Reorganization of Thalamic Inputs to Lesioned Cortex Following Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) disrupts thalamic and cortical integrity. The effect of post-injury reorganization and plasticity in thalamocortical pathways on the functional outcome remains unclear. We evaluated whether TBI causes structural changes in the thalamocortical axonal projection terminals in the primary somatosensory cortex (S1) that lead to hyperexcitability. TBI was induced in adult male Sprague Dawley rats with lateral fluid-percussion injury. A virus carrying the fluorescent-tagged opsin channel rhodopsin 2 transgene was injected into the ventroposterior thalamus. We then traced the thalamocortical pathways and analyzed the reorganization of their axonal terminals in S1. Next, we optogenetically stimulated the thalamocortical relays from the ventral posterior lateral and medial nuclei to assess the post-TBI functionality of the pathway. Immunohistochemical analysis revealed that TBI did not alter the spatial distribution or lamina-specific targeting of projection terminals in S1. TBI reduced the axon terminal density in the motor cortex by 44% and in S1 by 30%. A nematic tensor-based analysis revealed that in control rats, the axon terminals in layer V were orientated perpendicular to the pial surface (60.3°). In TBI rats their orientation was more parallel to the pial surface (5.43°, difference between the groups p < 0.05). Moreover, the level of anisotropy of the axon terminals was high in controls (0.063) compared with TBI rats (0.045, p < 0.05). Optical stimulation of the sensory thalamus increased alpha activity in electroencephalography by 312% in controls (p > 0.05) and 237% (p > 0.05) in TBI rats compared with the baseline. However, only TBI rats showed increased beta activity (33%) with harmonics at 5 Hz. Our findings indicate that TBI induces reorganization of thalamocortical axonal terminals in the perilesional cortex, which alters responses to thalamic stimulation.

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Dynamics of clusterin protein expression in the brain and plasma following experimental traumatic brain injury

Scientific Reports ◽

10.1038/s41598-019-56683-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Shalini Das Gupta ◽

Anssi Lipponen ◽

Kaisa M. A. Paldanius ◽

Noora Puhakka ◽

Asla Pitkänen

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protein Expression ◽

Fold Increase ◽

Mrna Levels ◽

Sprague Dawley ◽

Post Injury ◽

Fluid Percussion Injury ◽

Clusterin Protein ◽

The Brain

AbstractProgress in the preclinical and clinical development of neuroprotective and antiepileptogenic treatments for traumatic brain injury (TBI) necessitates the discovery of prognostic biomarkers for post-injury outcome. Our previous mRNA-seq data revealed a 1.8–2.5 fold increase in clusterin mRNA expression in lesioned brain areas in rats with lateral fluid-percussion injury (FPI)-induced TBI. On this basis, we hypothesized that TBI leads to increases in the brain levels of clusterin protein, and consequently, increased plasma clusterin levels. For evaluation, we induced TBI in adult male Sprague-Dawley rats (n = 80) by lateral FPI. We validated our mRNA-seq findings with RT-qPCR, confirming increased clusterin mRNA levels in the perilesional cortex (FC 3.3, p < 0.01) and ipsilateral thalamus (FC 2.4, p < 0.05) at 3 months post-TBI. Immunohistochemistry revealed a marked increase in extracellular clusterin protein expression in the perilesional cortex and ipsilateral hippocampus (7d to 1 month post-TBI), and ipsilateral thalamus (14d to 12 months post-TBI). In the thalamus, punctate immunoreactivity was most intense around activated microglia and mitochondria. Enzyme-linked immunoassays indicated that an acute 15% reduction, rather than an increase in plasma clusterin levels differentiated animals with TBI from sham-operated controls (AUC 0.851, p < 0.05). Our findings suggest that plasma clusterin is a candidate biomarker for acute TBI diagnosis.

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Hypobaria-Induced Oxidative Stress Facilitates Homocysteine Transsulfuration and Promotes Glutathione Oxidation in Rats with Mild Traumatic Brain Injury

Journal of Central Nervous System Disease ◽

10.1177/1179573520988193 ◽

2021 ◽

Vol 13 ◽

pp. 117957352098819

Author(s):

Flaubert Tchantchou ◽

Catriona Miller ◽

Molly Goodfellow ◽

Adam Puche ◽

Gary Fiskum

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Glutathione Metabolism ◽

Compensatory Mechanism ◽

Oxidative Stress Markers ◽

Sprague Dawley ◽

Post Injury ◽

Stress Markers ◽

Glutathione Oxidation

Background: United States service members injured in combat theatre are often aeromedically evacuated within a few days to regional military hospitals. Animal and epidemiological research indicates that early exposure to flight hypobaria may worsen brain and other injuries. The mechanisms by which secondary exposure to hypobaria worsen trauma outcomes are not well elucidated. This study tested the hypothesis that hypobaria-induced oxidative stress and associated changes in homocysteine levels play a role in traumatic brain injury (TBI) pathological progression caused by hypobaria. Methods: Male Sprague Dawley rats were exposed to a 6 h hypobaria 24 h after mild TBI by the controlled cortical impact. Plasma and brain tissues were assessed for homocysteine levels, oxidative stress markers or glutathione metabolism, and behavioral deficits post-injury in the absence and presence of hypobaria exposure. Results: We found that hypobaria after TBI increased oxidative stress markers, altered homocysteine metabolism, and promoted glutathione oxidation. Increased glutathione metabolism was driven by differential upregulation of glutathione metabolizing genes. These changes correlated with increased anxiety-like behavior. Conclusion: These data provide evidence that hypobaria exposure after TBI increases oxidative stress and alters homocysteine elimination likely through enhanced glutathione metabolism. This pathway may represent a compensatory mechanism to attenuate free radical formation. Thus, hypobaria-induced enhancement of glutathione metabolism represents a potential therapeutic target for TBI management.

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Traumatic brain injury augurs ill for prolonged deficits in the brain’s structural and functional integrity following controlled cortical impact injury

Scientific Reports ◽

10.1038/s41598-021-00660-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Abdalla Z. Mohamed ◽

Paul Cumming ◽

Fatima A. Nasrallah

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Functional Connectivity ◽

Diffusion Tensor ◽

Sprague Dawley ◽

Post Injury ◽

Controlled Cortical Impact ◽

Cci Model ◽

Cortical Impact

AbstractPrevious neuroimaging studies in rodents investigated effects of the controlled cortical impact (CCI) model of traumatic brain injury (TBI) within one-month post-TBI. This study extends this temporal window to monitor the structural–functional alterations from two hours to six months post-injury. Thirty-seven male Sprague–Dawley rats were randomly assigned to TBI and sham groups, which were scanned at two hours, 1, 3, 7, 14, 30, 60 days, and six months following CCI or sham surgery. Structural MRI, diffusion tensor imaging, and resting-state functional magnetic resonance imaging were acquired to assess the dynamic structural, microstructural, and functional connectivity alterations post-TBI. There was a progressive increase in lesion size associated with brain volume loss post-TBI. Furthermore, we observed reduced fractional anisotropy within 24 h and persisted to six months post-TBI, associated with acutely reduced axial diffusivity, and chronic increases in radial diffusivity post-TBI. Moreover, a time-dependent pattern of altered functional connectivity evolved over the six months’ follow-up post-TBI. This study extends the current understanding of the CCI model by confirming the long-term persistence of the altered microstructure and functional connectivity, which may hold a strong translational potential for understanding the long-term sequelae of TBI in humans.

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Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats

Brain Communications ◽

10.1093/braincomms/fcaa042 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Dhyey Bhatt ◽

Ali Hazari ◽

Glenn R Yamakawa ◽

Sabrina Salberg ◽

Marissa Sgro ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Prefrontal Cortex ◽

Brain Injury ◽

Nucleus Accumbens ◽

Mild Traumatic Brain Injury ◽

Brain Injuries ◽

Therapeutic Benefit ◽

Sprague Dawley ◽

Post Injury ◽

Beneficial Effects

Abstract The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.

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Structural Changes in Children’s Brain with Traumatic Brain Injury of Different Degree of Severity

Ukraïnsʹkij žurnal medicini bìologìï ta sportu ◽

10.26693/jmbs04.05.173 ◽

2019 ◽

Vol 4 (5) ◽

pp. 173-179

Author(s):

V. N. Petrenko ◽

◽

T. M. Prihodko ◽

M. V. Hekova ◽

V. V. Shevchenko

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Structural Changes ◽

Degree Of Severity

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A-126 Clinical Utility of Risk Factors to Predict Self-reported Neurobehavioral Outcome Following Traumatic Brain Injury: PTSD, Sleep, Resilience, and Lifetime Blast Exposure

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acaa068.126 ◽

2020 ◽

Vol 35 (6) ◽

pp. 919-919

Author(s):

Lange R ◽

Lippa S ◽

Hungerford L ◽

Bailie J ◽

French L ◽

...

Keyword(s):

Risk Factors ◽

Traumatic Brain Injury ◽

Risk Factor ◽

Brain Injury ◽

Clinical Utility ◽

Poor Sleep ◽

Post Injury ◽

Poor Outcome ◽

Blast Exposure ◽

Neurobehavioral Outcome

Abstract Objective To examine the clinical utility of PTSD, Sleep, Resilience, and Lifetime Blast Exposure as ‘Risk Factors’ for predicting poor neurobehavioral outcome following traumatic brain injury (TBI). Methods Participants were 993 service members/veterans evaluated following an uncomplicated mild TBI (MTBI), moderate–severe TBI (ModSevTBI), or injury without TBI (Injured Controls; IC); divided into three cohorts: (1) < 12 months post-injury, n = 237 [107 MTBI, 71 ModSevTBI, 59 IC]; (2) 3-years post-injury, n = 370 [162 MTBI, 80 ModSevTBI, 128 IC]; and (3) 10-years post-injury, n = 386 [182 MTBI, 85 ModSevTBI, 119 IC]. Participants completed a 2-hour neurobehavioral test battery. Odds Ratios (OR) were calculated to determine whether the ‘Risk Factors’ could predict ‘Poor Outcome’ in each cohort separately. Sixteen Risk Factors were examined using all possible combinations of the four risk factor variables. Poor Outcome was defined as three or more low scores (< 1SD) on five TBI-QOL scales (e.g., Fatigue, Depression). Results In all cohorts, the vast majority of risk factor combinations resulted in ORs that were ‘clinically meaningful’ (ORs > 3.00; range = 3.15 to 32.63, all p’s < .001). Risk factor combinations with the highest ORs in each cohort were PTSD (Cohort 1 & 2, ORs = 17.76 and 25.31), PTSD+Sleep (Cohort 1 & 2, ORs = 18.44 and 21.18), PTSD+Sleep+Resilience (Cohort 1, 2, & 3, ORs = 13.56, 14.04, and 20.08), Resilience (Cohort 3, OR = 32.63), and PTSD+Resilience (Cohort 3, OR = 24.74). Conclusions Singularly, or in combination, PTSD, Poor Sleep, and Low Resilience were strong predictors of poor outcome following TBI of all severities and injury without TBI. These variables may be valuable risk factors for targeted early interventions following injury.

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The Challenge of Managing Patients Suffering from TBI: The Utility of Multiparametric MRI

CNS Spectrums ◽

10.1017/s109285292000293x ◽

2021 ◽

Vol 26 (2) ◽

pp. 178-179

Author(s):

John L. Sherman ◽

Laurence J. Adams ◽

Christen F. Kutz ◽

Deborah York ◽

Mitchell S. Szymczak

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Family History ◽

Diffusion Tensor ◽

Multiparametric Mri ◽

Psychiatric History ◽

Post Injury ◽

Negative Family History ◽

Imaging Result ◽

The Brain

AbstractTraumatic brain injury (TBI) is a complex phenomenon affecting multiple areas of the brain in multiple ways. Both right and left hemispheres are affected as well as supratentorial and infratentorial compartments. These multifocal injuries are caused by many factors including acute mechanical injury, focal intracranial hemorrhage, blunt and rotational forces, epidural and subdural hematoma, hypoxemia, hypotension, edema, axonal damage, neuronal death, gliosis and blood brain barrier disruption. Clinicians and patients benefit by precise information about the neuroanatomical areas that are affected macroscopically, microscopically and biochemically in an individual patient.Standard imaging studies are frequently negative or grossly underestimate the severity of TBI and may exacerbate and prolong patient suffering with an imaging result of “no significant abnormality”. Specifically, sophisticated imaging tools have been developed which reveal significant damage to the brain structure including atrophy, MRI spectroscopy showing variations in neuronal metabolite N-acetyl-aspartate, elevations of membrane related Choline, and the glial metabolite myo-inositol is often observed to be increased post injury. In addition, susceptibility weighted imaging (SWI) has been shown to be more reliable for detecting microbleeds versus calcifications.We have selected two TBI patients with diffuse traumatic brain injury.The first patient is a 43-year-old male who suffered severe traumatic brain injury from a motorcycle accident in 2016. Following the accident, the patient was diagnosed with seizures, major depression, and intermittent explosive disorder. He has attempted suicide and has neurobehavioral disinhibition including severe anger, agitation and irritability. He denies psychiatric history prior to TBI and has negative family history. Following the TBI, he became physically aggressive and assaultive in public with minimal provocation. He denies symptoms of thought disorder and mania. He is negative for symptoms of cognitive decline or encephalopathy.The second patient is a 49-year-old male who suffered at least 3 concussive blasts in the Army and a parachute injury. Following the last accident, the patient was diagnosed with major depressive disorder, panic disorder, PTSD and generalized anxiety disorder. He denies any psychiatric history prior to TBI including negative family history of psychiatric illness. In addition, he now suffers from nervousness, irritability, anger, emotional lability and concurrent concentration issues, problems completing tasks and alterations in memory.Both patients underwent 1.5T multiparametric MRI using standard T2, FLAIR, DWI and T1 sequences, and specialized sequences including susceptibility weighted (SWAN/SWI), 3D FLAIR, single voxel MRI spectroscopy (MRS), diffusion tensor imaging (DTI), arterial spin labeling perfusion (ASL) and volumetric MRI (NeuroQuant). Importantly, this exam can be performed in 30–45 minutes and requires no injections other than gadolinium in some patients. We will discuss the insights derived from the MRI which detail the injured areas, validate the severity of the brain damage, and provide insight into the psychological, motivational and physical disabilities that afflict these patients. It is our expectation that this kind of imaging study will grow in value as we link specific patterns of injury to specific symptoms and syndromes resulting in more targeted therapies in the future.

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Blood Biomarkers Relate to Cognitive Performance Years after Traumatic Brain Injury in Service Members and Veterans

Journal of the International Neuropsychological Society ◽

10.1017/s1355617720001071 ◽

2020 ◽

pp. 1-7

Author(s):

Sara M. Lippa ◽

Jessica Gill ◽

Tracey A. Brickell ◽

Louis M. French ◽

Rael T. Lange

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Outcome ◽

Service Members ◽

Neurocognitive Performance ◽

Blood Biomarkers ◽

Post Injury ◽

Blood Draw ◽

Neurofilament Light ◽

History Of

Abstract Objective: This study examines the relationship of serum total tau, neurofilament light (NFL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) with neurocognitive performance in service members and veterans with a history of traumatic brain injury (TBI). Method: Service members (n = 488) with a history of uncomplicated mild (n = 172), complicated mild, moderate, severe, or penetrating TBI (sTBI; n = 126), injured controls (n = 116), and non-injured controls (n = 74) prospectively enrolled from Military Treatment Facilities. Participants completed a blood draw and neuropsychological assessment a year or more post-injury. Six neuropsychological composite scores and presence/absence of mild neurocognitive disorder (MNCD) were evaluated. Within each group, stepwise hierarchical regression models were conducted. Results: Within the sTBI group, increased serum UCH-L1 was related to worse immediate memory and delayed memory (R2Δ = .065–.084, ps < .05) performance, while increased GFAP was related to worse perceptual reasoning (R2Δ = .030, p = .036). Unexpectedly, within injured controls, UCH-L1 and GFAP were inversely related to working memory (R2Δ = .052–.071, ps < .05), and NFL was related to executive functioning (R2Δ = .039, p = .021) and MNCD (Exp(B) = 1.119, p = .029). Conclusions: Results suggest GFAP and UCH-L1 could play a role in predicting poor cognitive outcome following complicated mild and more severe TBI. Further investigation of blood biomarkers and cognition is warranted.

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Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01226-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Amer Toutonji ◽

Mamatha Mandava ◽

Silvia Guglietta ◽

Stephen Tomlinson

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Complement System ◽

Classical Pathway ◽

Post Injury ◽

Complement Inhibition ◽

Time Points ◽

Complement Gene ◽

The Complement System

AbstractActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

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3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22158276 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8276

Author(s):

Pen-Sen Huang ◽

Ping-Yen Tsai ◽

Ling-Yu Yang ◽

Daniela Lecca ◽

Weiming Luo ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Short Term Memory ◽

Post Injury ◽

Behavioral Deficits ◽

Cognitive Behaviors ◽

Moderate Traumatic Brain Injury ◽

Short And Long Term ◽

Behavioral Impairments ◽

Hippocampal Neurodegeneration

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

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