Metabolic disorder and functional disturbance in the central executive network in minimal hepatic encephalopathy.

The aim of this paper is to investigate dynamical functional disturbance in central executive network in minimal hepatic encephalopathy and determine its association with metabolic disorder and cognitive impairment. Data of magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging were obtained from 27 cirrhotic patients without minimal hepatic encephalopathy, 20 minimal hepatic encephalopathy patients, and 24 healthy controls. Central executive network was identified utilizing seed-based correlation approach. Dynamic functional connectivity across central executive network was calculated using sliding-window approach. Functional states were estimated by K-means clustering. Right dorsolateral prefrontal cortex metabolite ratios (i.e. glutamate and glutamine complex/total creatine, myo-inositol / total creatine, and choline / total creatine) were determined. Neurocognitive performance was determined by psychometric hepatic encephalopathy scores. Minimal hepatic encephalopathy patients had decreased myo-inositol / total creatine and choline / total creatine and increased glutamate and glutamine complex / total creatine in right dorsolateral prefrontal cortex (all P ≤ 0.020); decreased static functional connectivity between bilateral dorsolateral prefrontal cortex and between right dorsolateral prefrontal cortex and lateral-inferior temporal cortex (P ≤ 0.001); increased frequency and mean dwell time in state-1 (P ≤ 0.001), which exhibited weakest functional connectivity. Central executive network dynamic functional indices were significantly correlated with right dorsolateral prefrontal cortex metabolic indices and psychometric hepatic encephalopathy scores. Right dorsolateral prefrontal cortex myo-inositol / total creatine and mean dwell time in state-1 yielded best potential for diagnosing minimal hepatic encephalopathy. Dynamic functional disturbance in central executive network may contribute to neurocognitive impairment and could be correlated with metabolic disorder.

Evaluation of brown adipose tissue with intermolecular double-quantum coherence magnetic resonance spectroscopy at 3.0 T.

In the current study, we propose a single-voxel (SV) magnetic resonance spectroscopy (MRS) pulse sequence, based on intermolecular double-quantum coherence (iDQC), for in vivo specific assessment of brown adipose tissue (BAT) at 3 T. The multilocular adipocyte, present in BAT, typically contains a large number of small lipid droplets surrounded by abundant intracellular water, while the monolocular adipocyte, present in white adipose tissue (WAT), accommodates only a single large lipid droplet with much less water content. The SV-iDQC sequence probes the spatial correlation between water and fat spins at a distance of about the size of an adipocyte, thus can be used for assessment of BAT, even when mixed with WAT and/or muscle tissues. This sequence for measurement of water-to-fat (water-fat) iDQC signals was tested on phantoms and mouse BAT and WAT tissues. It was then used to differentiate adipose tissues in the supraclavicular and subcutaneous regions of healthy youth human volunteers (n = 6). Phantom results with water-fat emulsions demonstrated enhanced water-fat iDQC signal with increased voxel size, increased energy level of emulsification, or increased distribution balance of water and fat spins. The animal tissue experiments resulted in obvious water-fat iDQC signal in mouse BAT, while this signal was almost absent in the WAT spectrum. The optimal choice of the dipolar coupling distance for the observation was approximately 100 µm, as tested on both emulsion phantom and animal tissue. The water-fat iDQC signals observed in the supraclavicular adipose tissues were higher than in the subcutaneous adipose tissues in healthy young volunteers (0.43 ± 0.36 vs. 0.10 ± 0.06, p = 0.06). It was concluded that the iDQC-based sequence has potential for assessment of mouse and human BAT at 3 T, which is of interest for clinical research and the diagnosis of obesity and associated diseases.

Improvement in Signal-to-Noise Ratio of Liquid-State NMR Spectroscopy via a Deep Neural Network DN-Unet.

Nuclear magnetic resonance (NMR) is one of the most powerful analytical tools and is extensively applied in many fields. However, compared to other spectroscopic techniques, NMR has lower sensitivity, impeding its wider applications. Using data postprocessing techniques to increase the NMR spectral signal-to-noise ratio (SNR) is a relatively simple and cost-effective method. In this work, a deep neural network, termed as DN-Unet, is devised to suppress noise in liquid-state NMR spectra to enhance SNR. It combines structures of encoder-decoder and convolutional neural network. Different from traditional deep learning training strategy, M-to-S strategy is developed to enhance DN-Unet capability that multiple noisy spectra (inputs) correspond to a same single noiseless spectrum (label) in the training stage. The trained 1D model can be used for denoising not only 1D but also high dimension spectra, further improving DN-Unet's performance. 1D, 2D, and 3D NMR spectra were utilized to evaluate DN-Unet performance. The results suggest that DN-Unet provides larger than 200-fold increase in SNR with weak peaks hidden in noise perfectly recovered and spurious peaks suppressed well. Since DN-Unet developed here to increase SNR is based on data postprocessing, it is universal for a variety of samples and NMR platforms. The great SNR enhancement and extreme excellence in differentiating signal and noise would greatly promote various liquid-state NMR applications.

High-resolution 2-D NMR spectroscopy based on the Radon transform and pure shift technique for studying chemical shifts perturbations.

Chemical shift plays an important role in molecular analysis. However, chemical shifts are influenced by temperature, solvent concentration, pressure, and so forth. Therefore, measuring chemical shift perturbations caused by these factors is helpful to molecular studies. A new form of 2-D spectroscopy (projection spectroscopy) has been introduced whose indirect dimension is derived by implementing the Radon transform on a series of conventional 1-D proton spectra and indicates such perturbations. However, signal overlap may exist in the conventional 1-D spectra and hence in the resulting projection spectra, hampering clear multiplet analysis and accurate extraction of perturbations. Here, the pure shift decoupling technique is employed to obtain clearer projection spectrum with higher spectral resolution. The combination of pure shift technique and the Radon transform is helpful to accurately extract chemical shift perturbations. It is believed that this application will open up a vast prospect for molecular analysis.

Fully Exploiting the Power of 2D NMR J-Resolved Spectroscopy.

Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical tool that enables one to study molecular properties and interactions. Homonuclear couplings provide valuable structural information but are often difficult to disentangle in crowded 1H NMR spectra where complex multiplets and signal overlap commonly exist. Multidimensional NMR experiments push the power of NMR to a new level by providing better signal dispersion. Among them, 2D J-resolved spectroscopy is widely used for multiplet analysis and the measurement of scalar coupling constants. Here, we present a new 2D J-resolved method, CASCADE, through which easier multiplet analysis and unambiguous measurement of specific coupling constants can be achieved at the same time, fully exploiting the power of 2D J-resolved spectroscopy. It is expected that this method may replace a conventional 2D J experiment in many cases, facilitating structural and configurational studies as well as chemical and biological analyses.

Pushing resolution limits for extracting 1H-1H scalar coupling constants by a resolution-enhanced selective refocusing method.

Nuclear magnetic resonance (NMR) spectroscopy enables one to study molecular structure and dynamics in a noninvasive manner and has long served as a versatile and indispensable analytical tool in physics, chemistry, and biology. Scalar coupling, an essential feature in NMR spectroscopy, provides rich information regarding molecular structure and conformation. The measurement of scalar coupling constants, therefore, constitutes an important issue in NMR spectroscopy. Homonuclear 2D J-resolved spectroscopy is a powerful tool for multiplet analysis and coupling measurement. Recently, a number of phase-sensitive J-resolved methods and selective measuring methods have been developed to facilitate the extraction of coupling constants. However, resolution remains a crucial challenge when extracting small coupling constants or under inhomogeneous fields. In this paper, we present a resolution-enhanced selective refocusing (RESERF) method for the extraction of coupling constants. The effect of magnetic field inhomogeneity can be eliminated, resulting in very narrow linewidths. Therefore, samples with small coupling constants or under inhomogeneous fields can be well analyzed. The RESERF method may be of great value for structural and conformational studies in chemistry and biology.

Localized one-dimensional single voxel magnetic resonance spectroscopy without J coupling modulations.

PURPOSE: To acquire single voxel localized one-dimensional 1 H magnetic resonance spectroscopy (MRS) without J coupling modulations, free from amplitude and phase distortions. METHODS: A pulse sequence, named PRESSIR, is developed for volume localized MRS without J modulations at arbitrary echo time (TE). The J coupling evolution is suppressed by the J-refocused module that uses a 90° pulse at the midpoint of a double spin echo. RESULTS: The localization performance of the PRESSIR sequence was tested with a two-compartment phantom. The proposed sequence shows similar voxel localization accuracy as PRESS. Both PRESSIR and PRESS sequences were performed on MRS brain phantom and pig brain tissue. PRESS spectra suffer from amplitude and phase distortions due to J modulations, especially under moderate and long TEs, while PRESSIR spectra are almost free from distortions. CONCLUSION: The PRESSIR sequence proposed herein enables the acquisition of single voxel in-phase MRS within a single scan. It allows an enhanced signal intensity of J coupling metabolites and reducing undesired broad resonances with short T2s while suppressing J modulations. Moreover, it provides an approach for direct measurement of nonoverlapping J coupling peaks and of transverse relaxation times T2s. Magn Reson Med 76:1661-1667, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

High-resolution nuclear magnetic resonance measurements in inhomogeneous magnetic fields: A fast two-dimensional J-resolved experiment.

High spectral resolution in nuclear magnetic resonance (NMR) is a prerequisite for achieving accurate information relevant to molecular structures and composition assignments. The continuous development of superconducting magnets guarantees strong and homogeneous static magnetic fields for satisfactory spectral resolution. However, there exist circumstances, such as measurements on biological tissues and heterogeneous chemical samples, where the field homogeneity is degraded and spectral line broadening seems inevitable. Here we propose an NMR method, named intermolecular zero-quantum coherence J-resolved spectroscopy (iZQC-JRES), to face the challenge of field inhomogeneity and obtain desired high-resolution two-dimensional J-resolved spectra with fast acquisition. Theoretical analyses for this method are given according to the intermolecular multiple-quantum coherence treatment. Experiments on (a) a simple chemical solution and (b) an aqueous solution of mixed metabolites under externally deshimmed fields, and on (c) a table grape sample with intrinsic field inhomogeneity from magnetic susceptibility variations demonstrate the feasibility and applicability of the iZQC-JRES method. The application of this method to inhomogeneous chemical and biological samples, maybe in vivo samples, appears promising.

High-resolution localized spatiotemporal encoding correlated spectra under inhomogeneous magnetic fields via asymmetrical gradient encoding/decoding.

Applications of conventional localized nuclear magnetic resonance correlated spectroscopy are restrained by long acquisition times and poor performance under inhomogeneous magnetic fields. Here, a method that combines the spatiotemporal encoding technique with the localization technique and implements the encoding and decoding in unison with suitable asymmetrical gradients is proposed to obtain high-resolution localized correlated spectra under inhomogeneous fields in greatly reduced times. Experiments on phantom solutions prove its insensitivity to linear field inhomogeneities along three orthogonal axes. Moreover, this method is applied to adipose study of marrow tissue with resolution improvements. The proposed method may offer promising perspectives for fast analyses of biological tissues.

Line broadening interference for high-resolution nuclear magnetic resonance spectra under inhomogeneous magnetic fields.

Nuclear magnetic resonance spectroscopy serves as an important tool for analyzing chemicals and biological metabolites. However, its performance is subject to the magnetic-field homogeneity. Under inhomogeneous fields, peaks are broadened to overlap each other, introducing difficulties for assignments. Here, we propose a method termed as line broadening interference (LBI) to provide high-resolution information under inhomogeneous magnetic fields by employing certain gradients in the indirect dimension to interfere the magnetic-field inhomogeneity. The conventional spectral-line broadening is thus interfered to be non-diagonal, avoiding the overlapping among adjacent resonances. Furthermore, an inhomogeneity correction algorithm is developed based on pattern recognition to recover the high-resolution information from LBI spectra. Theoretical deductions are performed to offer systematic and detailed analyses on the proposed method. Moreover, experiments are conducted to prove the feasibility of the proposed method for yielding high-resolution spectra in inhomogeneous magnetic fields.

Ultrafast localized two-dimensional magnetic resonance correlated spectroscopy via spatially encoded technique.

PURPOSE: To speed up acquisition of localized two-dimensional (2D) correlated spectroscopy (LCOSY). METHODS: A new pulse sequence, dubbed as spatially encoded localized COSY (SLCOSY), based on spatially encoded technique, was developed for localized 2D correlated spectroscopy. It can be used to collect a full 2D spectrum in a single scan and thus on a subsecond timescale. RESULTS: SLCOSY spectrum of a two-compartment phantom was obtained with a total acquisition time of 773 ms, with its volume localization confirmed. Localized 2D COSY spectrum of a proton magnetic resonance spectroscopy brain phantom within 12 s shows the ability of SLCOSY to detect the metabolites at physiological concentrations. All 10 constituent metabolites in this phantom are reliably detected. SLCOSY spectrum of a sample of pig brain tissue with the acquisition time of 32 s demonstrates the feasibility of SLCOSY for the detection of biological tissues. Twelve pairs of cross peaks are identified. CONCLUSION: The new method proposed herein enables ultrafast collection of a full 2D COSY spectrum, and it can also be used for fast in vivo analysis of metabolites, when signal-to-noise ratio is not a limiting factor.

Reverse detection for spectral width improvements in spatially encoded dimensions of ultrafast two-dimensional NMR spectra.

Recently, the spatially encoded technique has been broadly used in the fast analyses of chemical systems and real-time detections of chemical reactions. In spatially encoded ultrafast 2D spectra, spectral widths and resolution in spatially encoded dimensions are contradictive, leading to the risk of insufficient spectral widths when providing satisfactory resolution values for all resonances. Here, a method named as reverse detection is proposed to improve the spectral width in the spatially encoded dimension. Experimental results show that spectral width improvements are at least twofold with reverse detection solely, and more improvements can be expected along with the gradient-controlled folding method. The proposed method can be applied to almost any spatially encoded scheme with echo planar spectroscopic imaging--like detection module and may promote wide applications of ultrafast 2D spectroscopy techniques in chemical analyses.

Deep Learning Methodology for Obtaining Ultraclean Pure Shift Proton Nuclear Magnetic Resonance Spectra.

Nuclear magnetic resonance (NMR) is one of the most powerful analytical techniques. In order to obtain high-quality NMR spectra, a real-time Zangger-Sterk (ZS) pulse sequence is employed to collect low-quality pure shift NMR data with high efficiency. Then, a neural network named AC-ResNet and a loss function named SM-CDMANE are developed to train a network model. The model with excellent abilities of suppressing noise, reducing line widths, discerning peaks, and removing artifacts is utilized to process the acquired NMR data. The processed spectra with noise and artifact suppression and small line widths are ultraclean and high-resolution. Peaks overlapped heavily can be resolved. Weak peaks, even hidden in the noise, can be discerned from noise. Artifacts, even as high as spectral peaks, can be removed completely while not suppressing peaks. Eliminating perfectly noise and artifacts and smoothing baseline make spectra ultraclean. The proposed methodology would greatly promote various NMR applications.

Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques.

Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the "shock-and-kill" strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the "shock-and-kill" strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.

Simultaneous acquirement of pure shift 2D homonuclear correlation spectra.

Two dimensional homonuclear correlation spectra like COSY, TOCSY and NOESY are classic two-dimensional spectra for analyzing coupling networks and delivering structural information of molecules. Two main challenges of the homonuclear correlation spectra are resolution and efficiency. Because of the complexity of the molecular structure and the effect of scalar coupling, spectral resolution is still difficult to meet the demand, and a higher resolution is needed to improve the quality of the homonuclear correlation spectrum. On the other hand, although some homonuclear correlation spectra are often used together (such as COSY and TOCSY), they are generally sampled separately, and as the number of sampling points in the indirect dimension increases, experiment time increases dramatically. Here, we propose a scheme that can be used to simultaneously obtain indirect dimension pure shift COSY and TOCSY or indirect dimension pure shift COSY and NOESY to improve the resolution of them, while reducing the sampling time and improving the efficiency.

Fast Acquisition of High-Quality Nuclear Magnetic Resonance Pure Shift Spectroscopy via a Deep Neural Network.

Pure shift methods improve the resolution of proton nuclear magnetic resonance spectra at the cost of time. The pure shift yielded by chirp excitation (PSYCHE) method is a promising pure shift method. We propose a method of reconstructing the undersampled PSYCHE spectra based on deep learning to accelerate the spectra acquisition. It only takes 17 s to obtain a high-quality pure shift spectrum. The network can completely remove undersampling artifacts and chunking sidebands and improve the signal-to-noise ratio, obtaining completely clean pure shift spectra. The reconstruction quality is better than the iterative soft thresholding method. In addition, the network can differentiate low-level signals and chunking sidebands with similar intensities in the mixture, remove sidebands, and retain signals, promoting correct mixture analysis.

Signal-to-noise ratio enhancement of intermolecular double-quantum coherence MR spectroscopy in inhomogeneous fields with phased array coils on a 3 Tesla whole-body scanner.

PURPOSE: To improve signal-to-noise ratio (SNR) of intermolecular double-quantum coherence (iDQC) MRS on a 3 Tesla (T) whole-body scanner. MATERIALS AND METHODS: A 32-channel phased array coil was used to acquire iDQC signal of a MRS phantom in the presence of large field inhomogeneity. The obtained individual spectra from the array elements were combined together in the time domain using a multichannel nonparametric singular value decomposition algorithm. The results were compared quantitatively with those acquired with a circularly polarized (CP) head coil. RESULTS: The achieved gain in SNR ranges from 1.63 to 2.10 relative to the CP coil, mainly depending on the relative position between the surface of the phased array coil and the voxel of acquisition. CONCLUSION: SNR enhancement of iDQC MRS in inhomogeneous fields on a 3T whole-body scanner is feasible with phased array coils. This can facilitate iDQC applications of high-resolution in vivo spectroscopy in the presence of field inhomogeneity for potential disease diagnosis in humans.

A simple data post-processing method for axial peaks free 2D PSYCHEDELIC NMR spectra.

Homonuclear scalar coupling plays an important role in the elucidation of molecular structure and dynamics. However, complex multiplets due to 1H-1H scalar coupling splittings complicate the assignment of peaks in overcrowded spectral regions. Although many methods focusing on disentangling couplings have been proposed in recent years, some defects like intense axial peaks and dispersive components still exist. Herein, a simple data post-processing method based on the interleaved acquisition mode PSYCHEDELIC (Pure Shift Yielded by CHirp Excitation to DELiver Individual Couplings) is designed to acquire absorption-mode 2D J spectrum while eradicating axial peaks. This approach provides a high resolution and pure absorptive spectrum, permitting unambiguous and accurate measurement of scalar coupling constants involving a given proton.

Unambiguous and accurate measurement of scalar coupling constants through a selective refocusing NMR experiment.

Scalar coupling plays an important role in the analysis of molecular structure and dynamics. A great number of nuclear magnetic resonance (NMR) selective refocusing experiments, such as 2D G-SERF and PSYCHEDELIC, were developed to extract scalar coupling constants involving a selected proton from overlapped spectra. However, intense axial peaks occur in this type of experiments, leading to possible ambiguity in the assignment of spectral peaks and subsequent accurate measurement of 1H-1H scalar coupling constants. Here, a method based on selective coherence transfer and PSYCHEDELIC module is designed to acquire absorption-mode selective refocusing spectrum while suppressing intense axial peaks. Therefore, unambiguous and accurate measurement of scalar coupling constants involving the selectively excited proton can be achieved. The performances of the proposed method are demonstrated on several samples.

High-resolution MRS in the presence of field inhomogeneity via intermolecular double-quantum coherences on a 3-T whole-body scanner.

Signals from intermolecular double-quantum coherences (iDQCs) have been shown to be insensitive to macroscopic field inhomogeneities and thus enable acquisition of high- resolution MR spectroscopy in the presence of large inhomogeneous fields. In this paper, localized iDQC (1)H spectroscopy on a whole-body 3-T MR scanner is reported. Experiments with a brain metabolite phantom were performed to quantify characteristics of the iDQC signal under different conditions. The feasibility of in vivo iDQC high-resolution MR spectroscopy in the presence of large intrinsic and external field inhomogeneity (in the order of hundreds of hertz) was demonstrated in the whole cerebellum of normal volunteers in a scan time of about 6.5 min. Major metabolite peaks were well resolved in the reconstructed one-dimensional spectra projected from two-dimensional iDQC acquisitions. Investigations on metabolite ratios, signal-to-noise ratio, and line width were performed and compared with results obtained with conventional point-resolved spectroscopy/MR spectroscopy in homogeneous fields. Metabolite ratios from iDQC results showed excellent consistency under different in vitro and in vivo conditions, and they were similar to those from point-resolved spectroscopy with small voxel sizes in homogeneous fields. MR spectroscopy with iDQCs can be applied potentially for quantification of gross metabolite changes due to diseases in large brain volumes with high field inhomogeneity.