Research shows that approximately 14% of school age children with mild traumatic brain injury (TBI) including sports-related concussions (SRCs) remain symptomatic three months after injury. Advanced ...imaging studies early after injury have shown evidence of axonal damage, reduced N-acetyl aspartate (NAA) and impaired cerebral blood flow (CBF) in individuals with mild TBI. This study was undertaken to determine whether these techniques can provide valuable information in pediatric SRC patients with persistent post-concussive symptoms. Fifteen pediatric subjects ages 8 to 17 years with persistent post-concussive symptoms were evaluated using perfusion-weighted imaging (PWI), three-dimensional (3D) magnetic resonance spectroscopic imaging, and diffusion tensor imaging (DTI) three to 12 months post-SRC. Data were compared with 15 demographically similar (age, gender, and body mass index) controls. In the bilateral thalami, SRC patients showed reduced CBF (p=0.02 and p=0.02) and relative cerebral blood volume (CBV; p=0.05 and p=0.03), compared with controls. NAA/creatine (Cr) and NAA/choline (Cho) ratios were reduced in the corpus callosum (p=0.003; p=0.05) and parietal white matter (p<0.001; p=0.006) of SRC subjects, compared with controls. Significant differences in DTI metrics differentiated patients with cognitive symptoms, compared with those without cognitive symptoms and controls. Advanced imaging methods detect a spectrum of injury including impaired axonal function, neuronal metabolism and perfusion, suggesting involvement of the neurovascular unit in the presence of persistent symptoms in pediatric SRC patients.
This article identifies emerging neuroimaging measures considered by the inter-agency Pediatric Traumatic Brain Injury (TBI) Neuroimaging Workgroup. This article attempts to address some of the ...potential uses of more advanced forms of imaging in TBI as well as highlight some of the current considerations and unresolved challenges of using them. We summarize emerging elements likely to gain more widespread use in the coming years, because of 1) their utility in diagnosis, prognosis, and understanding the natural course of degeneration or recovery following TBI, and potential for evaluating treatment strategies; 2) the ability of many centers to acquire these data with scanners and equipment that are readily available in existing clinical and research settings; and 3) advances in software that provide more automated, readily available, and cost-effective analysis methods for large scale data image analysis. These include multi-slice CT, volumetric MRI analysis, susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), arterial spin tag labeling (ASL), functional MRI (fMRI), including resting state and connectivity MRI, MR spectroscopy (MRS), and hyperpolarization scanning. However, we also include brief introductions to other specialized forms of advanced imaging that currently do require specialized equipment, for example, single photon emission computed tomography (SPECT), positron emission tomography (PET), encephalography (EEG), and magnetoencephalography (MEG)/magnetic source imaging (MSI). Finally, we identify some of the challenges that users of the emerging imaging CDEs may wish to consider, including quality control, performing multi-site and longitudinal imaging studies, and MR scanning in infants and children.
Neuroimaging is commonly used for the assessment of children with traumatic brain injury and has greatly advanced how children are acutely evaluated. More recently, emphasis has focused on how ...advanced magnetic resonance imaging methods can detect subtler injuries that could relate to the structural underpinnings of the neuropsychological and behavioral alterations that frequently occur. We examine several methods used for the assessment of pediatric brain injury. Susceptibility-weighted imaging is a sensitive 3-dimensional high-resolution technique in detecting hemorrhagic lesions associated with diffuse axonal injury. Magnetic resonance spectroscopy acquires metabolite information, which serves as a proxy for neuronal (and glial, lipid, etc) structural integrity and provides sensitive assessment of neurochemical alterations. Diffusion-weighted imaging is useful for the early detection of ischemic and shearing injury. Diffusion tensor imaging allows better structural evaluation of white matter tracts. These methods are more sensitive than conventional imaging in demonstrating subtle injury that underlies a child’s clinical symptoms. There also is an increasing desire to develop computational methods to fuse imaging data to provide a more integrated analysis of the extent to which components of the neurovascular unit are affected. The future of traumatic brain injury neuroimaging research is promising and will lead to novel approaches to predict and improve outcomes.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
To determine the prevalence of parenchymal brain microhemorrhages (MHs) in infants with nonaccidental trauma (NAT) by using susceptibility-weighted (SW) magnetic resonance (MR) imaging and to assess ...whether the presence of MH results in improved prediction of the long-term neurologic outcome.
A retrospective case-control analysis of the data for 101 children aged 1-32 months with forensic pediatric specialist-confirmed NAT was performed with institutional review board approval. Sixty-two patients were boys (mean age, 8.4 months +/- 7.4 standard deviation), and 39 were girls (mean age, 7.4 months +/- 7.8). The imaging findings and clinical data of the children who were examined with SW imaging were collected. Exclusion criteria included pre-existing cognitive delays, central nervous system malformations, previous brain injuries, and/or birth before 30 weeks gestation. Dichotomized long-term neurologic outcomes (good normal, mild disability, or moderate disability versus poor severe disability, vegetative state, or death) at greater than or equal to 6 months (mean, 33 months; range 6-95 months) were available for 53 patients (36 boys mean age, 7.3 months +/- 5.9; 17 girls mean age, 7.4 months +/- 7.9; overall range, 2-32 months). Logistic regression was used to determine whether the presence of SW imaging-depicted MH, as compared with other radiologic findings, resulted in improved prediction of long-term neurologic outcome.
Imaging findings showed that of the 101 patients, 29 (29%) had MH at SW imaging, 66 (65%) had extraaxial hemorrhages, 52 (51%) had retinal hemorrhages, and 35 (35%) had evidence of acute ischemic injury. A significantly larger number of children with poor outcomes than children with good outcomes had brain MH (nine of 14 vs seven of 39; P = .001) and ischemic injury (13 of 14 vs 17 of 39; P = .006). Logistic regression analysis revealed presence of MH at SW imaging-followed by acute ischemic injury, initial Glasgow Coma Scale score, and age-to be the most significant single variable in the final model, with an overall predictive accuracy of 92.5%.
Presence of intraparenchymal brain MH in children with NAT, as detected on SW images, correlates with significantly poor long-term neurologic outcome, improves outcome prediction compared with the predictions made by using other tested clinical and imaging findings, and is most predictive when combined with presence of ischemic injury.
To determine whether the pattern of brain injury in term neonatal encephalopathy is associated with distinct prenatal and perinatal factors and to determine whether the pattern of injury is ...associated with 30-month neurodevelopmental outcome.
A total of 173 term newborns with neonatal encephalopathy from 2 centers underwent magnetic resonance imaging (MRI) at a median of 6 days of age (range, 1-24 days). Patterns of injury on MRI were defined on the basis of the predominant site of injury: watershed predominant, basal ganglia/thalamus predominant, and normal.
The watershed pattern of injury was seen in 78 newborns (45%), the basal ganglia/thalamus pattern was seen in 44 newborns (25%), and normal MRI studies were seen in 51 newborns (30%). Antenatal conditions such as maternal substance use, gestational diabetes, premature rupture of membranes, pre-eclampsia, and intra-uterine growth restriction did not differ across patterns. The basal ganglia/thalamus pattern was associated with more severe neonatal signs, including more intensive resuscitation at birth (
P
=
.001), more severe encephalopathy (
P
=
.0001), and more severe seizures (
P
=
.0001). The basal ganglia/thalamus pattern was associated with the most impaired motor and cognitive outcome at 30 months.
The patterns of brain injury in term neonatal encephalopathy are associated with different clinical presentations and neurodevelopmental outcomes. Measured prenatal risk factors did not predict the pattern of brain injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
There is evidence from various models of hypoxic-ischemic injury (HII) that nitric oxide (NO) is protective. We hypothesized that either inhaled NO (iNO) or nitrite would alleviate brain injury in ...neonatal HII via modulation of mitochondrial function.
We tested the effects of iNO and nitrite on the Rice-Vannucci model of HII in 7-day-old rats. Brain mitochondria were isolated for flow cytometry, aconitase activity, electron paramagnetic resonance, and Seahorse assays.
Pretreatment of pups with iNO decreased survival in the Rice-Vannucci model of HII, while iNO administered post-insult did not. MRI analysis demonstrated that pre-HII iNO at 40 ppm and post-HII iNO at 20 ppm decreased the brain lesion sizes from 6.3±1.3% to 1.0±0.4% and 1.8±0.8%, respectively. Intraperitoneal nitrite at 0.165 μg/g improved neurobehavioral performance but was harmful at higher doses and had no effect on brain infarct size. NO reacted with complex IV at the heme a3 site, decreased the oxidative stress of mitochondria challenged with anoxia and reoxygenation, and suppressed mitochondrial oxygen respiration.
This study suggests that iNO administered following neonatal HII may be neuroprotective, possibly via its modulation of mitochondrial function.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background There is evidence from various models of hypoxic-ischemic injury (HII) that nitric oxide (NO) is protective. We hypothesized that either inhaled NO (iNO) or nitrite would alleviate brain ...injury in neonatal HII via modulation of mitochondrial function. Methods We tested the effects of iNO and nitrite on the Rice-Vannucci model of HII in 7-day-old rats. Brain mitochondria were isolated for flow cytometry, aconitase activity, electron paramagnetic resonance, and Seahorse assays. Results Pretreatment of pups with iNO decreased survival in the Rice-Vannucci model of HII, while iNO administered post-insult did not. MRI analysis demonstrated that pre-HII iNO at 40 ppm and post-HII iNO at 20 ppm decreased the brain lesion sizes from 6.3±1.3% to 1.0±0.4% and 1.8±0.8%, respectively. Intraperitoneal nitrite at 0.165 μg/g improved neurobehavioral performance but was harmful at higher doses and had no effect on brain infarct size. NO reacted with complex IV at the heme a3 site, decreased the oxidative stress of mitochondria challenged with anoxia and reoxygenation, and suppressed mitochondrial oxygen respiration. Conclusions This study suggests that iNO administered following neonatal HII may be neuroprotective, possibly via its modulation of mitochondrial function.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An inception cohort of 40 children and adolescents with traumatic brain injury and suspected diffuse axonal injury were studied using a new high‐resolution magnetic resonance imaging ...susceptibility‐weighted technique that is very sensitive for hemorrhage. A blinded comparison was performed between the extent of parenchymal hemorrhage and initial clinical variables as well as outcomes measured at 6 to 12 months after injury. Children with lower Glasgow Coma Scale scores (≤8, n = 30) or prolonged coma (>4 days, n = 20) had a greater average number (p = 0.007) and volume (p = 0.008) of hemorrhagic lesions. Children with normal outcomes or mild disability (n = 30) at 6 to 12 months had, on average, fewer hemorrhagic lesions (p = 0.003) and lower volume (p = 0.003) of lesions than those who were moderately or severely disabled or in a vegetative state. Significant differences also were observed when comparing regional injury to clinical variables. Because susceptibility‐weighted imaging is much more sensitive than conventional T2*‐weighted gradient‐echo sequences in detecting hemorrhagic diffuse axonal injury, more accurate and objective assessment of injury can be obtained early after insult, and may provide better prognostic information regarding duration of coma as well as long‐term outcome. Ann Neurol 2004;56:36–50
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To compare the effectiveness of a high-spatial-resolution susceptibility-weighted (SW) magnetic resonance (MR) imaging technique with that of a conventional gradient-recalled-echo (GRE) MR imaging ...technique for detection of hemorrhage in children and adolescents with diffuse axonal injury (DAI).
Seven young patients with a mean Glasgow Coma Scale score of 7 +/- 4 (SD) at admission were imaged a mean of 5 days +/- 3 after injury. High-spatial-resolution three-dimensional GRE imaging performed with postprocessing by using a normalized phase mask was compared with conventional GRE MR imaging. The total and mean values of lesion number and apparent hemorrhage volume load determined with both examinations were compared. Mean values were compared by using paired t test analysis. Differences were considered to be significant at P < or =.05.
Hemorrhagic lesions were much more visible on SW MR images than on conventional GRE MR images. SW MR imaging depicted 1,038 hemorrhagic DAI lesions with an apparent total hemorrhage volume of 57,946 mm3. GRE MR imaging depicted 162 lesions with an apparent total hemorrhage volume of 28,893 mm3. SW MR imaging depicted a significantly higher mean number of lesions in all patients than did GRE MR imaging, according to results of visual (P =.004) and computer (P =.004) counting analyses. The mean hemorrhage volume load for all patients also was significantly greater (P =.014) by using SW MR imaging according to computer analysis. SW MR imaging appeared to depict much smaller hemorrhagic lesions than GRE MR imaging. The majority (59%) of individual hemorrhagic DAI lesions seen on SW MR images were small in area (<10 mm(2)), whereas the majority (43%) of lesions seen on GRE images were larger in area (10-20 mm(2)).
SW MR imaging depicts significantly more small hemorrhagic lesions than does conventional GRE MR imaging and therefore has the potential to improve diagnosis of DAI.
The prognostic ability of global white matter and gray matter metabolite ratios following pediatric traumatic brain injury (TBI) and their relationship to 12-month neuropsychological assessments of ...intelligence quotient (IQ), attention, and memory is presented. Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) in pediatric subjects with complicated mild (cMild), moderate, and severe TBI was acquired acutely (6-18 days) and 12 months post-injury and compared to age-matched typically developing adolescents. A global linear regression model, co-registering MRSI metabolite maps with 3D high-resolution magnetic resonance images, was used to identify longitudinal white matter and gray matter metabolite ratio changes. Acutely, gray matter NAA/Cr, white matter NAA/Cr, and white matter NAA/Cho ratios were significantly lower in TBI groups compared to controls. Gray matter NAA/Cho was reduced only in the severe TBI group. At 12 months, all metabolite ratios normalized to control levels in each of the TBI groups. Acute gray matter and white matter NAA ratios were significantly correlated to 12-month assessments of IQ, attention, and memory. These findings suggest that whole brain gray matter and white matter metabolite ratios reflect longitudinal changes in neuronal metabolism following TBI, which can be used to predict neuropsychological outcomes in pediatric subjects.
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