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

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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Severity of Ongoing Post-Concussive Symptoms as a Predictor of Cognitive Performance Following a Pediatric Mild Traumatic Brain Injury

Journal of the International Neuropsychological Society ◽

10.1017/s1355617720001228 ◽

2020 ◽

pp. 1-11

Author(s):

Veronik Sicard ◽

Danielle C. Hergert ◽

Sharvani Pabbathi Reddy ◽

Cidney R. Robertson-Benta ◽

Andrew B. Dodd ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Performance ◽

Mild Traumatic Brain Injury ◽

Parental Education ◽

Visual Learning ◽

Learning Task ◽

Risk Scores ◽

Group Differences ◽

Post Injury

Abstract Objective: This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury. Method: 203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8–18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1–11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (∼4 months) phase. Results: Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not. Conclusions: The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.

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Language function in a child following mild traumatic brain injury: Evidence from pre- and post-injury language testing

Developmental Neurorehabilitation ◽

10.3109/17518423.2011.620576 ◽

2011 ◽

Vol 14 (6) ◽

pp. 348-354 ◽

Cited By ~ 3

Author(s):

Fiona M. Lewis ◽

Bruce E. Murdoch

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Language Testing ◽

Language Function ◽

Post Injury

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Characterization of neurobehavioral changes following mild traumatic brain injury in male Sprague–Dawley rats

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2013.01.029 ◽

2013 ◽

Vol 68 (1) ◽

pp. e5

Author(s):

Kristy Bruse ◽

Yung Sung Cheng ◽

Hammad Irshad ◽

Michael Weisend ◽

Andrew Mayer

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Sprague Dawley ◽

Sprague Dawley Rats

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Exosomal MicroRNA Differential Expression in Plasma of Young Adults with Chronic Mild Traumatic Brain Injury and Healthy Control

Biomedicines ◽

10.3390/biomedicines10010036 ◽

2021 ◽

Vol 10 (1) ◽

pp. 36

Author(s):

Rany Vorn ◽

Maiko Suarez ◽

Jacob C. White ◽

Carina A. Martin ◽

Hyung-Suk Kim ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Young Adults ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Pathophysiological Mechanism ◽

Post Injury ◽

Persistent Symptoms ◽

Healthy Control ◽

Underlying Mechanisms

Chronic mild traumatic brain injury (mTBI) has long-term consequences, such as neurological disability, but its pathophysiological mechanism is unknown. Exosomal microRNAs (exomiRNAs) may be important mediators of molecular and cellular changes involved in persistent symptoms after mTBI. We profiled exosomal microRNAs (exomiRNAs) in plasma from young adults with or without a chronic mTBI to decipher the underlying mechanisms of its long-lasting symptoms after mTBI. We identified 25 significantly dysregulated exomiRNAs in the chronic mTBI group (n = 29, with 4.48 mean years since the last injury) compared to controls (n = 11). These miRNAs are associated with pathways of neurological disease, organismal injury and abnormalities, and psychological disease. Dysregulation of these plasma exomiRNAs in chronic mTBI may indicate that neuronal inflammation can last long after the injury and result in enduring and persistent post-injury symptoms. These findings are useful for diagnosing and treating chronic mTBIs.

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Structural brain connectivity predicts acute pain after mild traumatic brain injury

10.1101/2021.11.12.468345 ◽

2021 ◽

Author(s):

Paulo Branco ◽

Noam Bosak ◽

Jannis Bielefeld ◽

Olivia Cong ◽

Yelena Granovsky ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

White Matter ◽

Mild Traumatic Brain Injury ◽

Acute Pain ◽

Pain Perception ◽

Strong Predictor ◽

Pain Modulation ◽

Acute Injury ◽

Post Injury

Mild traumatic brain injury, mTBI, is a leading cause of disability worldwide, with acute pain manifesting as one of its most debilitating symptoms. Understanding acute post-injury pain is important since it is a strong predictor of long-term outcomes. In this study, we imaged the brains of 172 patients with mTBI, following a motorized vehicle collision and used a machine learning approach to extract white matter structural and resting state fMRI functional connectivity measures to predict acute pain. Stronger white matter tracts within the sensorimotor, thalamic-cortical, and default-mode systems predicted 20% of the variance in pain severity within 72 hours of the injury. This result generalized in two independent groups: 39 mTBI patients and 13 mTBI patients without whiplash symptoms. White matter measures collected at 6-months after the collision still predicted mTBI pain at that timepoint (n = 36). These white-matter connections were associated with two nociceptive psychophysical outcomes tested at a remote body site – namely conditioned pain modulation and magnitude of suprathreshold pain–, and with pain sensitivity questionnaire scores. Our validated findings demonstrate a stable white-matter network, the properties of which determine a significant amount of pain experienced after acute injury, pinpointing a circuitry engaged in the transformation and amplification of nociceptive inputs to pain perception.

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Self-Reported Complaints as Prognostic Markers for Outcome After Mild Traumatic Brain Injury in Elderly: A Machine Learning Approach

Frontiers in Neurology ◽

10.3389/fneur.2021.751539 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mayra Bittencourt ◽

Sebastián A. Balart-Sánchez ◽

Natasha M. Maurits ◽

Joukje van der Naalt

Keyword(s):

Machine Learning ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Elderly Patients ◽

Neck Pain ◽

Functional Outcome ◽

Mild Traumatic Brain Injury ◽

Prognostic Markers ◽

The Elderly ◽

Post Injury

Self-reported complaints are common after mild traumatic brain injury (mTBI). Particularly in the elderly with mTBI, the pre-injury status might play a relevant role in the recovery process. In most mTBI studies, however, pre-injury complaints are neither analyzed nor are the elderly included. Here, we aimed to identify which individual pre- and post-injury complaints are potential prognostic markers for incomplete recovery (IR) in elderly patients who sustained an mTBI. Since patients report many complaints across several domains that are strongly related, we used an interpretable machine learning (ML) approach to robustly deal with correlated predictors and boost classification performance. Pre- and post-injury levels of 20 individual complaints, as self-reported in the acute phase, were analyzed. We used data from two independent studies separately: UPFRONT study was used for training and validation and ReCONNECT study for independent testing. Functional outcome was assessed with the Glasgow Outcome Scale Extended (GOSE). We dichotomized functional outcome into complete recovery (CR; GOSE = 8) and IR (GOSE ≤ 7). In total 148 elderly with mTBI (median age: 67 years, interquartile range [IQR]: 9 years; UPFRONT: N = 115; ReCONNECT: N = 33) were included in this study. IR was observed in 74 (50%) patients. The classification model (IR vs. CR) achieved a good performance (the area under the receiver operating characteristic curve [ROC-AUC] = 0.80; 95% CI: 0.74–0.86) based on a subset of only 8 out of 40 pre- and post-injury complaints. We identified increased neck pain (p = 0.001) from pre- to post-injury as the strongest predictor of IR, followed by increased irritability (p = 0.011) and increased forgetfulness (p = 0.035) from pre- to post-injury. Our findings indicate that a subset of pre- and post-injury physical, emotional, and cognitive complaints has predictive value for determining long-term functional outcomes in elderly patients with mTBI. Particularly, post-injury neck pain, irritability, and forgetfulness scores were associated with IR and should be assessed early. The application of an ML approach holds promise for application in self-reported questionnaires to predict outcomes after mTBI.

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Effect Sizes for Symptomatic and Cognitive Improvements in Traumatic Brain Injury Following Hyperbaric Oxygen Therapy

Journal of Applied Physiology ◽

10.1152/japplphysiol.01084.2020 ◽

2021 ◽

Author(s):

Adam Thomas Biggs ◽

Hugh M. Dainer ◽

Lanny F Littlejohn

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Hyperbaric Oxygen ◽

Hyperbaric Oxygen Therapy ◽

Oxygen Therapy ◽

Brain Injuries ◽

Statistical Significance ◽

Traumatic Brain Injuries ◽

Therapeutic Benefit ◽

Effect Sizes

Hyperbaric oxygen therapy has been proposed as a method to treat traumatic brain injuries. The combination of pressure and increased oxygen concentration produces a higher content of dissolved oxygen in the bloodstream, which could generate a therapeutic benefit for brain injuries. This dissolved oxygen penetrates deeper into damaged brain tissue than otherwise possible and promotes healing. The result includes improved cognitive functioning and an alleviation of symptoms. However, randomized controlled trials have failed to produce consistent conclusions across multiple studies. There are numerous explanations that might account for the mixed evidence, although one possibility is that prior evidence focuses primarily on statistical significance. The current analyses explored existing evidence by calculating an effect size from each active treatment group and each control group among previous studies. An effect size measure offers several advantages when comparing across studies as it can be used to directly contrast evidence from different scales, and it provides a proximal measure of clinical significance. When exploring the therapeutic benefit through effect sizes, there was a robust and consistent benefit to individuals who underwent hyperbaric oxygen therapy. Placebo effects from the control condition could account for approximately one-third of the observed benefits, but there appeared to be a clinically significant benefit to using hyperbaric oxygen therapy as a treatment intervention for traumatic brain injuries. This evidence highlights the need for design improvements when exploring interventions for traumatic brain injury as well as the importance of focusing on clinical significance in addition to statistical significance.

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Highly Sensitive Single Molecular Array Immunoassay Measurement of t-Tau, NF-L, GFAP, and UCH-L1 Biomarkers in Acute Concussion/Mild Traumatic Brain Injury (mTBI) Patient Serum and Saliva Samples

Neurology ◽

10.1212/01.wnl.0000581020.28808.bd ◽

2019 ◽

Vol 93 (14 Supplement 1) ◽

pp. S19.3-S20

Author(s):

Ahmed Chenna ◽

Christos Petropoulos ◽

John Winslow

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Limited Information ◽

Post Injury ◽

Time Points ◽

Highly Sensitive ◽

Biomarker Analysis ◽

T Tau ◽

Control Samples

ObjectiveTo determine if t-Tau, NF-L, GFAP and UCH-L1 protein biomarkers are elevated in early time points of acute concussion/mild traumatic brain injury patient serum and saliva, relative to control samples.Backgroundt-Tau, NF-L, GFAP and UCH-L1 levels have been reported to increase in cerebral spinal fluid (CSF) and blood following head trauma within 24 hours or longer, and are candidate diagnostic and prognostic biomarkers of concussion and mild to moderate TBI. However, limited information exists on the relationship between these biomarkers at short time points post-injury, and detectability in saliva of mTBI patients.Design/MethodsBiomarker analysis of serum from a total of 120 participants, derived from two independent sample groups consisting of 60 concussion/mTBI patients each, with blood collected within 1-4 hr and 8-16 hr post-injury, respectively, was compared with 30 healthy control sera. Saliva samples were collected after 8-16 hr post-injury from a n = 30 subset of the same patients. Quanterix Simoa 4-plex immunoassay was used for highly sensitive measurements of these biomarkers.ResultsMedian levels of NF-L, GFAP and UCH-L1 were significantly higher in independent sets of patient serum samples (n = 60 each), both at early (1–4 hr) and later (8–16 hr) time points post-mTBI/concussion, relative to control samples (n = 30) (p < 0.0001, = 0.0001, <0.0001, respectively). Low levels of t-Tau are detected, but are significantly elevated post-concussion relative to controls (p = 0.0001). Significant correlations were observed between levels of t-Tau and UCH-L1, NF-L and GFAP, and t-Tau and GFAP in both post-injury time-point groups, and between NF-L and UCH-L1 levels in the 8-16 hr group. The four biomarkers were detected in saliva from concussion/mTBI patients (n = 30).ConclusionsThis study supports the utility of ultra-sensitive multiplex immunoassays to detect increases in CNS proteins at high sensitivity in serum and saliva within 1-4 and 8-16 hr of concussion/mTBI.

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Outcomes after Complicated and Uncomplicated Mild Traumatic Brain Injury at Three-and Six-Months Post-Injury: Results from the CENTER-TBI Study

Journal of Clinical Medicine ◽

10.3390/jcm9051525 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1525 ◽

Cited By ~ 1

Author(s):

Daphne C. Voormolen ◽

Marina Zeldovich ◽

Juanita A. Haagsma ◽

Suzanne Polinder ◽

Sarah Friedrich ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Functional Outcome ◽

Mild Traumatic Brain Injury ◽

Intracranial Injury ◽

Post Injury ◽

Long Term Outcome ◽

Sf 36 ◽

Disease Specific

The objective of this study was to provide a comprehensive examination of the relation of complicated and uncomplicated mild traumatic brain injury (mTBI) with multidimensional outcomes at three- and six-months after TBI. We analyzed data from the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) research project. Patients after mTBI (Glasgow Coma scale (GCS) score of 13–15) enrolled in the study were differentiated into two groups based on computed tomography (CT) findings: complicated mTBI (presence of any traumatic intracranial injury on first CT) and uncomplicated mTBI (absence of any traumatic intracranial injury on first CT). Multidimensional outcomes were assessed using seven instruments measuring generic and disease-specific health-related quality of life (HRQoL) (SF-36 and QOLIBRI), functional outcome (GOSE), and psycho-social domains including symptoms of post-traumatic stress disorder (PTSD) (PCL-5), depression (PHQ-9), and anxiety (GAD-7). Data were analyzed using a multivariate repeated measures approach (MANOVA-RM), which inspected mTBI groups at three- and six-months post injury. Patients after complicated mTBI had significantly lower GOSE scores, reported lower physical and mental component summary scores based on the SF-36 version 2, and showed significantly lower HRQoL measured by QOLIBRI compared to those after uncomplicated mTBI. There was no difference between mTBI groups when looking at psychological outcomes, however, a slight improvement in PTSD symptoms and depression was observed for the entire sample from three to six months. Patients after complicated mTBI reported lower generic and disease specific HRQoL and worse functional outcome compared to individuals after uncomplicated mTBI at three and six months. Both groups showed a tendency to improve from three to six months after TBI. The complicated mTBI group included more patients with an impaired long-term outcome than the uncomplicated group. Nevertheless, patients, clinicians, researchers, and decisions-makers in health care should take account of the short and long-term impact on outcome for patients after both uncomplicated and complicated mTBI.

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