Traumatic brain injury and adverse life events: Group differences in young adults injured as children.

OBJECTIVES: To investigate whether individuals with a history of traumatic brain injury (TBI) experience a greater number of adverse life events (ALE) compared to controls, to identify significant predictors of experiencing ALE and whether the severity of childhood TBI negatively influences adult life outcomes. DESIGN: A total of 167 individuals, injured prior to age 18, 5 or more years post-injury and 18 or more years of age, were recruited in the Canterbury region of New Zealand, with 124 having sustained childhood TBI (62 mild, 62 moderate/severe) and 43 orthopaedic injury controls. Participants were asked about ALE they had experienced and other adult life outcomes. RESULTS: Individuals with a history of TBI experienced more ALE compared to controls. The number of ALE experienced by an individual was associated with more visits to the doctor, lower education level and lower satisfaction with material standard of living. CONCLUSIONS: Childhood TBI is associated with an increased number of ALE and adult negative life outcomes. Understanding factors that contribute to negative outcomes following childhood TBI will provide an avenue for rehabilitation and support to reduce any problems in adulthood.

Hypothermic neuroprotection is associated with recovery of spectral edge frequency after asphyxia in preterm fetal sheep.

BACKGROUND AND PURPOSE: Electroencephalographic recovery is predictive of outcome after perinatal hypoxia-ischemia, but it is unknown whether early changes in electroencephalographic can predict the response to therapeutic hypothermia in the preterm brain. METHODS: 0.7 gestation fetal sheep received umbilical cord occlusion or sham occlusion for 25 minutes, followed by sham hypothermia or whole-body cooling started either 30 minutes or 5 hours after occlusion and continued for 72 hours. RESULTS: Early but not delayed hypothermia reduced neuronal loss and microglial induction in the striatum, with faster recovery of spectral edge frequency, reduced seizure burden, and less suppression of electroencephalographic amplitude (P<0.05). CONCLUSIONS: Recovery of higher electroencephalographic frequencies may be a biomarker of effective hypothermic neuroprotection in the preterm-equivalent brain.

Asphyxia and therapeutic hypothermia modulate plasma nitrite concentrations and carotid vascular resistance in preterm fetal sheep.

In this study, we tested the hypothesis that cerebral hypoperfusion after asphyxia and induced hypothermia is associated with reduced circulating nitrite levels as an index of nitric oxide synthase (NOS) activity. The preterm fetal sheep at 0.7 gestation (103-104 days, term = 147 days) received 25-minute umbilical cord occlusion, followed by mild whole-body cooling from 30 minutes to 72 hours after occlusion. Occlusion and induced hypothermia were independently associated with reduced carotid vascular conductance (CaVC) from 2 to 72 hours, and with transiently suppressed plasma nitrite levels at 6 hours. There was a significant within-subjects correlation (r(2) = 0.33, P = .002) between CaVC and plasma nitrite values in the first 24 hours after occlusion but not after sham occlusion. These findings suggest that in preterm fetal sheep, changes in NOS activity are an important mediator of changes in carotid vascular tone in the early recovery phase after asphyxia and may help mediate some of the vascular effects of induced hypothermia.

Self versus family ratings of the frontal systems behaviour scale and measured executive functions: adult outcomes following childhood traumatic brain injury.

Traumatic brain injury (TBI) frequently occurs during childhood and adolescence with long-term neuropsychological and behavioral effects. Greater personal awareness of injury is associated with better outcomes. However, personal awareness is often assessed using ratings obtained from family members or significant others. Surprisingly, the accuracy of family-ratings compared with self-ratings has not been well studied in the TBI population. Thus, the purpose of this study was to examine self versus family-ratings of frontal dysfunction and secondly, the association between self/family reported frontal dysfunction and measured executive function outcomes. A total of 60 participants, approximately 10 years post-TBI, comprised 3 groups including; moderate/severe TBI (N=26; mean age 22.9, SD=3.0), mild TBI (N=20; mean age, 21.7, SD=2.7), and control (N=14: mean age, 21.6, SD=3.7). Neuropsychological testing was used to obtain domain scores for executive function and working memory/attention for each participant, and nominated family members and participants with TBI were asked to complete the Frontal Systems Behaviour Scale (FrSBe), consisting of three sub-scales; apathy, disinhibition, and executive dysfunction. Using the FrSBe there was no significant difference between the groups in executive function score, but the moderate/severe and mild groups had significantly lower working memory/attention scores compared with the control group (p<0.05). Repeated measures analysis of variance showed higher self-ratings on all sub-scales compared with family in each group (p<0.05). Scores on executive function and working memory/attention domains correlated with self, but not family reported executive dysfunction. Self-rated executive dysfunction explained 36% of the variance in executive function (p<0.001). While agreement between self-rated and family-rated total FrSBe scores was significant in all groups (p<0.001), our results showed that self-ratings were of higher predictive utility for executive functioning compared with family ratings. Further, at 10 years post-TBI, patients show greater awareness of deficits compared with family who rate consistently closer to the normal functioning range.

Nonadditive neuroprotection with early glutamate receptor blockade and delayed hypothermia after asphyxia in preterm fetal sheep.

BACKGROUND AND PURPOSE: Hypothermia induced after perinatal hypoxia-ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl-d-aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28-32 weeks in humans). METHODS: Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion. RESULTS: Delayed hypothermia was associated with improved neuronal survival (P<0.02) and reduced microglia (P=0.004) and caspase-3-positive cells (P<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (P<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (P<0.05) with no apparent additive effect with delayed hypothermia. CONCLUSIONS: Early N-methyl-d-aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain.

Destruction and reconstruction: hypoxia and the developing brain.

Preterm infants have a high rate of neurodevelopmental handicap. Recent imaging studies have revealed that adverse outcomes are strongly associated with reduced brain growth and neural complexity in later life. Increasing data suggest that these chronic deficits primarily reflect acute neuronal and glial injury sustained during adverse in utero events, such as exposure to severe hypoxia-ischemia and inflammation. In the present review we examine recent evidence that this chronic impairment is partly due to upregulation of physiological apoptosis, related to input deprivation, and output isolation secondary to acute white and gray matter damage and axonal injury. However, progenitor cells in the subventricular zone (SVZ) are also vulnerable to injury, and loss of part of this critical population likely further compromises brain development. Based on these concepts the impact of proposed interventions such as induced hypothermia and endogenous growth factors are likely to be complex, but potentially offer focused ways of improving the outcomes of premature birth.