BackgroundFew studies have described the neuropsychological outcomes and frequency of structural brain or genetic abnormalities in adolescents with single ventricle who underwent the Fontan procedure.Methods and ResultsIn a cross‐sectional, single‐center study, we enrolled 156 subjects with single ventricle, mean age 14.5±2.9 years, who had undergone the Fontan procedure. Scores in the entire cohort on a standard battery of neuropsychological tests were compared with those of normative populations or to those of a group of 111 locally recruited healthy adolescents. They also underwent brain magnetic resonance imaging and were evaluated by a clinical geneticist. Genetic abnormalities were definite in 16 subjects (10%) and possible in 49 subjects (31%). Mean Full‐Scale IQ was 91.6±16.8, mean Reading Composite score was 91.9±17.2, and mean Mathematics Composite score was 92.0±22.9, each significantly lower than the population means of 100±15. Mean scores on other neuropsychological tests were similarly lower than population norms. In multivariable models, risk factors for worse neuropsychological outcomes were longer total support and circulatory arrest duration at first operation, presence of a genetic abnormality, more operations and operative complications, more catheterization complications, and seizure history. The frequency of any abnormality on magnetic resonance imaging was 11 times higher among Fontan adolescents than referents (66% versus 6%); 19 (13%) patients had evidence of a stroke, previously undiagnosed in 7 patients (40%).ConclusionsThe neuropsychological deficits and high frequencies of structural brain abnormalities in adolescents who underwent the Fontan procedure highlight the need for research on interventions to improve the long‐term outcomes in this high‐risk group.
Objective To describe the relationship between altered white matter microstructure and neurodevelopment in children with d-transposition of the great arteries (d-TGA). Study design We report correlations between regional white matter microstructure as measured by fractional anisotropy (FA) and cognitive outcome in a homogeneous group of adolescents with d-TGA. Subjects with d-TGA (n=49) and controls (n=29) underwent diffusion tensor imaging and neurocognitive testing. In the group with d-TGA, we correlated neurocognitive scores with FA in 14 composite regions of interest in which subjects with d-TGA had lower FA than controls. Results Among the patients with d-TGA, mathematics achievement correlated with left parietal FA (r=0.39, p=0.006), inattention/hyperactivity symptoms with right precentral FA (r=−0.39, p=0.006) and left parietal FA (r=−0.30, p=0.04), executive function with right precentral FA (r=−0.30, p=0.04), and visual-spatial skills with right frontal FA(r=0.30, p=0.04). We also found an unanticipated correlation between memory and right posterior limb of the internal capsule FA (r=0.29, p=0.047). Conclusion Within the group with d-TGA, regions of reduced white matter microstructure are associated with cognitive performance in a pattern similar to healthy adolescents and adults. Diminished white matter microstructure may contribute to cognitive compromise in adolescents who underwent open-heart surgery in infancy.
Patients with congenital heart disease (CHD) are at risk for neurocognitive impairments. Little is known about the impact of CHD on the organization of large-scale brain networks. We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 49 adolescents with dextro-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and 29 healthy referent adolescents. We examined whether differences in neurocognitive functioning were related to white matter network topology. We developed mediation models revealing the respective contributions of peri-operative variables and network topology on cognitive outcome. Adolescents with d-TGA had reduced global efficiency at a trend level (p = 0.061), increased modularity (p = 0.012), and increased small-worldness (p = 0.026) as compared to controls. Moreover, these network properties mediated neurocognitive differences between the d-TGA and referent adolescents across every domain assessed. Finally, structural network topology mediated the neuroprotective effect of longer duration of core cooling during reparative neonatal cardiac surgery, as well as the detrimental effects of prolonged hospitalization. Taken together, worse neurocognitive function in adolescents with d-TGA is mediated by global differences in white matter network topology, suggesting that disruption of this configuration of large-scale networks drives neurocognitive dysfunction. These data provide new insights into the interplay between perioperative factors, brain organization, and cognition in patients with complex CHD.
Objective To use diffusion tensor imaging (DTI) to compare white matter microstructure in adolescents with d-transposition of the great arteries (d-TGA) who underwent the arterial switch operation in early infancy with typically developing control adolescents. We also examined correlates between patient and medical risk factors and white matter as assessed by regional fractional anisotropy (FA) values. Methods We studied 49 adolescents with d-TGA and 29 control adolescents with magnetic resonance imaging (MRI). MRI data, including whole brain DTI and conventional anatomic MRI, were acquired from each subject. Each subject’s data were analyzed using random effects analysis to evaluate regional white matter differences in FA between d-TGA and control adolescents. Results While multifocal punctate MRI hypointensities on T1-weighted (T1W) imaging suggestive of mineralization were found, other evidence of gross white matter injury was absent. Eighteen discrete regions of significantly reduced FA in d-TGA adolescents compared to controls were observed in deep white matter of cerebral hemispheres, cerebellum, and midbrain. Among d-TGA adolescents, lower FA correlated with younger gestational age, shorter duration of intraoperative cooling, higher intraoperative minimum tympanic temperature, longer intensive care unit stay after repair and greater total number of open heart operations. Conclusions Despite scant white matter injury on conventional brain MRI, adolescents with d-TGA repaired in infancy demonstrate significant white matter FA reduction that may relate to their reported neurocognitive deficits. Among d-TGA adolescents, FA values are associated with patient and perioperative factors, some of which are modifiable.
ObjectiveLittle is currently known about the impact of congenital heart disease (CHD) on the organization of large‐scale brain networks in relation to neurobehavioral outcome. We investigated whether CHD might impact ADHD symptoms via changes in brain structural network topology in a cohort of adolescents with d‐transposition of the great arteries (d‐TGA) repaired with the arterial switch operation in early infancy and referent subjects. We also explored whether these effects might be modified by apolipoprotein E (APOE) genotype, as the APOE ε2 allele has been associated with worse neurodevelopmental outcomes after repair of d‐TGA in infancy.MethodsWe applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 47 d‐TGA adolescents and 29 healthy referents to construct measures of structural topology at the global and regional levels. We developed statistical mediation models revealing the respective contributions of d‐TGA, APOE genotype, and structural network topology on ADHD outcome as measured by the Connors ADHD/DSM‐IV Scales (CADS).ResultsChanges in overall network connectivity, integration, and segregation mediated worse ADHD outcomes in d‐TGA patients compared to healthy referents; these changes were predominantly in the left and right intrahemispheric regional subnetworks. Exploratory analysis revealed that network topology also mediated detrimental effects of the APOE ε4 allele but improved neurobehavioral outcomes for the APOE ε2 allele.ConclusionOur results suggest that disruption of organization of large‐scale networks may contribute to neurobehavioral dysfunction in adolescents with CHD and that this effect may interact with APOE genotype.
Objective To investigate the structural brain characteristics of adolescent patients with d-transposition of the great arteries (d-TGA), repaired with the arterial switch operation in early infancy, using quantitative volumetric magnetic resonance imaging (MRI). Study design Ninety-two patients with d-TGA from the Boston Circulatory Arrest Study (76% male; median age at scan 16.1 years) and 49 control subjects (41% male; median age at scan 15.7 years ) were scanned using a 1.5-Tesla magnetic resonance imaging (MRI) system. Subcortical and cortical gyral volumes and cortical gyral thicknesses were measured using surface-based morphometry. Group differences were assessed with linear regression. Results Compared with controls, patients with d-TGA demonstrated significantly reduced subcortical volumes bilaterally in the striatum and pallidum. Cortical regions that showed significant volume and thickness differences between groups were distributed throughout parietal, medial frontoparietal, cingulate, and temporal gyri. Among adolescents with d-TGA, volumes and thicknesses correlated with several perioperative variables, including age at surgery, cooling duration, total support time, and days in the cardiac intensive care unit. Conclusion Adolescents with d-TGA repaired early in life exhibit widespread differences from control adolescents in gray matter volumes and thicknesses, particularly in parietal, midline, and subcortical brain regions, corresponding to white matter regions already known to demonstrate altered microstructure. These findings complement observations made in white matter in this group and suggest that the adolescent d-TGA cognitive profile derives from altered brain development involving both white and gray matter.
ObjectiveTo evaluate brai structural connectivity in children with traumatic injury (TI) following a motor vehicle accident using graph theory analysis of DTI tractography data.MethodsDTI scans were acquired on a 3 T Philips scanner from children aged 8–15 years approximately 2 months post-injury. The TI group consisted of children with traumatic brain injury (TBI; n = 44) or extracranial injury (EI; n = 23). Healthy control children (n = 36) were included as an age-matched comparison group. A graph theory approach was applied to DTI tractography data to investigate injury-related differences in connectivity network characteristics. Group differences in structural connectivity evidenced by graph metrics including efficiency, strength, and modularity were assessed using the multi-threshold permutation correction (MTPC) and network-based statistic (NBS) methods.ResultsAt the global network level, global efficiency and mean network strength were lower, and modularity was higher, in the TBI than in the control group. Similarly, strength was lower and modularity higher when comparing the EI to the control group. At the vertex level, nodal efficiency, vertex strength, and average shortest path length were different between all pairwise comparisons of the three groups. Both nodal efficiency and vertex strength were higher in the control than in the EI group, which in turn were higher than in the TBI group. The opposite between-group relationships were seen with path length. These between-group differences were distributed throughout the brain, in both hemispheres. NBS analysis resulted in a cluster of 22 regions and 21 edges with significantly lower connectivity in the TBI group compared to controls. This cluster predominantly involves the frontal lobe and subcortical gray matter structures in both hemispheres.ConclusionsGraph theory analysis of DTI tractography showed diffuse differences in structural brain network connectivity in children 2 months post-TI. Network differences were consistent with lower network integration and higher segregation in the injured groups compared to healthy controls. Findings suggest that inclusion of trauma-exposed comparison groups in studies of TBI outcome is warranted to better characterize the indirect effect of stress on brain networks.
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