Mechanical stiffness and anisotropy measured by MRE during brain development in the minipig

The relationship between brain development and mechanical properties of brain tissue is important, but remains incompletely understood, in part due to the challenges in measuring these properties longitudinally over time. In addition, white matter, which is composed of aligned, myelinated, axonal fibers, may be mechanically anisotropic. Here we use data from magnetic resonance elastography (MRE) and diffusion tensor imaging (DTI) to estimate anisotropic mechanical properties in six female Yucatan minipigs at ages from 3 to 6 months. Fiber direction was estimated from the principal axis of the diffusion tensor in each voxel. Harmonic shear waves in the brain were excited by three different configurations of a jaw actuator and measured using a motion-sensitive MR imaging sequence. Anisotropic mechanical properties are estimated from displacement field and fiber direction data with a finite element- based, transversely-isotropic nonlinear inversion (TI-NLI) algorithm. TI-NLI finds spatially resolved TI material properties that minimize the error between measured and simulated displacement fields. Maps of anisotropic mechanical properties in the minipig brain were generated for each animal at all four ages. These maps show that white matter is more dissipative and anisotropic than gray matter, and reveal significant effects of brain development on brain stiffness and structural anisotropy. Changes in brain mechanical properties may be a fundamental biophysical signature of brain development

A numerical framework for interstitial fluid pressure imaging in poroelastic MRE

A numerical framework for interstitial fluid pressure imaging (IFPI) in biphasic materials is investigated based on three-dimensional nonlinear finite element poroelastic inversion. The objective is to reconstruct the time-harmonic pore-pressure field from tissue excitation in addition to the elastic parameters commonly associated with magnetic resonance elastography (MRE). The unknown pressure boundary conditions (PBCs) are estimated using the available full-volume displacement data from MRE. A subzone-based nonlinear inversion (NLI) technique is then used to update mechanical and hydrodynamical properties, given the appropriate subzone PBCs, by solving a pressure forward problem (PFP). The algorithm was evaluated on a single-inclusion phantom in which the elastic property and hydraulic conductivity images were recovered. Pressure field and material property estimates had spatial distributions reflecting their true counterparts in the phantom geometry with RMS errors around 20% for cases with 5% noise, but degraded significantly in both spatial distribution and property values for noise levels > 10%. When both shear moduli and hydraulic conductivity were estimated along with the pressure field, property value error rates were as high as 58%, 85% and 32% for the three quantities, respectively, and their spatial distributions were more distorted. Opportunities for improving the algorithm are discussed

Standard‐space atlas of the viscoelastic properties of the human brain

Standard anatomical atlases are common in neuroimaging because they facilitate data analyses and comparisons across subjects and studies. The purpose of this study was to develop a standardized human brain atlas based on the physical mechanical properties (i.e., tissue viscoelasticity) of brain tissue using magnetic resonance elastography (MRE). MRE is a phase contrast-based MRI method that quantifies tissue viscoelasticity noninvasively and in vivo thus providing a macroscopic representation of the microstructural constituents of soft biological tissue. The development of standardized brain MRE atlases are therefore beneficial for comparing neural tissue integrity across populations. Data from a large number of healthy, young adults from multiple studies collected using common MRE acquisition and analysis protocols were assembled (N = 134; 78F/ 56 M; 18–35 years). Nonlinear image registration methods were applied to normalize viscoelastic property maps (shear stiffness, μ, and damping ratio, ξ) to the MNI152 standard structural template within the spatial coordinates of the ICBM-152. We find that average MRE brain templates contain emerging and symmetrized anatomical detail. Leveraging the substantial amount of data assembled, we illustrate that subcortical gray matter structures, white matter tracts, and regions of the cerebral cortex exhibit differing mechanical characteristics. Moreover, we report sex differences in viscoelasticity for specific neuroanatomical structures, which has implications for understanding patterns of individual differences in health and disease. These atlases provide reference values for clinical investigations as well as novel biophysical signatures of neuroanatomy. The templates are made openly available (github.com/mechneurolab/mre134) to foster collaboration across research institutions and to support robust cross-center comparisons

Recent Arctic climate change and its remote forcing of Northwest Atlantic shelf ecosystems

Author Posting. © The Oceanography Society, 2012. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 25, no. 3 (2012): 208-213, doi:10.5670/oceanog.2012.64.During recent decades, historically unprecedented changes have been observed in the Arctic as climate warming has increased precipitation, river discharge, and glacial as well as sea-ice melting. Additionally, shifts in the Arctic's atmospheric pressure field have altered surface winds, ocean circulation, and freshwater storage in the Beaufort Gyre. These processes have resulted in variable patterns of freshwater export from the Arctic Ocean, including the emergence of great salinity anomalies propagating throughout the North Atlantic. Here, we link these variable patterns of freshwater export from the Arctic Ocean to the regime shifts observed in Northwest Atlantic shelf ecosystems. Specifically, we hypothesize that the corresponding salinity anomalies, both negative and positive, alter the timing and extent of water-column stratification, thereby impacting the production and seasonal cycles of phytoplankton, zooplankton, and higher-trophic-level consumers. Should this hypothesis hold up to critical evaluation, it has the potential to fundamentally alter our current understanding of the processes forcing the dynamics of Northwest Atlantic shelf ecosystems.Funding for this research was provided by the National Science Foundation as part of the Regional and Pan-Regional Synthesis Phases of the US Global Ocean Ecosystem (GLOBEC) Program

Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial

<p>Abstract</p> <p>Background</p> <p>As the worldwide dietary pattern becomes more westernized, the metabolic syndrome is reaching epidemic proportions. Lifestyle modifications including diet and exercise are recommended as first-line intervention for treating metabolic syndrome. Previously, we reported that a modified Mediterranean-style, low glycemic load diet with soy protein and phytosterols had a more favorable impact than the American Heart Association Step 1 diet on cardiovascular disease (CVD) risk factors. Subsequently, we screened for phytochemicals with a history of safe use that were capable of increasing insulin sensitivity through modulation of protein kinases, and identified hops <it>rho </it>iso-alpha acid and acacia proanthocyanidins. The objective of this study was to investigate whether enhancement of a modified Mediterranean-style, low glycemic load diet (MED) with specific phytochemicals (soy protein, phytosterols, <it>rho </it>iso-alpha acids and proanthocyanidins; PED) could improve cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia.</p> <p>Methods</p> <p>Forty-nine subjects with metabolic syndrome and hypercholesterolemia, aged 25–80, entered a randomized, 2-arm, 12-week intervention trial; 23 randomized to the MED arm; 26 to the PED arm. Forty-four subjects completed at least 8 weeks [MED (<it>n </it>= 19); PED (<it>n </it>= 25)]. All subjects were instructed to follow the same aerobic exercise program. Three-day diet diaries and 7-day exercise diaries were assessed at each visit. Fasting blood samples were collected at baseline, 8 and 12 weeks for analysis.</p> <p>Results</p> <p>Both arms experienced equal weight loss (MED: -5.7 kg; PED: -5.9 kg). However, at 12 weeks, the PED arm experienced greater reductions (<it>P </it>< 0.05) in cholesterol, non-HDL cholesterol, triglycerides (TG), cholesterol/HDL and TG/HDL compared with the MED arm. Only the PED arm experienced increased HDL (<it>P </it>< 0.05) and decreased TG/HDL (<it>P </it>< 0.01), and continued reduction in apo B/apo A-I from 8 to 12 weeks. Furthermore, 43% of PED subjects vs. only 22% of MED subjects had net resolution of metabolic syndrome. The Framingham 10-year CVD risk score decreased by 5.6% in the PED arm (<it>P </it>< 0.01) and 2.9% in the MED arm (<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>These results demonstrate that specific phytochemical supplementation increased the effectiveness of the modified Mediterranean-style low glycemic load dietary program on variables associated with metabolic syndrome and CVD.</p

IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression