Sex-specific responses of Taxus mairei to UV-B radiation involved altering the interactions between the microbiota assembly and host secondary metabolism.

BACKGROUND: To adapt to constantly changing environments, ancient gymnosperms have coevolved with diverse endophytic fungi that are essential for the fitness and adaptability of the plant host. However, the effect of sex on plant-endophyte interactions in response to environmental stressors remains unknown. RNA-seq integrated with ITS analysis was applied to reveal the potential mechanisms underlying the sex-specific responses of Taxus mairei to ultraviolet (UV)-B radiation. RESULTS: Enrichment analysis suggested that sex influenced the expression of several genes related to the oxidation-reduction system, which might play potential roles in sex-mediated responses to UV-B radiations. ITS-seq analysis clarified the effects of UV-B radiation and sex on the composition of endophytic fungal communities. Sex influenced various secondary metabolic pathways, thereby providing chemicals for T. mairei host to produce attractants and/or inhibitors to filter microbial taxa. Analysis of fungal biomarkers suggested that UV-B radiation reduced the effect of sex on fungal communities. Moreover, Guignardia isolate #1 was purified to investigate the role of endophytic fungi in sex-mediated responses to UV-B radiation. Inoculation with spores produced by isolate #1 significantly altered various oxidation-reduction systems of the host by regulating the expression of APX2, GST7 NCED1, ZE1, CS1, and CM1. CONCLUSION: These results revealed the roles of endophytic fungi in sex-mediated responses to UV-B radiation and provided novel insights into the sex-specific responses of Taxus trees to environmental stressors. Video Abstract.

Fungal endophytes of Taxus species and regulatory effect of two strains on taxol synthesis.

BACKGROUND: Taxol, derived from Taxus trees, is a valuable natural resource for the development of anticancer drugs. Endophytic fungi from Taxus trees are a promising alternative source of Taxol. However, the impact of plant-endophytic microbial interaction on the host's Taxol biosynthesis is largely unknown. RESULTS: In the current study, the diversity of endophytic fungi in three different Taxus species was analyzed using Internal Transcribed Spacer sequencing. A total of 271 Operational Taxonomic Units (OTUs) were identified, grouping into 2 phyla, 8 classes, 16 orders, 19 families, and 19 genera. Alpha and beta diversity analysis indicated significant differences in endophytic fungal communities among the various Taxus trees. At the genus level, Alternaria and Davidiella were predominantly found in T. mairei and T. media, respectively. By utilizing a previously published dataset, a Pearson correlation analysis was conducted to predict the taxol biosynthesis-related fungal genera. Following screening, two isolates of Alternaria (L7 and M14) were obtained. Effect of inoculation with Alternaria isolates on the gene expression and metabolite accumulation of T. mairei was determined by transcriptomic and untargeted metabolomic studies. The co-inoculation assay suggests that the two Alternaria isolates may have a negative regulatory effect on taxol biosynthesis by influencing hormone signaling pathways. CONCLUSION: Our findings will serve as a foundation for advancing the production and utilization of Taxus and will also aid in screening endophytic fungi related to taxol production.

Mass Spectrometry-Imaging Analysis of Active Ingredients in the Leaves of Taxus cuspidata.

BACKGROUND: Taxus cuspidata is an endangered evergreen conifer mainly found in Northeast Asia. In addition to the well-known taxanes, several active ingredients were detected in the leaves of T. cuspidata. However, the precise spatial distribution of active ingredients in the leaves of T. cuspidata is largely unknown. RESULTS: in the present study, timsTOF flex MALDI-2 analysis was used to uncover the accumulation pattern of active ingredients in T. cuspidata leaves. In total, 3084 ion features were obtained, of which 944 were annotated according to the mass spectrometry database. The principal component analysis separated all of the detected metabolites into four typical leaf tissues: mesophyll cells, upper epidermis, lower epidermis, and vascular bundle cells. Imaging analysis identified several leaf tissues that specifically accumulated active ingredients, providing theoretical support for studying the regulation mechanism of compound biosynthesis. Furthermore, the relative accumulation levels of each identified compound were analyzed. Two flavonoid compounds, ligustroflavone and Morin, were identified with high content through quantitative analysis of the ion intensity. CONCLUSIONS: our data provides fundamental information for the protective utilization of T. cuspidata.

Electroassisted Propane Dehydrogenation at Low Temperatures: Far beyond the Equilibrium Limitation.

Propylene production by propane dehydrogenation (PDH) generally requires high temperatures due to thermodynamic equilibrium limitations. This study developed a novel type of catalytic system for low-temperature PDH by combining a surface protonics methodology with intermetallic active sites. By application of an electric current, the intermetallic Pt-In/TiO2 catalyst gave a propylene yield of 10.2% with high selectivity, even at 250 °C, where the thermodynamic equilibrium yield was only 0.15%. Electroassisted proton collisions with propane allowed an unusual reaction pathway for low-temperature PDH. Alloying of Pt with In drastically enhanced the activity and selectivity due to the increased electron density of Pt.

Atlas-based GABA mapping with 3D MEGA-MRSI: Cross-correlation to single-voxel MRS.

The purpose of this work is to develop and validate a new atlas-based metabolite quantification pipeline for edited magnetic resonance spectroscopic imaging (MEGA-MRSI) that enables group comparisons of brain structure-specific GABA levels. By using brain structure masks segmented from high-resolution MPRAGE images and coregistering these to MEGA-LASER 3D MRSI data, an automated regional quantification of neurochemical levels is demonstrated for the example of the thalamus. Thalamic gamma-aminobutyric acid + coedited macromolecules (GABA+) levels from 21 healthy subjects scanned at 3 T were cross-validated both against a single-voxel MEGA-PRESS acquisition in the same subjects and same scan sessions, as well as alternative MRSI processing techniques (ROI approach, four-voxel approach) using Pearson correlation analysis. In addition, reproducibility was compared across the MRSI processing techniques in test-retest data from 14 subjects. The atlas-based approach showed a significant correlation with SV MEGA-PRESS (correlation coefficient r [GABA+] = 0.63, P < 0.0001). However, the actual values for GABA+, NAA, tCr, GABA+/tCr and tNAA/tCr obtained from the atlas-based approach showed an offset to SV MEGA-PRESS levels, likely due to the fact that on average the thalamus mask used for the atlas-based approach only occupied 30% of the SVS volume, ie, somewhat different anatomies were sampled. Furthermore, the new atlas-based approach showed highly reproducible GABA+/tCr values with a low median coefficient of variance of 6.3%. In conclusion, the atlas-based metabolite quantification approach enables a more brain structure-specific comparison of GABA+ and other neurochemical levels across populations, even when using an MRSI technique with only cm-level resolution. This approach was successfully cross-validated against the typically used SVS technique as well as other different MRSI analysis methods, indicating the robustness of this quantification approach.

Diffusion Imaging in the Post HCP Era.

Diffusion imaging is a critical component in the pursuit of developing a better understanding of the human brain. Recent technical advances promise enabling the advancement in the quality of data that can be obtained. In this review the context for different approaches relative to the Human Connectome Project are compared. Significant new gains are anticipated from the use of high-performance head gradients. These gains can be particularly large when the high-performance gradients are employed together with ultrahigh magnetic fields. Transmit array designs are critical in realizing high accelerations in diffusion-weighted (d)MRI acquisitions, while maintaining large field of view (FOV) coverage, and several techniques for optimal signal-encoding are now available. Reconstruction and processing pipelines that precisely disentangle the acquired neuroanatomical information are established and provide the foundation for the application of deep learning in the advancement of dMRI for complex tissues. Level of Evidence: 3 Technical Efficacy Stage: Stage 3.

7T Epilepsy Task Force Consensus Recommendations on the Use of 7T MRI in Clinical Practice.

Identifying a structural brain lesion on MRI has important implications in epilepsy and is the most important factor that correlates with seizure freedom after surgery in patients with drug-resistant focal onset epilepsy. However, at conventional magnetic field strengths (1.5 and 3T), only approximately 60%-85% of MRI examinations reveal such lesions. Over the last decade, studies have demonstrated the added value of 7T MRI in patients with and without known epileptogenic lesions from 1.5 and/or 3T. However, translation of 7T MRI to clinical practice is still challenging, particularly in centers new to 7T, and there is a need for practical recommendations on targeted use of 7T MRI in the clinical management of patients with epilepsy. The 7T Epilepsy Task Force-an international group representing 21 7T MRI centers with experience from scanning over 2,000 patients with epilepsy-would hereby like to share its experience with the neurology community regarding the appropriate clinical indications, patient selection and preparation, acquisition protocols and setup, technical challenges, and radiologic guidelines for 7T MRI in patients with epilepsy. This article mainly addresses structural imaging; in addition, it presents multiple nonstructural MRI techniques that benefit from 7T and hold promise as future directions in epilepsy. Answering to the increased availability of 7T MRI as an approved tool for diagnostic purposes, this article aims to provide guidance on clinical 7T MRI epilepsy management by giving recommendations on referral, suitable 7T MRI protocols, and image interpretation.

A field-monitoring-based approach for correcting eddy-current-induced artifacts of up to the 2nd spatial order in human-connectome-project-style multiband diffusion MRI experiment at 7T: A pilot study.

Over the recent years, significant advances in Spin-Echo (SE) Echo-Planar (EP) Diffusion MRI (dMRI) have enabled improved fiber tracking conspicuity in the human brain. At the same time, pushing the spatial resolution and using higher b-values inherently expose the acquired images to further eddy-current-induced distortion and blurring. Recently developed data-driven correction techniques, capable of significantly mitigating these defects, are included in the reconstruction pipelines developed for the Human Connectome Project (HCP) driven by the NIH BRAIN initiative. In this case, however, corrections are derived from the original diffusion-weighted (DW) magnitude images affected by distortion and blurring. Considering the complexity of k-space deviations in the presence of time varying high spatial order eddy currents, distortion and blurring may not be fully reversed when relying on magnitude DW images only. An alternative approach, consisting of iteratively reconstructing DW images based on the actual magnetic field spatiotemporal evolution measured with a magnetic field monitoring camera, has been successfully implemented at 3T in single band dMRI (Wilm et al., 2017, 2015). In this study, we aim to demonstrate the efficacy of this eddy current correction method in the challenging context of HCP-style multiband (MB â€‹= â€‹2) dMRI protocol. The magnetic field evolution was measured during the EP-dMRI readout echo train with a field monitoring camera equipped with 16 19F NMR probes. The time variation of 0th, 1st and 2nd order spherical field harmonics were used to reconstruct DW images. Individual DW images reconstructed with and without field correction were compared. The impact of eddy current correction was evaluated by comparing the corresponding direction-averaged DW images and fractional anisotropy (FA) maps. 19F field monitoring data confirmed the existence of significant field deviations induced by the diffusion-encoding gradients, with variations depending on diffusion gradient amplitude and direction. In DW images reconstructed with the field correction, residual aliasing artifacts were reduced or eliminated, and when high b-values were applied, better gray/white matter delineation and sharper gyri contours were observed, indicating reduced signal blurring. The improvement in image quality further contributed to sharper contours and better gray/white matter delineation in mean DW images and FA maps. In conclusion, we demonstrate that up-to-2nd-order-eddy-current-induced field perturbation in multiband, in-plane accelerated HCP-style dMRI acquisition at 7T can be corrected by integrating the measured field evolution in image reconstruction.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism.

Genetic mutations are the major pathogenic factor of Autism Spectrum Disorder (ASD). In recent years, more and more ASD risk genes have been revealed, among which there are a group of transcriptional regulators. Considering the similarity of the core clinical phenotypes, it is possible that these different factors may regulate the expression levels of certain key targets. Identification of these targets could facilitate the understanding of the etiology and developing of novel diagnostic and therapeutic methods. Therefore, we performed integrated transcriptome analyses of RNA-Seq and microarray data in multiple ASD mouse models and identified a number of common downstream genes in various brain regions, many of which are related to the structure and function of the synapse components or drug addiction. We then established protein-protein interaction networks of the overlapped targets and isolated the hub genes by 11 algorithms based on the topological structure of the networks, including Sdc4, Vegfa, and Cp in the Cortex-Adult subgroup, Gria1 in the Cortex-Juvenile subgroup, and Kdr, S1pr1, Ubc, Grm2, Grin2b, Nrxn1, Pdyn, Grin3a, Itgam, Grin2a, Gabra2, and Camk4 in the Hippocampus-Adult subgroup, many of which have been associated with ASD in previous studies. Finally, we cross compared our results with human brain transcriptional data sets and verified several key candidates, which may play important role in the pathology process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRIN2A, GABRA2, and CAMK4. In summary, by integrated bioinformatics analysis, we have identified a series of potentially important molecules for future ASD research. Autism Res 2020, 13: 352-368. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Abnormal transcriptional regulation accounts for a significant portion of Autism Spectrum Disorder. In this study, we performed transcriptome analyses of mouse models to identify common downstream targets of transcriptional regulators involved in ASD. We identified several recurrent target genes that are close related to the common pathological process of ASD, including SDC4, CP, S1PR1, UBC, PDYN, GRM2, NRXN1, GRIN3A, ITGAM, GRIN2A, GABRA2, and CAMK4. These results provide potentially important targets for understanding the molecular mechanism of ASD.

Eliminating susceptibility induced hyperintensities in T1w MPRAGE brain images at 7 T.

INTRODUCTION: At ultrahigh field, local susceptibility induced hyperintensities are pronounced in brain areas close to air-tissue boundaries in the inferior frontal lobe and temporal lobes on T1w MPRAGE images. Resulting from incomplete inversion, these artefacts can introduce biases in brain volumetry and erroneously suggest the existence of local tissular anomaly. We propose a straightforward approach to eliminate these artefacts by applying a shift (ΔfIR) to the center frequency of the adiabatic inversion pulse while widening the bandwidth of the latter by shortening the pulse duration (ΔtIR). METHODS: An MPRAGE sequence was customized allowing to change the duration (standard: 10,240 µs) and center frequency of the hyperbolic secant inversion RF pulse (IR). All measurements were performed on a 7 T whole body scanner (Siemens, Erlangen, Germany). 13 healthy volunteers (7 female and 6 male, average age (SD) = 38 ±â€¯15 yrs) were recruited for the study, 3 of which were scanned for protocol optimization and the rest for performance evaluation. ΔB0 was mapped through the brain with a gradient echo sequence. The effects of ΔfIR and ΔtIR were studied separately and jointly to determine optimal parameter combinations to achieve the largest spatial extent of complete inversion throughout the brain. RESULTS: Applying a positive ΔfIR restored inversion efficiency in the inferior frontal and temporal lobes, but also introduced undesired hyperintensities in the anterior temporal lobes. Widening the bandwidth alone could also partially reduce hyperintensities in the frontal area but with a limited efficiency. By simultaneously applying a positive ΔfIR of 300 Hz and shortening ΔtIR by 40%, these artefacts were eliminated across the whole cerebrum. CONCLUSION: A robust elimination of susceptibility induced hyperintensities near air-tissue boundaries in T1w MPRAGE 7 T brain images is demonstrated. This technique only requires limited MR sequence modifications.

Reversibility of Neuroimaging Markers Influenced by Lifetime Occupational Manganese Exposure.

Manganese (Mn) is a neurotoxicant that many workers are exposed to daily. There is limited knowledge about how changes in exposure levels impact measures in magnetic resonance imaging (MRI). We hypothesized that changes in Mn exposure would be reflected by changes in the MRI relaxation rate R1 and thalamic γ-aminobutyric acid (GABAThal). As part of a prospective cohort study, 17 welders were recruited and imaged on 2 separate occasions approximately 2 years apart. MRI relaxometry was used to assess changes of Mn accumulation in the brain. Additionally, GABA was measured using magnetic resonance spectroscopy in the thalamic and striatal regions of the brain. Air Mn exposure ([Mn]Air) and cumulative exposure indexes of Mn (Mn-CEI) for the past 3 months (Mn-CEI3M), past year (Mn-CEI12M), and lifetime (Mn-CEILife) were calculated using personal air sampling and a comprehensive work history, whereas toenails were collected for analysis of internal Mn body burden. Finally, welders' motor function was examined using the Unified Parkinson's Disease Rating Scale (UPDRS). Median exposure decreased for all exposure measures between the first and second scan. ΔGABAThal was significantly correlated with ΔMn-CEI3M (ρ = 0.66, adjusted p = .02), ΔMn-CEI12M (ρ = 0.70, adjusted p = .006), and Δ[Mn]Air (ρ = 0.77, adjusted p = .002). ΔGABAThal significantly decreased linearly with ΔMn-CEI3M (quantile regression, ß = 15.22, p = .02) as well as Δ[Mn]Air (ß = 1.27, p = .04). Finally, Mn-CEILife interacted with Δ[Mn]Air in the substantia nigra where higher Mn-CEILife lessened the ΔR1 per Δ[Mn]Air (F-test, p = .005). Although R1 and GABA changed with Mn exposure, UPDRS was unaffected. In conclusion, our study shows that effects from changes in Mn exposure are reflected in thalamic GABA levels and brain Mn levels, as measured by R1, in most brain regions.

Relationship of auditory electrophysiological responses to magnetic resonance spectroscopy metabolites in Early Phase Psychosis.

Both auditory evoked responses and metabolites measured by magnetic resonance spectroscopy (MRS) are altered in schizophrenia and other psychotic disorders, but the relationship between electrophysiological and metabolic changes are not well characterized. We examined the relation of MRS metabolites to cognitive and electrophysiological measures in individuals during the early phase of psychosis (EPP) and in healthy control subjects. The mismatch negativity (MMN) of the auditory event-related potential to duration deviant tones and the auditory steady response (ASSR) to 40 Hz stimulation were assessed. MRS was used to quantify glutamate+glutamine (Glx), N-Acetylasparate (NAA), creatine (Cre), myo-inositol (Ins) and choline (Cho) at a voxel placed medially in the frontal cortex. MMN amplitude and ASSR power did not differ between groups. The MRS metabolites Glx, Cre and Cho were elevated in the psychosis group. Partial least squares analysis in the patient group indicated that elevated levels of MRS metabolites were associated with reduced MMN amplitude and increased 40 Hz ASSR power. There were no correlations between the neurobiological measures and clinical measures. These data suggest that elevated neurometabolites early in psychosis are accompanied by altered auditory neurotransmission, possibly indicative of a neuroinflammatory or excitotoxic disturbance which disrupts a wide range of metabolic processes in the cortex.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls.

Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. CONTROLS: One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.

Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI.

Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson's disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N=39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N=26; mean air Mn=0.13±0.1mg/m3; High: N=13; mean air Mn=0.23±0.18mg/m3), as well as unexposed control workers (N=22, mean air Mn=0.002±0.001mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p<0.01, F(1,33)=9.55), as well as significantly worse performance in general motor function (p<0.01, F(1,33)=11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect.

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Effect of Primidone on Dentate Nucleus γ-Aminobutyric Acid Concentration in Patients With Essential Tremor.

OBJECTIVES: It is not known whether current use of the medication primidone affects brain γ-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking primidone versus 26 ET patients not taking primidone. METHODS: (1)H magnetic resonance spectroscopy was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in 2 cerebellar volumes of interest (left and right) that included the dentate nucleus. RESULTS: The right dentate GABA concentration was similar in the 2 groups (2.21 ± 0.46 [on primidone] vs 1.93 ± 0.39 [not on primidone], P = 0.15), as was the left dentate GABA concentration (1.61 ± 0.35 [on primidone] vs 1.67 ± 0.34 [not on primidone], P = 0.72). The daily primidone dose was not associated with either right or left dentate GABA concentrations (P = 0.89 and 0.76, respectively). CONCLUSIONS: We did not find a difference in dentate GABA concentrations between 6 ET patients taking daily primidone and 26 ET patients not taking primidone. Furthermore, there was no association between daily primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on primidone from magnetic resonance spectroscopy studies of dentate GABA concentration, and if assessment of these concentrations was to be developed as a biomarker for ET, primidone usage would not confound interpretation of the results.

Reproducibility and effect of tissue composition on cerebellar γ-aminobutyric acid (GABA) MRS in an elderly population.

MRS provides a valuable tool for the non-invasive detection of brain γ-aminobutyric acid (GABA) in vivo. GABAergic dysfunction has been observed in the aging cerebellum. The study of cerebellar GABA changes is of considerable interest in understanding certain age-related motor disorders. However, little is known about the reproducibility of GABA MRS in an aged population. Therefore, this study aimed to explore the feasibility and reproducibility of GABA MRS in the aged cerebellum at 3.0 T and to examine the effect of differing tissue composition on GABA measurements. MRI and (1)H MRS examinations were performed on 10 healthy elderly volunteers (mean age, 75.2 ± 6.5 years) using a 3.0-T Siemens Tim Trio scanner. Among them, five subjects were scanned twice to assess the short-term reproducibility. The MEGA-PRESS (Mescher-Garwood point-resolved spectroscopy) J-editing sequence was used for GABA detection in two volumes of interest (VOIs) in the left and right cerebellar dentate. MRS data processing and quantification were performed with LCModel 6.3-0L using two separate basis sets, generated from density matrix simulations using published values for chemical shifts and J couplings. Raw metabolite levels from LCModel outputs were corrected for cerebrospinal fluid contamination and relaxation. GABA-edited spectra yielded robust and stable GABA measurements with averaged intra-individual coefficients of variation for corrected GABA+ between 4.0 ± 2.8% and 13.4 ± 6.3%, and inter-individual coefficients of variation between 12.6% and 24.2%. In addition, there was a significant correlation between GABA+ obtained with the two LCModel basis sets. Overall, our results demonstrated the feasibility and reproducibility of cerebellar GABA-edited MRS at 3.0 T in an elderly population. This information might be helpful for studies using this technique to study GABA changes in normal or diseased aging brain, e.g. for power calculations and the interpretation of longitudinal observations.

Striatal and thalamic GABA level concentrations play differential roles for the modulation of response selection processes by proprioceptive information.

The selection of appropriate responses is a complex endeavor requiring the integration of many different sources of information in fronto-striatal-thalamic circuits. An often neglected but relevant piece of information is provided by proprioceptive inputs about the current position of our limbs. This study examines the importance of striatal and thalamic GABA levels in these processes using GABA-edited magnetic resonance spectroscopy (GABA-MRS) and a Simon task featuring proprioception-induced interference in healthy subjects. As a possible model of deficits in the processing of proprioceptive information, we also included Parkinson's disease (PD) patients in this study. The results show that proprioceptive information about unusual postures complicates response selection processes in controls, but not in PD patients. The well-known deficits of PD patients in processing proprioceptive information can turn into a benefit when altered proprioceptive information would normally complicate response selection processes. Striatal and thalamic GABA levels play dissociable roles in the modulation of response selection processes by proprioceptive information: Striatal GABA levels seem to be important for the general speed of responding, most likely because striatal GABA promotes response selection. In contrast, the modulation of response conflict by proprioceptive information is closely related to thalamic GABA concentrations with higher concentration being related to a smaller response conflict effect. The most likely explanation for this finding is that the thalamus is involved in the integration of sensorimotor, attentional, and cognitive information for the purpose of response formation. Yet, this effect in the thalamus vanishes when controls and PD patients were analyzed separately.