When asked to imagine a visual scene, such as an ant crawling on a checkered table cloth toward a jar of jelly, individuals subjectively report different vividness in their mental visualization. We show that reported vividness can be correlated with two objective measures: the early visual cortex activity relative to the whole brain activity measured by functional magnetic resonance imaging (fMRI) and the performance on a novel psychophysical task. These results show that individual differences in the vividness of mental imagery are quantifiable even in the absence of subjective report.

Mild traumatic brain injury (mTBI) results from a transfer of mechanical energy into the brain from traumatic events such as rapid acceleration/deceleration, a direct impact to the head, or an explosive blast. Transfer of energy into the brain can cause structural, physiological, and/or functional changes in the brain that may yield neurological, cognitive, and behavioral symptoms that can be long-lasting. Because mTBI can cause these symptoms in the absence of positive neuroimaging findings, its diagnosis can be subjective and often is based on self-reported neurological symptoms. Further, proper diagnosis can be influenced by the motivation to conceal or embellish signs and/or an inability of the patient to notice subtle dysfunctions or alterations of consciousness. Therefore, appropriate diagnosis of mTBI would benefit from objective indicators of injury. Concussion and mTBI are often used interchangeably, with concussion being primarily used in sport medicine, whereas mTBI is used in reference to traumatic injury. This review provides a critical assessment of the status of current biomarkers for the diagnosis of human mTBI. We review the status of biomarkers that have been tested in TBI patients with injuries classified as mild, and introduce a new concept for the discovery of biomarkers (termed symptophenotypes) to predict common and unique symptoms of concussion. Finally, we discuss the need for biomarker/biomarker signatures that can detect mTBI in the context of polytrauma, and to assess the consequences of repeated injury on the development of secondary injury syndrome, prolongation of post-concussion symptoms, and chronic traumatic encephalopathy.

The pathophysiology of traumatic brain injury (TBI) is complex and not well understood. Because pathophysiology has ramifications for injury progression and outcome, we sought to identify metabolic cascades that are altered after acute human mild and severe TBI. Because catabolism of branched-chain amino acids (BCAAs; i.e., valine, isoleucine, and leucine) leads to glucose and energy metabolism, and neurotransmitter synthesis and availability, we investigated BCAA metabolites in plasma samples collected within 24 h of injury from mild TBI (Glasgow Coma Scale [GCS] score >12), severe TBI (GCS ≤8), orthopedic injury, and healthy volunteers. We report decreased levels of all three BCAAs in patients with mild TBI relative to healthy volunteers, while these BCAAs levels in patients with severe TBI were further reduced compared with all groups. Orthopedic patients exhibited reductions in BCAA comparable to those in patients with mild TBI. The decrease in patients with mild and severe TBI persisted for derivatives of BCAA catabolic intermediates. Only plasma levels of methylglutarylcarnitine, a derivative of a leucine metabolite, were increased in patients with severe TBI compared with all other groups. Notably, logistic regression combination of three BCAA metabolites whose levels were changed by 24 h post-injury provided prognostic value (area under the curve=0.92) in identifying patients with severe TBI in whom elevated intracranial pressure (≥25 mm Hg) developed. These changes suggest alteration of BCAA metabolism after TBI may contribute to decreased energy production and neurotransmitter synthesis and may contribute to TBI pathophysiology. Supplementation of BCAAs and/or their metabolites may reduce TBI pathology and improve outcome.

Methionine is an essential proteinogenic amino acid that is obtained from the diet. In addition to its requirement for protein biosynthesis, methionine is metabolized to generate metabolites that play key roles in a number of cellular functions. Metabolism of methionine via the transmethylation pathway generates S-adenosylmethionine (SAM) that serves as the principal methyl (−CH3) donor for DNA and histone methyltransferases (MTs) to regulate epigenetic changes in gene expression. SAM is also required for methylation of other cellular proteins that serve various functions and phosphatidylcholine synthesis that participate in cellular signaling. Under conditions of oxidative stress, homocysteine (which is derived from SAM) enters the transsulfuration pathway to generate glutathione, an important cytoprotective molecule against oxidative damage. As both experimental and clinical studies have shown that traumatic brain injury (TBI) alters DNA and histone methylation and causes oxidative stress, we examined if TBI alters the plasma levels of methionine and its metabolites in human patients. Blood samples were collected from healthy volunteers (HV; n = 20) and patients with mild TBI (mTBI; GCS > 12; n = 20) or severe TBI (sTBI; GCS < 8; n = 20) within the first 24 h of injury. The levels of methionine and its metabolites in the plasma samples were analyzed by either liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry (LC-MS or GC-MS). sTBI decreased the levels of methionine, SAM, betaine and 2-methylglycine as compared to HV, indicating a decrease in metabolism through the transmethylation cycle. In addition, precursors for the generation of glutathione, cysteine and glycine were also found to be decreased as were intermediate metabolites of the gamma-glutamyl cycle (gamma-glutamyl amino acids and 5-oxoproline). mTBI also decreased the levels of methionine, α-ketobutyrate, 2 hydroxybutyrate and glycine, albeit to lesser degrees than detected in the sTBI group. Taken together, these results suggest that decreased levels of methionine and its metabolic products are likely to alter cellular function in multiple organs at a systems level.

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