Traumatic Brain Injury

Making Soccer Safer for the Brain: DTI-defined Exposure Thresholds for White Matter Injury Due to Soccer Heading

Authors: Molly Zimmerman PhD., Richard Lipton, Walter Stewart PhD., Edwin Gulko MD., Michael Lipton MD, PhD., Craig Branch PhD

PURPOSE: Heading the soccer ball may represent a form of repetitive mild trauma and may be associated with cognitive impairment. Because abnormally low white matter FA has been associated with cognitive impairment in patients with TBI, we hypothesized that a threshold level exists for heading exposure above which evidence of white matter injury is detectable.

METHOD AND MATERIALS: 32 amateur soccer players were recruited. Heading exposure was assessed with a standardized questionnaire and DTI was performed. Regions of Interest (ROI) were determined using a voxelwise t-test comparing FA between subjects with heading frequency ≥1,320/year with those <1,320/year. Based on our threshold hypothesis, we assumed an S or inverse S shape, nonlinear regression model based on Inverse Logit functions with four parameters: (1) associational direction and scale factor (β1), (2) baseline (β2) in FA measures for players with low frequency of headings, (3) departure position (β3) in heading-exposure scales from baseline and (4) slope (β4) of the curve. These parameters were estimated utilizing a stochastic search algorithm, simulated annealing (Kirkpatrick et al., 1983).
  
RESULTS: 5 ROIs were identified in temporooccipital white matter and one frontal white matter. Nonlinear regression reduced mean square error by 14% to 93% across all ROIs when compared to linear regression fits. All curve fitting detected an inverse S shape, indicating that FA decreases as exposure to heading increases. Estimates of departure position (β3) in heading-exposure scales were around 1500 in 4 temporooccipital ROIs 1000 in the 5th ROI. β3 was 1300 in the frontal ROI.

CONCLUSION: Greater heading frequency is associated with low FA. Exceeding a threshold for heading frequency (1000-1500) may result in brain abnormalities similar to those seen in TBI. Investigation of the relationship of the imaging abnormalities to cognitive performance is needed.

CLINICAL RELEVANCE/APPLICATION: Soccer heading is associated with DTI findings similar to TBI. The exposure threshold we identify suggests public health interventions to minimize excess exposure and, thereby, the adverse outcomes.

The Relationship Between Intracranial Pressure and Brain Oxygenation in Children with Severe Traumatic Brain Injury

Authors: Rohlwink UK, Zwane E, Fieggen AG, Argent AC, Leroux PD, Figaji AA.

BACKGROUND: Intracranial pressure (ICP) monitoring is a cornerstone of care for severe traumatic brain injury (TBI). Management of ICP can help ensure adequate cerebral blood flow and oxygenation. However, studies indicate that brain hypoxia may occur despite 'normal' ICP and the relationship between ICP and brain oxygenation is poorly defined. This is particularly important for children in whom less is known about intracranial dynamics.

OBJECTIVE: To examine the relationship between ICP and brain tissue oxygen (PbtO2) in children with severe TBI (Glasgow Comma Score ≤ 8) admitted to Red Cross War Memorial Children's Hospital, Cape Town.

METHODS: The relationship between time-linked hourly and high frequency ICP and PbtO2 data was examined using correlation, regression and generalized estimating equations. Thresholds for ICP were examined against reduced PbtO2 using age bands and receiver-operating curves.

RESULTS: Analysis using over 8300 hourly (N=75) and 1 million high frequency data points (N=30) demonstrated a weak relationship between ICP and PbtO2 (r = .05, r=.04). No critical ICP threshold for low PbtO2 was identified. Individual patients revealed a strong relationship between ICP and PbtO2 at specific times, but different relationships were evident over longer periods.

CONCLUSION: The relationship between ICP and PbtO2 appears complex and several factors likely influence both variables separately and in combination. Although very high ICP is associated with reduced PbtO2, in general, absolute ICP has a poor relationship with PbtO2. Since reduced PbtO2 is independently associated with poor outcome, a better understanding of ICP and PbtO2 management in pediatric TBI seems needed.

Nemo-like Kinase (NLK) Involves in Neuronal Apoptosis after Traumatic Brain Injury

Authors: Li Z, Cui G, Wang J, Yu Z, Zhao L, Lv Z.

Traumatic brain injury (TBI) consists of two phases: an immediate phase in which damage is caused as a direct result of the mechanical impact: and a late phase of altered biochemical events that results in delayed tissue damage and is therefore amenable to therapeutic treatment. Because the molecular mechanisms of delayed post-traumatic neuronal cell death are still poorly understood, we investigated whether nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase involved in neuronal apoptosis following TBI. In the model of TBI, western blot analysis, double immunofluorescent staining and immunohistochemistry were used to analyze the role of NLK in the process. The results showed a significant down-regulation of NLK and a concomitant up-regulation of caspase-3 during the early stage of TBI. In the model of glutamate inducing PC12 apoptosis, we analyzed the effect of over-expression of NLK on the neuronal cell line PC12 apoptosis by cck-8, western blot and TUNEL assays. Together with previous reports. We hypothesize NLK was related to the down-regulation of caspase-3 expression after TBI, and such an event may be associated with neuronal apoptosis.

Effect of estrogens on blood glutamate levels in relation to neurological outcome after TBI in male rats

Authors: Zlotnik A, Leibowitz A, Gurevich B, Ohayon S, Boyko M, Klein M, Knyazer B, Shapira Y, Teichberg VI.

PURPOSE: Estrogen has been shown to possess neuroprotective properties both in vitro and in vivo. Traumatic brain injury (TBI) in ovulating females results in favorable neurological outcomes when compared to males with similar insults. The brain-to-blood glutamate gradient removes excess glutamate from brain extracellular fluids (ECF). Enhancing this gradient leads to improved neurological outcomes following TBI. In this study we investigate the effect of female gonadal steroids on blood glutamate levels and neurological outcomes.

METHODS: Forty male Sprague-Dawley rats were assigned to one of five groups: (1) sham, (2) Premarin treatment, (3) TBI, (4) TBI + Premarin treatment, and (5) TBI + Premarin pretreatment. TBI was induced, and estrogen and glutamate levels were determined at 0, 60, 120, 135, and 150 min. Neurological recovery was evaluated using the Neurological Severity Score (NSS) at 1 h and reassessed at 24 h post TBI.

RESULTS: Premarin treatment groups demonstrated a decline in blood glutamate levels by 60 min. This decline was found to be more pronounced in the TBI + Premarin group, which maintained the decline throughout the experiment. At 120 min, the difference between groups was most pronounced (TBI + Premarin 99 ± 36 μM/l vs. control 200 ± 46 μM/l, p < 0.01). Neurological recovery was significantly better in the Premarin treatment group (NSS at 24 h 6 ± 1 vs. control 11 ± 1).

CONCLUSIONS: Premarin injected into male rats significantly decreases blood glutamate levels in rats suffering TBI. This decrease is associated with improved neurological outcomes, thus implicating the role of estrogen in neuroprotection.

The effects of brain injury on heart rate variability and the innate immune response in critically ill patients

Authors: Kox M, Vrouwenvelder MQ, Pompe JC, van der Hoeven JG, Pickkers P, Hoedemaekers CW.

Brain injury and related increased intracranial pressure (ICP) may lead to increased vagus nerve activity and subsequent suppression of innate immunity via the cholinergic ant-inflammatory pathway. This may explain the observed increased susceptibility to infection in these patients. In the present study, we investigated the association between brain injury, vagus nerve activity, and innate immunity. We determined heart rate variability (HRV) as a measure of vagus nerve activity, plasma cytokines and cytokine production of ex vivo lipopolysaccharide-stimulated whole blood in the first 4 days of admission to the neurological ICU in 34 patients with various forms of brain damage. HRV, immune parameters and the correlations between these measures were analyzed in the entire group of patients and in subgroups of patients with conditions associated with high (intracranial hemorrhage ) and normal ICP (subarachnoid hemorrhage with an extraventricular drain alleviating ICP). Healthy volunteers were used for comparison. HRV total spectral power and ex vivo stimulated cytokine production was severely depressed in patients compared with healthy volunteers (p<0.05). Furthermore, HRV analysis showed that normalized units high frequency power (HFnu, corresponding with vagus nerve activity) was higher, and the low frequency/high frequency ratio (LF/HF, corresponding with sympathovagal balance) was lower in patients compared to healthy volunteers (p<0.05). HFnu correlated inversely with ex vivo-stimulated TNF-α production (r=-0.22, p=0.025). The most pronounced suppression of ex vivo stimulated cytokine production was observed in the ICH group. Furthermore, in ICH patients, HFnu correlated strongly with lower plasma TNF-α levels (r=-0.73, p=0.002). Our data suggest that brain injury, and especially conditions associated with increased ICP, is associated with vagus nerve-mediated immune suppression.

Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trials

Authors: Roberts DJ, Hall RI, Kramer AH, Robertson HL, Gallagher CN, Zygun DA.

OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury.

DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles.

STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury.

DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results.

DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure.

CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.

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