High-resolution proton metabolic mapping of the human brain at 7 T using free induction decay rosette spectroscopic imaging.

Magnetic resonance spectroscopic imaging (MRSI) provides information about the spatial distribution of metabolites in the brain. These metabolite maps can be valuable in diagnosing central nervous system pathology. However, MRSI generally suffers from a long acquisition time, poor spatial resolution, and a low metabolite signal-to-noise ratio (SNR). Ultrahigh field strengths (≥ 7 T) can benefit MRSI with an improved SNR and allow high-resolution metabolic mapping. Non-Cartesian spatial-spectral encoding techniques, such as rosette spectroscopic imaging, can efficiently sample spatial and temporal domains, which significantly reduces the imaging time and enables high-resolution metabolic mapping in a clinically relevant scan time. In the current study, high-resolution (in-plane resolution of 2 × 2 mm2 ) mapping of proton (1 H) metabolites in the human brain at 7 T, is demonstrated. Five healthy subjects participated in the study. Using a time-efficient rosette trajectory and short TR/TE free induction decay MRSI, high-resolution maps of 1 H metabolites were obtained in a clinically relevant imaging time (6 min). Suppression of the water signal was achieved with an optimized water suppression enhanced through T1 effects approach and lipid removal was performed using L2 -regularization in the postprocessing. Spatial distributions of N-acetyl-aspartate, total choline, creatine, N-acetyl-aspartyl glutamate, myo-inositol, and glutamate were generated with Cramer-Rao lower bounds of less than 20%.

Harmonized Multisite MRI-Based Quantification of Human Liver Fat and Stiffness: A Pilot Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of end-stage liver disease. NAFLD diagnosis and follow-up relies on a combination of clinical data, liver imaging, and/or liver biopsy. However, intersite imaging differences impede diagnostic consistency and reduce the repeatability of the multisite clinical trials necessary to develop effective treatments. PURPOSE/HYPOTHESIS: The goal of this pilot study was to harmonize commercially available 3 T magnetic resonance imaging (MRI) measurements of liver fat and stiffness in human participants across academic sites and MRI vendors. STUDY TYPE: Cohort. SUBJECTS: Four community-dwelling adults with obesity. FIELD STRENGTH/SEQUENCE: 1.5 and 3 T, multiecho 3D imaging, PRESS, and GRE. ASSESSMENT: Harmonized proton density fat fraction (PDFF) and magnetic resonance spectroscopy (MRS) protocols were used to quantify the FF of synthetic phantoms and human participants with obesity using standard acquisition parameters at four sites that had four different 3 T MRI instruments. In addition, a harmonized magnetic resonance elastography (MRE) protocol was used to quantify liver stiffness among participants at two different sites at 1.5 and 3 T field strengths. Data were sent to a single data coordinating site for postprocessing. STATISTICAL TESTS: Linear regression in MATLAB, ICC analyses using SAS 9.4, one-sided 95% confidence intervals for the ICC. RESULTS: PDFF and MRS FF measurements were highly repeatable among sites in both humans and phantoms. MRE measurements of liver stiffness in three individuals at two sites using one 1.5 T and one 3 T instrument showed repeatability that was high although lower than that of MRS and PDFF. CONCLUSIONS: We demonstrated harmonization of PDFF, MRS, and MRE-based quantification of liver fat and stiffness through synthetic phantoms, traveling participants, and standardization of postprocessing analysis. Multisite MRI harmonization could contribute to multisite clinical trials assessing the efficacy of interventions and therapy for NAFLD. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Non-contrast estimate of blood-brain barrier permeability in humans using arterial spin labeling and magnetization transfer at 7 T.

Blood-brain barrier (BBB) dysfunction is associated with a number of central nervous system diseases. This study demonstrates the application of a novel noninvasive technique to measure the BBB permeability in the human brain at 7 T. The technique exploits the fact that, when tissue macromolecules are saturated by off-resonance RF pulse, the intravascular and the extravascular (tissue) water experience different magnetization transfer effects. This principle was combined with arterial spin labeling to distinguish between the intravascular and the tissue water, and was used to calculate perfusion, water extraction fraction (E), and BBB permeability surface area product for water (PS). Simultaneous coregistered magnetization transfer ratio maps were also generated that can provide valuable additional information. Eighteen healthy volunteers (seven females), age = 27 ± 11 years and weight = 65 ± 9 kg, participated in the study. Average perfusion was 67 ± 5 and 29 ± 4 ml/100 g/min (p < 0.05); and E was 0.921 ± 0.025 and 0.962 ± 0.015 (p < 0.05) in the gray matter (GM) and the white matter (WM), respectively. PS was higher in the GM (171 ± 20 ml/100 g/min) compared with the WM (95 ± 18 ml/100 g/min) (p < 0.05). The parameters exhibited good reliability with test re-test experiments. The sensitivity of this technique was demonstrated by 200 mg caffeine intake, which resulted in a decrease in the resting PS by ~31%.

Dog-human social relationship: representation of human face familiarity and emotions in the dog brain.

This study investigated the behavioral and neural indices of detecting facial familiarity and facial emotions in human faces by dogs. Awake canine fMRI was used to evaluate dogs' neural response to pictures and videos of familiar and unfamiliar human faces, which contained positive, neutral, and negative emotional expressions. The dog-human relationship was behaviorally characterized out-of-scanner using an unsolvable task. The caudate, hippocampus, and amygdala, mainly implicated in reward, familiarity and emotion processing, respectively, were activated in dogs when viewing familiar and emotionally salient human faces. Further, the magnitude of activation in these regions correlated with the duration for which dogs showed human-oriented behavior towards a familiar (as opposed to unfamiliar) person in the unsolvable task. These findings provide a bio-behavioral basis for the underlying markers and functions of human-dog interaction as they relate to familiarity and emotion in human faces.

Echocardiographic diagnosis of left ventricular diastolic dysfunction: Impact of coronary artery disease.

BACKGROUND: In 2016, the American Society of Echocardiography (ASE) released guidelines for identifying left ventricular (LV) diastolic dysfunction (DD), but its ability to detect early hemodynamic abnormalities is not well established, especially in the setting of subclinical coronary artery disease (CAD). We hypothesize that the accuracy of ASE categorization of early LVDD is affected by knowledge of whether CAD history is present. METHODS: We studied 34 patients (age 62 ± 7 years) with NYHA class I to II symptoms and with transthoracic echocardiography without findings suggesting myocardial disease (all with preserved LV ejection fraction), who underwent cardiac catheterization with high-fidelity LV pressure measurement. Echocardiographic images were evaluated for LVDD using ASE algorithm without and with knowledge of CAD history and angiography findings. CAD was considered as having DD for the algorithm. RESULTS: CAD was identified in 22 patients at catheterization (65%). Using ASE guidelines without including history of CAD or angiographic results, 29 patients were DD-, 3 were DD+ (all grade II), and 2 were indeterminate. Inclusion of CAD history recategorized 59% (n = 20) patients to DD+ (all grade I) from DD- (P < .0001). Nineteen of the recategorized patients (95%) had increased isovolumetric relaxation time (IVRT). The addition of echocardiographic IVRT improved discrimination between DD- and DD+, when the presence of CAD is unknown. CONCLUSIONS: 2016-ASE algorithm reasonably accurately identifies early LVDD at rest as reflected by LV catheterization when CAD is disclosed, but without knowledge of the presence of CAD, it underdiagnoses DD+ grade I. The addition of IVRT may improve early LVDD diagnostics.

3-T MRI mapping is a valid in vivo method of quantitatively evaluating the anterior cruciate ligament: rater reliability and comparison across age.

OBJECTIVE: As biologic augmentation methods emerge, objective measures of soft tissues are necessary for developmental study. The purpose of this study was to develop a quantitative MRI mapping protocol for the ACL. The objectives were (1) to provide age-based T2 relaxation, T2* relaxation, and volume values in healthy individuals, (2) to establish the intra-rater and inter-rater reliability of ACL mapping, and (3) to determine whether 3-T or 7-T MRI is more appropriate for future clinical trials. MATERIALS AND METHODS: Thirty healthy participants, aged 18-62, asymptomatic for knee pathology and without history of knee injury underwent both a 3-T and 7-T MRI. Manual image mapping of the anterior cruciate ligament was performed by two observers and processed to obtain T2, T2*, and volume values. Analysis of variance and two-way random effects model were used to calculate statistical significance and intraclass correlation coefficients. RESULTS: Across all participants, 3-T and 7-T mean T2, T2* and volume values were 37.1 ± 7.9 and 39.7 ± 6.2 ms (p = 0.124), 10.9 ± 1.3 and 10.9 ± 0.9 ms (p = 0.981), and 2380 ± 602 and 2484 ± 736 mm3 (p = 0.551), respectively. The T2, T2*, and volume did not vary between age cohorts (p > 0.05). Excellent inter-rater and intra-rater reliability regarding T2 and T2* values was found. While ACL volume exhibited good inter-rater reliability and excellent intra-rater reliability. CONCLUSIONS: T2 relaxation values and ACL volume do not vary with age and therefore can be used as a quantifiable, non-invasive method to assess ACL graft maturation. 7-T MRI analysis was not superior to 3-T MRI analysis, suggesting that 3-T MRI is practical and capable for future comparative studies.

Identifying disease foci from static and dynamic effective connectivity networks: Illustration in soldiers with trauma.

Brain connectivity studies report group differences in pairwise connection strengths. While informative, such results are difficult to interpret since our understanding of the brain relies on region-based properties, rather than on connection information. Given that large disruptions in the brain are often caused by a few pivotal sources, we propose a novel framework to identify the sources of functional disruption from effective connectivity networks. Our approach integrates static and time-varying effective connectivity modeling in a probabilistic framework, to identify aberrant foci and the corresponding aberrant connectomics network. Using resting-state fMRI, we illustrate the utility of this novel approach in U.S. Army soldiers (N = 87) with posttraumatic stress disorder (PTSD), mild traumatic brain injury (mTBI) and combat controls. Additionally, we employed machine-learning classification to identify those significant connectivity features that possessed high predictive ability. We identified three disrupted foci (middle frontal gyrus [MFG], insula, hippocampus), and an aberrant prefrontal-subcortical-parietal network of information flow. We found the MFG to be the pivotal focus of network disruption, with aberrant strength and temporal-variability of effective connectivity to the insula, amygdala and hippocampus. These connectivities also possessed high predictive ability (giving a classification accuracy of 81%); and they exhibited significant associations with symptom severity and neurocognitive functioning. In summary, dysregulation originating in the MFG caused elevated and temporally less-variable connectivity in subcortical regions, followed by a similar effect on parietal memory-related regions. This mechanism likely contributes to the reduced control over traumatic memories leading to re-experiencing, hyperarousal and flashbacks observed in soldiers with PTSD and mTBI. Hum Brain Mapp 39:264-287, 2018. © 2017 Wiley Periodicals, Inc.

Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model.

GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible. Significant alterations were noted in CSF and blood of GM1 humans and cats, with partial or full normalization after gene therapy in cats. Gene therapy improved the rhythmic slowing of electroencephalograms (EEGs) in GM1 cats, a phenomenon present also in GM1 patients, but nonetheless the epileptiform activity persisted. After gene therapy, MR-based analyses revealed remarkable preservation of brain architecture and correction of brain metabolites associated with microgliosis, neuroaxonal loss, and demyelination. Therapeutic benefit of AAV gene therapy in GM1 cats, many of which maintain near-normal function >5 years post-treatment, supports the strong consideration of human clinical trials, for which the biomarkers described herein will be essential for outcome assessment.

Separate brain areas for processing human and dog faces as revealed by awake fMRI in dogs (Canis familiaris).

Functional magnetic resonance imaging (fMRI) has emerged as a viable method to study the neural processing underlying cognition in awake dogs. Working dogs were presented with pictures of dog and human faces. The human faces varied in familiarity (familiar trainers and unfamiliar individuals) and emotional valence (negative, neutral, and positive). Dog faces were familiar (kennel mates) or unfamiliar. The findings revealed adjacent but separate brain areas in the left temporal cortex for processing human and dog faces in the dog brain. The human face area (HFA) and dog face area (DFA) were both parametrically modulated by valence indicating emotion was not the basis for the separation. The HFA and DFA were not influenced by familiarity. Using resting state fMRI data, functional connectivity networks (connectivity fingerprints) were compared and matched across dogs and humans. These network analyses found that the HFA mapped onto the human fusiform area and the DFA mapped onto the human superior temporal gyrus, both core areas in the human face processing system. The findings provide insight into the evolution of face processing.

Lifelong quercetin enrichment and cardioprotection in Mdx/Utrn+/- mice.

Duchenne Muscular Dystrophy (DMD) is associated with progressive cardiac pathology; however, the SIRT1/PGC1-α activator quercetin may cardioprotect dystrophic hearts. We tested the extent to which long-term 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in Mdx/Utrn+/- mice. At 2 mo, Mdx/Utrn+/- mice were fed quercetin-enriched (Mdx/Utrn+/--Q) or control diet (Mdx/Utrn+/-) for 8 mo. Control C57BL/10 (C57) animals were fed a control diet for 10 mo. Cardiac function was quantified by MRI at 2 and 10 mo. Spontaneous physical activity was quantified during the last week of treatment. At 10 mo hearts were excised for histological and biochemical analysis. Quercetin feeding improved various physiological indexes of cardiac function in diseased animals. Mdx/Utrn+/--Q also engaged in more high-intensity physical activity than controls. Histological analyses of heart tissues revealed higher expression and colocalization of utrophin and α-sarcoglycan. Lower abundance of fibronectin, cardiac damage (Hematoxylin Eosin-Y), and MMP9 were observed in quercetin-fed vs. control Mdx/Utrn+/- mice. Quercetin evoked higher protein abundance of PGC-1α, cytochrome c, ETC complexes I-V, citrate synthase, SOD2, and GPX compared with control-fed Mdx/Utrn+/- Quercetin decreased abundance of inflammatory markers including NFκB, TGF-ß1, and F4/80 compared with Mdx/Utrn+/-; however, P-NFκB, P-IKBα, IKBα, CD64, and COX2 were similar between groups. Dietary quercetin enrichment improves cardiac function in aged Mdx/Utrn+/- mice and increases mitochondrial protein content and dystrophin glycoprotein complex formation. Histological analyses indicate a marked attenuation in pathological cardiac remodeling and indicate that long-term quercetin consumption benefits the dystrophic heart. NEW & NOTEWORTHY: The current investigation provides first-time evidence that quercetin provides physiological cardioprotection against dystrophic pathology and is associated with improved spontaneous physical activity. Secondary findings suggest that quercetin-dependent outcomes are in part due to PGC-1α pathway activation.

Compromised hippocampus-striatum pathway as a potential imaging biomarker of mild-traumatic brain injury and posttraumatic stress disorder.

OBJECTIVES: Military service members risk acquiring posttraumatic stress disorder (PTSD) and mild-traumatic brain injury (mTBI), with high comorbidity. Owing to overlapping symptomatology in chronic mTBI or postconcussion syndrome (PCS) and PTSD, it is difficult to assess the etiology of a patient's condition without objective measures. Using resting-state functional MRI in a novel framework, we tested the hypothesis that their neural signatures are characterized by functionally hyperconnected brain regions which are less variable over time. Additionally, we predicted that such connectivities possessed the highest ability in predicting the diagnostic membership of a novel subject (top-predictors) in addition to being statistically significant. METHODS: U.S. Army Soldiers (N = 87) with PTSD and comorbid PCS + PTSD were recruited along with combat controls. Static and dynamic functional connectivities were evaluated. Group differences were obtained in accordance with our hypothesis. Machine learning classification (MLC) was employed to determine top predictors. RESULTS: From whole-brain connectivity, we identified the hippocampus-striatum connectivity to be significantly altered in accordance with our hypothesis. Diffusion tractography revealed compromised white-matter integrity between aforementioned regions only in the PCS + PTSD group, suggesting a structural etiology for the PCS + PTSD group rather than being an extreme subset of PTSD. Employing MLC, connectivities provided worst-case accuracy of 84% (9% more than psychological measures). Additionally, the hippocampus-striatum connectivities were found to be top predictors and thus a potential biomarker of PTSD/mTBI. CONCLUSIONS: PTSD/mTBI are associated with hippocampal-striatal hyperconnectivity from which it is difficult to disengage, leading to a habit-like response toward episodic traumatic memories, which fits well with behavioral manifestations of combat-related PTSD/mTBI. Hum Brain Mapp 38:2843-2864, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Enhancement of Odor-Induced Activity in the Canine Brain by Zinc Nanoparticles: A Functional MRI Study in Fully Unrestrained Conscious Dogs.

Using noninvasive in vivo functional magnetic resonance imaging (fMRI), we demonstrate that the enhancement of odorant response of olfactory receptor neurons by zinc nanoparticles leads to increase in activity in olfaction-related and higher order areas of the dog brain. To study conscious dogs, we employed behavioral training and optical motion tracking for reducing head motion artifacts. We obtained brain activation maps from dogs in both anesthetized state and fully conscious and unrestrained state. The enhancement effect of zinc nanoparticles was higher in conscious dogs with more activation in higher order areas as compared with anesthetized dogs. In conscious dogs, voxels in the olfactory bulb and hippocampus showed higher activity to odorants mixed with zinc nanoparticles as compared with pure odorants, odorants mixed with gold nanoparticles as well as zinc nanoparticles alone. These regions have been implicated in odor intensity processing in other species including humans. If the enhancement effect of zinc nanoparticles observed in vivo are confirmed by future behavioral studies, zinc nanoparticles may provide a way for enhancing the olfactory sensitivity of canines for detection of target substances such as explosives and contraband substances at very low concentrations, which would otherwise go undetected.

Impact of clinical input variable uncertainties on ten-year atherosclerotic cardiovascular disease risk using new pooled cohort equations.

BACKGROUND: Recently released American College of Cardiology/American Heart Association (ACC/AHA) guideline recommends the Pooled Cohort equations for evaluating atherosclerotic cardiovascular risk of individuals. The impact of the clinical input variable uncertainties on the estimates of ten-year cardiovascular risk based on ACC/AHA guidelines is not known. METHODS: Using a publicly available the National Health and Nutrition Examination Survey dataset (2005-2010), we computed maximum and minimum ten-year cardiovascular risks by assuming clinically relevant variations/uncertainties in input of age (0-1 year) and ±10 % variation in total-cholesterol, high density lipoprotein- cholesterol, and systolic blood pressure and by assuming uniform distribution of the variance of each variable. We analyzed the changes in risk category compared to the actual inputs at 5 % and 7.5 % risk limits as these limits define the thresholds for consideration of drug therapy in the new guidelines. The new-pooled cohort equations for risk estimation were implemented in a custom software package. RESULTS: Based on our input variances, changes in risk category were possible in up to 24 % of the population cohort at both 5 % and 7.5 % risk boundary limits. This trend was consistently noted across all subgroups except in African American males where most of the cohort had ≥7.5 % baseline risk regardless of the variation in the variables. CONCLUSIONS: The uncertainties in the input variables can alter the risk categorization. The impact of these variances on the ten-year risk needs to be incorporated into the patient/clinician discussion and clinical decision making. Incorporating good clinical practices for the measurement of critical clinical variables and robust standardization of laboratory parameters to more stringent reference standards is extremely important for successful implementation of the new guidelines. Furthermore, ability to customize the risk calculator inputs to better represent unique clinical circumstances specific to individual needs would be highly desirable in the future versions of the risk calculator.

Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.

Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme ß-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.

Left ventricular torsion shear angle volume analysis in patients with hypertension: a global approach for LV diastolic function.

BACKGROUND: Torsion shear angle φ is an important measure of left ventricular (LV) systolic and diastolic functions. Here we provide a novel index utilizing LV normalized torsion shear angle φ ^ volume V ^ loop to assess LV diastolic functional properties. We defined the area within φ ^ V ^ loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the φ ^ changes to increased V ^ during early diastole - d φ ^ / d V ^ as a potential measure of LV suction. METHODS: Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated. RESULTS: HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A (1.33 ± 1.13 vs. 2.19 ± 1.07, P < 0.0001) vs. control. Torsion hysteresis area was greater (0.11 ± 0.07 vs. 0.079 ± 0.045, P < 0.001) and peak - d φ ^ / d V ^ at early diastole was higher (10.46 ± 8.51 vs. 6.29 ± 3.85, P = 0.002) than control. Torsion hysteresis area was significantly correlated with E/A (r = -0.23, P = 0.025). Thirteen HTN patients had both E/A ratio < 1.12 (Control mean E/A-1SD) and torsion hysteresis area > 0.12 (Control mean torsion hysteresis area + 1SD). CONCLUSIONS: Torsion hysteresis area and peak early diastolic - d φ ^ / d V ^ were significantly increased in hypertensive concentric remodeling. The φ ^ V ^ loop takes into account the active and passive recoil processes of LV diastolic and systolic phases, therefore provides a new global description of LV diastolic function.

Spironolactone improves left atrial function and atrioventricular coupling in patients with resistant hypertension.

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4 ± 12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6 ± 9.8 vs. 25.6 ± 8.1 mL/m2; median LAVIminimum 18.5 [13.9-24.8] vs. 14.1 [10.9-19.2] mL/m2); left atrioventricular coupling index was reduced (28.2 ± 11.5 vs. 22.7 ± 9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7-60.3] vs. 55.9 [50.3-61.1] %; active LAEF 40.2 ± 8.6 vs. 43.1 ± 7.8%). LA global longitudinal strain in the active phase was increased (16.3 ± 4.1 vs. 17.8 ± 4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

Two Separate Brain Networks for Predicting Trainability and Tracking Training-Related Plasticity in Working Dogs.

Functional brain connectivity based on resting-state functional magnetic resonance imaging (fMRI) has been shown to be correlated with human personality and behavior. In this study, we sought to know whether capabilities and traits in dogs can be predicted from their resting-state connectivity, as in humans. We trained awake dogs to keep their head still inside a 3T MRI scanner while resting-state fMRI data was acquired. Canine behavior was characterized by an integrated behavioral score capturing their hunting, retrieving, and environmental soundness. Functional scans and behavioral measures were acquired at three different time points across detector dog training. The first time point (TP1) was prior to the dogs entering formal working detector dog training. The second time point (TP2) was soon after formal detector dog training. The third time point (TP3) was three months' post detector dog training while the dogs were engaged in a program of maintenance training for detection work. We hypothesized that the correlation between resting-state FC in the dog brain and behavior measures would significantly change during their detection training process (from TP1 to TP2) and would maintain for the subsequent several months of detection work (from TP2 to TP3). To further study the resting-state FC features that can predict the success of training, dogs at TP1 were divided into a successful group and a non-successful group. We observed a core brain network which showed relatively stable (with respect to time) patterns of interaction that were significantly stronger in successful detector dogs compared to failures and whose connectivity strength at the first time point predicted whether a given dog was eventually successful in becoming a detector dog. A second ontologically based flexible peripheral network was observed whose changes in connectivity strength with detection training tracked corresponding changes in behavior over the training program. Comparing dog and human brains, the functional connectivity between the brain stem and the frontal cortex in dogs corresponded to that between the locus coeruleus and left middle frontal gyrus in humans, suggestive of a shared mechanism for learning and retrieval of odors. Overall, the findings point toward the influence of phylogeny and ontogeny in dogs producing two dissociable functional neural networks.

Gene expression and ultra-structural evidence for metabolic derangement in the primary mitral regurgitation heart.

Aims: Chronic neurohormonal activation and haemodynamic load cause derangement in the utilization of the myocardial substrate. In this study, we test the hypothesis that the primary mitral regurgitation (PMR) heart shows an altered metabolic gene profile and cardiac ultra-structure consistent with decreased fatty acid and glucose metabolism despite a left ventricular ejection fraction (LVEF) > 60%. Methods and results: Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate-to-severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT4), GLUT1, and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase, and O-linked N-acetylglucosaminyl transferase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of neuropeptide Y were four-fold higher than simultaneous plasma, indicative of increased sympathetic drive. Quantitative transmission electron microscopy showed glycogen accumulation, glycophagy, increased lipid droplets (LDs), and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3ß, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance and positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma haemoglobin A1C, free fatty acids, and mitochondrial damage-associated molecular patterns in a separate cohort of patients with stable moderate PMR with an LVEF > 60% (n = 8) vs. normal controls (n = 8). Conclusion: The PMR heart has a global ultra-structural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and LDs. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.

The Use of Generative Adversarial Network and Graph Convolution Network for Neuroimaging-Based Diagnostic Classification.

Functional connectivity (FC) obtained from resting-state functional magnetic resonance imaging has been integrated with machine learning algorithms to deliver consistent and reliable brain disease classification outcomes. However, in classical learning procedures, custom-built specialized feature selection techniques are typically used to filter out uninformative features from FC patterns to generalize efficiently on the datasets. The ability of convolutional neural networks (CNN) and other deep learning models to extract informative features from data with grid structure (such as images) has led to the surge in popularity of these techniques. However, the designs of many existing CNN models still fail to exploit the relationships between entities of graph-structure data (such as networks). Therefore, graph convolution network (GCN) has been suggested as a means for uncovering the intricate structure of brain network data, which has the potential to substantially improve classification accuracy. Furthermore, overfitting in classifiers can be largely attributed to the limited number of available training samples. Recently, the generative adversarial network (GAN) has been widely used in the medical field for its generative aspect that can generate synthesis images to cope with the problems of data scarcity and patient privacy. In our previous work, GCN and GAN have been designed to investigate FC patterns to perform diagnosis tasks, and their effectiveness has been tested on the ABIDE-I dataset. In this paper, the models will be further applied to FC data derived from more public datasets (ADHD, ABIDE-II, and ADNI) and our in-house dataset (PTSD) to justify their generalization on all types of data. The results of a number of experiments show the powerful characteristic of GAN to mimic FC data to achieve high performance in disease prediction. When employing GAN for data augmentation, the diagnostic accuracy across ADHD-200, ABIDE-II, and ADNI datasets surpasses that of other machine learning models, including results achieved with BrainNetCNN. Specifically, in ADHD, the accuracy increased from 67.74% to 73.96% with GAN, in ABIDE-II from 70.36% to 77.40%, and in ADNI, reaching 52.84% and 88.56% for multiclass and binary classification, respectively. GCN also obtains decent results, with the best accuracy in ADHD datasets at 71.38% for multinomial and 75% for binary classification, respectively, and the second-best accuracy in the ABIDE-II dataset (72.28% and 75.16%, respectively). Both GAN and GCN achieved the highest accuracy for the PTSD dataset, reaching 97.76%. However, there are still some limitations that can be improved. Both methods have many opportunities for the prediction and diagnosis of diseases.

Magnetic resonance imaging with 3-dimensional analysis of left ventricular remodeling in isolated mitral regurgitation: implications beyond dimensions.

BACKGROUND: Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographic parameters measured at the base of the heart. METHODS AND RESULTS: Ninety-four patients (age, 54 ± 11 years; 38% female) with degenerative isolated MR underwent cine magnetic resonance imaging with tissue tagging and 3-dimensional analysis. In 51 control subjects (age, 44 ± 14 years; 53% female), the relation between LVES volume (LVESV) and LVES dimension was quadratic, whereas in 94 MR patients, this relation was cubic, indicating a greater increase in LVESV per LVES dimension among MR patients. Moreover, magnetic resonance imaging LVESV from summated serial short-axis slices was significantly greater than LVESV assessed with the Bullet formula in MR patients, attributed to a more spherical remodeling distal to the tips of the papillary muscles (P<0.001). Thirty-five patients underwent mitral valve repair per current guideline recommendations. LV ejection fraction decreased from 61 ± 7% to 54 ± 8% (P<0.0001) and maximum shortening decreased significantly below normal at 1 year postoperatively (P<0.0001). Despite normalization of LV stroke volume and LV end-diastolic volume/mass ratio, there was a persistent significant increase in distal LVES 3-dimensional radius/wall thickness ratio and LVESV index after surgery. CONCLUSIONS: Despite apparently preserved LVES dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR.