Robust estimation of hemo-dynamic parameters in traditional DCE-MRI models.

PURPOSE: In dynamic contrast enhanced (DCE) MRI, separation of signal contributions from perfusion and leakage requires robust estimation of parameters in a pharmacokinetic model. We present and quantify the performance of a method to compute tissue hemodynamic parameters from DCE data using established pharmacokinetic models. METHODS: We propose a Bayesian scheme to obtain perfusion metrics from DCE MRI data. Initial performance is assessed through digital phantoms of the extended Tofts model (ETM) and the two-compartment exchange model (2CXM), comparing the Bayesian scheme to the standard Levenberg-Marquardt (LM) algorithm. Digital phantoms are also invoked to identify limitations in the pharmacokinetic models related to measurement conditions. Using computed maps of the extra vascular volume (ve) from 19 glioma patients, we analyze differences in the number of un-physiological high-intensity ve values for both ETM and 2CXM, using a one-tailed paired t-test assuming un-equal variance. RESULTS: The Bayesian parameter estimation scheme demonstrated superior performance over the LM technique in the digital phantom simulations. In addition, we identified limitations in parameter reliability in relation to scan duration for the 2CXM. DCE data for glioma and cervical cancer patients was analyzed with both algorithms and demonstrated improvement in image readability for the Bayesian method. The Bayesian method demonstrated significantly fewer non-physiological high-intensity ve values for the ETM (p<0.0001) and the 2CXM (p<0.0001). CONCLUSION: We have demonstrated substantial improvement of the perceptive quality of pharmacokinetic parameters from advanced compartment models using the Bayesian parameter estimation scheme as compared to the LM technique.

The effect of carotid artery stenting on capillary transit time heterogeneity in patients with carotid artery stenosis.

INTRODUCTION: Carotid revascularisation improves haemodynamic compromise in cerebral circulation as an additional benefit to the primary goal of reducing future thromboembolic risk. We determined the effect of carotid artery stenting on cerebral perfusion and oxygenation using a perfusion-weighted MRI algorithm that is based on assessment of capillary transit-time heterogeneity together with other perfusion and metabolism-related metrics. PATIENTS AND METHODS: A consecutive series of 33 patients were evaluated by dynamic susceptibility contrast perfusion-weighted MRI prior to and within 24 h of the endovascular procedure. The level of relative change induced by stenting, and relationship of these changes with respect to baseline stenosis degree were analysed. RESULTS: Stenting led to significant increase in cerebral blood flow (p < 0.001), and decrease in cerebral blood volume (p = 0.001) and mean transit time (p < 0.001); this was accompanied by reduction in oxygen extraction fraction (p < 0.001) and capillary transit-time heterogeneity (p < 0.001), but an overall increase in relative capillary transit-time heterogeneity (RTH: CTH divided by MTT; p = 0.008). No significant change was observed with respect to cerebral metabolic rate of oxygen. The median volume of tissue with MTT > 2s decreased from 24 ml to 12 ml (p = 0.009), with CTH > 2s from 29 ml to 19 ml (p = 0.041), and with RTH < 0.9 from 61 ml to 39 ml (p = 0.037) following stenting. These changes were correlated with the baseline degree of stenosis.Discussion: Stenting improved the moderate stage of haemodynamic compromise at baseline in our cohort. The decreased relative transit-time heterogeneity, which increases following stenting, is probably a reflection of decreased functional capillary density secondary to chronic hypoperfusion induced by the proximal stenosis.Conclusion: Carotid artery stenting, is not only important for prophylaxis of future vascular events, but also is critical for restoration of microvascular function in the cerebral tissue.

Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary transit time heterogeneity - CTH), and the CTH:MTT ratio (relative transit time heterogeneity), which is expected to remain constant during changes in perfusion pressure in a microvasculature consisting of passive, compliant vessels. To aid data interpretation, we also developed a computational model that relates graded microvascular failure to changes in these parameters. In perfusion-diffusion mismatch tissue, prolonged mean transit time (>5 seconds) and very low cerebral blood flow (≤6 mL/100 mL/min) was associated with high risk of infarction, largely independent of recanalization status. In the remaining mismatch region, low relative transit time heterogeneity predicted subsequent infarction if recanalization was not achieved. Our model suggested that transit time homogenization represents capillary no-flow. Consistent with this notion, low relative transit time heterogeneity values were associated with lower cerebral blood volume. We speculate that low RTH may represent a novel biomarker of penumbral microvascular failure.

Automated estimation of salvageable tissue: Comparison with expert readers.

PURPOSE: To assess the performance of an automatic perfusion-diffusion mismatch outlining algorithm, in a cohort of acute ischemic stroke patients imaged as part of a multicenter study. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) from 167 patients with anterior circulation strokes scanned at either 3T or 1.5T systems were analyzed retrospectively through an automatic perfusion-diffusion mismatch detection algorithm. In addition, four expert raters manually outlined perfusion lesions on time-to-peak (TTP) maps and diffusion lesions on diffusion-weighted images (DWI), and reference perfusion-diffusion mismatch masks were obtained as the areas where at least three experts were in agreement that tissue was part of the perfusion-weighted imaging (PWI) lesion, but not the diffusion lesion. Per-subject analyses of mismatch volumes and mismatch overlap were subsequently performed. RESULTS: The use of the automatic perfusion-diffusion mismatch detection algorithm resulted in a 4.0 ml mean (standard deviation 28.7 ml) difference in mismatch volume compared to the reference expert consensus (Pearson correlation, r = 0.91, P < 0.0001). The median spatial agreement was 0.71, with an interquartile range of 0.28. CONCLUSION: We demonstrated excellent agreement between the perfusion-diffusion mismatch masks estimated by our proposed automatic algorithm and those achieved by expert consensus.

Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline.

Cerebral small vessel disease (SVD) gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline in the elderly. SVD is known to occur in relation to hypertension, diabetes, smoking, radiation therapy and in a range of inherited and genetic disorders, autoimmune disorders, connective tissue disorders, and infections. Until recently, changes in capillary patency and blood viscosity have received little attention in the aetiopathogenesis of SVD and the high risk of subsequent stroke and cognitive decline. Capillary flow patterns were, however, recently shown to limit the extraction efficacy of oxygen in tissue and capillary dysfunction therefore proposed as a source of stroke-like symptoms and neurodegeneration, even in the absence of physical flow-limiting vascular pathology. In this review, we examine whether capillary flow disturbances may be a shared feature of conditions that represent risk factors for SVD. We then discuss aspects of capillary dysfunction that could be prevented or alleviated and therefore might be of general benefit to patients at risk of SVD, stroke or cognitive decline.

Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans.

In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [(11)C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [(11)C]acetate. No significant differences of the rate constant of oxidation of [(11)C]acetate (k 3) were found among the three groups of subjects. The net metabolic clearance of [(11)C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P < 0.05), which we interpret to be an effect of reduced cerebral blood flow rather than a reflection of low [(11)C]acetate metabolism. We conclude that the characteristic decline of whole-brain oxidative metabolism in patients with cirrhosis with HE is not due to malfunction of oxidative metabolism in astrocytes. Thus, the observed decline of brain oxidative metabolism implicates changes of neurons and their energy turnover in patients with HE.

Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study.

Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF(max)), and the resulting maximum cerebral metabolic rate of oxygen (CMRO2(max)) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF(max) was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO2(max) (3.40±1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63±1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5±18.7 mm Hg) and conservative (163.0±10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2±11.9 versus 35.8±9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF(max) (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO2(max) (3.16±1.66 versus 3.68±1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH.

Automated decision-support system for prediction of treatment responders in acute ischemic stroke.

MRI is widely used in the assessment of acute ischemic stroke. In particular, it identifies the mismatch between hypoperfused and the permanently damaged tissue, the PWI-DWI mismatch volume. It is used to help triage patients into active or supportive treatment pathways. COMBAT Stroke is an automated software tool for estimating the mismatch volume and ratio based on MRI. Herein, we validate the decision made by the software with actual clinical decision rendered. Furthermore, we evaluate the association between treatment decisions (both automated and actual) and outcomes. COMBAT Stroke was used to determine PWI-DWI mismatch volume and ratio in 228 patients from two European multi-center stroke databases. We performed confusion matrix analysis to summarize the agreement between the automated selection and the clinical decision. Finally, we evaluated the clinical and imaging outcomes of the patients in the four entries of the confusion matrix (true positive, true negative, false negative, and false positive). About 186 of 228 patients with acute stroke underwent thrombolytic treatment, with the remaining 42 receiving supportive treatment only. Selection based on radiographic criteria using COMBAT Stroke classified 142 patients as potential candidates for thrombolytic treatment and 86 for supportive treatment; 60% sensitivity and 29% specificity. The patients deemed eligible for thrombolytic treatment by COMBAT Stroke demonstrated significantly higher rates of compromised tissue salvage, less neurological deficit, and were more likely to experience thrombus dissolving and reestablishment of normal blood flow at 24 h follow-up compared to those who were treated without substantial PWI-DWI mismatch. These results provide evidence that COMBAT Stroke, in addition to clinical assessment, may offer an optimal framework for a fast, efficient, and standardized clinical support tool to select patients for thrombolysis in acute ischemic stroke.

Using diffusion anisotropy to characterize neuronal morphology in gray matter: the orientation distribution of axons and dendrites in the NeuroMorpho.org database.

Accurate mathematical modeling is integral to the ability to interpret diffusion magnetic resonance (MR) imaging data in terms of cellular structure in brain gray matter (GM). In previous work, we derived expressions to facilitate the determination of the orientation distribution of axonal and dendritic processes from diffusion MR data. Here we utilize neuron reconstructions available in the NeuroMorpho database (www.neuromorpho.org) to assess the validity of the model we proposed by comparing morphological properties of the neurons to predictions based on diffusion MR simulations using the reconstructed neuron models. Initially, the method for directly determining neurite orientation distributions is shown to not depend on the line length used to quantify cylindrical elements. Further variability in neuron morphology is characterized relative to neuron type, species, and laboratory of origin. Subsequently, diffusion MR signals are simulated based on human neocortical neuron reconstructions. This reveals a bias in which diffusion MR data predict neuron orientation distributions to have artificially low anisotropy. This bias is shown to arise from shortcomings (already at relatively low diffusion weighting) in the Gaussian approximation of diffusion, in the presence of restrictive barriers, and data analysis methods involving higher moments of the cumulant expansion are shown to be capable of reducing the magnitude of the observed bias.

If You Know Something, Say Something: Young Children's Problem with False Beliefs.

Whether young children understand that others may hold false beliefs is a hotly debated topic in psychology and neuroscience. Much evidence suggests that children do not pass this milestone in their understanding of other people until the age of 5 years. Other evidence suggests that they understand already in their second year. This study proposes a novel account of the logic of conversations about certain mental states. By modifying the discourse accordingly, children passed three false belief tasks at 3 years of age while they failed standard false belief tasks. The results support the view that even young children construe other people in adult-like psychological terms.

New Formulation and Implementation of Vibrational Self-Consistent Field Theory.

A new implementation of the vibrational self-consistent field (VSCF) method is presented on the basis of a second quantization formulation. A so-called active terms algorithm is shown to be a significant improvement over a standard implementation reducing the computational effort by one order in the number of degrees of freedom. Various types of screening provide even further reductions in computational scaling and absolute CPU time. VSCF calculations on large polyaromatic hydrocarbon model systems are presented. Further, it is demonstrated that in cases where distant modes are not directly coupled in the Hamiltonian, down to linear scaling of the required CPU time with respect to the number of vibrational modes can be obtained. This is illustrated with calculations on simple model systems with up to 1 million degrees of freedom.

Using Electronic Energy Derivative Information in Automated Potential Energy Surface Construction for Vibrational Calculations.

The availability of an accurate representation of the potential energy surface (PES) is an essential prerequisite in an anharmonic vibrational calculation. At the same time, the high dimensionality of the fully coupled PES and the adverse scaling properties with respect to the molecular size make the construction of an accurate PES a computationally demanding task. In the past few years, our group tested and developed a series of tools and techniques aimed at defining computationally efficient, black-box protocols for the construction of PESs for use in vibrational calculations. This includes the definition of an adaptive density-guided approach (ADGA) for the construction of PESs from an automatically generated set of evaluation points. Another separate aspect has been the exploration of the use of derivative information through modified Shepard (MS) interpolation/extrapolation procedures. With this article, we present an assembled machinery where these methods are embedded in an efficient way to provide both a general machinery as well as concrete computational protocols. In this framework we introduce and discuss the accuracy and computational efficiency of two methods, called ADGA[2gx3M] and ADGA[2hx3M], where the ADGA recipe is used (with MS interpolation) to automatically define modest sized grids for up to two-mode couplings, while MS extrapolation based on, respectively, gradients only and gradients and Hessians from the ADGA determined points provides access to sufficiently accurate three-mode couplings. The performance of the resulting potentials is investigated in vibrational coupled cluster (VCC) calculations. Three molecular systems serve as benchmarks: a trisubstituted methane (CHFClBr), methanimine (CH2NH), and oxazole (C3H3NO). Furthermore, methanimine and oxazole are addressed in accurate calculations aiming to reproduce experimental results.

Children's use of mutual exclusivity to learn labels for parts of objects.

When teaching children part terms, adults frequently outline the relevant part rather than simply point. This pragmatic information very likely helps children interpret the label correctly. But the importance of gestures may not negate the need for default lexical biases such as the whole object assumption and mutual exclusivity. On this view, children initially assume that a novel label refers to a whole object. If the label for the object is familiar, mutual exclusivity blocks this assumption and frees children to look for a part referent. In this study, the authors taught children part terms by outlining a novel part of a real object. We made mutual exclusivity available by showing children familiar whole objects with novel parts and unavailable by showing unfamiliar whole objects with novel parts. During test, the object was oriented with the part facing away from the child to distinguish pointing to the object from pointing to the part. Both 2-year-olds and 3-year-olds learned more part labels when mutual exclusivity was available. Thus, mutual exclusivity is indispensable even when part labeling is accompanied by naturalistic communicative gestures.

Vibrational contributions to indirect spin-spin coupling constants calculated via variational anharmonic approaches.

Zero-point vibrational contributions to indirect spin-spin coupling constants for N2, CO, HF, H2O, C2H2, and CH4 are calculated via explicitly anharmonic approaches. Thermal averages of indirect spin-spin coupling constants are calculated for the same set of molecules and for C2X4, X = H, F, Cl. Potential energy surfaces have been calculated on a grid of points and analytic representations have been obtained by a linear least-squares fit in a direct product polynomial basis. Property surfaces have been represented by a fourth-order Taylor expansion around the equilibrium geometry. The electronic structure calculations employ density functional theory, and vibrational contributions to indirect spin-spin coupling constants are calculated employing vibrational self-consistent-field and vibrational configuration-interaction methods. The performance of vibrational perturbation theory and various approximate variational calculations are discussed. Thermal averages are computed by state-specific and virtual vibrational self-consistent-field methods.

Learning words: children disregard some pragmatic information that conflicts with mutual exclusivity.

Children tend to infer that when a speaker uses a new label, the label refers to an unlabeled object rather than one they already know the label for. Does this inference reflect a default assumption that words are mutually exclusive? Or does it instead reflect the result of a pragmatic reasoning process about what the speaker intended? In two studies, we distinguish between these possibilities. Preschoolers watched as a speaker pointed toward (Study 1) or looked at (Study 2) a familiar object while requesting the referent for a new word (e.g. 'Can you give me the blicket?'). In both studies, despite the speaker's unambiguous behavioral cue indicating an intent to refer to a familiar object, children inferred that the novel label referred to an unfamiliar object. These results suggest that children expect words to be mutually exclusive even when a speaker provides some kinds of pragmatic evidence to the contrary.

Appearance questions can be misleading: a discourse-based account of the appearance-reality problem.

Preschoolers' success on the appearance-reality task is a milestone in theory-of-mind development. On the standard task children see a deceptive object, such as a sponge that looks like a rock, and are asked, "What is this really?" and "What does this look like?" Children below 412 years of age fail saying that the object not only is a sponge but also looks like a sponge. We propose that young children's difficulty stems from ambiguity in the meaning of "looks like." This locution can refer to outward appearance ("Peter looks like Paul") but in fact often refers to likely reality ("That looks like Jim"). We propose that "looks like" is taken to refer to likely reality unless the reality is already part of the common ground of the conversation. Because this joint knowledge is unclear to young children on the appearance-reality task, they mistakenly think the appearance question is about likely reality. Study 1 analyzed everyday conversations from the CHILDES database and documented that 2 and 3-year-olds are familiar with these two different uses of the locution. To disambiguate the meaning of "looks like," Study 2 clarified that reality was shared knowledge as part of the appearance question, e.g., "What does the sponge look like?" Study 3 used a non-linguistic measure to emphasize the shared knowledge of the reality in the appearance question. Study 4 asked children on their own to articulate the contrast between appearance and reality. At 91%, 85%, and 81% correct responses, children were at near ceiling levels in each of our manipulations while they failed the standard versions of the tasks. Moreover, we show how this discourse-based explanation accounts for findings in the literature. Thus children master the appearance-reality distinction by the age of 3 but the standard task masks this understanding because of the discourse structure involved in talking about appearances.

Use of the mutual exclusivity assumption by young word learners.

A critical question about early word learning is whether word learning constraints such as mutual exclusivity exist and foster early language acquisition. It is well established that children will map a novel label to a novel rather than a familiar object. Evidence for the role of mutual exclusivity in such indirect word learning has been questioned because: (1) it comes mostly from 2 and 3-year-olds and (2) the findings might be accounted for, not by children avoiding second labels, but by the novel object which creates a lexical gap children are motivated to fill. Three studies addressed these concerns by having only a familiar object visible. Fifteen to seventeen and 18-20-month-olds were selected to straddle the vocabulary spurt. In Study 1, babies saw a familiar object and an opaque bucket as a location to search. Study 2 handed babies the familiar object to play with. Study 3 eliminated an obvious location to search. On the whole, babies at both ages resisted second labels for objects and, with some qualifications, tended to search for a better referent for the novel label. Thus mutual exclusivity is in place before the onset of the naming explosion. The findings demonstrate that lexical constraints enable babies to learn words even under non-optimal conditions--when speakers are not clear and referents are not visible. The results are discussed in relation to an alternative social-pragmatic account.