P23 Investigating synaptopathy following traumatic brain injury in a preclinical model

ObjectivesThe impact of Traumatic Brain Injury (TBI) on the synapse is poorly understood. We examined the impact of TBI on the distribution of two postsynaptic density proteins (PSD95 and SAP102) at single-synapse resolution.Subjects44 male transgenic knock-in mice, aged 8–16 weeks, expressing fluorescently labelled PSD95 and SAP102.MethodsMice were randomised to a mild lateral fluid percussion injury (LFPI) or sham treatment and brain sections were examined at 7 and 28 days. Using high resolution confocal microscopy and machine learning algorithms, the synaptic puncta density, size and intensity were mapped across 222 brain regions. Microglia and presynaptic changes were indexed using Iba1 and SV2A immunostaining. Pearson correlation and t-tests were used (significance p<0.05).ResultsWe found a significant reduction in synaptic puncta density at 28 days post-injury in brain regions distal to the injury site including the hippocampus. PSD95 and SAP102 density changes had a strong positive correlation at 28 days (r=0.8; p<0.0001). We also observed evidence of synapse recovery in the ipsilateral cortex between 7 and 28 days. Puncta density had a positive correlation with SV2A (r=0.7; p<0.01) and a negative correlation with (r=−0.6; p<0.001) Iba1 count.ConclusionsFocal LFPI induced progressive region-specific loss of synapses for which microglia may play a role. Our study highlights the value of brain-wide synaptome mapping technology and suggests a capacity for synaptic recovery which could be a therapeutic target.

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The Impact of Neurocognitive Functioning on the Course of Posttraumatic Stress Symptoms following Civilian Traumatic Brain Injury

Journal of Clinical Medicine ◽

10.3390/jcm10215109 ◽

2021 ◽

Vol 10 (21) ◽

pp. 5109

Author(s):

Dominique L. G. Van Praag ◽

Filip Van Den Eede ◽

Kristien Wouters ◽

Lindsay Wilson ◽

Andrew I. R. Maas ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Posttraumatic Stress ◽

Visual Information ◽

Verbal Learning ◽

Neurocognitive Functioning ◽

Ptsd Symptoms ◽

Post Injury ◽

Change Scores ◽

The Impact

Background: One out of seven individuals who have suffered a traumatic brain injury (TBI) develops a posttraumatic stress disorder (PTSD), which is often associated with neurocognitive impairment. The present study explores the impact of neurocognitive functioning after mild, moderate, and severe TBI on the course of PTSD symptoms. Methods: The data of 671 adults admitted to hospital for a TBI was drawn from the Collaborative European Neurotrauma Effectiveness Research (CENTER-TBI) study. After six- and 12-months post-injury, participants completed the PTSD Checklist-5 (PCL-5), from which change scores were calculated. At six months, participants also completed a neurocognitive assessment including the Rey Auditory Verbal Learning Test, the Trail Making Test, and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Linear regressions were performed to identify associations between cognitive functioning and PCL-5 change scores. Results: Overall, mean PCL-5 change scores showed no clear change (−0.20 ± 9.88), but 87 improved and 80 deteriorated by a change score of 10 or more. CANTAB Rapid Visual Information Processing scores were significantly associated with PCL-5 change scores. Conclusions: Strong sustained attention was associated with improvement in PTSD symptoms. Assessing cognitive performance may help identify individuals at risk of developing (persisting) PTSD post-TBI and offer opportunities for informing treatment strategies.

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Connectomic Assessment of Injury Burden and Longitudinal Structural Network Alterations in Moderate-to-severe Traumatic Brain Injury

10.1101/2021.04.20.440635 ◽

2021 ◽

Author(s):

Yusuf Osmanlioglu ◽

Drew Parker ◽

Jacob A Alappatt ◽

James J Gugger ◽

Ramon R Diaz-Arrastia ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Structural Connectivity ◽

Public Health Problem ◽

Brain Regions ◽

Brain Network ◽

Major Public Health Problem ◽

Post Injury ◽

Structural Network ◽

Injury Burden

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been very scarce. In this study, we propose a novel connectomic measure that we call network anomaly score (NAS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients are more heterogeneous and are significantly different than that of healthy controls at 3 months post-injury, where dissimilarity further increases up to 12 months. We also show that NAS captures injury burden as quantified by post-traumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally we compare NAS to major graph theory measures used in TBI literature and demonstrate the superiority of NAS in characterizing the disease.

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Examining the Prospective Relationship between Family Affective Responsiveness and Theory of Mind in Chronic Paediatric Traumatic Brain Injury

Brain Impairment ◽

10.1017/brimp.2016.20 ◽

2016 ◽

Vol 18 (1) ◽

pp. 88-101 ◽

Cited By ~ 5

Author(s):

Nicholas P. Ryan ◽

Kim Mihaljevic ◽

Miriam H. Beauchamp ◽

Cathy Catroppa ◽

Louise Crossley ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Theory Of Mind ◽

Childhood And Adolescence ◽

Post Injury ◽

Related Factors ◽

Lesion Location ◽

Severe Tbi ◽

The Impact ◽

Affective Responsiveness

Childhood and adolescence coincide with rapid structural and functional maturation of brain networks implicated in Theory of Mind (ToM); however, the impact of paediatric traumatic brain injury (TBI) on the development of these higher order skills is not well understood. ToM can be partitioned intoconative ToM, defined as the ability to understand how indirect speech acts involving irony and empathy are used to influence the mental or affective state of the listener; andaffective ToM, concerned with understanding that facial expressions are often used for social purposes to convey emotions that we want people to think we feel. In a sample of 84 children with mild-severe TBI and 40 typically developing controls, this study examined the effect of paediatric TBI on affective and conative ToM; and evaluated the respective contributions of injury-related factors (injury severity/lesion location) and non-injury-related environmental variables (socio-economic status (SES)/family functioning) to long-term ToM outcomes. Results showed that the poorest ToM outcomes were documented in association with mild-complicated and moderate TBI, rather than severe TBI. Lesion location and SES did not significantly contribute to conative or affective ToM. Post-injury family affective responsiveness was the strongest and most significant predictor of conative ToM. Results suggest that clinicians should exercise caution when prognosticating based on early clinical indicators, and that group and individual-level outcome prediction should incorporate assessment of a range of injury- and non-injury-related factors. Moreover, the affective quality of post-injury family interactions represents a potentially modifiable risk factor, and might be a useful target for family-centred interventions designed to optimise social cognitive outcomes after paediatric TBI.

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What Do Machines Tell us About Dementia? Machine Learning Applied to Aging, Dementia and Traumatic Brain Injury Study

10.21203/rs.3.rs-840907/v1 ◽

2021 ◽

Author(s):

Denis Arthur Pinheiro Moura ◽

Joao Ricardo Mendes de Oliveira

Keyword(s):

Gene Expression ◽

Machine Learning ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Expression Profiles ◽

Brain Regions ◽

Machine Learning Algorithms ◽

Differentially Expressed ◽

Classification Model ◽

Specific Gene

Abstract Dementia, a syndrome characterized by the progressive deterioration of memory and cognition, arises from different pathologies, with Alzheimer's Disease (AD) its most common cause. Patterns of gene expression during dementia of different etiologies may function as generalist biomarkers of the condition. We used RNA-Seq data from the Allen Dementia and Traumatic Brain Injury Study (ADTBI) to identify differentially expressed genes in brains with dementia. Machine Learning algorithms Decision Trees (DT) and Random Forest (RF) were used to create models to identify dementia samples based on their gene expression profile. Importance analyses were conducted to identify the most relevant genes in each classification model. A total of 1629 differentially expressed (DE) genes were found in brains with the condition. Gene PAN3-AS1 was the only DE gene across more than three brain regions. The artificial intelligence models were capable of identifying correctly up to 92.85% of dementia samples. Our analyses provide interesting insights regarding using brain-specific gene expression profiles as biomarkers of dementia, identifying genes possibly involved with dementia, and guiding future studies in prediction and early identification of the syndrome.

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A-125 The Impact of Bilingualism on Symbol Digit Modalities Test Performance Following Traumatic Brain Injury

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.143 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1175-1175

Author(s):

Raelynn Munoz ◽

Daniel W Lopez-Hernandez ◽

Rachel A Rugh-Fraser ◽

Jasman Sidhu ◽

Pavel Y Litvin ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Deficits ◽

Test Performance ◽

Oral Performance ◽

Neurocognitive Performance ◽

Post Injury ◽

Cognitive Speed ◽

The Impact ◽

Larger Sample

Abstract Objective Traumatic brain injury (TBI) survivors exhibit cognitive deficits. Research suggests that multilingualism can influence neurocognitive performance. We examined the effects of TBI and bilingualism/monolingualism on a test of attention and cognitive speed (i.e., Symbol Digit Modalities Test; SDMT). Method The sample consisted of 55 healthy comparison (27 Spanish-English bilinguals; 28 English-monolinguals), 34 acute TBI (14 Spanish-English bilinguals; 23 English-monolinguals), and 27 chronic TBI (13 Spanish-English bilinguals; 12 English-monolinguals) participants. Acute TBI participants were tested 6 months post-injury; chronic TBI participants were tested 12 months or more post-injury. A series of 3X2 ANOVAs were conducted to determine the effect of TBI and language on SDMT written and oral performance. Results ANOVAs revealed the healthy comparison group outperformed both TBI groups on SDMT written, p = 0.000, ηp2 = 0.21. Also, the healthy comparison and chronic TBI groups outperformed the acute TBI group on SDMT oral, p = 0.000, ηp2 = 0.13. Interaction effects emerged between TBI and bilingualism/monolingualism. On SDMT written and oral, acute TBI English-monolinguals outperformed acute TBI Spanish-English bilinguals; meanwhile, chronic TBI Spanish-English bilinguals outperformed chronic TBI English-monolinguals, p < 0.05, ηp2 = 0.09–0.10. Conclusion The acute TBI group performed worse than healthy comparison adults on both SDMT tasks. Furthermore, the chronic TBI group demonstrated better SDMT oral abilities compared to the acute TBI group. Relative to monolinguals with TBI, our findings suggest better cognitive recovery of attention and cognitive speed in bilingual TBI participants. Future studies with larger sample sizes should examine if learning English first or second impacts Spanish-English bilingual TBI survivors’ SDMT performance compared to English-monolingual TBI survivors.

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The effect of dietary supplementation with high- or low-dose omega-3 fatty acid on inflammatory pathology after traumatic brain injury in rats

Translational Neuroscience ◽

10.1515/tnsci-2021-0010 ◽

2021 ◽

Vol 12 (1) ◽

pp. 76-82

Author(s):

Elise K. Black ◽

Jack K. Phillips ◽

Jack Seminetta ◽

Julian Bailes ◽

John M. Lee ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Fatty Acid ◽

Brain Injury ◽

Dietary Supplementation ◽

Preclinical Model ◽

High Dose ◽

Omega 3 ◽

Response Curves ◽

Post Injury ◽

Omega 3 Fatty Acid

Abstract This study investigated dietary supplementation as a prophylactic for neuroinflammation following traumatic brain injury (TBI) in a preclinical model. Adult male Sprague-Dawley rats received 30 days of supplementation with either water or two dietary supplements. The first consisted of high-dose omega-3 fatty acid (O3FA) (supplement A) along with vitamin D3 and vitamin E. The second had the same ingredients at different doses with an addition of cannabidiol (supplement B). Rats were subjected to an impact TBI and then euthanized 7 days post-injury and neuroinflammation quantified by histological detection of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and CD68, a marker of microglial activity. There was a trend toward increased GFAP staining in injured, unsupplemented animals as compared to sham, unsupplemented animals, consistent with increased activation of astrocytes in response to trauma which was reversed by supplement A but not by supplement B. The pattern of CD68 staining across groups was similar to that of GFAP staining. There was a trend toward an increase in the injured unsupplemented group, relative to sham which was reversed by supplement A but not by supplement B. CD68 staining in injured animals was concentrated in the perivascular domain. The consistency between trends across different measures of neuroinflammation showing benefits of high-dose O3FA supplementation following TBI suggests that the observed effects are real. These findings are preliminary, but they justify further study to determine the functional benefits associated with improvements in histological outcomes and understand associated dose-response curves.

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Effects of Traumatic Brain Injury on Regional Cerebral Blood Flow in Rats as Measured with Radiolabeled Microspheres

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.16 ◽

1989 ◽

Vol 9 (1) ◽

pp. 117-124 ◽

Cited By ~ 170

Author(s):

Iwao Yamakami ◽

Tracy K. McIntosh

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Regions ◽

Post Injury ◽

Fluid Percussion ◽

Hemodynamic Variables ◽

Acute Changes ◽

Injury Recovery ◽

Left Parietal Cortex ◽

Experimental Traumatic Brain Injury

To clarify the effect of experimental brain injury on regional CBF (rCBF), repeated rCBF measurements were performed using radiolabeled microspheres in rats Subjected to fluid-percussion traumatic brain injury. Three consecutive microsphere injections in six uninjured control rats substantiated that the procedure induces no significant changes in hemodynamic variables or rCBF. Animals were subjected to left parietal fluid-percussion brain injury of moderate severity (2.1–2.4 atm) and rCBF values were determined (a) prior to injury and 15 min and 1 h following injury (n = 7); and (b) prior to injury and 30 min and 2 h following injury (n = 7). At 15 min post injury, there was a profound reduction of rCBF in all brain regions studied (p < 0.01). Although rCBF in the hindbrain had recovered to near-normal by 30 min post injury, rCBF in both injured and contralateral (uninjured) forebrain areas remained significantly suppressed up to 1 h post injury. At 2 h post injury, recovery of rCBF to near-normal values was observed in all brain regions except the focal area of injury (left parietal cortex) where rCBF remained significantly depressed (p < 0.01). This prolonged focal oligemia at the injury site was associated with the development of reproducible cystic necrosis in the left parietotemporal cortex at 4 weeks post injury. Our results demonstrate that acute changes in rCBF occur following experimental traumatic brain injury in rats and that rCBF remains significantly depressed up to 2 h post injury in the area circumscribing the trauma site.

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Global Characterisation of Coagulopathy in Isolated Traumatic Brain Injury (iTBI): A CENTER-TBI Analysis

Neurocritical Care ◽

10.1007/s12028-020-01151-7 ◽

2020 ◽

Author(s):

Julia K. Böhm ◽

◽

Helge Güting ◽

Sophie Thorn ◽

Nadine Schäfer ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Antiplatelet Therapy ◽

Post Injury ◽

Coagulation Profile ◽

Trauma Induced Coagulopathy ◽

Increased Risk ◽

Independent Risk Factors ◽

The Impact ◽

Admission Glasgow Coma Scale

Abstract Background Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood. Methods This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis. Results Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to − 6, hypothermia and hypotension increased risk significantly. Conclusion Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.

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The impact of deployment and traumatic brain injury on the health and behavior of children of US military service members and veterans

Clinical Child Psychology and Psychiatry ◽

10.1177/1359104517740405 ◽

2017 ◽

Vol 23 (3) ◽

pp. 425-441

Author(s):

Tracey A Brickell ◽

Louis M French ◽

Sara M Lippa ◽

Rael T Lange

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Military Service ◽

Emotional Health ◽

Post Injury ◽

Number Of Children ◽

Us Military ◽

Combat Deployment ◽

And Behavior ◽

The Impact

This study examined the impact of service member/veteran (SMV) combat deployment and traumatic brain injury (TBI) on the health and behavior of his or her children. Participants were 104 female spouse caregivers of US SMVs who had sustained a mild, severe, or penetrating TBI. Participants completed the Children’s Health and Behavior Questionnaire (CHBQ; r = .758 to .881) that evaluates school grades, behavior, medical health, emotional health, and social participation: (a) prior to the first combat deployment, (b) in the month prior to the TBI, (c) within 2 years after the TBI, and (d) 2 or more years after the TBI. A substantial number of children experienced a decline in health and behavior following the TBI (41.7%–79.1%). Of those who declined (a) 68.8%–75.5% declined within the first 2 years post-injury, followed by improvement or stabilization; (b) 6.7%–15.6% declined only after 2 or more years post-injury; (c) 15.6%–25.0% declined within the first 2 years post-injury and then again 2 or more years post-injury; and (d) 16.9%–26.5% experienced a decline as a result of deployment, followed by an additional decline after the SMV’s TBI. Services are required for children of SMVs following TBI and deployment, particularly children at risk for poor outcome.

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Beta blocker use in traumatic brain injury based on the high-sensitive troponin status (BBTBBT): methodology and protocol implementation of a double-blind randomized controlled clinical trial

Trials ◽

10.1186/s13063-021-05872-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ayman El-Menyar ◽

Mohammad Asim ◽

Ahmed Abdel-Aziz Bahey ◽

Talat Chughtai ◽

Abdulnasser Alyafai ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Calcium Binding ◽

Troponin T ◽

Controlled Clinical Trial ◽

Post Injury ◽

Double Blind ◽

Severity Of Injury ◽

The Impact ◽

High Sensitive Troponin

Abstract Background Beta-adrenergic receptor blockers (BB) play an important role in the protection of organs that are susceptible for secondary injury due to stress-induced adrenergic surge. However, the use of BB in traumatic brain injury (TBI) patients is not yet the standard of care which necessitates clear scientific evidence to be used. The BBTBBT study aims to determine whether early administration of propranolol based on the high-sensitive troponin T(HsTnT) status will improve the outcome of TBI patients. We hypothesized that early propranolol use is effective in reducing 10- and 30-day mortality in TBI patients. Secondary outcomes will include correlation between serum biomarkers (troponin, epinephrine, cytokines, enolase, S100 calcium binding protein B) and the severity of injury and the impact of BB use on the duration of hospital stay and functional status at a 3-month period. Methods The BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status. All enrolled patients will be tested for HsTnT at the first 4 and 6 h post-injury. Patients with positive HsTnT will receive BB if there is no contraindication (group 1). Patients with negative HsTnT will be randomized to receive either propranolol (group 2) or placebo (group 3). The time widow for receiving the study treatment is the first 24 h post-injury. Discussion Early BB use may reduce the catecholamine storm and subsequently the cascade of immune and inflammatory changes associated with TBI. HsTnT could be a useful fast diagnostic and prognostic tool in TBI patients. This study will be of great clinical interest to improve survival and functional outcomes of TBI patients. Trial registration ClinicalTrials.gov NCT04508244. Registered on 7 August 2020. Recruitment started on 29 December 2020 and is ongoing.

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