Previous research has demonstrated that sport-related concussions can have short-term effects on cognitive processes, but the long-term consequences are less understood and warrant more research. This study was the first to utilize event-related functional magnetic resonance imaging (fMRI) to examine long-term differences in neural activity during memory tasks in former athletes who have sustained multiple sport-related concussions. In an event-related fMRI study, former football players reporting multiple sport-related concussions (i.e., three or more) were compared to players who reported fewer than three concussions during a memory paradigm examining item memory (i.e., memory for the particular elements of an event) and relational memory (i.e., memory for the relationships between elements). Behaviorally, we observed that concussion history did not significantly affect behavioral performance, as individuals in the low and high concussion groups had equivalent performance on both memory tasks, and additionally, that concussion history was not associated with any behavioral memory measures. Despite demonstrating equivalent behavioral performance, the two groups of former players demonstrated different neural recruitment patterns during relational memory retrieval, suggesting that multiple concussions may be associated with functional inefficiencies in the relational memory network. In addition, the number of prior concussions significantly correlated with functional activity in a number of brain regions, including the medial temporal lobe and inferior parietal lobe. Our results provide important insights in understanding the long-term functional consequences of sustaining multiple sports-related concussions. Keywords: MRI, cognitive function, head trauma.

Traumatic brain injury (TBI) is a significant public health problem in the U.S. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed.¹ Recently, sex steroid hormones have sparked interest as possible neuroprotective agents following traumatic injury. One of these is 17β-estradiol (E2), the most abundant and potent endogenous vertebrate estrogen. The goal of our study was to investigate the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 when administered in an intravenous bolus dose one hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. The results of this study show that, when assessed at 24 hours post-injury, E2 or G-1 confers protection in adult male rats subjected to LFP brain injury. Specifically, we found that an acute bolus dose of E2 or G-1 administered intravenously one hour post-TBI significantly increases neuronal survival in the ipsilateral CA 2/3 region of the hippocampus and decreases neuronal degeneration and apoptotic cell death in both the ipsilateral cortex and CA 2/3 region of the hippocampus. We also report a significant reduction in astrogliosis in the ipsilateral cortex, hilus, and CA 2/3 region of the hippocampus. Finally, these effects were observed to be chiefly dose-dependent for E2, with the 5mg/kg dose generating a more robust level of protection. Our findings further elucidate estrogenic compounds as a clinically-relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER.

Multiple cellular, molecular, and biochemical changes contribute to the etiology and treatment outcome of contusion spinal cord injury (SCI). Dysregulation of miRNAs has been found following spinal cord injury (SCI) in recent studies. However, little is known about the functional significance of the unique role of miRNAs in SCI. We analyzed the miRNA expression patterns 1 and 3 days following rat spinal cord injury using miRNA microarray. Microarray data revealed that 9 miRNAs were upregulated and 5 miRNAs were downregulated 1 day post-injury, and 3 miRNAs were upregulated and 5 miRNAs were downregulated 3 days post-injury, in the sites of contused when compared to sham rat spinal cords. Because miR-21 was one of the miRNAs being most significantly upregulated, we investigated its function. In the miR-21 knockdown animals by antagomir-21, attenuated recovery in hindlimb motor function, increased lesion size and decreased tissue sparing were found in vivo. Compared with a negative control group, treatment with antagomir-21 significantly increased apoptosis following SCI. Pro-apoptosis genes FasL, PTEN and PDCD4 were proved to be direct targets of miR-21 in many diseases and cell types. In vivo treatment with antagomir-21 increased the expression of FasL and PTEN, but did not affect PDCD4. These results suggested that miR-21 played an important role in limiting secondary cell death following SCI, and that the protective effects of miR-21 might have been due to its regulation on pro-apoptotic genes. Thus, miR-21 may play an important role in the pathophysiology of SCI.

Letter to the editor.

The objective of the current research was to examine the current epidemiology of traumatic brain injury (TBI); to determine the effects of geographic region, co-morbidities, year of injury, injury severity and demographics on hospital costs, length of stay (LOS), and mortality. All subjects were drawn from the Thomas Reuters Marketscan database. Statistical methods used included descriptive analysis, bivariate analysis, logistic regression, and the Geographic Information System (GIS) software, ArcMap. We studied 76,313 TBI patients from 2004 to 2009 (52,721 with commercial insurance and 23,592 with Medicare) from the Marketscan database. As age increased, mortality rate and median LOS increased. The median hospital costs for adults were the highest ($13,000 for age 18-64) compared to children ($8,000 for age 0-14) and elderly people ($9,000 for age≥65). The mortality rate for the elderly population has decreased slightly (11.1% in 2004 to 9.9% in 2009 for male; and 7.0% to 6.9% for female), however their hospital costs have increased significantly ($6,899 in 2004 to $11,567 in 2009 for males; $6,784 to $9,782 for females). Concerning the impact of geography, the western United States (e.g., Washington and California) had lower mortality rates and higher median costs while the south-east US had the highest mortality and mixed median costs. Both overall mortality and median LOS have remained relatively stable over the years. However, hospital cost has increased for the elderly population even after accounting for the inflation. There is significant geographic variation for both mortality and hospital costs. Keywords: traumatic brain injury, mortality rate, length of stay, hospital cost.

Bradykinin (BK) was shown to stimulate the production of physiologically active metabolites, blood-brain-barrier disruption and brain edema. Purpose of this prospective study was to measure BK concentrations in blood and cerebrospinal fluid (CSF) of patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) and ischemic stroke and to correlate BK levels with the extent of cerebral edema and intracranial pressure (ICP). Blood and CSF samples of 29 patients suffering from acute cerebral lesions (TBI: 7, SAH: 10, ICH: 8, ischemic stroke: 4) were collected for up to 8 days after the insult. 7 patients with lumbar drainage were used as controls. Edema (5-point scale), ICP, and the GCS (Glasgow Coma Score) at the time of sample withdrawal were correlated with BK concentrations. While all plasma-BK samples were not significantly elevated, CSF-BK levels of all patients were significantly elevated in overall (n=73) and in early (≤72h) measurements (n=55) (4.3±6.9 fmol/ml and 5.6±8.9 fmol/ml) compared to 1.2±0.7 fmol/ml of the controls (p=0.05 and p=0.006). Within 72h after ictus patients suffering from TBI (p=0.01), ICH (p=0.001) and ischemic stroke (p=0.02) showed significant increases. CSF-BK concentrations correlated with the extent of edema formation (r=0.53, p<0.001) and with ICP (r=0.49, p<0.001). Our results demonstrate that acute cerebral lesions are associated with increased CSF-BK levels. Especially after TBI, subarachnoid and intracerebral hemorrhage CSF-BK levels correlate with the extent of edema evolution and ICP. Bradykinin-blocking agents may turn out to be effective remedies in brain injuries.

Cellular transplantation using neural stem cells and progenitors is a promising therapeutic strategy that has the potential to replace lost cells, modulate the injury environment, and create a permissive environment for the regeneration of injured host axons. We have focused our studies on the use of human glial restricted progenitors (hGRP) and derived astrocytes. Here we examined the morphological and phenotypic properties of hGRP prepared from the fetal CNS by clinically approved protocols, in comparison to astrocytes derived from hGRP prepared by treatment with ciliary neurotrophic factor (CNTF) or bone morphogenetic protein 4 (BMP-4). These differentiation protocols generated astrocytes that showed morphological differences and could be classified along an immature to mature spectrum, respectively. Despite these differences, the cells retained morphological and phenotypic plasticity upon a challenge with an alternate differentiation protocol. Importantly, when hGRP and derived astrocytes were transplanted acutely into a cervical dorsal column lesion, they survived and promoted regeneration of long ascending host sensory axons into the graft/lesion site, with no differences among the groups. Furthermore, hGRP taken directly from frozen stocks behaved similarly and also supported regeneration of host axons into the lesion. Our results underscore the dynamic and permissive properties of human fetal astrocytes to promote axonal regeneration. They also suggest that a time-consuming process of pre-differentiation may not be necessary for therapeutic efficacy, and that the banking of large quantities of readily available hGRP can be an appropriate source of permissive cells for transplantation.

Deficits in working memory are a common consequence of pediatric traumatic brain injury (TBI), and are believed to contribute to difficulties in a range of cognitive and academic domains. Reduced integrity of the corpus callosum (CC) following TBI may disrupt connectivity between bilateral frontoparietal neural networks underlying working memory. In the present investigation, diffusion tensor imaging (DTI) tractography of eight callosal subregions (CC1-CC8) was examined in relation to measures of verbal and visuospatial working memory in 74 children sustaining TBI and 49 typically developing (TD) comparison children. Relative to the comparison group, children with TBI demonstrated poorer visuospatial working memory, but comparable verbal working memory. Microstructure of the CC was significantly compromised in brain-injured children, with lower FA and higher axial and radial diffusivity metrics in all callosal subregions. In both groups of children, lower FA and/or higher radial diffusivity in callosal subregions connecting anterior and posterior parietal cortical regions predicted poorer verbal working memory; higher radial diffusivity in callosal subregions connecting anterior and posterior parietal, as well as temporal, cortical regions predicted poorer visuospatial working memory. DTI metrics, especially radial diffusivity, in predictive callosal subregions accounted for significant variance in working memory over and above remaining callosal subregions. Reduced microstructural integrity of the CC, particularly in subregions connecting parietal and temporal cortices, may act as a neuropathological mechanism contributing to long-term working memory deficits. The future clinical use of neuroanatomical biomarkers may allow for the early identification of children at highest risk for working memory deficits and earlier provision of interventions for these children.