Neurotrauma reports最新文献

Traumatic brain injury (TBI) in children often leads to poor developmental outcomes attributable to progressive cell loss caused by secondary injuries, including endoplasmic reticulum (ER) stress. Buprenorphine (BPN) is commonly used in children for pain management; however, the effects of BPN on ER stress in the pediatric population are still inconclusive. This study investigated the sex-specific effects of BPN on ER stress, abnormal protein accumulation, and cell loss in a mouse impact acceleration model of pediatric TBI. On post-natal day 20-21 (P20-21), male and female littermates were randomized into sham, TBI + saline and TBI + BPN groups. BPN (0.075 mg/kg) was administered to TBI + BPN mice at 30 min after injury and then every 6-12 h for 2 days. The impact of BPN was evaluated at 1, 3, and 7 days post-injury. We found that TBI induced more prominent ER stress pathway activation at 1 and 3 days post-injury in males, compared to females, whereas abnormal protein accumulation and cell loss were more severe in females at 7 days post-injury, compared with males. Although BPN partially ameliorated abnormal protein accumulation and cell loss in both males and females, BPN only decreased ER stress pathway activation in males, not in females. In conclusion, BPN exhibits sex-specific effects on ER stress, abnormal protein accumulation, and cell loss in a time-dependent manner at the acute phase after pediatric TBI, which provides the rationale to assess the potential effects of BPN on long-term outcomes after pediatric TBI in both males and females.

Traumatic brain injury (TBI) is a major cause of death and disability among the American population, but the impact TBIs have on the school experience of high school, and post-secondary students, is poorly understood. In this study, a cohort of 79 students, ages 15-22, with mild-to-severe TBIs, were retrospectively identified from the University of Washington Traumatic Brain Injury Database and Sample Repository. The Sickness Impact Profile (SIP) was used to determine the frequency at which schooling was impacted by a TBI and identify the most common self-reported issues students faced in their return to school. At 1 month post-injury, 70% of students either had not returned to school as a result of their TBI or had returned to school but experienced issues related to their TBI. The most-reported issues at 1 month were a difficulty keeping up with school work as a result of it taking longer to complete assignments, tiring easily, having to take frequent rests, and grades that were not as good as they used to be. At 1 year post-injury, the number of students whose TBIs were affecting their school situation dropped 20 percentage points to 49%. The most reported issues at 1 year were forgetting more quickly what was learned in class and having more difficulty understanding new concepts and material. These findings indicate that TBIs have a profound effect on a student's school experiences up to at least 1 year post-injury.

Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ∼14% of the population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic spinal cord injury (SCI) and spinal cord diseases such as cervical myelopathy. To date, there is no intervention to promote recovery of function after SCI/spinal cord diseases that is specifically targeted at ApoE4-associated impairment. Studies in the human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that degrades phosphoinositol 4,5-bisphosphate (PIP₂) into inositol 4-monophosphate. Synj1 regulates rearrangements of the cytoskeleton as well as endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 messenger RNA and protein were elevated in spinal cords of healthy ApoE4 mice associated with lower PIP₂ levels. Using a moderate-severity model of contusion SCI in mice, we found that genetic reduction of synj1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recovery of ApoE3 mice after SCI. Bulk RNA sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice, up to 14 days post-injury, through mechanisms that may involve the function of excitatory glutaminergic neurons.

This study aimed to investigate the impact of traumatic subarachnoid hemorrhage (tSAH) on cardiac autonomic control system (CACS) function in children after severe traumatic brain injury (TBI) during the subacute rehabilitation period. Thirty-three participants, 8-18 years of age, 42 (14-149) days after severe TBI at the beginning of the subacute rehabilitation, were included in the study. Six participants were diagnosed with tSAH during acute medical care (tSAH group). Heart rate variability (HRV) was assessed by the standard deviation of the N-N interval (SDNN) and the square root of the mean square differences of successive R-R interval (RMSSD) using a Polar RS800CX device while sitting at rest for 5 min. A second assessment was performed 8 weeks later. No significant difference between the tSAH and non-tSAH groups were found in the demographic and functional characteristics or injury severity. However, in comparison to the non-tSAH group, the tSAH group had lower SDNN (23.9 [10.5-47.3] vs. 43.9 [21.8-118.8], respectively; p = 0.005) and RMSSD values (11.8 [5.9-24.5] vs. 29.6 [8.9-71.7], respectively; p = 0.004). Neither group demonstrated changes in HRV values at rest in the second assessment, whereas the significant difference in SDNN (p = 0.035) and RMSSD (p = 0.008) remained. Children diagnosed with SAH after severe TBI presented poorer CACS function during the subacute rehabilitation. Given that reduced HRV values may be a marker for potential heart disease, the medical team should be aware of the influence of existing tSAH. Future studies with larger sample sizes and longer follow-up periods are warranted to further investigate this topic. ClinicalTrials.gov number: NCT03215082.

Myelin loss and oligodendrocyte death are well documented in patients with traumatic brain injury (TBI), as well as in experimental animal models after moderate-to-severe TBI. In comparison, mild TBI (mTBI) does not necessarily result in myelin loss or oligodendrocyte death, but causes structural alterations in the myelin. To gain more insight into the impact of mTBI on oligodendrocyte lineage in the adult brain, we subjected mice to mild lateral fluid percussion injury (mFPI) and characterized the early impact (1 and 3 days post-injury) on oligodendrocytes in the corpus callosum using multiple oligodendrocyte lineage markers (platelet-derived growth factor receptor [PDGFR]-α, glutathione S-transferase [GST]-π, CC1, breast carcinoma-amplified sequence 1 [BCAS1], myelin basic protein [MBP], myelin-associated glycoprotein [MAG], proteolipid protein [PLP], and FluoroMyelin™). Two regions of the corpus callosum in relation to the impact site were analyzed: areas near (focal) and anterior (distal) to the impact site. mFPI did not result in oligodendrocyte death in either the focal or distal corpus callosum, nor impact on oligodendrocyte precursors (PDGFR-α⁺) and GST-π⁺ oligodendrocyte numbers. In the focal but not distal corpus callosum, mFPI caused a decrease in CC1⁺ as well as BCAS1⁺ actively myelinating oligodendrocytes and reduced FluoroMyelin intensity without altering myelin protein expression (MBP, PLP, and MAG). Disruption in node-paranode organization and loss of Nav1.6⁺ nodes were observed in both the focal and distal regions, even in areas without obvious axonal damage. Altogether, our study shows regional differences in mature and myelinating oligodendrocyte in response to mFPI. Further, mFPI elicits a widespread impact on node-paranode organization that affects regions both close to and remotely located from the site of injury.

Odontoid fractures are common, often presenting in the elderly after a fall and infrequently associated with traumatic spinal cord injury (tSCI). The goal of this study was to analyze predictors of mortality and neurological outcome when odontoid fractures were associated with signal change on magnetic resonance imaging (MRI) at admission. Over an 18-year period (2001-2019), 33 patients with odontoid fractures and documented tSCI on MRI were identified. Mean age was 65.3 years (standard deviation [SD] = 17.2), and 21 patients were male. The mechanism of injury was falls in 25 patients, motor vehicle accidents in 5, and other causes in 3. Mean Injury Severity Score (ISS) was 40.5 (SD = 30.2), Glasgow Coma Scale (GCS) score was 13 (SD = 3.4), and American Spinal Injury Association (ASIA) motor score (AMS) was 51.6 (SD = 42.7). ASIA Impairment Scale (AIS) grade was A, B, C, and D in 9, 2, 3, and 19 patients, respectively. Mean intramedullary lesion length was 32.3 mm (SD = 18.6). The odontoid peg was displaced ventral or dorsal in 15 patients. Twenty patients had surgical intervention: anterior odontoid screw fixation in 7 and posterior spinal fusion in 13. Eleven (33.3%) patients died in this series: withdrawal of medical care in 5; anoxic brain injury in 4; and failure of critical care management in 2. Univariate logistic regression indicated that GCS score (p < 0.014), AMS (p < 0.002), AIS grade (p < 0.002), and ISS (p < 0.009) were risk factors for mortality. Multi-variate regression analysis indicated that only AMS (p < 0.002) had a significant relationship with mortality when odontoid fracture was associated with tSCI (odds ratio, 0.963; 95% confidence interval, 0.941-0.986).

Non-human primate (NHP) spinal cord injury experiments exhibit high intersubject variability in biomechanical parameters even when a consistent impact protocol is applied to each subject. Optimizing impact parameters to reduce this variability through experiments is logistically challenging in NHP studies. Finite element models provide a complimentary tool to inform experimental design without the cost and complexity of live animal studies. A morphologically variable virtual population (N = 10) of NHPs quantified the interaction of morphological variability and different impact conditions in a unilateral cervical contusion, including impactor size (4 and 5 mm) and mediolateral alignment over the cord midline (0.5 and 1 mm). We explored the effect of these conditions on the magnitude and intersubject variability of impact force and cord lateral slippage. The study demonstrated that a 1-mm mediolateral alignment maximized peak forces and minimized lateral slippage. A 5-mm impactor was beneficial in increasing peak forces, whereas a 4-mm impactor reduced lateral slippage. Comparatively, intersubject variability in peak forces and lateral slippage were minimized with a 0.5-mm mediolateral alignment. The study highlights that impact parameters selected based on peak forces may not be beneficial in reducing variability. The study also showed that morphology was an important contributor to variability. Integrating morphology variability through a virtual population in an injury simulation to investigate mechanistic research questions will more effectively capture the heterogeneity of experiments and provide better insights for effective experimental design.

The objectives were to compare differences in telomere length (TL) among younger (21-54 years) and older adults (≥55) with mild traumatic brain injury (mTBI) to non-injured controls and to examine the association between TL and the severity of post-concussive symptoms over time. We performed a quantitative polymerase chain reaction to determine the TL (Kb/genome) of peripheral blood mononuclear cell samples (day 0, 3 months, and 6 months) from 31 subjects. The Rivermead Post-Concussion Symptoms Questionnaire was used to assess symptoms. Group-by-time comparisons of TL and symptom severity were evaluated with repeated-measures analysis of variance. Multiple linear regression examined the relationship between TL, group (mTBI and non-injured controls), and symptom severity total and subscale scores. Significant aging-related differences in TL were found within mTBI groups by time (day 0, 3 months, and 6 months; p = 0.025). Older adults with mTBI experienced significant worsening of changes in total symptom severity scores over time (day 0, 3 months, and 6 months; p = 0.016). Shorter TLs were associated with higher total symptom burden among each of the four groups at day 0 (baseline; p = 0.035) and 3 months (p = 0.038). Shorter TL was also associated with higher cognitive symptom burden among the four groups at day 0 (p = 0.008) and 3 months (p = 0.008). Shorter TL was associated with higher post-injury symptom burden to 3 months in both older and younger persons with mTBI. Large-scale, longitudinal studies of factors associated with TL may be useful to delineate the mechanistic underpinnings of higher symptom burden in adults with mTBI.

Cognitive impairment after traumatic brain injury (TBI) is persistent and disabling. Assessing cognitive function in a reliable and valid manner, using measures that are sensitive to the integrity of underlying neural substrates, is crucial in clinical research. The Attention Network Test (ANT) is one such assessment measure that has demonstrated associations with neural regions involved in attention; however, clinical utility of the ANT is limited because its relationship with neuropsychological measures of cognitive function (i.e., its construct validity) has not yet been established in TBI. We evaluated the association between the ANT and 1) a neuropsychological battery assessing executive function and memory and 2) global function assessed by the Glasgow Outcome Scale-Extended (GOSE). Forty-eight adults with complicated mild-severe TBI were evaluated ∼5 months post-injury. Using principal component analysis and multi-variate linear regression adjusted for age, gender, education, and cause of injury, we found that ANT reaction time and executive network scores predicted a principal component assessing processing speed and executive function. Conversely, the ANT did not predict a principal component assessing memory. The ANT was weakly associated with the GOSE. Among persons with TBI during the post-acute phase of recovery, the ANT has good construct validity as evidenced by its associations with neuropsychological measures of processing speed and executive function, but not memory. Given that ANT networks are known to relate to specific neuroanatomical regions, the ANT may be a useful outcome measure for evaluating novel therapeutics targeting attention and executive functions after TBI.