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A modeling approach to characterize the nonlinear dynamic transformations of the dentate gyrus of the hippocampus is presented and experimentally validated. The dentate gyrus is the first region of the hippocampus which receives and integrates sensory information via the perforant path. The perforant path is composed of two distinct pathways: 1) the lateral path and 2) the medial perforant path. The proposed approach examines and captures the short-term dynamic characteristics of these two pathways using a nonparametric, third-order Poisson-Volterra model. The nonlinear characteristics of the two pathways are represented by Poisson-Volterra kernels, which are quantitative descriptors of the nonlinear dynamic transformations. The kernels were computed with experimental data from in vitro hippocampal slices. The electrophysiological activity was measured with custom-made multielectrode arrays, which allowed selective stimulation with random impulse trains and simultaneous recordings of extracellular field potential activity. The results demonstrate that this mathematically rigorous approach is suitable for the multipathway complexity of the hippocampus and yields interpretable models that have excellent predictive capabilities. The resulting models not only accurately predict previously reported electrophysiological descriptors, such as paired pulses, but more important, can be used to predict the electrophysiological activity of dentate granule cells to arbitrary stimulation patterns at the perforant path. Index Terms--Dentate gyrus, electrophysiology, hippocampus, Laguerre expansion, multielectrode arrays, nonlinear modeling, perforant path, synaptic transmission, Volterra kernel.

One of the fundamental principles of cortical brain regions, including the hippocampus, is that information is represented in the ensemble firing of populations of neurons, i.e., spatio-temporal patterns of electrophysiological activity. The hippocampus has long been known to be responsible for the formation of declarative, or fact-based, memories. Damage to the hippocampus disrupts the propagation of spatio-temporal patterns of activity through hippocampal internal circuitry, resulting in a severe anterograde amnesia. Developing a neural prosthesis for the damaged hippocampus requires restoring this multiple-input, multiple-output transformation of spatio-temporal patterns of activity. Because the mechanisms underlying synaptic transmission and generation of electrical activity in neurons are inherently nonlinear, any such prosthesis must be based on a nonlinear multiple-input, multiple-output model. In this paper, we have formulated the transformational process of multi-site propagation of spike activity between two subregions of the hippocampus (CA3 and CA1) as the identification of a multiple-input, multiple-output (MIMO) system, and proposed that it can be decomposed into a series of multiple-input, single-output (MISO) systems. Each MISO system is modeled as a physiologically plausible structure that consists of 1) linear/nonlinear feedforward Volterra kernels modeling synaptic transmission and dendritic integration, 2) a linear feedback Volterra kernel modeling spike-triggered after-potentials, 3) a threshold for spike generation, 4) a summation process for somatic integration, and 5) a noise term representing intrinsic neuronal noise and the contributions of unobserved inputs. Input and output spike trains were recorded from hippocampal CA3 and CA1 regions of rats performing a spatial delayed-nonmatch-to-sample memory task that requires normal hippocampal function. Kernels were expanded with Laguerre basis functions and estimated using a maximum-likelihood method. Complexity of the feedforward kernel was progressively increased to capture higher-order system nonlinear dynamics. Results showed higher prediction accuracies as kernel complexity increased. Self-kernels describe the nonlinearities within each input. Cross-kernels capture the nonlinear interaction between inputs. Second- and third-order nonlinear models were found to successfully predict the CA1 output spike distribution based on CA3 input spike trains. First-order, linear models were shown to be insufficient. Index Terms--Feedback, hippocampus, Laguerre expansion, multiple-input, multiple-output system, spatio-temporal pattern, spike, time-rescaling theorem, Volterra kernel.

This paper presents a novel segmentation methodology for automated classification and differentiation of soft tissues using multiband data obtained with the newly developed system of high-resolution ultrasonic transmission tomography (HUTT) for imaging biological organs. This methodology extends and combines two existing approaches: the L-level set active contour (AC) segmentation approach and the agglomerative hierarchical k-means approach for unsupervised clustering (UC). To prevent the trapping of the current iterative minimization AC algorithm in a local minimum, we introduce a multiresolution approach that applies the level set functions at successively increasing resolutions of the image data. The resulting AC clusters are subsequently rearranged by the UC algorithm that seeks the optimal set of clusters yielding the minimum within-cluster distances in the feature space. The presented results from Monte Carlo simulations and experimental animal-tissue data demonstrate that the proposed methodology outperforms other existing methods without depending on heuristic parameters and provides a reliable means for soft tissue differentiation in HUTT images. Index Terms--Active contour segmentation, multiband imaging, soft tissue differentiation, ultrasound transmission tomography, unsupervised clustering.

An analytical model of multilayer ultrasonic transducers with an inversion layer is presented. The analysis of the wave propagation problem of an inversion layer transducer includes a functional decomposition of the electrical input impedance.

In this paper, we are interested in soft tissue differentiation by multiband images obtained from the High-Resolution Ultrasonic Transmission Tomography (HUTT) system using a spectral target detection method based on constrained energy minimization (CEM). We have developed a new tissue differentiation method (called 'CEM filter bank') consisting of multiple CEM filters specially designed for detecting multiple types of tissues. Statistical inference on the output of the CEM filter bank is used to make a decision based on the maximum statistical significance rather than the magnitude of each CEM filter output. We test and validate this method through three-dimensional interphantom/intraphantom soft tissue classification where target profiles obtained from an arbitrary single slice are used for differentiation over multiple other tomographic slices. The performance of the proposed classifier is assessed using receiver operating characteristic analysis. We also apply our method to classify tiny structures inside a bovine kidney and sheep kidneys. Using the proposed method we can detect physical objects and biological tissues such as styrofoam balls, chicken tissue, calyces, and vessel-duct successfully. Index Terms--Constrained energy minimization (CEM), filter bank, high-resolution ultrasound transmission tomography (HUTT), multiband signatures, soft tissue differentiation.

Half-thickness inversion layer high-frequency ultrasonic transducers were fabricated using lithium niobate (LiNbO(sub 3)) single crystal plate and the transducers used a 36 degree Celsius rotated Y-cut LiNbO3 thin plate with an active element thickness of 115 mum. The measured resonant frequency was consistent with the modeled data.

The effect of spontaneous beat-to-beat mean arterial blood pressure fluctuations and breath-to-breath end-tidal C[O.sub.2] fluctuations on beat-to-beat cerebral blood flow velocity variations is studied using the Laguerre-Volterra network methodology for multiple-input nonlinear systems. The observations made from experimental measurements from ten healthy human subjects reveal that, whereas pressure fluctuations explain most of the high-frequency blood flow velocity variations (above 0.04 Hz), end-tidal C[O.sub.2] fluctuations as well as nonlinear interactions between pressure and C[O.sub.2] have a considerable effect in the lower frequencies (below 0.04 Hz). They also indicate that cerebral autoregulation is strongly nonlinear and dynamic (frequency-dependent). Nonlinearities are mainly active in the low-frequency range (below 0.04 Hz) and are more prominent in the dynamics of the end-tidal C[O.sub.2]-blood flow velocity relationship. Significant nonstationarities are also revealed by the obtained models, with greater variability evident for the effects of C[O.sub.2] on blood flow velocity dynamics. Index Terms--Cerebral autoregulation, cerebral hemodynamics, Laguerre-Volterra network, nonlinear modeling, nonstationary systems, Volterra kernels.

Background: Recent studies have utilized data-based dynamic modeling to establish strong association between dysregulation of cerebral perfusion and Mild Cognitive Impairment (MCI), expressed in terms of impaired CO2 dynamic vasomotor reactivity in the cerebral vasculature. This raises the question of whether this is due to dysregulation of central mechanisms (baroreflex and chemoreflex) or mechanisms of cortical tissue oxygenation (CTO) in MCI patients. We seek to answer this question using data-based input-output predictive dynamic models. Objective: To use subject-specific data-based multivariate input-output dynamic models to quantify the effects of systemic hemodynamic and blood CO2 changes upon CTO and to examine possible differences in CTO regulation in MCI patients versus age-matched controls, after the dynamic effects of central regulatory mechanisms have been accounted for by using cerebral flow measurements as another input. Methods: The employed model-based approach utilized the general dynamic modeling methodology of Laguerre expansions of kernels to analyze spontaneous time-series data in order to quantify the dynamic effects upon CTO (an index of relative capillary hemoglobin saturation distribution measured via near-infrared spectroscopy) of contemporaneous changes in end-tidal CO2 (proxy for arterial CO2), arterial blood pressure and cerebral blood flow velocity in the middle cerebral arteries (measured via transcranial Doppler). Model-based indices (physio-markers) were computed for these distinct dynamic relationships. Results: The obtained model-based indices revealed significant statistical differences of CO2 dynamic vasomotor reactivity in cortical tissue, combined with "perfusivity" that quantifies the dynamic relationship between flow velocity in cerebral arteries and CTO in MCI patients versus age-matched controls (p = 0.006). Significant difference between MCI patients and age-matched controls was also found in the respective model-prediction accuracy (p = 0.0001). Combination of these model-based indices via the Fisher Discriminant achieved even smaller p -value (p = 5 × 10–5) when comparing MCI patients with controls. The differences in dynamics of CTO in MCI patients are in lower frequencies (<0.05 Hz), suggesting impairment in endocrine/metabolic (rather than neural) mechanisms. Conclusion: The presented model-based approach elucidates the multivariate dynamic connectivity in the regulation of cerebral perfusion and yields model-based indices that may serve as physio-markers of possible dysregulation of CTO during transient CO2 changes in MCI patients. [ABSTRACT FROM AUTHOR]

Volterra models have been increasingly popular in modeling studies of nonlinear physiological systems. In this paper, feedforward artificial neural networks with two types of activation functions (sigmoidal and polynomial) are utilized for modeling the nonlinear dynamic relation between renal blood pressure and flow data, and their performance is compared to Volterra models obtained by use of the leading kernel estimation method based on Laguerre expansions. The results for the two types of artificial neural networks (sigmoidal and polynomial) and the Volterra models are comparable in terms of normalized mean-square error (NMSE) of the respective output prediction for independent testing data. However, the Volterra models obtained via the Laguerre expansion technique achieve this prediction NMSE with approximately half the number of free parameters relative to either neural-network model. Nonetheless, both approaches are deemed effective in modeling nonlinear dynamic systems and their cooperative use is recommended in general, since they may exhibit different strengths and weaknesses depending on the specific characteristics of each application. Index Terms - Artificial neural networks, autoregulation, Laguerre functions, myogenic, nonlinear, TGF, Volterra models.

We compared the dynamic characteristics in renal autoregulation of blood flow of normotensive Sprague-Dawley rats (SDR) and spontaneously hypertensive rats (SHR), using both linear and nonlinear systems analysis. Linear analysis yielded only limited information about the differences in dynamics between SDR and SHR. The predictive ability, as determined by normalized mean-square errors (NMSE), of a third-order Volterra model is better than for a linear model. This decrease in NMSE with a third-order model from that of a linear model is especially evident at frequencies below 0.2 Hz. Furthermore, NMSE are significantly higher in SHR than SDR, suggesting a more complex nonlinear system in SHR. The contribution of the third-order kernel in describing the dynamics of renal autoregulation in arterial blood pressure and blood flow was found to be important. Moreover, we have identified the presence of nonlinear interactions between the oscillatory components of the myogenic mechanism and tubuloglomerular feedback (TGF) at the level of whole kidney blood flow in SDR. An interaction between these two mechanisms had previously been revealed for SDR only at the single nephron level. However, nonlinear interactions between the myogenic and TGF mechanisms are not detected for SHR. Index Terms - Hypertensive, Laguerre functions, myogenic, nonlineal system identification, renal autoregulation, TGF.

This paper proposes the use of a class of feedforward artificial neural networks with polynomial activation functions (distinct for each hidden unit) for practical modeling of high-order Volterra systems. Discrete-time Volterra models (DVM's) are often used in the study of nonlinear physical and physiological systems using stimulus-response data. However, their practical use has been hindered by computational limitations that confine them to low-order nonlinearities (i.e., only estimation of low-order kernels is practically feasible). Since three-layer perceptrons (TLP's) can be used to represent input - output nonlinear mappings of arbitrary order, this paper explores the basic relations between DVM and TLP with tapped-delay inputs in the context of nonlinear system modeling. A variant of TLP with polynomial activation functions - termed 'separable Volterra networks' (SVN's) - is found particularly useful in deriving explicit relations with DVM and in obtaining practicable models of highly nonlinear systems from stimulus-response data. The conditions under which the two approaches yield equivalent representations of the input-output relation are explored, and the feasibility of DVM estimation via equivalent SVN training using backpropagation is demonstrated by computer-simulated examples and compared with results from the Laguerre expansion technique (LET). The use of SVN models allows practicable modeling of high-order nonlinear systems, thus removing the main practical limitation of the DVM approach. Index Terms - Laguerre kernel expansion, nonlinear system modeling, polynomial activation functions, separable Volterra network, three-layer perceptrons, Volterra kernels, Volterra models.

A methodology for modeling spike-output neural systems from input-output data is proposed, which makes use of 'neuronal modes' (NM) and 'multi-input threshold' (MT) operators. The modeling concept of NM's was introduced in a previously published paper in order to provide concise and general mathematical representations of the nonlinear dynamics involved in signal transformation and coding by a class of neural systems. This paper presents and demonstrates (with computer simulations) a method by which the NM's are determined using the 1st- and 2nd-order kernel estimates of the system, obtained from input-output data. The MT operator (i.e., a binary operator with multiple real-valued operands which are the outputs of the NM's) possesses an intrinsic refractory mechanism and generates the sequence of output spikes. The spike-generating characteristics of the MT operator are determined by the 'trigger regions' defined on the basis of data. This approach is offered as a reasonable compromise between modeling complexity and prediction accuracy, which may provide a common methodological framework for modeling a certain class of neural systems.

In order to assess the linearity of the mechanisms subserving renal blood flow autoregulation, broad-band arterial pressure fluctuations at three different power levels were induced experimentally and the resulting renal blood flow responses were recorded. Linear system analysis methods were applied in both the time and frequency domain. In the frequency domain, spectral estimates employing FFT, autoregressive moving average (ARMA) and moving average (MA) methods were used; only the MA model showed two vascular control mechanisms active at 0.02-0.05 Hz and 0.1-0.18 Hz consistent with previous experimental findings (Holstein-Rathlou et al., Amer. J. Physiol., vol. 258, 1990.). In the time domain, impulse response functions obtained from the MA model indicated likewise the presence of these two vascular control mechanisms, but the ARMA model failed to show any vascular control mechanism at 0.02-0.05 Hz. The residuals (i.e., model prediction errors) of the MA model were smaller than the ARMA model for all levels of arterial pressure forcings. The observed low coherence values and the significant model residuals in the 0.02-0.05 Hz frequency range suggest that the tubuloglomerular feedback (TGF) active in this frequency range is a nonlinear vascular control mechanism. In addition, experimental results suggest that the operation of the TGF mechanism is more evident at low/moderate pressure fluctuations and becomes overwhelmed when the arterial pressure forcing is too high.

The study of dynamic cerebral autoregulation (DCA) in essential hypertension has received considerable attention because of its clinical importance. Several studies have examined the dynamic relationship between spontaneous beat-to-beat arterial blood pressure data and contemporaneous cerebral blood flow velocity measurements (obtained via transcranial Doppler at the middle cerebral arteries) in the form of a linear input-output model using transfer function analysis. This analysis is more reliable when the contemporaneous effects of changes in blood CO2 tension are also taken into account, because of the significant effects of CO2 dynamic vasomotor reactivity (DVR) upon cerebral flow. In this article, we extract such input-output predictive models from spontaneous time series hemodynamic data of 24 patients with essential hypertension and 20 normotensive control subjects under resting conditions, using the novel methodology of principal dynamic modes (PDMs) that achieves improved estimation accuracy over previous methods for relatively short and noisy data. The obtained data-based models are subsequently used to compute indexes and markers that quantify DCA and DVR in each subject or patient and therefore can be used to assess the effects of essential hypertension. These model-based DCA and DVR indexes were properly defined to capture the observed effects of DCA and VR and found to be significantly different (P < 0.05) in the hypertensive patients. We also found significant differences between patients and control subjects in the relative contribution of three PDMs to the model output prediction, a finding that offers the prospect of identifying the physiological mechanisms affected by essential hypertension when the PDMs are interpreted in terms of specific physiological mechanisms. [ABSTRACT FROM AUTHOR]

The development of a new laser-induced fluorescence (LIF) spectroscopy technique for the measurement of the attenuation spectrum of tissue is described. The technique, termed laser-induced fluorescence attenuation spectroscopy (LIFAS), has been applied to study the effects of hypoxia on the in vivo optical properties of renal and myocardial tissue in the 350-600-nm band. Excimer laser (Xe-Cl) is used to excite a small volume of the tissue (rabbit model, N = 20) and induce autofluorescence. The emitted LIF is monitored fiberoptically at two locations that are unevenly displaced about the fluorescing volume. The optical attenuation of the tissue is calculated from the dual LIF measurements by assuming an exponential decay of the fluorescence with distance. The results indicate that hypoxia modulates the attenuation spectrum leading to characteristic changes in its shape. Primarily, the spectral profile becomes more concave between 455 nm and 505 nm and two spectral peaks at about 540 and 580 nm disappear leaving in their place a single peak at about 555 nm. The attenuation spectra of normoxic and hypoxic tissue are used to train partial least squares multivariate model for spectral classification. The model detected acute renal and myocardial hypoxia with an accuracy greater than 90% (range: 90%-96%) and 74% (range: 74%-90%), respectively. Index Terms--Heart, hyperoxia, hypoxia, ischemia, kidney, laser-induced fluorescence spectroscopy (LIFS) , myocardium, optical absorption, optical attenuation, renal, spectroscopy.