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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 introduction to ASL labeling techniques.

Arterial spin labeling (ASL) methods allow for quantitative mapping of tissue perfusion in absolute units, without the use of contrast agents. In this technique, the magnetization of arterial blood water is labeled by magnetic inversion or saturation, and the delivery of labeled blood water to tissues is observed. In this review three classes of labeling methods for ASL are described and compared: continuous, pulsed, and velocity-selective. The quantification of perfusion from ASL data is discussed, and methods for the extraction of new types of information using ASL and related techniques, such as mapping of vascular territories or venous oxygenation, are described.

New developments in arterial spin labeling pulse sequences.

Since it was introduced over 20 years ago, arterial spin labeling and related methods have steadily evolved over the years, and the field has seen not only improvements in technical specifications, such as signal-to-noise ratio and accuracy, but also the introduction of methods that allow for the collection of new information, such as maps of vascular territories and measurement of venous oxygenation. Some of these recent advances are reviewed here.

Immunomodulatory activities of Ganoderma sinense polysaccharides in human immune cells.

Medicinal mushrooms have been traditionally used as food nutrient supplements in China for thousands of years. The present study aimed to evaluate the immunomodulatory activities of Ganoderma sinense (GS), an allied species of G. lucidum, using human peripheral blood mononuclear cells (PBMC). Our results showed that the polysaccharide-enriched fraction of GS hot water extract (400 µg/ml) exhibited significant stimulatory effects on PBMC proliferation. When the fruiting bodies of GS were divided into pileus and stipe parts and were separately extracted, the GS stipe polysaccharide-enriched fraction (50-400 µg/ml) showed concentration-dependent immunostimulating effects in PBMC. The productions of tumor necrosis factor-α, interleukin (IL)-10, and transforming growth factor -ß were significantly enhanced by this fraction. In addition, the proportion of CD14(+) monocyte subpopulation within the PBMC was specifically increased. The IL-10 and IL-12 productions in monocyte-derived dendritic cells were significantly enhanced by GS stipe fraction. The composition of monosaccharides of this fraction was determined by ultra performance liquid chromatography and ion exchange chromatography. Our study demonstrated for the first time the immunostimulatory effects of GS stipe polysaccharide-enriched fraction on PBMC and dendritic cells. The findings revealed the potential use of GS (especially including the stipes of fruiting bodies) as adjuvant nutrient supplements for patients, who are receiving immunosuppressive chemotherapies.

Local head gradient coils: window(s) of opportunity.

At the Medical College of Wisconsin (MCW), prior to the 1991 announcement of the discovery of BOLD fMRI, all of the technical pieces that were needed for efficient BOLD fMRI imaging were assembled for other applications, allowing MCW to jump into the fMRI business just days after the announcement. Central among these pieces was single shot EPI, implemented at MCW using a three axis local head gradient coil. This article describes the development of local gradient coil technology at MCW, and a historical perspective on local head gradient coils in general.

Venous oxygenation mapping using velocity-selective excitation and arterial nulling.

A new MRI technique to map the oxygenation of venous blood is presented. The method uses velocity-selective excitation and arterial nulling pulses, combined with phase sensitive signal detection to isolate the venous blood signal. T2 of this signal along with a T2-Y calibration curve yields estimates of venous oxygenation in situ. Results from phantoms and healthy human subjects under normoxic and hypoxic conditions are shown, and venous saturation levels estimated from both sagittal sinus and gray matter-based regions of interest are compared with the related techniques TRUST and QUIXOTIC. In addition, combined with an additional scan without arterial nulling pulses, the oxygen saturation level on arterial side can also be estimated.

On multiple alternating steady states induced by periodic spin phase perturbation waveforms.

Direct measurement of neural currents by means of MRI can potentially open a high temporal resolution (10-100 ms) window applicable for monitoring dynamics of neuronal activity without loss of the high spatial resolution afforded by MRI. Previously, we have shown that the alternating balanced steady state imaging affords high sensitivity to weak periodic currents owing to its amplification of periodic spin phase perturbations. This technique, however, requires precise synchronization of such perturbations to the radiofrequency pulses. Herein, we extend alternating balanced steady state imaging to multiple balanced alternating steady states for estimation of neural current waveforms. Simulations and phantom experiments show that the off-resonance profile of the multiple alternating steady state signal carries information about the frequency content of driving waveforms. In addition, the method is less sensitive than alternating balanced steady state to precise waveform timing relative to radiofrequency pulses. Thus, multiple alternating steady state technique is potentially applicable to MR imaging of the waveforms of periodic neuronal activity.

Pseudocontinuous arterial spin labeling with optimized tagging efficiency.

The adiabatic inversion of blood in pseudocontinuous arterial spin labeling (PCASL) is highly sensitive to off-resonance effects and gradient imperfections and this sensitivity can lead to tagging efficiency loss and unpredictable variations in cerebral blood flow estimates. This efficiency loss is caused by a phase tracking error between the RF pulses and the flowing spins. This article introduces a new method, referred to as Optimized PCASL (OptPCASL), that minimizes the phase tracking error by applying an additional compensation RF phase term and in-plane gradients to the PCASL pulse train. The optimal RF phase and gradient amplitudes are determined using a prescan procedure, which consists of a series of short scans interleaved with automated postprocessing routines integrated to the scanner console. The prescan procedure is shown to minimize the phase tracking error in a robust and time efficient manner. As an example of its application, the use of OptPCASL for the improved detection of functional activation in the visual cortex is demonstrated and temporal signal-to-noise ratio (SNR), image SNR, and baseline cerebral blood flow measures are compared to those acquired from conventional PCASL.