Traumatic Brain Injury Recovery Research Articles

The Effect of Curcumin on the Recovery of Severe Traumatic Brain Injury: A Double-blind Randomized Controlled Trial

Background and Aim: Traumatic brain injury (TBI) is one of the critical causes of death in trauma patients. In this study, the effect of nanocurcumin on the outcome of severe TBI was investigated for the first time in humans. Methods and Materials/Patients: This randomized, double-blind, and paralleled controlled study included 128 patients aged from 18 to 70 years with severe brain trauma. Patients were randomly assigned to control group (standard care treatment+placebo) and intervention group (standard care treatment+oral nanocurcumin). Changes in the level of consciousness, cerebral edema, kidney function, liver enzymes, sodium and potassium electrolytes, and brain function were followed up and compared until 6 months after discharge. Results: The Mean±SD in the intervention (14.44±31.86 years) and control patients (14.86±33.34 years) had no significant difference (P=0.543). Both groups were similar in terms of gender (P=0.669). The average level of consciousness in the intervention group increased by about 3 units (P=0.004) and more than 2 units (P=0.002) at discharge compared with the control group. By comparing the optimal performance of patients in the first (P=0.389) trimester and second (P=0.309) trimester after discharge, no significant difference was observed between the intervention and control groups. The amount of brain edema caused by severe brain trauma on the seventh day of treatment in the intervention group was lower than that in the control group (P=0.038). Conclusion: Administrating oral nanocurcumin supplement in patients with severe brain trauma along with their routine treatment is effective in improving brain edema and their level of consciousness without causing coagulation, and liver and kidney complications. These findings are not only statistically significant but also clinically vital.

Family experiences of supporting a relative with agitation during early recovery after traumatic brain injury

ABSTRACT During the early recovery period after traumatic brain injury (TBI), referred to as post-traumatic amnesia (PTA), approximately 44% of individuals may exhibit agitated behaviours. Agitation can impede recovery and poses a significant management challenge for healthcare services. As families provide significant support for their injured relatives during this time, this study aimed to explore the family’s experience during PTA to better understand their role in agitation management. There were 20 qualitative semi-structured interviews conducted with 24 family members of patients exhibiting agitation during early TBI recovery (75% female, aged 30–71 years), predominantly parents (n = 12), spouses (n = 7) and children (n = 3). The interviews explored the family’s experience of supporting their relative exhibiting agitation during PTA. The interviews were analyzed using reflexive thematic analysis, which revealed three key themes: family contributions to patient care, expectations of the health care service and supporting families to support patients. This study emphasized the significant role of families in managing agitation during early TBI recovery and highlighted that families who are well-informed and well-supported have the potential to minimize their relative’s agitation during PTA, which may reduce the burden on healthcare staff and promote patient recovery.

Trigeminal nerve stimulation restores hippocampal dopamine deficiency to promote cognitive recovery in traumatic brain injury

Cognitive impairment (CI) is a common neurological disease resulting from traumatic brain injury (TBI). Trigeminal nerve stimulation (TNS) is an emerging, non-invasive, and effective neuromodulation therapy especially for patients suffering from brain function disorders. However, the treatment and recovery mechanisms of TNS remain poorly understood. By using combined advanced technologies, we revealed here that the neuroprotective potential of TNS to improve CI caused by TBI. The study results found that 40 Hz TNS treatment has the ability to improve CI in TBI mice and communicates with central nervous system via the trigeminal ganglion (TG). Transsynaptic virus experiments revealed that TG is connected to the hippocampus (HPC) through the corticotropin-releasing hormone (CRH) neurons of paraventricular hypothalamic nucleus (PVN) and the dopamine transporter (DAT) neurons of substantia nigra pars compacta/ventral tegmental area (SNc/VTA). Mechanistically, the data showed that TNS can increase the release of dopamine in the HPC by activating the following neural circuit: TG→CRH+ PVN→DAT+ SNc/VTA → HPC. Bulk RNA sequencing confirmed changes in the expression of dopamine-related genes in the HPC. This work preliminarily explains the efficacy and mechanism of TNS and adds to the increasing evidence demonstrating that nerve stimulation is an effective method to treat neurological diseases.

Delayed CO2 postconditioning promotes neurological recovery after cryogenic traumatic brain injury by downregulating IRF7 expression.

Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO2 inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO2 postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI. Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO2 for various time-courses (one/two/three cycles of 10-min inhalation/10-min break) at Days 3-7, 3-14 or 7-18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP-43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno-associated virus were applied to investigate the molecular mechanisms. DCPC significantly promoted recovery of motor function in a concentration and time-course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO3 . DCPC also increased puncta density of GAP-43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation-related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC. We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI.

Spatial amine metabolomics and histopathology reveal localized brain alterations in subacute traumatic brain injury and the underlying mechanism of herbal treatment.

Spatial changes of amine metabolites and histopathology of the whole brain help to reveal the mechanism of traumatic brain injury (TBI) and treatment. A newly developed liquid microjunction surface sampling-tandem mass tag-ultra performance liquid chromatography-mass spectrometry technique is applied to profile brain amine metabolites in five brain regions after impact-induced TBI at the subacute stage. H&E, Nissl, and immunofluorescence staining are performed to spatially correlate microscopical changes to metabolic alterations. Then, bioinformatics, molecular docking, ELISA, western blot, and immunofluorescence are integrated to uncover the mechanism of Xuefu Zhuyu decoction (XFZYD) against TBI. Besides the hippocampus and cortex, the thalamus, caudate-putamen, and fiber tracts also show differentiated metabolic changes between the Sham and TBI groups. Fourteen amine metabolites (including isomers such as L-leucine and L-isoleucine) are significantly altered in specific regions. The metabolic changes are well matched with the degree of neuronal damage, glia activation, and neurorestoration. XFZYD reverses the dysregulation of several amine metabolites, such as hippocampal Lys-Phe/Phe-Lys and dopamine. Also, XFZYD enhances post-TBI angiogenesis in the hippocampus and the thalamus. This study reveals the local amine-metabolite and histological changes in the subacute stage of TBI. XFZYD may promote TBI recovery by normalizing amine metabolites and spatially promoting dopamine production and angiogenesis.

A systematic review of heart rate variability (HRV) biofeedback treatment following traumatic brain injury (TBI)

ABSTRACT Objective Autonomic nervous system dysregulation is a common consequence of traumatic brain injury (TBI). Heart rate variability (HRV) is a cost-effective measure of autonomic nervous system functioning, with studies suggesting decreased HRV following moderate-to-severe TBI. HRV biofeedback treatment may improve post-TBI autonomic nervous system functioning and post-injury emotional and cognitive functioning. We provide a systematic evidence-based review of the state of the literature and effectiveness of HRV biofeedback following TBI. Method We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two coders coded each article and provided quality ratings. Seven papers met inclusion criteria. All studies included a measure of emotional functioning and 5 studies (63%) included neuropsychological outcomes. Results Participants completed 11 sessions of HRV biofeedback on average (range = 1 to 40). HRV biofeedback was associated with improved HRV following TBI. There was a positive relationship between increased HRV and TBI recovery following biofeedback, including improvements in cognitive and emotional functioning, and physical symptoms such as headaches, dizziness, and sleep problems. Conclusion The literature on HRV biofeedback for TBI is promising, but in its infancy; effectiveness is unclear due to poor-to-fair study quality, and potential publication bias (all studies reported positive results).

Feasibility and acceptability of a brief intervention to improve mild traumatic brain injury recovery: Problem-solving training-concussion.

Mild traumatic brain injuries (mTBIs) are common among Veterans. Although the majority of neurobehavioral symptoms resolve following mTBI, studies with Veteran samples demonstrate a high frequency and chronicity of neurobehavioral complaints (e.g., difficulties with attention, frustration tolerance) often attributed to mTBI. Recent opinions suggest the primacy of mental health treatment, and existing mTBI practice guidelines promote patient-centered intervention beginning in primary care (PC). However, trial evidence regarding effective clinical management in PC is lacking. This study evaluated the feasibility and acceptability of a brief, PC-based problem-solving intervention to reduce psychological distress and neurobehavioral complaints. Mixed method open clinical trial of 12 combat Veterans with a history of mTBI, chronic neurobehavioral complaints, and psychological distress. Measures included qualitative and quantitative indicators of feasibility (recruitment and retention metrics, interview feedback), patient acceptability (treatment satisfaction, perceived effectiveness), and change in psychological distress as measured by the Brief Symptom Inventory-18. The protocol was successfully delivered via in-person and telehealth treatment modalities (4.3 sessions attended on average; 58% completed the full protocol). Patient interview data suggested that treatment content was personally relevant, and patients were satisfied with their experience. Treatment completers described the intervention as helpful and reported corresponding reductions in psychological distress (ES = 1.8). Dropout was influenced by the onset of the COVID-19 pandemic. Further study with a more diverse, randomized sample is warranted. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Microbiota-derived SCFAs Promote Chronic Neurogenesis and Anti-inflammatory Gene Expression after Traumatic Brain Injury (P1-6.008)

<h3>Objective:</h3> To evaluate whether short-chain fatty acids (SCFAs) will benefit the long-term recovery of traumatic brain injury (TBI) in mice. <h3>Background:</h3> SCFAs, including acetate and butyrate, are the main metabolites generated by gut microbiota consuming dietary fiber in the colon. SCFAs have pleotropic effects throughout the body including influences on immunity and neurogenesis. We hypothesized that SCFAs could influence recovery from TBI. <h3>Design/Methods:</h3> Adult C57BL6/J mice (n=4/group) were randomized to standard high-amylose maize starch (HAMS) chow or acetylated- and butyrylated-HAMS (HAMS-AB). Fermentation of HAMS-AB by gut bacteria releases acetate and butyrate in the intestinal lumen. The controlled cortical impact (CCI) model of TBI (6m/s, 2.2mm depth, 50msec dwell) was performed. Sham mice received anesthesia and skin incision without craniotomy. At 6 months post-injury, mice were sacrificed and single-cell mRNA from pericontusional tissue sequenced following the 10X Genomics protocol. After pre-processing by <i>CellRanger</i> and SCT normalization by <i>Seurat</i>, cells were annotated based on canonical markers. Cell subtype gene modules were clustered by weighted gene co-expression network analysis (WGCNA) and enriched at gene-ontology (GO) pathways. The GO pathway and regulon activity were evaluated by <i>AUCell</i> and <i>SCENIC</i> respectively. <h3>Results:</h3> In a total of 116,134 cells, consisting of 12 cell types, from 3 groups (41,509 from sham_control, 36,409 from injury_control, 38,216 from injury_SCFA,) passed the quality control and doublet filtering. Both the cell composition and transcriptome were different in each group. SCFAs decreased gene expression associated with neuronal activity and increased the immature neuron frequency. During immature neuron differentiation, SCFAs downregulated neurodegenerative disease-related genes expression in injured mice. In addition, SCFAs decreased chronic microglia/macrophage activation and promoted an M2-like phenotype. Lastly, SCFAs attenuated T cell activation and cytotoxic-related pathways. <h3>Conclusions:</h3> SCFAs impact gene expression in multiple cell types at 6 months after TBI. The pathways affected suggest a beneficial role for gut-derived SCFA administration for recovery after TBI. <b>Disclosure:</b> Dr. Xiong has nothing to disclose. Mrs. Nelson has nothing to disclose. Mr. Sneiderman has nothing to disclose. Ms. Feldman has nothing to disclose. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Johns Hopkins Health System. The institution of Patrick M. Kochanek, MD, MCCM has received research support from Chuck Noll Foundation. The institution of Patrick M. Kochanek, MD, MCCM has received research support from NIH. Patrick M. Kochanek, MD, MCCM has received publishing royalties from a publication relating to health care. Dr. Rajasundaram has nothing to disclose. Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. An immediate family member of Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Legal fees. The institution of Dr. Jha has received research support from NIH/NINDS, Chuck Noll Foundation, University of Pittsburgh, Barrow Neurological Foundation. The institution of Dr. Kohanbash has received research support from NIH. Dr. Simon has nothing to disclose.

Impact of Return-to-Exercise on Traumatic Brain Injury Recovery in a Community Setting (P7-1.008)

<h3>Objective:</h3> To investigate the relationship between exercise modalities, intensities, and patterns following TBI and recovery, and to identify health inequities and barriers to recovery that may negatively impact recovery. <h3>Background:</h3> Recommendations on return-to-exercise post-traumatic brain injury (TBI) remain controversial. This study surveyed Hawaii’s diverse population to identify trends in exercise and recovery for TBI patients to shape recommendations on return-to-exercise. This study also aimed to identify health inequities and factors contributing to different outcomes, allowing inequities to be addressed. <h3>Design/Methods:</h3> Retrospective review of 100 patients diagnosed with TBI between January 2020 and January 2022 was performed. Variables collected include demographics, etiologies, and symptoms at diagnosis. Self-generated phone surveys were completed to evaluate exercise patterns post-TBI and barriers to recovery. Statistical analysis was performed using RStudio. <h3>Results:</h3> Patients who recovered within two years displayed similar exercise patterns to patients who took longer than two years. Exercise frequency, intensity, and duration did not differ significantly (p=0.75, p=0.51, p=0.80, respectively). Hiking/walking for exercise was more common in the long recovery group (p=0.018), likely reflecting advanced age compared to the short recovery group (50 vs. 39 years old, p=0.003). Otherwise, exercise modalities did not differ significantly. Additionally, no correlation exists between exercise intensity and symptom change (p=0.920), suggesting patients exhibit exercise patterns suitable for their specific condition. Finally, when comparing TBI recovery resources accessed across races or insurance types, Caucasian patients and individuals with private insurance utilized the most resources (p=0.032). <h3>Conclusions:</h3> Return-to-exercise does not appear to be a predictor for TBI recovery. If encouraged to exercise post-TBI, patients will self-regulate a regimen not likely exacerbating their symptoms or recovery time, thus it may be suitable to recommend return-to-exercise as tolerated. The study also found worrying inequitable trends in TBI recovery resources accessed, and these disparities should be further investigated to rectify this issue. <b>Disclosure:</b> Mr. Weldon has nothing to disclose. Mr. Nakamura has received personal compensation for serving as an employee of Hawaii Health &amp; Harm Reduction Center. Miss Van has nothing to disclose. Ms. Nakamura has nothing to disclose. Mr. Law has nothing to disclose. Mr. Goo has nothing to disclose. Ms. Roman has nothing to disclose. Enrique Carrazana has received personal compensation for serving as an employee of Neurelis. Enrique Carrazana has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Neurelis, Alexza, Zogenix. Enrique Carrazana has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Hawaii-Biotech, CND Life Sciences. Enrique Carrazana has stock in Neurelis, Marinus, . Dr. Viereck has nothing to disclose. The institution of Dr. Liow has received research support from UCB. The institution of Dr. Liow has received research support from Livanova. The institution of Dr. Liow has received research support from Biogen. The institution of Dr. Liow has received research support from Novartis. The institution of Dr. Liow has received research support from Eisai. The institution of Dr. Liow has received research support from Engage Therapeutics. The institution of Dr. Liow has received research support from SK Lifescience. The institution of Dr. Liow has received research support from Cerevel. The institution of Dr. Liow has received research support from Xenon. The institution of Dr. Liow has received research support from NeuroDerm. The institution of Dr. Liow has received research support from Avanir. The institution of Dr. Liow has received research support from Annovis. The institution of Dr. Liow has received research support from Acadia.

Exploring the Social Determinants of Health and Health Disparities in Traumatic Brain Injury: A Scoping Review.

Traumatic brain injury (TBI) is a global health concern, that can leave lasting physical, cognitive, and/or behavioral changes for many who sustain this type of injury. Because of the heterogeneity of this population, development of appropriate intervention tools can be difficult. Social determinants of health (SDoH) are factors that may impact TBI incidence, recovery, and outcome. The purpose of this study is to describe and analyze the existing literature regarding the prevailing SDoH and health disparities (HDs) associated with TBI in adults. A scoping review, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework was used to explore three electronic databases-PubMed, Medline, and CINAHL. Searches identified peer-reviewed empirical literature addressing aspects of SDoH and HDs related to TBI. A total of 123 records were identified and reduced to 27 studies based on inclusion criteria. Results revealed race/ethnicity was the most commonly reported SDoH impacting TBI, followed by an individual's insurance status. Health disparities were noted to occur across the continuum of TBI, including TBI risk, acute hospitalization, rehabilitation, and recovery. The most frequently reported HD was that Whites are more likely to be discharged to inpatient rehabilitation compared to racial/ethnic minorities. Health disparities associated with TBI are most commonly associated with the race/ethnicity SDoH, though insurance status and socioeconomic status commonly influence health inequities as well. The additional need for evidence related to the impact of other, lesser researched, SDoH is discussed, as well as clinical implications that can be used to target intervention for at-risk groups using an individual's known SDoH.

The Influence of Substance Use on Traumatic Brain Injury Recovery and Rehabilitation Outcomes: The Outcome-ABI Study

ObjectiveThis study characterized substance use (alcohol, illicit drugs, amphetamines) in patients with traumatic brain injury (TBI) receiving rehabilitation to determine potential benefit of rehabilitation and whether substance use influenced outcomes in moderate–severe TBI. DesignProspective, longitudinal study of adults with moderate or severe TBI receiving inpatient rehabilitation. SettingSpecialist-staffed acquired brain injury rehabilitation center in Melbourne, Australia. ParticipantsA total of 153 consecutive inpatients with TBI admitted between January 2016 and December 2017 (24 months). InterventionsAll inpatients with TBI (n=153) received specialist-provided brain injury rehabilitation in accordance with evidence-based guideline care at one 42-bed rehabilitation center. Main Outcome MeasuresData were collected at time of TBI, upon rehabilitation admission, and discharge and 12 months’ post-TBI. Recovery was measured by posttraumatic amnesia posttraumatic amnesia length-days and change in Glasgow Coma Scale (admission–discharge). Functional independence was measured on the FIM, Functional Assessment Measure, and Mayo Portland Adaptability Index. Quality of life (QOL) was measured on the EuroQOL-5D-5L and Quality of Life After Brain Injury (QOLIBRI) instruments. ResultsInpatients with history of illicit drug use (n=54) reported lower QOL and adjustment at 12 months’ post-TBI compared with those with no history (QOLIBRI social relationships: ratio of means=0.808, P=.028; Mayo Portland Adaptability Index adjustment: incidence rate ratio, 1.273; P=.032). Amphetamine use at time of injury (n=10) was associated with quicker recovery (posttraumatic amnesia length-days: incidence rate ratio, 0.173; P<.01); however, lower QOL at 12 months post-TBI was noted in those with a history of amphetamine use (n=34) compared with those without (QOLIBRI bothered feelings: ratio of means, 0.489, P=.036). ConclusionsAll participants made improvements with rehabilitation post-TBI; however, a history of substance use was associated with lower reported 12-month QOL. These findings add insight to the associations between substance use and acute recovery, potentially suggestive of a short-term recovery-promoting effect of amphetamines but highlighting the importance of rehabilitation to address long-term sequalae.

Poor nutritional status is associated with incomplete functional recovery in elderly patients with mild traumatic brain injury.

The geriatric nutritional risk index (GNRI) is a simple index for evaluating the nutrition status of elderly patients. Many investigations have demonstrated that this index is associated with the prognosis of several diseases. This study aims to identify the relationship between the GNRI and recovery in elderly mild traumatic brain injury (mTBI) patients. A total of 228 mTBI patients older than 65 years were included in this study. mTBI was defined as an injury to the brain with a loss of consciousness of 30 min or less, a duration of posttraumatic amnesia of <24 h, and an admission Glasgow Coma Scale (GCS) score of 13-15. The Glasgow Outcome Scale Extended (GOSE), an outcome scale assessing functional independence, work, social activities, and personal relationships, was applied to assess the recovery of the patients. The clinical outcome was divided into complete recovery (GOSE = 8) and incomplete recovery (GOSE ≤ 7) at 6 months after the injury. Multivariate logistic regression was applied to evaluate the association between the GNRI and recovery of elderly mTBI patients, with adjustment for age, sex, hypertension, diabetes, and other important factors. The receiver operating curve (ROC) analysis demonstrated that the cutoff value of GNRI was 97.85, and the area under the curve (AUC) was 0.860. Compared to the patients with a high GNRI, the patients with a low GNRI were older, had a higher prevalence of anemia, acute subdural hematoma, and subarachnoid hemorrhage, had a higher age-adjusted Charlson Comorbidity Index value, and had lower levels of albumin, lymphocytes, and hemoglobin. Multivariable analysis showed that high GNRI was associated with a lower risk of 6-month incomplete recovery (OR, 0.770, 95% CI: 0.709-0.837, p < 0.001). The GNRI has utility as part of the objective risk assessment of incomplete 6-month functional recovery in elderly patients with mTBI.

Loading neural stem cells on hydrogel scaffold improves cell retention rate and promotes functional recovery in traumatic brain injury.

Neural stem cell (NSC) has gained considerable attention in traumatic brain injury (TBI) treatment because of their ability to replenish dysfunctional neurons and stimulate endogenous neurorestorative processes. However, their therapeutic effects are hindered by the low cell retention rate after transplantation into the dynamic brain. In this study, we found cerebrospinal fluid (CSF) flow after TBI is an important factor associated with cell loss following NSC transplantation. Recently, several studies have shown that hydrogels could serve as a beneficial carrier for stem cell transplantation, which provides a solution to prevent CSF flow-induced cell loss after TBI. For this purpose, we evaluated three different hydrogel scaffolds and found the gelatin methacrylate (GelMA)/sodium alginate (Alg) (GelMA/Alg) hydrogel scaffold showed the best capabilities for NSC adherence, growth, and differentiation. Additionally, we detected that pre-differentiated NSCs, which were loaded on the GelMA/Alg hydrogel and cultured for 7 days in neuronal differentiation medium (NSC [7d]), had the highest cell retention rate after CSF impact. Next, the neuroprotective effects of the NSC-loaded GelMA/Alg hydrogel scaffold were evaluated in a rat model of TBI. NSC [7d]-loaded GelMA/Alg markedly decreased microglial activation and neuronal death in the acute phase, reduced tissue loss, alleviated astrogliosis, promoted neurogenesis, and improved neurological recovery in the chronic phase. In summary, we demonstrated that the integration with the GelMA/Alg and modification of NSC differentiation could inhibit the influence of CSF flow on transplanted NSCs, leading to increased number of retained NSCs and improved neuroprotective effects, providing a promising alternative for TBI treatment.

Social Determinants of Health and Traumatic Brain Injury: Implications for Rehabilitation Service Delivery and Outcomes.

Social Determinants of Health and Traumatic Brain Injury: Implications for Rehabilitation Service Delivery and Outcomes.

Decellularized extracellular matrix and mesenchymal stem cells promote recovery in traumatic brain injury by synergistically enhancing neurogenesis and attenuating neuroinflammation

• The innovative decellularization method via freeze-thaw cycles and detergent-enzymatic cycles endowed the decellularized brain with extremely few cellular immunogenic components and abundant ECM constituents. • The MSCs-encapsulated decellularized brain ECM (dBECM)-based hydrogel can effectively promote neuron compensation and neural recovery in TBI mice, owing to the capacity to up-regulate the neural-related genes and promote the neural differentiation of MSCs into NSCs and neurons. • The MSCs-encapsulated dBECM-based hydrogel can potentially regulate the neuroinflammation after TBI, since the hydrogel works synergistically with MSCs to stimulate the M1-to-M2 polarization and down-regulate the pro-inflammatory cytokines of microglia. Damaged neurons and harsh microenvironments contribute to the injury cascades following traumatic brain injury (TBI). Mesenchymal stem cell (MSC) therapy is considered a viable choice for brain injury treatment; however, its clinical use is hindered by limited engraftment, low survival ratio, and uncontrolled differentiation. Herein, the decellularized brain extracellular matrix (dBECM) was prepared through a new method as a delivery system for MSCs. dBECM-based hydrogel with favorable biochemical and biomechanical features provides a microenvironment for MSCs in nerve repair. The MSCs-encapsulated dBECM-based hydrogel is shown to improve neuron compensation and structural regeneration, alleviate neuroinflammation, and promote M1-to-M2 polarization of microglia. Our results first demonstrate that the combination of dBECM and MSCs is a critical vehicle to promote TBI repair from neurogenesis and immunoregulation, showing promise for the physiological recovery of neurogenic diseases and injuries.

The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review

Sleep disturbances are widely prevalent following a traumatic brain injury (TBI) and have the potential to contribute to numerous post-traumatic physiological, psychological, and cognitive difficulties developing chronically, including chronic pain. An important pathophysiological mechanism involved in the recovery of TBI is neuroinflammation, which leads to many downstream consequences. While neuroinflammation is a process that can be both beneficial and detrimental to individuals' recovery after sustaining a TBI, recent evidence suggests that neuroinflammation may worsen outcomes in traumatically injured patients, as well as exacerbate the deleterious consequences of sleep disturbances. Additionally, a bidirectional relationship between neuroinflammation and sleep has been described, where neuroinflammation plays a role in sleep regulation and, in turn, poor sleep promotes neuroinflammation. Given the complexity of this interplay, this review aims to clarify the role of neuroinflammation in the relationship between sleep and TBI, with an emphasis on long-term outcomes such as pain, mood disorders, cognitive dysfunctions, and elevated risk of Alzheimer's disease and dementia. In addition, some management strategies and novel treatment targeting sleep and neuroinflammation will be discussed in order to establish an effective approach to mitigate long-term outcomes after TBI.

Longitudinal Trajectories of Post-Concussive Symptoms Following Mild Traumatic Brain Injury

ABSTRACT Background Individuals recovering from mild traumatic brain injury (TBI) represent a heterogenous population that requires distinct treatment approaches. Identification of recovery trajectories improves our ability to understand the natural history of mild TBI recovery and develop targeted interventions. Objective To utilize group-based trajectory modeling (GBTM) to identify distinct patterns of symptom recovery following mild TBI in the first 6 months after mild TBI. Methods This study is comprised of 253 adults who presented to the emergency department with mild TBI and completed assessments for six-months post-injury. Patients were recruited for the prospective observational cohort study, HeadSMART. The primary outcome measure was the Rivermead Postconcussion Symptom Questionnaire. GBTM was used to identify longitudinal trajectories of recovery following mild TBI using Rivermead scores at baseline, one, three, and six months following diagnosis. Results Findings identified four distinct trajectories of symptom recovery follwing mild TBI including 9% of participants who were categorized with minimal acute symptoms that decreased over time, 45% with mild acute symptoms that decreased over time, 33% with relatively higher acute symptoms that decreased over time, and 13% with relatively higher acute symptoms that increased over time. Conclusions GBTM identified four distinct trajectories of recovery following mild TBI and GBTM may be useful for research interventions that can alter recovery trajectories.

Hyaluronan-based hydrogel integrating exosomes for traumatic brain injury repair by promoting angiogenesis and neurogenesis

With wide clinical demands, therapies for traumatic brain injury (TBI) are far from satisfactory. Combining the merits of stem cells but avoiding the risk of immunologic rejection, bone marrow mesenchymal stem cell-derived exosomes (BME) attract increasing interests and have been proved effective for TBI repair by intravenous or in situ injection. However, difficulties in sustained delivery or aggregation in lesion sites remain obstacle to using BME for TBI. Inspired by that hydrogels are promising to bridge the destroyed neural gap and provide neural niches, we raised a novel strategy of incorporating BME into hyaluronan-collagen hydrogel (DHC-BME) to achieve both mimicking of brain matrix and steady release of exosomes, and thus realizing TBI repair. External characterizations proved that the BME and DHC synergistically promoted neural stem cells (NSCs) differentiation into neurons and oligodendrocytes while inhibited astrocytes differentiation. DHC-BME induced angiogenesis and neurogenesis, from endogenous NSC recruitment to neuronal differentiation and vascularization to synergistically promote axonal regeneration, remyelination, synapse formation and even brain structural remodeling, and lastly, neurological functional recovery of TBI.

Surveying the Landscape: A Review of Longitudinal Traumatic Brain Injury Studies in Service Member and Veteran Populations.

Traumatic brain injury (TBI) is known to be a signature wound of the post-9/11 conflicts. In response, the U.S. Department of Defense (DOD) and other federal organizations have directed significant investments toward TBI research on characterizing injury populations and understanding long-term outcomes. To address legislative requirements and research gaps, several observational, longitudinal TBI studies were initiated as an effective means of investigating TBI clinical management, outcomes, and recovery. This review synthesizes the landscape (i.e., requirements and gaps, infrastructure, geography, timelines, TBI severity definitions, military and injury populations of interest, and measures) of DOD-funded longitudinal TBI studies being conducted in service member and veteran (SMV) populations. Based on the landscape described here, we present recommended actions and solutions that would allow a consolidated and cooperative future state of longitudinal TBI research, optimized continued investments, and advances in the state of the science without redundancy.

Therapeutic Role of microRNAs of Small Extracellular Vesicles from Human Mesenchymal Stromal/Stem Cells in Treatment of Experimental Traumatic Brain Injury.

Mesenchymal stem/stromal cells (MSC)-derived small extracellular vesicles (sEVs) possess therapeutic potential for treatment of traumatic brain injury (TBI). The essential role of micro ribonucleic acids (miRNAs) underlying the beneficial effects of MSC-derived sEVs for treatment of TBI remains elusive. The present study was designed to investigate the role of microRNAs in sEVs from MSCs with Argonaute 2 knockdown (Ago2-KD) in neurological recovery, neuroinflammation, and neurovascular remodeling in TBI rats. Therapeutic effects of sEVs derived from naïve MSCs (naïve-sEV), MSCs transfected with a vector carrying scramble control short hairpin RNA (shRNA; vector-sEV), and MSCs transfected with a lentiviral vector-based shRNA against Ago2 to knock down Ago2 (Ago2-KD-sEV) were determined in adult male rats subjected to a moderate TBI induced by controlled cortical impact (CCI). sEVs (naïve-sEV, vector-sEV, and Ago2-KD-sEV) or vehicle (phosphate-buffered solution [PBS]) were given intravenously 1 day post-injury (PI). Multiple neurological functional tests were performed weekly PI for 5 weeks. The Morris water maze (MWM) test was performed for spatial learning and memory 31-35 days PI. All animals were euthanized 5 weeks PI and the brains were collected for analyses of lesion volume, cell loss, neurovascular remodeling, and neuroinflammation. Ago2-KD reduced global sEV miRNA levels. Compared with the vehicle treatment, both naïve-sEV and vector-sEV treatments significantly improved functional recovery, reduced hippocampal neuronal cell loss, inhibited neuroinflammation, and promoted neurovascular remodeling (angiogenesis and neurogenesis). However, Ago2-KD-sEV treatment had a significantly less therapeutic effect on all the parameters measured above than did naïve-sEV and vector-sEV treatments. The therapeutic effects of Ago2-KD-sEV were comparable to that of vehicle treatment. Our findings demonstrate that attenuation of Ago2 protein in MSCs reduces miRNAs in MSC-derived sEVs and abolishes exosome treatment-induced beneficial effects in TBI recovery, suggesting that miRNAs in MSC-derived sEVs play an essential role in reducing neuronal cell loss, inhibiting neuroinflammation, and augmenting angiogenesis and neurogenesis, as well as improving functional recovery in TBI. The findings underscore the important role of miRNAs in MSC-derived sEVs in the treatment of TBI.