Assessing Metabolism and Injury in Acute Human Traumatic Brain Injury with Magnetic Resonance Spectroscopy: Current and Future Applications

Matthew G. Stovell, Jiun-Lin Yan, Alison Sleigh, Marius O. Mada, T. Adrian Carpenter, Peter J. A. Hutchinson, Keri L. H. Carpenter

Traumatic brain injury (TBI) triggers a series of complex pathophysiological processes. These include abnormalities in brain energy metabolism; consequent to reduced tissue pO2 arising from ischemia or abnormal tissue oxygen diffusion, or due to a failure of mitochondrial function. In vivo magnetic resonance spectroscopy (MRS) allows non-invasive interrogation of brain tissue metabolism in patients with acute brain injury. Nuclei with "spin," e.g., (1)H, (31)P, and (13)C, are detectable using MRS and are found in metabolites at various stages of energy metabolism, possessing unique signatures due to their chemical shift or spin-spin interactions (J-coupling). The most commonly used clinical MRS technique, (1)H MRS, uses the great abundance of hydrogen atoms within molecules in brain tissue. Spectra acquired with longer echo-times include N-acetylaspartate (NAA), creatine, and choline. NAA, a marker of neuronal mitochondrial activity related to adenosine triphosphate (ATP), is reported to be lower in patients with TBI than healthy controls, and the ratio of NAA/creatine at early time points may correlate with clinical outcome. (1)H MRS acquired with shorter echo times produces a more complex spectrum, allowing detection of a wider range of metabolites.(31) P MRS detects high-energy phosphate species, which are the end products of cellular respiration: ATP and phosphocreatine (PCr). ATP is the principal form of chemical energy in living organisms, and PCr is regarded as a readily mobilized reserve for its replenishment during periods of high utilization. The ratios of high-energy phosphates are thought to represent a balance between energy generation, reserve and use in the brain. In addition, the chemical shift difference between inorganic phosphate and PCr enables calculation of intracellular pH.(13) C MRS detects the (13)C isotope of carbon in brain metabolites. As the natural abundance of (13)C is low (1.1%), (13)C MRS is typically performed following administration of (13)C-enriched substrates, which permits tracking of the metabolic fate of the infused (13)C in the brain over time, and calculation of metabolic rates in a range of biochemical pathways, including glycolysis, the tricarboxylic acid cycle, and glutamate-glutamine cycling. The advent of new hyperpolarization techniques to transiently boost signal in (13)C-enriched MRS in vivo studies shows promise in this field, and further developments are expected.