A mathematical model for velocity-selective arterial spin labeling.

PURPOSE: To present a theoretical framework that rigorously defines and analyzes key concepts and quantities for velocity selective arterial spin labeling (VSASL). THEORY AND METHODS: An expression for the VSASL arterial delivery function is derived based on (1) labeling and saturation profiles as a function of velocity and (2) physiologically plausible approximations of changes in acceleration and velocity across the vascular system. The dependence of labeling efficiency on the amplitude and effective bolus width of the arterial delivery function is defined. Factors that affect the effective bolus width are examined, and timing requirements to minimize quantitation errors are derived. RESULTS: The model predicts that a flow-dependent negative bias in the effective bolus width can occur when velocity selective inversion (VSI) is used for the labeling module and velocity selective saturation (VSS) is used for the vascular crushing module. The bias can be minimized by choosing a nominal labeling cutoff velocity that is lower than the nominal cutoff velocity of the vascular crushing module. CONCLUSION: The elements of the model are specified in a general fashion such that future advances can be readily integrated. The model can facilitate further efforts to understand and characterize the performance of VSASL and provide critical theoretical insights that can be used to design future experiments and develop novel VSASL approaches.

Metabolic energetics underlying attractors in neural models.

Neural population modeling, including the role of neural attractors, is a promising tool for understanding many aspects of brain function. We propose a modeling framework to connect the abstract variables used in modeling to recent cellular-level estimates of the bioenergetic costs of different aspects of neural activity, measured in ATP consumed per second per neuron. Based on recent work, an empirical reference for brain ATP use for the awake resting brain was estimated as ∼2 × 109 ATP/s-neuron across several mammalian species. The energetics framework was applied to the Wilson-Cowan (WC) model of two interacting populations of neurons, one excitatory (E) and one inhibitory (I). Attractors were considered to exhibit steady-state behavior and limit cycle behavior, both of which end when the excitatory stimulus ends, and sustained activity that persists after the stimulus ends. The energy cost of limit cycles, with oscillations much faster than the average neuronal firing rate of the population, is tracked more closely with the firing rate than the limit cycle frequency. Self-sustained firing driven by recurrent excitation, though, involves higher firing rates and a higher energy cost. As an example of a simple network in which each node is a WC model, a combination of three nodes can serve as a flexible circuit element that turns on with an oscillating output when input passes a threshold and then persists after the input ends (an "on-switch"), with moderate overall ATP use. The proposed framework can serve as a guide for anchoring neural population models to plausible bioenergetics requirements.NEW & NOTEWORTHY This work bridges two approaches for understanding brain function: cellular-level studies of the metabolic energy costs of different aspects of neural activity and neural population modeling, including the role of neural attractors. The proposed modeling framework connects energetic costs, in ATP consumed per second per neuron, to the more abstract variables used in neural population modeling. In particular, this work anchors potential neural attractors to physiologically plausible bioenergetics requirements.

Velocity-selective arterial spin labeling perfusion MRI: A review of the state of the art and recommendations for clinical implementation.

This review article provides an overview of the current status of velocity-selective arterial spin labeling (VSASL) perfusion MRI and is part of a wider effort arising from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. Since publication of the 2015 consensus paper on arterial spin labeling (ASL) for cerebral perfusion imaging, important advancements have been made in the field. The ASL community has, therefore, decided to provide an extended perspective on various aspects of technical development and application. Because VSASL has the potential to become a principal ASL method because of its unique advantages over traditional approaches, an in-depth discussion was warranted. VSASL labels blood based on its velocity and creates a magnetic bolus immediately proximal to the microvasculature within the imaging volume. VSASL is, therefore, insensitive to transit delay effects, in contrast to spatially selective pulsed and (pseudo-) continuous ASL approaches. Recent technical developments have improved the robustness and the labeling efficiency of VSASL, making it a potentially more favorable ASL approach in a wide range of applications where transit delay effects are of concern. In this review article, we (1) describe the concepts and theoretical basis of VSASL; (2) describe different variants of VSASL and their implementation; (3) provide recommended parameters and practices for clinical adoption; (4) describe challenges in developing and implementing VSASL; and (5) describe its current applications. As VSASL continues to undergo rapid development, the focus of this review is to summarize the fundamental concepts of VSASL, describe existing VSASL techniques and applications, and provide recommendations to help the clinical community adopt VSASL.

VESPA ASL: VElocity and SPAtially Selective Arterial Spin Labeling.

PURPOSE: Spatially selective arterial spin labeling (ASL) perfusion MRI is sensitive to arterial transit times (ATT) that can result in inaccurate perfusion quantification when ATTs are long. Velocity-selective ASL is robust to this effect because blood is labeled within the imaging region, allowing immediate label delivery. However, velocity-selective ASL cannot characterize ATTs, which can provide important clinical information. Here, we introduce a novel pulse sequence, called VESPA ASL, that combines velocity-selective and pseudo-continuous ASL to simultaneously label different pools of arterial blood for robust cerebral blood flow (CBF) and ATT measurement. METHODS: The VESPA ASL sequence is similar to velocity-selective ASL, but the velocity-selective labeling is made spatially selective, and pseudo-continuous ASL is added to fill the inflow time. The choice of inflow time and other sequence settings were explored. VESPA ASL was compared to multi-delay pseudo-continuous ASL and velocity-selective ASL through simulations and test-retest experiments in healthy volunteers. RESULTS: VESPA ASL is shown to accurately measure CBF in the presence of long ATTs, and ATTs < TI can also be measured. Measurements were similar to established ASL techniques when ATT was short. When ATT was long, VESPA ASL measured CBF more accurately than multi-delay pseudo-continuous ASL, which tended to underestimate CBF. CONCLUSION: VESPA ASL is a novel and robust approach to simultaneously measure CBF and ATT and offers important advantages over existing methods. It fills an important clinical need for noninvasive perfusion and transit time imaging in vascular diseases with delayed arterial transit.

Distributed Phase Oscillatory Excitation Efficiently Produces Attractors Using Spike-Timing-Dependent Plasticity.

The brain is thought to represent information in the form of activity in distributed groups of neurons known as attractors. We show here that in a randomly connected network of simulated spiking neurons, periodic stimulation of neurons with distributed phase offsets, along with standard spike-timing-dependent plasticity (STDP), efficiently creates distributed attractors. These attractors may have a consistent ordered firing pattern or become irregular, depending on the conditions. We also show that when two such attractors are stimulated in sequence, the same STDP mechanism can create a directed association between them, forming the basis of an associative network. We find that for an STDP time constant of 20 ms, the dependence of the efficiency of attractor creation on the driving frequency has a broad peak centered around 8 Hz. Upon restimulation, the attractors self-oscillate, but with an oscillation frequency that is higher than the driving frequency, ranging from 10 to 100 Hz.

Predictors of the Use of Mineralocorticoid Receptor Antagonists in Patients With Left Ventricular Dysfunction Post-ST-Segment-Elevation Myocardial Infarction.

Background Guidelines recommend mineralocorticoid receptor antagonist (MRA) use in patients with left ventricular ejection fraction ≤40% following a myocardial infarction plus heart failure or diabetes mellitus, based on mortality benefit in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial. The objective of this study was to evaluate the real-world utilization of MRAs for patients with ST-segment-elevation myocardial infarction (STEMI) with left ventricular dysfunction. Methods and Results The prospective, population-based, Vancouver Coastal Health Authority STEMI database was linked with local outpatient cardiology records from 2007 to 2018. EPHESUS criteria were used to define post-STEMI MRA eligibility (left ventricular ejection fraction ≤40% plus clinical heart failure or diabetes mellitus, and no dialysis-dependent renal dysfunction). The primary outcome was MRA prescription among eligible patients at discharge and the secondary outcome was MRA prescription within 3 months postdischarge. Of 2691 patients with STEMI, 317 (12%) were MRA eligible, and 70 (22%) eligible patients were prescribed an MRA at discharge. Among eligible patients with no MRA at discharge, 12/126 (9.5%) with documented postdischarge follow-up were prescribed an MRA within 3 months. In multivariable analysis, left ventricular ejection fraction (odds ratio [OR], 1.55 per 5% left ventricular ejection fraction decrease; 95% CI, 1.26-1.90) and calendar year (OR, 1.23 per year, 95% CI, 1.11-1.37) were associated with MRA prescription at discharge. Other prespecified variables were not associated with MRA prescription. Conclusions In this contemporary STEMI cohort, only 1 in 4 MRA-eligible patients were prescribed an MRA within 3 months following hospitalization despite high-quality evidence for use. Novel decision-support tools are required to optimize pharmacotherapy decisions during hospitalization and follow-up to target this gap in post-STEMI care.

Awake Mouse Imaging: From Two-Photon Microscopy to Blood Oxygen Level-Dependent Functional Magnetic Resonance Imaging.

BACKGROUND: Functional magnetic resonance imaging (fMRI) in awake behaving mice is well positioned to bridge the detailed cellular-level view of brain activity, which has become available owing to recent advances in microscopic optical imaging and genetics, to the macroscopic scale of human noninvasive observables. However, though microscopic (e.g., two-photon imaging) studies in behaving mice have become a reality in many laboratories, awake mouse fMRI remains a challenge. Owing to variability in behavior among animals, performing all types of measurements within the same subject is highly desirable and can lead to higher scientific rigor. METHODS: We demonstrated blood oxygenation level-dependent fMRI in awake mice implanted with long-term cranial windows that allowed optical access for microscopic imaging modalities and optogenetic stimulation. We started with two-photon imaging of single-vessel diameter changes (n = 1). Next, we implemented intrinsic optical imaging of blood oxygenation and flow combined with laser speckle imaging of blood flow obtaining a mesoscopic picture of the hemodynamic response (n = 16). Then we obtained corresponding blood oxygenation level-dependent fMRI data (n = 5). All measurements could be performed in the same mice in response to identical sensory and optogenetic stimuli. RESULTS: The cranial window did not deteriorate the quality of fMRI and allowed alternation between imaging modalities in each subject. CONCLUSIONS: This report provides a proof of feasibility for multiscale imaging approaches in awake mice. In the future, this protocol could be extended to include complex cognitive behaviors translatable to humans, such as sensory discrimination or attention.

In vitro drug release and percutaneous behavior of poloxamer-based hydrogel formulation containing traditional Chinese medicine.

For the treatment of atopic dermatitis (AD), we have developed a transdermal functionalized textile therapy based on thermosensitive poloxamer 407 (P407) hydrogel containing a traditional Chinese herbal medicine. This study aims to investigate the effects of various formulation variables of P407/carboxymethyl cellulose sodium (P407/CMCs) composite hydrogel on the release of Cortex Moutan (CM) extract. Concentrations of P407 and CMCs showed significant influence on the release due to alteration of bulk viscosity of the system. An increase in pH values of release medium was found to appreciably impede the release of polar drug (CM) due to ionization. Elevated temperatures were also shown to facilitate the drug release. Moreover, the diffusional release behavior of CM from P407/CMCs composite hydrogel was found to follow the first-order kinetic model. Additionally, transdermal studies showed that permeability of the drug through the skin can be enhanced with addition of CMCs in the hydrogel formulation.

Dual-functional transdermal drug delivery system with controllable drug loading based on thermosensitive poloxamer hydrogel for atopic dermatitis treatment.

The treatment of atopic dermatitis (AD) has long been viewed as a problematic issue by the medical profession. Although a wide variety of complementary therapies have been introduced, they fail to combine the skin moisturizing and drug supply for AD patients. This study reports the development of a thermo-sensitive Poloxamer 407/Carboxymethyl cellulose sodium (P407/CMCs) composite hydrogel formulation with twin functions of moisture and drug supply for AD treatment. It was found that the presence of CMCs can appreciably improve the physical properties of P407 hydrogel, which makes it more suitable for tailored drug loading. The fabricated P407/CMCs composite hydrogel was also characterized in terms of surface morphology by field emission scanning electron microscopy (FE-SEM), rheological properties by a rheometer, release profile in vitro by dialysis method and cytotoxicity test. More importantly, the findings from transdermal drug delivery behavior revealed that P407/CMCs showed desirable percutaneous performance. Additionally, analysis of cytotoxicity test suggested that P407/CMCs composite hydrogel is a high-security therapy for clinical trials and thus exhibits a promising way to treat AD with skin moisturizing and medication.

Anti-Inflammatory Activities of Pentaherbs Formula, Berberine, Gallic Acid and Chlorogenic Acid in Atopic Dermatitis-Like Skin Inflammation.

Atopic dermatitis (AD) is a common allergic skin disease, characterized by dryness, itchiness, thickening and inflammation of the skin. Infiltration of eosinophils into the dermal layer and presence of edema are typical characteristics in the skin biopsy of AD patients. Previous in vitro and clinical studies showed that the Pentaherbs formula (PHF) consisting of five traditional Chinese herbal medicines, Flos Lonicerae, Herba Menthae, Cortex Phellodendri, Cortex Moutan and Rhizoma Atractylodis at w/w ratio of 2:1:2:2:2 exhibited therapeutic potential in treating AD. In this study, an in vivo murine model with oxazolone (OXA)-mediated dermatitis was used to elucidate the efficacy of PHF. Active ingredients of PHF water extract were also identified and quantified, and their in vitro anti-inflammatory activities on pruritogenic cytokine IL-31- and alarmin IL-33-activated human eosinophils and dermal fibroblasts were evaluated. Ear swelling, epidermis thickening and eosinophils infiltration in epidermal and dermal layers, and the release of serum IL-12 of the murine OXA-mediated dermatitis were significantly reduced upon oral or topical treatment with PHF (all p < 0.05). Gallic acid, chlorogenic acid and berberine contents (w/w) in PHF were found to be 0.479%, 1.201% and 0.022%, respectively. Gallic acid and chlorogenic acid could suppress the release of pro-inflammatory cytokine IL-6 and chemokine CCL7 and CXCL8, respectively, in IL-31- and IL-33-treated eosinophils-dermal fibroblasts co-culture; while berberine could suppress the release of IL-6, CXCL8, CCL2 and CCL7 in the eosinophil culture and eosinophils-dermal fibroblasts co-culture (all p < 0.05). These findings suggest that PHF can ameliorate allergic inflammation and attenuate the activation of eosinophils.

Wedge-shaped slice-selective adiabatic inversion pulse for controlling temporal width of bolus in pulsed arterial spin labeling.

PURPOSE: In pulsed arterial spin labeling (PASL) methods, arterial blood is labeled by inverting a slab with uniform thickness, resulting in different temporal widths of boluses in vessels with different flow velocities. This limits the temporal resolution and signal-to-noise ratio (SNR) efficiency gains in PASL-based methods intended for high temporal resolution and SNR efficiency, such as turbo-ASL and turbo-QUASAR. THEORY AND METHODS: A novel wedge-shaped (WS) adiabatic inversion pulse is developed by adding in-plane gradient pulses to a slice-selective (SS) adiabatic inversion pulse to linearly modulate the inversion thicknesses at different locations while maintaining the adiabatic properties of the original pulse. A hyperbolic secant (HS)-based WS inversion pulse was implemented. Its performance was tested in simulations and in phantom and human experiments and compared with an SS HS inversion pulse. RESULTS: Compared with the SS inversion pulse, the WS inversion pulse was capable of inducing different inversion thicknesses at different locations. It could be adjusted to generate a uniform temporal width of boluses in arteries at locations with different flow velocities. CONCLUSION: The WS inversion pulse can be used to control the temporal widths of labeled boluses in PASL experiments. This should benefit PASL experiments by maximizing labeling duty cycle and improving temporal resolution and SNR efficiency. Magn Reson Med 76:838-847, 2016. © 2015 Wiley Periodicals, Inc.

Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis.

RATIONALE: Despite the demonstrated advantageous systemic changes in response to regular exercise for individuals with cystic fibrosis (CF), exercise is still viewed as an elective rather than a vital component of therapy, and it is likely that these benefits extend to and are partially mediated by exercise-induced changes in ion regulation. OBJECTIVE: We sought to determine if exercise could provide comparable improvements in ion regulation in the CF lung as albuterol, measured using exhaled breath condensate (EBC) collection and nasal potential difference (NPD). METHODS: Fourteen CF (13-42 yrs.) and sixteen healthy (18-42 yrs.) subjects completed a randomized crossover study of albuterol and submaximal exercise. EBC was collected at baseline, 30- and 60-min post-albuterol administration, and at baseline and during three separate 15 min cycling exercise bouts at low, moderate, and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). NPD was performed at 30- and 80-min post albuterol or following moderate and vigorous intensity exercise. RESULTS: CF subjects had lower EBC Cl(-), but no difference in EBC Na(+) at baseline when compared to healthy subjects. EBC Cl(-) increased four-fold with moderate exercise which was similar to that seen 60-min post albuterol administration for CF subjects. Neither exercise nor albuterol altered EBC Na(+). The change in NPD voltage with amiloride (ΔAmil) was greater and there was minimal Cl(-) secretion (ΔTCC) seen at baseline in the CF compared to the healthy subjects. ΔAmil was greater with both albuterol and exercise when compared to baseline within both CF and healthy groups, but there was no significant difference in the ΔTCC response with either treatment. CONCLUSION: Both exercise and albuterol can alter ion regulation increasing Cl(-) secretion to a significant and similar degree in individuals with CF.

Enhanced identification of BOLD-like components with multi-echo simultaneous multi-slice (MESMS) fMRI and multi-echo ICA.

The recent introduction of simultaneous multi-slice (SMS) acquisitions has enabled the acquisition of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) data with significantly higher temporal sampling rates. In a parallel development, the use of multi-echo fMRI acquisitions in conjunction with a multi-echo independent component analysis (ME-ICA) approach has been introduced as a means to automatically distinguish functionally-related BOLD signal components from signal artifacts, with significant gains in sensitivity, statistical power, and specificity. In this work, we examine the gains that can be achieved with a combined approach in which data obtained with a multi-echo simultaneous multi-slice (MESMS) acquisition are analyzed with ME-ICA. We find that ME-ICA identifies significantly more BOLD-like components in the MESMS data as compared to data acquired with a conventional multi-echo single-slice acquisition. We demonstrate that the improved performance of MESMS derives from both an increase in the number of temporal samples and the enhanced ability to filter out high-frequency artifacts.

Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis.

BACKGROUND: Although exercise is a vital component of the therapy prescribed to individuals with cystic fibrosis (CF), it is not a priority due to a finite amount of treatment time and the view that exercise is not as beneficial as pharmacological treatments by many individuals with CF. We sought to compare the therapeutic benefits of exercise and their prescribed bronchodilator albuterol. METHODS: CF (n = 14) and healthy (n = 16) subjects completed three visits, a baseline screening with VO2 max test and two treatment visits. On the two treatment visits, subjects completed spirometry and diffusing capacity of the lungs for nitric oxide (DLNO) maneuvers either at baseline, 60, and 110 min post-albuterol administration, or at baseline and the midway point of three separate 15 min exercise bouts at low, moderate and vigorous intensity (25, 50 and 65% of the maximum workload, respectively). RESULTS: With moderate exercise the increase in DLNO was double (39 ± 8 vs 15  ± 6% change) and the level of bronchodilation similar (23% change) when compared to 110 min post-albuterol in individuals with CF. During exercise FVC became reduced (-309 ± 66 mL with moderate exercise) and the increase in FEV1 was attenuated (103 ± 39 vs 236 ± 58 mL, exercise vs. albuterol) when compared with the response to albuterol in individuals with CF. Epinephrine (EPI) release increased 39, 72 and 144% change with low, moderate and vigorous intensity exercise respectively for individuals with CF, but this increase was blunted when compared to healthy subjects. CONCLUSION: Our results suggest that moderate intensity exercise is the optimal intensity for individuals with CF, as low intensity exercise increases EPI less than 50% and vigorous intensity exercise is over taxing, such that airflow can be restricted. Although the duration of the beneficial effect is uncertain, exercise can promote greater improvements in gas diffusion and comparable bronchodilation when compared to albuterol.

Increased SNR efficiency in velocity selective arterial spin labeling using multiple velocity selective saturation modules (mm-VSASL).

PURPOSE: Velocity-selective arterial spin labeling (VSASL) is theoretically insensitive to transit delay (TD) effects. However, it uses saturation instead of inversion, resulting in compromised signal to noise ratio (SNR). In this study we explore the use of multiple velocity-selective saturation (VSS) modules in VSASL (mm-VSASL) to improve SNR. METHODS: Theoretical SNR efficiency improvement and optimized parameters were calculated from simulations for mm-VSASL. VSASL with two VSS modules (VSASL-2VSS) was implemented to measure cerebral blood flow in vivo, compared with conventional VSASL (VSASL-1VSS), pulsed ASL (PASL), and pseudo-continuous ASL (PCASL). TDs and bolus durations (BDs) were measured to validate the simulations and to examine the TD sensitivity of these preparations. RESULTS: Compared with VSASL-1VSS, VSASL-2VSS achieved a significant improvement of SNR (22.1 ± 1.9%, P = 1.7 × 10(-6) ) in vivo, consistent with a 22.7% improvement predicted from simulations. The SNR was comparable to or higher (in gray matter, P = 4.3 × 10(-3) ) than that using PCASL. VSASL was experimentally verified to have minimal TD effects. CONCLUSION: Utilizing multiple VSS modules can improve the SNR efficiency of VSASL. Mm-VSASL may result in an SNR that is comparable to or even higher than that of PCASL in applications where long postlabeling delays are required.

Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia.

This review provides a summary statement of recommended implementations of arterial spin labeling (ASL) for clinical applications. It is a consensus of the ISMRM Perfusion Study Group and the European ASL in Dementia consortium, both of whom met to reach this consensus in October 2012 in Amsterdam. Although ASL continues to undergo rapid technical development, we believe that current ASL methods are robust and ready to provide useful clinical information, and that a consensus statement on recommended implementations will help the clinical community to adopt a standardized approach. In this review, we describe the major considerations and trade-offs in implementing an ASL protocol and provide specific recommendations for a standard approach. Our conclusion is that as an optimal default implementation, we recommend pseudo-continuous labeling, background suppression, a segmented three-dimensional readout without vascular crushing gradients, and calculation and presentation of both label/control difference images and cerebral blood flow in absolute units using a simplified model.

An optimized design to reduce eddy current sensitivity in velocity-selective arterial spin labeling using symmetric BIR-8 pulses.

PURPOSE: Velocity-selective arterial spin labeling (VSASL) tags arterial blood on a velocity-selective (VS) basis and eliminates the tagging/imaging gap and associated transit delay sensitivity observed in other ASL tagging methods. However, the flow-weighting gradient pulses in VS tag preparation can generate eddy currents (ECs), which may erroneously tag the static tissue and create artificial perfusion signal, compromising the accuracy of perfusion quantification. METHODS: A novel VS preparation design is presented using an eight-segment B1 insensitive rotation with symmetric radio frequency and gradient layouts (sym-BIR-8), combined with delays after gradient pulses to optimally reduce ECs of a wide range of time constants while maintaining B0 and B1 insensitivity. Bloch simulation, phantom, and in vivo experiments were carried out to determine robustness of the new and existing pulse designs to ECs, B0 , and B1 inhomogeneity. RESULTS: VSASL with reduced EC sensitivity across a wide range of EC time constants was achieved with the proposed sym-BIR-8 design, and the accuracy of cerebral blood flow measurement was improved. CONCLUSION: The sym-BIR-8 design performed the most robustly among the existing VS tagging designs, and should benefit studies using VS preparation with improved accuracy and reliability.