Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types.

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.

Abnormal Right-Hemispheric Sulcal Patterns Correlate with Executive Function in Adolescents with Tetralogy of Fallot.

Neurodevelopmental disabilities are the most common noncardiac conditions in patients with congenital heart disease (CHD). Executive function skills have been frequently observed to be decreased among children and adults with CHD compared with peers, but a neuroanatomical basis for the association is yet to be identified. In this study, we quantified sulcal pattern features from brain magnetic resonance imaging data obtained during adolescence among 41 participants with tetralogy of Fallot (ToF) and 49 control participants using a graph-based pattern analysis technique. Among patients with ToF, right-hemispheric sulcal pattern similarity to the control group was decreased (0.7514 vs. 0.7553, P = 0.01) and positively correlated with neuropsychological testing values including executive function (r = 0.48, P < 0.001). Together these findings suggest that sulcal pattern analysis may be a useful marker of neurodevelopmental risk in patients with CHD. Further studies may elucidate the mechanisms leading to different alterations in sulcal patterning.

Altered White Matter Microstructure Correlates with IQ and Processing Speed in Children and Adolescents Post-Fontan.

OBJECTIVE: To compare white matter microstructure in children and adolescents with single ventricle who underwent the Fontan procedure with healthy controls, and to explore the association of white matter injury with cognitive performance as well as patient and medical factors. STUDY DESIGN: Fontan (n = 102) and control subjects (n = 47) underwent diffusion tensor imaging (DTI) at ages 10-19 years. Mean DTI measures (fractional anisotropy, radial diffusivity, axial diffusivity, and mean diffusivity) were calculated for 33 fiber tracts from standard white matter atlases. Voxel-wise group differences in DTI measures were assessed using Tract-Based Spatial Statistics. Associations of regional fractional anisotropy with IQ and processing speed as well as medical characteristics were examined. RESULTS: Subjects with Fontan, compared with controls, had reduced bilateral regional and voxel-wise fractional anisotropy in multiple white matter tracts along with increased regional radial diffusivity in several overlapping tracts; regional mean diffusivity differed in 2 tracts. The groups did not differ in voxel-wise radial diffusivity or mean diffusivity. Among subjects with Fontan, fractional anisotropy in many tracts correlated positively with Full-Scale Intelligence Quotient and processing speed, although similar findings were absent in controls. Lower mean fractional anisotropy in various tracts was associated with more complications in the first operation, a greater number of total operations, and history of neurologic event. CONCLUSIONS: Children and adolescents who have undergone the Fontan procedure have widespread abnormalities in white matter microstructure. Furthermore, white matter microstructure in several tracts is associated with cognitive performance and operative and medical history characteristics.

Sleep environments and sleep physiology: A review.

Sleep loss impairs task performance and post-physical activity recovery, cognitive performance and mood, heightens fatigue and decreases vigour; poor sleep quality impairs decision-making, the speed and accuracy of task performance, and post-exercise recovery. Sleep time and quality are affected by age, psychological and physiological conditions, culture and environmental factors. Skin temperature, rapid temperature change and sweating during sleep can significantly reduce sleep quality. Hence, the thermal properties of bedding and sleepwear, both in steady-state and transient ambient temperature conditions, are logically important factors. Research to date on sleeping thermal microclimates and their effect on sleep quality is scarce. This present review covers the fundamental elements of human sleep, highlighting physically active people, such as athletes, and the influence of sleepwear and bedding on sleep thermal microclimates, as well as the research methods that have been and could be used in this field. This review identifies opportunity for future research direction and approaches to understanding thermal environments that may support better human sleep.

Reduced cortical volume and thickness and their relationship to medical and operative features in post-Fontan children and adolescents.

BACKGROUND: We compared brain cortical and subcortical gray matter volumes and cortical thickness between post-Fontan patients and healthy controls, and examined brain anatomical associations with operative and medical history characteristics. METHODS: Post-Fontan (n = 128 volumes; n = 115 thickness) and control subjects (n = 48 volumes; n = 45 thickness) underwent brain MRI at ages 10-19 y. Subcortical and cortical volumes and cortical thicknesses were measured for intergroup comparison. Associations between brain measures and clinical measures were assessed in the Fontan group. RESULTS: Widespread, significant reduction in brain volumes and thicknesses existed in the Fontan group compared to controls, spanning all brain lobes and subcortical gray matter. Fontan subjects treated with vs. without the Norwood procedure had smaller volumes in several terminal clusters, but did not differ in cortical thickness. Older age at first operation and increasing numbers of cardiac catheterizations, operative complications, and catheterization complications were associated with lower regional volumes and thicknesses. Increasing numbers of operative complications and cardiac catheterizations were associated with smaller regional volumes in the Norwood group. CONCLUSION: The post-Fontan adolescent brain differs from the normal control brain. Some of these differences are associated with potentially modifiable clinical variables, suggesting that interventions might improve long-term neurocognitive outcome.

Arterial Spin Labeling Perfusion Magnetic Resonance Imaging Performed in Acute Perinatal Stroke Reveals Hyperperfusion Associated With Ischemic Injury.

BACKGROUND AND PURPOSE: Perfusion-weighted imaging in adults with acute stroke often reveals hypoperfusion in the ischemic core and in a surrounding area of nondiffusion-restricted penumbral tissue. Perinatal stroke is common, but the perfusion pattern is rarely documented. We aimed to describe the perfusion pattern in newborns with perinatal stroke. METHODS: Neonates with clinical features of acute stroke underwent magnetic resonance imaging. Perfusion data were obtained using pseudocontinuous arterial spin labeling. Strokes were classified as arterial, venous, or both. Core infarction was determined by the presence of restricted diffusion on diffusion-weighted imaging. Perfusion-weighted imaging and susceptibility-weighted imaging signal in the ischemic area were visually compared with the homologous region in the contralesional hemisphere. Electroencephalogram data were evaluated for seizure activity. RESULTS: In 25 neonates with acute stroke, 8 of 11 (73%) with arterial ischemic stroke demonstrated hyperperfusion, 1 of 9 (11%) with venous stroke, and 4 of 5 (80%) with both. Hypoperfusion was observed in 3 of 9 (33%) with venous and none with arterial ischemic stroke. Perfusion was normal in 4 of 9 (45%) with venous and 1 of 5 (20%) with both. Twenty-one of 24 patients (88%) with electroencephalogram data had either electrographic seizures or focal sharp waves in the ipsilesional hemisphere (11/11 arterial ischemic stroke, 6/9 venous, and 4/5 both). CONCLUSIONS: Perfusion-weighted imaging can be obtained in neonates with acute stroke and often reveals hyperperfusion in the infarct core. Penumbra in arterial ischemic stroke is seldom found. Hyperperfusion may be caused by poststroke reperfusion or to neuronal hyperexcitability of stroke-associated seizure. Its identification may be useful for consideration of therapy for acute neonatal stroke.

Predictors of Stroke After Transient Ischemic Attack in Children.

BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) in children has received far less attention compared with TIA in adults. The risk factors of stroke after TIA in children are relatively unknown. We aimed to determine the percentage of children who have stroke after TIA and the risk factors associated with stroke after TIA. METHODS: We searched the medical records at Boston Children's Hospital for the year 2010 to find children who were evaluated for TIA to determine associated risk factors of stroke after TIA. We included children who were evaluated in 2009 through 2010 for TIA and had magnetic resonance imaging. We examined follow-up imaging through August 2014 for subsequent stroke. Logistic regression was used to calculate odds ratios for factors in our cohort who are associated with stroke after presentation with TIA. RESULTS: We identified 63 children who experienced a TIA. The mean time of imaging follow-up was 4.5 years after TIA presentation. Of the 63 children, 10 (16%) developed radiological evidence of ischemic cerebral injury within the follow-up period. Four of the 10 (6%) demonstrated diffusion abnormalities on magnetic resonance imaging at TIA presentation, whereas 8 (13%) had a stroke after their TIA. Arteriopathy, female sex, and autoimmune disorders were significantly associated with stroke after TIA. CONCLUSIONS: In our cohort of children, stroke occurred after TIA at a rate similar to that seen in adults, but the risk factors for stroke after TIA in children are different.

Altered Gray Matter in Adolescents with d-Transposition of the Great Arteries.

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. 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 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. CONCLUSIONS: 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.

White matter microstructure and cognition in adolescents with congenital heart disease.

OBJECTIVE: To describe the relationship between altered white matter microstructure and neurodevelopment in children with dextro-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 = .006), inattention/hyperactivity symptoms correlated with right precentral FA (r = -0.39; P = .006) and left parietal FA (r = -0.30; P = .04), executive function correlated with right precentral FA (r = -0.30; P = .04), and visual-spatial skills correlated with right frontal FA (r = 0.30; P = .04). We also found an unanticipated correlation between memory and right posterior limb of the internal capsule FA (r = 0.29; P = .047). CONCLUSION: Within the group with d-TGA, regions of reduced white matter microstructure are associated with cognitive performance in a pattern similar to that seen in healthy adolescents and adults. Diminished white matter microstructure may contribute to cognitive compromise in adolescents who underwent open-heart surgery in infancy.

Reorganization of the functional connectome from rest to a visual perception task in schizophrenia and bipolar disorder.

Functional connectome organization is altered in schizophrenia (SZ) and bipolar disorder (BD). However, it remains unclear whether network reorganization during a task relative to rest is also altered in these disorders. This study examined connectome organization in patients with SZ (N = 43) and BD (N = 42) versus healthy controls (HC; N = 39) using fMRI data during a visual object-perception task and at rest. Graph analyses were conducted for the whole-brain network using indices selected a priori: three reflecting network segregation (clustering coefficient, local efficiency, modularity), two reflecting integration (characteristic path length, global efficiency). Group differences were limited to network segregation and were more evident in SZ (clustering coefficient, modularity) than in BD (clustering coefficient) compared to HC. State differences were found across groups for segregation (local efficiency) and integration (characteristic path length). There was no group-by-state interaction for any graph index. In summary, aberrant network organization compared to HC was confirmed, and was more evident in SZ than in BD. Yet, reorganization was largely intact in both disorders. These findings help to constrain models of dysconnection in SZ and BD, suggesting that the extent of functional dysconnectivity in these disorders tends to persist across changes in mental state.

Challenges and opportunities for neuroimaging in young patients with traumatic brain injury: a coordinated effort towards advancing discovery from the ENIGMA pediatric moderate/severe TBI group.

Traumatic brain injury (TBI) is a major cause of death and disability in children in both developed and developing nations. Children and adolescents suffer from TBI at a higher rate than the general population, and specific developmental issues require a unique context since findings from adult research do not necessarily directly translate to children. Findings in pediatric cohorts tend to lag behind those in adult samples. This may be due, in part, both to the smaller number of investigators engaged in research with this population and may also be related to changes in safety laws and clinical practice that have altered length of hospital stays, treatment, and access to this population. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric Moderate/Severe TBI (msTBI) group aims to advance research in this area through global collaborative meta-analysis of neuroimaging data. In this paper, we discuss important challenges in pediatric TBI research and opportunities that we believe the ENIGMA Pediatric msTBI group can provide to address them. With the paucity of research studies examining neuroimaging biomarkers in pediatric patients with TBI and the challenges of recruiting large numbers of participants, collaborating to improve statistical power and to address technical challenges like lesions will significantly advance the field. We conclude with recommendations for future research in this field of study.

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes. METHODS: Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline. RESULTS: Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between d=-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027). CONCLUSIONS: WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically-meaningful patient subtypes.

Graph theory analysis of DTI tractography in children with traumatic injury.

OBJECTIVE: To evaluate brai structural connectivity in children with traumatic injury (TI) following a motor vehicle accident using graph theory analysis of DTI tractography data. METHODS: DTI 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. RESULTS: At 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. CONCLUSIONS: Graph 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.

Post-Traumatic Stress Symptoms after Pediatric Injury: Relation to Pre-Frontal Limbic Circuitry.

Pre-frontal limbic circuitry is vulnerable to effects of stress and injury. We examined microstructure of pre-frontal limbic circuitry after traumatic brain injury (TBI) or extracranial injury (EI) and its relation to post-traumatic stress symptoms (PTSS). Participants aged 8 to 15 years who sustained mild to severe TBI (n = 53) or EI (n = 26) in motor vehicle incidents were compared with healthy children (n = 38) in a prospective longitudinal study. At the seven-week follow-up, diffusion tensor imaging was obtained in all groups; injured children completed PTSS ratings using a validated scale. Using probabilistic diffusion tensor tractography, pathways were seeded from bilateral amygdalae and hippocampi to estimate the trajectory of white matter connecting them to each other and to targeted pre-frontal cortical (PFC) regions. Microstructure was estimated using fractional anisotropy (FA) in white matter and mean diffusivity (MD) in gray matter. Pre-frontal limbic microstructure was similar across groups, except for reduced FA in the right hippocampus to orbital PFC pathway in the injured versus healthy group. We examined microstructure of components of pre-frontal limbic circuitry with concurrently obtained PTSS cluster scores in the injured children. Neither microstructure nor PTSS scores differed significantly in the TBI and EI groups. Across PTSS factors, specific symptom clusters were related positively to higher FA and MD. Higher hyperarousal, avoidance, and re-experiencing symptoms were associated with higher FA in amygdala to pre-frontal and hippocampus to amygdala pathways. Higher hippocampal MD had a central role in hyperarousal and emotional numbing symptoms. Age moderated the relation of white and gray matter microstructure with hyperarousal scores. Our findings are consistent with models of traumatic stress that implicate disrupted top-down PFC and hippocampal moderation of overreactive subcortical threat arousal systems. Alterations in limbic pre-frontal circuitry and PTSS place children with either brain or body injuries at elevated risk for both current and future psychological health problems.

Graph theory analysis of cortical thickness networks in adolescents with d-transposition of the great arteries.

Objective: Adolescents with d-transposition of the great arteries (d-TGA) who had the arterial switch operation in infancy have been found to have structural brain differences compared to healthy controls. We used cortical thickness measurements obtained from structural brain MRI to determine group differences in global brain organization using a graph theoretical approach. Methods: Ninety-two d-TGA subjects and 49 controls were scanned using one of two identical 1.5-Tesla MRI systems. Mean cortical thickness was obtained from 34 regions per hemisphere using Freesurfer. A linear model was used for each brain region to adjust for subject age, sex, and scanning location. Structural connectivity for each group was inferred based on the presence of high inter-regional correlations of the linear model residuals, and binary connectivity matrices were created by thresholding over a range of correlation values for each group. Graph theory analysis was performed using packages in R. Permutation tests were performed to determine significance of between-group differences in global network measures. Results: Within-group connectivity patterns were qualitatively different between groups. At lower network densities, controls had significantly more long-range connections. The location and number of hub regions differed between groups: controls had a greater number of hubs at most network densities. The control network had a significant rightward asymmetry compared to the d-TGA group at all network densities. Conclusions: Using graph theory analysis of cortical thickness correlations, we found differences in brain structural network organization among d-TGA adolescents compared to controls. These may be related to the white matter and gray matter differences previously found in this cohort, and in turn may be related to the cognitive deficits this cohort presents.

Ascending Aorta Size at Birth Predicts White Matter Microstructure in Adolescents Who Underwent Fontan Palliation.

Background In neonates with single ventricle, smaller ascending aorta diameter is associated with cerebral white matter ( WM ) microstructural abnormalities. We sought to determine whether this association persists into adolescence. Methods and Results Ascending aorta Z scores were obtained from first postnatal echocardiogram. Brain magnetic resonance imaging with diffusion tensor imaging was acquired in adolescence and used to obtain fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity in 33 WM tract regions of interest. Partial Pearson correlation coefficients were evaluated for associations between ascending aorta Z scores and WM microstructure measures, adjusting for sex, age at magnetic resonance imaging, scanner field strength, and Norwood status. Among 42 single ventricle patients aged 10 to 19 years, 31 had undergone the Norwood procedure as neonates. Lower ascending aorta Z scores were associated with lower fractional anisotropy in bilateral pontine crossing tracts ( P=0.02), inferior fronto-occipital fasciculus ( P=0.02), and inferior longitudinal fasciculus ( P=0.01); left cingulum-cingulate bundle ( P=0.01), superior longitudinal fasciculus ( P=0.04), and superior longitudinal fasciculus-temporal component ( P=0.01); and right cingulum-hippocampal bundle (P=0.009) and inferior cerebellar peduncle ( P=0.01). Lower ascending aorta Z scores were associated with higher radial diffusivity and mean diffusivity in a similar regional pattern but not with axial diffusivity. Conclusions In adolescents with single ventricle, smaller aorta diameter at birth is associated with abnormalities of WM microstructure in a subset of WM tracts, mostly those located in deeper brain regions. Our findings suggest that despite multiple intervening medical or surgical procedures, prenatal cerebral blood flow may have a lasting influence on WM microstructure in single-ventricle patients.

The Potential for Advanced Magnetic Resonance Neuroimaging Techniques in Pediatric Stroke Research.

BACKGROUND: This article was written to provide clinicians and researchers with an overview of a number of advanced neuroimaging techniques in an effort to promote increased utility and the design of future studies using advanced neuroimaging in childhood stroke. The current capabilities of advanced magnetic resonance imaging techniques provide the opportunity to build on our knowledge of the consequences of stroke on the developing brain. These capabilities include providing information about the physiology, metabolism, structure, and function of the brain that are not routinely evaluated in the clinical setting. METHODS: During the Proceedings of the Stroke Imaging Laboratory for Children Workshop in Toronto in June 2015, a subgroup of clinicians and imaging researchers discussed how the application of advanced neuroimaging techniques could further our understanding of the mechanisms of stroke injury and repair in the pediatric population. This subgroup was established based on their interest and commitment to design collaborative, advanced neuroimaging studies in the pediatric stroke population. RESULTS: In working toward this goal, we first sought to describe here the magnetic resonance imaging techniques that are currently available for use, and how they have been applied in other stroke populations (e.g., adult and perinatal stroke). CONCLUSIONS: With the continued improvement in advanced neuroimaging techniques, including shorter acquisition times, there is an opportunity to apply these techniques to their full potential in the research setting and learn more about the effects of stroke in the developing brain.

Organizational topology of brain and its relationship to ADHD in adolescents with d-transposition of the great arteries.

OBJECTIVE: Little 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. METHODS: We 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). RESULTS: Changes 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. CONCLUSION: Our 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.

Relationship of white matter network topology and cognitive outcome in adolescents with d-transposition of the great arteries.

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.

Neuropsychological Status and Structural Brain Imaging in Adolescents With Single Ventricle Who Underwent the Fontan Procedure.

BACKGROUND: Few 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 RESULTS: In 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%). CONCLUSIONS: The 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.