Diffuse Axonal Injury Research Articles

Hyperglycemia Aggravates Blood-Brain Barrier Disruption Following Diffuse Axonal Injury by Increasing the Levels of Inflammatory Mediators through the PPARγ/Caveolin-1/TLR4 Pathway.

Hyperglycemia aggravates brain damage after diffuse axonal injury (DAI), but the underlying mechanisms are not fully defined. In this study, we aimed to investigate a possible role for hyperglycemia in the disruption of blood-brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50% glucose was intraperitoneally injected after DAI to establish the hyperglycemia model. Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of inflammatory factors, including TNF-α, IL-1β, and IL-6. It also exacerbated BBB disruption and decreased the expression of tight junction-associated proteins, including ZO-1, claudin-5, and occludin-1, whereas the PPARγ agonist rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs). Hyperglycemia induction worsened the loss of BBB integrity induced by oxygen and glucose deprivation (OGD) by increasing the release of inflammatory factors and decreasing the expression of tight junction-associated proteins. Hyperglycemia further reduced the expression of PPARγ and caveolin-1, which significantly decreased after DAI and OGD. Hyperglycemia also further increased the expression of toll-like receptor 4 (TLR4), which significantly increased after OGD. Subsequently, the PPARγ agonist RSG increased caveolin-1 expression and decreased TLR4 expression and inflammatory factor levels. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of hyperglycemia by increasing TLR4 and Myd88 expression and the levels of inflammatory factors, including TNF-α, IL-1β, and IL-6. Collectively, we demonstrated that hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing inflammation through the PPARγ/caveolin-1/TLR4 pathway.

Segmented 3D Echo Planar Acquisition for Rapid Susceptibility-Weighted Imaging: Application to Microhemorrhage Detection in Traumatic Brain Injury.

Susceptibility-weighted imaging (SWI) provides superior image contrast of cerebral microhemorrhages (CMBs). It is based on a three-dimensional (3D) gradient echo (GRE) sequence with a relatively long imaging time. To evaluate whether an accelerated 3D segmented echo planar imaging SWI is comparable to GRE SWI in detecting CMBs in traumatic brain injury (TBI). Prospective. Four healthy volunteers and 46 consecutive subjects (38.0 ± 14.4 years, 16 females; 12 mild, 13 moderate, and 7 severe TBI). A 3 T scanner/3D gradient echo and 3D segmented echo planar imaging (segEPI). Brain images were acquired using GRE and segEPI in a single session (imaging time=9minutes 47 seconds and 1minute 30 seconds, respectively). The signal-to-noise ratio (SNR) calculated from healthy volunteer thalamus and centrum semiovale were compared. CMBs were counted by three raters blinded to diagnostic information. A t-test was used to assess SNR difference. Pearson correlation and Wilcoxon signed-rank test were performed using CMB counts. The intermethod agreement was evaluated using Bland-Altman method. Intermethod and interrater reliabilities of image-based diffuse axonal injury (DAI) diagnoses were evaluated using Cohen's kappa and percent agreement. P ≤ 0.05 was considered statistically significant. Thalamus SNRs were 16.9 ± 2.2 and 16.5 ± 3 for GRE and segEPI (P=0.84), respectively. Centrum semiovale SNRs were 25.8 ± 4.6 and 21.1 ± 2.7 (P=0.13). The correlation coefficient of CMBs was 0.93, and differences were not significant (P=0.56-0.85). For DAI diagnoses, Cohen's kappa was 0.62-0.84 and percent agreement was 85%-94%. CMB counts on segEPI and GRE were highly correlated, and DAI diagnosis was made equally effectively. segEPI SWI can potentially replace GRE SWI in detecting TBI CMBs, especially when time constraints are critical. 1 TECHNICAL EFFICACY: Stage 2.

Time to Follow Commands in Severe Traumatic Brain Injury Survivors With Favorable Recovery at 2 Years.

The recovery of severe traumatic brain injury (TBI) survivors with long-term favorable outlook is understudied. Time to follow commands varies widely in this patient population but has important clinical implications. To (1) evaluate time to follow commands in severe patients with TBI with favorable outcomes, (2) characterize their trajectory of recovery, and (3) identify predictors associated with delayed cognitive improvement. Participants were recruited prospectively at a Level I trauma center through the Brain Trauma Research Center from 2003 to 2018. Inclusion criteria were age 16 to 80 years, Glasgow Coma Scale score ≤8 and motor score <6, and Glasgow Outcome Scale-Extended measure ≥4 at 2 years postinjury. In 580 patients, there were 229 (39.5%) deaths and 140 (24.1%) patients had favorable outcomes at 2 years. The mean age was 33.7 ± 14.5 years, median Glasgow Coma Scale was 7 (IQR 6-7), and median Injury Severity Score was 30 (IQR 26-38). The mean time to follow commands was 12.7 ± 11.8 days. On multivariable linear regression, the presence of diffuse axonal injury (B = 9.2 days [4.8, 13.7], P < .0001) or intraventricular hemorrhage (B = 6.4 days [0.5, 12.3], P < .035) was associated with longer time before following commands and patients who developed nosocomial infections (B = 6.5 days [1.6-11.4], P < .01). In severe TBI survivors with favorable outcomes, time to follow commands varied widely. Most patients began to follow commands within 2 weeks. Evidence of diffuse axonal injury, intraventricular hemorrhage, and infections can delay cognitive improvement in the acute period. Patients make considerable recovery up to 2 years after their injury.

Combining advanced magnetic resonance imaging (MRI) with finite element (FE) analysis for characterising subject-specific injury patterns in the brain after traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability. The way mechanical impact is transferred to the brain has been shown to be a major determinant for structural damage and subsequent pathological sequalae. Although finite element (FE) models have been used extensively in the investigation of various aspects of TBI and have been instrumental in characterising a TBI injury threshold and the pattern of diffuse axonal injuries, subject-specific analysis has been difficult to perform due to the complexity of brain structures and its material properties. We have developed an efficient computational pipeline that can generate subject-specific FE models of the brain made up of conforming hexahedral elements directly from advanced MRI scans. This pipeline was applied and validated in our sheep model of TBI. Our FE model of the sheep brain accurately predicted the damage pattern seen on post-impact MRI scans. Furthermore, our model also showed a complex time-varying strain distribution pattern, which was not present in the homogeneous model without subject-specific material descriptions. To our knowledge, this is the first fully subject-specific FE model of the sheep brain able to predict structural damage after a head impact. The pipeline developed has the potential to augment the analysis of human brain MRI scans to detect changes in brain structures and function after TBI.

Impaired neuronal integrity in traumatic brain injury detected by 123I-iomazenil single photon emission computed tomography and MRI

This study was aiming at investigating the extent of neuronal damage in cases of traumatic brain injury (TBI) with diffuse axonal injury (DAI) using 123I-iomazenil(IMZ) SPECT and MRI. We compared the findings in 31 patients with TBI without any major focal brain lesions and 25 age-matched normal controls. Subjects underwent 123I-IMZ SPECT and MRI, and also assessment by cognitive function tests. The partial volume effect of 123I-IMZ SPECT was corrected using MRI. In the patients with TBI, decreased spatial concentration of 123I-IMZ binding was detected in the medial frontal/orbitofrontal cortex, posterior cingulate gyrus, cuneus, precuneus, and superior region of the cerebellum. ROC analysis of 123I-IMZ SPECT for the detection of neuronal injury showed a high diagnostic ability of 123I-IMZ binding density for TBI in these areas. The decreased 123I-IMZ uptake density in the cuneus and precuneus was associated with cognitive decline after the injury. In the patients with TBI, brain atrophy was detected in the frontal lobe, anterior temporal and parietal cortex, corpus callosum, and posterior part of the cerebellum. Evaluation of the neuronal integrity by 123I-IMZ SPECT and MRI provides important information for the diagnosis and pathological interpretation in cases of TBI with DAI.

Evaluation of Laboratory Variables Related to Diffuse Axonal Injury: A Cross-sectional Study

Background: Diffuse axonal injury (DAI) is an injury that occurs after the onset of traumatic brain injury (TBI), leading to many problems for patients and imposing high costs on the treatment system. Objectives: This study was conducted to investigate the status of laboratory variables in patients with DAI. Methods: This cross-sectional study included 140 patients. Data collection tools were a demographic profile form and magnetic resonance imaging (MRI). Laboratory tests, including glucose, LDL-C, HDL-C, total cholesterol, triglycerides, Hb, HCT, PT, PTT, INR, BUN, creatinine, and CRP were evaluated. Also, specialized devices were used to study the laboratory and radiology variables. Results: Most (61.5%) of the patients were male, 47.1% had a non-governmental occupation, and 55.7% were less than 30 years old. Also, in 87.9% of cases, traffic accidents were the cause of DAI and in 65% of patients, the Glasgow Coma Scale (GCS) was less than 7. In all the laboratory variables differences were observed between the experimental and the control groups. Conclusions: The laboratory variables in patients with DAI had a statistically significant difference compared to the case group, which indicates the negative effect of DAI on laboratory variables. Further studies are required to confirm our results.

Association Between Serum Electrolyte Disturbances and Glasgow Coma Scale Score in Patients With Diffuse Axonal Injury

Background: Appropriate clinical measures to prevent secondary brain damage in traumatic brain injury are of critical importance. Objectives: This study aims to investigate the relationships between serum electrolyte disturbances and Glasgow Coma Scale (GCS) score in patients with Diffuse Axonal Injury (DAI) at the time of admission and discharge. Materials & Methods: In this retrospective cross-sectional study, we evaluated 101 patients with DAI having GCS score <15 admitted to Poursina Hospital in Rasht, Iran from 2019 to 2020. Based on the presence or absence of serum potassium (K), sodium (Na), magnesium (Mg), and zinc (Zn), disturbances on the first day of hospitalization, patients were divided into two study groups of with and without abnormal electrolyte levels. The GCS scores of the two groups at the time of admission and discharge were recorded and the relationship between electrolyte disturbances and GCS score was evaluated. Results: There were no significant differences in the mean GCS score at the time of admission and discharge between patients with and without disturbances in serum Na, K, Zn and Mg levels based on the crude analysis. Regarding the simultaneous effects of the study variables on the GCS score, only Mg serum level exerted a significant impact on the GCS score at the time of admission (P=0.041) and discharge (P=0.017). Conclusion: The GCS score in patients with DAI at the time of admission and discharge has an association with the Mg serum level but not with Na, K, and Zn levels.

The Concept and Pathological Mechanism of Diffuse Axonal Injury

The Concept and Pathological Mechanism of Diffuse Axonal Injury

Role of Diffusion Tensor Imaging in the Diagnosis of Traumatic Axonal Injury in Individual Patients with a Concussion or Mild Traumatic Brain Injury: A Mini-Review.

Present review paper aims to understand role of diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) in diagnosis of traumatic axonal injury (TAI), induced by head trauma, in individual patients with a concussion or mild traumatic brain injury (mTBI). Precise information on presence and severity of TAI in brain is necessary for determining appropriate therapeutic strategies. Several hundred DTI-based studies have reported TAI in concussion or mTBI. Majority of these DTI-based studies have been performed in a group of patients, whereas case studies that have reported TAI in individual patients with a concussion or mTBI are fewer. Summary of these DTI-based studies for individual patients is as follows: DTI can be used as a non-invasive tool for determining presence and severity of TAI in individual patients with concussion or mTBI. However, for diagnosis of TAI in an individual patient, several conditions are required to be met: no past history of head trauma, presence of possible conditions for TAI occurrence during head trauma, development of new clinical features after head trauma, and DTI observed abnormality of a neural structure that coincides with a newly developed clinical feature. However, further studies for a more precise diagnosis of TAI in individual patients should be encouraged.

A proposed novel traumatic brain injury classification system – an overview and inter-rater reliability validation on behalf of the Society of British Neurological Surgeons

Introduction The measurement of traumatic brain injury (TBI) ‘severity’ has traditionally been based on the earliest Glasgow Coma Score (GCS) recorded, however, the underlying parenchymal pathology is highly heterogonous. This heterogeneity renders prediction of outcome on an individual patient level inaccurate and makes comparison between patients both in clinical practice and research difficult. The complexity of this heterogeneity has resulted in generic all encompassing ‘traumatic brain injury protocols’. Early management and studies of neuro-protectants are often done irrespective of TBI type, yet it may well be that a specific treatment may be beneficial in a subset of TBI pathologies. Methods A simple CT-based classification system rating the recognised types of blunt TBI (extradural, subdural, subarachnoid haemorrhage, contusions/intracerebral haematoma and diffuse axonal injury) as mild (1), moderate (2) or severe (3) is proposed. Hypoxic brain injury, a common secondary injury following TBI, is also included. Scores can be combined to reflect concomitant types of TBI and predominant location of injury is also recorded. To assess interrater reliability, 50 patient CT images were assessed by 5 independent clinicians of varying experience. Interrater reliability was calculated using overall agreement through Cronbach’s alpha including confidence intervals for intra-class coefficients. Results Interrater reliability scores showed strong agreement for same score and same injury for TBIs with blood on CT and Cronbach’s alpha co-efficient (range 0.87–0.93) demonstrated excellent correlation between raters. Cronbach’s alpha was not affected when individual raters were removed. Conclusions The proposed simple CT classification system has good inter-rater reliability and hence potentially could enable better individual prognostication and targeted treatments to be compared while also accounting for multiple intracranial injury types. Further studies are proposed and underway.

Somatostatin interneurons exhibit enhanced functional output and resilience to axotomy after mild traumatic brain injury

Mild traumatic brain injury (mTBI) gives rise to a remarkable breadth of pathobiological consequences, principal among which are traumatic axonal injury and perturbation of the functional integrity of neuronal networks that may arise secondary to the elimination of the presynaptic contribution of axotomized neurons. Because there exists a vast diversity of neocortical neuron subtypes, it is imperative to elucidate the relative vulnerability to axotomy among different subtypes. Toward this end, we exploited SOM-IRES-Cre mice to investigate the consequences of the central fluid percussion model of mTBI on the microanatomical integrity and the functional efficacy of the somatostatin (SOM) interneuron population, one of the principal subtypes of neocortical interneuron. We found that the SOM population is resilient to axotomy, representing only 10% of the global burden of inhibitory interneuron axotomy, a result congruous with past work demonstrating that parvalbumin (PV) interneurons bear most of the burden of interneuron axotomy. However, the intact structure of SOM interneurons after injury did not translate to normal cellular function. One day after mTBI, the SOM population is more intrinsically excitable and demonstrates enhanced synaptic efficacy upon post-synaptic layer 5 pyramidal neurons as measured by optogenetics, yet the global evoked inhibitory tone within layer 5 is stable. Simultaneously, there exists a significant increase in the frequency of miniature inhibitory post-synaptic currents within layer 5 pyramidal neurons. These results are consistent with a scheme in which 1 day after mTBI, SOM interneurons are stimulated to compensate for the release from inhibition of layer 5 pyramidal neurons secondary to the disproportionate axotomy of PV interneurons. The enhancement of SOM interneuron intrinsic excitability and synaptic efficacy may represent the initial phase of a dynamic process of attempted autoregulation of neocortical network homeostasis secondary to mTBI.

Paravalvular Leak Immediately Following Repeat Mitral Valve Replacement: Considerations for Repair in a High-Risk Patient

A PARAVALVULAR LEAK (PVL) immediately after mitral valve replacement (MVR) surgery is a well-known and dreaded complication shown to affect 2% to 30% of patients. The patients with a PVL often suffer debilitating congestive heart failure symptoms resulting from retrograde blood flow and hemolytic anemia from the shearing injury caused by high velocity jets.1 As a result, these patients are more likely to require repeated blood product transfusions, reoperation, and have an increased risk of mortality.

Analysis and outcomes of diffuse axonal injury in tertiary care centre

To report the clinical features, radiological features and outcomes of patients with diffuse axonal injury in a tertiary care centre. Fifty five patients with history of trauma with low GCS and radiological evidence of DAI were studied from August 2016 to December 2018. It consisted 46 (84%) males and 9 (16%) females. Majority of the patients were in age group of 16-25. Most common modality of injury was RTA. Seven (12.7%) patients had grade 1 DAI, 36 (65.5%) patients had grade 2 DAI and 12 (21.8%) patients had grade 3 DAI. Follow up was done after 3 months of injury. Patients outcome was analysed using the Glasgow Outcome Scale. Patients with GCS 3-8 had GOS 1-3. Patients with GCS of 9-12 had GOS of 3-4 and Patients with GCS of 13-15 had GOS of 4-5. Most patients in our study had grade 2 DAI and GOS 4. Diffuse axonal injury is devastating types of traumatic brain injury. The acceleration-deceleration mechanism is responsible for DAI. It is most commonly analyzed based on the outcomes of GOS Scale. Most of the patients in this study had grade 2 DAI. Good recovery was seen in grade 1 and 2 DAI and high mortality in grade 3 DAI.

Cerebral Autoregulation and Cardiovascular Physiology Dysfunction in Traumatic Brain Injury Cases: A Brief Review

Introduction: Traumatic brain injury (TBI) is one of the leading causes of death and disability in the early years of life. Post-TBI physiological alterations vary across adult and pediatric patients and severity. This disease affects the quality of life of most people. Acute hemiparesis can cause cognitive impairments. It may also impact mood, memory, and decision-making. Furthermore, parasympathetic dysfunction and sympathetic activation appear to contribute to cardiac injury via modulation of the myocardial inflammatory response via acetylcholine receptors.
 Purpose: This review aims to explain the neuronal response and cardiac dysfunction after traumatic brain injury cases.
 Methods: The review used Pubmed and Google Scholar to search for articles on traumatic brain injury, neuronal response, and cardiac biomarkers. The articles were chosen for their language, publishing, content, exposure, and outcome. The main reference is obtained from up to 79 articles that meet the inclusion requirements.
 Results: TBI can cause localized brain injury or diffuse brain injury from physical trauma such as diffuse axonal injury or brain edema. Repeated concussions raise the likelihood of chronic neurological, cognitive, and behavioral issues. Stress-induced catecholamine surges and inflammatory mediator production in response to trauma may also endanger cardiac disturbances. ECG changes in patients with severe traumatic brain injury are associated with cardiac dysfunction. Cardiac enzymes can be used as a diagnostic tool and indicate the patient's prognosis.
 Conclusion: Cerebral autoregulation and cardiac physiological responses have a synergistic relationship in maintaining tissue homeostasis in patients with traumatic brain injury. Patients with TBI may experience cardiac dysfunction as a result of the body’s exaggerated systemic response to brain injury.

Rehabilitation of Diffuse Axonal Injury Deficit Caused by Traumatic Brain Injury Through Ayurvedic Treatment Protocol- A Case Study.

One of the most important types of brain damage that can occur as a result of non-missile head injury is diffuse axonal injury. Though DAI is a histological diagnosis, clinically it may be defines as a state of unconsciousness lasting for minimum 6 hours or more after traumatic brain injury  except cases of swelling or ischemic brain lesions. DAI is the considered the most important factor in determining the morbidity and mortality in the traumatic brain injury. DIA causes behavioral, physical, and cognitive changes that effect on social and personal life of a patient also quality of life of patients and their families is affected. Ayurveda describes Head as a marma point. Head injury is termed as Shiromarma abhigata in Ayurveda classical books. Ayurveda treats this with the help of some herbal remedies and Panchakarma like Snehan, Pinda sweda, Nasya, Basti and Marma therapy

Cerebral Microbleeds and Structural White Matter Integrity in Patients With Traumatic Brain Injury-A Diffusion Tensor Imaging Study.

Diffuse axonal injury (DAI) is a common neuropathological manifestation of traumatic brain injury (TBI), presenting as traumatic alterations in the cerebral white matter (WM) microstructure and often leading to long-term neurocognitive impairment. These WM alterations can be assessed using diffusion tensor imaging (DTI). Cerebral microbleeds (CMBs) are a common finding on head imaging in TBI and are often considered a visible sign of DAI, although they represent diffuse vascular injury. It is poorly known how they associate with long-term white matter integrity. This study included 20 patients with TBI and CMBs, 34 patients with TBI without CMBs, and 11 controls with orthopedic injuries. DTI was used to assess microstructural WM alterations. CMBs were detected using susceptibility-weighted imaging (SWI) and graded according to their location in the WM and total lesion load was counted. Patients underwent SWI within 2 months after injury. DTI and clinical outcome assessment were performed at an average of eight months after injury. Outcome was assessed using the extended Glasgow Outcome Scale (GOSe). The Glasgow Coma Scale (GCS) and length of post-traumatic amnesia (PTA) were used to assess clinical severity of the injury. We found that CMB grading and total lesion load were negatively associated with fractional anisotropy (FA) and positively associated with mean diffusivity (MD). Patients with TBI and CMBs had decreased FA and increased MD compared with patients with TBI without CMBs. CMBs were also associated with worse clinical outcome. When adjusting for the clinical severity of the injury, none of the mentioned associations were found. Thus, the difference in FA and MD is explained by patients with TBI and CMBs having more severe injuries. Our results suggest that CMBs are not associated with greater WM alterations when adjusting for the clinical severity of TBI. Thus, CMBs and WM alterations may not be strongly associated pathologies in TBI.

Observation on the Clinical Effect of Different Pressures in Hyperbaric Oxygen Therapy on Patients with Diffuse Axonal Injury

Objective: To observe the efficacy and significance of hyperbaric oxygen at different pressures in the treatment of diffuse axonal injury (DAI). Methods: Sixty patients with DAI were randomly divided into 1.8 ATA group (30 cases) and 2.2 ATA group (30 cases). The routine treatment for each group was the same. The 1.8 ATA group received hyperbaric oxygen therapy under 1.8 ATA on the basis of routine treatment, whereas the 2.2 ATA group received hyperbaric oxygen therapy under 2.2 ATA on the basis of routine treatment. The therapy was given once a day over 3 consecutive courses, with each course having 10 sessions. The Glasgow Coma Scale (GCS) on day 10, day 20, and day 30 after treatment, as well as the Glasgow Outcome Scale (GOS) after 6 months were compared between the two groups. Results: The mean GCS on day 10, day 20, and day 30 after treatment, as well as the mean GOS after 6 months of treatment in the 2.2 ATA group were significantly higher than those in the 1.8 ATA group (p < 0.05). Conclusion: For patients with diffuse axonal injury, hyperbaric oxygen therapy is more effective with 2.2 ATA compared with 1.8 ATA.

Hidden Truth in Cerebral Concussion-Traumatic Axonal Injury: A Narrative Mini-Review.

This study reviewed traumatic axonal injury (TAI) in patients with concussion. Concussion refers to transient changes in the neurological function of the brain resulting from head trauma that should not involve any organic brain injury. On the other hand, TAI has been reported in autopsy studies of the human brain and histopathological studies of animal brains following concussion before the development of diffusion tensor imaging (DTI). The diagnosis of TAI in live patients with concussion is limited because of the low resolution of conventional brain magnetic resonance imaging. Since the first study by Arfanakis et al. in 2002, several hundred studies have reported TAI in patients with concussion using DTI. Furthermore, dozens of studies have demonstrated TAI using diffusion tensor tractography for various neural tracts in individual patients with concussion. Hence, DTI provides valuable data for the diagnosis of TAI in patients with concussion. Nevertheless, the confirmation of TAI in live patients with concussion can be limited because a histopathological study via a brain biopsy is required to confirm TAI. Accordingly, further studies for a diagnostic approach to TAI using DTI without a histopathological test in individual patients with concussion will be necessary in the clinical field.

Histological, immunohistochemical, and morphometric analysis of negative pressure-assisted in-vivo nerve stretch-growth

Axons respond well to mechanical stimuli and can be stretched mechanically to increase their growth rate. Although stretch growth of axons and their transient lengthening ex-vivo has been discussed in literature extensively, however, real applications of this phenomenon are scarcely found. This work presents a technique to translate ex-vivo axonal stretch growth to in-vivo nerve stretch growth. By establishing a rat model of completely transected sciatic nerve injury, the regrowth rate of the proximal nerve stump was examined under the effect of a stretching force developed by negative pressure. In this manuscript, results have been presented based on quantitative and qualitative analysis of the stained nerve tissues. Gross observations have explicitly confirmed that the proximal stump of a whole sectioned sciatic nerve of a Wistar rat stretched in a T-shaped nerve prosthesis using a controlled amount of negative pressure displayed a better outcome in terms of an increase in the total length of proximal nerve stump post-treatment and a higher number of blood vessels with respect to control. The histological and morphometric analyses confirmed that negative pressure-assisted nerve growth provides an alluring control over nerve’s regrowth rate. Immunohistochemical staining also supported the existence of a positive correlation between nerve growth and in-vivo application of axial stress on it. This work presents the first holistic evidence on growing nerves in the continuum of in-vivo nerve stretch growth using negative pressure and concludes that systematic and controlled negative pressure applied directly to the resected ends of a sciatic nerve resulted in the enhanced growth rate of regenerating nerve fibres.

The pathological progression of repetitive and mild traumatic brain injury in mice

Traumatic brain injury (TBI) is defined as an impact to the head by an external force that causes brain alterations and subsequent long‐term functional deficits. TBI contributes to an economic burden of $17 billion USD annually and is a leading cause of death and disability for individuals under 45. The severity of TBI varies from mild to severe with repetitive and mild (rm) TBI, and accounts for the highest percentage of TBI‐cases, leading to long‐term cognitive impairment. There are no current treatment(s) for repetitive and mild TBI, therefore, we sought to identify novel signaling molecules/pathways that could contribute to TBI.We employed a clinically relevant (non‐surgical) closed‐head impact model of engineered rotational acceleration (CHIMERA) that allows free rotation of the head upon impact generated from an air‐compressed piston. Our data suggest a novel role for PRMT7 (protein arginine methyltransferases) in the disease progression as indicated by the temporal decrease in protein expression post‐rmTBI. Our central hypothesis is that the loss of PRMT7, due to repetitive and mild TBI, mediates excitotoxicity, increased cellular death, disturbed mitochondrial dynamics and contributes to behavioral deficits. PRMTs are novel targets that catalyze the methylation of arginine residues (a constitutive post‐translational modification) involved in transcription, translation, receptor trafficking, and protein stability. There are currently 11 known PRMT isoforms (PRMT1‐11), with PRMT7 gene deletion in human patients causing neurological deficits such as intellectual disability, microcephaly, and brachydactyly, along with hyperexcitability and impaired social behaviors in murine in vivo models.We assessed diffuse axonal injury in our model of mild and repetitive TBI (via CHIMERA) to suggest enhanced silver deposition (dark stained regions) throughout the brain, similar to human pathology. Next, we measured PRMT7 protein levels that were decreased in the cortex and hippocampus 7‐days post‐rmTBI. Relative PRMT7 mRNA (via real‐time qPCR) was enhanced in the cortex 1‐day post‐rmTBI. Using LC‐MS, we measured excitatory neurotransmitters to suggest that glutamate was enhanced in the hippocampus 3‐day post‐rmTBI. In addition, mitochondrial fission and fusion was assessed by measuring DRP1 and OPA1 and our results indicated increased polarization towards fission as indicated by significant increase of DRP1 protein expression 1,3,7 days post rmTBI. Furthermore, mitochondrial oxygen consumption rates were analyzed via Seahorse XF analyzer and indicated dynamic changes in ATP‐linked respiration and maximal respiration 1 and 3 days post‐rmTBI. Finally, learning, working memory, and locomotor skills were significantly impaired as indicated by decreased alternation ratios via T‐maze, novel object recognition, and rotarod assessment. Overall, our results suggest that PRMT7 can mediate neuronal hyperexcitability, altered mitochondrial dynamics and can affect functional outcomes post‐rmTBI.