Novel Metabolomic Comparison of Arterial and Jugular Venous Blood in Severe Adult Traumatic Brain Injury Patients and the Impact of Pentobarbital Infusion.

Treatment of severe traumatic brain injury (TBI) in the intensive care unit focuses on controlling intracranial pressure, ensuring sufficient cerebral perfusion, and monitoring for secondary injuries. However, there are limited prognostic tools and no biomarkers or tests of the evolving neuropathology. Metabolomics has the potential to be a powerful tool to indirectly monitor evolving dysfunctional metabolism. We compared metabolite levels in simultaneously collected arterial and jugular venous samples in acute TBI patients undergoing intensive care as well as in healthy control volunteers. Our results show that, first, many circulating metabolites are decreased in TBI patients compared with healthy controls days after injury; both proline and hydroxyproline were depleted by ≥60% compared with healthy controls, as was gluconate. Second, both arterial and jugular venous plasma metabolomic analysis separates TBI patients from healthy controls and shows that distinct combinations of metabolites are driving the group separation in the two blood types. Third, TBI patients under heavy sedation with pentobarbital at the time of blood collection were discernibly different from patients not receiving pentobarbital. These results highlight the importance of accounting for medications in metabolomics analysis. Jugular venous plasma metabolomics shows potential as a minimally invasive tool to identify and study dysfunctional cerebral metabolism after TBI.

A Comparative Study of Automatic Approaches for Preclinical MRI-based Brain Segmentation in the Developing Rat.

Accurate pre-clinical study reporting requires validated processing tools to increase data reproducibility within and between laboratories. Segmentation of rodent brain from non-brain tissue is an important first step in preclinical imaging pipelines for which well validated tools are still under development. The current study aims to clarify the best approach to automatic brain extraction for studies in the immature rat. Skull stripping modules from AFNI, PCNN-3D, and RATS software packages were assessed for their ability to accurately segment brain from non-brain by comparison to manual segmentation. Comparison was performed using Dice coefficient of similarity. Results showed that the RATS package outperformed the others by including a lower percentage of false positive, non-brain voxels in the brain mask. However, AFNI resulted in a lower percentage of false negative voxels. Although the automatic approaches for brain segmentation significantly facilitate the data stream process, the current study findings suggest that the task of rodent brain segmentation from T2 weighted MRI needs to be accompanied by a supervised quality control step when developmental brain imaging studies were targeted.

Lactate supplementation in severe traumatic brain injured adults by primed constant infusion of sodium L-lactate.

Carbohydrate fuel augmentation following traumatic brain injury may be a viable treatment to improve recovery when cerebral oxidative metabolism of glucose is depressed. We performed a primed constant sodium L-lactate infusion in 11 moderate to severely brain injured adults. Blood was collected before and periodically during the infusion study. We quantified global cerebral uptake of glucose and lactate and other systemic metabolites associated with energy metabolism. Our hypothesis was that cerebral lactate uptake, as measured by the arteriovenous difference of lactate (AVDlac), would increase in severely injured TBI patients in the neurocritical care unit. Infusion of sodium L-lactate changed net cerebral lactate release, where the arteriovenous difference of lactate is negative, to net cerebral lactate uptake. Results from a mixed effects model of AVDlac with the fixed effects of infusion time, arterial lactate concentration, arterial glucose concentration and arteriovenous difference of glucose shows that doubling arterial lactate concentration (from .92 to 1.84 mM) results in an increase in AVDlac from -.078 mM to .090 mM. We did not detect changes in systemic glucose during the course of the infusion study and observed significant changes in alanine (30% [20 39]), glutamine (34% [24 43]), acetate (87% [60 113]), valine (40% [28 51]), and leucine (24% [16 32]) from baseline levels. Further studies are required to establish the impact of lactate supplementation on cerebral and systemic flux of lactate, on gluconeogenesis, and on the impact on cerebral energetics following injury. © 2017 Wiley Periodicals, Inc.

Influence of Glycemic Control on Endogenous Circulating Ketone Concentrations in Adults Following Traumatic Brain Injury.

BACKGROUND: The objective was to investigate the impact of targeting tight glycemic control (4.4-6.1 mM) on endogenous ketogenesis in severely head-injured adults. METHODS: The data were prospectively collected during a randomized, within-patient crossover study comparing tight to loose glycemic control, defined as 6.7-8.3 mM. Blood was collected periodically during both tight and loose glycemic control epochs. Post hoc analysis of insulin dose and total nutritional provision was performed. RESULTS: Fifteen patients completed the crossover study. Total ketones were increased 81 µM ([38 135], p < 0.001) when blood glucose was targeted to tight (4.4-6.1 mM) compared with loose glycemic control (6.7-8.3 mM), corresponding to a 60 % increase. There was a significant decrease in total nutritional provisions (p = 0.006) and a significant increase in insulin dose (p = 0.008). CONCLUSIONS: Permissive underfeeding was tolerated when targeting tight glycemic control, but total nutritional support is an important factor when treating hyperglycemia.

Role of Metabolomics in Traumatic Brain Injury Research.

Metabolomics is an important member of the omics community in that it defines which small molecules may be responsible for disease states. This article reviews the essential principles of metabolomics from specimen preparation, chemical analysis, to advanced statistical methods. Metabolomics in traumatic brain injury has so far been underutilized. Future metabolomics-based studies focused on the diagnoses, prognoses, and treatment effects need to be conducted across all types of traumatic brain injury.

A robust approach to correct for pronounced errors in temperature measurements by controlling radiation damping feedback fields in solution NMR.

Accurate temperature measurement is a requisite for obtaining reliable thermodynamic and kinetic information in all NMR experiments. A widely used method to calibrate sample temperature depends on a secondary standard with temperature-dependent chemical shifts to report the true sample temperature, such as the hydroxyl proton in neat methanol or neat ethylene glycol. The temperature-dependent chemical shift of the hydroxyl protons arises from the sensitivity of the hydrogen-bond network to small changes in temperature. The frequency separation between the alkyl and the hydroxyl protons are then converted to sample temperature. Temperature measurements by this method, however, have been reported to be inconsistent and incorrect in modern NMR, particularly for spectrometers equipped with cryogenically-cooled probes. Such errors make it difficult or even impossible to study chemical exchange and molecular dynamics or to compare data acquired on different instruments, as is frequently done in biomolecular NMR. In this work, we identify the physical origins for such errors to be unequal amount of dynamical frequency shifts on the alkyl and the hydroxyl protons induced by strong radiation damping (RD) feedback fields. Common methods used to circumvent RD may not suppress such errors. A simple, easy-to-implement solution was demonstrated that neutralizes the RD effect on the frequency separation by a "selective crushing recovery" pulse sequence to equalize the transverse magnetization of both spin species. Experiments using cryoprobes at 500 MHz and 800 MHz demonstrated that this approach can effectively reduce the errors in temperature measurements from about ±4.0 K to within ±0.4 K in general.

A small MRI contrast agent library of gadolinium(III)-encapsulated supramolecular nanoparticles for improved relaxivity and sensitivity.

We introduce a new category of nanoparticle-based T(1) MRI contrast agents (CAs) by encapsulating paramagnetic chelated gadolinium(III), i.e., Gd(3+)·DOTA, through supramolecular assembly of molecular building blocks that carry complementary molecular recognition motifs, including adamantane (Ad) and ß-cyclodextrin (CD). A small library of Gd(3+)·DOTA-encapsulated supramolecular nanoparticles (Gd(3+)·DOTA⊂SNPs) was produced by systematically altering the molecular building block mixing ratios. A broad spectrum of relaxation rates was correlated to the resulting Gd(3+)·DOTA⊂SNP library. Consequently, an optimal synthetic formulation of Gd(3+)·DOTA⊂SNPs with an r(1) of 17.3 s(-1) mM(-1) (ca. 4-fold higher than clinical Gd(3+) chelated complexes at high field strengths) was identified. T(1)-weighted imaging of Gd(3+)·DOTA⊂SNPs exhibits an enhanced sensitivity with a contrast-to-noise ratio (C/N ratio) ca. 3.6 times greater than that observed for free Gd(3+)·DTPA. A Gd(3+)·DOTA⊂SNPs solution was injected into foot pads of mice, and MRI was employed to monitor dynamic lymphatic drainage of the Gd(3+)·DOTA⊂SNPs-based CA. We observe an increase in signal intensity of the brachial lymph node in T(1)-weighted imaging after injecting Gd(3+)·DOTA⊂SNPs but not after injecting Gd(3+)·DTPA. The MRI results are supported by ICP-MS analysis ex vivo. These results show that Gd(3+)·DOTA⊂SNPs not only exhibits enhanced relaxivity and high sensitivity but also can serve as a potential tool for diagnosis of cancer metastasis.

Improving MRI differentiation of gray and white matter in epileptogenic lesions based on nonlinear feedback.

A new method for enhancing MRI contrast between gray matter (GM) and white matter (WM) in epilepsy surgery patients with symptomatic lesions is presented. This method uses the radiation damping feedback interaction in high-field MRI to amplify contrast due to small differences in resonance frequency in GM and WM corresponding to variations in tissue susceptibility. High-resolution radiation damping-enhanced (RD) images of in vitro brain tissue from five patients were acquired at 14 T and compared with corresponding conventional T(1)-, T(2) (*)-, and proton density (PD)-weighted images. The RD images yielded a six times better contrast-to-noise ratio (CNR = 44.8) on average than the best optimized T(1)-weighted (CNR = 7.92), T(2) (*)-weighted (CNR = 4.20), and PD-weighted images (CNR = 2.52). Regional analysis of the signal as a function of evolution time and initial pulse flip angle, and comparison with numerical simulations confirmed that radiation damping was responsible for the observed signal growth. The time evolution of the signal in different tissue regions was also used to identify subtle changes in tissue composition that were not revealed in conventional MR images. RD contrast is compared with conventional MR methods for separating different tissue types, and its value and limitations are discussed.