Assessing metabolism and injury in acute human traumatic brain injury with magnetic resonance spectroscopy: Current and future applications

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., ¹H, ³¹P, and ¹³C, 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, ¹H 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. ¹H MRS acquired with shorter echo times produces a more complex spectrum, allowing detection of a wider range of metabolites. ³¹P 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. ¹³C MRS detects the ¹³C isotope of carbon in brain metabolites. As the natural abundance of ¹³C is low (1.1%), ¹³C MRS is typically performed following administration of ¹³C-enriched substrates, which permits tracking of the metabolic fate of the infused ¹³C 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 ¹³C-enriched MRS in vivo studies shows promise in this field, and further developments are expected.