Oded Gonen
Traumatic brain injury (TBI) annually accounts for 1.6 million emergency department visits and hospitalizations in the United States.1 More than 85% of TBIs are classified as “mild” (MTBI), whose radiologic findings are minimal, if any, and do not correspond to clinical symptoms; consequently, it is suspected that many more victims do not seek medical attention or are seen at their doctor’s office. TBI is most common in 15–24-year-olds, peaking in 20–24-year-old males by an order of magnitude over any other age or gender group. Overall, men are more than twice as likely to sustain TBI.2,3 Patients who do not recover add to the 1% of the US population living with long-term TBI-related disability,4 with a consequence of direct expenses and lost income of over $40 billion, ~0.5% of the GNP.5 Moreover, TBI from blast exposure has been described as the “signature injury” of the recent wars in Iraq and Afghanistan,6 with ~20% of veterans reporting probable MTBI.7
TBI damage is assumed to result from the mechanical strain of sudden acceleration and deceleration that damages the axonal cytoskeleton and disrupts ionic balances. Abnormally high calcium influx impairs transport along the axon and can lead to dysfunction or axotomy followed by cell death.8,9 This strain can also cause vascular damage—hemorrhages, hemosiderin, and enlarged Virchow-Robin spaces—seen by clinical MRI and CT and crucial for the acute assessment of MTBI.10 All of these are presumed to be associated with underlying diffuse axonal injury (DAI),11 which, however, is usually occult on MRI and CT. This inability to assess the total disease load leads to weak correlation of imaging with clinical metrics,12 and motivates the search for other MTBI biomarkers to direct pharmacological regimens and predict outcome.
MRI-occult MTBI damage can be studied with quantitative MR methods, eg, diffusion tensor,13 functional MRI,14 and proton MR spectroscopy (1H-MRS).15 The latter adds unique specificity to pathologic processes by quantifying surrogates, most notably the amino acid derivative N‑acetylaspartate (NAA), for neuronal integrity; creatine, for cellular energy/density; choline, for membrane turnover; and myo-inositol, for astroglial proliferation.15 Most TBI studies to date, however, use single-voxel or 2D 1H-MRS covering under 10% of the brain: regions-of-interest (ROIs) that may not be globally representative and that also make it impossible to distinguish focal from diffuse injury.
These shortcomings can be reduced with absolute metabolic quantification of the whole-brain NAA concentration (WBNAA).16 That, based on the involvement of complex neurocognitive pathways and the paucity of clinical MRI findings, can be used to detect MTBI’s diffuse damage that affects the integrity of neurons and their axonal processes via 1) its global decline, and 2) global, GM, and WM atrophy.7 Analyzing the entire brain as a unit improves the signal-to-noise ratio (SNR) for better precision, ie, sensitivity to smaller global changes, at the cost of averaging out regional metabolic variations—a reasonable trade-off for diffuse disorders because MTBI often leads to neurologic symptoms, even without clinical MRI findings.17
Indeed, our findings reveal that patients with MTBI, both “recent” (months) and “chronic” (years) post-MTBI, suffer significant WBNAA deficits relative to controls, with and without adjusting for age and gender. On the other hand, patients and controls were indistinguishable in each of the three brain tissue volumetric measures, fractional WM, GM, and intracranial volumes, underscoring the diagnostic sensitivity and specificity power of 1H-MRS compared with MRI.7
We now also routinely apply 3D multivoxel 1H-MR spectroscopic imaging (3D 1H-MRSI) at 0.75 ml spatial resolution over a large, ~0.5 liter brain volume.18 Analyzing all voxels in the GM and WM together also improves the SNR for better precision, ie, sensitivity to smaller global changes, at the cost of averaging out regional metabolic variations.19–21 The findings show diffuse WM injury (with sparing of the GM NAA) between 0–60 days post-MTBI, consistent with the accepted DAI model. The advantage of the global approach, however, is that it does not require assumptions of where the DAI is (splenium of the corpus callosum is a common example). Due to the heterogeneity in injury type, focusing on a single region, mandated by single voxel 1H-MRS, may reduce the power of the study per given cohort, given their variable injury types.22 Furthermore, the availability of the (multivoxel) data at 1 ml spatial resolution in a 3D 1H-MRSI experiment also allows us to analyze changes on structural basis. This analysis has recently shown deep gray matter (mainly putaminal, but not thalamic) dysfunction in patients with MTBI versus healthy controls.19,23