Does Altered Brain Connectivity Correlate with Developmental Outcomes and Executive Function in Congenital Heart Disease?

Congenital heart disease (CHD) is the most common birth defect in the U.S. and affects ~1% of all live births. Over 85% live well into adulthood, and over 50% of those with moderate or complex CHD suffer from neurodevelopmental disabilities - most commonly impaired being executive function (EF). As EF is important for

independent living and mental health, predicting who will have greater EF impairment and needs intervention is important as EF is particularly amenable to treatment. However, current routinely measured patient and medical factors do not reliably predict EF in CHD - better predictors are needed to appropriately allocate services and

improve outcomes. In utero and postnatal factors may lead to impaired EF in CHD. Lack of substrate in utero or abnormal gene expression may impact early neurodevelopmental (ND) processes. This includes formation of

the white matter “backbone”, the structural “rich club” of the brain that is critical for EF. Additional environmental factors, including surgery, parenting style and life experiences, further alter brain structure through secondary adaptive processes which include development of cortico-cortical connections, axonal pruning and myelination.

Differentiating between early in utero factors from later adaptive changes is key to understanding the potential and optimal timing of interventions and the relative importance of developing novel in utero therapies. We propose to employ our advanced connectome measures of “information transport” to understand early and later

environmental effects on white matter connectivity, by determining the impact of CHD on rich club versus secondary, non-rich club connections. We leverage two cohorts with dextro-transposition of the great arteries (d- TGA) CHD – infants with pre-operative MRI and 22-month ND outcomes, and adults aged 26-34-years old with

MRI and cognitive testing. d-TGA is the more common severe CHD that is corrected soon after birth and additional surgery is rare. Thus d-TGA patients have the most uniform postnatal course of all CHDs but, like other CHDs, have significant yet variable impairment in EF. The overarching goal is to understand how brain

structure in d-TGA patients differ to controls, and the impact of pre- and post-natal factors on outcome measures. This will help us to identify when to intervene, and therefore better manage the appropriate factors that can improve longer-term ND and EF outcomes. To address this, Aim 1 is to determine how the connectome is altered

in pre-operative infants, and whether an altered prenatally established rich club is associated with outcomes at 22-months. Postnatal measures on surgery, socioeconomic status and upbringing will be modelled to study their influence on this association. In Aim 2, we investigate alterations in rich club/non-rich club connectivity in the d-

TGA adults and their association with EF. We include similar clinical and environmental factors to this model to ascertain whether they play a role in the above relationship. Successful completion will determine the effect of pre- and post-natal factors on brain structure during two stages of life, and the relative roles of the rich club and

secondary adaptive pathways on cognitive outcomes in d-TGA CHD.