Mikkel Bo Hansen

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

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.

Reliable estimation of capillary transit time distributions using DSC-MRI

The regional availability of oxygen in brain tissue is traditionally inferred from the magnitude of cerebral blood flow (CBF) and the concentration of oxygen in arterial blood. Measurements of CBF are therefore widely used in the localization of neuronal response to stimulation and in the evaluation of patients suspected of acute ischemic stroke or flow-limiting carotid stenosis. It was recently demonstrated that capillary transit time heterogeneity (CTH) limits maximum oxygen extraction fraction (OEFmax) that can be achieved for a given CBF. Here we present a statistical approach for determining CTH, mean transit time (MTT), and CBF using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Using numerical simulations, we demonstrate that CTH, MTT, and OEFmax can be estimated with low bias and variance across a wide range of microvascular flow patterns, even at modest signal-to-noise ratios. Mean transit time estimated by singular value decomposition (SVD) deconvolution, however, is confounded by CTH. The proposed technique readily identifies malperfused tissue in acute stroke patients and appears to highlight information not detected by the standard SVD technique. We speculate that this technique permits the non-invasive detection of tissue with impaired oxygen delivery in neurologic disorders such as acute ischemic stroke and Alzheimers disease during routine diagnostic imaging.

Mean Diffusional Kurtosis in Patients with Glioma: Initial Results with a Fast Imaging Method in a Clinical Setting

BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an MR imaging technique that provides microstructural information in biologic systems. Its application in clinical studies, however, is hampered by long acquisition and postprocessing times. We evaluated a new and fast (2 minutes 46 seconds) diffusional kurtosis imaging method with regard to glioma grading, compared it with conventional diffusional kurtosis imaging, and compared the diagnostic accuracy of fast mean kurtosis (MK′) to that of the widely used mean diffusivity. MATERIALS AND METHODS: MK′ and mean diffusivity were measured in the contrast-enhancing tumor core, the perifocal hyperintensity (indicated on T2 FLAIR images), and the contralateral normal-appearing white and gray matter of 34 patients (22 with high-grade and 12 with low-grade gliomas). MK′ and mean diffusivity in the different tumor grades were compared by using a Wilcoxon rank sum test. Receiver operating characteristic curves and the areas under the curve were calculated to determine the diagnostic accuracy of MK′ and mean diffusivity. RESULTS: MK′ in the tumor core, but not mean diffusivity, differentiated high-grade from low-grade gliomas, and MK′ differentiated glioblastomas from the remaining gliomas with high accuracy (area under the curveMK′ = 0.842; PMK′ < .001). MK′ and mean diffusivity identified glioblastomas in the group of high-grade gliomas with similar significance and accuracy (area under the curveMK′ = 0.886; area under the curvemean diffusivity = 0.876; PMK′ = .003; Pmean diffusivity = .004). The mean MK′ in all tissue types was comparable to that obtained by conventional diffusional kurtosis imaging. CONCLUSIONS: The diffusional kurtosis imaging approach used here is considerably faster than conventional diffusional kurtosis imaging methods but yields comparable results. It can be accommodated in clinical protocols and enables exploration of the role of MK′ as a biomarker in determining glioma subtypes or response evaluation.

Towards fast computations of correlated vibrational wave functions : Vibrational coupled cluster response excitation energies at the two-mode coupling level

An efficient implementation of vibrational coupled cluster theory with two-mode excitations and a two-mode Hamiltonian is described. The algorithm is shown to scale cubically with respect to the number of modes which is identical to the scaling of the corresponding vibrational configuration interaction algorithm. This is achieved through the use of special intermediates. The same algorithm can also be used in vibrational Møller-Plesset calculations. To improve performance, screening techniques have been implemented as well. Test calculations on polyaromatic hydrocarbons with up to 264 coupled modes and model systems with up to 1140 modes are used to illustrate the various features of the algorithm.

Vibrational absorption spectra calculated from vibrational configuration interaction response theory using the Lanczos method

The Lanczos method is used to efficiently obtain the linear vibrational response function for all frequencies in an arbitrary interval. The complex part of the response function gives the absorption spectrum which can subsequently be analyzed. The method provides a way to obtain global information on the absorption spectrum without explicitly converging all vibrational eigenstates of the system. The tridiagonal Lanczos matrix used to obtain the response functions needs only be constructed once for each operator. Example calculations on cyclopropene and uracil are presented.

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 (OEFmax), and the resulting maximum cerebral metabolic rate of oxygen (CMRO2max) 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 OEFmax was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO2max (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 OEFmax (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO2max (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.

A Lanczos-chain driven approach for calculating damped vibrational configuration interaction response functions

We present an approach based on the Lanczos method for calculating the vibrational configuration interaction response functions necessary for evaluating the pure vibrational contributions to the polarizabilities and first hyperpolarizabilities of molecules. The method iteratively builds a tridiagonal representation of the central response matrix, which is subsequently used for solving the response equations. From the same chain, the response functions can be evaluated approximately for any frequency as well as using any complex damping factor. Applications to formaldehyde, cyclopropene, and uracil illustrate the concepts presented.

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.

Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [11C]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 [11C]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 [11C]acetate. No significant differences of the rate constant of oxidation of [11C]acetate (k3) were found among the three groups of subjects. The net metabolic clearance of [11C]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 [11C]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.