are discussed.

Journal Article↗

PubMed2006

Numerical study of the steady state fluctuation relations far from equilibrium.

A thermostatted dynamical model with five degrees of freedom is used to test the fluctuation relation of Evans and Searles (Omega-FR) and that of Gallavotti and Cohen (Lambda-FR). In the absence of an external driving field, the model generates a time-independent ergodic equilibrium state with two conjugate pairs of Lyapunov exponents. Each conjugate pair sums to zero. The fluctuation relations are tested numerically both near and far from equilibrium. As expected from previous work, near equilibrium the Omega-FR is verified by the simulation data while the Lambda-FR is not confirmed by the data. Far from equilibrium where a positive exponent in one of these conjugate pairs becomes negative, we test a conjecture regarding the Lambda-FR [Bonetto et al., Physica D 105, 226 (1997); Giuliani et al., J. Stat. Phys. 119, 909 (2005)]. It was conjectured that when the number of nontrivial Lyapunov exponents that are positive becomes less than the number of such negative exponents, then the form of the Lambda-FR needs to be corrected. We show that there is no evidence for this conjecture in the empirical data. In fact, when the correction factor differs from unity, the corrected form of Lambda-FR is less accurate than the uncorrected Lambda-FR. Also as the field increases the uncorrected Lambda-FR appears to be satisfied with increasing accuracy. The reason for this observation is likely to be that as the field increases, the argument of the Lambda-FR more and more accurately approximates the argument of the Omega-FR. Since the Omega-FR works for arbitrary field strengths, the uncorrected Lambda-FR appears to become ever more accurate as the field increases. The final piece of evidence against the conjecture is that when the smallest positive exponent changes sign, the conjecture predicts a discontinuous change in the "correction factor" for Lambda-FR. We see no evidence for a discontinuity at this field strength.

Journal Article↗

PubMed2006

Linear response domain in glassy systems.

Molecular dynamics simulations are performed on a realistic glass forming model system. The linear and nonlinear response domains are explored numerically for the case where one of the particles interacts with a constant external force. As the temperature is lowered towards the glass transition, we find that the range of fields over which the response is linear shrinks towards zero. We show that the time required for convergence of the steady state fluctuation theorem and the valid application of the central limit theorem becomes very large as the glass transition is approached. This in turn implies that the domain over which a linear response can be observed becomes progressively smaller.

Journal Article↗

PubMed2006

Robust quantification of short echo time 1H magnetic resonance spectra using the Padé approximant.

Accurate quantification of in vivo short echo time spectra is hampered by the presence of overlapping peaks and a significant baseline. In this work the Padé approximant in conjunction with Monte Carlo simulation is used to extract peak areas from short echo time 1H spectra. We exploit the fact that the Padé approximant is known to model broad non-Lorentzian signals as arbitrary sums of Lorentzian components to separate baseline components from sharper metabolite signals by combining the Padé approximant with Monte Carlo simulation. The simulation results demonstrate that the Padé approximant-Monte Carlo hybrid analysis is able to separate the metabolite signals from the baseline, while a least squares fitting of a time domain model may result in significant bias of the peak area estimations. For the in vivo data the estimates of the peak areas using the Padé approximant and AMARES compare well, with the exception of the NAA peak at 2.02 ppm. We suggest that the discrepancy may be due to the baseline contamination as supported by the simulation results; however, without an in vivo gold standard this remains difficult to demonstrate.

Adult↗

PubMed2005

Encoding and decoding of dendritic excitation during active states in pyramidal neurons.

Neocortical neurons spontaneously fire action potentials during active network states; how are dendritic synaptic inputs integrated into the ongoing action potential output pattern of neurons? Here, the efficacy of barrages of simulated EPSPs generated at known dendritic sites on the rate and pattern of ongoing action potential firing is determined using multisite whole-cell recording techniques from rat layer 5 neocortical pyramidal neurons in vitro. Under quiescent conditions, the somatic impact of proximal (253 +/- 15 microm from soma; n = 28) dendritic barrages of simulated EPSPs was 4.7-fold greater than identical barrages of EPSPs generated from distal (572 +/- 13 microm from soma) sites. In contrast, barrages of proximal simulated EPSPs enhanced the rate of ongoing action potential firing, evoked by somatic simulated EPSPs, by only 1.6-fold more than distal simulated EPSPs. This relationship was apparent across a wide frequency range of action potential firing (6-22 Hz) and dendritic excitation (100-500 Hz). The efficacy of distal dendritic EPSPs was formed by the recruitment of active dendritic processes that transformed the ongoing action potential firing pattern, promoting action potential burst firing. Paired recordings (n = 42) revealed that patterns of action potential firing generated by concerted somatic and distal dendritic excitation reliably and powerfully drove postsynaptic excitation as a result of enhanced reliability of transmitter release during bursts of action potential firing. During active states, therefore, distal excitatory synaptic inputs decisively control the excitatory synaptic output of layer 5 neocortical pyramidal neurons and so powerfully influence network activity in the neocortex.

Action Potentials↗

PubMed2005

Effects of intramolecular dipolar coupling on the isotropic-nematic phase transition of a hard spherocylinder fluid.

The thermodynamics of a simple model, containing the minimum set of features required to provide liquid crystal-like phase behavior and the dipolar coupling observable in the NMR spectrum of orientationally ordered fluids, are presented within the framework of Onsager theory. The model comprises a fluid of hard spherocylinders with a pair of embedded freely rotating magnetic dipoles. The behavior of the isotropic-nematic phase transition is explored as a function magnetic field strength and of the relative orientation between the nematic director and the external magnetic field. When the field and director are aligned the phase diagram is similar to those predicted for a hard rod fluid in flow fields, electric fields, and magnetic fields, with the field promoting orientational order in the fluid and the isotropic-nematic phase transition being replaced by a paranematic-nematic phase transition. In contrast, when the field and director are perpendicular, the field destabilizes the nematic phase and the phase transition is shifted to higher densities. The variation of the mean magnetic moment and the dipolar coupling are examined as a function of the orientational structure of the fluid. The model is used to support the hypothesis that dipolar couplings observed in the spectra of human leg muscle originate from nematic-like liquid crystal phases in relatively small metabolite molecules. The fitted theoretical predictions of the dependence of the dipolar coupling on the orientation of the field with respect to the nematic director are shown to provide a good description of the experimental data.

Journal Article↗

PubMed2005

Is anoxic depolarisation associated with an ADC threshold? A Markov chain Monte Carlo analysis.

A Bayesian nonlinear hierarchical random coefficients model was used in a reanalysis of a previously published longitudinal study of the extracellular direct current (DC)-potential and apparent diffusion coefficient (ADC) responses to focal ischaemia. The main purpose was to examine the data for evidence of an ADC threshold for anoxic depolarisation. A Markov chain Monte Carlo simulation approach was adopted. The Metropolis algorithm was used to generate three parallel Markov chains and thus obtain a sampled posterior probability distribution for each of the DC-potential and ADC model parameters, together with a number of derived parameters. The latter were used in a subsequent threshold analysis. The analysis provided no evidence indicating a consistent and reproducible ADC threshold for anoxic depolarisation.

Algorithms↗

PubMed2004

Independence of the transient fluctuation theorem to thermostatting details.

The fluctuation theorems show how macroscopic irreversibility arises from time reversible microscopic dynamics. They have been confirmed in computer simulations and in laboratory experiments. The standard proofs of the transient fluctuation theorems involve the use of time reversible deterministic thermostats to control the temperature of the system of interest. These mathematical thermostats do not occur in Nature. However, since in a gedanken experiment the thermostatting regions can be removed arbitrarily far from the system of interest, it has been argued that the precise details of the thermostat cannot be important and that the resulting fluctuation theorems apply to natural systems. In this paper we give a detailed analysis showing how the fluctuation theorem is independent of the precise mathematical details of the thermostatting mechanism for an infinite class of fictitious time reversible deterministic thermostats. Our analysis reinforces the implications of the gedanken experiment and implies that thermostats used in the derivations of fluctuation theorems are a convenient but ultimately irrelevant device.

Journal Article↗

PubMed2004

Spatial compartmentalization and functional impact of conductance in pyramidal neurons.

Dendritic spikes signal synaptic integration at remote apical dendritic sites in neocortical pyramidal neurons in vitro. Do dendritic spikes have a salient signaling role under in vivo conditions, where neocortical pyramidal neurons are bombarded with synaptic input? In the present study, levels of synaptic conductance apparent during active network states in vivo were emulated in vitro. Pronounced enhancement of somatic or apical dendritic conductance was spatially compartmentalized and 'visible' over a dendritic length ( approximately 200 microm) on the order of half the voltage length constant, as predicted by passive cable models. The spatial compartmentalization of conductance allowed independent subthreshold synaptic integration at axo-somatic and apical dendritic sites. Furthermore, spikes generated at distal apical dendritic sites efficiently propagated to the axon to initiate action potentials under high synaptic conductance states. The dendritic arborization and voltage-activated channel complement of rat neocortical pyramidal neurons are therefore optimized to allow distributed processing under realistic conductance states.

Action Potentials↗

PubMed2004

Heart energy metabolism after intestinal ischaemia and reperfusion.

BACKGROUND/PURPOSE: Multiple organ failure subsequent to intestinal ischaemia and reperfusion (I/R) includes cardiac failure, but little is known about heart energy metabolism in this setting. This study investigates the effects of intestinal I/R on heart energy metabolism and evaluates the effects of moderate hypothermia. METHODS: Adult rats underwent intestinal ischaemia for 60 minutes followed by 120 minutes of reperfusion. Animals were maintained at either normothermia (36 degrees to 38 degrees C) or moderate hypothermia (30 degrees to 32 degrees C). In experiment A, 2 groups were studied: (1) sham at normothermia; (2) I/R at normothermia. After death, the heart was removed. Cardiac phosphoenergetics were assessed by 31P magnetic resonance spectroscopy; data are expressed as micromoles per gram. In experiment B, 4 groups were studied: (1) sham at normothermia, (2) I/R at normothermia, (3) sham at hypothermia, (4) I/R at hypothermia. At the end of the experiment, the heart was harvested. The activity of carnitine palmitoyl transferase I (CPT I), an important enzyme in the control of fatty acid oxidation, was measured; data are expressed as nanomoles per minute per unit citrate synthase. Results are expressed as mean +/- SEM. RESULTS: In experiment A, there were no differences between the 2 study groups in cardiac phosphocreatine, inorganic phosphate, adenosine triphosphate (ATP), or in the ratio of inorganic phosphate to ATP. In experiment B, CPT I activity was decreased significantly after I/R at normothermia compared with normothermic sham, but this enzyme inhibition was prevented by hypothermia (3.9 +/- 0.2; v I/R). CONCLUSIONS: These results suggest that although cardiac ATP supply was maintained during intestinal I/R at normothermia, the balance of substrate utilisation was shifted from fatty acid oxidation to carbohydrate utilisation. However, moderate hypothermia modified these changes. The beneficial effect of moderate hypothermia on cardiac metabolism during intestinal I/R has potential clinical application in various surgical conditions.

Adenosine Triphosphate↗

PubMed2003

Voltage- and site-dependent control of the somatic impact of dendritic IPSPs.

Inhibitory interneurons target specific subcellular compartments of cortical pyramidal neurons, where location-specific interactions of IPSPs with voltage-activated ion channels are likely to influence the inhibitory control of neuronal output. To investigate this, we simulated IPSPs as a conductance source at sites across the somato-apical dendritic axis (up to 750 microm) of neocortical layer 5 pyramidal neurons. Analysis revealed that the electrotonic architecture of cortical pyramidal neurons is highly voltage dependent, resulting in a significant site-dependent disparity between the amplitude, kinetics, and dendro-somatic attenuation of IPSPs generated from depolarized (-50 mV) and hyperpolarized (-80 mV) membrane potentials. At the soma, the time course of IPSPs evoked from depolarized potentials was greatest when generated from proximal dendritic sites and decreased as events were generated more distally, whereas the somatic time course of IPSPs evoked from hyperpolarized potentials was independent of the dendritic site of generation. This behavior resulted from the concerted actions of axo-somatic sodium channels that increased the duration of proximal dendritic IPSPs generated at depolarized potentials and distal dendritic hyperpolarization-activated channels that mediated site independence of somatic IPSP time course at hyperpolarized potentials. Functionally, this voltage-dependent control of IPSPs shaped the spatial and temporal profile of inhibition of axonal action potential firing and dendritic spike generation. Together, these findings demonstrate that the somatic impact of dendritic IPSPs is highly voltage dependent and controlled by classes of ion channels differentially distributed across axodendritic domains, directly revealing site-dependent inhibitory synaptic processing in cortical pyramidal neurons.

Action Potentials↗

PubMed2003

Role of dendritic synapse location in the control of action potential output.

How effective are synaptic inputs made at different dendritic sites in the control of action potential output? Recent technical advances have allowed direct observation of the amplitude and time course of excitatory synaptic inputs generated at defined dendritic sites. These findings indicate that contrasting mechanisms exist to enhance the impact of dendritic excitatory inputs to pyramidal neurons of the neocortex and hippocampus. Furthermore, multiple sites of synaptic integration have been revealed, suggesting that proximal and distal inputs are likely to be integrated in different ways. Taken together, these data emphasize the cell- and input-specific strategies used by neurons to enhance the impact of dendritic inputs on action potential generation.

Action Potentials↗

PubMed2003

Temporal relation between the ADC and DC potential responses to transient focal ischemia in the rat: a Markov chain Monte Carlo simulation analysis.

Markov chain Monte Carlo simulation was used in a reanalysis of the longitudinal data obtained by Harris et al. (J Cereb Blood Flow Metab 20:28-36) in a study of the direct current (DC) potential and apparent diffusion coefficient (ADC) responses to focal ischemia. The main purpose was to provide a formal analysis of the temporal relationship between the ADC and DC responses, to explore the possible involvement of a common latent (driving) process. A Bayesian nonlinear hierarchical random coefficients model was adopted. DC and ADC transition parameter posterior probability distributions were generated using three parallel Markov chains created using the Metropolis algorithm. Particular attention was paid to the within-subject differences between the DC and ADC time course characteristics. The results show that the DC response is biphasic, whereas the ADC exhibits monophasic behavior, and that the two DC components are each distinguishable from the ADC response in their time dependencies. The DC and ADC changes are not, therefore, driven by a common latent process. This work demonstrates a general analytical approach to the multivariate, longitudinal data-processing problem that commonly arises in stroke and other biomedical research.

Animals↗

PubMed2002

Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics.

In this review, we summarize three sets of findings that have recently been observed in thalamic astrocytes and neurons, and discuss their significance for thalamocortical loop dynamics. (i) A physiologically relevant 'window' component of the low-voltage-activated, T-type Ca(2+) current (I(Twindow)) plays an essential part in the slow (less than 1 Hz) sleep oscillation in adult thalamocortical (TC) neurons, indicating that the expression of this fundamental sleep rhythm in these neurons is not a simple reflection of cortical network activity. It is also likely that I(Twindow) underlies one of the cellular mechanisms enabling TC neurons to produce burst firing in response to novel sensory stimuli. (ii) Both electrophysiological and dye-injection experiments support the existence of gap junction-mediated coupling among young and adult TC neurons. This finding indicates that electrical coupling-mediated synchronization might be implicated in the high and low frequency oscillatory activities expressed by this type of thalamic neuron. (iii) Spontaneous intracellular Ca(2+) ([Ca(2+)](i)) waves propagating among thalamic astrocytes are able to elicit large and long-lasting N-methyl-D-aspartate-mediated currents in TC neurons. The peculiar developmental profile within the first two postnatal weeks of these astrocytic [Ca(2+)](i) transients and the selective activation of these glutamate receptors point to a role for this astrocyte-to-neuron signalling mechanism in the topographic wiring of the thalamocortical loop. As some of these novel cellular and intracellular properties are not restricted to thalamic astrocytes and neurons, their significance may well apply to (patho)physiological functions of glial and neuronal elements in other brain areas.

Action Potentials↗

PubMed2002

Dependence of EPSP efficacy on synapse location in neocortical pyramidal neurons.

Neurons receive thousands of synaptic inputs throughout elaborate dendritic trees. Here we determine the somatic impact of excitatory postsynaptic potentials (EPSPs) generated at known dendritic sites in neocortical pyramidal neurons. As inputs became more distal, somatic EPSP amplitude decreased, whereas use-dependent depression increased. Despite marked attenuation (>40-fold), when coactivated within a narrow time window (approximately 10 milliseconds), distal EPSPs could directly influence action potential output following dendritic spike generation. These findings reveal that distal EPSPs are ineffective sources of background somatic excitation, but through coincidence detection have a powerful transient signaling role.

Action Potentials↗

PubMed2002

Membrane potential bistability is controlled by the hyperpolarization-activated current I(H) in rat cerebellar Purkinje neurons in vitro.

We investigated the role of the hyperpolarization-activated mixed cation current, I(H), in the control of spontaneous action potential firing of rat cerebellar Purkinje neurons in brain slices. Extracellular recordings revealed that the continual action potential firing of Purkinje neurons was disrupted by the pharmacological blockade of I(H). Blockade of I(H) revealed spontaneous transitions between periods of tonic action potential firing and quiescence, without effects on the frequency or variance of action potential generation. Whole-cell recordings revealed that blockade of I(H) unmasked a form of membrane potential bistability, where transitions between tonic firing and quiescent states (separated by approximately 20 mV) were evoked by excitatory and inhibitory postsynaptic potentials, or by the delivery of brief (20 ms) somatic or dendritic positive and negative current pulses. The stable upper state of tonic action potential firing was maintained by the recruitment of axo-somatic voltage-activated sodium, but not calcium, channels. Negative modulation of I(H) by serotonin unmasked bistability, indicating that bistability of Purkinje neurons is likely to occur under physiological conditions. These data indicate that I(H) acts as a 'safety net', maintaining the membrane potential of Purkinje neurons within the range necessary for the generation of tonic action potential firing. Following the downregulation of I(H), synaptic inhibition can generate long periods (seconds) of quiescence, the duration of which can be controlled by climbing fibre activation and by the underlying 'tone' of parallel fibre activity.

Action Potentials↗

PubMed2002

MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the starch microsphere model of ischemia.

Quantification of the acute increases in blood-brain barrier (BBB) permeability that occur subsequent to experimental ischemic injury has been limited to single time-point, invasive methodologies. Although permeability can be qualitatively assessed to visualise regional changes during sequential studies on the same animal using contrast-enhanced magnetic resonance imaging (MRI), quantitative information on the magnitude of change is required to compare barrier function during sequential studies on the same animal or between different animals. Recently, improvements in MRI tracer kinetic models and in MR hardware design mean that an estimate of permeability in vivo can now be obtained with acceptable accuracy and precision. We report here the use of such methods to study acute changes following spontaneous reperfusion in an animal model of ischemia. We have obtained estimates of BBB permeability following spontaneous reperfusion, subsequent to forebrain ischemia by unilateral carotid injection of starch microspheres in the rat. T2*-weighted and diffusion-trace imaging were used to monitor the initial reduction in CBF and the time-course of ischemia, respectively. Following reperfusion, an intraveneous bolus of dimeglumine gadopentetate (Gd-DTPA) and horseradish peroxidase (HRP) was given during a continuous acquisition of T1 maps with a 48 s temporal resolution. Permeability maps were constructed using a 4-compartment model; K(trans), the permeability-surface area product of the capillary walls was estimated to be 9.2 +/- 0.6 x 10(-4) min(-1) in the cortex. Visualisation of the regional extent of HRP extravasation on histological sections following termination of the experiment demonstrated very little correspondence to the region of Gd-DTPA leakage. Quantitative MRI assessment of BBB permeability following ischemia-reperfusion is consistent with published values obtained by invasive methods. Differences between Gd-DTPA-enhancement and HRP may reflect differences in the molecular size of the tracers.

Animals↗