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Fast numerical methods for simulating large-scale integrate-and-fire neuronal networks.

We discuss numerical methods for simulating large-scale, integrate-and-fire (I&F) neuronal networks. Important elements in our numerical methods are (i) a neurophysiologically inspired integrating factor which casts the solution as a numerically tractable integral equation, and allows us to obtain stable and accurate individual neuronal trajectories (i.e., voltage and conductance time-courses) even when the I&F neuronal equations are stiff, such as in strongly fluctuating, high-conductance states; (ii) an iterated process of spike-spike corrections within groups of strongly coupled neurons to account for spike-spike interactions within a single large numerical time-step; and (iii) a clustering procedure of firing events in the network to take advantage of localized architectures, such as spatial scales of strong local interactions, which are often present in large-scale computational models-for example, those of the primary visual cortex. (We note that the spike-spike corrections in our methods are more involved than the correction of single neuron spike-time via a polynomial interpolation as in the modified Runge-Kutta methods commonly used in simulations of I&F neuronal networks.) Our methods can evolve networks with relatively strong local interactions in an asymptotically optimal way such that each neuron fires approximately once in [Formula: see text] operations, where N is the number of neurons in the system. We note that quantifications used in computational modeling are often statistical, since measurements in a real experiment to characterize physiological systems are typically statistical, such as firing rate, interspike interval distributions, and spike-triggered voltage distributions. We emphasize that it takes much less computational effort to resolve statistical properties of certain I&F neuronal networks than to fully resolve trajectories of each and every neuron within the system. For networks operating in realistic dynamical regimes, such as strongly fluctuating, high-conductance states, our methods are designed to achieve statistical accuracy when very large time-steps are used. Moreover, our methods can also achieve trajectory-wise accuracy when small time-steps are used.

Algorithms↗

Head and body space to left and right, front and rear--I. Unidirectional competitive auditory stimulation.

Very substantial right ear advantages (REAs) and right side advantages (RSAs) are reported for vocal shadowing latencies to laterally presented competitive verbal stimuli from a single earphone or loudspeaker. When head and body hemispace were dissociated by inducing a 90 degree head turn, with presentations either lateral or front-back with respect to the body, RSAs and REAs vanished, indicating that stimuli neither in the head nor in the body hemispace alone appear capable of generating any lateral asymmetries. However, a front-of-body (but not front-of-head) superiority compared with the rear was obtained. Most importantly, a powerful ventriloquism effect was obtained whereby a laterally placed dummy loudspeaker produced "pseudo"-RSAs with anterior-posterior-located sound sources. This suggests that it is the perceived position of a sound source rather than its actual position or ear of entry which determines asymmetries.

Auditory Perception↗

Direction perception in complex dynamic displays: the integration of direction information.

We created random-dot cinematograms in which each dot's successive movements were independently drawn from a Gaussian distribution of directions of some characteristic bandwidth. Such a display, comprising many different, spatially intermingled local motion vectors, can produce a percept of global coherent motion in a single direction. Using pairs of cinematograms, direction discrimination of global motion was measured under various conditions of direction distribution bandwidth, exposure duration, and constancy of each dot's path. A line-element model gave an excellent account of the results: (i) over a considerable range, discrimination was unaffected by the cinematogram's direction distribution bandwidth; (ii) only for the briefest presentations did changes in duration have an effect; (iii) so long as the overall directional content of the cinematogram remained unchanged, the constancy or randomness of individual dots' paths did not affect discrimination. Finally, the line-element model continued to give a good account of the results when we made additional measurements with uniform rather than Gaussian distributions of directions.

Discrimination, Psychological↗

Uniform System for the Evaluation of Substances. IV. Distribution and intake.

This is the fourth article in the series on USES, the Uniform System for the Evaluation of Substances. This article describes the modelling approach used to predict concentrations in the environmental media (air, surface water, agricultural soil and groundwater) and the intake media for humans (fish, drinking water, root crops, leaf crops, meat and milk) and for predatory birds and mammals (fish and earthworms). Distribution and intake are estimated on two spatial scales: locally near a point source, and regionally over a larger area. This article focuses on the local distribution and the general intake models. Local distribution is modelled in a hypothetical standard environment, using typical environmental characteristics. Humans and predators are assumed to be exposed to food products from the contaminated system. The choice of models in a system like USES, is limited by the small data sets legally required for risk assessment purposes. Therefore, USES focuses on relatively simple models, and is able to work with the limited input data.

Air Pollutants↗

Modelling the spatial distribution of Echinococcus multilocularis infection in foxes.

Alveolar echinococcosis is a rare but fatal disease in humans and is caused by the fox tapeworm Echinococcus multilocularis. The densities of fox and grassland rodent populations and the interactions between them influence E. multilocularis transmission rates in Europe. Successful rabies control has caused fox populations and E. multilocularis prevalence rates to increase in many European countries. The potential increase of the infection pressure on the human population motivates the monitoring of the infection status of foxes over space and time. Detection of E. multilocularis antigen levels in fox faecal samples collected in the field might provide a pragmatic methodology for epidemiological surveillance of the infection status in wildlife hosts across large areas, as well as providing an indication of the spatial distribution of infected faeces contaminating the environment. In this paper, a spatial analysis of antigen levels detected in faeces collected in the Franche-Comté region of eastern France is presented. In Franche-Comté, rodent outbreaks have been observed to originate in areas rich in grassland. Spatial trends in fox infection levels were modelled here as a function of the composition ratio of grassland in the landscape derived from the CORINE land-cover map. Kriging models incorporating the grassland trend term were compared to a variety of models in which five alternative trend expressions were used: the alternative trend expressions included linear and quadratic polynomials on the x and y coordinates with and without a grassland term, and a constant mean model. Leave-one-out cross-validation indicated that the estimation errors of kriging with a trend models were significantly lower when the trend expression contained the grassland index term only. The relationship between observed and predicted antigen levels was strongest when the estimated range of autocorrelation was within the home range size of a single fox. The over-dispersion of E. multilocularis in foxes may therefore account for the majority of spatial autocorrelation locally, while regional trends can be successfully modelled as a function of habitat availability for intermediate hosts.

Animals↗

Maternal immune activation perturbs the brain epitranscriptome.

Maternal immune activation (MIA) results in abnormal fetal neurodevelopment and an increased risk of neurodevelopmental disorders. Altered RNA translation has been implicated in the pathophysiology of MIA-associated neurodevelopmental deficits, but more precise mechanisms underlying disruption in RNA metabolism are lacking. Here, we characterize key components of the RNA epitranscriptomic machinery, which refers to the set of reversible chemical modifications on RNA molecules that influence RNA function, including translation, stability, splicing, and localization. Using spatial transcriptomics, we define cell type- and brain region-specific distribution of epitranscriptome regulators in the developing mouse brain. We also use direct RNA sequencing to define how MIA changes the brain epitranscriptome landscape. We identify the demethylase FTO as being notably perturbed in the context of MIA. Using pharmacological and genetic approaches, we target FTO to ameliorate behavioral phenotypes in MIA offspring. In total, this work expands upon mechanisms of translational misregulation in MIA and identifies new targets for therapeutic manipulation.

Animals↗

Label-free detection of nucleic acid and protein microarrays by scanning Kelvin nanoprobe.

A high-resolution scanning Kelvin nanoprobe is introduced as an alternative technique to the conventional fluorescence and mass spectrometric detection methods currently employed in nucleic acid and protein microarray technology. The new instrument is capable of the highly sensitive discernment of surface biochemical events taking place at molecular level such as nucleic acid hybridization and antibody-antigen interaction. The method involves measurement of changes in work function and surface potential instigated by such interactions. Being a label-free and non-contact technique, the structure, spatial configuration, local properties or function of the molecular system under study are not affected, nor perturbed by intercalating dyes, a strong electric field or ionizing beam. Subsequent to scanning, the microarray can be examined by other alternative approaches. Nucleic acids and proteins have been printed in microarray format on slides with a gold film in place using gold-sulphur interactive chemistry. Hybridization of nucleic acids for complementary and mismatched configurations shows consistent and reproducible values of work function. Differentiation of single internal mismatches is demonstrated. Protein concentration and formation of antibody-antigen pairs can be visualized and examined with high sensitivity and good inter-spot reproducibility.

Amplifiers, Electronic↗

Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423.

At present, the conformation-dependent monoclonal antibodies (mAb) provide the only information on folding of tau in the core PHF. Monoclonal antibody MN423 recognizes all and only those Alzheimer's disease (AD) core paired helical filaments (PHFs) subunits, which terminate at Glu391. Using recombinant analogs of the core PHF subunit corresponding to tau residues tau297-391, we found that the C-terminal pentapeptide (387)DHGAE(391) represented only one component of the structure recognized by mAb 423. Therefore, deletion mutants of the core subunit were generated to identify assembled parts of this conformational structure. We localized two spatially close components in the region 306-325 ((306)VQIVYK(311) and (321)KCGSL(325)) contributing to formation of the structure identified by mAb 423. Thus, the spatial proximity of three subunit segments (306)VQIVYK(311), (321)KCGSL(325) and (387)DHGAE(391) represents constraints for intramolecular folding of the core PHF subunit. Since PHF represents a compelling drug target in AD, structural knowledge presented could contribute to structure-based drug design.

Alzheimer Disease↗

How reliable are fMRI-EEG studies of epilepsy? A nonparametric approach to analysis validation and optimization.

Simultaneously acquired functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data hold great promise for localizing the spatial source of epileptiform events detected in the EEG trace. Despite a number of studies applying this method, there has been no independent and systematic validation of the approach. The present study uses a nonparametric method to show that interictal discharges lead to a blood oxygen level dependent (BOLD) response that is significantly different to that obtained by examining random 'events'. We also use this approach to examine the optimization of analysis strategy for detecting these BOLD responses. Two patients with frequent epileptiform events and a healthy control were studied. The fMRI data for each patient were analyzed using a model derived from the timings of the epileptiform events detected on EEG during fMRI scanning. Twenty sets of random pseudoevents were used to generate a null distribution representing the level of chance correlation between the EEG events and fMRI data. The same pseudoevents were applied to control data. We demonstrate that it is possible to detect blood oxygen level-dependent (BOLD) changes related to interictal discharges with specific and independent knowledge about the reliability of this activation. Biologically generated events complicate the fMRI-EEG experiment. Our proposed validation examines whether identified events have an associated BOLD response beyond chance and allows optimization of analysis strategies. This is an important step beyond standard analysis. It informs clinical interpretation because it permits assessment of the reliability of the connection between interictal EEG events and the BOLD response to those events.

Analysis of Variance↗

Localization of sensorimotor cortical rhythms induced by tactile stimulation using spatially filtered MEG.

We applied the synthetic aperture magnetometry (SAM) spatial filtering method to localize sensorimotor mu (8-14 Hz) and beta (15-35 Hz) rhythms following tactile (brush) stimulation. Neuromagnetic activity was recorded from 10 adult subjects. Transient brush stimuli were applied separately to the right index finger, medial right toe and lower right lip. Differential images of mu and beta band source power were created for periods during (event-related desynchronization; ERD) or following (event-related synchronization; ERS) tactile stimulation, relative to prestimulus baseline activity. Mu ERD to finger brushing was localized to the contralateral somatosensory cortex and was organized somatotopically. Mu ERS, however, was not consistently observed for each subject. Beta ERD was consistently localized to sensory cortical areas and organized somatotopically in the post-central gyrus (SI), and beta ERS was observed to be organized motorotopically in the precentral gyrus (MI). Longer duration (2-3 s) stimulation of the index finger also produced beta ERS in the primary motor cortex, and its time course demonstrated that these oscillatory changes are an off-response to the termination of the presented sensory stimulus. Interestingly, lip and toe stimulation also produced post-stimulus increases in beta rhythms in the bilateral motor hand areas for all subjects, suggesting that common neural systems in the primary motor cortex are activated during tactile stimulation of different body regions.

Adult↗

Assessing and improving the spatial accuracy in MEG source localization by depth-weighted minimum-norm estimates.

Cerebral currents responsible for the extra-cranially recorded magnetoencephalography (MEG) data can be estimated by applying a suitable source model. A popular choice is the distributed minimum-norm estimate (MNE) which minimizes the l2-norm of the estimated current. Under the l2-norm constraint, the current estimate is related to the measurements by a linear inverse operator. However, the MNE has a bias towards superficial sources, which can be reduced by applying depth weighting. We studied the effect of depth weighting in MNE using a shift metric. We assessed the localization performance of the depth-weighted MNE as well as depth-weighted noise-normalized MNE solutions under different cortical orientation constraints, source space densities, and signal-to-noise ratios (SNRs) in multiple subjects. We found that MNE with depth weighting parameter between 0.6 and 0.8 showed improved localization accuracy, reducing the mean displacement error from 12 mm to 7 mm. The noise-normalized MNE was insensitive to depth weighting. A similar investigation of EEG data indicated that depth weighting parameter between 2.0 and 5.0 resulted in an improved localization accuracy. The application of depth weighting to auditory and somatosensory experimental data illustrated the beneficial effect of depth weighting on the accuracy of spatiotemporal mapping of neuronal sources.

Adult↗

Differential regulation of CYP46A1 in ischemic core and peri-infarct regions of male mouse brain after permanent middle cerebral artery occlusion.

Cholesterol 24-hydroxylase (CYP46A1) regulates brain cholesterol homeostasis and synaptic plasticity, playing a crucial role in ischemic stroke. Although previous studies have reported post-ischemic CYP46A1 upregulation, its spatiotemporal dynamics remain poorly defined. To elucidate these dynamics, we investigated the expression of CYP46A1 and other essential cholesterol homeostasis-related genes from 6 h to 3 days after permanent middle cerebral artery occlusion (pMCAO) in CB-17 mice. We utilized single-cell and single-nucleus transcriptomics, regional quantitative PCR, and high-resolution immunohistochemistry. CYP46A1 is predominantly expressed in neurons. Following ischemia, the cholesterol network exhibited a dynamic spatiotemporal divergence. Acutely (6 h post-ischemia), surviving regions transiently upregulated cell-autonomous cholesterol synthesis genes and CYP46A1. Subacutely (3 days), this response shifted toward a widespread upregulation of glia-dependent cholesterol transport genes and general CYP46A1 downregulation. At 24 h, CYP46A1 protein was substantially reduced in the necrotic core and superficial layer II/III of the peri-infarct cortex, but upregulated in deeper layer V, hippocampus, and lateral striatum. Notably, this localized upregulation spatially coincided with reactive microglial hypertrophy. These findings indicate that CYP46A1 is dynamically modulated in viable tissues following ischemic stress. This spatial divergence likely reflects a synergistic interaction between inflammatory propagation and neural circuit-mediated oxidative stress. Resolving these spatiotemporal profiles provides a rigorous foundation for evaluating CYP46A1 functionality and developing stage-specific therapeutic interventions.

Cholesterol 24-hydroxylase↗

Parasite infectivity to hybridising host species: a link between hybrid resistance and allopolyploid speciation?

Variation in host-specific infectivity was studied in monogenean polystome parasites (Protopolystoma spp.) of the interfertile, parapatric anurans Xenopus laevis laevis and Xenopus muelleri. Laboratory-raised host F1 hybrids were resistant to parasites respectively specific to each parent taxon in nature. This resistance occurred against parasite isolates from both inside and outside a host hybrid/sympatric zone (and no isolate was compatible with the foreign host species under experimental conditions). Geographical Protopolystoma xenopodis isolates showed variable infectivity to a single full-sib group of their usual host, X. l. laevis, and strains with high or low infectivity to these sibs co-occurred in spatially distant local areas (separated by 1,700 km). The host compatibility of P. xenopodis was also subject to host genotypexparasite genotype interactions. Refractoriness to some parasites or pathogens, as a consequence of hybridisation, may have conferred a selective advantage on the allopolyploid pathway by which most Xenopus spp. are believed to have evolved.

Animals↗

Shapes, surfaces and saccades.

Saccadic localization of spatially extended objects requires the computation of a single saccadic landing position. What representation of the target guides saccades? Saccades were examined for various targets composed of dots to determine whether landing position corresponded to the center-of-gravity (average location) of the dots, the center-of-area of the shape, or the symmetric axis. Targets were composed of dots configured as outline drawings of circles, ellipses, cardioids, wiggly lines, or amorphous blobs. In some cases, dot spacing was varied, extraneous dot clusters were superimposed, or different distributions of dots inside the boundary were added. Quasi-random dot clusters without a well-defined contour were also studied. Instructions were to look at the target as a whole, and keep latency long enough to avoid compromising accuracy. Saccades landed with a high level of precision (S.D.s 7-10% of target eccentricity) near the center-of-area of the target shape, rather than at the center-of-gravity of the dots or on the symmetric axis. Landing position was unaffected by the spacing of dots along the boundary, the addition of dots within the boundary, or the addition of the extraneous dot clusters. When the target was a cluster of quasi-random dots, saccades landed closer to the center-of-area of the implied surface than to the average location of the dots. Overall, the positions of individual dots were important only insofar as the dots affected overall target shape. The results show that a representation of target shape guides saccades, rather than a more primitive representation of individual elements within the attended region.

Female↗

Two sources of inhibition affecting binaural evoked responses in the rat's inferior colliculus: the dorsal nucleus of the lateral lemniscus and the superior olivary complex.

The present study was undertaken to determine the influence of two extrinsic sources of inhibition on auditory binaural evoked responses recorded from the rat's inferior colliculus. The first source, the dorsal nucleus of the lateral lemniscus (DNLL), is predominantly GABAergic and has both ipsi- and contralateral projections to the central nucleus of the inferior colliculus (ICC). The second, the superior olivary complex (SOC), has a large glycinergic projection from the lateral superior olive (LSO) to the ipsilateral ICC. Thus, both structures are candidates for imposing an inhibitory effect on responses in the ICC. Neural activity was experimentally blocked by local injection of the excitatory amino acids antagonist, kynurenic acid (KYNA), into either DNLL or SOC. Binaural evoked responses were recorded from the ICC as the intensity of the sound in the ipsilateral ear was increased. Interaural intensity difference functions based on the amplitude of the evoked responses were generated before and after the KYNA injection. An injection into the contralateral DNLL greatly reduced the response suppression produced by stimulation of the ipsilateral ear. Injection into the ipsilateral DNLL, however, had no effect. Injection into the ipsilateral SOC reduced the amount of binaural suppression but the effect was apparent only in cases with surgical transection of the contralateral lateral lemniscus at a level below the DNLL. These data support the conclusion that binaural responses in the rat's ICC are shaped by inhibitory projections from both contralateral DNLL and ipsilateral SOC.

Acoustic Stimulation↗

Wavelet based multiresolution expectation maximization image reconstruction algorithm for positron emission tomography.

Maximum Likelihood (ML) estimation based Expectation Maximization (EM) [IEEE Trans Med Imag, MI-1 (2) (1982) 113] reconstruction algorithm has shown to provide good quality reconstruction for positron emission tomography (PET). Our previous work [IEEE Trans Med Imag, 7(4) (1988) 273; Proc IEEE EMBS Conf, 20(2/6) (1998) 759] introduced the multigrid (MG) and multiresolution (MR) concept for PET image reconstruction using EM. This work transforms the MGEM and MREM algorithm to a Wavelet based Multiresolution EM (WMREM) algorithm by extending the concept of switching resolutions in both image and data spaces. The MR data space is generated by performing a 2D-wavelet transform on the acquired tube data that is used to reconstruct images at different spatial resolutions. Wavelet transform is used for MR reconstruction as well as adapted in the criterion for switching resolution levels. The advantage of the wavelet transform is that it provides very good frequency and spatial (time) localization and allows the use of these coarse resolution data spaces in the EM estimation process. The MR algorithm recovers low-frequency components of the reconstructed image at coarser resolutions in fewer iterations, reducing the number of iterations required at finer resolution to recover high-frequency components. This paper also presents the design of customized biorthogonal wavelet filters using the lifting method that are used for data decomposition and image reconstruction and compares them to other commonly known wavelets.

Algorithms↗

Extending the coalescent to multilocus systems: the case of balancing selection.

Natural populations are structured spatially into local populations and genetically into diverse 'genetic backgrounds' defined by different combinations of selected alleles. If selection maintains genetic backgrounds at constant frequency then neutral diversity is enhanced. By contrast, if background frequencies fluctuate then diversity is reduced. Provided that the population size of each background is large enough, these effects can be described by the structured coalescent process. Almost all the extant results based on the coalescent deal with a single selected locus. Yet we know that very large numbers of genes are under selection and that any substantial effects are likely to be due to the cumulative effects of many loci. Here, we set up a general framework for the extension of the coalescent to multilocus scenarios and we use it to study the simplest model, where strong balancing selection acting on a set of n loci maintains 2n backgrounds at constant frequencies and at linkage equilibrium. Analytical results show that the expected linked neutral diversity increases exponentially with the number of selected loci and can become extremely large. However, simulation results reveal that the structured coalescent approach breaks down when the number of backgrounds approaches the population size, because of stochastic fluctuations in background frequencies. A new method is needed to extend the structured coalescent to cases with large numbers of backgrounds.

Alleles↗

Electrophoretic concentration of proteins at laser-patterned nanoporous membranes in microchips.

Laser-patterning of nanoporous membranes at the junction of a cross channel in a microchip is used to integrate protein concentration with an electrokinetic injection scheme. Upon application of voltage, linear electrophoretic concentration of charged proteins is achieved at the membrane surface because buffer ions can easily pass through the membrane while proteins larger than the molecular weight cutoff of the membrane (>5700) are retained. Simple buffer systems can be used, and the concentration results constitute outward evidence that the uniformity of buffer ion concentration is maintained throughout the process. Local and spatially averaged concentration are increased by 4 and 2 orders of magnitude, respectively, upon injection with moderate voltages (70-150 V) and concentration times (100 s). The degree of concentration is limited only by the solubility limit of the proteins. The porous polymer membrane can be used repeatedly as long as care is taken to avoid protein precipitation.

Electrophoresis↗