Cassidy, Adam R.

Despite major advances in cardiac care and decades of research, neurodevelopmental (ND) outcomes among children with congenital heart disease (CHD) have shown little improvement over time, substantial variability in outcomes remains unexplained, and prediction of individual developmental trajectories remains limited. This article argues that one contributor to these limitations is the field's reliance on descriptive but mechanistically underspecified models that catalog risk factors without clearly explaining how specific environmental experiences influence neurobehavioral development. To address this gap, this paper proposes an integrated dimensional model of neurodevelopment in CHD that conceptualizes ND outcomes as arising from the independent and interactive effects of CHD-related brain vulnerability and exposure to environmental medical adversity organized along the dimensions of deprivation and threat. Drawing from the Dimensional Model of Adversity and Psychopathology, the framework integrates prenatal dysmaturation, perioperative brain injury, and persistent alterations in brain structure and connectivity with adverse experiences occurring across prenatal, intensive care, caregiving, educational, and socioeconomic contexts. The model predicts that deprivation-related exposures will preferentially affect cognitive, language, and executive functioning systems, whereas threat-related exposures will more strongly influence emotional learning, stress regulation, and risk for psychopathology. By organizing CHD-related experiences according to developmentally meaningful dimensions of adversity, this framework provides a more mechanistic account of ND heterogeneity in CHD, generates testable hypotheses regarding developmental trajectories, and may support more precise developmental surveillance and targeted intervention strategies.

Introduction The WHO/UNICEF Nurturing Care Framework (NCF) features five domains necessary for child development—physical/mental health, responsive caregiving, adequate nutrition, security and safety and opportunities for early learning. We explored caregiver perspectives on the NCF in two African settings. Methods Between November 2023 and July 2024, 14 focus group discussions (FGDs) were conducted with caregivers living with and without HIV; eight with mothers in Gaborone, Botswana, and six with mothers and fathers in Nairobi, Kenya. FGDs were stratified by country, sex, HIV status and partnership status. Semi-structured interviews with interactive activities elicited caregiver perspectives on the NCF to identify the most ‘important’, ‘easiest’ and ‘challenging’ domains to fulfil. Thematic analyses identified key themes and compared perspectives. Results Our qualitative study included 101 caregivers, 55 from Kenya (30 mothers, 25 fathers) and 46 mothers from Botswana. Overall, caregivers identified physical/mental health as the ‘most important’ domain to fulfil for children and caregivers, noting how closely tied they were (“ If you have pain, that pain affects your child” ). The ‘most challenging’ domain was adequate nutrition in Botswana and security and safety in Kenya. The ‘easiest’ domains were responsive caregiving in Botswana and opportunities for early learning in Kenya. Kenyan caregivers noted that spiritual nourishment was also critical for well-being but missing from the NCF. Caregivers emphasised the importance of receiving social support with childcare. Caregivers living with HIV expressed similar views compared with caregivers without HIV, but mentioned that social isolation, stigma and treatment disruption impact their ability to provide adequate nurturing care. Conclusions Caregivers face unique parenting challenges depending on cultural environment. HIV disrupts caregivers’ health, which has important implications for raising children within families affected by HIV. Interventions that support caregivers’ abilities to fulfil all NCF domains and address challenges are essential to ensure children reach their developmental potential.

Adults with congenital heart disease (CHD) constitute a growing population with challenges related to cardiovascular and neurological health. Many individuals born with CHD experience neurodevelopmental delays in childhood. Ongoing neurocognitive and psychological concerns impact education, employment, and quality of life. Despite this, interventions to address these issues are largely unexplored. Collaborations among multidisciplinary experts and patient partners culminated at a 2‐day Adult Congenital Heart Disease (ACHD)/Neuro Conference (April 2024) to review the current state of knowledge and guide future directions for research and clinical care. Three working groups separately focused on genetics and brain health, characterizing outcomes, and interventions among patients with ACHD. This article focuses on the work of the interventions group. A consensus statement was created to synthesize current knowledge, identify key gaps, and recommend next steps around 5 critical questions designed to guide research and clinical care for interventions with ACHD: (1) What interventions are effective for improving neurocognitive functioning? (2) What interventions are effective for improving psychological wellbeing? (3) What evidence do we have about safety and efficacy of psychotropic medications? (4) What interventions can improve health literacy? (5) What are modifiable facilitators and barriers to accessing high‐quality neurocognitive and psychological interventions? Limited research and fragmented health systems hinder interventions in ACHD. Efforts from pediatric congenital heart disease could inform the ACHD community. Although interventions are costly and resource intensive, neglecting neurocognitive and psychological needs could lead to lower quality of life and higher health care costs. By ultimately shifting to prevention and intervention, the ACHD community could facilitate positive outcomes.

Individuals with congenital heart disease are living well into adulthood, resulting in a growing population at risk for neurocognitive and psychosocial challenges. Numerous studies have described these risks in childhood, but significant gaps remain in our understanding of how those challenges evolve across stages of adulthood and how to optimally integrate neurocognitive and psychosocial care for adults with congenital heart disease. A multidisciplinary group of experts and patient partners assembled in April 2024 in Atlanta, GA, forming 3 working groups: (1) Genetics and Brain Health, (2) Characterizing Neuropsychological and Psychological Outcomes, and (3) Neuropsychological and Psychosocial Interventions. Current knowledge was reviewed, knowledge gaps were identified, and recommendations to address these gaps were formulated. Five critical questions regarding the characterization of neuropsychological and psychological outcomes of adults with congenital heart disease were prioritized for discussion: which neurocognitive and psychosocial domains should be prioritized in research and clinical care, what are the trajectories of neurocognitive and psychosocial functioning over the lifespan, how should neurocognitive and psychosocial screening be deployed, what should neurocognitive and psychosocial assessments include, and how do we make comprehensive neurocognitive and psychosocial care a reality. Although many gaps in knowledge were identified, particularly around characterizing neurocognitive trajectories throughout adulthood, there is substantial evidence of increased risk for poor psychosocial outcomes among adults with with congenital heart disease. Clinical and research advances must progress in tandem to address these risks. Specific recommendations for advancing this field over the next decade are offered.

With improvement in medical and surgical care, the number of adults with congenital heart disease (CHD) is soaring. Adults with CHD commonly have impairments in brain health. However, significant gaps in knowledge remain regarding the relevant types and prevalence of neurologic and psychiatric risk and their associated risk factors. We sought to review current evidence, identify gaps in knowledge, and develop key next steps to improve scientific understanding and clinical care. Three working groups—Genetics and Brain Health, Characterizing Neuropsychological and Psychological Outcomes, and Neuropsychological and Psychosocial Interventions—were composed of multidisciplinary experts in relevant clinical and research domains, as well as adults with CHD. Each group identified 5 key knowledge gaps and associated next investigations needed to address those gaps. For Genetics and Brain Health, 5 key knowledge gaps were identified: lack of a standardized neuroimaging protocol for adults with CHD, need to understand neuroradiological–pathological–neuropsychological correlates, role of gene–environment interactions, what can be learned from brain health risk models from other groups, and how existing multimodal approaches influence risk and neuroresilience. Adults with CHD can benefit from routine assessment of brain health, as well as increased clinical and basic research into the underlying factors that contribute to risk and neuroresilience for neurologic and psychiatric sequalae. Multidisciplinary collaborative efforts that incorporate adults with CHD across the research cycle are essential for all key next steps.

ABSTRACT The lower infrastructure requirements of portable ultra‐low field MRI (ULF‐MRI) systems have enabled their use in diverse settings such as intensive care units and remote medical facilities. The UNITY Project is an international neuroimaging network harnessing this technology, deploying portable ULF‐MRI systems globally to expand access to MRI for studies into brain development. Given the wide range of environments where ULF‐MRI systems may operate, there are external factors that might influence image quality. This work aims to introduce the quality control (QC) framework used by the UNITY Project to investigate how robust the systems are and how QC metrics compare between sites and over time. We present a QC framework using a commercially available phantom, scanned with 64 mT portable MRI systems at 17 sites across 12 countries on four continents. Using automated, open‐source analysis tools, we quantify signal‐to‐noise, image contrast, and geometric distortions. Our results demonstrated that the image quality is robust to the varying operational environment, for example, electromagnetic noise interference and temperature. The Larmor frequency was significantly correlated to room temperature, as was image noise and contrast. Image distortions were less than 2.5 mm, with high robustness over time. Similar to studies at higher field, we found that changes in pulse sequence parameters from software updates had an impact on QC metrics. This study demonstrates that portable ULF‐MRI systems can be deployed in a variety of environments for multi‐center neuroimaging studies and produce robust results.

Abstract Purpose Ultra‐low field MRI scanners have the potential to improve health care delivery, both through improved access in areas where there are few MRI scanners and allowing more frequent monitoring of disease progression and treatment response. This may be particularly true in white matter disorders, including leukodystrophies and multiple sclerosis, in which frequent myelin‐sensitive imaging, such as magnetization transfer (MT) imaging, might improve clinical care and patient outcomes. Methods We implemented an on‐resonance approach to MT imaging on a commercial point‐of‐care 64 mT scanner using a non‐balanced steady‐state free precession sequence. Phantom and in vivo experiments were used to evaluate and optimize the sequence sensitivity and reproducibility, and to demonstrate in vivo performance and inter‐site reproducibility. Results From phantom experiments, T 1 and T 2 effects were determined to have a negligible effect on the differential MT weighting. MT ratio (MTR) values in white matter were 23.1 ± 1.0% from 10 healthy volunteers, with an average reproducibility coefficient of variation of 1.04%. Normal‐appearing white matter MTR values in a multiple sclerosis participant (21.5 ± 6.2%) were lower, but with a similar spread of values, compared to an age‐matched healthy volunteer (23.3 ± 6.2%). Conclusion An on‐resonance MT imaging approach was developed at 64 mT that can be performed in as little as 4 min. A semi‐quantitative myelin‐sensitive imaging biomarker at this field strength is available for assessing both myelination and demyelination.

Objective: To examine the impact of in-utero exposure to dolutegravir (DTG)-based or efavirenz (EFV)-based antiretroviral treatment (ART) on child neurodevelopmental outcomes. Design: Prospective cohort design, enrolling three cohorts of 2-year-olds: children HIV-negative born to mothers with HIV (CHEU) receiving either DTG-based or EFV-based three-drug ART during pregnancy, and children born to mothers without HIV (CHUU). Methods: Primary child neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and compared between cohorts using generalized estimating equation models adjusted for confounders. Children were classified as having an ‘adverse ND outcome’ if they scored at least 1 standard deviation (SD) below the mean or were unable to complete the BSID-III. Results: Five hundred and sixty-four participants (202 DTG-exposed, 202 EFV-exposed, 160 HIV-unexposed; mean age 25.7 months, 49% female). Mean (SD) Gross Motor scores were slightly lower among CHEU vs. CHUU [54.6 (3.6) vs. 55.6 (4.3)] and among EFV-exposed vs. DTG-exposed [54.3 (3.5) vs. 54.9 (3.6)]. CHEU were more likely to be classified as having an ‘adverse’ expressive language outcome [13.2 vs 7%, adjusted risk ratio (aRR) = 2.06, 95% confidence interval (CI) 1.05–4.03] than CHUU, but other neurodevelopmental outcomes were similar. DTG exposure was associated with less frequent ‘adverse’ classification in Cognitive (2.5 vs. 7.4%, aRR = 0.33, 95% CI 0.13–0.79) and Expressive Language domains (10.0 vs. 16.4%, aRR = 0.58, 95% CI 0.35, 0.95), compared to EFV exposure. Conclusion: Two-year neurodevelopmental outcomes among Botswana children DTG-exposed, EFV-exposed, and HIV-unexposed were mostly comparable. Children exposed in utero to EFV-based ART had higher risk of ‘adverse’ cognitive and expressive language outcomes compared with children DTG-exposed.

Importance Data are limited on the longitudinal implications of socioeconomic status (SES) for neurodevelopmental outcomes among persons with complex congenital heart disease (CHD). Objectives To examine the association of family SES, maternal educational level, and maternal IQ with the neurodevelopment of individuals with dextro-transposition of the great arteries (d-TGA) from age 1 to 16 years and to identify how SES-related disparities change with age. Design, Setting, and Participants This cohort study analyzed data of participants enrolled in the Boston Circulatory Arrest Study, a randomized clinical trial conducted in Boston, Massachusetts, from 1988 to 1992. Participants were infants with d-TGA who underwent arterial switch operation and, after operation, underwent in-person neurodevelopmental status evaluations at ages 1, 4, 8, and 16 years. Analyses were conducted from April 2021 to August 2024. Exposures Mean Hollingshead scores at birth, age 1 year, and age 4 years were used to assign participants to SES tertiles (lowest, middle, or highest). Main Outcomes and Measures Age-appropriate neurodevelopmental outcomes assessed at 4 study time points (ages 1, 4, 8, and 16 years) via in-person administration of a range of well-validated measures. Standardized neurodevelopmental composite scores from each evaluation were derived from principal component analysis and compared across SES tertiles, adjusting for birth and medical characteristics. These scores were used to categorize the sample into latent classes; patient and medical factors for a 3-class model were used to estimate latent class using multinomial regression. Results The sample included 164 patients with d-TGA (123 males [75%]; mean [SD] gestational age at birth, 39.8 [1.2] weeks; 3 with Asian [2%], 6 with Black [4%], 5 with Hispanic [3%], and 146 with White [89%] race and ethnicity) and their mothers (mean [SD] age at birth, 28.5 [5.2] years). Lower SES tertile was associated with worse scores on most individual neurodevelopmental tests and worse neurodevelopmental composite scores at ages 4, 8, and 16 years. For example, mean (SD) neurodevelopmental composite scores at age 4 years were –0.49 [0.83] for lowest, 0.00 [0.81] for middle, and 0.47 [1.10] for highest SES tertile ( F 2 = 15.5; P < .001). When measured at consecutive time points, differences between SES tertiles were of similar magnitude. A latent class analysis produced 2- and 3-class models representing patients with stable (103 [64%] and 85 [53%]), improving (20 [13%]), and declining (57 [36%] and 55 [34%]) neurodevelopmental status. Those experiencing declines in neurodevelopmental status were more likely to have younger maternal age at childbirth (26.6 [5.1] vs 29.6 [4.9] and 29.1 [5.1] years; P = .002), lower maternal IQ (91.0 [14.1] vs 100.1 [11.1] and 96.2 [11.0]; P < .001), and lower SES (35.2 [10.8] vs 40.9 [9.9] and 35.8 [10.1]; P = .003) compared with those with stable or improving status. Conclusions and Relevance This cohort study of individuals with d-TGA found an association between lower family SES and worse neurodevelopmental outcomes in childhood and continuing throughout adolescence as well as greater decline in neurodevelopmental status over time. Effective strategies are needed to improve access to neurodevelopmental monitoring and intervention services for children with CHD from lower socioeconomic backgrounds.