Elsevier

NeuroImage

Volume 22, Issue 2, June 2004, Pages 611-618
NeuroImage

Proton MRI of metabolically produced H217O using an efficient 17O2 delivery system

https://doi.org/10.1016/j.neuroimage.2004.02.024Get rights and content

Abstract

In vivo detection of H217O produced via metabolic reduction of inhaled 17O-enriched gas is demonstrated using proton magnetic resonance imaging (MRI). Specifically, 1H T-weighted MRI, which may be readily implemented on any MRI scanner, is applied as an indirect 17O imaging method to quantitatively monitor the distribution of metabolically produced 17O water (mpH217O) in the rat brain. The delivery of 17O2 to rats is conducted via a specially designed closed respiration circuit that conserves the expensive gas. Quantitative mapping of H217O performed via 1H T-weighted MRI is validated by direct 17O-magnetic resonance spectroscopy. The MRI data show that a steady-state H217O concentration of 25.7 ± 1.66 mM (n = 4) is achieved in the rat brain within approximately 30 min under the 17O inhalation paradigm used. From the first minute of the mpH217O time courses, cerebral metabolic rate of oxygen (CMRO2) is estimated to be 2.10 ± 0.44 μmol g−1 min−1 (n = 4), a value that is consistent with the literature.

Introduction

Functional brain mapping with magnetic resonance imaging (MRI) has focused primarily on the blood-oxygen-level-dependent (BOLD) effect sensitive to vascular paramagnetic deoxyhemoglobin. However, despite a plethora of BOLD MRI data suggestive of correlation with a variety of neural stimulation paradigms, the overall complexity of the BOLD signal precludes derivation of the underlying metabolic activity central to neuronal function. This difficulty with interpretation of the BOLD signal is in part motivation for development of MRI methods that enable more direct assessment of brain function. One approach for imaging brain metabolism is to use 17O as a marker for the final reaction in the electron transport chain. Because cellular respiration relies on the reduction of oxygen to water as the final step in oxidative metabolism, a technique that can detect this relatively small amount of metabolically produced water, in the large pool of water already present in biological tissue, can serve as a reliable tool for quantifying metabolic activity. 17O-MR is well suited for such a technique because neither molecular 17O2 dissolved in plasma nor 17O2 bound to hemoglobin is detectable unless converted to H217O. This property of 17O-MR helps to avoid blood volume and blood flow artifacts encountered by 15O positron emission tomography (PET) due to PET's inability to distinguish between 15O2 bound to oxyhemoglobin and 15O incorporated in H215O.

Direct 17O-MRI has been applied successfully for the detection of metabolically produced 17O water (mpH2 17O) from inhaled 17O2 Arai et al., 1991, Fiat et al., 1992, Pekar et al., 1991. Although methods based on direct 17O detection are highly specific for 17O, they suffer from poor signal-to-noise ratio (SNR) and spatial resolution. The relatively small gyromagnetic ratio of 17O, short transverse relaxation time (T2) of 17O (1–2 ms), and the inability to achieve high concentrations of H217O in vivo all contribute to poor SNR when imaging 17O directly. Significantly higher SNR and spatial resolution are achieved by direct 17O-magnetic resonance spectroscopic imaging (Zhu et al., 2002); however, this technique cannot be implemented on an MRI scanner. As a result, focus has remained shifted towards development of methods for 1H-MRI, or indirect, detection of H217O that can be readily implemented on any MRI scanner.

H217O has been applied as a 1H T2 relaxation agent Hopkins and Barr, 1987, Hopkins et al., 1988, Hopkins et al., 1991, Kwong et al., 1991 and indirectly quantitated from the T2-weighted 1H image; however, this approach suffers from misregistration artifacts and susceptibility effects. Another method for quantifying H217O concentrations using selective 17O-decoupled T2-weighted 1H-MRI has been proposed and demonstrated Ronen and Navon, 1994, Ronen et al., 1998. This 17O decoupling method was also implemented using a double-tuned radiofrequency (RF) coil Charagundla et al., 2000, Reddy et al., 1996. Although this method is highly specific for 17O, it is difficult to implement on an MRI scanner because it requires a second RF channel for decoupling. Furthermore, the decoupling power required is too high for human application.

Our group developed a new method for quantifying 17O that is based on proton T-dispersion imaging and can be implemented readily on any MRI scanner (Reddy et al., 1995). Subsequently, this method was optimized for imaging H217O in the rat brain and murine tumors Tailor et al., 2003a, Tailor et al., 2003b at submillimeter in-plane spatial resolution and 13-s temporal resolution, and its utility was also demonstrated in the same studies by mapping (cerebral blood flow CBF) in the rat and relative tumor blood flow in murine RIF-1 tumors.

In this study, we apply our proton T-weighted MRI approach for in vivo detection and quantitative mapping of mpH217O. No such demonstration using any 1H-MRI method is reported in the literature. Additionally, considering the formidable cost of 17O (approximately US$2 per ml of 40 at.% 17O), we introduce an efficient delivery system for 17O inhalation-based metabolic imaging studies. Compared to conventional approaches, our new system reduces the 17O2 required by an order of magnitude. A carefully designed closed respiration circuit is implemented such that volume is minimized far below what is available in commercial ventilators and unused 17O may be retrieved. At the same time, actively pumped gas in the circuit avoids re-breathing, and end-expiratory pressure and work of breathing are minimized to allow spontaneous respiration. This 17O delivery system and the 1H T-weighted MRI method are developed under the constraint that they are feasible for safe human application after simple scale-up with readily available components.

Section snippets

Animal preparation

Five female Sprague–Dawley rats (150–250 g) were anesthetized with an intraperitoneal injection of 50 mg kg−1 pentobarbital. After assessment of anesthetic depth, each rat was secured in the dorsal recumbent position, a rectal temperature probe was inserted, and core temperature was maintained with a heating lamp. A 16-gauge cannula was placed in the trachea via midline tracheostomy, and sealed in the trachea with silk sutures. After cannulation, the rat was wrapped with a heated recirculating

Results and discussion

Fig. 3A displays a representative, sagittal, fast-gradient-recalled-echo (FGRE) 1H-MR image of a rat's head and neck region obtained with the same hardware used for 1H T-weighted MRI. Fig. 3B shows a representative 1500 Hz spin-locked T-weighted image acquired from the 3-mm slice indicated by the white rectangle in Fig. 3A. This 3-mm slice incorporates a significant portion of the fronto-parietal cortex and depicts the anatomical localization used consistently for all animals imaged. T

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