The mechanisms underlying the formation of the glial scar after injury are poorly understood. In this report, we demonstrate that after cortical injury Olig2 is upregulated in reactive astrocytes coincident with proliferation of these cells. Short-term lineage tracing studies with glial subtype-restricted transgenic reporter lines indicate that Olig2-expressing cells in the astroglial but not the oligodendroglial lineage are the essential source of reactive astrocytes. In addition, cortical Olig2 ablation results in a decrease in proliferation of reactive astrocytes in response to injury. Cell-type-specific mutagenesis indicates that Olig2 ablation in GFAPϩ astrocytes and their precursors rather than in neuronal or oligodendroglial cells is responsible for the reduction of reactive astrocyte proliferation. Thus, our studies suggest that Olig2 is critical for postinjury gliosis.

Patterns of hypoxic-ischemic brain injury in infants and children suggest vulnerability in regions of white matter development, and injured patients develop defects in myelination resulting in cerebral palsy and motor deficits. Reperfusion exacerbates the oxidative stress that occurs after such injuries and may impair recovery. Resuscitation after hypoxic-ischemic injury is routinely performed using 100% oxygen, and this practice may increase the oxidative stress that occurs during reperfusion and further damage an already compromised brain. We show that brief exposure (30 mins) to 100% oxygen during reperfusion worsens the histologic injury in young mice after unilateral brain hypoxia-ischemia, causes an accumulation of the oxidative metabolite nitrotyrosine, and depletes preoligodendrocyte glial progenitors present in the cortex. This damage can be reversed with administration of the antioxidant ebselen, a glutathione peroxidase mimetic. Moreover, mice recovered in 100% oxygen have a more disrupted pattern of myelination and develop a static motor deficit that mimics cerebral palsy and manifests itself by significantly worse performance on wire hang and rotorod motor testing. We conclude that exposure to 100% oxygen during reperfusion after hypoxic-ischemic brain injury increases secondary neural injury, depletes developing glial progenitors, interferes with myelination, and ultimately impairs functional recovery.

Although the phenomenon of ongoing neurogenesis in the hippocampus is well described, it remains unclear what relevance this has in terms of brain self-repair following injury. In a highly regulated developmental program, new neurons are added to the inner granular cell layer of the dentate gyrus (DG) where slowly dividing radial glial-like type 1 neural stem/progenitors (NSPs) give rise to rapidly proliferating type 2 neural progenitors which undergo selection and maturation into functional neurons. The induction of these early hippocampal progenitors after injury may represent an endogenous mechanism for brain recovery and remodeling. To determine what role early hippocampal progenitors play in remodeling following injury, we utilized a model of hypoxic-ischemic injury on young transgenic mice that express green fluorescent protein (GFP) specifically in neural progenitors. We demonstrate that this injury selectively activates programmed cell death in committed but immature neuroblasts, which is followed by proliferation of both early type 1 and later type 2 progenitors. This subsequently leads to newly generated neurons becoming stably incorporated into the DG.

Adult neural stem and progenitor cells may help remodel the brain in response to injury. The pro-apoptotic molecule Bax has recently been identified as a key player in adult neural stem cell survival. In Bax-deficient mice that have undergone traumatic brain injury, we find increased numbers of neural progenitor cells in the dentate gyrus and improved remodeling of the hippocampus. Exogenous potassium chloride mimics spreading depression (SD)-like events in vitro, and Bax-deficient neural stem cells proliferate in response to these events more robustly than wild-type neural stem cells. Selective potassium channel blockers interrupt SD-mediated stimulation of stem cells. In addition, the potassium channel Kv4.1 is expressed within neural stem and progenitor cells in the dentate gyrus and is increased in Bax-deficiency. These data suggest that the neuroprotection observed after injury in Bax-deficiency may be due to increased neurogenesis via activation of the Kv4 family of potassium channels.

Transcranial Doppler ultrasonography (TCD) is being used in many pediatric intensive care units (PICUs) to aid in the diagnosis and monitoring of children with known or suspected pathophysiological changes to cerebral hemodynamics. Standardized approaches to scanning protocols, interpretation, and documentation of TCD examinations in this setting are lacking. A panel of multidisciplinary clinicians with expertise in the use of TCD in the PICU undertook a three-round modified Delphi process to reach unanimous agreement on 34 statements and then create practice recommendations for TCD use in the PICU. Use of these recommendations will help to ensure that high quality TCD images are captured, interpreted, and reported using standard nomenclature. Furthermore, use will aid in ensuring reproducible and meaningful study results between TCD practitioners and across PICUs.

Objectives Small series have suggested that outcomes after abusive head trauma (AHT) are less favorable than after other injury mechanisms. We sought to determine the impact of AHT on mortality and identify factors that differentiate children with AHT from those with TBI from other mechanisms. Design First 200 subjects from the Approaches and Decisions in Acute Pediatric TBI (ADAPT) Trial – a comparative effectiveness study using an observational, cohort study design. Setting Pediatric intensive care units in tertiary children’s hospitals in USA and abroad. Participants Consecutive children (age <18 y) with severe TBI (GCS ≤ 8; intracranial pressure (ICP) monitoring). Interventions None Measurements and Main Results Demographics, injury-related scores, prehospital and resuscitation events were analyzed. Children were dichotomized based on likelihood of AHT. A total of 190 children were included (n = 35 with AHT). AHT subjects were younger (1.87 y ± 0.32 vs. 9.23 y ± 0.39, p < 0.001) and a greater proportion were female (54.3% vs. 34.8%, p = 0.032). AHT were more likely to (i) be transported from home (60.0% vs. 33.5%, p < 0.001), (ii) have apnea (34.3% vs. 12.3%, p = 0.002) and (iii) seizures (28.6% vs. 7.7%, p < 0.001) during pre-hospital care. AHT had a higher incidence of seizures during resuscitation (31.4 vs. 9.7%, p = 0.002). After adjusting for covariates, there was no difference in mortality (AHT, 25.7% vs. non-AHT, 18.7%, HR 1.758, p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (AHT, 66.7% vs. non-AHT, 69.0%). Conclusion In this large, multicenter series, children with AHT had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other TBI populations in children, female predominance was seen in AHT in our cohort. Similar mortality rates and refractory ICP deaths suggest that children with severe AHT may benefit from therapies including invasive monitoring and adherence to evidenced-based guidelines.

Brain lesions after traumatic brain injury (TBI) are heterogeneous, rendering outcome prognostication difficult. The aim of this study is to investigate whether early magnetic resonance imaging (MRI) of lesion location and lesion volume within discrete brain anatomical zones can accurately predict long-term neurological outcome in children post-TBI. Fluidattenuated inversion recovery (FLAIR) MRI hyperintense lesions in 63 children obtained 6.2 -5.6 days postinjury were correlated with the Glasgow Outcome Scale Extended-Pediatrics (GOS-E Peds) score at 13.5 -8.6 months. FLAIR lesion volume was expressed as hyperintensity lesion volume index (HLVI) = (hyperintensity lesion volume / whole brain volume) · 100 measured within three brain zones: zone A (cortical structures); zone B (basal ganglia, corpus callosum, internal capsule, and thalamus); and zone C (brainstem). HLVI-total and HLVI-zone C predicted good and poor outcome groups ( p < 0.05). GOS-E Peds correlated with HLVI-total (r = 0.39; p = 0.002) and HLVI in all three zones: zone A (r = 0.31; p < 0.02); zone B (r = 0.35; p = 0.004); and zone C (r = 0.37; p = 0.003). In adolescents ages 13-17 years, HLVItotal correlated best with outcome (r = 0.5; p = 0.007), whereas in younger children under the age of 13, HLVI-zone B correlated best (r = 0.52; p = 0.001). Compared to patients with lesions in zone A alone or in zones A and B, patients with lesions in all three zones had a significantly higher odds ratio (4.38; 95% confidence interval, 1.19-16.0) for developing an unfavorable outcome.

Key Points Question Is cerebrospinal fluid (CSF) diversion associated with improved outcomes or intracranial pressure in children with severe traumatic brain injury (TBI)? Findings In this comparative effectiveness study of 1000 children with severe TBI, there was no association between CSF diversion and Glasgow Outcome Score–Extended for Pediatrics at 6 months after injury in propensity-matched participants. However, CSF diversion was associated with decreased intracranial pressure in the propensity-matched participants. Meaning These findings suggest that the current evidenced-based guidelines that support CSF diversion as a first-line therapy for TBI in children should be reconsidered.