Neuroprotection Following Concussion: The Potential Role for Cannabidiol.

Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.

Analysis of magnetic resonance spectroscopy relative metabolite ratios in mild traumatic brain injury and normative controls.

INTRODUCTION: We evaluated magnetic resonance spectroscopy (MRS) in United States military personnel with persistent symptoms after mild traumatic brain injury (mTBI), comparing over time two groups randomized to receive hyperbaric oxygen or sham chamber sessions and a third group of normative controls. METHODS: Active-duty or veteran military personnel and normative controls underwent MRS outcome measures at baseline, 13 weeks (mTBI group only), and six months. Participants received 3.0 Tesla brain MRS for analysis of water-suppressed two-dimensional (2D) multivoxel 1H-MRS of the brain using point resolved spectroscopy (PRESS) with volume selection localized above the lateral ventricles and within the brain parenchyma, of which one voxel was chosen in each hemisphere without artifact. Script-based automatic data processing was used to assess N-acetylaspartate (NAA), creatine (Cr), and choline (Cho). Metabolite ratios for white matter were then calculated for NAA/Cr (Area), Cho/Cr (Area), and Cho/NAA (Area). These ratios were compared using standard analysis methodology. RESULTS: There were no observable differences between participants with mTBI and normative controls nor any observable changes over time in the NAA/Cr (area), Cho/Cr (area), and Cho/NAA (area) ratios. Similarly, the control and injured participants were indistinguishable. DISCUSSION: While participants with mild TBI showed no difference in MRS compared to normative controls, our results are limited by the few voxels chosen and potentially by less sensitive MRS markers.

Role of brain metabolites during acute phase of mild traumatic brain injury in prognosis of post-concussion syndrome: A 1H-MRS study.

This study has investigated the potency and accuracy of early magnetic resonance spectroscopy (MRS) to predict post-concussion syndrome (PCS) in adult patients with a single mild traumatic brain injury (mTBI) without abnormality on a routine brain scan. A total of 48 eligible mTBI patients and 24 volunteers in the control group participated in this project. Brain MRS over regions of interest (ROI) and signal stop task (SST) were done within the first 72 hours of TBI onset. After six months, PCS appearance and severity were determined. In non-PCS patients, N-acetyl aspartate (NAA) levels significantly increased in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to the control group, however, this increase of NAA levels were recorded in all ROI versus PCS subjects. There were dramatic declines in creatinine (Cr) levels of all ROI and a decrease in choline levels of corpus callosum (CC) in the PCS group versus control and non-PCS ones. NAA and NAA/Cho values in ACC were the main predictors of PCS appearance. The Cho/Cr level in ACC was the first predictor of PCS severity. Predicting accuracy was higher in ACC than in other regions. This study suggested the significance of neuro-markers in ACC for optimal prediction of PCS and rendered a new insight into the biological mechanism of mTBI that underpins PCS.

Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms.

Disagreement exists regarding the extent to which persistent post-concussive symptoms (PCS) reported by Iraq combat Veterans with repeated episodes of mild traumatic brain injury (mTBI) from explosive blasts represent structural or functional brain damage or an epiphenomenon of comorbid depression or posttraumatic stress disorder (PTSD). Objective assessment of brain function in this population may clarify the issue. To this end, twelve Iraq war Veterans (32.0 ± 8.5 [mean ± standard deviation (SD)] years of age) reporting one or more blast exposures meeting American Congress of Rehabilitation Medicine criteria for mTBI and persistent PCS and 12 cognitively normal community volunteers (53.0 ± 4.6 years of age) without history of head trauma underwent brain fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological assessments and completed PCS and psychiatric symptom rating scales. Compared to controls, Veterans with mTBI (with or without PTSD) exhibited decreased cerebral metabolic rate of glucose in the cerebellum, vermis, pons, and medial temporal lobe. They also exhibited subtle impairments in verbal fluency, cognitive processing speed, attention, and working memory, similar to those reported in the literature for patients with cerebellar lesions. These FDG-PET imaging findings suggest that regional brain hypometabolism may constitute a neurobiological substrate for chronic PCS in Iraq combat Veterans with repetitive blast-trauma mTBI. Given the potential public health implications of these findings, further investigation of brain function in these Veterans appears warranted.

Metabolic changes in concussed American football players during the acute and chronic post-injury phases.

BACKGROUND: Despite negative neuroimaging findings many athletes display neurophysiological alterations and post-concussion symptoms that may be attributable to neurometabolic alterations. METHODS: The present study investigated the effects of sports concussion on brain metabolism using 1H-MR Spectroscopy by comparing a group of 10 non-concussed athletes with a group of 10 concussed athletes of the same age (mean: 22.5 years) and education (mean: 16 years) within both the acute and chronic post-injury phases. All athletes were scanned 1-6 days post-concussion and again 6-months later in a 3T Siemens MRI. RESULTS: Concussed athletes demonstrated neurometabolic impairment in prefrontal and motor (M1) cortices in the acute phase where NAA:Cr levels remained depressed relative to controls. There was some recovery observed in the chronic phase where Glu:Cr levels returned to those of control athletes; however, there was a pathological increase of m-I:Cr levels in M1 that was only present in the chronic phase. CONCLUSIONS: These results confirm cortical neurometabolic changes in the acute post-concussion phase as well as recovery and continued metabolic abnormalities in the chronic phase. The results indicate that complex pathophysiological processes differ depending on the post-injury phase and the neurometabolite in question.

Growth hormone deficiency testing and treatment following mild traumatic brain injury.

Pituitary dysfunction, specifically growth hormone (GH) deficiency, can occur following traumatic brain injury. Our objective was to characterize the prevalence of GH deficiency (GHD) testing and response to recombinant human GH (rhGH) treatment in adults with persistent symptoms following mild traumatic brain injury (mTBI) referred for assessment of pituitary dysfunction. A retrospective chart review was conducted of patients seen at an outpatient brain injury clinic with a diagnosis of mTBI and persistent post-concussive symptoms who were referred to endocrinology. Clinical assessments of symptoms were collected. Investigations and results of GHD were collected, including initiation of rhGH treatment and treatment response. Of the 253 patients seen in both brain injury and endocrinology clinics, 97 with mTBI were referred for investigation of pituitary dysfunction and 73 (75%) had dynamic testing for assessment of GHD. Of the 26 individuals diagnosed with GHD, 23 (88%) started rhGH. GH therapy was inconsistently offered based on interpretation of GH dynamic testing results. Of those who started rhGH, 18 (78%) had a useful treatment response. This study suggests that clinical management of these patients is varied, highlighting a need for clear guidelines for the diagnosis and management of GHD following mTBI.

Cerebrovascular Responses to O2-CO2 Exchange Ratio under Brief Breath-Hold Challenge in Patients with Chronic Mild Traumatic Brain Injury.

Breath-by-breath oxygen-carbon dioxide (O2-CO2) exchange ratio (bER) is a respiratory gas exchange (RGE) metric, which is the ratio of the changes in the partial pressure of O2 (ΔPO2) to CO2 (ΔPCO2) between end-inspiration and end-expiration, has been demonstrated to characterize the cerebrovascular responses to breath-hold challenge in healthy individuals. We aimed to explore whether bER could characterize cerebrovascular responses in patients with chronic mild traumatic brain injury (mTBI) under breath-hold challenge. We also investigated the correlation between bER and the severity of post-concussion symptoms. Blood-oxygenation-level-dependent (BOLD) images were acquired using functional magnetic resonance imaging (fMRI) on 10 patients with chronic mTBI and 10 controls without brain injury history when performing a breath-hold task. Time series of RGE metrics of ΔPO2, ΔPCO2, and bER were computed, and their cross-correlation with regional change in BOLD (ΔBOLD) was calculated. Symptom burden was assessed using the Rivermead Post Concussion Questionnaire (RPQ), and its correlation with RGE changes was also measured. Compared with controls, a diffuse decrease in the correlation between regional ΔBOLD and bER was found in the brain of patients with mTBI (pfdr < 0.05). No significant difference was found between patients and controls for the correlation of regional ΔBOLD with ΔPO2 and ΔPCO2. Symptom severity indicated by RPQ scores increased with a decrease in the averaged changes of bER (ρ = 0.79, p = 0.01) and ΔPO2 (ρ = 0.70, p = 0.03) in breath-hold epochs. Our imaging and symptom severity findings suggest that bER can be used to characterize cerebrovascular responses to breath hold in patients with mTBI. The RGE may contribute to the post-concussive symptom severity.

Sleep Parameters and Overnight Urinary Melatonin Production in Children With Persistent Post-concussion Symptoms.

BACKGROUND: Sleep disturbance is common after a mild traumatic brain injury (mTBI) in children, yet its biology is poorly understood. We aimed to explore sleep-related problems (SRPs), sleep-activity patterns, and endogenous melatonin production in children with different recovery trajectories following mTBI. We hypothesized that children with delayed recovery would have more SRPs and abnormal sleep-activity patterns, which would correlate with lower overnight melatonin production. METHODS: In this prospective controlled cohort study, we enrolled 83 children with persistent symptoms, 26 children who had clinically recovered following mTBI, and 25 healthy controls. SRPs were evaluated using the sleep subscale of the Post-Concussion Symptom Inventory. Sleep actigraphy was performed for five to seven days at 37 (S.D. 7) days post-injury. Health-related quality of life and mood disturbance was assessed using the Child Health Questionnaire and the Behavior Assessment System for Children, respectively. Endogenous melatonin production was assessed using overnight urine collection. RESULTS: The groups were similar in age (13.9 [S.D. 2.6] years) and sex (52% female). Regression analysis demonstrated increased SRP in the symptomatic group (9.0; 95% confidence interval: 7.6, 11.1) compared with the recovered group (1.6; 95% confidence interval: 1.0, 2.4) and controls (2.0; 95% confidence intervals: 1.2, 3.2). Actigraphy parameters and urinary melatonin levels were not significantly different between groups. Neither SRPs nor actigraphy parameters correlated with anxiety and depression scores. CONCLUSIONS: Although children with persistent post-concussion symptoms reported more SRPs, this was not related to actigraphy sleep parameters or melatonin production. Further research is warranted to understand the pathophysiology of post-traumatic sleep disturbance.

Tau Biology, Tauopathy, Traumatic Brain Injury, and Diagnostic Challenges.

There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau's binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the "tau prion". Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.

Cerebral Glucose Metabolism in Patients with Chronic Mental and Cognitive Sequelae after a Single Blunt Mild Traumatic Brain Injury without Visible Brain Lesions.

The aim of this study is to investigate glucose uptake on 18F-fluorodeoxyglucose positron emission tomography positron emission tomography (FDG-PET) in patients with chronic mental and cognitive symptoms following a single blunt mild traumatic brain injury (TBI) and without visible brain lesions on computed tomography (CT)/magnetic resonance imaging (MRI). Eighty-nine consecutive patients (mean age 43.8 ± 10.75 years) who had a single blunt mild TBI from a traffic accident and suffering from chronic mental and cognitive symptoms without visible brain lesions on CT/MRI were enrolled in the study. Patients underwent FDG-PET imaging, and the mean interval between the TBI and FDG-PET was 50.0 months. The Wechsler Adult Intelligence Scale version III (WAIS-III) testing was performed within 1 month of the FDG-PET. A control group consisting of 93 healthy adult volunteers (mean age 42.2 ± 14.3 years) also underwent FDG-PET. The glucose uptake pattern from FDG-PET in the patient group was compared with that from normal controls using statistical parametric mapping. Glucose uptake was significantly decreased in the bilateral prefrontal area and significantly increased around the limbic system in the patient group compared with normal controls. This topographical pattern of glucose uptake is different from that reported previously in patients with diffuse axonal injury (DAI), but may be similar to that seen in patients with major depression disorder. These results suggest that the pathological mechanism causing chronic mental and cognitive symptoms in patients with a single blunt mild TBI and without visible brain lesions might be different from that due to primary axonopathy in patients with DAI.

Regulatory and autoregulatory physiological dysfunction as a primary characteristic of post concussion syndrome: implications for treatment.

Although most patients with concussion recover within days to weeks, a small but significant minority develop persistent signs and symptoms of post-concussion syndrome (PCS). The standard treatments of PCS, rest and cognitive adaptation, have limited effectiveness. PCS patients are advised not to exercise because of the concern for symptom exacerbation. Prolonged rest, however, leads to deconditioning (especially in athletes) and may cause secondary effects including depressive symptoms. Concussion is associated with metabolic and physiological changes in the brain and in other organ systems (for example, autonomic function of the heart and altered cerebral autoregulation, sleep, and circadian rhythms). We propose that PCS results from ongoing central and systemic physiologic regulatory dysfunction after traumatic brain injury (TBI) and we further propose that this physiologic dysfunction may be reduced or alleviated by individualized controlled sub-symptom threshold aerobic exercise rehabilitation.

Serum biochemical markers for post-concussion syndrome in patients with mild traumatic brain injury.

Mild traumatic brain injury (MTBI) is a major public health problem in the United States. A significant subset of MTBI patients develop persistent and distressing neurological, cognitive, and behavioral symptoms, known as the post-concussion syndrome (PCS). To date, multiple studies have assessed the relationship between brain-related proteins found in the serum at the time of injury, and the development of PCS. We conducted a systematic review of prospective cohort studies that assessed the ability of serum biochemical markers to predict PCS after MTBI. A total of 11 studies assessing three different potential biochemical markers of PCS--S100 proteins, neuron-specific enolase (NSE), and cleaved Tau protein (CTP)--met selection criteria. Of these markers, S100 appeared to be the best researched. We conclude that no biomarker has consistently demonstrated the ability to predict PCS after MTBI. A combination of clinical factors in conjunction with biochemical markers may be necessary to develop a comprehensive decision rule that more accurately predicts PCS after MTBI.

Brain magnetic resonance imaging CO2 stress testing in adolescent postconcussion syndrome.

OBJECT A neuroimaging assessment tool to visualize global and regional impairments in cerebral blood flow (CBF) and cerebrovascular responsiveness in individual patients with concussion remains elusive. Here the authors summarize the safety, feasibility, and results of brain CO2 stress testing in adolescents with postconcussion syndrome (PCS) and healthy controls. METHODS This study was approved by the Biomedical Research Ethics Board at the University of Manitoba. Fifteen adolescents with PCS and 17 healthy control subjects underwent anatomical MRI, pseudo-continuous arterial spin labeling MRI, and brain stress testing using controlled CO2 challenge and blood oxygen level-dependent (BOLD) MRI. Post hoc processing was performed using statistical parametric mapping to determine voxel-by-voxel regional resting CBF and cerebrovascular responsiveness of the brain to the CO2 stimulus (increase in BOLD signal) or the inverse (decrease in BOLD signal). Receiver operating characteristic (ROC) curves were generated to compare voxel counts categorized by control (0) or PCS (1). RESULTS Studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study participants. No differences in CO2 stimuli were seen between the 2 participant groups. No group differences in global mean CBF were detected between PCS patients and healthy controls. Patient-specific differences in mean regional CBF and CO2 BOLD responsiveness were observed in all PCS patients. The ROC curve analysis for brain regions manifesting a voxel response greater than and less than the control atlas (that is, abnormal voxel counts) produced an area under the curve of 0.87 (p < 0.0001) and 0.80 (p = 0.0003), respectively, consistent with a clinically useful predictive model. CONCLUSIONS Adolescent PCS is associated with patient-specific abnormalities in regional mean CBF and BOLD cerebrovascular responsiveness that occur in the setting of normal global resting CBF. Future prospective studies are warranted to examine the utility of brain MRI CO2 stress testing in the longitudinal assessment of acute sports-related concussion and PCS.

Preliminary evidence of reduced brain network activation in patients with post-traumatic migraine following concussion.

Post-traumatic migraine (PTM) (i.e., headache, nausea, light and/or noise sensitivity) is an emerging risk factor for prolonged recovery following concussion. Concussions and migraine share similar pathophysiology characterized by specific ionic imbalances in the brain. Given these similarities, patients with PTM following concussion may exhibit distinct electrophysiological patterns, although researchers have yet to examine the electrophysiological brain activation in patients with PTM following concussion. A novel approach that may help differentiate brain activation in patients with and without PTM is brain network activation (BNA) analysis. BNA involves an algorithmic analysis applied to multichannel EEG-ERP data that provides a network map of cortical activity and quantitative data during specific tasks. A prospective, repeated measures design was used to evaluate BNA (during Go/NoGo task), EEG-ERP, cognitive performance, and concussion related symptoms at 1, 2, 3, and 4 weeks post-injury intervals among athletes with a medically diagnosed concussion with PTM (n = 15) and without (NO-PTM) (n = 22); and age, sex, and concussion history matched controls without concussion (CONTROL) (n = 20). Participants with PTM had significantly reduced BNA compared to NO-PTM and CONTROLS for Go and NoGo components at 3 weeks and for NoGo component at 4 weeks post-injury. The PTM group also demonstrated a more prominent deviation of network activity compared to the other two groups over a longer period of time. The composite BNA algorithm may be a more sensitive measure of electrophysiological change in the brain that can augment established cognitive assessment tools for detecting impairment in individuals with PTM.

Fluid biomarkers for mild traumatic brain injury and related conditions.

Diagnostic and prognostic biomarkers for mild traumatic brain injury (TBI), also known as concussion, remain a major unmet clinical need. Moderate to severe TBI can be diagnosed definitively by clinical assessment and standard neuroimaging techniques that detect the gross damage to the brain parenchyma. Diagnostic tools for mild TBI are lacking and, currently, the diagnosis has to be made on clinical grounds alone, because most patients show no gross pathological changes on CT. Most patients with mild TBI recover quickly, but about 15% develop an ill-defined condition called postconcussive syndrome (PCS). Repeated concussions have been associated with a chronic neurodegenerative disorder called chronic traumatic encephalopathy (CTE), which can only currently be diagnosed post mortem. Fluid biomarkers are needed to better define and detect mild TBI and related conditions. Here, we review the literature on fluid biomarkers for neuronal, axonal, oligodendrocytic, astroglial and blood-brain barrier injury, as well as markers for neuroinflammation and metabolic dysregulation, in the context of mild TBI, PCS and CTE. We also discuss technical and standardization issues and potential pathways to advance the most promising biomarker candidates into clinical laboratory practice.

Functional near-infrared spectroscopy reveals reduced interhemispheric cortical communication after pediatric concussion.

Concussion, or mild traumatic brain injury (mTBI), is a growing concern, especially among the pediatric population. By age 25, as many as 30% of the population are likely to have had a concussion. Many result in long-term disability, with some evolving to postconcussion syndrome. Treatments are being developed, but are difficult to assess given the lack of measures to quantitatively monitor concussion. There is no accepted quantitative imaging metric for monitoring concussion. We hypothesized that because cognitive function and fiber tracks are often impacted in concussion, interhemispheric brain communication may be impaired. We used functional near-infrared spectroscopy (fNIRS) to quantify functional coherence between the left and right motor cortex as a marker of interhemispheric communication. Studies were undertaken during the resting state and with a finger-tapping task to activate the motor cortex. Pediatric patients (ages 12-18) had symptoms for 31-473 days, compared to controls, who have not had reported a previous concussion. We detected differences between patients and controls in coherence between the contralateral motor cortices using measurements of total hemoglobin and oxy-hemoglobin with a p<0.01 (n=8, control; n=12 mTBI). Given the critical need for a quantitative biomarker for recovery after a concussion, we present these data to highlight the potential of fNIRS coupled with interhemispheric coherence analysis as a biomarker of concussion injury.

Clinical relevance of optimizing vitamin D status in soldiers to enhance physical and cognitive performance.

Vitamin D deficiency initiates a loss of combat effectiveness by impairing physical and cognitive functioning of combat Operators. Synthesized in response to sunlight and consumed in the diet, vitamin D functions as a hormone and regulates gene expression for nearly 300 genes throughout the human body. These target genes are involved processes essential to combat operations, such as immune function, response to stress, inflammation, and regulation of calcium movement. Since widespread vitamin D deficiency is observed across the U.S. population, poor vitamin D status is expected in Servicemembers. Physical conditions linked to vitamin D deficiency include increased risk for muscle or bone injury, muscle weakness, and reduced neuromuscular function. Hormonally, vitamin D levels have been positively correlated with testosterone levels. Vitamin D deficiency is also associated with cognitive decline, depression, and may prolong recovery following mild traumatic brain injury (mTBI). Since vitamin D deficiency elevates systemic inflammation, poor vitamin D status at the time of brain injury may prolong the inflammatory response and exacerbate postconcussive symptoms. Furthermore, veterans with mTBI experience chronic endocrine dysfunction. While vitamin D status has not been assessed post-mTBI, it is plausible that vitamin D levels are altered along with testosterone and growth hormone, raising the question of whether vitamin D deficiency results from trauma-related hormonal abnormalities or whether vitamin D deficiency increases the risk for endocrine dysfunction. Through its association with testosterone production, vitamin D deficiency may increase the risk for posttraumatic stress disorder (PTSD) since testosterone levels are altered in veterans with PTSD. Therefore, vitamin D status has a significant impact on Operator health and performance. Supplementing vita-min D to deficient Operators provides a noninvasive and low-cost intervention to maintain combat force.

Longitudinal and prognostic evaluation of mild traumatic brain injury: A 1H-magnetic resonance spectroscopy study.

In the majority of patients with mild traumatic brain injury (mTBI), brain tissue impairment is undetectable by computed tomography and/or structural magnetic resonance imaging. Even in confirmed cases of head injury, conventional neuroimaging methods lack sensitivity in predicting neuropsychological outcomes of patients. The objectives of this study were to (1) cross-sectionally determine deviations in the neurometabolic profile of patients with mTBI from healthy controls at different stages of mTBI using tightly controlled examination windows, and (2) determine associations between acute neurometabolic markers of mTBI and chronic neurocognitive performance. Patients were examined at the early subacute (n=43; 5.44 ± 3.15 days post-injury (DPI)), late subacute (n=33; 37.00 ± 12.26 DPI) and chronic (n=27; 195.30 ± 19.60 DPI) stages of mTBI. Twenty-one neurologically intact subjects were used as controls. Proton magnetic resonance spectroscopy imaging ((1)H-MRSI) was used to obtain metabolic measurements from different brain regions. The Automated Neuropsychological Assessment Metrics (ANAM) was used for cognitive evaluation of patients at the chronic stage of mTBI. Measurements in the thalamus and centrum semiovale (CSV) emerged as the most indicative of injury and were used to predict neurocognitive outcome. The major findings of this study are (1) decreases in Cho/Cre (choline-to-creatine ratio) measured in the thalamus (p=0.042) and CSV (p=0.017) at the late subacute stage of mTBI; (2) positive associations of early subacute Cre measurements in the CSV with chronic ANAM scores measuring performance in delayed (r=0.497, p=0.019) and immediate (r=0.391, p=0.072) code substitution. These findings show that metabolic measurements in the thalamus and CSV can potentially serve as diagnostic and prognostic markers of mTBI.