Journal of neurotrauma最新文献

Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists' prazosin (α₁-adrenoceptors) and atipamezole (α₂-adrenoceptors), and the serotonin 5-HT₃ receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT₃ receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal α₂-adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an α₂- to an α₁-adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via α₁-adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.

At least 27% of women who report a history of intimate partner violence (IPV) also report experiencing IPV-related head trauma (IPV-HT) or probable brain injury (IPV-BI). Prior studies of non-IPV-related traumatic BI and IPV-BI suggest that adverse childhood experiences (ACEs) may be associated with the severity of common neurobehavioral symptoms after the injury, potentially due to their association with elevated post-traumatic stress disorder (PTSD) symptoms. This study sought to examine PTSD symptom severity as an intermediary of the relationship between ACEs and measures of symptoms commonly reported after HT among 121 women with exposure to IPV-HT. Linear regressions examined the association between ACEs and neurobehavioral symptoms assessed by the Rivermead Postconcussion Symptoms Questionnaire (RPQ), Headache Impact Test-6 (HIT-6), and Quality of Life in Neurological Disorders Cognitive Function-Version 2 (Neuro-QoL), while adjusting for other common influences on the severity of these symptoms: IPV-HT and other HT severity, time since most recent, worst IPV-HT (determined using the Brain Injury Screening Questionnaire), past year partner abuse frequency (determined using the Revised Conflict Tactics Scale), and age. Cross-sectional mediation analyses examined whether ACEs indirectly covaried with neurobehavioral symptoms via PTSD symptom severity (determined using the PTSD Checklist for DSM-5 [PCL-5]). ACE score was significantly associated with RPQ score (b = 1.65, p < 0.001) and Neuro-QoL T-score (b = -0.64, p = 0.03). The association between ACE score and RPQ score, and ACE score and Neuro-QoL T-score indirectly covaried by PCL-5 score (unstandardized indirect effect [bootstrapped 95% confidence interval]: RPQ: 0.680 [0.221,1.308]; Neuro-QoL: -0.658 [-1.255,-0.113]). The findings suggest that ACEs are associated with worse symptoms after IPV-HT, potentially by way of the association between ACEs and heightened PTSD symptom severity. Longitudinal studies are needed to determine the causality of these relationships. However, our findings suggest that ACEs and elevated PTSD symptoms may be important considerations for individuals reporting symptoms associated with IPV-HT. As such, providers of these individuals may want to consider whether childhood adversity may be impacting current symptom burden in conjunction with IPV, PTSD, and associated HT/BI.

Macrophage-mediated efferocytosis is crucial for hematoma absorption and inflammation resolution in intracranial hemorrhages. We previously demonstrated that atorvastatin (ATO) expedites the absorption of subdural hematoma (SDH); however, the extent to which this therapeutic effect is associated with ATO-mediated modulation of macrophage efferocytosis remains unclear. In this study, we established a rat model of SDH through autologous blood transfusion into the subdural space. We used primary bone marrow-derived macrophages (BMDMs) to investigate the roles of heme and ATO. The results of enzyme-linked immunosorbent assay and flow cytometry demonstrated that, in addition to its proinflammatory effect, heme also inhibits macrophage efferocytosis. However, ATO reversed this inhibition of efferocytosis in both in vivo and in vitro experiments. Transcriptomic analysis of BMDMs revealed that ATO promotes Krüppel-like factor 4 (KLF4) expression and is mainly enriched in phagocytosis and lysosome-related pathways. Finally, ATO restored the heme-induced reduction in the macrophage phagocytic rate and impairment of lysosomal function. However, KLF4 knockout abolished the beneficial effects of ATO. In conclusion, this study demonstrated that ATO ameliorates heme-inhibited efferocytosis via KLF4, thereby promoting hematoma absorption. We demonstrated a novel mechanism of ATO in the treatment of SDH, providing a new therapeutic prospect for patients (IRB2022-YX-007-01).

Repetitive head impacts (RHIs) in soccer have been associated with long-term risk for neurodegenerative disease. The pathophysiology is largely unknown. This study aims to investigate alterations in cerebral blood flow (CBF) in athletes exposed to RHI compared with athlete controls (CTL). Given that females are known to exhibit higher CBF than males, we also explore sex-specific differences. Finally, we investigate the relationship between CBF and neuropsychological functioning and RHI measures. This study includes 82 amateur athletes (mean age 22.8 ± 1.6 years; 48.9% female). Participants underwent 3T magnetic resonance imaging and completed neuropsychological testing, including questionnaires on stress, resilience, and sleep quality, and computerized assessment of executive function, memory, and processing speed. CBF was assessed using MR pulsed arterial spin labeling. Analysis of covariance was applied to assess the effect of RHI exposure and sex on CBF. Associations between CBF and neuropsychological functioning were analyzed using linear regression models. The analysis was conducted hierarchically, beginning with global gray matter CBF (level 1), followed by cortical and deep gray matter (level 2), and finally brain lobes (level 3). Correction for multiple comparisons was applied at each hierarchical level using false discovery rate, with a significance threshold set at p < 0.05 after correction. We found higher CBF in athletes with RHI exposure (RHI group) compared with athletes with <5 years of exposure to RHI (CTL group; Δ 95% confidence interval [95% CI] = 3.9 [0.5, 7.3] mL/100g/min, p = 0.027). Female athletes with RHI exposure exhibited higher CBF in the global gray matter compared with female CTL (Δ[95% CI] = 6.6 [1.6, 11.5] mL/100g/min, p = 0.013). Among males, individuals with RHI exposure demonstrated higher CBF in the occipital lobe compared with male CTL (Δ[95% CI] = 4.9 [0.3, 9.5] mL/100g/min, p = 0.047). There were no statistically significant associations between CBF and neuropsychological functioning. In the RHI group, years of soccer play were positively associated with whole-brain CBF. Results from this study suggest an association between RHI exposure and higher CBF, a measure of brain activity. Furthermore, we report sex-specific patterns of higher CBF in individuals exposed to RHI, with more widespread elevated CBF in women and more localized higher CBF in men. While these findings highlight the importance of investigating sex-specific effects, there were no associations between CBF and neuropsychological functioning. Future studies are warranted to determine the clinical relevance of the observed sex-specific effects to RHI.

There is limited information about long-term outcomes following severe acquired brain injury (ABI). This is due, in part, to the lack of validated longitudinal assessment measures that can be administered remotely. To address this gap, we developed a caregiver-administered telephone interview designed for the remote evaluation of the functional status of patients who are too impaired to provide reliable self-report. The interview comprises items drawn from three existing standardized instruments: the Coma Recovery Scale-Revised (CRS-R), Cognitive Impairment subscale of the Confusion Assessment Protocol (CAP-Cog), and Galveston Orientation and Amnesia Test (GOAT) (subsequently referred to as the CRS-RT, CAP-CogT, and GOAT-T to reflect telephone administration). The CRS-RT items evaluate the level of consciousness, while the CAP-CogT and GOAT-T items assess basic aspects of cognition. We administered the caregiver interview to 48 caregivers of persons with severe acquired disability (i.e., vegetative state to confusional state) and validated caregiver responses by conducting in-person patient examinations using the original versions of the assessment instruments. To establish the concurrent validity of the caregiver interview, we assessed the correlation between the findings from the caregiver interview and the patient examination, using Lin's concordance correlation coefficient (CCC). The mean (standard error) sensitivity, specificity, and accuracy across both sets of interview items were 0.82 (0.03), 0.68 (0.04), and 0.75 (0.03), respectively. Lin's CCC between caregiver responses to the nine interview items addressing the level of consciousness and the corresponding patient examination findings was 0.78 (95% confidence interval [CI]: 0.65, 0.90), with six items exceeding our a priori cut-off of ≥0.70. However, the correlation between caregiver responses to the eight basic cognition items and the patient examination findings was poor (Lin's CCC = 0.37, 95% CI: -0.09, 0.82), with only three items at or above the cut-off. These results indicate that the CRS-RT can be administered remotely to caregivers of persons with severe ABI-related disability to monitor neurobehavioral status longitudinally. The CAP-CogT and GOAT-T items require further study before they can be used for clinical outcome assessment.

Cerebrovascular reactivity (CVR) mapping is a promising biomarker for evaluating vascular dysfunction following traumatic brain injury (TBI). Traditional CVR assessment requires carbon dioxide (CO₂) administration. Assessing CVR from resting-state blood-oxygen-level-dependent (BOLD) sequences (RS-CVR) offers a task-free alternative, but its validity in TBI has not yet been established. We aimed to evaluate whether RS-CVR can reliably detect cerebrovascular impairment in patients with TBI by comparing it with CO₂-inhalation CVR (CO₂-CVR). We enrolled 23 chronic moderate-to-severe TBI patients and 13 healthy controls (HC) who underwent both CO₂-CVR and RS-CVR imaging using BOLD functional magnetic resonance imaging (BOLD fMRI). RS-CVR maps were computed using a voxel-wise general linear model (GLM) across 120 bandpass filters. Spatial correlations between RS-CVR and CO₂-CVR were calculated to identify the optimal frequency bands. Z-score analyses and lesion-based comparisons were performed to assess CVR reductions in TBI. In the TBI cohort, lesion-based CVR was correlated with clinical outcomes using GLM adjusted for age and sex. The highest whole-brain spatial correlation between RS-CVR and CO₂-CVR in HC occurred at [0-116.4 mHz] (r = 0.5239 ± 0.1107). In TBI, the peak correlation slightly shifted to [0-74.5 mHz] (r = 0.5217 ± 0.1108) but remained comparable at [0-116.4 mHz] (r = 0.5093 ± 0.1263). As expected, regions of encephalomalacia, fluid-attenuated inversion recovery hyperintensity, showed CVR reductions on RS-CVR and CO₂-CVR maps, but low CVR was also identified through both methods in normal-appearing brain tissue. Across lesion areas, RS-CVR detected deficits consistent with CO₂-CVR, with mean z-scores of -0.217 ± 0.334 and -0.391 ± 0.294 for encephalomalacia and hyperintensities, respectively. Lesion-based CVR values were associated with clinical outcomes, with both CO₂-CVR and RS-CVR positively correlated with days in the intensive care unit (ICU; p < 0.05) and showing negative associations with Rivermead post-concussion symptoms questionnaire scores, statistically significant for CO₂-CVR (p = 0.031) and trending for RS-CVR (p = 0.089). RS-CVR closely mirrors CO₂-CVR in both global and lesion-specific analyses, validating its use as a noninvasive method for detecting vascular deficits in TBI. This task-free and scalable tool for cerebrovascular assessment offers a valuable approach for characterizing vascular health relevant to TBI prognosis and guiding neurorehabilitation efforts.