Advanced In Vivo Heteronuclear MRS Approaches for Studying Brain Bioenergetics Driven by Mitochondria

Abstract

The greatest merit of in vivo magnetic resonance spectroscopy (MRS) methodology used in biomedical research is its ability for noninvasively measuring a variety of metabolites inside a living organ. It, therefore, provides an invaluable tool for determining metabolites, chemical reaction rates and bioenergetics, as well as their dynamic changes in the human and animal. The capability of in vivo MRS is further enhanced at higher magnetic fields because of significant gain in detection sensitivity and improvement in the spectral resolution. Recent progress of in vivo MRS technology has further demonstrated its great potential in many biomedical research areas, particularly in brain research. Here, we provide a review of new developments for in vivo heteronuclear 31P and 17O MRS approaches and their applications in determining the cerebral metabolic rates of oxygen and ATP inside the mitochondria, in both animal and human brains.

In Vivo Heteronuclear Magnetic Resonance Spectroscopy

“…The most commonly studied nuclei are 1 H, 31 P, and 13 C, although nuclei from isotopes of many other elements (e.g., 2 H, 6 Li, 10 B, 11 B, 14 N, 15 N, 17 O, 19 F, 23 Na, 29 Si, 35 Cl, 113 Cd, 129 Xe, 195 Pt) have been used in high-field NMR spectroscopy [3]. Overall, the frequency at which a specific nucleus resonates depends on the external magnetic field strength applied, the gyromagnetic ratio of the nucleus, and its chemical environment.…”

“…In preclinical research, applications rely on the ability of MRS to noninvasively measure metabolites inside living organs, assessing the content of nuclei like 13 C, 15 N, 17 O, 19 F, and 31 P. One of the most common applications in heteronuclear MRS is in vivo 13 C spectroscopy, which can be used to determine rates of neurotransmission and neuroenergetics [1]. Notably, 17 O and 31 P measurements can determine cerebral metabolic rates of oxygen and ATP inside the mitochondria [2] and its usage is quite extended in preclinical MRS. Nonetheless, in vivo MRS of X-nuclei is challenging due to the low sensitivity detection of the non-proton nuclei; they have a substantially lower gyromagnetic ratio and typically lower natural abundance than the 1 H nucleus.…”

Evidence for the importance of measuring total brain activity in neuroimaging

“…1A can be obtained by integrating each histogram using a linear relationship (4) between oxidative energy demand (E) and the number of cells (N i ) firing at a given rate (v i ) given scaling factors for neurons (G). For different brain states, relative total neuronal energy calculated from experimentally measured histograms (i.e., E = G ∑ N i v i ) agrees quite well with oxidative energy demand measured by techniques like calibrated fMRI and 13 C or 17 O magnetic resonance spectroscopy (MRS) (14,17,18). However, careful considerations are necessary when histogram distributions span high and low frequencies in disproportionate fractions (4).…”

“…Despite the fact both awake humans (8,9) and anesthetized animals (1-7) demonstrate this phenomenon, how anesthetics (which are used to vary the baseline) affect various brain regions should be studied more specifically, because for example, thalamic structures that innervate the cerebral cortex but not the olfactory bulb (23) are directly affected by anesthesia (20). In summary, it is crucial for neuroscientists to err on the side of baseline neuronal activity (or energy) and account for it in absolute terms by using methods like calibrated fMRI and others (14)(15)(16)(17)(18)(19)(20) so as to improve quantitative neuroimaging of brain function. A vital question, however, is whether it is the total neuronal activity (or energy) during task (N) or the difference from rest (ΔN = N -N o ) that is most relevant for understanding brain function (10).…”

“…Traditionally, subtracting the baseline signal was justified by an assumption that there was very little baseline neuronal activity (and by inference, demanded energy) in the awake state (10). However, recent methodsincluding 13 C or 17 O MRS and PET-have shown this hypothesis to be incorrect (15,(17)(18)(19)(20). In the awake human brain, in fact, the total neuronal activity (or energy) in the baseline state is much higher than the incremental activity (or energy) evoked by stimuli (19).…”