Processing Speed Partially Mediates Executive Function Impairments in Adolescents with Congenital Heart Disease: Results from a Prospective Cohort Study.

OBJECTIVE: To assess processing speed, fine motor function, attention, and executive function (EF) impairments in adolescents with complex congenital heart disease (CHD) who underwent open-heart surgery during infancy. STUDY DESIGN: We administered a comprehensive neuropsychological test battery evaluating 5 EF domains: working memory, inhibition, cognitive flexibility, fluency, and planning and primary neurodevelopmental processes (PNPs): processing speed, fine motor function, and attention. The sample included 100 adolescents with complex CHD from a previous University Children's Hospital Zurich study, with 104 healthy controls for comparison. We generated scores for each EF domain and computed an EF summary score. Group comparisons and associations were analyzed with multiple regressions accounting for parental education. Mediation analysis explored how PNPs mediate the effect between a CHD diagnosis and EF. RESULTS: In adolescents with complex CHD, all EF domains and the EF summary score were impaired (ß = 0.20 to 0.37, all P < .05). Furthermore, they exhibited slower processing speed (ß = 0.27, P < .01) than healthy controls, with no differences in attention (ß = -0.07, P = .34) and fine motor function (ß = 0.08, P = .34). Processing speed showed a strong association with the EF summary score (ß = 0.60, P < .001) and partially mediated the relationship between CHD diagnosis and the EF summary score (ß = 0.37, 95% CI [0.24, 0.50], P < .001). CONCLUSION: Adolescents with complex CHD show difficulties in EFs and processing speed. Notably, processing speed is strongly associated with EFs and partly accounts for EFs disparities between patients and healthy controls. Early detection and interventions for processing speed difficulties may improve EF outcomes in these patients.

Congenital heart disease in school-aged children: Cognition, education, and participation in leisure activities.

BACKGROUND: Children with congenital heart disease (CHD) are at risk for neurodevelopmental deficits. This study aimed to investigate the impact of cognitive deficits on educational outcome and participation in leisure activities. METHODS: A prospective cohort of 134 children with CHD who underwent cardiopulmonary bypass surgery (CPB) was examined at 10 years of age. IQ was assessed with the WISC-IV and executive functions with the BRIEF (parent- and teacher-report). Parents reported on type and level of education and educational support, and leisure activity participation. Ordinal regression analyses assessed the association between cognitive deficits and educational outcome and participation. RESULTS: Total IQ (P = 0.023), working memory (P < 0.001), processing speed (P = 0.008), and teacher-reported metacognition (P = 0.022) were lower than norms. Regular school was attended by 82.4% of children with CHD compared to 97% of the general Swiss population (P < 0.001). Seventy-five percent of children participated in leisure activities. Lower total IQ and teacher-rated global executive functions were associated with more educational support and lower IQ was associated with less participation. CONCLUSION: As school-aged children with CHD experience cognitive deficits, follow-up is required to provide optimal support with regard to educational outcome and participation in leisure activities. IMPACT: Contemporary cohorts of children with congenital heart disease undergoing cardiopulmonary bypass surgery remain at increased risk for cognitive deficits. Cognitive deficits affect educational outcome and leisure activities. These findings underline the importance of early detection of cognitive deficits and recommend support with respect to cognitive functioning.

Counting on random number generation: Uncovering mild executive dysfunction in congenital heart disease.

Congenital heart disease (CHD) is associated with various neurocognitive deficits, particularly targeting executive functions (EFs), of which random number generation (RNG) is one indicator. RNG has, however, never been investigated in CHD. We administered the Mental Dice Task (MDT) to 67 young adults with CHD and 55 healthy controls. This 1-minute-task requires the generation of numbers 1 to 6 in a random sequence. RNG performance was correlated with a global EF score. Participants underwent MRI to examine structural-volumetric correlates of RNG. Compared to controls, CHD patients showed increased backward counting, reflecting deficient inhibition of automatized behavior. They also lacked a small-number bias (higher frequency of small relative to large numbers). RNG performance was associated with global EF scores in both groups. In CHD patients, MRI revealed an inverse association of counting bias with most of the volumetric measurements and the amount of small numbers was positively associated with corpus callosum volume, suggesting callosal involvement in the "pseudoneglect in number space". In conclusion, we found an impaired RNG performance in CHD patients, which is associated with brain volumetric measures. RNG, reportedly resistant to learning effects, may be an ideal task for the longitudinal assessment of EFs in patients with CHD.

Mental health-related quality of life in mothers of children with surgically repaired congenital heart disease: a 13-year longitudinal study.

AIMS: Having a child with congenital heart disease (CHD) can affect parental health-related quality of life (HR-QoL). We investigated the long-term trajectories of mental HRQoL (m-HRQoL) in mothers of children with CHD and examined risk factors for persistent low m-HRQoL. METHODS: One hundred twenty-five mothers of children with CHD completed a standardized questionnaire on m-HRQoL (mental subscale SF-12) after the children's first open-heart surgery and subsequently when the children were 1, 4, 6, 10, and 13 years old. A z-score for m-HRQoL was calculated with national norms. Latent class growth analysis (LCGA) was used to identify subgroups of mothers with regards to their m-HRQoL trajectories over time. Regression analysis investigated predictors for chronically low m-HRQoL. RESULTS: Compared to norms, mothers of children with CHD had significantly lower m-HRQoL immediately after open-heart surgery (ß = -0.30 (CI-95: -0.44, -0.15)). Subsequently, m-HRQoL increased to a normal level (m-HRQoL compared to the norm from 1 to 13 years: ß ranges between 0.05 and 0.27). LCGA revealed two distinct groups of m-HRQoL trajectories: A group with normal m-HRQoL (75% of mothers, means z-scores range between - 0.76 and 0.62) and a group with chronically low m-HRQoL (25% of mothers, mean z-scores range between -1.32 and -0.10). Chronically, low m-HRQoL was associated with poorer social support (OR = 3.39 (CI-95: 1.40, 8.49), p = 0.008) but not with parental education, migration background, number of open-heart surgeries, diagnosis of a univentricular CHD, or low IQ. CONCLUSION: A quarter of mothers of children with CHD have chronically low m-HRQoL throughout their child's development, especially those mothers with poor social support. Further studies of family-oriented approaches are needed to identify and support these mothers and reinforce parental well-being.

Mental sequelae of the COVID-19 pandemic in children with and without complex medical histories and their parents: well-being prior to the outbreak and at four time-points throughout 2020 and 2021.

The objective of this study is to understand the long-term mental sequelae for families over the course of the COVID-19 pandemic by longitudinally investigating the well-being of children with and without complex medical histories and their parents. Well-being of 200 children (between 7 and 18 years of age; 73 typically developing, 46 born very preterm, 73 with complex congenital heart disease) and 175 of their parents was assessed prior to and during the first (April-May 2020), second (October-November 2020), third (April-May 2021), and fourth wave (October-November 2021) of the pandemic with standardized questionnaires. Linear mixed models were used to investigate longitudinal changes in child and parent well-being compared to before the pandemic. Social and COVID-19-specific determinants were investigated as predictors of impaired well-being. To illustrate clinical relevance, the proportion of children and parents scoring > 1 SD below normative mean/median was reported. Compared to before the pandemic, child proxy-reported well-being was lower during the first but not the second, third, and fourth waves. Child self-reported well-being was not lower during the pandemic compared to before. Parent well-being dropped during the first wave and remained low throughout the subsequent waves. Proxy-reported child and self-reported parent well-being was lower in families with sparse social support and poor family functioning. Parents of typically developing children reported lower well-being than parents of children born very preterm or with a complex congenital heart disease. In November 2021, 20% of children (both self- and proxy-report) and 24% of parents scored below the normal range compared to 11% (child self-report), 10% (child proxy-report), and 16% (parent self-report), respectively, before the pandemic. The pandemic continues to impact the well-being of parents of school-aged children with and without complex medical histories more than 1 year after its outbreak. Children's well-being was specifically affected during the first wave of the pandemic and has recovered thereafter. Families with sparse social support and poor family functioning are particularly at risk for compromised well-being and support should be provided to them.

Perioperative Course and Socioeconomic Status Predict Long-Term Neurodevelopment Better Than Perioperative Conventional Neuroimaging in Children with Congenital Heart Disease.

OBJECTIVE: The objective of the study was to compare the use of neonatal conventional brain magnetic resonance imaging (MRI) with that of clinical factors and socioeconomic status (SES) to predict long-term neurodevelopment in children with severe congenital heart disease (CHD). STUDY DESIGN: In this prospective cohort study, perioperative MRIs were acquired in 57 term-born infants with CHD undergoing cardiopulmonary bypass surgery during their first year of life. Total brain volume (TBV) was measured using an automated method. Brain injury severity (BIS) was assessed by an established scoring system. The neurodevelopmental outcome was assessed at 6 years using standardized test batteries. A multiple linear regression model was used for cognitive and motor outcomes with postoperative TBV, perioperative BIS, CHD complexity, length of hospital stay, and SES as covariates. RESULTS: CHD diagnoses included univentricular heart defect (n = 15), transposition of the great arteries (n = 33), and acyanotic CHD (n = 9). Perioperative moderate-to-severe brain injury was detected in 15 (26%) patients. The total IQ was similar to test norms (P = .11), whereas the total motor score (P < .001) was lower. Neither postoperative TBV nor perioperative BIS predicted the total IQ, but SES (P < .001) and longer hospital stay (P = .004) did. No factor predicted the motor outcome. CONCLUSION: Although the predictive value of neonatal conventional MRIs for long-term neurodevelopment is low, duration of hospital stay and SES better predict the outcome in this CHD sample. These findings should be considered in initiating early therapeutic support.

Impact of the COVID-19 pandemic on children with and without risk for neurodevelopmental impairments.

AIM: To examine how the ongoing COVID-19 pandemic impacts child well-being and family functioning, particularly among children at risk for neurodevelopmental impairments. METHODS: Families of 73 typically developing children, 54 children born very preterm (VPT) and 73 children with congenital heart disease (CHD) from two prospective cohort studies were assessed prior to (mean age: 10.4 [SD: 1.2] years) and during (mean age: 12.8 [SD: 2.0] years) the pandemic, more specifically, in April/May 2020. Child well-being and family functioning were assessed with validated, parent-reported questionnaires and tested with linear mixed models. Group comparison of child distress and parental concerns related to medical implications of COVID-19 and homeschooling, assessed with 5-point Likert scales, was done with Mann-Whitney U tests. RESULTS: Children's psychological well-being and family functioning (both, p < 0.001) decreased significantly during the pandemic, irrespective of group. Children with CHD were reported to be more concerned about becoming infected with SARS-CoV-2 than were others. Child distress due to homeschooling and parents' concerns about children's academic achievements were significantly higher in VPT and CHD children than in typically developing peers (all p < 0.001). CONCLUSION: The COVID-19 pandemic substantially impacts the whole family and leads to additional distress in families with children at risk for neurodevelopmental impairments. These families should receive individualised counselling and assistance from healthcare providers and schools during the pandemic.

Reducing Amygdala Activity and Phobic Fear through Cognitive Top-Down Regulation.

The amygdala is critically involved in emotional processing, including fear responses, and shows hyperactivity in anxiety disorders. Previous research in healthy participants has indicated that amygdala activity is down-regulated by cognitively demanding tasks that engage the PFC. It is unknown, however, if such an acute down-regulation of amygdala activity might correlate with reduced fear in anxious participants. In an fMRI study of 43 participants (11 men) with fear of snakes, we found reduced amygdala activity when visual stimuli were processed under high cognitive load, irrespective of whether the stimuli were of neutral or phobic content. Furthermore, dynamic causal modeling revealed that this general reduction in amygdala activity was partially mediated by a load-dependent increase in dorsolateral PFC activity. Importantly, high cognitive load also resulted in an acute decrease in perceived phobic fear while viewing the fearful stimuli. In conclusion, our data indicate that a cognitively demanding task results in a top-down regulation of amygdala activity and an acute reduction of fear in phobic participants. These findings may inspire the development of novel psychological intervention approaches aimed at reducing fear in anxiety disorders.

Pitfalls of using IQ short forms in neurodevelopmental disorders: a study in patients with congenital heart disease.

BACKGROUND: Short forms of IQ (S-IQ) assessments are time efficient and highly predictive of the full IQ (F-IQ) in healthy individuals. To investigate the validity of S-IQs for patients with neurodevelopmental impairments, this study tested a well-established S-IQ version in patients with congenital heart disease (CHD). METHODS: The Wechsler Intelligence Scale for Children, Fourth Edition was applied in 107 children with complex CHD aged 9-11 years. F-IQ and a well-established S-IQ version were calculated for each patient. The agreement between S-IQ and F-IQ was investigated across the whole spectrum of IQ scores. Finally, we tested a method to adjust IQs to resolve potential bias and validated this method in an independent sample of 55 CHD patients. RESULTS: S-IQ and F-IQ correlated strongly. Nevertheless, the size of the bias correlated with the true IQ, indicating larger error at the tails of the distribution. Estimating a corrected IQ by adjusting the S-IQ with correction parameters substantially improved agreement. CONCLUSION: We here report that substantial bias may underestimate low IQ scores and overestimate high ones. This bias should be considered when at-risk populations are assessed with S-IQs. Importantly, the bias can be minimized by using a correction formula.

Stress Markers, Executive Functioning, and Resilience Among Early Adolescents With Complex Congenital Heart Disease.

Importance: Infants with complex congenital heart disease (cCHD) may experience prolonged and severe stress when undergoing open heart surgery. However, little is known about long-term stress and its role in neurodevelopmental impairments in this population. Objective: To investigate potential differences between early adolescents aged 10 to 15 years with cCHD and healthy controls in physiological stress markers by hair analysis, executive function (EF) performance, and resilience. Design, Setting, and Participants: This single-center, population-based case-control study was conducted at the University Children's Hospital Zurich, Switzerland. Patients with different types of cCHD who underwent cardiopulmonary bypass surgery during the first year of life and who did not have a genetic disorder were included in a prospective cohort study between 2004 and 2012. A total of 178 patients were eligible for assessment at ages 10 to 15 years. A control group of healthy term-born individuals was cross-sectionally recruited. Data assessment was between 2019 and 2021. Statistical analysis was performed from January to April 2023. Exposure: Patients with cCHD who underwent infant open heart surgery. Main Outcomes and Measures: Physiological stress markers were quantified by summing cortisol and cortisone concentrations measured with liquid chromatography with tandem mass spectrometry in a 3-centimeter hair strand. EFs were assessed with a neuropsychological test battery to produce an age-adjusted EF summary score. Resilience was assessed with a standardized self-report questionnaire. Results: The study included 100 patients with cCHD and 104 controls between 10 and 15 years of age (mean [SD] age, 13.3 [1.3] years); 110 (53.9%) were male and 94 (46.1%) were female. When adjusting for age, sex, and parental education, patients had significantly higher sums of hair cortisol and cortisone concentrations (ß, 0.28 [95% CI, 0.12 to 0.43]; P < .001) and lower EF scores (ß, -0.36 [95% CI, -0.49 to -0.23]; P < .001) than controls. There was no group difference in self-reported resilience (ß, -0.04 [95% CI, -0.23 to 0.12]; P = .63). A significant interaction effect between stress markers and EFs was found, indicating a stronger negative association in patients than controls (ß, -0.65 [95% CI, -1.15 to -0.15]; P = .01). The contrast effects were not significant in patients (ß, -0.21 [95% CI, -0.43 to -0.00]; P = .06) and controls (ß, 0.09 [95% CI, -0.11 to 0.30]; P = .38). Conclusions and Relevance: This case-control study provides evidence for altered physiological stress levels in adolescents with cCHD and an association with poorer EF. These results suggest that future studies are needed to better understand the neurobiological mechanisms and timing of alterations in the stress system and its role in neurodevelopment.

Social cognition and behavioral outcomes in congenital heart disease: profiles and neuropsychiatric comorbidities.

Autism spectrum disorders are more prevalent in children with congenital heart disease (CHD) than in the general population. Children with CHD without diagnosed autism are also at increased risk for neurodevelopmental and psychiatric impairments. We characterized social and behavioral outcomes in children with CHD and examined neurodevelopmental and psychiatric comorbidities. Children without diagnosed autism who underwent infant open-heart surgery were eligible. Parent-reports assessed social communication, unusual behaviors, self-regulation, anxiety, and executive function (EF). Neuropsychological tests assessing theory of mind (ToM), working memory, and verbal comprehension were administered. Outcomes were compared to normative data. Linear regressions were estimated with parent-reported scores and ToM abilities as outcomes. Predictors were anxiety symptoms, parent-reported EF, and working memory scores. Covariates were age, parental education, ADHD diagnosis, and verbal comprehension. Clinically relevant comorbidities were identified (N children scoring ≥1SD below the norm). Fifty-six children (10.8 ± 1.8 years) participated virtually. Compared to norms, children with CHD had impaired ToM, more unusual behaviors (p = .002), and less self-regulation (p = .018), but better social communication (p = .014). "Autism-like" traits were positively associated with anxiety symptoms (ß(95% CI) = 0.28(0.08-0.49), p = .008) and worse working memory (ß(95% CI) = -0.36(-0.59-0.13), p = .003). Twenty-one out of 22 children who displayed clinically relevant social and behavioral scores also showed anxiety symptoms (n = 4), impaired EF (n = 7), or both (n = 10). Children with CHD without diagnosed autism have elevated unusual behaviors, lower self-regulation, and impaired ToM. There is a high risk of co-existing anxiety and impaired EF which may increase disease burden. Targeted therapeutic interventions are needed to reduce long-term psychosocial risks in these children.AbbreviationAttention deficit/hyperactivity disorder (ADHD), Autism Spectrum Rating Scale (ASRS), Behavior Rating Inventory of Executive Functions for school-aged children, 2nd Edition (BRIEF-2), cardiopulmonary bypass (CPB), congenital heart disease (CHD), Empathy/Systematizing Quotient Child Version (ESQ-C), Multidimensional Anxiety Scale for Children, 2nd Edition (MASC-2), Social Responsiveness Scale (School-age form), 2nd Edition (SRS-2), theory of mind (ToM), Theory of Mind Task Battery (ToM-TB), Wechsler Intelligence Scale for Children, 5th edition (WISC-V).

White matter microstructure and executive functions in congenital heart disease from childhood to adulthood: A pooled case-control study.

Congenital heart disease (CHD) patients are at risk for alterations in the cerebral white matter microstructure (WMM) throughout development. It is unclear whether the extent of WMM alterations changes with age, especially during adolescence when the WMM undergoes rapid maturation. We investigated differences in WMM between patients with CHD and healthy controls from childhood until early adulthood in a pooled sample of children, adolescents, and young adults. The association between WMM and EF was assessed. Patients with CHD (N=78) and controls (N=137) between 9 and 32 years of age underwent diffusion tensor imaging and an executive function test-battery. Mean fractional anisotropy (FA) was calculated for each white matter tract. Linear regression tested age and group effects (CHD vs control) and their interaction on FA. Relative Variable Importance (RI) estimated the independent contribution of tract FA, presence of CHD, CHD complexity, and parental education to the variability in EF. Mean FA was lower in patients compared to controls in almost all tracts (p between 0.057 and <0.001). WMM alterations in patients were not different depending on age (all interaction effects p>0.074). Predictors of EF were CHD group (RI=43%), parental education (RI=23%), CHD complexity (RI=10%), FA of the hippocampal cingulum (RI=6%) and FA of the corticospinal tract (RI=6%). The lack of group-FA-interactions indicates that the extent of altered FA remains similar across age. Altered FA is associated with EF impairments. CHD is a chronic disease with cerebral and neurocognitive impairments persisting into adulthood and, thus, long-term follow-up programs may improve overall outcome for this population.

Multimodal personalised executive function intervention (E-Fit) for school-aged children with complex congenital heart disease: protocol for a randomised controlled feasibility study.

INTRODUCTION: Children with congenital heart disease (CHD) are at risk for executive functions (EF) impairments. To date, interventions have limited effects on EF in children and adolescents with complex CHD. Therefore, we developed a new multimodal and personalised EF intervention (E-Fit). This study aims to test the feasibility of this intervention called 'E-Fit' for children with complex CHD and EF impairments. METHODS AND ANALYSIS: This is a single-centre, single-blinded, randomised controlled feasibility study exploring the E-Fit intervention. We aim to enrol 40 children with CHD aged 10-12 years who underwent infant cardiopulmonary bypass surgery and show clinically relevant EF impairments (T-score ≥60 on any Behaviour Rating Inventory for Executive Function questionnaire summary scale). The multimodal intervention was developed with focus groups and the Delphi method involving children and adolescents with CHD, their parents and teachers, and health professionals. The intervention is composed of three elements: computer-based EF training using CogniFit Inc 2022, performed three times a week at home; weekly EF remote strategy coaching and analogue games. The content of the computer and strategy training is personalised to the child's EF difficulties. The control group follows their daily routines as before and completes a diary about their everyday activities four times a week. Participants will be randomised in a 1:1 ratio. Feasibility is measured by the participants' and providers' ratings of the participants' adherence and exposure to the intervention, recruitment rates and the evaluation of the intended effects of the programme. ETHICS AND DISSEMINATION: Local ethics committee approval was obtained for the study (BASEC-Nr: 2021-02413). Parents provide written informed consent. Key outputs from the trial will be disseminated through presentations at conferences, peer-reviewed publications and directly to participating families. Furthermore, these results will inform the decision whether to proceed to a randomised controlled trial to investigate effectiveness. TRIAL REGISTRATION NUMBER: NCT05198583.

Altered white matter microstructure is related to cognition in adults with congenital heart disease.

Adults with congenital heart disease are at risk for persisting executive function deficits, which are known to affect academic achievement and quality of life. Alterations in white -matter microstructure are associated with cognitive impairments in adolescents with congenital heart disease. This study aimed to identify microstructural alterations potentially associated with executive function deficits in adults with congenital heart disease. Diffusion tensor imaging and tract-based spatial statistics were conducted in 45 patients (18 females) and 54 healthy controls (26 females) aged 18-32 years. Fractional anisotropy of white matter diffusion was compared between groups and correlated with an executive function score, derived from an extensive neuropsychological test battery. Patients showed widespread bilateral reduction in fractional anisotropy (P < 0.05, multiple comparison corrected) compared to controls. Lower fractional anisotropy was driven by patients with moderate and severe defect complexity (compared to controls: P < 0.001). Executive function scores were lower in patients (P < 0.05) and associated with lower fractional anisotropy in the left superior corona radiata and the corticospinal tract (corrected P < 0.05). Our findings confirm alterations of white matter microstructure in adults with congenital heart disease, mainly in those patients of moderate to severe complexity. These alterations are associated with impairments in executive functioning. A better understanding of the neurocognitive deficits may help counselling and care of patients with congenital heart disease across their lifespan and have the potential to improve their outcome and quality of life.

Cognitive and Executive Function in Congenital Heart Disease: A Meta-analysis.

CONTEXT: Cognitive function and executive function (EF) impairments contribute to the long-term burden of congenital heart disease (CHD). However, the degree and profile of impairments are insufficiently described. OBJECTIVE: To systematically review and meta-analyze the evidence on cognitive function and EF outcomes in school-aged children operated for CHD and identify the risk factors for an unfavorable outcome. DATA SOURCES: Cochrane, Embase, Medline, and PsycINFO. STUDY SELECTION: Original peer-reviewed studies reporting cognitive or EF outcome in 5- to 17-year old children with CHD after cardiopulmonary bypass surgery. DATA EXTRACTION: Results of IQ and EF assessments were extracted, and estimates were transformed to means and SE. Standardized mean differences were calculated for comparison with healthy controls. RESULTS: Among 74 studies (3645 children with CHD) reporting total IQ, the summary estimate was 96.03 (95% confidence interval: 94.91 to 97.14). Hypoplastic left heart syndrome and univentricular CHD cohorts performed significantly worse than atrial and ventricular septum defect cohorts (P = .0003; P = .027). An older age at assessment was associated with lower IQ scores in cohorts with transposition of the great arteries (P = .014). Among 13 studies (774 children with CHD) reporting EF compared with controls, the standardized mean difference was -0.56 (95% confidence interval: -0.65 to -0.46) with no predilection for a specific EF domain or age effect. LIMITATIONS: Heterogeneity between studies was large. CONCLUSIONS: Intellectual impairments in CHD are frequent, with severity and trajectory depending on the CHD subtype. EF performance is poorer in children with CHD without a specific EF profile. The heterogeneity in studied populations and applied assessments is large. A uniform testing guideline is urgently needed.

Microstructural alterations of the corticospinal tract are associated with poor motor function in patients with severe congenital heart disease.

Congenital heart disease (CHD) patients are at risk for neurodevelopmental impairments, including altered motor function. However, little is known about the neuroanatomical correlates of persistent motor deficits in CHD. Thus, we examined the link between corticospinal tract (CST) microstructure and motor function in adolescent and adult CHD patients compared to healthy controls. This study investigated 89 CHD patients (N(adolescents) = 47, N(adults) = 42, mean age = 19.9 years) and 97 age-matched healthy controls (N(adolescents) = 44, N(adults) = 53, mean age = 20.6 years). Diffusion tensor imaging was conducted and fractional anisotropy (FA) of the left and right CST was extracted for each participant. Fine (pegboard) and pure motor (repeated finger, hand and foot movements) performance was evaluated with a standardized test battery. FA and motor performance were correlated and the effect of CHD complexity was tested using multivariate linear regression. Clinically relevant motor impairments (>2SD below normative mean) were evident in 24% of patients and 9% of controls. On average, motor performance was lower in CHD patients compared to controls, particularly in those with more complex CHD (fine motor: p = 0.023; pure motor: p < 0.001). FA CST was lower in patients compared to controls, particularly in those with more complex CHD (left: p < 0.001, right: p = 0.003). There was a significant interaction between CHD complexity and FA CST (left: p = 0.025, right: p = 0.025), indicating that FA correlates significantly with pure motor in patients with severe CHD, while there is only a weak association in moderate CHD and no association in patients with simple CHD and controls. Microstructure of the CST is altered in CHD patients, and is associated with pure motor impairments in patients with severe CHD. This indicates that persistent motor impairments may arise from atypical development of the primary motor pathway in the presence of a complex CHD. Early interventions promoting brain maturation in infancy may prevent persisting impairments across the lifetime.

Altered frontal white matter microstructure is associated with working memory impairments in adolescents with congenital heart disease: A diffusion tensor imaging study.

Children and adolescents with congenital heart disease (CHD) are at risk for mild to moderate cognitive impairments. In particular, impaired working memory performance has been found in CHD patients of all ages. Working memory is an important domain of higher order cognitive function and is crucial for everyday activities, with emerging importance in adolescence. However, the underlying neural correlate of working memory impairments in CHD is not yet fully understood. Diffusion tensor imaging and tract based spatial statistics analyses were conducted in 47 adolescent survivors of childhood cardiopulmonary bypass surgery (24 females) and in 44 healthy controls (24 females) between 11 and 16 years of age (mean age = 13.9, SD = 1.6). Fractional anisotropy (FA) of white matter diffusion was compared between groups and was correlated with working memory performance, derived from the Wechsler Intelligence Scale for Children-IV. CHD patients had significantly poorer working memory compared to controls (p = 0.001). Widespread bilateral reduction in FA was observed in CHD patients compared to healthy controls (threshold-free cluster enhancement (TFCE) corrected p < 0.05). This reduction in FA was present both in cyanotic and acyanotic CHD patients compared to healthy controls (both p < 0.001). The FA reduction in the frontal lobe, mainly in the forceps minor, was associated with poorer working memory performance in both patients with CHD and healthy controls (TFCE corrected p < 0.05). The current findings underline that in CHD patients, irrespective of disease severity, disrupted or delayed maturation of white matter may persist into adolescence and is associated with working memory impairments, particularly if present in the frontal lobe. Adolescence, which is a crucial period for prefrontal brain maturation, may offer a window of opportunity for intervention in order to support the maturation of frontal brain regions and therefore improve higher order cognitive function in patients with CHD.

Social and Behavioral Difficulties in 10-Year-Old Children With Congenital Heart Disease: Prevalence and Risk Factors.

Children with congenital heart disease (CHD) may be at increased risk for neurodevelopmental impairments. Long-term behavioral profiles and respective risk factors are less frequently described. The aim of this study was to evaluate multidimensional behavioral outcomes and associated medical, psychological, and social risk factors in children with complex CHD. At 10-years of age, 125 children with CHD were assessed for general behavioral difficulties, attention deficit hyperactivity disorder (ADHD)-related behavior, and social interaction problems and were compared to normative data. Medical and cardiac factors, IQ, maternal mental health at 4 years of age and parental socioeconomic status were tested as predictors for all behavioral outcomes. Children with CHD showed no significant differences in general behavioral difficulties. However, increased ADHD-related symptoms (p < 0.05) and difficulties in social interaction (p < 0.05) were observed. In 23% of the children, a combination of ADHD-related symptoms and social interaction problems was reported by parents. In multivariate analyses, IQ (p < 0.01) and maternal mental health (p < 0.03) at 4 years of age were found to be predictive for all behavioral outcomes at 10 years while medical and cardiac risk factors were not. Our findings reveal significant difficulties in ADHD-related symptoms and social interaction problems with a significant comorbidity. Behavioral difficulties were not detected with a screening tool but with disorder-specific questionnaires. Furthermore, we demonstrate the importance of maternal mental health during early childhood on later behavioral outcomes of children with CHD. This underlines the importance of identifying and supporting parents with mental health issues at an early stage in order to support the family and improve the child's neurodevelopment.

Executive function and brain development in adolescents with severe congenital heart disease (Teen Heart Study): protocol of a prospective cohort study.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent congenital malformation. With recent advances in medical care, the majority of patients with CHD survive into adulthood. As a result, interest has shifted towards the neurodevelopmental outcome of these patients, and particularly towards the early detection and treatment of developmental problems. A variety of mild to moderate cognitive impairments as well as emotional and behavioural problems has been observed in this population. However, a more detailed assessment of the various domains of executive function and their association with structural and functional brain development is lacking. Therefore, the current study will examine all domains of executive function and brain development in detail in a large sample of children and adolescents with CHD and healthy control children. METHODS AND ANALYSIS: A total of 192 children and adolescents with CHD aged 10-15 years, who participated in prospective cohort studies at the University Children's Hospital Zurich, will be eligible for this study. As a control group, approximately 100 healthy children will be enrolled. Primary outcome measures will include executive function abilities, while secondary outcomes will consist of other neurodevelopmental measures, including intelligence, processing speed, attention, fine motor abilities and brain development. An MRI will be performed to assess structural and functional brain development. Linear regression analyses will be applied to investigate group differences and associations between executive function performance and neurodevelopmental measures. ETHICS AND DISSEMINATION: This study is supported by the Swiss National Science Foundation (SNF 32003B_172914) and approved by the ethical committee of the Canton Zurich (KEK 2019-00035). Written informed consent will be obtained from all the parents and from children aged 14 years or older. Findings from this study will be published in peer-reviewed journals and presented at national and international conferences for widespread dissemination of the results.