Journal of neurotrauma最新文献

Severe traumatic brain injury (sTBI) is a prominent contributor to both morbidity and mortality in the elderly population. The monitoring of intracranial pressure (ICP) is crucial in the management of sTBI patients. Nevertheless, the appropriate timing for the placement of ICP monitor in elderly sTBI patients remains uncertain. To determine the optimal timing for the placement of ICP monitor in elderly sTBI patients, in this retrospective cohort study, we collected data from elderly patients (> 65 years) who suffered sTBI and received ICP monitors at Tangdu Hospital, The Fourth Military Medical University, between January 2011 and December 2021. To examine the relationship between the time of ICP monitor placement and in-hospital mortality, we conducted a multi-variate-adjusted restricted cubic spline (RCS) analysis. Additionally, logistic regression analysis was applied to further analyze the influencing factors contributing to early or late ICP monitor placements. A total of 283 eligible elderly TBI patients were included in the current analysis. The in-hospital mortality rate was 73 out of 283 (26%). The RCS analysis demonstrated an inverted U-shaped curve in the relationship between the timing of ICP monitor placement and in-hospital mortality. For the elderly sTBI patient cohort, 6 h was identified as the crucial moment for the treatment strategy. In addition, the protective time window for ICP placement was less than 4.92 h for the GCS 3-5 group, and less than 8.26 h for the GCS 6-8 group. However, the clinical benefit of ICP placement decreased gradually over time. The relationship between ICP placement and in-hospital mortality was non-linear, exhibiting an inverted U-shaped curve in elderly patients with sTBI. For elderly patients with sTBI, early (≤ 6 h) ICP placement was associated with reduced in-hospital mortality. The clinical benefit of ICP placement decreased beyond the optimal time window.

Traumatic brain injury (TBI)-induced intracerebral hematoma is a major driver of secondary injury pathology such as neuroinflammation, cerebral edema, neurotoxicity, and blood-brain barrier dysfunction, which contribute to neuronal loss, motor deficits, and cognitive impairment. Cluster of differentiation 47 (CD47) is an antiphagocytic cell surface protein inhibiting hematoma clearance. This study was designed to evaluate the safety and efficacy of blockade of CD47 via intravenous (i.v.) administration of anti-CD47 antibodies following penetrating ballistic-like brain injury (PBBI) with significant traumatic intracerebral hemorrhage (tICH). The pharmacokinetic (PK) profile of the anti-CD47 antibody elicited that antibody concentration decayed over 7 days post-administration. Blood tests and necropsy analysis indicated no severe adverse events following treatment. Cerebral hemoglobin levels were significantly increased after injury, however, anti-CD47 antibody administration at 0.1 mg/kg resulted in a significant reduction in cerebral hemoglobin levels at 72 h post-administration, indicating augmentation of hematoma clearance. Immunohistochemistry assessment of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) demonstrated a significant reduction of GFAP levels in the lesion core and peri-lesional area. Based on these analyses, the optimal dose was identified as 0.1 mg/kg. Lesion volume showed a reduction following treatment. Rotarod testing revealed significant motor deficits in all injured groups but no significant therapeutic benefits. Spatial learning performance revealed significant deficits in all injured groups, which were significantly improved by the last testing day. Anti-CD47 antibody treated rats showed significantly improved attention deficits, but not retention scores. These results provide preliminary evidence that blockade of CD47 using i.v. administration of anti-CD47 antibodies may serve as a potential therapeutic for TBI with ICH.

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency of neurostimulation in the normal cerebral cortex and after mild traumatic brain injury (mTBI), to inform therapies to strengthen or weaken neural circuits in injured brains, as well as to better understand the role of these factors in normal brain plasticity. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials in individual neurons, as well as field potential (FP) recordings, were made from layer 2/3 of visual cortex in response to stimulation of layer 4, in acute slices from control (naive), sham operated, and mTBI rats. We compared synaptic plasticity induced by different stimulation protocols, each consisting of a specific frequency (1 Hz, 10 Hz, or 100 Hz), continuity (continuous or discontinuous), and temporal pattern (perfectly regular, slightly irregular, or highly irregular). At the individual neuron level, dramatic differences in plasticity outcome occurred when the highly irregular stimulation protocol was used at 1 Hz or 10 Hz, producing an overall LTD in controls and shams, but a robust overall LTP after mTBI. Consistent with the individual neuron results, the plasticity outcomes for simultaneous FP recordings were similar, indicative of our results generalizing to a larger scale synaptic network than can be sampled by individual WC recordings alone. In addition to the differences in plasticity outcome between control (naive or sham) and injured brains, the dynamics of the changes in synaptic responses that developed during stimulation were predictive of the final plasticity outcome. Our results demonstrate that the temporal pattern of stimulation plays a role in the polarity and magnitude of synaptic plasticity induced in the cerebral cortex while highlighting differences between normal and injured brain responses. Moreover, these results may be useful for optimization of neurostimulation therapies to treat mTBI and other brain disorders, in addition to providing new insights into downstream plasticity signaling mechanisms in the normal brain.

Concussion often results in psychological symptoms, including anxiety. Post-concussion anxiety has been well documented, although much of this research has focused on collegiate athletes. The purpose of this study was to compare (1) anxiety symptoms in concussed and healthy controls over time and (2) to explore sex differences in post-concussion anxiety within the context of pubertal development. Participants (N = 126, mean age = 15.1 years old), including concussed (n = 86) and healthy adolescents (n = 40), completed the Pubertal Development Scale (PDS) and the Screen for Child Anxiety and Related Disorders (SCARED-C). The concussed groups completed SCARED-C at three visits (<10 days, 4 weeks, 3 months). Results of an analysis of covariance (ANCOVA) and multi-variate analysis of covariance (MANCOVA) found concussed adolescents reported higher SCARED-C total, generalized, and panic anxiety scores than healthy controls, after controlling for sex, age, and PDS score (PDSS). A three-way mixed ANCOVA examined the effects of sex, PDSS, time, and their interaction on SCARED-C total score in concussed adolescents while controlling for age. There was a significant three-way interaction between sex, age, and PDSS on SCARED-C total score while controlling for age. Overall, we observed increased anxiety in concussed adolescents, compared with controls, as well as greater post-concussion anxiety reported by females compared with males, including within PDSS groups. Concussion providers should be prepared to receive training to administer well-validated measures of psychopathology and should consider that female adolescents, compared with males, regardless of pubertal development, may be at greater risk for post-concussion anxiety.

Diffusion tensor imaging (DTI) has emerged as a promising neuroimaging tool for detecting blast-induced mild traumatic brain injury (bmTBI). However, lack of refined acute-phase monitoring and reliable imaging biomarkers hindered its clinical application in early diagnosis of bmTBI, leading to potential long-term disability of patients. In this study, we used DTI in a rat model of bmTBI generated by exposing to single lateral blast waves (151.16 and 349.75 kPa, lasting 47.48 ms) released in a confined bioshock tube, to investigate whole-brain DTI changes at 1, 3, and 7 days after injury. Combined assessment of immunohistochemical analysis, transmission electron microscopy, and behavioral readouts allowed for linking DTI changes to synchronous cellular damages and identifying stable imaging biomarkers. The corpus callosum (CC) and brainstem were identified as predominantly affected regions, in which reduced fractional anisotropy (FA) was detected as early as the first day after injury, with a maximum decline occurring at 3 days post-injury before returning to near normal levels by 7 days. Axial diffusivity (AD) values within the CC and brainstem also significantly reduced at 3 days post-injury. In contrast, the radial diffusivity (RD) in the CC showed acute elevation, peaking at 3 days after injury before normalizing by the 7-day time point. Damages to nerve fibers, including demyelination and axonal degeneration, progressed in lines with changes in DTI parameters, supporting a real-time macroscopic reflection of microscopic neuronal fiber injury by DTI. The most sensitive biomarker was identified as a decrease in FA, AD, and an increase in RD within the CC on the third day after injury, supporting the diagnostic utility of DTI in cases of bmTBI in the acute phase.

There is a growing body of evidence that the delivery of cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord injury and improve outcomes. Exosomes are nanometer-sized vesicles that are released by Schwann cells and may have neuroprotective effects by reducing post-traumatic inflammatory processes as well as promoting tissue healing and functional recovery. The purpose of this study was to evaluate the beneficial effects of human Schwann-cell exosomes (hSC-Exos) in a severe model of penetrating ballistic-like brain injury (PBBI) in rats and investigate effects on multiple outcomes. Human Schwann cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction and purification steps approved by the Food and Drug Administration for an expanded access single ALS patient Investigational New Drug. Anesthetized male Sprague-Dawley rats (280-350g) underwent PBBI surgery or Sham procedures and, starting 30 min after injury, received either a dose of hSC-Exos or phosphate-buffered saline through the jugular vein. At 48h after PBBI, flow cytometry analysis of cortical tissue revealed that hSC-Exos administration reduced the number of activated microglia and levels of caspase-1, a marker of inflammasome activation. Neuropathological analysis at 21 days showed that hSC-Exos treatment after PBBI significantly reduced overall contusion volume and decreased the frequency of Iba-1 positive activated and amoeboid microglia by immunocytochemical analysis. This study revealed that the systemic administration of hSC-Exos is neuroprotective in a model of severe TBI and reduces secondary inflammatory injury mechanisms and histopathological damage. The administration of hSC-Exos represents a clinically relevant cell-based therapy to limit the detrimental effects of neurotrauma or other progressive neurological injuries by impacting multiple pathophysiological events and promoting neurological recovery.

The kallikrein-kinin system is one of the first inflammatory pathways to be activated following traumatic brain injury (TBI) and has been shown to exacerbate brain edema formation in the acute phase through activation of bradykinin 2 receptors (B2R). However, the influence of B2R on chronic post-traumatic damage and outcome is unclear. In the current study, we assessed long-term effects of B2R-knockout (KO) after experimental TBI. B2R KO mice (heterozygous, homozygous) and wild-type (WT) littermates (n = 10/group) were subjected to controlled cortical impact (CCI) TBI. Lesion size was evaluated by magnetic resonance imaging up to 90 days after CCI. Motor and memory function were regularly assessed by Neurological Severity Score, Beam Walk, and Barnes maze test. Ninety days after TBI, brains were harvested for immunohistochemical analysis. There was no difference in cortical lesion size between B2R-deficient and WT animals 3 months after injury; however, hippocampal damage was reduced in B2R KO mice (p = 0.03). Protection of hippocampal tissue was accompanied by a significant improvement of learning and memory function 3 months after TBI (p = 0.02 WT vs. KO), whereas motor function was not influenced. Scar formation and astrogliosis were unaffected, but B2R deficiency led to a gene-dose-dependent attenuation of microglial activation and a reduction of CD45+ cells 3 months after TBI in cortex (p = 0.0003) and hippocampus (p < 0.0001). These results suggest that chronic hippocampal neurodegeneration and subsequent cognitive impairment are mediated by prolonged neuroinflammation and B2R. Inhibition of B2R may therefore represent a novel strategy to reduce long-term neurocognitive deficits after TBI.