Treatment Of Brain Injury Research Articles

Human Neural Stem Cell Therapy for Traumatic Brain Injury-A Systematic Review of Pre-Clinical Studies.

Human neural stem cells (hNSCs) possess significant therapeutic potential for the treatment of traumatic brain injury (TBI), a leading cause of global death and disability. Recent pre-clinical studies have shown that hNSCs reduce tissue damage and promote functional recovery through neuroprotective and regenerative signaling and cell replacement. Yet the overall efficacy of hNSCs for TBI indications remains unclear. Therefore, this systematic review aims to evaluate hNSC interventions compared with controls in pre-clinical TBI models. Through this process, variations in hNSC administration protocols were consolidated, and key knowledge gaps were identified. Meta-analysis was applied to primary outcomes of lesion volume, Morris Water Maze (MWM) performance, modified Neurological Severity Scores (mNSS), and the rotarod task. Narrative review of secondary outcomes included hNSC survival and differentiation, endogenous neuron survival, axonal injury, and inflammation. Overall, hNSC intervention reduced lesion volume, enhanced MWM performance, and led to trending decreases in acute and chronic neurological deficits at acute and chronic time points. These results suggest hNSCs demonstrate clear efficacy in pre-clinical TBI models. However, further studies are needed to address key questions regarding optimal hNSC administration (e.g., dosing, treatment window) and underlying mechanisms of action prior to progressing to human clinical trials.

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.

Modulating Ferroptosis: A Novel Approach to Promote Neural Repair in Brain Injury.

The increasing prevalence of brain injuries resulting in cognitive and motor function impairments poses a substantial global medical challenge. Nerve repair therapies offer promise for addressing brain injury-related disorders. Ferroptosis, as a cell death mechanism associated with oxidative stress and inflammation. Certain ferroptosis inhibitors, such as iron chelators and antioxidants, exhibit therapeutic potential for brain injury-related conditions. This review explores the fundamental processes and associated mechanisms that regulate neural repair by inhibiting ferroptosis, thereby alleviating brain injury and promoting neuroregeneration. Furthermore, it examines the action mechanisms and potential therapeutic applications of ferroptosis inhibitors in neural repair, aiming to provide novel insights for treating brain injuries.

Applications of hydrogels and nanoparticles in the treatment of traumatic brain injury.

Traumatic brain injury (TBI) represents a significant global public health issue, with effective management posing numerous challenges. The pathophysiology of TBI is typically categorized into two phases: primary and secondary injuries. Secondary injury involves pathophysiological mechanisms such as blood-brain barrier (BBB) disruption, mitochondrial dysfunction, oxidative stress, and inflammatory responses. Current pharmacological strategies often encounter obstacles in treating TBI effectively, primarily due to challenges in BBB penetration, inadequate target site accumulation, and off-target toxicity. Versatile hydrogels and nanoparticles offer potential solutions to these limitations. This review discusses recent progress in utilizing hydrogels and nanoparticles for TBI treatment over the past 5years, highlighting their relevance to the underlying injury pathophysiology. Hydrogels and nanoparticles demonstrate substantial promise in addressing secondary brain injury, providing a broad spectrum of future therapeutic opportunities.

Unravelling Secondary Brain Injury: Insights from a Human-Sized Porcine Model of Acute Subdural Haematoma.

Traumatic brain injury (TBI) remains one of the leading causes of death. Because of the individual nature of the trauma (brain, circumstances and forces), humans experience individual TBIs. This makes it difficult to generalise therapies. Clinical management issues such as whether intracranial pressure (ICP), cerebral perfusion pressure (CPP) or decompressive craniectomy improve patient outcome remain partly unanswered. Experimental drug approaches for the treatment of secondary brain injury (SBI) have not found clinical application. The complex, cellular and molecular pathways of SBI remain incompletely understood, and there are insufficient experimental (animal) models that reflect the pathophysiology of human TBI to develop translational therapeutic approaches. Therefore, we investigated different injury patterns after acute subdural hematoma (ASDH) as TBI in a post-hoc approach to assess the impact on SBI in a long-term, human-sized porcine TBI animal model. Post-mortem brain tissue analysis, after ASDH, bilateral ICP, CPP, cerebral oxygenation and temperature monitoring, and biomarker analysis were performed. Extracerebral, intraparenchymal-extraventricular and intraventricular blood, combined with brainstem and basal ganglia injury, influenced the experiment and its outcome. Basal ganglia injury affects the duration of the experiment. Recognition of these different injury patterns is important for translational interpretation of results in this animal model of SBI after TBI.

Acute Treatment with Fucoidan Ameliorates Traumatic Brain Injury-Induced Neurological Damages and Memory Deficits in Rats: Role of BBB Integrity, Microglial Activity, Neuroinflammation, and Oxidative Stress.

There is no acquiesced remedy for the treatment of traumatic brain injury (TBI)-associated impairment, especially cognitive decline. The first 24h after TBI is a golden time for preventing the progress of the impairments. The present study aimed to examine the acute effects of fucoidan on neurological outcomes and memory performance and investigate its potential mechanisms in rats with TBI. Fucoidan (25, 50, and 100mg/kg, i.p.) was injected immediately after TBI induction. Veterinary coma scale (VCS), brain edema, blood-brain barrier (BBB) integrity, passive avoidance memory and spatial memory, neuroplasticity, myeloperoxidase (MPO) activity, oxidative stress, and histological alteration were evaluated after TBI induction and fucoidan treatment. The findings revealed that TBI resulted in an enhancement in brain water content and BBB permeability and diminished the performance of passive avoidance memory and spatial memory. These were accompanied by long-term potentiation (LTP) suppression in the hippocampus and the prevention of activities of SOD, catalase, and GPx and enhancement of MPO activity, TNF-α, IL-6, and lipid peroxidation levels in the hippocampus as well as hippocampal neuronal loss. Fascinatingly, acute treatment of TBI rats with fucoidan especially in the higher doses (50 and 100mg/kg) significantly ameliorated (p < 0.05) neurological outcomes of VCS, cerebral edema, BBB integrity, passive avoidance memory, spatial memory, LTP impairment, and oxidative-antioxidative balance. Also, fucoidan significantly ameliorated hippocampal neuronal loss, TNF-α and IL-6 levels, and MPO activity as an indicator of microglial activation. These outcomes imply that fucoidan can be a hopeful remedy for TBI-associated neuronal impairments. However, further research is necessary to endorse this issue.

CXCR2 immunomodulatory therapy protects against microstructural white matter injury and gait abnormalities but does not mitigate deficits of cognition in a preclinical model of cerebral palsy.

Minimizing central nervous system (CNS) injury from preterm birth depends upon understanding the critical pathways that underlie essential neurodevelopmental and CNS pathophysiology. Signaling by chemokine (C-X-C motif) ligand 1 (CXCL1) through its cognate receptor, CXCR2 [(C-X-C motif) receptor 2] is essential for neurodevelopment. Increased CXCR2 signaling, however, is implicated in a variety of uterine and neuropathologies, and their role in the CNS injury associated with perinatal brain injury is poorly defined. To evaluate the long-term efficacy of CXCR2 blockade in functional repair of brain injury secondary to chorioamnionitis (CHORIO), we used an established preclinical rat model of cerebral palsy. We tested the hypothesis that transient postnatal CXCR2 antagonism with SB225002 would reduce gait deficits, hypermobility, hyperactivity, and disinhibition concomitant with repair of functional and anatomical white and gray matter injury. CHORIO was induced in pregnant Sprague Dawley rats on embryonic day 18 (E18). SB225002 (3 mg/kg) was administered intraperitoneally from postnatal day 1 (P1)-P5. Rats were aged to adulthood and tested for gait, open-field behavior and cognitive and executive function deficits using a touchscreen cognitive assessment platform. Results show that transient CXCR2 blockade attenuated microstructural white matter injury after CHORIO consistent with improved anatomical connectivity, and mitigated deficits in gait coordination, posture, balance, paw placement, and stepping (p < 0.05). Animals with CHORIO were hyperactive and hypermobile with fMRI deficits in neural circuitry central to cognition. However, CXCR2 antagonism in CHORIO animals did not normalize open-field behavior, neural activity, or cognition on a touchscreen task of discrimination learning (all p > 0.05). Studies in CXCR2 knockout mice confirmed significantly impaired cognitive performance independent of CHORIO. Taken together, transient postnatal blockade of CXCR2 ameliorates aspects of the lasting neural injury after CHORIO including normalizing gait deficits and white matter injury. However, improvement in essential functional and cognitive domains are not achieved limiting the utility of this therapeutic approach for treatment of perinatal brain injury. This study emphasizes the complex, multi-faceted role of chemokines in typical neurodevelopment, circuit formation, neural network function, and injury response.

Unveiling Interactions between Self-Assembling Peptides and Neuronal Membranes.

The use of self-assembling peptide hydrogels in the treatment of spinal cord and brain injuries, especially when combined with adult neural stem cells, has shown great potential. To advance tissue engineering, it is essential to understand the effect of mechanochemical signaling on cellular differentiation. The elucidation of the molecular interactions at the level of the neuronal membrane still represents a promising area of investigation for many drug delivery and tissue engineering applications. An innovative molecular dynamics framework has been introduced to investigate the effect of SAP fibrils with different charges on neural membrane lipid domain dynamics. Such advance enables the in silico exploration of the biomimetic properties of SAP hydrogels and other polymeric biomaterials for tissue engineering applications.

Astrocyte–neuron crosstalk through extracellular vesicle-shuttled miRNA-382-5p promotes traumatic brain injury

Although astrocytes undergo functional changes in response to brain injury and may be the driving force of subsequent neuronal death, the underlying mechanisms remain incompletely elucidated. Here, we showed that extracellular vesicle (EV)-shuttled miRNA-382-5p may serve as a biomarker for the severity of traumatic brain injury (TBI), as the circulating EV-miRNA-382-5p level was significantly increased in both human patients and TBI model mice. Mechanistically, astrocyte-derived EVs delivered the shuttled miRNA-382-5p to mediate astrocyte–neuron communication, which promoted neuronal mitochondrial dysfunction by inhibiting the expression of optic atrophy-1 (OPA1). Consistent with these findings, genetic ablation of neuronal OPA1 exacerbated mitochondrial damage and neuronal apoptosis in response to TBI. Moreover, engineered RVG-miRNA-382-5p inhibitor-EVs, which can selectively deliver a miRNA-382-5p inhibitor to neurons, significantly attenuated mitochondrial damage and improved neurological function after TBI. Taken together, our data suggest that EV-shuttled miRNA-382-5p may be a critical mediator of astrocyte-induced neurotoxicity under pathological conditions and that targeting miRNA-382-5p-OPA1 signaling has potential for clinical translation in the treatment of traumatic brain injury.

Tibetan golden acupuncture inhibits JNK/caspase-3 signaling pathway to alleviate neuronal apoptosis in cerebral ischemia-reperfusion injury

BackgroundApoptosis induced by cerebral ischemia-reperfusion is one of the key pathological processes of nerve injury. Tibetan golden acupuncture (GA) is a common treatment for ischemic brain injury in Tibetan. The aim of this study was to explore whether GA prevents cerebral ischemia-reperfusion-induced apoptosis in mice by blocking the JNK/caspase-3 pathway. MethodsIn experiment I, 36 mice were randomly divided into a Sham group, CI/RI group, CI/RI + GA group. Morris water maze tests, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and flow cytometry (FCM) were used to evaluate the effect of the GA intervention on CI/RI. In experiment II, 30 mice were randomly divided into a Sham group, CI/RI group, CI/RI + GA group, CI/RI + SP group and CI/RI + SP + EA group. Western blotting was used to detect protein expression of key factors in the JNK signaling pathway in the hippocampus. ResultsAfter 7 and 14 interventions, behavioral evaluations in CI/RI + GA group was significantly different from those in CI/RI groups (p < 0.01), pathological injury and apoptosis were significantly reduced (p < 0.01). Compared with CI/RI group, the expression of P-JNK/JNK, Cleaved caspase-3/caspase-3, Bax, and Bad proteins in CI/RI + GA group, CI/RI + SP and CI/RI + SP + GA groups were significantly decreased (p < 0.01). The expression of B-cell lymphoma 2 (Bcl-2) was significantly increased (p < 0.01, p < 0.05). ConclusionsGA can restore neurological dysfunction and inhibit hippocampal neuronal apoptosis in CI/RI mice, at least partially through inhibition of the JNK/Caspase-3 signaling pathway and regulation of apoptosis signals.

Neuroprotective Effects of Ethanol Extract Polyscias guilfoylei (EEPG) Against Glutamate Induced Neurotoxicity in HT22 Cells.

Oxidative stress induced by glutamate is a significant contributor to neuronal cell damage and can lead to neurodegenerative diseases such as Alzheimer's, Huntington's, and ischemic brain injury. At the cellular level, oxidative stress increases Ca2+ ion influx and reactive oxygen species (ROS), which activate the MAPK signaling pathway. Additionally, the generation of ROS causes mitochondrial dysfunction, triggering apoptosis by promoting the translocation of AIF to the nucleus from the mitochondria. The neuroprotective potential of Polyscias guilfoylei has not yet been reported. Therefore, in this study, the ethanol extract of Polyscias guilfoylei (EEPG) was examined for its protective effect against oxidative cell damage caused by glutamate in neuronal cells. EEPG treatment increased the viability of HT22 cells exposed to high concentrations of glutamate. Cellular Ca2+ ion influx and ROS generation decreased with EEPG treatment in glutamate-treated HT22 cells. EEPG treatment inhibited MAPK activation and AIF nuclear translocation. In an in vivo study, EEPG attenuated brain cell death in an ischemic brain injury rat model. This study demonstrates the potential therapeutic effects of Polyscias guilfoylei in the treatment of ischemic brain injury.

Design and methodology of a randomized clinical trial of quetiapine to reduce central nervous system polypharmacy in veterans with postconcussive syndrome symptoms

Lack of evidence to guide medication treatments for mild traumatic brain injury (mTBI) in veterans too often results in polypharmacy practices attempting to provide symptomatic relief from multiple postconcussive syndrome symptoms. Therefore, the field needs to find an effective medication that reduces the burden of postconcussive symptoms without complicating the treatment burden of veterans. This clinical trial seeks to determine whether switching veterans to quetiapine monotherapy (intervention) is superior to continuing to receive treatment as usual (TAU, control) polypharmacy for veterans with symptoms of postconcussive syndrome and posttraumatic stress disorder who are receiving rehabilitation treatment for mTBI. This study will test the conceptual mediation model hypothesis that quetiapine monotherapy may enhance recovery from mTBI by (1) increasing engagement in rehabilitation services, and/or (2) reducing the adverse effects of TAU polypharmacy. This study will enroll 146 patients from two Veterans Administration Medical Centers into a 12- week phase III, randomized, pragmatic clinical trial comparing outcomes from treatment with quetiapine monotherapy and TAU. Quetiapine will be cross tapered up to a maximum dose of 200 mg (as tolerated) as other medications are discontinued. The primary outcome measures are postconcussive syndrome symptoms (Neurobehavioral Symptom Inventory), functional disability (World Health Organization Disability Assessment), and quality of life (World Health Organization Quality of Life Assessment). Overall, this study aims to determine whether quetiapine monotherapy is superior to TAU polypharmacy and improves the quality of life for veterans with comorbid postconcussive syndrome and posttraumatic stress disorder symptoms who are receiving rehabilitation treatment for mTBI.

Systematic quantitative evaluation of gene polymorphism and therapeutic effect of xingnaojing injection in patients with brain injury.

The incidence of brain injury is increasing year by year, and it has become one of the major diseases threatening human life in today's society. From the perspective of the causes of brain injury, it is mainly due to falls from high places, traffic accidents, etc. Severe brain injury patients often lose consciousness. In recent years, the emergence of integrated traditional Chinese and Western medicine has provided a new approach and new ideas for the treatment of craniocerebral trauma. The article systematically and scientifically expounded the role of Xingnaojing injection in the treatment of brain injury by comparing the GCS (Glasgow Coma Scale) score, changes in intracranial pressure, the incidence of complications after brain injury, the transformation from moderate brain injury to severe brain injury, and recovery of consciousness. For the problem of gene polymorphism in patients with brain injury, this article discussed the role of APOE2 (Apolipoprotein E2), ε3, ε4 in brain injury. All patients had a clear history of trauma and received strict nervous system examination and CT scanning when they were admitted to the hospital. After craniocerebral trauma surgery or conservative therapy, patients should take a Xingnaojing injection of 30 ml and a 0.9% sodium chloride injection of 250 ml after admission. After the operation, respiratory tract nursing should be strengthened, and patients who cannot eat should be given nasal feeding, acupuncture, and physiotherapy to prevent bedridden complications. The probability of epilepsy after brain injury was 27%. The article would help to evaluate the degree of brain damage and prognosis of patients.

Antisecretory Factor 16 (AF16): A Promising Avenue for the Treatment of Traumatic Brain Injury—An In Vitro Model Approach

Traumatic brain injury (TBI) is caused by an external mechanical force to the head, resulting in abnormal brain functioning and clinical manifestations. Antisecretory factor (AF16) is a potential therapeutic agent for TBI treatment due to its ability to inhibit fluid secretion and decrease inflammation, intracranial pressure, and interstitial fluid build-up, key hallmarks presented in TBI. Here, we investigated the effect of AF16 in an in vitro model of neuronal injury, as well as its impact on key components of the autophagy pathway and mitochondrial dynamics. N2Awt cells were treated with AF16, injured using a scratch assay, and analysed using confocal microscopy, correlative light and electron microscopy (CLEM), flow cytometry, and western blotting. Our results reveal that AF16 enhances autophagy activity, regulates mitochondrial dynamics, and provides protection as early as 6 h post-injury. Fluorescently labelled AF16 was observed to localise to lysosomes and the autophagy compartment, suggesting a role for autophagy and mitochondrial quality control in conferring AF16-associated neuronal protection. This study concludes that AF16 has potential as a therapeutic agent for TBI treatment through is regulation of autophagy and mitochondrial dynamics.

Comorbid treatment of traumatic brain injury and mental health disorders.

The Emory Healthcare Veterans Program (EHVP) is a multidisciplinary intensive outpatient treatment program for post-9/11 veterans and service members with invisible wounds, including posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), substance use disorders (SUD), and other anxiety- and depression-related disorders. This article reviews the EHVP. The different treatment tracks that provide integrated and comprehensive treatment are highlighted along with a review of the standard, adjunctive, and auxiliary services that complement individualized treatment plans. This review particularly emphasizes the adjunctive neurorehabilitation service offered to veterans and service members with a TBI history and the EVHP data that indicate large reductions in PTSD and depression symptoms across treatment tracks that are maintained across 12 months follow up. Finally, there is a discussion of possible suboptimal treatment response and the pilot programs related to different treatment augmentation strategies being deploying to ensure optimal treatment response for all. Published data indicate that the two-week intensive outpatient program is an effective treatment program for a variety of complex presentations of PTSD, TBI, SUD, and other anxiety- and depression-related disorders in veterans and active duty service members.

Dynamic Craniotomy With Khanna NuCrani Plates as an Alternative to Craniotomy With Fixed Plates in Traumatic Brain Injury.

Dynamic craniotomy as opposed to a fixed plate craniotomy provides cranial decompression with a controlled outward bone flap movement to accommodate postoperative cerebral swelling and/or hemorrhage. The objective of this study was to evaluate if fixation of the bone flap following a trauma craniotomy with dynamic plates provides any advantage over fixed plates. A review of our clinical series of 25 consecutive adult patients undergoing dynamic craniotomy with the Khanna NuCrani reversibly expandable bone flap fixation plates for the treatment of traumatic brain injury associated with mass lesions including subdural, epidural, and cerebral hematomas was conducted. Postoperative cerebral swelling was encountered in 21 of 25 patients (84%), which was compensated for with outward bone flap movement in all these patients and associated decreased midline shift. Severe brain swelling with outward bone flap movement of 8 mm or more was noted in 40% of the patients. All patients had a normal intracranial pressure after surgery. None of the patients required any reoperations for hematoma evacuation, rescue decompressive craniectomies, cranioplasty, or complications related to wound healing. The bone flap retracted after the resolution of the brain swelling, and none of the patients reported cosmetic symptoms related to bone flap or wound healing. Overall, 84% (21 of 25) of the patients achieved a good outcome. Craniotomy bone flap fixation with dynamic plates is an alternative to craniotomy with fixed plates. The main advantage of dynamic craniotomy over a craniotomy with fixed plates is that it allows for immediate intracranial volume expansion with reversible outward bone flap migration in patients who may develop postoperative worsening brain swelling and/or hemorrhage, with decreased need for repeat surgeries and associated complications.

Targeting glycolysis for neuroprotection in early LPS-induced neuroinflammation

Neuroinflammation is a pathophysiological feature of numerous neurological and psychiatric disorders. The immune response in the central nervous system, driven by microglia and astrocytes, leads to metabolic reprogramming towards aerobic glycolysis, a phenomenon known as the Warburg effect. The control of metabolic reprogramming via immunomodulation may represent a potential therapeutic target for providing protection against neuroinflammation, which contributes to neuronal dysfunction and death in several neurological disorders. For this purpose, we investigated putative neuroprotective effects of the downregulation of aerobic glycolysis using the 3PO inhibitor, and the downregulation of neuroinflammation using MCC950, in the early LPS-induced neuroinflammation model. The LPS-induced shift towards glycolysis, inflammatory and glial changes (IL-1β, NF-κB, COX2, Iba1, GFAP) were reversed by 3PO, which improved animal behavior. Additionally, MCC950 (an NLRP3 inhibitor) downregulated TLR4/Akt/p38 MAPK/NF-κB/STAT3 signaling, expressions of COX2 and IL-1β, and the astrocyte reactivity (decreasing GFAP) induced by early neuroinflammation, resulting in low glucose uptake. Our data support the occurrence of the Warburg effect during early neuroinflammation and suggest potential new approaches for the treatment of brain injury, given the role of neuroinflammation in such events.

Unraveling the Emerging Niche Role of Extracellular Vesicles (EVs) in Traumatic Brain Injury (TBI).

Extracellular vesicles or exosomes, often known as EVs, have acquired significant attention in the investigations of traumatic brain injury (TBI) and have a distinct advantage in actively researching the fundamental mechanisms underlying various clinical symptoms and diagnosing the wide range of traumatic brain injury cases. The mesenchymal stem cells (MSCs) can produce and release exosomes, which offer therapeutic benefits. Exosomes are tiny membranous vesicles produced by various cellular entities originating from endosomes. Several studies have reported that administering MSC-derived exosomes through intravenous infusions improves neurological recovery and promotes neuroplasticity in rats with traumatic brain damage. The therapeutic advantages of exosomes can be attributed to the microRNAs (miRNAs), which are small non-coding regulatory RNAs that significantly impact the regulation of posttranscriptional genes. Exosome-based therapies, which do not involve cells, have lately gained interest as a potential breakthrough in enhancing neuroplasticity and accelerating neurological recovery for various brain injuries and neurodegenerative diseases. This article explores the benefits and drawbacks of exosome treatment for traumatic brain injury while emphasizing the latest advancements in this field with clinical significance.

A Partner-Engaged Approach to Developing an Implementation Research Logic Model for a Traumatic Brain Injury-Intensive Evaluation and Treatment Program.

A partnered evaluation project with Veterans Health Administration Physical Medicine and Rehabilitation program office uses a partner-engaged approach to characterize and evaluate the national implementation of traumatic brain injury (TBI)Intensive Evaluation and Treatment Program (IETP). This paper illustrates a partner-engaged approach to contextualizing the IETP within an implementation research logic model (IRLM) to inform program sustainment and spread. The project was conducted at five IETP sites: Tampa, Richmond, San Antonio, Palo Alto, and Minneapolis. Partners included national and site program leaders, clinicians, Department of Defense Referral Representatives, and researchers. Participants included program staff ( n =46) and Service Members/Veterans ( n =48). This paper represents a component of a larger participatory-based concurrent mixed methods quality improvement project. Participant scripts and demographic surveys. Datasets were analyzed using rapid iterative content analysis; IETP model was iteratively revised with partner feedback. Each site had an IETP clinical team member participate. The IRLM was contextualized within the Consolidated Framework for Implementation Research (CFIR); systematic consensus building expert reviewed implementation strategies; RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance); and Implementation Outcomes Framework (IOF). Analyses and partner feedback identified key characteristics, determinants, implementation strategies, mechanisms, and outcomes. This partner-engaged IRLM informs implementation and sustainment of a rehabilitation program for individuals with TBI. Findings will be leveraged to examine implementation, standardize core outcome measurements, and inform knowledge translation.

EEG hyperexcitability and hyperconnectivity linked to GABAergic inhibitory interneuron loss following traumatic brain injury.

Traumatic brain injury represents a significant global health burden and has the highest prevalence among neurological disorders. Even mild traumatic brain injury can induce subtle, long-lasting changes that increase the risk of future neurodegeneration. Importantly, this can be challenging to detect through conventional neurological assessment. This underscores the need for more sensitive diagnostic tools, such as electroencephalography, to uncover opportunities for therapeutic intervention. Progress in the field has been hindered by a lack of studies linking mechanistic insights at the microscopic level from animal models to the macroscale phenotypes observed in clinical imaging. Our study addresses this gap by investigating a rat model of mild blast traumatic brain injury using both immunohistochemical staining of inhibitory interneurons and translationally relevant electroencephalography recordings. Although we observed no pronounced effects immediately post-injury, chronic time points revealed broadband hyperexcitability and increased connectivity, accompanied by decreased density of inhibitory interneurons. This pattern suggests a disruption in the balance between excitation and inhibition, providing a crucial link between cellular mechanisms and clinical hallmarks of injury. Our findings have significant implications for the diagnosis, monitoring, and treatment of traumatic brain injury. The emergence of electroencephalography abnormalities at chronic time points, despite the absence of immediate effects, highlights the importance of long-term monitoring in traumatic brain injury patients. The observed decrease in inhibitory interneuron density offers a potential cellular mechanism underlying the electroencephalography changes and may represent a target for therapeutic intervention. This study demonstrates the value of combining cellular-level analysis with macroscale neurophysiological recordings in animal models to elucidate the pathophysiology of traumatic brain injury. Future research should focus on translating these findings to human studies and exploring potential therapeutic strategies targeting the excitation-inhibition imbalance in traumatic brain injury.