Search PubMed⌕ Search

Biomedical subjects

E N Brown

Publications and source records attributed to E N Brown.

At least 19 recordsLinked to original sources
PubMed2001

An analysis of neural receptive field plasticity by point process adaptive filtering.

Neural receptive fields are plastic: with experience, neurons in many brain regions change their spiking responses to relevant stimuli. Analysis of receptive field plasticity from experimental measurements is crucial for understanding how neural systems adapt their representations of relevant biological information. Current analysis methods using histogram estimates of spike rate functions in nonoverlapping temporal windows do not track the evolution of receptive field plasticity on a fine time scale. Adaptive signal processing is an established engineering paradigm for estimating time-varying system parameters from experimental measurements. We present an adaptive filter algorithm for tracking neural receptive field plasticity based on point process models of spike train activity. We derive an instantaneous steepest descent algorithm by using as the criterion function the instantaneous log likelihood of a point process spike train model. We apply the point process adaptive filter algorithm in a study of spatial (place) receptive field properties of simulated and actual spike train data from rat CA1 hippocampal neurons. A stability analysis of the algorithm is sketched in the. The adaptive algorithm can update the place field parameter estimates on a millisecond time scale. It reliably tracked the migration, changes in scale, and changes in maximum firing rate characteristic of hippocampal place fields in a rat running on a linear track. Point process adaptive filtering offers an analytic method for studying the dynamics of neural receptive fields.

Adaptation, Physiological↗
PubMed2001

Autonomic healing of polymer composites.

Structural polymers are susceptible to damage in the form of cracks, which form deep within the structure where detection is difficult and repair is almost impossible. Cracking leads to mechanical degradation of fibre-reinforced polymer composites; in microelectronic polymeric components it can also lead to electrical failure. Microcracking induced by thermal and mechanical fatigue is also a long-standing problem in polymer adhesives. Regardless of the application, once cracks have formed within polymeric materials, the integrity of the structure is significantly compromised. Experiments exploring the concept of self-repair have been previously reported, but the only successful crack-healing methods that have been reported so far require some form of manual intervention. Here we report a structural polymeric material with the ability to autonomically heal cracks. The material incorporates a microencapsulated healing agent that is released upon crack intrusion. Polymerization of the healing agent is then triggered by contact with an embedded catalyst, bonding the crack faces. Our fracture experiments yield as much as 75% recovery in toughness, and we expect that our approach will be applicable to other brittle materials systems (including ceramics and glasses).

Journal Article↗
PubMed2001

Construction and analysis of non-Poisson stimulus-response models of neural spiking activity.

A paradigm for constructing and analyzing non-Poisson stimulus-response models of neural spike train activity is presented. Inhomogeneous gamma (IG) and inverse Gaussian (IIG) probability models are constructed by generalizing the derivation of the inhomogeneous Poisson (IP) model from the exponential probability density. The resultant spike train models have Markov dependence. Quantile-quantile (Q-Q) plots and Kolmogorov-Smirnov (K-S) plots are developed based on the rate-rescaling theorem to assess model goodness-of-fit. The analysis also expresses the spike rate function of the neuron directly in terms of its interspike interval (ISI) distribution. The methods are illustrated with an analysis of 34 spike trains from rat CA1 hippocampal pyramidal neurons recorded while the animal executed a behavioral task. The stimulus in these experiments is the animal's position in its environment and the response is the neural spiking activity. For all 34 pyramidal cells, the IG and IIG models gave better fits to the spike trains than the IP. The IG model more accurately described the frequency of longer ISIs, whereas the IIG model gave the best description of the burst frequency, i.e. ISIs < or = 20 ms. The findings suggest that bursts are a significant component of place cell spiking activity even when position and the background variable, theta phase, are taken into account. Unlike the Poisson model, the spatial and temporal rate maps of the IG and IIG models depend directly on the spiking history of the neurons. These rate maps are more physiologically plausible since the interaction between space and time determines local spiking propensity. While this statistical paradigm is being developed to study information encoding by rat hippocampal neurons, the framework should be applicable to stimulus-response experiments performed in other neural systems.

Action Potentials↗
PubMed2001

Locally regularized spatiotemporal modeling and model comparison for functional MRI.

In this work we treat fMRI data analysis as a spatiotemporal system identification problem and address issues of model formulation, estimation, and model comparison. We present a new model that includes a physiologically based hemodynamic response and an empirically derived low-frequency noise model. We introduce an estimation method employing spatial regularization that improves the precision of spatially varying noise estimates. We call the algorithm locally regularized spatiotemporal (LRST) modeling. We develop a new model selection criterion and compare our model to the SPM-GLM method. Our findings suggest that our method offers a better approach to identifying appropriate statistical models for fMRI studies.

Arousal↗
PubMed2001

Biodistribution of NX211, liposomal lurtotecan, in tumor-bearing mice.

Prolonging tumor exposure to topoisomerase I inhibitors has been correlated to enhance the efficacy of those agents. Lurtotecan, a water-soluble camptothecin analog, was formulated as a liposomal drug, NX211, to enhance the delivery of drug to tumors. Tumor-bearing mice were treated with either [14C]NX211 containing [14C]lurtotecan, [3H]NX211 containing [3H]phosphatidylcholine or [14C]lurtotecan, euthanized at selected times post-injection, and tissues, plasma, urine and feces were collected. These studies demonstrated that KB tumors of [14C]NX211-treated mice had approximately 70-fold greater concentrations of [14C]lurtotecan at 24 h, respectively, compared to concentrations of [14C]lurtotecan of the KB tumors of [14C]lurtotecan-treated mice. The area under curve (AUC) from 0 to 48 h of [14C]lurtotecan for the KB tumors of [14C]NX211-treated animals was over 17-fold greater than the AUC of [14C]lurtotecan for the tumors of [14C]lurtotecan-treated animals. Treatment with [3H]NX211 demonstrated that the lipid component continually accumulated over 24 h in the tissues. HPLC analysis of extracted material from tumors of [14C]NX211-treated mice showed that more than 95% of the radioactive material was intact [14C]lurtotecan. These findings are one of the keys justifying the development of a liposomal formulation of lurtotecan, which has the intent to increase tumor exposure and increase antitumor efficacy.

Animals↗
PubMed2001

A stochastic differential equation model of diurnal cortisol patterns.

Circadian modulation of episodic bursts is recognized as the normal physiological pattern of diurnal variation in plasma cortisol levels. The primary physiological factors underlying these diurnal patterns are the ultradian timing of secretory events, circadian modulation of the amplitude of secretory events, infusion of the hormone from the adrenal gland into the plasma, and clearance of the hormone from the plasma by the liver. Each measured plasma cortisol level has an error arising from the cortisol immunoassay. We demonstrate that all of these three physiological principles can be succinctly summarized in a single stochastic differential equation plus measurement error model and show that physiologically consistent ranges of the model parameters can be determined from published reports. We summarize the model parameters in terms of the multivariate Gaussian probability density and establish the plausibility of the model with a series of simulation studies. Our framework makes possible a sensitivity analysis in which all model parameters are allowed to vary simultaneously. The model offers an approach for simultaneously representing cortisol's ultradian, circadian, and kinetic properties. Our modeling paradigm provides a framework for simulation studies and data analysis that should be readily adaptable to the analysis of other endocrine hormone systems.

Adrenal Glands↗
PubMed2001

A comparison of the firing properties of putative excitatory and inhibitory neurons from CA1 and the entorhinal cortex.

The superficial layers of the entorhinal cortex (EC) provide the majority of the neocortical input to the hippocampus, and the deep layers of the EC receive the majority of neocortically bound hippocampal outputs. To characterize information transmission through the hippocampal and EC circuitry, we recorded simultaneously from neurons in the superficial EC, the CA1 region of hippocampus, and the deep EC while rodents ran for food reward in two environments. Spike waveform analysis allowed us to classify units as fast-spiking (FS) putative inhibitory cells or putative excitatory (PE) cells. PE and FS units' firing were often strongly correlated at short time scales, suggesting the presence a monosynaptic connection from the PE to FS units. EC PE units, unlike those found in CA1, showed little or no tendency to fire in bursts. We also found that the firing of FS and PE units from all regions was modulated by the approximately 8 Hz theta rhythm, although the firing of deep EC FS units tended to be less strongly modulated than that of the other types of units. When we examined the spatial specificity of FS units, we determined that FS units in all three regions showed low specificity. At the same time, retrospective coding, in which firing rates were related to past position, was present in FS units from all three regions and deep EC FS units often fired in a "path equivalent" manner in that they were active in physically different, but behaviorally related positions both within and across environments. Our results suggest that while the firing of FS units from CA1 and the EC show similarly low levels of position specificity, FS units from each region differ from one another in that they mirrored the associated PE units in terms of their tendency to show more complex positional firing properties like retrospective coding and path equivalence.

Action Potentials↗
PubMed2001

Circadian rhythms of women with fibromyalgia.

Fibromyalgia syndrome is a chronic and debilitating disorder characterized by widespread nonarticular musculoskeletal pain whose etiology is unknown. Many of the symptoms of this syndrome, including difficulty sleeping, fatigue, malaise, myalgias, gastrointestinal complaints, and decreased cognitive function, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule or with local environmental time. Abnormalities in melatonin and cortisol, two hormones whose secretion is strongly influenced by the circadian pacemaker, have been reported in women with fibromyalgia. We studied the circadian rhythms of 10 women with fibromyalgia and 12 control healthy women. The protocol controlled factors known to affect markers of the circadian system, including light levels, posture, sleep-wake state, meals, and activity. The timing of the events in the protocol were calculated relative to the habitual sleep-wake schedule of each individual subject. Under these conditions, we found no significant difference between the women with fibromyalgia and control women in the circadian amplitude or phase of rhythms of melatonin, cortisol, and core body temperature. The average circadian phases expressed in hours posthabitual bedtime for women with and without fibromyalgia were 3:43 +/- 0:19 and 3:46 +/- 0:13, respectively, for melatonin; 10:13 +/- 0:23 and 10:32 +/- 0:20, respectively for cortisol; and 5:19 +/- 0:19 and 4:57 +/- 0:33, respectively, for core body temperature phases. Both groups of women had similar circadian rhythms in self-reported alertness. Although pain and stiffness were significantly increased in women with fibromyalgia compared with healthy women, there were no circadian rhythms in either parameter. We suggest that abnormalities in circadian rhythmicity are not a primary cause of fibromyalgia or its symptoms.

Adult↗
PubMed2000

Trajectory encoding in the hippocampus and entorhinal cortex.

We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences.

Algorithms↗
PubMed2000

A statistical model of the human core-temperature circadian rhythm.

We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator ( approximately 24 h) from both free-run and forced desynchrony studies. Although the van der Pol model approximates well the dynamical features of the circadian pacemaker, the optimal dynamical model of the human biological clock may have a harmonic structure different from that of the van der Pol oscillator.

Algorithms↗
PubMed1999

Stability, precision, and near-24-hour period of the human circadian pacemaker.

Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.

Adult↗
PubMed1999

Statistical model building and model criticism for human circadian data.

Mathematical models have played an important role in the analysis of circadian systems. The models include simulation of differential equation systems to assess the dynamic properties of a circadian system and the use of statistical models, primarily harmonic regression methods, to assess the static properties of the system. The dynamical behaviors characterized by the simulation studies are the response of the circadian pacemaker to light, its rate of decay to its limit cycle, and its response to the rest-activity cycle. The static properties are phase, amplitude, and period of the intrinsic oscillator. Formal statistical methods are not routinely employed in simulation studies, and therefore the uncertainty in inferences based on the differential equation models and their sensitivity to model specification and parameter estimation error cannot be evaluated. The harmonic regression models allow formal statistical analysis of static but not dynamical features of the circadian pacemaker. The authors present a paradigm for analyzing circadian data based on the Box iterative scheme for statistical model building. The paradigm unifies the differential equation-based simulations (direct problem) and the model fitting approach using harmonic regression techniques (inverse problem) under a single schema. The framework is illustrated with the analysis of a core-temperature data series collected under a forced desynchrony protocol. The Box iterative paradigm provides a framework for systematically constructing and analyzing models of circadian data.

Adult↗
PubMed1998

A statistical paradigm for neural spike train decoding applied to position prediction from ensemble firing patterns of rat hippocampal place cells.

The problem of predicting the position of a freely foraging rat based on the ensemble firing patterns of place cells recorded from the CA1 region of its hippocampus is used to develop a two-stage statistical paradigm for neural spike train decoding. In the first, or encoding stage, place cell spiking activity is modeled as an inhomogeneous Poisson process whose instantaneous rate is a function of the animal's position in space and phase of its theta rhythm. The animal's path is modeled as a Gaussian random walk. In the second, or decoding stage, a Bayesian statistical paradigm is used to derive a nonlinear recursive causal filter algorithm for predicting the position of the animal from the place cell ensemble firing patterns. The algebra of the decoding algorithm defines an explicit map of the discrete spike trains into the position prediction. The confidence regions for the position predictions quantify spike train information in terms of the most probable locations of the animal given the ensemble firing pattern. Under our inhomogeneous Poisson model position was a three to five times stronger modulator of the place cell spiking activity than theta phase in an open circular environment. For animal 1 (2) the median decoding error based on 34 (33) place cells recorded during 10 min of foraging was 8.0 (7.7) cm. Our statistical paradigm provides a reliable approach for quantifying the spatial information in the ensemble place cell firing patterns and defines a generally applicable framework for studying information encoding in neural systems.

Action Potentials↗
PubMed1997

A mathematical model of diurnal variations in human plasma melatonin levels.

Studies in animals and humans suggest that the diurnal pattern in plasma melatonin levels is due to the hormone's rates of synthesis, circulatory infusion and clearance, circadian control of synthesis onset and offset, environmental lighting conditions, and error in the melatonin immunoassay. A two-dimensional linear differential equation model of the hormone is formulated and is used to analyze plasma melatonin levels in 18 normal healthy male subjects during a constant routine. Recently developed Bayesian statistical procedures are used to incorporate correctly the magnitude of the immunoassay error into the analysis. The estimated parameters [median (range)] were clearance half-life of 23.67 (14.79-59.93) min, synthesis onset time of 2206 (1940-0029), synthesis offset time of 0621 (0246-0817), and maximum N-acetyltransferase activity of 7.17(2.34-17.93) pmol x l(-1) x min(-1). All were in good agreement with values from previous reports. The difference between synthesis offset time and the phase of the core temperature minimum was 1 h 15 min (-4 h 38 min-2 h 43 min). The correlation between synthesis onset and the dim light melatonin onset was 0.93. Our model provides a more physiologically plausible estimate of the melatonin synthesis onset time than that given by the dim light melatonin onset and the first reliable means of estimating the phase of synthesis offset. Our analysis shows that the circadian and pharmacokinetics parameters of melatonin can be reliably estimated from a single model.

Adult↗
PubMed1997

The parathyroid hormone circadian rhythm is truly endogenous--a general clinical research center study.

While circulating levels of PTH follow a diurnal pattern, it has been unclear whether these changes are truly endogenous or are dictated by external factors that themselves follow a diurnal pattern, such as sleep-wake cycles, light-dark cycles, meals, or posture. We evaluated the diurnal rhythm of PTH in 11 normal healthy male volunteers in our Intensive Physiologic Monitoring Unit. The first 36 h spent under baseline conditions were followed by 28-40 h of constant routine conditions (CR; enforced wakefulness in the strict semirecumbent position, with the consumption of hourly snacks). During baseline conditions, PTH levels followed a bimodal diurnal rhythm with an average amplitude of 4.2 pg/mL. A primary peak (t1max) occurred at 0314 h, and the secondary peak (t2max) occurred at 1726 h, whereas the primary and secondary nadirs (t1min and t2min) took place, on the average, at 1041 and 2103 h, respectively. This rhythm was preserved under CR conditions, albeit with different characteristics, thus confirming its endogenous nature. The serum ionized calcium (Cai) demonstrated a rhythm in 3 of the 5 subjects studied that varied widely between individuals and did not have any apparent relation to PTH. Urinary calcium/creatinine (UCa/Cr), phosphate/Cr (UPO4/Cr), and sodium/Cr (UNa/Cr) ratios all followed a diurnal rhythm during the baseline day. These rhythms persisted during the CR, although with different characteristics for the first two parameters, whereas that of UNa/Cr was unchanged. In general, the temporal pattern for the UCa/Cr curve was a mirror image of the PTH curve, whereas the UPO4/Cr pattern moved in parallel with the PTH curve. In conclusion, PTH levels exhibit a diurnal rhythm that persists during a CR, thereby confirming that a large component of this rhythm is an endogenous circadian rhythm. The clinical relevance of this rhythm is reflected in the associated rhythms of biological markers of PTH effect at the kidney, namely UCa/Cr and UPO4/Cr.

Adult↗