Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Simulation-based cheminformatic analysis of organelle-targeted molecules: lysosomotropic monobasic amines

Cell-based molecular transport simulations are being developed to facilitate exploratory cheminformatic analysis of virtual libraries of small drug-like molecules. For this purpose, mathematical models of single cells are built from equations capturing the transport of small molecules across membranes. In turn, physicochemical properties of small molecules can be used as input to simulate intracellular drug distribution, through time. Here, with mathematical equations and biological parameters adjusted so as to mimic a leukocyte in the blood, simulations were performed to analyze steady state, relative accumulation of small molecules in lysosomes, mitochondria, and cytosol of this target cell, in the presence of a homogenous extracellular drug concentration. Similarly, with equations and parameters set to mimic an intestinal epithelial cell, simulations were also performed to analyze steady state, relative distribution and transcellular permeability in this non-target cell, in the presence of an apical-to-basolateral concentration gradient. With a test set of ninety-nine monobasic amines gathered from the scientific literature, simulation results helped analyze relationships between the chemical diversity of these molecules and their intracellular distributions

Independent variations of CH4 emissions and isotopic composition over the past 160,000 years

During the last glacial cycle, greenhouse gas concentrations fluctuated on decadal and longer timescales. Concentrations of methane, as measured in polar ice cores, show a close connection with Northern Hemisphere temperature variability, but the contribution of the various methane sources and sinks to changes in concentration is still a matter of debate. Here we assess changes in methane cycling over the past 160,000 years by measurements of the carbon isotopic composition δ13C of methane in Antarctic ice cores from Dronning Maud Land and Vostok. We find that variations in the δ13C of methane are not generally correlated with changes in atmospheric methane concentration, but instead more closely correlated to atmospheric CO2 concentrations. We interpret this to reflect a climatic and CO2-related control on the isotopic signature of methane source material, such as ecosystem shifts in the seasonally inundated tropical wetlands that produce methane. In contrast, relatively stable δ13C values occurred during intervals of large changes in the atmospheric loading of methane. We suggest that most methane sources—most notably tropical wetlands—must have responded simultaneously to climate changes across these periods

Clinical applications of musculoskeletal modelling for the shoulder and upper limb

Musculoskeletal models have been developed to estimate internal loading on the human skeleton, which cannot directly be measured in vivo, from external measurements like kinematics and external forces. Such models of the shoulder and upper extremity have been used for a variety of purposes, ranging from understanding basic shoulder biomechanics to assisting in preoperative planning. In this review, we provide an overview of the most commonly used large-scale shoulder and upper extremity models and categorise the applications of these models according to the type of questions their users aimed to answer. We found that the most explored feature of a model is the possibility to predict the effect of a structural adaptation on functional outcome, for instance, to simulate a tendon transfer preoperatively. Recent studies have focused on minimising the mismatch in morphology between the model, often derived from cadaver studies, and the subject that is analysed. However, only a subset of the parameters that describe the model's geometry and, perhaps most importantly, the musculotendon properties can be obtained in vivo. Because most parameters are somehow interrelated, the others should be scaled to prevent inconsistencies in the model's structure, but it is not known exactly how. Although considerable effort is put into adding complexity to models, for example, by making them subject-specific, we have found little evidence of their superiority over current models. The current trend in development towards individualised, more complex models needs to be justified by demonstrating their ability to answer questions that cannot already be answered by existing models.</p