Cerebral perfusion differences are linked to executive function performance in very preterm-born children and adolescents.

Children and adolescents born very preterm are at risk of cognitive impairment, particularly affecting executive functions. To date, the neural correlates of these cognitive differences are not yet fully understood, although converging evidence points to a pattern of structural and functional brain alterations, including reduced brain volumes, altered connectivity, and altered brain activation patterns. In very preterm neonates, alterations in brain perfusion have also been reported, but the extent to which these perfusion alterations persist into later childhood is not yet known. This study evaluated global and regional brain perfusion, measured with arterial spin labelling (ASL) MRI, in 26 very preterm children and adolescents and 34 term-born peers. Perfusion was compared between groups and relative to executive function (EF) scores, derived from an extensive EF battery assessing working memory, cognitive flexibility, and planning. Very preterm children and adolescents showed regions of altered perfusion, some of which were also related to EF scores. Most of these regions were located in the right hemisphere and included regions like the thalamus and hippocampus, which are known to play a role in executive functioning and can be affected by prematurity. In addition, perfusion decreased with age during adolescence and showed a significant interaction between birth status and sex, such that very preterm girls showed lower perfusion than term-born girls, but this trend was not seen in boys. Taken together, our results indicate a regionally altered perfusion in very preterm children and adolescents, with age and sex related changes during adolescence.

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.

Inhibition abilities and functional brain connectivity in school-aged term-born and preterm-born children.

BACKGROUND: Inhibition abilities are known to have impact on self-regulation, behavior, and academic success, and they are frequently impaired in children born preterm. We investigated the possible contributions of resting-state functional brain connectivity to inhibition following preterm birth. METHODS: Forty-four preterm and 59 term-born participants aged 8-13 years were administered two inhibition tasks and resting-state functional MRI was performed. Functional connectivity (FC) networks were compared between groups using network-based statistics. Associations of FCNs and inhibition abilities were investigated through multivariate linear regression models accounting for the interaction between birth status and inhibition. RESULTS: NBS revealed weaker FC in children born preterm compared to term-born peers in connections between motor and supplementary motor regions, frontal lobe, precuneus, and insula. Irrespective of birth status, connections between the cerebellum, frontal, and occipital lobes and inter-lobar, subcortical, intra-hemispheric long-range connections were positively correlated with one of the two inhibition tasks. CONCLUSIONS: Preterm birth results in long-term alterations of FC at network level but these FCN alterations do not specifically account for inhibition problems in children born very preterm. IMPACT: Irrespective of birth status, significant associations were found between the subdomain of response inhibition and functional connectivity in some subnetworks. A group comparisons of functional brain connectivity measured by rsfMRI in school-aged children born very preterm and at term. The investigation of network-level functional connectivity at rest does not appear adequate to explain differences in inhibition abilities between children born very preterm and at term, hence other imaging techniques might be more suited to explore the underlying neural mechanisms of inhibition abilities in school-aged children born very preterm.

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 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.

Similarities and Differences in the Neurodevelopmental Outcome of Children with Congenital Heart Disease and Children Born Very Preterm at School Entry.

OBJECTIVE: To describe the similarities and differences in the neurodevelopmental outcome of children with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery compared with children born very preterm (VPT) at school entry. STUDY DESIGN: IQ, motor abilities, behavior, and therapy use were assessed in 155 children with CHD as part of a prospective, single-center, longitudinal study, and in 251 children born VPT as part of a national follow-up register at the same center. Group differences were tested using independent t-tests and χ2-tests. Equivalence testing was used to investigate similarities between the groups. RESULTS: Mild (ie, 70 ≤ IQ < 85) and severe intellectual impairments (ie, IQ < 70) occurred in 17.4% and 4.5% of children with CHD compared with 22.1% and 5.5% in children VPT, respectively. Motor and behavioral functions were impaired in 57.0% and 15.3% of children with CHD compared with 37.8% and 11.5% of children born VPT, respectively. Children with CHD had poorer global motor abilities (d = -0.26) and poorer dynamic balance (d = -0.62) than children born VPT, and children born VPT had poorer fine motor abilities than children with CHD (d = 0.34; all P < .023). Peer problems were statistically similar between the groups (P = .020). Therapies were less frequent in children with CHD compared with children born VPT (23.4% vs 40.3%; P < .001). CONCLUSIONS: Children with CHD undergoing cardiopulmonary bypass surgery and children born VPT share an overall risk for neurodevelopmental impairments that manifest in different domains. Despite this, children with CHD receive fewer therapies, indicating a lack of awareness of the neurodevelopmental burden these children face.

Neurocognitive functioning in young adults with congenital heart disease: insights from a case-control study.

BACKGROUND: While there is evidence that cognitive impairment of children with congenital heart disease (CHD) may persist into adolescence, little is known about the spectrum of neurocognitive functioning of young adults with this disorder. The aim of this study was to assess neurocognitive functioning in a population of young adults with different types of CHD. METHODS: Cross-sectional cohort study in young adults with CHD and a group-matched healthy control group. We assessed neurocognitive and general intellectual functioning with a comprehensive battery of standardised neuropsychological tests. In addition to task-based assessments, questionnaire data of executive dysfunctions in everyday life were measured with the Behaviour Rating Inventory of Executive Function - Adult Version. RESULTS: A total of 67 patients (55% men) with CHD and 55 healthy controls (51% men) were included for analysis. Mean age at assessment was 26.9 (3.68) and 26.0 (3.32) years, respectively. The CHD group performed poorer in the domains of Executive Functions, Memory, Attention & Speed, and general intellectual functioning. Patients with a CHD of severe complexity were more affected than patients with simple or moderate complexity. Behaviour Rating Inventory of Executive Function - Adult Version scores indicated that patients' self-rated deficits in behaviour regulation in everyday life was higher compared with healthy controls. CONCLUSION: Our findings indicate lower neurocognitive functioning in young adults with a CHD, particularly in those with severe defect complexity. In view of the potentially enhanced risk for cerebrovascular and neurodegenerative disease in this patient group as reported in the literature, systematic longitudinal monitoring of cognitive functioning is recommended.

Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis.

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Effects of Correcting for Prematurity on Executive Function Scores of Children Born Very Preterm at School Age.

OBJECTIVE: To investigate whether correction for prematurity affects executive function scores in school-aged children born very preterm. STUDY DESIGN: Executive functions were assessed with standardized neuropsychological tests in 142 children born very preterm (born at ≤32 weeks of gestational age or with a birth weight of ≤1500 g) and 391 control children, aged 7-13 years. Four-month age bands were established from the data of control children. Differences between uncorrected and corrected scores were compared against zero difference and between very preterm children born before and after 28 weeks of gestation. Regression models were used to compare the uncorrected and corrected scores of children born very preterm with control children. RESULTS: For all executive functions, significant, larger-than-zero differences between uncorrected and corrected scores were apparent in children born very preterm. Mean differences ranged from 0.04 to 0.18 SDs. Weak evidence was found that the effect of age correction is more pronounced in very preterm children born before 28 weeks of gestation than in those born after 28 weeks. Differences in executive function scores between children born very preterm and control children were attenuated if scores were corrected for prematurity. CONCLUSIONS: Test scores based on corrected rather than uncorrected age may more accurately determine the developmental stage of very preterm children's executive functions at school age. Potential consequences for clinical and research practice need to be discussed in the future.

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.

Inhibition is associated with whole-brain structural brain connectivity on network level in school-aged children born very preterm and at term.

Inhibition abilities are often impaired in children born very preterm. In typically-developing individuals, inhibition has been associated with structural brain connectivity (SC). As SC is frequently altered following preterm birth, this study investigated whether aberrant SC underlies inhibition deficits in school-aged children born very preterm. In a group of 67 very preterm participants aged 8-13 years and 69 term-born peers, inhibition abilities were assessed with two tasks. In a subgroup of 50 very preterm and 62 term-born participants, diffusion tensor imaging (DTI) data were collected. Using network-based statistics (NBS), mean fractional anisotropy (FAmean) was compared between groups. Associations of FAmean and inhibition abilities were explored through linear regression. The composite score of inhibition abilities was lower in the very preterm group (M â€‹= â€‹-0.4, SD â€‹= â€‹0.8) than in the term-born group (M â€‹= â€‹0.0, SD â€‹= â€‹0.8) but group differences were not significant when adjusting for age, sex and socio-economic status (ߠ​= â€‹-0.13, 95%-CI [-0.30, 0.04], p â€‹= â€‹0.13). In the very preterm group, FAmean was significantly lower in a network comprising thalamo-frontal, thalamo-temporal, frontal, cerebellar and intra-hemispheric connections than in the term-born group (t â€‹= â€‹5.21, lowest p-value â€‹= â€‹0.001). Irrespective of birth status, a network comprising parietal, cerebellar and subcortical connections was positively associated with inhibition abilities (t â€‹= â€‹4.23, lowest p-value â€‹= â€‹0.02). Very preterm birth results in long-term alterations of SC at network-level. As networks underlying inhibition abilities do not overlap with those differing between the groups, FAmean may not be adequate to explain inhibition problems in very preterm children. Future studies should combine complementary measures of brain connectivity to address neural correlates of inhibition abilities.

Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm.

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10-16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r â€‹= â€‹.53 â€‹± .10; range â€‹= â€‹0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 â€‹± .06; 0.35 to 0.51 and 0.43 â€‹± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r â€‹= â€‹.43 â€‹± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r â€‹= â€‹-.53 â€‹± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.

Altered brain metabolism contributes to executive function deficits in school-aged children born very preterm.

BACKGROUND: Executive function deficits in children born very preterm (VPT) have been linked to anatomical abnormalities in white matter and subcortical brain structures. This study aimed to investigate how altered brain metabolism contributes to these deficits in VPT children at school-age. METHODS: Fifty-four VPT participants aged 8-13 years and 62 term-born peers were assessed with an executive function test battery. Brain metabolites were obtained in the frontal white matter and the basal ganglia/thalami, using proton magnetic resonance spectroscopy (MRS). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, glutamate + glutamine (Glx)/Cr, and myo-Inositol (mI)/Cr were compared between groups and associations with executive functions were explored using linear regression. RESULTS: In the frontal white matter, VPT showed lower Glx/Cr (mean difference: -5.91%, 95% CI [-10.50, -1.32]), higher Cho/Cr (7.39%, 95%-CI [2.68, 12.10]), and higher mI/Cr (5.41%, 95%-CI [0.18, 10.64]) while there were no differences in the basal ganglia/thalami. Lower executive functions were associated with lower frontal Glx/Cr ratios in both groups (ß = 0.16, p = 0.05) and higher mI/Cr ratios in the VPT group only (interaction: ß = -0.17, p = 0.02). CONCLUSION: Long-term brain metabolite alterations in the frontal white matter may be related to executive function deficits in VPT children at school-age. IMPACT: Very preterm birth is associated with long-term brain metabolite alterations in the frontal white matter. Such alterations may contribute to deficits in executive function abilities. Injury processes in the brain can persist for years after the initial insult. Our findings provide new insights beyond structural and functional imaging, which help to elucidate the processes involved in abnormal brain development following preterm birth. Ultimately, this may lead to earlier identification of children at risk for developing deficits and more effective interventions.

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.

Cohort and Individual Neurodevelopmental Stability between 1 and 6 Years of Age in Children with Congenital Heart Disease.

OBJECTIVE: To assess cohort and individual neurodevelopmental stability in children with congenital heart disease across childhood. STUDY DESIGN: The Reachout Study is a cohort study at the University Children's Hospital Zurich. Data from 148 children with congenital heart disease who underwent cardiopulmonary bypass surgery and 1-, 4-, and 6-year neurodevelopmental assessment were analyzed using mixed models. RESULTS: Cognitive and motor functions of the total cohort improved over time (cognitive: P = .01; motor: P <.001). The prevalence of children with cognitive impairment at age 6 years was 22.3%. Socioeconomic status showed a significant interaction with age on cognitive and motor development (cognitive: P <.001; motor: P = .001): higher socioeconomic status was associated with better neurodevelopmental outcome over time. Weight and head circumference at birth showed a significant interaction with age on motor development (weight: P = .048; head: P = .006). The correlation between test scores at different ages was weak to moderate (cognition: age 1-6 years: rho = 0.20, age 4-6 years: rho = 0.56, motor: age 1-6 years: rho = 0.23, age 4-6 years: rho = 0.50). CONCLUSIONS: Children with congenital heart disease show a mild improvement in cognitive and motor functions within the first 6 years of life, particularly those with higher socioeconomic status and larger head circumference and weight at birth. However, individual stability is moderate at best. Therefore, follow-up assessments are crucial to target therapeutic intervention effectively.

How do children fall asleep? A high-density EEG study of slow waves in the transition from wake to sleep.

INTRODUCTION: Slow waves, the hallmarks of non-rapid eye-movement (NREM) sleep, are thought to reflect maturational changes that occur in the cerebral cortex throughout childhood and adolescence. Recent work in adults has revealed evidence for two distinct synchronization processes involved in the generation of slow waves, which sequentially come into play in the transition to sleep. In order to understand how these two processes are affected by developmental changes, we compared slow waves between children and young adults in the falling asleep period. METHODS: The sleep onset period (starting 30s before end of alpha activity and ending at the first slow wave sequence) was extracted from 72 sleep onset high-density EEG recordings (128 electrodes) of 49 healthy subjects (age 8-25). Using an automatic slow wave detection algorithm, the number, amplitude and slope of slow waves were analyzed and compared between children (age 8-11) and young adults (age 20-25). RESULTS: Slow wave number and amplitude increased linearly in the falling asleep period in children, while in young adults, isolated high-amplitude slow waves (type I) dominated initially and numerous smaller slow waves (type II) with progressively increasing amplitude occurred later. Compared to young adults, children displayed faster increases in slow wave amplitude and number across the falling asleep period in central and posterior brain regions, respectively, and also showed larger slow waves during wakefulness immediately prior to sleep. CONCLUSIONS: Children do not display the two temporally dissociated slow wave synchronization processes in the falling asleep period observed in adults, suggesting that maturational factors underlie the temporal segregation of these two processes. Our findings provide novel perspectives for studying how sleep-related behaviors and dreaming differ between children and adults.

Remission of encephalopathy with status epilepticus (ESES) during sleep renormalizes regulation of slow wave sleep.

OBJECTIVE: In previous studies, we showed an altered overnight decrease of non-rapid-eye-movement (NREM) sleep slow waves in children with encephalopathy related to status epilepticus during sleep (ESES). Here, we test the hypothesis that these alterations renormalize after remission of ESES. Because overnight decrease of slow waves has been linked to brain recovery and cognition, we investigate whether cognitive outcome is related to overnight changes of slow waves. METHODS: We performed a retrospective analysis of longitudinal overnight electroencephalography (EEG) in 10 patients with idiopathic ESES. Automated slow wave detection and calculation of slope of slow waves during the first and last hour of NREM sleep were employed. Intraindividual comparisons were undertaken of the slope during active phase and after remission of ESES, and between patients after remission of ESES and healthy controls. Explorative analysis of the relationship between slow wave slope and cognitive outcome was performed. RESULTS: The slope of slow waves did not decrease significantly across the night during active ESES, particularly at the spike focus. After remission of ESES, the slope decreased significantly overnight. Compared to controls, there was no difference in overnight slope decrease. Association between slope and neuropsychological outcome showed best cognitive outcome after remission in those children (n = 3) who showed some degree of slope decline during active ESES. SIGNIFICANCE: This study provides evidence that alterations of overnight changes of NREM-sleep slow waves during active ESES are reversible when ESES resolves, and that the severity of neuropsychological compromise might be related to the extent of slow wave impairment during ESES. Our findings suggest that analysis of slow waves might serve as a prognostic factor regarding cognitive outcome. ESES may serve as disease model of pathologic slow wave sleep and our results might be expanded to epilepsies with spike wave activation in slow wave sleep not only in children but also in adults.