Abstract Introduction Since the re-discovery of the glymphatic system, there has been an increased interest in perivascular spaces (PVS) and cerebrospinal fluid (CSF) characteristics in relation to sleep. Enlarged PVS (ePVS) are associated with neurological disorders and sleep problems, and excessive extra-axial CSF (EA-CSF) volume is associated with autism spectrum disorder (ASD). However, ePVS has not been studied in infancy in relation to autism, EA-CSF volume, or sleep problems. The objectives of this study, therefore, are to examine whether ePVS is 1) more prevalent in infants who later develop ASD, 2) related to EA-CSF volume, and 3) associated with later sleep problems. Methods The study was conducted on a prospective, longitudinal cohort from the Infant Brain Imaging Study (IBIS). Participants underwent neuroimaging at 6-, 12-, and 24-months of age, and parent-reported Children’s Sleep Habits Questionnaires (CSHQ) were collected at a follow-up visit at school age (age range = 7-12 years, M = 10.0). A total of 311 participants were included: 47 infants at high familial likelihood for ASD who were later diagnosed with ASD (HL+), 180 high likelihood infants not diagnosed with ASD (HL-), and 84 low likelihood control infants (LL-). The CSHQ was available on a subset of 109 participants. Results Significant group differences in ePVS rates were found at 24 months of age (p=0.041), with 44.7% of the HL+ group having ePVS, compared to 26.7% in the HL- group (p=0.017) and 26.2% in the LL- group (p=0.031). ePVS at 24 months was associated with greater EA-CSF volume from 6-24 months (p=0.002) and greater sleep disturbances at school-age (p=0.006), regardless of ASD diagnosis. Conclusion The presence of ePVS during infancy was associated with ASD diagnosis, elevated EA-CSF volume, and more frequent sleep disturbances. Results suggest that infants with ePVS should be monitored for early signs of ASD and potential long-term sleep problems, particularly sleep disturbances. Further examination is needed to establish whether early ePVS is ASD-specific or an indication of early glymphatic system dysfunction that can put infants and children at risk for atypical brain development and later sleep problems. Support (if any)

There are no published studies that examine the safety and tolerability of medication to treat attention-deficit/hyperactivity disorder (ADHD) in children with histories of Fontan palliation (Fontan) or heart transplant (HT), despite the high prevalence of ADHD in these populations. To address this gap, we examined the cardiac course, somatic growth, and incidence of side effects for one year after medication initiation amongst children with Fontan or HT and comorbid ADHD. The final sample comprised 24 children with Fontan (12 medication-treated, 12 control) and 20 children with HT (10 medication-treated, 10 control). Demographic, somatic growth (height and weight percentile-for age), and cardiac data (blood pressure, heart rate, results of 24 h Holter monitoring, electrocardiograms) were extracted from electronic medical records. Medication-treated and control subjects were matched by cardiac diagnosis (Fontan or HT), age, and sex. Nonparametric statistical tests were utilized to compare between- and within-group differences prior to, and one year post, medication initiation. There were no differences in somatic growth or cardiac data when comparing medication-treated participants to matched controls, regardless of cardiac diagnosis. Within the medication group, a statistically significant increase in blood pressure was observed, though the group average remained within clinically acceptable limits. While results are preliminary in nature due to our very limited sample size, our findings suggest that ADHD medications can be tolerated with minimal cardiac or somatic growth effects amongst complex cardiac patients. Our preliminary results favor treating ADHD with medication, which has considerable implications for long-term academic/employment outcomes and quality of life for this population. Close collaboration between pediatricians, psychologists, and cardiologists is essential to individualizing and optimizing interventions and outcomes for children with Fontan or HT.

Objective:Approximately half of all children and adults newly diagnosed with epilepsy also show behavioral and/or cognitive difficulties upon evaluation. While neuropsychological screening is recommended as a routine part of care at seizure onset, in reality, access to care is often restricted by many factors. In order to better define the extent of the problem, we developed a survey to understand how frequently youth with new onset epilepsy currently undergo neuropsychological evaluation or screening and whether virtual assessment tools are used to extend access to care.Participants and Methods:We created an online survey to better understand new onset epilepsy care provided within neuropsychological practice settings in the United States and Canada. The survey was disseminated via multiple listservs (e.g., AACN listservs, APPCN, PERF neuropsychologists) and respondents included 45 neuropsychologists. Survey questions were grouped by the following domains: 1) location characteristics (e.g., urban versus rural location, type of practice, affiliation with comprehensive epilepsy center); 2) volume of new onset epilepsy patient cases (e.g., number of neuropsychologists within practice who see new onset patients, percentage of new onset cases who received neuropsychological evaluations/screeners, wait time), and 3) tele-neuropsychology procedures (e.g., use of virtual testing, frequency of virtual testing, frequency of virtual intakes/feedbacks).Results:Practice locations of the 45 respondents included academic medical center (n=34, 75.6%), community medical center (n=10, 22.2%), and private practice (n=1, 2.2%). All but one respondent practiced in an urban setting. Respondents were generally affiliated with Comprehensive Epilepsy Centers (level 3 or 4) (n=39, 86.7%). Practice settings typically included < 3 epilepsy neuropsychologists (n=29, 65.9%). Of interest, neuropsychological evaluation of new onset pediatric epilepsy patients generally ranged from 0-25% of cases (n=32, 71%; mode=11-25%). Reported barriers included: insurance, poor access to rural populations, interdisciplinary communication, departmental referral patterns, limited number of providers, and need to prioritize pre-surgical patients. In terms of access, neuropsychology waitlist times for patients with nonsurgical epilepsy ranged from <1 to 6 months (n=34, 75%) with an equal proportion of patients waiting 1-3 months (33%) and 4-6 months (33%). Telehealth was not frequently utilized in non-surgical epilepsy test administration (Do not use, n=39; 86.7%), but frequently incorporated for non-testing purposes (i.e., intakes, feedbacks) (n=40, 88.9%).Conclusions:Results of this provider survey indicate that children with new-onset epilepsy do not routinely undergo neuropsychological evaluation (< 25%). Barriers included prioritizing presurgical workups, referral patterns, access to care, and limited provider bandwidth. Clearly, there is a need to improve access to care. Possible solutions include developing more time efficient screening batteries with measures most sensitive to early cognitive and psychosocial deficits, and incorporating the use of virtual technology all in the service of improving the lives of children with epilepsy.

Objective: This study was undertaken to characterize the relationship between neighborhood disadvantage and cognitive function as well as clinical, sociodemographic, and family factors in children with new onset idiopathic epilepsy and healthy controls. Methods: Research participants were 288 children aged 8-18 years with recent onset epilepsy (CWE; n = 182; mean age = 12.2 +/- 3.2 years), healthy first-degree cousin controls (HC; n = 106; mean age = 12.5 +/- 3.0), and one biological or adopted parent per child (n = 279). All participants were administered a comprehensive neuropsychological battery (reasoning, language, memory, executive function, motor function, and academic achievement). Family residential addresses were entered into the Neighborhood Atlas to determine each family's Area Deprivation Index (ADI), a metric used to quantify income, education, employment, and housing quality. A combination of parametric and nonparametric (chi(2)) tests examined the effect of ADI by group (epilepsy and controls) across cognitive, academic, clinical, and family factors. Results: Disadvantage (ADI) was equally distributed between groups (p = .63). For CWE, high disadvantage was associated with lower overall intellectual quotient (IQ; p =.04), visual naming/expressive language (p = .03), phonemic (letter) fluency (p < .01), passive inattention (omission errors; p = .03), delayed verbal recall (p =.04), and dominant fine motor dexterity and speed (p < .01). Cognitive status of the HC group did not differ by level of disadvantage (p = .40). CWE exhibited greater academic difficulties in comparison to HC (p < .001), which were exacerbated by disadvantage in CWE (p =.02) but not HC (p < .05). High disadvantage was associated with a threefold risk for academic challenges prior to epilepsy onset (odds ratio = 3.31, p = .024). Significance: Socioeconomic hardship (increased neighborhood disadvantage) exerts a significant adverse impact on the cognitive and academic status of youth with new and recent onset epilepsies, an impact that needs to be incorporated into etiological models of the neurobehavioral comorbidities of epilepsy.

Importance Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume. Objective To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood. Design, Setting, and Participants This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022. Exposure PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging). Main Outcomes and Measures Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years. Results A total of 311 infants (197 [63.3%] male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group ( P = .02) and 22 infants in the control group (26.2%) ( P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (β = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age ( F = 7.76; η 2 = 0.08; P = .006). Conclusions and Relevance These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.

Objective:ADHD and anxiety symptoms are highly comorbid in childhood. While worse functional outcomes are typically expected for children with comorbid ADHD and anxiety symptoms, an emerging body of literature has suggested that anxiety symptoms may actually contribute to compensatory effects for executive functioning (EF) skills in children with ADHD symptoms. However, the results of studies investigating this claim have been quite mixed, possibly due to the use of smaller sample sizes and cross-sectional datasets. The current study extends the previous literature by examining the possible compensatory effects of anxiety symptoms in the context of ADHD symptoms on EF abilities (e.g., working memory [WM] and inhibition) both cross-sectionally and longitudinally in a large, well-validated sample.Participants and Methods:547 children and adolescents (8-16 years) were included from a population-based sample of twins (CLDRC sample) with enrichment for reading and attention challenges. Participants were retested at a second time point approximately 5 years later. ADHD symptoms (inattention and hyperactivity-impulsivity) were measured by a DSM-based ADHD rating scale, anxiety symptoms were measured by the RCMAS, inhibition was measured by stop-signal reaction time (SSRT), and working memory was measured by Digit Span Backwards (WISC/WAIS-R/III). Covariates included age and sex assigned at birth. Multiple regression models examined cross-sectional and longitudinal associations between ADHD (inattention and H-I) symptoms, anxiety symptoms, and the interaction between ADHD and anxiety symptoms on WM and inhibition abilities.Results:As expected, higher anxiety, inattention, and H-I symptoms were generally associated with lower inhibition and WM abilities both cross-sectionally and longitudinally. While no significant interactions between ADHD and anxiety symptoms were identified cross-sectionally at Time 1, significant interactions between Time 1 ADHD and anxiety symptoms predicted Time 2 inhibition scores. An inattention x anxiety interaction (p=.002) and a H-I x anxiety (p=.016) interaction significantly predicted Time 2 inhibition. Simple slopes analysis confirmed a compensatory interaction pattern, where ADHD symptoms showed a stronger association with inhibition weaknesses in children without anxiety symptoms compared to those with anxiety symptoms. This suggests that anxiety symptoms may be serving as a compensatory factor for children with ADHD symptoms as compared to their peers without ADHD symptoms.Conclusions:These findings help clarify a previously mixed literature. Our findings suggest that the compensatory effect of anxiety symptoms on inhibition abilities in children with ADHD symptoms may be a developmental mechanism that takes time to emerge. The fact that the compensatory effect may take time to emerge may explain conflicting results within prior cross-sectional samples. These findings also have implications for research investigating the link between ADHD symptoms and EF abilities, as anxiety symptoms may be an important moderator to consider when attempting to explain why the correlation between ADHD symptoms and EF abilities is often weaker than expected. Finally, clinical implications for this work help to provide empirical evidence to support anecdotal experiences reported by individuals with ADHD and the clinicians who assess them, who often report that anxiety symptoms help them to improve EF performance.

This study examined whether strong cognitive skills (i.e. vocabulary, rapid naming, verbal working memory [VWM], and processing speed [PS]) contributed to resilience in single-word reading skills in children at risk for reading difficulties because of low phonological awareness scores (PA). Promotive factors were identified by main effects and protective factors through PA x cognition interactions. This study included 1,807 children ages 8-16. As predicted, all cognitive skills were significantly related to reading, consistent with promotive effects. A significant, but small effect PA x vocabulary interaction (R2 change=.002, p=.00038) was detected but its form was not consistent with a classic protective effect. Rather, the PA x vocabulary interaction was consistent with a "skill-enhancement" pattern, such that children with strong PA and vocabulary skills had better than expected reading. This study provides a framework for reading resilience research and directs attention to promotive mechanisms underlying reading success.