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.

The germinal matrix of premature infants is selectively vulnerable to hemorrhage within the first 48 h of life. To assess the role of vascular immaturity in germinal matrix hemorrhage (GMH), we evaluated germinal matrix angiogenesis in human fetuses and premature infants, as well as in premature rabbit pups, and noted active vessel remodeling in all three. Vascular endothelial growth factor (VEGF), angiopoietin-2 and endothelial cell proliferation were present at consistently higher levels in the germinal matrix relative to the white matter anlagen and cortical mantle. On that basis, we asked whether prenatal treatment with either of two angiogenic inhibitors, the COX-2 inhibitor celecoxib, or the VEGFR2 inhibitor ZD6474, could suppress the incidence of GMH in premature rabbit pups. Celecoxib treatment decreased angiopoietin-2 and VEGF levels as well as germinal matrix endothelial proliferation. Furthermore, treatment with celecoxib or ZD6474 substantially decreased the incidence of GMH. Thus, by suppressing germinal matrix angiogenesis, prenatal celecoxib or ZD6474 treatment may be able to reduce both the incidence and severity of GMH in susceptible premature infants.

Germinal matrix (GM) is a richly vascularized collection of neuronal-glial precursor cells in the developing brain, which is selectively vulnerable to hemorrhage in premature infants. It has rapid angiogenesis associated with high levels of vascular endothelial growth factor (VEGF). Because pericytes provide structural stability to blood vessels, we asked whether pericytes were fewer in the GM than in the subjacent white matter and neocortex and, if so, whether angiogenic inhibition could increase the pericyte density in the GM. We found pericyte coverage and density less in the GM vasculature than in the cortex or white matter in human fetuses, premature infants, and premature rabbit pups. Notably, although VEGF suppression significantly enhanced pericyte coverage in the GM, it remained less than in other brain regions. Therefore, to further elucidate the basis of fewer pericytes in the GM vasculature, we examined expression of ligand-receptor systems responsible for pericyte recruitment. Transforming growth factor-␤1 (TGF-␤1) protein expression was lower, whereas sphingosine-1-phosphate1 (S1P1) and N-cadherin levels were higher in the GM than in the cortex or white matter. Low TGF-␤1 may be involved in promoting endothelial proliferation, whereas elevated S1P1 with N-cadherin may assist vascular maturation. Hence, a paucity of pericytes in the GM vasculature may contribute to its propensity to hemorrhage, and a lower expression of TGF-␤1 could be a basis of reduced pericyte density in its vasculature.

The study provides an instructive animal model of IVH with evidence of acute brain injuries that can be used to evaluate strategies in prevention of IVH and acute posthemorrhagic complications.

Accurate and reliable quantification of brain metabolites measured in vivo using 1 H magnetic resonance spectroscopy (MRS) is a topic of continued interest in the field. 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, we analyze spectrally edited -aminobutyric acid (GABA) MRS data and quantify GABA levels relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using standard GABA+ editing. Unsuppressed water acquisitions from the same volume of interest were acquired for signal referencing. Whole-brain T1-weighted structural images were acquired and tissue-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%, which was largely driven by vendor-related differences according to a linear mixed-effects analysis. The mean within-site coefficient of variation was 9%. Vendor differences contributed 53% to the total variance in the data, while the remaining variance was attributed to site-(11%) and participant-level (36%) effects. Results from an exploratory analysis suggested that the vendor differences were related to the water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA+ measurements exhibit levels of variance similar to creatine-referenced GABA+ measurements. It is concluded that quantification using internal tissue water referencing remains a viable and reliable method for the in vivo quantification of GABA+ levels.

BackgroundComputerized multi-model training has been widely studied for its effect on delaying cognitive decline. In this study, we designed the first Chinese-version computer-based multi-model cognitive training for mild cognitive impairment (MCI) patients. Neuropsychological effects and neural activity changes assessed by functional MRI were both evaluated.MethodMCI patients in the training group were asked to take training 3–4 times per week for 6 months. Neuropsychological and resting-state fMRI assessment were performed at baseline and at 6 months. Patients in both groups were continuously followed up for another 12 months and assessed by neuropsychological tests again.Results78 patients in the training group and 63 patients in the control group accomplished 6-month follow-up. Training group improved 0.23 standard deviation (SD) of mini-mental state examination, while control group had 0.5 SD decline. Addenbrooke's cognitive examination-revised scores in attention (p = 0.002) and memory (p = 0.006), as well as stroop color-word test interference index (p = 0.038) and complex figure test-copy score (p = 0.035) were also in favor of the training effect. Difference between the changes of two groups after training was not statistically significant. The fMRI showed increased regional activity at bilateral temporal poles, insular cortices and hippocampus. However, difference between the changes of two groups after another 12 months was not statistically significant.ConclusionsMulti-model cognitive training help MCI patients to gained cognition benefit, especially in memory, attention and executive function. Functional neuroimaging provided consistent neural activation evidence. Nevertheless, after one-year follow up after last training, training effects were not significant. The study provided new evidence of beneficial effect of multi-model cognitive training.

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 P boot ). Results:In total, 296 participants (mean age, 26 years 6 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 (P boot . .90), N-acetylaspartate and N-acetylaspartylglutamate (P boot = .13), or glutamate and glutamine (P boot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (P boot = .08), aspartate (P boot . .90), glutathione (P boot . .90), or lactate (P boot = .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 siterelated effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols.

Germinal matrix is selectively vulnerable to hemorrhage in premature infants, and use of prenatal betamethasone is associated with a lower occurrence of germinal matrix hemorrhage. Because the major components of extracellular matrix of the cerebral vasculature-laminin, fibronectin, collagen IV, and perlecan-provide structural stability to blood vessels, we examined whether the expression of these molecules was decreased in the germinal matrix and affected by betamethasone. In both human fetuses and premature infants, fibronectin was significantly lower in the germinal matrix than in the cortical mantle or white matter anlagen. Conversely, laminin alpha1 gene expression was greater in the human germinal matrix compared with the cortical mantle or white matter. Expression of alpha1- and alpha2(IV) collagen chains increased with advancing gestational age. Low-dose prenatal betamethasone treatment enhanced fibronectin level by 1.5-2-fold whereas a high dose reduced fibronectin expression by 2-fold in rabbit pups. Because fibronectin provides structural stability to the blood vessels, its reduced expression in the germinal matrix may contribute to the fragility of germinal matrix vasculature and the propensity to hemorrhage in premature neonates.