Brain abnormalities in cognition, anxiety, and depression regulatory regions in adolescents with single ventricle heart disease

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Among the most challenging types of complex congenital heart disease (CHD) are conditions that lack two well‐developed ventricles (single ventricle heart disease [SVHD]), which affect approximately 1 per 2,000 live births in the US (Khairy et al., 2008). The evolution of palliative and reconstructive cardiac operations has had an enormous impact on the increased life expectancy with the use of the Fontan procedure. However, SVHD patients are at greater risk for brain injury and neurocognitive deficits, both from innate or patient‐related factors (Donofrio & Massaro, 2010; Marelli, Miller, Marino, Jefferson, & Newburger, 2016; Miller & McQuillen, 2007; Sethi et al., 2013) and multiple surgical procedures to treat the condition (Gaynor et al., 2015). Adolescents with palliated SVHD show autonomic dysfunction (Davos et al., 2003; Ohuchi et al., 2001), depression, anxiety (Bromberg, Beasley, D'Angelo, Landzberg, & DeMaso, 2003; Cohen, Mansoor, Langut, & Lorber, 2007; Moon et al., 2009), and cognitive (memory and executive function skills) abnormalities (Gerstle, Beebe, Drotar, Cassedy, & Marino, 2016; Pike, Poulsen, & Woo, 2016; Wernovsky et al., 2000), indicating the probability of brain injury in regions that control these functions.
Despite multiple reports of cognitive deficits, anxiety, and depression in complex SVHD, the underlying causes for these adverse symptoms remain unclear (Cohen et al., 2007; Moon et al., 2009; Pike et al., 2016). Preoperative brain injury has been identified in over 60% of newborns with SVHD, which may be explained in part by structural brain immaturity (Donofrio & Massaro, 2010; Marelli et al., 2016; Miller & McQuillen, 2007; Sethi et al., 2013). Reduced global brain volumes have been identified in infants with complex CHD prior to surgical intervention shedding light on potential innate contributing factors related to fetal brain development (von Rhein et al., 2015). Furthermore, scattered cerebral lesions have been recognized by conventional brain magnetic resonance imaging (MRI) as ischemic infarcts in gray and white matter and intraventricular hemorrhages (Donofrio & Massaro, 2010; Mahle et al., 2002; Sethi et al., 2013). Additional brain changes induced by hypoxemia and hypotension develop in over 30–40% SVHD. These changes are described as either focal or scattered lesions in multiple brain areas (McQuillen et al., 2007), are not identified by routine cranial ultrasound scans (Abernethy, Klafkowski, Foulder‐Hughes, & Cooke, 2003; Block et al., 2010; Latal et al., 2015; McQuillen et al., 2007), and are mostly clinically silent in the neonatal period (Clancy et al., 2005). Moreover, the functional manifestations of these brain deficits may not be apparent until later in development and have not been consistently reported in brain regions that control cognition, anxiety, and depression in SVHD. However, one study on adolescents with dextro‐transposition of the great arteries (d‐TGA) showed worse cognitive function mediated by global differences in white matter topology, suggesting that this disruption could drive neurocognitive dysfunction in this population (Panigrahy et al., 2015).
Among non‐invasive techniques that can assess both white and gray matter injury, magnetic resonance imaging based T2‐relaxometry is useful. The procedure indicates the relative proportion of free and bound water protons in tissue (Abernethy et al., 2003), such as macromolecules, myelin, and cell membranes. Increased T2‐relaxation times could result from cerebral edema after hypoxia‐ischemia (Rumpel et al., 1995) as well as chronic pathologic conditions, including long‐lasting ischemia (Kato et al., 1986), gliosis (Kumar et al., 2002), and demyelination (Abernethy et al., 2003). The procedure has been used for evaluation of tissue changes in several brain conditions, including multiple sclerosis (Papanikolaou et al., 2004), Alzheimer's disease (Kirsch, Jacobs, Butcher, & Beatty, 1992), and epilepsy (Kumar et al., 2002; Townsend, Bernasconi, N., Pike, & Bernasconi, A.
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