Publications by authors named "Brian Hansen"

93 Publications

Rapid microstructural plasticity in the cortical semantic network following a short language learning session.

PLoS Biol 2021 06 14;19(6):e3001290. Epub 2021 Jun 14.

Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark.

Despite the clear importance of language in our life, our vital ability to quickly and effectively learn new words and meanings is neurobiologically poorly understood. Conventional knowledge maintains that language learning-especially in adulthood-is slow and laborious. Furthermore, its structural basis remains unclear. Even though behavioural manifestations of learning are evident near instantly, previous neuroimaging work across a range of semantic categories has largely studied neural changes associated with months or years of practice. Here, we address rapid neuroanatomical plasticity accompanying new lexicon acquisition, specifically focussing on the learning of action-related language, which has been linked to the brain's motor systems. Our results show that it is possible to measure and to externally modulate (using transcranial magnetic stimulation (TMS) of motor cortex) cortical microanatomic reorganisation after mere minutes of new word learning. Learning-induced microstructural changes, as measured by diffusion kurtosis imaging (DKI) and machine learning-based analysis, were evident in prefrontal, temporal, and parietal neocortical sites, likely reflecting integrative lexico-semantic processing and formation of new memory circuits immediately during the learning tasks. These results suggest a structural basis for the rapid neocortical word encoding mechanism and reveal the causally interactive relationship of modal and associative brain regions in supporting learning and word acquisition.
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http://dx.doi.org/10.1371/journal.pbio.3001290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202930PMC
June 2021

Magnetic Resonance Imaging for the Planning, Execution, and Follow-up of Implant-Based Oral Rehabilitation: Systematic Review.

Int J Oral Maxillofac Implants 2021 May-Jun;36(3):432-441

Purpose: To undertake a systematic literature review of magnetic resonance imaging (MRI) employed in the three phases of implant-based oral rehabilitation: planning, execution, and follow-up.

Materials And Methods: MEDLINE (PubMed) and EMBASE bibliographic databases were searched up to January 2020 for studies assessing the use of MRI alone or in connection with CT and/or CBCT in the planning, execution, or follow-up of dental implant placement and/or bone grafting procedures in the maxilla or the mandible. Included studies were also assessed according to the diagnostic imaging efficacy scale presented by Fryback and Thornbury (F&T).

Results: The search strategy yielded 10 studies, which were included in the systematic review. Six studies focused on the implant planning phase, one on the immediate follow-up phase, and three on both planning and follow-up. No studies acquired signal from the bone. There was no consensus on the gold standard, MRI sequence, or field strength (T). One study reached F&T level 1, eight reached level 2, and one reached level 3.

Conclusion: The possible transition from radiography to ionizing-radiation-free imaging through MRI is still a novelty in dentistry and has yet to establish itself as a viable imaging modality suitable for replacing CT and CBCT. More studies are needed on the accuracy of the diverse MRI possibilities when applied for implant planning, execution, and follow-up before this diagnostic method can be considered as a reality for the clinician.
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http://dx.doi.org/10.11607/jomi.8536DOI Listing
June 2021

Fibroblast-Specific Proteotranscriptomes Reveal Distinct Fibrotic Signatures of Human Sinoatrial Node in Nonfailing and Failing Hearts.

Circulation 2021 Jul 20;144(2):126-143. Epub 2021 Apr 20.

Department of Physiology & Cell Biology (A.K., N.L., E.J.A., B.J.H., P.M.L.J., P.J.M., V.V.F.), The Ohio State University Wexner Medical Center, Columbus.

Background: Up to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electric activity to the atria. Unlike the role of cardiac fibroblasts in pathologic fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment.

Methods: Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted nonfailing hearts (non-HF; n=22; 48.7±3.1 years of age) and human failing hearts (n=16; 54.9±2.6 years of age). Connective tissue content was quantified from Masson trichrome-stained head-center and center-tail SAN sections. Expression of extracellular matrix proteins, including collagens 1 and 3A1, CILP1 (cartilage intermediate layer protein 1), and POSTN (periostin), and fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (≈10×5×2 mm) and right atria were isolated, cultured, passaged once, and treated ± transforming growth factor β1 and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA, and proteomic analyses.

Results: Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF versus non-HF hearts (57.7±2.6% versus 44.0±1.2%; <0.0001). Proliferating phosphorylated histone 3/vimentin/CD31 (cluster of differentiation 31) fibroblasts were higher in HF SAN. Vimentin/α-smooth muscle actin/CD31 myofibroblasts along with increased interstitial POSTN expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long noncoding RNA, microRNA, and proteomic profiles between non-HF and HF SAN and right atria fibroblasts and transforming growth factor β1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with extracellular matrix flexibility, stiffness, focal adhesion, and metabolism were altered in HF SAN fibroblasts compared with non-HF SAN.

Conclusions: This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1, and POSTN-positive interstitial fibrosis only in HF versus non-HF human hearts. Comprehensive proteotranscriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN extracellular matrix in HF hearts. Fibroblast-specific profiles generated by our proteotranscriptomic analyses of the human SAN provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277727PMC
July 2021

Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging.

PLoS One 2021 4;16(2):e0245844. Epub 2021 Feb 4.

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Mean kurtosis (MK), one of the parameters derived from diffusion kurtosis imaging (DKI), has shown increased sensitivity to tissue microstructure damage in several neurological disorders.

Methods: Thirty-seven patients with relapsing-remitting MS and eleven healthy controls (HC) received brain imaging on a 3T MR scanner, including a fast DKI sequence. MK and mean diffusivity (MD) were measured in the white matter of HC, normal-appearing white matter (NAWM) of MS patients, contrast-enhancing lesions (CE-L), FLAIR lesions (FLAIR-L) and black holes (BH).

Results: Overall 1529 lesions were analyzed, including 30 CE-L, 832 FLAIR-L and 667 BH. Highest MK values were obtained in the white matter of HC (0.814 ± 0.129), followed by NAWM (0.724 ± 0.137), CE-L (0.619 ± 0.096), FLAIR-L (0.565 ± 0.123) and BH (0.549 ± 0.12). Lowest MD values were obtained in the white matter of HC (0.747 ± 0.068 10-3mm2/sec), followed by NAWM (0.808 ± 0.163 10-3mm2/sec), CE-L (0.853 ± 0.211 10-3mm2/sec), BH (0.957 ± 0.304 10-3mm2/sec) and FLAIR-L (0.976 ± 0.35 10-3mm2/sec). While MK differed significantly between CE-L and non-enhancing lesions, MD did not.

Conclusion: MK adds predictive value to differentiate between MS lesions and might provide further information about diffuse white matter injury and lesion microstructure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861404PMC
July 2021

Effect of Orally Administered Semaglutide Versus Dulaglutide on Diabetes-Related Quality of Life in Japanese Patients with Type 2 Diabetes: The PIONEER 10 Randomized, Active-Controlled Trial.

Diabetes Ther 2021 Feb 18;12(2):613-623. Epub 2021 Jan 18.

Novo Nordisk Pharma Ltd, Tokyo, Japan.

Introduction: In the randomized Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 10 trial, once-daily orally administered semaglutide-the first oral glucagon-like peptide 1 receptor agonist (GLP-1RA)-was similarly tolerated with comparable (at 7 mg) or better (at 14 mg) efficacy versus the injectable GLP-1RA dulaglutide 0.75 mg. Health-related quality of life (HRQoL) in PIONEER 10 was assessed using the Japanese-specific Diabetes Therapy-Related Quality of Life (DTR-QoL) questionnaire.

Methods: The DTR-QoL comprises 29 questions, providing four domain and total scores. Answers were converted to a score between 0 and 100, with higher scores indicating greater HRQoL. Two estimands were prespecified: treatment policy (regardless of treatment discontinuation or rescue medication use) and trial product (assuming on treatment without rescue medication) in all randomized patients. Outcomes were assessed at weeks 26 and 52.

Results: Mean baseline DTR-QoL domain scores were similar between treatment arms and were generally lower (giving more scope for improvement) for "anxiety and dissatisfaction with treatment" (62.1-65.3) and "satisfaction with treatment" (53.9-57.9) than "burden on social activities and daily activities" (76.5-77.7) and "hypoglycemia" (83.5-88.2). Using the treatment policy estimand, orally administered semaglutide 7 and 14 mg improved HRQoL versus dulaglutide 0.75 mg for the total score (estimated mean change from baseline [CfB] 7.3 and 8.1 vs 3.3; estimated treatment difference [ETD] 3.9 and 4.8) and the "anxiety and dissatisfaction with treatment" domain (CfB 9.7 and 10.9 vs 3.7; ETD 6.0 and 7.2) at week 52. Orally administered semaglutide 14 mg improved the "satisfaction with treatment" domain versus dulaglutide 0.75 mg (CFB 13.8 vs 5.7; ETD 8.1). DTR-QoL scores for orally administered semaglutide tended to be more durable (sustained over time) than for dulaglutide. Outcomes for the trial product estimand were similar.

Conclusion: Orally administered semaglutide 7 and 14 mg improved the patients' HRQoL measured by the Japanese-specific DTR-QoL instrument versus dulaglutide 0.75 mg at week 52.

Trial Registration: ClinicalTrials.gov NCT03015220.
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http://dx.doi.org/10.1007/s13300-020-00985-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846658PMC
February 2021

Microstructural changes in the brain after long-term post-concussion symptoms: A randomized trial.

J Neurosci Res 2021 03 15;99(3):872-886. Epub 2020 Dec 15.

Hammel Neurorehabilitation Centre and University Research Clinic, Hammel, Denmark.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident.
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http://dx.doi.org/10.1002/jnr.24773DOI Listing
March 2021

Comprehensive evaluation of electrophysiological and 3D structural features of human atrial myocardium with insights on atrial fibrillation maintenance mechanisms.

J Mol Cell Cardiol 2021 02 29;151:56-71. Epub 2020 Oct 29.

Department of Physiology & Cell Biology, Bob and Corrine Frick Center for Heart Failure and Arrhythmia, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments.
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http://dx.doi.org/10.1016/j.yjmcc.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880876PMC
February 2021

Unmasking Arrhythmogenic Hubs of Reentry Driving Persistent Atrial Fibrillation for Patient-Specific Treatment.

J Am Heart Assoc 2020 10 2;9(19):e017789. Epub 2020 Oct 2.

Department of Physiology & Cell Biology and Frick Center for Heart Failure and Arrhythmia The Ohio State University Wexner Medical Center Columbus OH.

Background Atrial fibrillation (AF) driver mechanisms are obscured to clinical multielectrode mapping approaches that provide partial, surface-only visualization of unstable 3-dimensional atrial conduction. We hypothesized that transient modulation of refractoriness by pharmacologic challenge during multielectrode mapping improves visualization of hidden paths of reentrant AF drivers for targeted ablation. Methods and Results Pharmacologic challenge with adenosine was tested in ex vivo human hearts with a history of AF and cardiac diseases by multielectrode and high-resolution subsurface near-infrared optical mapping, integrated with 3-dimensional structural imaging and heart-specific computational simulations. Adenosine challenge was also studied on acutely terminated AF drivers in 10 patients with persistent AF. Ex vivo, adenosine stabilized reentrant driver paths within arrhythmogenic fibrotic hubs and improved visualization of reentrant paths, previously seen as focal or unstable breakthrough activation pattern, for targeted AF ablation. Computational simulations suggested that shortening of atrial refractoriness by adenosine may (1) improve driver stability by annihilating spatially unstable functional blocks and tightening reentrant circuits around fibrotic substrates, thus unmasking the common reentrant path; and (2) destabilize already stable reentrant drivers along fibrotic substrates by accelerating competing fibrillatory wavelets or secondary drivers. In patients with persistent AF, adenosine challenge unmasked hidden common reentry paths (9/15 AF drivers, 41±26% to 68±25% visualization), but worsened visualization of previously visible reentry paths (6/15, 74±14% to 34±12%). AF driver ablation led to acute termination of AF. Conclusions Our ex vivo to in vivo human translational study suggests that transiently altering atrial refractoriness can stabilize reentrant paths and unmask arrhythmogenic hubs to guide targeted AF driver ablation treatment.
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http://dx.doi.org/10.1161/JAHA.120.017789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792422PMC
October 2020

Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production.

J Clin Invest 2021 01;131(1)

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Protection of the brain from viral infections involves the type I IFN (IFN-I) system, defects in which render humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels lead to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we showed that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, whereas lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices or mice treated with a caspase inhibitor exhibited lower viral load and an improved infection outcome. Collectively, we identify an activation-induced apoptosis program in brain immune cells that downmodulates local immune responses.
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http://dx.doi.org/10.1172/JCI136824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773356PMC
January 2021

Optical Mapping-Validated Machine Learning Improves Atrial Fibrillation Driver Detection by Multi-Electrode Mapping.

Circ Arrhythm Electrophysiol 2020 10 13;13(10):e008249. Epub 2020 Sep 13.

Department of Physiology and Cell Biology and Bob and Corrine Frick Center for Heart Failure and Arrhythmia (A.M.Z., B.J.H., K.M.H., N.L., P.M.L.J., P.J.M., V.V.F.), The Ohio State University Wexner Medical Center, Columbus, OH.

Background: Atrial fibrillation (AF) can be maintained by localized intramural reentrant drivers. However, AF driver detection by clinical surface-only multielectrode mapping (MEM) has relied on subjective interpretation of activation maps. We hypothesized that application of machine learning to electrogram frequency spectra may accurately automate driver detection by MEM and add some objectivity to the interpretation of MEM findings.

Methods: Temporally and spatially stable single AF drivers were mapped simultaneously in explanted human atria (n=11) by subsurface near-infrared optical mapping (NIOM; 0.3 mm resolution) and 64-electrode MEM (higher density or lower density with 3 and 9 mm resolution, respectively). Unipolar MEM and NIOM recordings were processed by Fourier transform analysis into 28 407 total Fourier spectra. Thirty-five features for machine learning were extracted from each Fourier spectrum.

Results: Targeted driver ablation and NIOM activation maps efficiently defined the center and periphery of AF driver preferential tracks and provided validated annotations for driver versus nondriver electrodes in MEM arrays. Compared with analysis of single electrogram frequency features, averaging the features from each of the 8 neighboring electrodes, significantly improved classification of AF driver electrograms. The classification metrics increased when less strict annotation, including driver periphery electrodes, were added to driver center annotation. Notably, f1-score for the binary classification of higher-density catheter data set was significantly higher than that of lower-density catheter (0.81±0.02 versus 0.66±0.04, <0.05). The trained algorithm correctly highlighted 86% of driver regions with higher density but only 80% with lower-density MEM arrays (81% for lower-density+higher-density arrays together).

Conclusions: The machine learning model pretrained on Fourier spectrum features allows efficient classification of electrograms recordings as AF driver or nondriver compared with the NIOM gold-standard. Future application of NIOM-validated machine learning approach may improve the accuracy of AF driver detection for targeted ablation treatment in patients.
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http://dx.doi.org/10.1161/CIRCEP.119.008249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577986PMC
October 2020

Remote, autonomous real-time monitoring of environmental DNA from commercial fish.

Sci Rep 2020 08 6;10(1):13272. Epub 2020 Aug 6.

Section for Marine Living Resources, National Institute of Aquatic Resources, Technical University of Denmark, Vejlsøvej 39, 8600, Silkeborg, Denmark.

Environmental DNA (eDNA) is increasingly used for monitoring marine organisms; however, offshore sampling and time lag from sampling to results remain problematic. In order to overcome these challenges a robotic sampler, a 2nd generation Environmental Sample Processor (ESP), was tested for autonomous analysis of eDNA from four commercial fish species in a 4.5 million liter mesocosm. The ESP enabled in situ analysis, consisting of water collection, filtration, DNA extraction and qPCR analysis, which allowed for real-time remote reporting and archival sample collection, consisting of water collection, filtration and chemical preservation followed by post-deployment laboratory analysis. The results demonstrate that the 2G ESP was able to consistently detect and quantify target molecules from the most abundant species (Atlantic mackerel) both in real-time and from the archived samples. In contrast, detection of low abundant species was challenged by both biological and technical aspects coupled to the ecology of eDNA and the 2G ESP instrumentation. Comparison of the in situ analysis and archival samples demonstrated variance, which potentially was linked to diel migration patterns of the Atlantic mackerel. The study demonstrates strong potential for remote autonomous in situ monitoring which open new possibilities for the field of eDNA and marine monitoring.
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http://dx.doi.org/10.1038/s41598-020-70206-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413362PMC
August 2020

On the Origins of Diffusion MRI Signal Changes in Stroke.

Front Neurol 2020 30;11:549. Epub 2020 Jun 30.

McKnight Brain Institute, University of Florida, Gainesville, FL, United States.

Magnetic resonance imaging (MRI) is a leading diagnostic technique especially for neurological studies. However, the physical origin of the hyperintense signal seen in MR images of stroke immediately after ischemic onset in the brain has been a matter of debate since it was first demonstrated in 1990. In this article, we hypothesize and provide evidence that changes in the glial cells, comprising roughly one-half of the brain's cells and therefore a significant share of its volume, accompanying ischemia, are the root cause of the MRI signal change. Indeed, a primary function of the glial cells is osmoregulation in order to maintain homeostasis in the neurons and nerve fibers for accurate and consistent function. This realization also impacts our understanding of signal changes in other tissues following ischemia. We anticipate that this paradigm shift will facilitate new and improved models of MRI signals in tissues, which will, in turn, impact clinical utility.
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http://dx.doi.org/10.3389/fneur.2020.00549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344185PMC
June 2020

Silencing miR-370-3p rescues funny current and sinus node function in heart failure.

Sci Rep 2020 07 9;10(1):11279. Epub 2020 Jul 9.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200N, Copenhagen, Denmark.

Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, I, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of I, and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and I in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.
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http://dx.doi.org/10.1038/s41598-020-67790-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347645PMC
July 2020

Visualization of live, mammalian neurons during Kainate-infusion using magnetic resonance microscopy.

Neuroimage 2020 10 31;219:116997. Epub 2020 May 31.

Department of Neuroscience, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA; Center for Structural Biology, University of Florida, Gainesville, FL, USA; National High Magnetic Field Laboratory, Tallahassee, FL, USA.

Since its first description and development in the late 20th century, diffusion magnetic resonance imaging (dMRI) has proven useful in describing the microstructural details of biological tissues. Signal generated from the protons of water molecules undergoing Brownian motion produces contrast based on the varied diffusivity of tissue types. Images employing diffusion contrast were first used to describe the diffusion characteristics of tissues, later used to describe the fiber orientations of white matter through tractography, and most recently proposed as a functional contrast method capable of delineating neuronal firing in the active brain. Thanks to the molecular origins of its signal source, diffusion contrast is inherently useful at describing features of the microenvironment; however, limitations in achievable resolution in magnetic resonance imaging (MRI) scans precluded direct visualization of tissue microstructure for decades following MRI's inception as an imaging modality. Even after advancements in MRI hardware had permitted the visualization of mammalian cells, these specialized systems could only accommodate fixed specimens that prohibited the observation and characterization of physiological processes. The goal of the current study was to visualize cellular structure and investigate the subcellular origins of the functional diffusion contrast mechanism (DfMRI) in living, mammalian tissue explants. Using a combination of ultra-high field spectrometers, micro radio frequency (RF) coils, and an MRI-compatible superfusion device, we are able to report the first live, mammalian cells-α-motor neurons-visualized with magnetic resonance microscopy (MRM). We are also able to report changes in the apparent diffusion of the stratum oriens within the hippocampus-a layer comprised primarily of pyramidal cell axons and basal dendrites-and the spinal cord's ventral horn following exposure to kainate.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510773PMC
October 2020

Applying stochastic spike train theory for high-accuracy human MEG/EEG.

J Neurosci Methods 2020 07 25;340:108743. Epub 2020 Apr 25.

Center for Music in the Brain, Department of Clinical Medicine, Aarhus University and Royal Academy of Music, Aarhus/Aalborg, Nørrebrogade 44, 8000 Aarhus C, Denmark; BioMag Laboratory, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland; Department of Education, Psychology, Communication, University of Bari Aldo Moro, Italy.

Background: The accuracy of electroencephalography (EEG) and magnetoencephalography (MEG) in measuring neural evoked responses (ERs) is challenged by overlapping neural sources. This lack of accuracy is a severe limitation to the application of ERs to clinical diagnostics.

New Method: We here introduce a theory of stochastic neuronal spike timing probability densities for describing the large-scale spiking activity in neural assemblies, and a spike density component analysis (SCA) method for isolating specific neural sources. The method is tested in three empirical studies with 564 cases of ERs to auditory stimuli from 94 humans, each measured with 60 EEG electrodes and 306 MEG sensors, and a simulation study with 12,300 ERs.

Results: The first study showed that neural sources (but not non-encephalic artifacts) in individual averaged MEG/EEG waveforms are modelled accurately with temporal Gaussian probability density functions (median 99.7 %-99.9 % variance explained). The following studies confirmed that SCA can isolate an ER, namely the mismatch negativity (MMN), and that SCA reveals inter-individual variation in MMN amplitude. Finally, SCA reduced errors by suppressing interfering sources in simulated cases.

Comparison With Existing Methods: We found that gamma and sine functions fail to adequately describe individual MEG/EEG waveforms. Also, we observed that principal component analysis (PCA) and independent component analysis (ICA) does not consistently suppress interference from overlapping brain activity in neither empirical nor simulated cases.

Conclusions: These findings suggest that the overlapping neural sources in single-subject or patient data can be more accurately separated by applying SCA in comparison to PCA and ICA.
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http://dx.doi.org/10.1016/j.jneumeth.2020.108743DOI Listing
July 2020

Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node.

Nat Commun 2020 01 24;11(1):512. Epub 2020 Jan 24.

Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that I is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.
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http://dx.doi.org/10.1038/s41467-019-14039-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981137PMC
January 2020

Evaluation of the Clinical and Economic Burden of Poor Glycemic Control Associated with Therapeutic Inertia in Patients with Type 2 Diabetes in the United States.

Adv Ther 2020 02 10;37(2):869-882. Epub 2020 Jan 10.

Novo Nordisk A/S, Søborg, Denmark.

Introduction: Therapeutic inertia refers to the failure to initiate or intensify treatment in a timely manner and is widespread in type 2 diabetes (T2D) despite the well-established importance of maintaining good glycemic control. The aim of this analysis was to quantify the clinical and economic burden associated with poor glycemic control due to therapeutic inertia in patients with T2D in the USA.

Methods: The IQVIA CORE Diabetes Model was used to simulate life expectancy, costs associated with diabetes-related complications, and lost workplace productivity in US patients. Baseline glycated hemoglobin (HbA1c) levels were 7.0% (53 mmol/mol), 9.0% (75 mmol/mol), 11.0% (97 mmol/mol) 13.0% (119 mmol/mol), or 15.0% (140 mmol/mol), with targets of 6.5% (48 mmol/mol), 7.0% (53 mmol/mol), 8.0% (64 mmol/mol), or 9.0% (75 mmol/mol) depending on baseline HbA1c, across several delayed intensification scenarios (values above target were defined as poor control). The burden associated with intensification delays of 1, 2, 3, 5, and 7 years was estimated over time horizons of 1-30 years. Future costs and clinical benefits were discounted at 3% annually.

Results: In a population of 13.4 million patients with T2D and baseline HbA1c of 9.0% (75 mmol/mol), delaying intensification of therapy by 1 year was associated with a loss of approximately 13,390 life-years and increased total costs of US dollars (USD) 7.3 billion (1-year time horizon). Longer delays in intensification were associated with a greater economic burden. Delaying intensification by 7 years was projected to cost approximately 3 million life-years and USD 223 billion over a 30-year time horizon.

Conclusion: Therapeutic inertia is common in routine clinical practice and makes a substantial contribution to the burden associated with type 2 diabetes in the USA. Initiatives and interventions aimed at preventing therapeutic inertia are needed to improve clinical outcomes and avoid excess costs.
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http://dx.doi.org/10.1007/s12325-019-01199-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004420PMC
February 2020

Oral Semaglutide Versus Empagliflozin, Sitagliptin and Liraglutide in the UK: Long-Term Cost-Effectiveness Analyses Based on the PIONEER Clinical Trial Programme.

Diabetes Ther 2020 Jan 12;11(1):259-277. Epub 2019 Dec 12.

Rotherham Institute of Obesity, Clifton Medical Centre, Doncaster Gate, Rotherham, UK.

Introduction: The PIONEER trial programme showed that, after 52 weeks, the novel oral glucagon-like peptide-1 (GLP-1) analogue semaglutide 14 mg was associated with significantly greater reductions in glycated haemoglobin (HbA1c) versus a sodium-glucose cotransporter-2 inhibitor (empagliflozin 25 mg), a dipeptidyl peptidase-4 inhibitor (sitagliptin 100 mg) and an injectable GLP-1 analogue (liraglutide 1.8 mg). The aim of the present analysis was to assess the long-term cost-effectiveness of oral semaglutide 14 mg versus each of these comparators in the UK setting.

Methods: Analyses were performed from a healthcare payer perspective using the IQVIA CORE Diabetes Model, in which outcomes were projected over patient lifetimes (50 years). Baseline cohort characteristics and treatment effects were based on 52-week data from the PIONEER 2, 3 and 4 randomised controlled trials, comparing oral semaglutide with empagliflozin, sitagliptin and liraglutide, respectively. Treatment switching occurred when HbA1c exceeded 7.5% (58 mmol/mol). Utilities, treatment costs and costs of diabetes-related complications (in pounds sterling [GBP]) were taken from published sources. The acquisition cost of oral semaglutide was assumed to match that of once-weekly semaglutide.

Results: Oral semaglutide was associated with improvements in quality-adjusted life expectancy of 0.09 quality-adjusted life years (QALYs) versus empagliflozin, 0.20 QALYs versus sitagliptin and 0.07 QALYs versus liraglutide. Direct costs over a patient's lifetime were GBP 971 and GBP 963 higher with oral semaglutide than with empagliflozin and sitagliptin, respectively, but GBP 1551 lower versus liraglutide. Oral semaglutide was associated with a reduced incidence of diabetes-related complications versus all comparators. Therefore, oral semaglutide 14 mg was associated with incremental cost-effectiveness ratios of GBP 11,006 and 4930 per QALY gained versus empagliflozin 25 mg and sitagliptin 100 mg, respectively, and was more effective and less costly (dominant) versus liraglutide 1.8 mg.

Conclusion: Oral semaglutide was cost-effective versus empagliflozin and sitagliptin, and dominant versus liraglutide, for the treatment of type 2 diabetes in the UK.
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http://dx.doi.org/10.1007/s13300-019-00736-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965564PMC
January 2020

Diffusion Kurtosis Imaging maps neural damage in the EAE model of multiple sclerosis.

Neuroimage 2020 03 10;208:116406. Epub 2019 Dec 10.

CFIN, Aarhus University, Aarhus, Denmark; Department of Physics, Aarhus University, Aarhus, Denmark.

Diffusion kurtosis imaging (DKI) is an imaging modality that yields novel disease biomarkers and in combination with nervous tissue modeling, provides access to microstructural parameters. Recently, DKI and subsequent estimation of microstructural model parameters has been used for assessment of tissue changes in neurodegenerative diseases and associated animal models. In this study, mouse spinal cords from the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) were investigated for the first time using DKI in combination with biophysical modeling to study the relationship between microstructural metrics and degree of animal dysfunction. Thirteen spinal cords were extracted from animals with varied grades of disability and scanned in a high-field MRI scanner along with five control specimen. Diffusion weighted data were acquired together with high resolution T* images. Diffusion data were fit to estimate diffusion and kurtosis tensors and white matter modeling parameters, which were all used for subsequent statistical analysis using a linear mixed effects model. T* images were used to delineate focal demyelination/inflammation. Our results reveal a strong relationship between disability and measured microstructural parameters in normal appearing white matter and gray matter. Relationships between disability and mean of the kurtosis tensor, radial kurtosis, radial diffusivity were similar to what has been found in other hypomyelinating MS models, and in patients. However, the changes in biophysical modeling parameters and in particular in extra-axonal axial diffusivity were clearly different from previous studies employing other animal models of MS. In conclusion, our data suggest that DKI and microstructural modeling can provide a unique contrast capable of detecting EAE-specific changes correlating with clinical disability.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116406DOI Listing
March 2020

Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States.

Adv Ther 2019 12 24;36(12):3483-3493. Epub 2019 Oct 24.

Ossian Health Economics and Communications, Basel, Switzerland.

Introduction: Oral semaglutide is the first orally administered glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes, and has been evaluated in the PIONEER clinical trial program. These trials assessed the proportions of patients achieving single and composite endpoints, encompassing glycemic control [defined in terms of glycated hemoglobin (HbA1c)], weight loss, and hypoglycemia. The present study assessed the cost of control with oral semaglutide versus empagliflozin, sitagliptin, and liraglutide in the US.

Methods: Four endpoints were evaluated: (1) HbA1c ≤ 6.5%; (2) HbA1c < 7.0%; (3) ≥ 1.0%-point HbA1c reduction and weight loss ≥ 3.0%; and (4) HbA1c < 7.0% without hypoglycemia and without weight gain. The proportions of patients achieving each endpoint were sourced from the PIONEER 2, 3 and 4 trials. Treatment costs were accounted over an annual time-period in 2019 US dollars (USD), based on wholesale acquisition cost. Cost of control was calculated by dividing treatment costs by the proportion of patients achieving each target.

Results: Oral semaglutide was consistently associated with the lowest cost of control for all four endpoints. For the targets of HbA1c ≤ 6.5% and HbA1c < 7.0%, oral semaglutide 14 mg was associated with lower cost of control than empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg by USD 15,036, 14,697, and 6996, respectively, and USD 931, 346 and 4497, respectively. For the double composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 525, 32,277 and 13,011, respectively versus empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg. For the triple composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 1255, 7510 and 5774, respectively.

Conclusion: Oral semaglutide was associated with lower cost of bringing patients with type 2 diabetes to four clinically-relevant treatment targets versus empagliflozin, sitagliptin, and liraglutide in the US.

Funding: Novo Nordisk A/S.
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http://dx.doi.org/10.1007/s12325-019-01125-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6860465PMC
December 2019

Orally Administered Semaglutide Versus GLP-1 RAs in Patients with Type 2 Diabetes Previously Receiving 1-2 Oral Antidiabetics: Systematic Review and Network Meta-Analysis.

Diabetes Ther 2019 Dec 10;10(6):2183-2199. Epub 2019 Oct 10.

Zedediah Consulting, Berkshire, UK.

Introduction: Orally administered semaglutide is the first glucagon-like peptide 1 receptor agonist (GLP-1 RA) for oral administration. As head-to-head trials assessing orally administered semaglutide as an add-on to 1-2 oral antidiabetic drugs (OADs) vs other GLP-1 RAs are limited, a network meta-analysis (NMA) was performed to assess the relative efficacy and safety of orally administered semaglutide 14 mg once-daily (QD) vs injectable GLP-1 RAs in patients with type 2 diabetes inadequately controlled on 1-2 OADs.

Methods: A systematic literature review was conducted to identify randomised controlled trials of GLP-1 RAs in patients inadequately controlled on 1-2 OADs. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA), weight, HbA target levels (< 7.0% and ≤ 6.5%), blood pressure, and any gastrointestinal adverse events specified in system organ class. Data were synthesised using NMA and a Bayesian framework.

Results: In total, 27 studies were included in the analyses. Orally administered semaglutide 14 mg QD was associated with significantly greater reductions in HbA vs most comparators, and numerically greater reductions vs semaglutide 0.5 mg once-weekly (QW), dulaglutide 1.5 mg QW and liraglutide 1.8 mg QD. HbA reductions with semaglutide 1 mg QW were numerically greater than those with orally administered semaglutide 14 mg QD. Reductions in body weight for orally administered semaglutide 14 mg QD were significantly greater than all comparators except semaglutide QW (both doses). Orally administered semaglutide QD 14 mg was associated with statistically similar odds of experiencing gastrointestinal adverse events vs injectable GLP-1 RAs.

Conclusion: Orally administered semaglutide 14 mg QD as an add-on to 1-2 OADs is one of the most efficacious GLP-1 RAs for reducing HbA and body weight at 26 ± 4 weeks. Orally administered semaglutide 14 mg QD is well tolerated, with a safety profile in line with the GLP-1 RA class.

Funding: Novo Nordisk.
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http://dx.doi.org/10.1007/s13300-019-00706-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848399PMC
December 2019

A robust computational framework for estimating 3D Bi-Atrial chamber wall thickness.

Comput Biol Med 2019 11 12;114:103444. Epub 2019 Sep 12.

Auckland Bioengineering Institute, The University of Auckland, Auckland, 1142, New Zealand. Electronic address:

Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia. The atrial wall thickness (AWT) can potentially improve our understanding of the mechanism underlying atrial structure that drives AF and provides important clinical information. However, most existing studies for estimating AWT rely on ruler-based measurements performed on only a few selected locations in 2D or 3D using digital calipers. Only a few studies have developed automatic approaches to estimate the AWT in the left atrium, and there are currently no methods to robustly estimate the AWT of both atrial chambers. Therefore, we have developed a computational pipeline to automatically calculate the 3D AWT across bi-atrial chambers and extensively validated our pipeline on both ex vivo and in vivo human atria data. The atrial geometry was first obtained by segmenting the atrial wall from the MRIs using a novel machine learning approach. The epicardial and endocardial surfaces were then separated using a multi-planar convex hull approach to define boundary conditions, from which, a Laplace equation was solved numerically to automatically separate bi-atrial chambers. To robustly estimate the AWT in each atrial chamber, coupled partial differential equations by coupling the Laplace solution with two surface trajectory functions were formulated and solved. Our pipeline enabled the reconstruction and visualization of the 3D AWT for bi-atrial chambers with a relative error of 8% and outperformed existing algorithms by >7%. Our approach can potentially lead to improved clinical diagnosis, patient stratification, and clinical guidance during ablation treatment for patients with AF.
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http://dx.doi.org/10.1016/j.compbiomed.2019.103444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817405PMC
November 2019

Diffusion Kurtosis Imaging as a Tool in Neurotoxicology.

Authors:
Brian Hansen

Neurotox Res 2020 01 17;37(1):41-47. Epub 2019 Aug 17.

Center of Functionally Integrative Neuroscience (CFIN), Aarhus University, Aarhus, Denmark.

This commentary serves as an introduction to the magnetic resonance imaging (MRI) technique called diffusion kurtosis imaging (DKI) employed in the study by Arab et al. in the present issue of Neurotoxicology Research. In their study, DKI is employed for longitudinal investigation of a methamphetamine intoxication model of Parkinson's disease. The study employs an impressive number of animals and combines DKI with behavioral analysis at multiple time points. The commentary discusses some aspects of the study design especially the strength of combining behavioral analysis with MRI in an effort to provide as thorough a characterization and validity assessment of the animal model and cohort as possible. The potential clinical value of combining multiple MRI techniques (multimodal MRI) in PD is discussed as well as the benefit of multimodal MRI combined with behavioral analysis and subsequent histological analysis for in-depth characterization of animal models.
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http://dx.doi.org/10.1007/s12640-019-00100-3DOI Listing
January 2020

Neurite atrophy in dorsal hippocampus of rat indicates incomplete recovery of chronic mild stress induced depression.

NMR Biomed 2019 03 1;32(3):e4057. Epub 2019 Feb 1.

Center of Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus, Denmark.

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http://dx.doi.org/10.1002/nbm.4057DOI Listing
March 2019

Human Atrial Fibrillation Drivers Resolved With Integrated Functional and Structural Imaging to Benefit Clinical Mapping.

JACC Clin Electrophysiol 2018 12 1;4(12):1501-1515. Epub 2018 Nov 1.

Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Objectives: This study sought to improve atrial fibrillation (AF) driver identification by integrating clinical multielectrode mapping with driver fingerprints defined by high-resolution ex vivo 3-dimensional (3D) functional and structural imaging.

Background: Clinical multielectrode mapping of AF drivers suffers from variable contact, signal processing, and structural complexity within the 3D human atrial wall, raising questions on the validity of such drivers.

Methods: Sustained AF was mapped in coronary-perfused explanted human hearts (n = 11) with transmural near-infrared optical mapping (∼0.3 mm resolution). Simultaneously, custom FIRMap catheters (∼9 × 9 mm resolution) mapped endocardial and epicardial surfaces, which were analyzed by Focal Impulse and Rotor Mapping activation and Rotational Activity Profile (Abbott Labs, Chicago, Illinois). Functional maps were integrated with contrast-enhanced cardiac magnetic resonance imaging (∼0.1 mm resolution) analysis of 3D fibrosis architecture.

Results: During sustained AF, near-infrared optical mapping identified 1 to 2 intramural, spatially stable re-entrant AF drivers per heart. Driver targeted ablation affecting 2.2 ± 1.1% of the atrial surface terminated and prevented AF. Driver regions had significantly higher phase singularity density and dominant frequency than neighboring nondriver regions. Focal Impulse and Rotor Mapping had 80% sensitivity to near-infrared optical mapping-defined driver locations (16 of 20), and matched 14 of 20 driver visualizations: 10 of 14 re-entries seen with Rotational Activity Profile; and 4 of 6 breakthrough/focal patterns. Focal Impulse and Rotor Mapping detected 1.1 ± 0.9 false-positive rotational activity profiles per recording, but these regions had lower intramural contrast-enhanced cardiac magnetic resonance imaging fibrosis than did driver regions (14.9 ± 7.9% vs. 23.2 ± 10.5%; p < 0.005).

Conclusions: The study revealed that both re-entrant and breakthrough/focal AF driver patterns visualized by surface-only clinical multielectrodes can represent projections of 3D intramural microanatomic re-entries. Integration of multielectrode mapping and 3D fibrosis analysis may enhance AF driver detection, thereby improving the efficacy of driver-targeted ablation.
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http://dx.doi.org/10.1016/j.jacep.2018.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323649PMC
December 2018

First In Vivo Use of High-Resolution Near-Infrared Optical Mapping to Assess Atrial Activation During Sinus Rhythm and Atrial Fibrillation in a Large Animal Model.

Circ Arrhythm Electrophysiol 2018 12;11(12):e006870

Department of Physiology and Cell Biology (B.J.H., N.L., K.M.H., S.H.A., E.J.A., P.J.M., V.V.F.), The Ohio State University Wexner Medical Center, Columbus.

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http://dx.doi.org/10.1161/CIRCEP.118.006870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300135PMC
December 2018

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1 mice.

Sci Rep 2018 11 7;8(1):16486. Epub 2018 Nov 7.

iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.

Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1 mice) using postmortem 3D MR imaging coupled with histology, immunostaining and regional mRNA marker analysis. In agreement with recent large-scale schizophrenia neuroimaging studies, Brd1 mice displayed subcortical abnormalities, including volumetric reductions of amygdala and striatum. Interestingly, we demonstrate that structural alteration in striatum correlates with a general loss of striatal neurons, differentially impacting subpopulations of medium-sized spiny neurons and thus potentially striatal output. Akin to parvalbumin interneuron dysfunction in patients, a decline in parvalbumin expression was noted in the developing cortex of Brd1 mice, mainly driven by neuronal loss within or near cortical layer V, which is rich in corticostriatal projection neurons. Collectively, our study highlights the translational value of the Brd1 mouse as a pre-clinical tool for schizophrenia research and provides novel insight into its developmental, structural, and cellular pathology.
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http://dx.doi.org/10.1038/s41598-018-34729-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220279PMC
November 2018

Rapid solution of the Bloch-Torrey equation in anisotropic tissue: Application to dynamic susceptibility contrast MRI of cerebral white matter.

Neuroimage 2019 01 15;185:198-207. Epub 2018 Oct 15.

UBC MRI Research Centre, University of British Columbia, 2221, Wesbrook Mall, Vancouver, BC, Canada; Department of Physics and Astronomy, University of British Columbia, 6224, Agricultural Road, Hennings Building, Room 325, Vancouver, BC, Canada; Department of Pediatrics, University of British Columbia Faculty of Medicine, Rm 2D19, 4480, Oak Street, BC Children's Hospital, Vancouver, BC, Canada.

Blood vessel related magnetic resonance imaging (MRI) contrast provides a window into the brain's metabolism and function. Here, we show that the spin echo dynamic susceptibility contrast (DSC) MRI signal of the brain's white matter (WM) strongly depends on the angle between WM tracts and the main magnetic field. The apparent cerebral blood flow and volume are 20% larger in fibres perpendicular to the main magnetic field compared to parallel fibres. We present a rapid numerical framework for the solution of the Bloch-Torrey equation that allows us to explore the isotropic and anisotropic components of the vascular tree. By fitting the simulated spin echo DSC signal to the measured data, we show that half of the WM vascular volume is comprised of vessels running in parallel with WM fibre tracts. The WM blood volume corresponding to the best fit to the experimental data was 2.82%, which is close to the PET gold standard of 2.6%.
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http://dx.doi.org/10.1016/j.neuroimage.2018.10.035DOI Listing
January 2019

Stroke infarct volume estimation in fixed tissue: Comparison of diffusion kurtosis imaging to diffusion weighted imaging and histology in a rodent MCAO model.

PLoS One 2018 26;13(4):e0196161. Epub 2018 Apr 26.

Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Diffusion kurtosis imaging (DKI) is a new promising MRI technique with microstructural sensitivity superior to conventional diffusion tensor (DTI) based methods. In stroke, considerable mismatch exists between the infarct lesion outline obtained from the two methods, kurtosis and diffusion tensor derived metrics. We aim to investigate if this mismatch can be examined in fixed tissue. Our investigation is based on estimates of mean diffusivity (MD) and mean (of the) kurtosis tensor (MKT) obtained using recent fast DKI methods requiring only 19 images. At 24 hours post stroke, rat brains were fixed and prepared. The infarct was clearly visible in both MD and MKT maps. The MKT lesion volume was roughly 31% larger than the MD lesion volume. Subsequent histological analysis (hematoxylin) revealed similar lesion volumes to MD. Our study shows that structural components underlying the MD/MKT mismatch can be investigated in fixed tissue and therefore allows a more direct comparison between lesion volumes from MRI and histology. Additionally, the larger MKT infarct lesion indicates that MKT do provide increased sensitivity to microstructural changes in the lesion area compared to MD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919652PMC
July 2018

Now You See a Rotor, Now You Don't.

JACC Clin Electrophysiol 2018 01 6;4(1):84-86. Epub 2017 Nov 6.

Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio.

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http://dx.doi.org/10.1016/j.jacep.2017.08.014DOI Listing
January 2018
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