Neuroendocrine Whiplash: Slamming the Breaks on Anabolic-Androgenic Steroids Following Repetitive Mild Traumatic Brain Injury in Rats May Worsen Outcomes

Sport-related concussion is an increasingly common injury among adolescents, with repetitive mild traumatic brain injuries (RmTBI) being a significant risk factor for long-term neurobiological and psychological consequences. It is not uncommon for younger professional athletes to consume anabolic-androgenic steroids (AAS) in an attempt to enhance their performance, subjecting their hormonally sensitive brains to potential impairment during neurodevelopment. Furthermore, RmTBI produces acute neuroendocrine dysfunction, specifically in the anterior pituitary, disrupting the hypothalamic-pituitary adrenal axis, lowering cortisol secretion that is needed to appropriately respond to injury. Some AAS users exhibit worse symptoms post-RmTBI if they quit their steroid regime. We sought to examine the pathophysiological outcomes associated with the abrupt cessation of the commonly abused AAS, Metandienone (Met) on RmTBI outcomes in rats. Prior to injury, adolescent male rats received either Met or placebo, and exercise. Rats were then administered RmTBIs or sham injuries, followed by steroid and exercise cessation (SEC) or continued treatment. A behavioral battery was conducted to measure outcomes consistent with clinical representations of post-concussion syndrome and chronic AAS exposure, followed by analysis of serum hormone levels, and qRT-PCR for mRNA expression and telomere length. RmTBI increased loss of consciousness and anxiety-like behavior, while also impairing balance and short-term working memory. SEC induced hyperactivity while Met treatment alone increased depressive-like behavior. There were cumulative effects whereby RmTBI and SEC exacerbated anxiety and short-term memory outcomes. mRNA expression in the prefrontal cortex, amygdala, hippocampus, and pituitary were modified in response to Met and SEC. Analysis of telomere length revealed the negative impact of SEC while Met and SEC produced changes in serum levels of testosterone and corticosterone. We identified robust changes in mRNA to serotonergic circuitry, neuroinflammation, and an enhanced stress response. Interestingly, Met treatment promoted glucocorticoid secretion after injury, suggesting that maintained AAS may be more beneficial than abstaining after mTBI

Ultrasound guided platelet rich plasma injections for post-traumatic greater occipital neuralgia following concussion: a pilot randomized controlled trial

BackgroundTreatment for post-traumatic greater occipital neuralgia (GON) includes serial injections of steroid/anesthetic. While these injections can alleviate pain, effects can be transient, frequently lasting only 1 month. As a potential alternative, platelet-rich plasma (PRP) injections are an emerging biological treatment with beneficial effects in peripheral nerve disorders. We investigated the feasibility, safety, and effectiveness of a single PRP injection for post-traumatic GON in comparison to saline or steroid/anesthetic injection.MethodsIn this pilot randomized, double-blinded, placebo-controlled trial, 32 adults with post-traumatic GON were allocated 1:1:1 to receive a single ultrasound-guided injection of (1) autologous PRP (2) steroid/anesthetic or (3) normal saline. Our primary outcome was feasibility (recruitment, attendance, retention) and safety (adverse events). Exploratory measures included headache intensity and frequency (daily headache diaries) and additional questionnaires (headache impact, and quality of life) assessed at pre-injection, 1 week, 1 month, and 3 months post-injection.ResultsWe screened 67 individuals, 55% were eligible and 95% of those participated. Over 80% of daily headache diaries were completed with 91% of participants completing the 3-month outcome questionnaires. No serious adverse events were reported. There were no significant differences between groups for headache intensity or frequency. Headache impact on function test-6 scores improved at 3 month in the PRP (β = −9.7, 95% CI [−15.6, −3.74], p = 0.002) and saline (β = −6.7 [−12.7, −0.57], p = 0.033) groups but not steroid/anesthetic group (p = 0.135).ConclusionPRP is a feasible and safe method for treating post-traumatic GON with comparable results to saline and steroid/anaesthetic. Further trials with larger sample sizes are required.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT04051203

Using Functional Near-Infrared Spectroscopy to Study the Effect of Repetitive Transcranial Magnetic Stimulation in Concussion: A Two-Patient Case Study

Background: Approximately 25% of concussion patients experience persistent post-concussion symptoms (PPCS). Repetitive transcranial magnetic stimulation (rTMS) has been explored as a treatment, and functional near-infrared spectroscopy (fNIRS) may be a cost-effective method for assessing response.Objectives: Evaluate rTMS for the treatment of PPCS and introduce fNIRS as a method of assessing treatment response.Methods:Design: Two-patient case study. Setting: Calgary Brain Injury Program. Participants: 47 and 49 years. male, with PPCS for 1–2 years (headache, cognitive difficulties, nausea, visual difficulties, irritability, anxiety, poor mood, sleep, and fatigue). Intervention: 10 sessions of rTMS therapy to the left dorsolateral prefrontal cortex (DLPFC), at 10 Hz (600 pulses) and 70% of resting motor threshold amplitude. Participants completed an 8-week headache diary and a battery of clinical questionnaires prior to each fNIRS session. fNIRS: Hemodynamic changes were recorded over the frontoparietal cortex during rest, finger tapping, and a graded working memory test. fNIRS was completed pre-rTMS, following rTMS (day 14), and at 1-month post-rTMS (day 45). For comparison, two healthy, sex-matched controls were scanned with fNIRS once daily for five consecutive days.Results: Clinical scores improved (headache severity, MoCA, HIT-6, PHQ-9, GAD-7, QOLIBRI, RPSQ, BCPSI) or remained stable (PCL-5, headache frequency) post-rTMS, for both participants. Participant 1 reported moderate symptom burden, and a fNIRS task-evoked hemodynamic response showing increased oxyhemoglobin was observed following a working memory task, as expected. Participant 2 exhibited a high symptom burden pre-treatment, with abnormal fNIRS hemodynamic response where oxyhemoglobin declined, in response to task. One month following rTMS treatment, participant 2 had a normal fNIRS hemodynamic response to task, corresponding to significant improvements in clinical outcomes.Conclusion: This case study suggests fNIRS may be sensitive to physiological changes that accompany rTMS treatment. Further studies exploring fNIRS as a cost-effective technology for monitoring rTMS response in patients with PPCS are suggested

Role of advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion: a systematic review

Objective To conduct a systematic review of published literature on advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion (SRC). Data sources Computerised searches of Medline, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Scopus and Cochrane Library from 1 January 2000 to 31 December 2016 were done. There were 3222 articles identified. Study selection In addition to medical subject heading terms, a study was included if (1) published in English, (2) represented original research, (3) involved human research, (4) pertained to SRC and (5) involved data from neuroimaging, fluid biomarkers or genetic testing collected within 6 months of injury. Ninety-eight studies qualified for review (76 neuroimaging, 16 biomarkers and 6 genetic testing). Data extraction Separate reviews were conducted for neuroimaging, biomarkers and genetic testing. A standardised data extraction tool was used to document study design, population, tests employed and key findings. Reviewers used a modified quality assessment of studies of diagnostic accuracy studies (QUADAS-2) tool to rate the risk of bias, and a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to rate the overall level of evidence for each search. Data synthesis Results from the three respective reviews are compiled in separate tables and an interpretive summary of the findings is provided. Conclusions Advanced neuroimaging, fluid biomarkers and genetic testing are important research tools, but require further validation to determine their ultimate clinical utility in the evaluation of SRC. Future research efforts should address current gaps that limit clinical translation. Ultimately, research on neurobiological and genetic aspects of SRC is predicted to have major translational significance to evidence-based approaches to clinical management of SRC, much like applied clinical research has had over the past 20 years

Regulation of cerebral blood flow and ventilation by oxygen and carbon dioxide in women

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Utility of serum IGF-1 for diagnosis of growth hormone deficiency following traumatic brain injury and sport-related concussion

Abstract Background Growth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population. Methods We conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z-score for determining GHD by GST or ITT. Results Sixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 μg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility. Conclusion Baseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels

Single voxel Magnetic Resonance Spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes and therefore must either define a small voxel contained within the anatomy of interest or include neighbouring tissue that is not of interest (i.e., partial volume effect). When studying cortical regions without clearly demarcated boundaries, such as the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. This study quantified total N-Acetylaspartate (tNAA), choline, glutamate, glutamate and glutamine (Glx), myo-inositol, and creatine values in two overlapping MRS voxels placed in the DLPFC, a large (30x30x30 mm3) and small (15x15x15 mm3) voxel to examine the correspondence of quantified metabolite levels to determine whether a large voxel is representative of a small voxel. Factors of signal to noise (SNR) and tissue type were specifically investigated. Spearman’s rho correlations were used to investigate the relationship between the small voxel and large voxel metabolite values. Only myo-inositol was significantly correlated between the two voxels when water-referencing was used, while all metabolites showed significant correlations when creatine-referencing was used. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC and suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time measuring to obtain specific, localized data

Reduced Functional Connectivity in Adults with Persistent Post-Concussion Symptoms: A Functional Near-Infrared Spectroscopy Study

Concussion, or mild traumatic brain injury (mTBI), accounts for ∼80% of all TBIs across North America. The majority of mTBI patients recover within days to weeks; however, 14-36% of the time, acute mTBI symptoms persist for months or even years and develop into persistent post-concussion symptoms (PPCS). There is a need to find biomarkers in patients with PPCS, to improve prognostic ability and to provide insight into the pathophysiology underlying chronic symptoms. Recent research has pointed toward impaired network integrity and cortical communication as a biomarker. In this study we investigated functional near-infrared spectroscopy (fNIRS) as a technique to assess cortical communication deficits in adults with PPCS. Specifically, we aimed to identify cortical communication patterns in prefrontal and motor areas during rest and task, in adult patients with persistent symptoms. We found that (1) the PPCS group showed reduced connectivity compared with healthy controls, (2) increased symptom severity correlated with reduced coherence, and (3) connectivity differences were best distinguishable during task and in particular during the working memory task (n-back task) in the right and left dorsolateral prefrontal cortex (DLPFC). These data show that reduced brain communication may be associated with the pathophysiology of mTBI and that fNIRS, with a relatively simple acquisition paradigm, may provide a useful biomarker of this injury.Canadian Institutes of Health Research - Other ProgramsNatural Sciences and Engineering Research Council - Collaborative Research & Development Gran

Improving symptom burden in adults with persistent post-concussive symptoms: a randomized aerobic exercise trial protocol

Abstract Background Persistent post-concussive symptoms (PPCS) affect up to 30% of individuals following mild traumatic brain injury. PPCS frequently includes exercise intolerance. Sub-symptom threshold aerobic exercise has been proposed as a treatment option for symptom burden and exercise intolerance in this population. The primary aim of this study is to evaluate whether a progressive, sub-symptom threshold aerobic exercise program can alleviate symptom burden in adults with PPCS. Methods Fifty-six adults (18–65) with PPCS (>3mos-5 yrs) will be randomized into two groups: an immediate start 12-week aerobic exercise protocol (AEP) or delayed start 6-week placebo-like stretching protocol (SP), followed by AEP. Aerobic or stretching activities will be completed 5x/week for 30 mins during the intervention. Online daily activity logs will be submitted. Exercise prescriptions for the AEP will be 70–80% of heart rate at the point of symptom exacerbation achieved on a treadmill test with heart rate monitoring. Exercise prescription will be updated every 3-weeks with a repeat treadmill test. The Rivermead Post-concussion Symptom Questionnaire will be the primary outcome measure at 6 and 12-weeks of intervention. Secondary outcomes include assessments of specific symptoms (headache, quality of life, mood, anxiety, fatigue, dizziness, sleep parameters, daytime sleepiness) in addition to blood biomarkers and magnetic resonance imaging and spectroscopy data for quantification of brain metabolites including γ-aminobutyric acid (GABA), glutathione, glutamate and N-acetyl aspartate (NAA) all measured at 6 and 12-weeks of intervention. Discussion This trial will evaluate the use of aerobic exercise as an intervention for adults with PPCS, thus expanding our knowledge of this treatment option previously studied predominantly for adolescent sport-related concussion. Trial registration ClinicalTrials.gov - NCT03895450 (registered 2019-Feb-11)