Neurite orientation dispersion and density imaging quantifies microstructural impairment in the thalamus and its connectivity in amyotrophic lateral sclerosis.

AIMS: To evaluate microstructural impairment in the thalamus and thalamocortical connectivity using neurite orientation dispersion and density imaging (NODDI) in amyotrophic lateral sclerosis (ALS). METHODS: This study included 47 healthy controls and 43 ALS patients, whose structural and diffusion-weighted data were collected. We used state-of-the-art parallel transport tractography to identify thalamocortical pathways in individual spaces. Thalamus was then parcellated into six subregions based on its connectivity pattern with the priori defined cortical (i.e., prefrontal/motor/somatosensory/temporal/posterior-parietal/occipital) regions. For each of the thalamic and cortical subregions and thalamo-cortical tracts, we compared the following NODDI metrics between groups: orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (ISO). We also used these metrics to conduct receiver operating characteristic curve (ROC) analyses and Spearman correlation. RESULTS: In ALS patients, we found decreased ODI and increased ISO in the thalamic subregion connecting the left motor cortex and other extramotor (e.g., somatosensory and occipital) cortex (Bonferroni-corrected p < 0.05). NDI decreased in the bilateral thalamo-motor and thalamo-somatosensory tracts and in the right thalamo-posterior-parietal and thalamo-occipital tracts (Bonferroni-corrected p < 0.05). NDI reduction in the bilateral thalamo-motor tract (p = 0.017 and 0.009) and left thalamo-somatosensory tract (p = 0.029) was correlated with disease severity. In thalamo-cortical tracts, NDI yielded a higher effect size during between-group comparisons and a greater area under ROC (p < 0.05) compared with conventional diffusion tensor imaging metrics. CONCLUSIONS: Microstructural impairment in the thalamus and thalamocortical connectivity is the hallmark of ALS. NODDI improved the detection of disrupted thalamo-cortical connectivity in ALS.

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.

Functional connectivity disruption of insular subregions in the cirrhotic patients with minimal hepatic encephalopathy.

We investigated abnormal functional connectivity (FC) patterns of insular subregions in patients with minimal hepatic encephalopathy (MHE) and examined their relationships with cognitive dysfunction using resting-state functional magnetic resonance imaging (fMRI). We collected resting-state fMRI data in 54 patients with cirrhosis [20 with MHE and 34 without MHE (NHE)] and 25 healthy controls. After defining six subregions of insula, we mapped whole-brain FC of the insular subregions and identified FC differences through three groups. FC of the insular subregions was correlated against clinical parameters (including venous blood ammonia level, Child-Pugh score, and cognitive score). The discrimination performance between the MHE and NHE groups was evaluated by performing a classification analysis using the FC index. Across three groups, the observed FC differences involved four insular subregions, including the left-ventral anterior insula, left-dorsal anterior insula, right-dorsal anterior insula, and left-posterior insula (P < 0.05 with false discovery rate correction). Moreover, the FC of these four insular subregions progressively attenuated from NHE to MHE. In addition, hypoconnectivity of insular subregions was correlated with the poor neuropsychological performance and the evaluated blood ammonia levels in patients (P < 0.05 with Bonferroni correction). The FC of insular subregions yielded moderate discriminative value between the MHE and NHE groups (AUC = 0.696-0.809). FC disruption of insular subregions is related to worse cognitive performance in MHE. This study extended our understanding about the neurophysiology of MHE and may assist for its diagnosis.

White matter microstructural disruption in minimal hepatic encephalopathy: a neurite orientation dispersion and density imaging (NODDI) study.

PURPOSE: To evaluate the ability of neurite orientation dispersion and density imaging (NODDI) for detecting white matter (WM) microstructural abnormalities in minimal hepatic encephalopathy (MHE). METHODS: Diffusion-weighted images, enabling the estimation of NODDI and diffusion tensor imaging (DTI) parameters, were acquired from 20 healthy controls (HC), 22 cirrhotic patients without MHE (NHE), and 15 cirrhotic patients with MHE. Tract-based spatial statistics were used to determine differences in DTI (including fractional anisotropy [FA] and mean/axial/radial diffusivity [MD/AD/RD]) and NODDI parameters (including neurite density index [NDI], orientation dispersion index [ODI], and isotropic volume fraction [ISO]). Voxel-wise analyses of correlations between diffusion parameters and neurocognitive performance determined by Psychometric Hepatic Encephalopathy Score (PHES) were completed. RESULTS: MHE patients had extensive NDI reduction and rare ODI reduction, primarily involving the genu and body of corpus callosum and the bilateral frontal lobe, corona radiata, external capsule, anterior limb of internal capsule, temporal lobe, posterior thalamic radiation, and brainstem. The extent of NDI and ODI reduction expanded from NHE to MHE. In both MHE and NHE groups, the extent of NDI change was quite larger than that of FA change. No significant intergroup difference in ISO/MD/AD/RD was observed. Tissue specificity afforded by NODDI revealed the underpinning of FA reduction in MHE. The NDI in left frontal lobe was significantly correlated with PHES. CONCLUSION: MHE is characterized by diffuse WM microstructural impairment (especially neurite density reduction). NODDI can improve the detection of WM microstructural impairments in MHE and provides more precise information about MHE-related pathology than DTI.

Corticospinal fibers with different origins impair in amyotrophic lateral sclerosis: A neurite orientation dispersion and density imaging study.

AIMS: To investigate microstructural impairments of corticospinal tracts (CSTs) with different origins in amyotrophic lateral sclerosis (ALS) using neurite orientation dispersion and density imaging (NODDI). METHODS: Diffusion-weighted imaging data acquired from 39 patients with ALS and 50 controls were used to estimate NODDI and diffusion tensor imaging (DTI) models. Fine maps of CST subfibers originating from the primary motor area (M1), premotor cortex, primary sensory area, and supplementary motor area (SMA) were segmented. NODDI metrics (neurite density index [NDI] and orientation dispersion index [ODI]) and DTI metrics (fractional anisotropy [FA] and mean/axial/radial diffusivity [MD/AD/RD]) were computed. RESULTS: The patients with ALS showed microstructural impairments (reflected by NDI, ODI, and FA reductions and MD, AD, and RD increases) in CST subfibers, especially in M1 fibers, which correlated with disease severity. Compared with other diffusion metrics, NDI yielded a higher effect size and detected the greatest extent of CST subfibers damage. Logistic regression analyses based on NDI in M1 subfiber yielded the best diagnostic performance compared with other subfibers and the whole CST. CONCLUSIONS: Microstructural impairment of CST subfibers (especially those originating from M1) is the key feature of ALS. The combination of NODDI and CST subfibers analysis may improve diagnosing performance for ALS.

Metabolic alterations in the right anterior insula among patients with cirrhosis without overt hepatic encephalopathy: a magnetic resonance spectroscopy study.

Purpose: We investigated metabolic alterations in the right anterior insula (rAI) in cirrhotic patients and determined its association with patients' cognitive dysfunction. Methods: In this study, 31 healthy controls (HCs) and 32 cirrhotic patients without overt hepatic encephalopathy participated. Both blood ammonia level and Child-Pugh score were measured. The psychometric hepatic encephalopathy score (PHES) was used to evaluate cognitive function. 1H-magnetic resonance spectroscopy (MRS) data located in the rAI were recorded on a commercially available 3T magnetic resonance imaging scanner. The ratios of metabolites were measured, including N-acetylaspartate (NAA)/total creatine (tCr), glutamate plus glutamine (Glx)/tCr, myo-inositol (mI)/tCr, and total choline (tCho)/tCr. We adopted the non-parametric Mann-Whitney U-test for intergroup comparison of metabolic ratios. To determine the association between metabolite concentration and clinical parameters, we performed Spearman correlation analyses. Results: Patients with cirrhosis performed worse on PHES in comparison with HCs (P < 0.001). Patients with cirrhosis had significantly decreased mI/tCr (0.87 ± 0.07 vs. 0.74 ± 0.19, P = 0.025) and increased Glx/tCr (1.79 ± 0.17 vs. 2.07 ± 0.29, P < 0.001) in the rAI. We did not observe any significant between-group differences in tCho/tCr and NAA/tCr. The blood ammonia level was correlated with Glx/tCr (r = 0.405, P = 0.022) and mI/tCr (r = -0.398, P = 0.024) of the rAI. In addition, PHES was negatively correlated with Glx/tCr of the rAI (r = -0.379, P = 0.033). Conclusion: Metabolic disturbance of the rAI, which is associated with ammonia intoxication, might account for the neural substrate of cirrhosis-related cognitive dysfunction to some extent.

Altered dynamic spontaneous neural activity in minimal hepatic encephalopathy.

Background and aims: Abnormal regional neural activity has been identified by the analysis of the static amplitude of low-frequency fluctuation (ALFF) in the setting of minimal hepatic encephalopathy (MHE). Brain activity is highly dynamic. This work sought to evaluate the temporal variability of ALFF to reveal MHE-related alterations in the dynamics of spontaneous neural activity. Methods: A total of 29 healthy controls and 49 patients with cirrhosis [including 20 patients with MHE and 29 patients without MHE (NHE)] who underwent resting-state functional magnetic resonance imaging and Psychometric Hepatic Encephalopathy Score (PHES) examination were enrolled in this investigation. Utilizing a sliding-window approach, we calculated the dynamic ALFF (dALFF) variability to reflect the temporal dynamics of regional neural activity. An analysis of the correlation between dALFF variability and PHES was performed, and receiver operating characteristic (ROC) curve analysis to determine the potential of the dALFF variability index in identifying MHE was completed. Results: The dALFF variability in the bilateral precuneus/posterior cingulate gyrus and left middle frontal gyrus progressively decreased from NHE to MHE group. In cirrhotic patients, the value of dALFF variability in the bilateral precuneus/posterior cingulate gyrus was positively correlated with their neurocognitive performance (r = 0.383 and P = 0.007). The index of dALFF variability in the bilateral precuneus/posterior cingulate gyrus could be used to distinguish NHE and MHE patients, with moderate power (area under the ROC curve = 0.712 and P = 0.012). Conclusion: Our findings highlight the existence of aberrant dynamic brain function in MHE, which could underlie the neural basis of cognitive impairments and could be associated with the development of the disease. Analyzing dALFF could facilitate new biomarker identification for MHE.

Aberrant stability of brain functional architecture in cirrhotic patients with minimal hepatic encephalopathy.

To investigate the stability changes of brain functional architecture and the relationship between stability change and cognitive impairment in cirrhotic patients. Fifty-one cirrhotic patients (21 with minimal hepatic encephalopathy (MHE) and 30 without MHE (NHE)) and 29 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and neurocognitive assessment using the Psychometric Hepatic Encephalopathy Score (PHES). Voxel-wise functional connectivity density (FCD) was calculated as the sum of connectivity strength between one voxel and others within the entire brain. The sliding window correlation approach was subsequently utilized to calculate the FCD dynamics over time. Functional stability (FS) is measured as the concordance of dynamic FCD. From HCs to the NHE and MHE groups, a stepwise reduction of FS was found in the right supramarginal gyrus (RSMG), right middle cingulate cortex, left superior frontal gyrus, and bilateral posterior cingulate cortex (BPCC), whereas a progressive increment of FS was observed in the left middle occipital gyrus (LMOG) and right temporal pole (RTP). The mean FS values in RSMG/LMOG/RTP (r = 0.470 and P = 0.001; r = -0.458 and P = 0.001; and r = -0.384 and P = 0.005, respectively) showed a correlation with PHES in cirrhotic patients. The FS index in RSMG/LMOG/BPCC/RTP showed moderate discrimination potential between the NHE and MHE groups. Changes in FS may be linked to neuropathological bias of cognitive impairment in cirrhotic patients and could serve as potential biomarkers for MHE diagnosis and monitoring the progression of hepatic encephalopathy.

Antimonate removal by diatomite modified with Fe-Mn oxides: application and mechanism study.

In this study, diatomite coated with Fe-Mn oxides (DFMO) was synthesized through calcination. The adsorption of antimonate (Sb(V)) by DFMO was studied, and environmental factors affecting the adsorption were investigated. The components of DFMO were identified as γ-Fe2O3, γ-MnO2, and SiO2, in the presence of diatomite covered with nanoscale metal oxides. Batch experiments were carried out to evaluate the antimonate adsorption performance in aqueous solution. Results showed that maximum Sb(V) adsorption capacity of DFMO reached 10.7 mg/g at pH 4, corresponding to 22.2 mg/g per unit metal oxides. Antimonate adsorption occurred on heterogenous surface, following the Freundlich and Pseudo-second order model. Overall, antimonate adsorption was favored at acidic condition due to low point of zero charge. However, when treating electroplating wastewater, neutral pH condition exhibited a higher efficiency than acidic pH, because co-existing ions in electroplating wastewater significantly affects antimony adsorption. Further investigation showed that among different potential co-existing ions, fluoride can strongly inhibit the adsorption of antimonate at 5 mg/L under pH 4. Density functional theory (DFT) analysis confirmed that adsorption energy on DFMO follows: HF < F- < Sb(OH)6-, indicating that fluoride is easier to bind with DFMO compared to antimonate, especially under pH 3.5 at which fluoride exists as HF. Moreover, the competitive adsorption of fluoride toward antimonate indicated the necessity of pre-treatment like neutralization and precipitation before adsorption process.

How nitrate affects perchlorate reduction in a methane-based biofilm batch reactor.

Nitrate (NO3-) affected perchlorate (ClO4-) reduction in a membrane batch biofilm reactor (MBBR), even though the electron donor, CH4, was available well in excess of its demand. For example, the perchlorate-reduction rate was 1.7 mmol/m2-d when perchlorate was the sole electron acceptor, but it dropped to 0.64 mmol/m2-d when nitrate also was present. The perchlorate-reduction rate returned to 1.60 mmol/m2-d after all nitrate was consumed. Denitratisoma and Azospirillum were main genera involved in perchlorate and nitrate reduction, and both could utilize NO3- and ClO4- as electron acceptors. Results of the reverse transcription-polymerase chain reaction (RT-PCR) showed that transcript abundances of nitrate reductase (narG), nitrite reductase (nirS), and perchlorate reductase (pcrA) increased when the perchlorate and nitrate concentrations were higher. Specifically, pcrA transcripts correlated to the sum of perchlorate and nitrate, rather than perchlorate individually. Analysis based on Density Functional Theory (DFT) suggests that bacteria able to utilize both acceptors, preferred NO3- over ClO4- due to nitrate reduction having lower energy barriers for proton and electron transfers.

Anaerobic methane oxidation coupled to chromate reduction in a methane-based membrane biofilm batch reactor.

Chromate can be reduced by methanotrophs in a membrane biofilm reactor (MBfR). In this study, we cultivated a Cr(VI)-reducing biofilm in a methane (CH4)-based membrane biofilm batch reactor (MBBR) under anaerobic conditions. The Cr(VI) reduction rate increased to 0.28 mg/L day when the chromate concentration was ≤ 2.2 mg/L but declined sharply to 0.01 mg/L day when the Cr(VI) concentration increased to 6 mg/L. Isotope tracing experiments showed that part of the 13C-labeled CH4 was transformed to 13CO2, suggesting that the biofilm may reduce Cr(VI) by anaerobic methane oxidation (AnMO). Microbial community analysis showed that a methanogen, i.e., Methanobacterium, dominated in the biofilm, suggesting that this genus is probably capable of carrying out AnMO. The abundance of Methylomonas, an aerobic methanotroph, decreased significantly, while Meiothermus, a potential chromate-reducing bacterium, was enriched in the biofilm. Overall, the results showed that the anaerobic environment inhibited the activity of aerobic methanotrophs while promoting AnMO bacterial enrichment, and high Cr(VI) loading reduced Cr(VI) flux by inhibiting the methane oxidation process.

Role of Extracellular Polymeric Substances in a Methane Based Membrane Biofilm Reactor Reducing Vanadate.

For the first time, we demonstrated vanadate (V(V)) reduction in a membrane biofilm reactor (MBfR) using CH4 as the sole electron donor. The V(V)-reducing capability of the biofilm kept increasing, with complete removal of V(V) achieved when the influent surface loading of V(V) was 363 mg m-2 day-1. Almost all V(V) was reduced to V(IV) precipitates, which is confirmed by a scanning electron microscope coupled to energy dispersive X-ray spectroscopy (SEM-EDS) and X-ray photoelectron spectroscopy (XPS). Microbial community analysis revealed that denitrifiers Methylomonas and Denitratisoma might be the main genera responsible for V(V) reduction. The constant enrichment of Methylophilus suggests that the intermediate (i.e., methanol) from CH4 metabolism might be used as the electron carriers for V(V) bioreduction. Intrusion of V(V) (2-5 mg/L, at the surface loading of 150-378 mg m-2 day-1) into the biofilm stimulated the secretion of extracellular polymeric substances (EPS), but high loading of V(V) (10 mg/L, at the surface loading of 668 mg m-2 day-1) decreased the amount of EPS. Metagenomic prediction analysis established the strong correlation between the secretion of EPS and the microbial metabolism associated with V(V) reduction, tricarboxylic acid cycle (TCA) cycle, methane oxidation, and ATP production, and EPS might relieve the oxidative stress induced by high loading of V(V). Colorimetric determination and a three-dimensional excitation-emission matrix (3D-EEM) showed that tryptophan and humic acid-like substances might play important roles in microbial cell protection and V(V) binding. Fourier transform infrared (FTIR) spectroscopy identified hydroxyl (-OH) and carboxyl (COO-) groups in EPS as the candidate functional groups for binding V(V).

Bioreduction of Antimonate by Anaerobic Methane Oxidation in a Membrane Biofilm Batch Reactor.

Employing a special anaerobic membrane biofilm batch reactor (MBBR), we demonstrated antimonate (Sb(V)) reduction using methane (CH4) as the sole electron donor. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and Raman and photoluminescence (PL) spectra identified that Sb2O3 microcrystals were the main reduced products. The Sb(V) reduction rate increased continually over the 111-day experiment, which supports the enrichment of the microorganisms responsible for Sb(V) reduction to Sb(III). Copy numbers of the mcrA gene and archaeal and bacterial 16 S rRNA genes increased in parallel. Clone library and Illumina sequencing of 16S rRNA gene demonstrated that Methanosarcina became the dominant archaea in the biofilm, suggesting that Methanosarcina might play an important role in Sb(V) reduction in the CH4-based MBBR.

Bromate and Nitrate Bioreduction Coupled with Poly-ß-hydroxybutyrate Production in a Methane-Based Membrane Biofilm Reactor.

This work demonstrates bromate (BrO3-) reduction in a methane (CH4)-based membrane biofilm reactor (MBfR), and it documents contrasting impacts of nitrate (NO3-) on BrO3- reduction, as well as formation of poly-ß-hydroxybutyrate (PHB), an internal C- and electron-storage material. When the electron donor, CH4, was in ample supply, NO3- enhanced BrO3- reduction by stimulating the growth of denitrifying bacteria ( Meiothermus, Comamonadaceae, and Anaerolineaceae) able to reduce BrO3- and NO3- simultaneously. This was supported by increases in denitrifying enzymes (e.g., nitrate reductase, nitrite reductase, nitrous-oxide reductase, and nitric-oxide reductase) through quantitative polymerase chain reaction (qPCR) analysis and metagenomic prediction of these functional genes. When the electron donor was in limited supply, NO3- was the preferred electron acceptor over BrO3- due to competition for the common electron donor; this was supported by the significant oxidation of stored PHB when NO3- was high enough to cause electron-donor limitation. Methanotrophs (e.g., Methylocystis, Methylomonas, and genera within Comamonadaceae) were implicated as the main PHB producers in the biofilms, and their ability to oxidize PHB mitigated the impacts of competition for CH4.

The effect of electron competition on chromate reduction using methane as electron donor.

We studied the effect of electron competition on chromate (Cr(VI)) reduction in a methane (CH4)-based membrane biofilm reactor (MBfR), since the reduction rate was usually limited by electron supply. A low surface loading of SO42- promoted Cr(VI) reduction. The Cr(VI) removal percentage increased from 60 to 70% when the SO42- loading increased from 0 to 4.7 mg SO42-/m2-d. After the SO42- loading decreased back to zero, the Cr(VI) removal further increased to 90%, suggesting that some sulfate-reducing bacteria (SRB) stayed in the reactor to reduce Cr(VI). However, a high surface loading of SO42- (26.6 mg SO42-/m2-d) significantly slowed down the Cr(VI) reduction to 40% removal, which was probably due to competition between Cr(VI) and SO42- reduction. Similarly, when 0.5 mg/L of Se(VI) was introduced into the MBfR, Cr(VI) removal percentage slightly decreased to 60% and then increased to 80% when input Se(VI) was removed again. The microbial community strongly depended on the loadings of Cr(VI) and SO42-. In the sulfate effect experiment, three genera were dominant. Based on the correlation between the abundances of the three genera and the loadings of Cr(VI) and SO42-, we conclude that Methylocystis, a type II methanotroph, reduced both Cr(VI) and sulfate, Meiothermus only reduced Cr(VI), and Ferruginibacter only reduced SO42-.

Oxygen exposure deprives antimonate-reducing capability of a methane fed biofilm.

This work is aiming at achieving antimonate (Sb(V)) bio-reduction in a methane (CH4) based membrane biofilm reactor (MBfR), and elucidating the effect of oxygen (O2) on the performance of the biofilm. Scanning electron microscope (SEM), energy dispersive X-ray (EDS) and X-ray photoelectron spectroscopy (XPS) confirm Sb2O3 precipitates were the main product formed from Sb(V) reduction in the CH4-fed biofilm. Illumina sequencing shows Thermomonas may be responsible for Sb(V) reduction. Moreover, we found 8 mg/L of O2 in the influent irreversibly inhibited Sb(V) reduction. Metagenomic prediction by Reconstruction of Unobserved State (PICRUSt) shows that the biofilm lacked efficient defense system to the oxidative stress, leading to the great suppress of key biological metabolisms such as TCA cycle, glycolysis and DNA replication, as well as potential Sb(V) reductases, by O2. However, methanotrophs Methylomonas and Methylosinus were enriched in the biofilm with O2 intrusion, in accordance with the enhanced abundance of genes encoding aerobic CH4 oxidation. These insights evoke the theoretical guidance of microbial remediation using CH4 as the electron donor towards Sb(V) contamination, and will give us a strong reference with regard to wastewater disposal.