Early Life Stress Exacerbates Outcome after Traumatic Brain Injury.

The neurocognitive impairments associated with mild traumatic brain injury (TBI) often resolve within 1-2 weeks; however, a subset of people exhibit persistent cognitive dysfunction for weeks to months after injury. The factors that contribute to these persistent deficits are unknown. One potential risk factor for worsened outcome after TBI is a history of stress experienced by a person early in life. Early life stress (ELS) includes maltreatment such as neglect, and interferes with the normal construction of cortical and hippocampal circuits. We hypothesized that a history of ELS contributes to persistent learning and memory dysfunction following a TBI. To explore this interaction, we modeled ELS by separating Sprague Dawley pups from their nursing mothers from post-natal days 2-14 for 3 h daily. At 2 months of age, male rats received sham surgery or mild to moderate parasagittal fluid-percussion brain injury. We found that the combination of ELS with TBI in adulthood impaired hippocampal-dependent learning, as assessed with contextual fear conditioning, the water maze task, and spatial working memory. Cortical atrophy was significantly exacerbated in TBI animals exposed to ELS compared with normal-reared TBI animals. Changes in corticosterone in response to restraint stress were prolonged in TBI animals that received ELS compared with TBI animals that were normally reared or sham animals that received ELS. Our findings indicate that ELS is a risk factor for worsened outcome after TBI, and results in persistent learning and memory deficits, worsened cortical pathology, and an exacerbation of the hormonal stress response.

T-cell infiltration into the perilesional cortex is long-lasting and associates with poor somatomotor recovery after experimental traumatic brain injury.

BACKGROUND: T-lymphocyte (T-cell) invasion into the brain parenchyma is a major consequence of traumatic brain injury (TBI). However, the role of T-cells in the post-TBI functional outcome and secondary inflammatory processes is unknown. We explored the dynamics of T-cell infiltration into the cortex after TBI to establish whether the infiltration relates to post-injury functional impairment/recovery and progression of the secondary injury. METHOD: TBI was induced in rats by lateral fluid-percussion injury, and the acute functional impairment was assessed using the neuroscore. Animals were killed between 1-90 d post-TBI for immunohistochemical analysis of T-cell infiltration (CD3), chronic macrophage/microglial reaction (CD68), blood-brain barrier (BBB) dysfunction (IgG), and endophenotype of the cortical injury. Furthermore, the occurrence of spontaneous seizures and spike-and-wave discharges were assessed using video-electroencephalography. RESULTS: The number of T-cells peaked at 2-d post-TBI, and then dramatically decreased by 7-d post-TBI (5% of 2-d value). Unexpectedly, chronic T-cell infiltration at 1 or 3 months post-TBI did not correlate with the severity of chronic inflammation (p > 0.05) or BBB dysfunction (p > 0.05). Multiple regression analysis indicated that inflammation and BBB dysfunction is associated with 48% of the perilesional T-cell infiltration even at the chronic time-point (r = 0.695, F = 6.54, p < 0.05). The magnitude of T-cell infiltration did not predict the pathologic endophenotype of cortical injury, but the higher the number of T-cells in the cortex, the poorer the recovery index based on the neuroscore (r = - 0.538, p < 0.05). T-cell infiltration was not associated with the number or duration of age-related spike-and-wave discharges (SWD). Nevertheless, the higher the number of SWD, the poorer the recovery index (r = - 0.767, p < 0.5). CONCLUSIONS: These findings suggest that acute infiltration of T-cells into the brain parenchyma after TBI is a contributing factor to poor post-injury recovery.

Is temperature an important variable in recovery after mild traumatic brain injury?

With nearly 42 million mild traumatic brain injuries (mTBIs) occurring worldwide every year, understanding the factors that may adversely influence recovery after mTBI is important for developing guidelines in mTBI management. Extensive clinical evidence exists documenting the detrimental effects of elevated temperature levels on recovery after moderate to severe TBI. However, whether elevated temperature alters recovery after mTBI or concussion is an active area of investigation. Individuals engaged in exercise and competitive sports regularly experience body and brain temperature increases to hyperthermic levels and these temperature increases are prolonged in hot and humid ambient environments. Thus, there is a strong potential for hyperthermia to alter recovery after mTBI in a subset of individuals at risk for mTBI. Preclinical mTBI studies have found that elevating brain temperature to 39°C before mTBI significantly increases neuronal death within the cortex and hippocampus and also worsens cognitive deficits. This review summarizes the pathology and behavioral problems of mTBI that are exacerbated by hyperthermia and discusses whether hyperthermia is a variable that should be considered after concussion and mTBI. Finally, underlying pathophysiological mechanisms responsible for hyperthermia-induced altered responses to mTBI and potential gender considerations are discussed.

Resuscitation with Pooled and Pathogen-Reduced Plasma Attenuates the Increase in Brain Water Content following Traumatic Brain Injury and Hemorrhagic Shock in Rats.

Traumatic brain injury and hemorrhagic shock is associated with blood-brain barrier (BBB) breakdown and edema formation. Recent animal studies have shown that fresh frozen plasma (FFP) resuscitation reduces brain swelling and improves endothelial function compared to isotonic NaCl (NS). The aim of this study was to investigate whether pooled and pathogen-reduced plasma (OctaplasLG® [OCTA]; Octapharma, Stockholm, Sweden) was comparable to FFP with regard to effects on brain water content, BBB permeability, and plasma biomarkers of endothelial glycocalyx shedding and cell damage. After fluid percussion brain injury, hemorrhage (20 mL/kg), and 90-min shock, 48 male Sprague-Dawley rats were randomized to resuscitation with OCTA, FFP, or NS (n = 16/group). Brain water content (wet/dry weight) and BBB permeability (transfer constant for 51Cr-EDTA) were measured at 24 h. Plasma osmolality, oncotic pressure, and biomarkers of systemic glycocalyx shedding (syndecan-1) and cell damage (histone-complexed DNA) were measured at 0 and 23 h. At 24 h, brain water content was 80.44 ± 0.39%, 80.82 ± 0.82%, and 81.15 ± 0.86% in the OCTA, FFP, and NS groups (lower in OCTA vs. NS; p = 0.026), with no difference in BBB permeability. Plasma osmolality and oncotic pressures were highest in FFP and OCTA resuscitated, and osmolality was further highest in OCTA versus FFP (p = 0.027). In addition, syndecan-1 was highest in FFP and OCTA resuscitated (p = 0.010). These results suggest that pooled solvent-detergent (SD)-treated plasma attenuates the post-traumatic increase in brain water content, and that this effect may, in part, be explained by a high crystalloid and colloid osmotic pressure in SD-treated plasma.

Level of bFGF and its receptor FGFR1 mRNA in rat brain following injury caused by moderate lateral fluid percussion / 中国法医学杂志

Objective Study on the pattern of changes of bFGF and FGFRl mRNA occurred in the experimental brain injury model in order to provide scientific basis for the diagnosis, forensic identification and clinical treatment, and also for further ascertaining the molecular mechanism of brain injury. Methods Male Sprague-Dawley rats were divided into 3 groups: normal control, sham operation, and injury groups. The rats of injury groups were subjected to moderate lateral fluid percussion brain injury (0.2MPa). The injury groups was then subdivided into 30min, 1h, 3h, 6h, 12h, 1d, 3d and 7d groups according to the time elapsed after injury. In situ hybridization (ISH) and RT-PCR were used for studying the mRNA expression of both bFGF and FGFRl factors. Results (1) In the brain of normal control and sham operation control groups, mRNA levels of bFGF and FGFRl were low; (2) There is gradual increase of bFGF and FGFRl mRNA levels could be observed 6h to 3d after injury both in cortex and brain stem, then partly declined at 7d; (3) In hippocampus, the gradual increase occurred during 3h- 1d after injury, then partly declined at 3d, and returned to basal level at 7d. Conclusions The results suggested that brain injury induced the gene expressions of bFGF and FGFR1. The bFGF may contribute to maintenance of nerve cell survival and the repair of damaged neural tissues after CNS injury and the patterns of their level change were quite regular. It is potentially useful for timing of injury in forensic medical practice.

The expression of TGF-?1 and type I receptor following moderate lateral fluid percussion brain injury in rats / 中国法医学杂志

Objective Study on the pattern of changes of TGF-?1 and type I receptor occurred in the experimental fluid percussion brain injury model for the purpose of providing the scientific basis for molecular pathological diagnosis, forensic identification, clinical treatment as well as further ascertaining the molecular mechanism of brain injury. Methods Male Sprague-Dawley rats were divided into normal control, sham operation control and injury groups. The rats of injury groups were subjected to moderate lateral fluid percussion brain injury (0.2 MPa). The injury groups were then subdivided into 30min, 1h, 3h, 6h, 12h,1d, 3d and 7d sub-groups according to the time elapsed after injury. Immunohistochemistry SP method was used for studing the immunoreactivity of both TGF-?1 and T?R I factors. Results (1) In the brain of normal control and sham operation control groups, the low expression levels of TGF-?1 and T?R I were observed; (2) The gradual increase of TGF-?1 and T?R I immunoreactivity could be observed 1 to 3d after injury both in cortex and brain stem, and sustained at the high level up to 7d; (3) In hippocampus, the gradual increase occur during 12h to Id after brain injury, and sustained the high level at 3d, then declined at 7d. Conclusion The results suggested that brain injury induced the gene eypressions of the TGF-?1/ T?R I . The TGF-?1/ T?R I may contribute to maintance of nerve cell survival and the repair of damaged neural tissues after CNS injury and the patterns of their level change were quite regular and can be used for timing of injury in forensic medicine aspect.