Research paperChildhood conduct problems are associated with reduced white matter fibre density and morphology
Introduction
Antisocial behaviour is increasingly recognised as a public health issue (National Institute for Health and Care Excellence (NICE), 2013) and conceptualised in research as a multifaceted neurodevelopmental construct with its origins emerging early in development (Raine, 2018). Childhood conduct problems - characterised by a pattern of antisocial behaviours including aggression, angry mood, rule-breaking, and oppositional behaviour - are therefore understood as a behavioural precursor to later antisocial behaviour (Fairchild, Van Goozen, Calder, & Goodyer, 2013; Piquero, Farrington, Nagin, & Moffitt, 2010; Raine, 2018). In addition, early conduct problems are a risk factor for a range of negative outcomes - such as imprisonment, psychopathology, substance misuse, lower educational attainment and poorer physical health (Fergusson, John Horwood, & Ridder, 2005; Moffitt & Scott, 2008; Mordre, Groholt, Kjelsberg, Sandstad, & Myhre, 2011; Odgers et al., 2007; Odgers et al., 2008). The adverse developmental trajectory of childhood conduct problem highlights the importance to investigate underlying neurodevelopmental factors early in development that may contribute to childhood conduct difficulties.
There is considerable evidence that children and adolescents with conduct problems are characterised by emotional processing impairments, such as reduced empathy, lower physiological affective responsivity, diminished capacity to learn about punishment and reward, and emotional dysregulation (Blair, 1999; Fanti et al., 2019; Gao, Raine, Venables, Dawson, & Mednick, 2010; Hunnikin, Wells, Ash, & Van Goozen, 2019; Van Goozen, Fairchild, Snoek, & Harold, 2007; Van Langen, Wissink, Van Vugt, Van der Stouwe, & Stams, 2014). Using magnetic resonance imaging (MRI), studies have identified that children with conduct difficulties showed structural and functional abnormalities in limbic brain regions important for processing emotion, in particular the amygdala, and prefrontal regions implicated in affective decision-making, learning and regulation, such as the orbitofrontal and ventromedial prefrontal cortex (Baker, Clanton, Rogers, & De Brito, 2015; Noordermeer, Luman, & Oosterlaan, 2016; Rogers & De Brito, 2016). In addition, youths high in antisocial behaviour demonstrated reduced functional connectivity between limbic and prefrontal regions (Finger et al., 2012; Stoddard et al., 2017). Theories of antisociality have therefore proposed that antisocial behaviour reflects dysfunction in neural networks implicated in emotional processing and learning, including disrupted connections between limbic and prefrontal regions (Blair, 2005; Kiehl, 2006; Raine, 2018).
More recent research has used diffusion tensor imaging (DTI) to examine white matter microstructure between brain regions within children and adolescents high in antisociality. DTI measures such as fractional anisotropy (FA) are sensitive to the anisotropic organisation of a white matter fibre and generally increases with age, whereas mean diffusivity (MD) can represent the mean mobility of water molecules and generally decreases with age (Lebel & Beaulieu, 2011). Given the theorised abnormality between limbic and prefrontal regions in relation to antisociality, there has been much focus on examining the microstructure of the uncinate fasciculus (UF) - a long range white matter pathway that connects limbic regions within the temporal lobe to frontal regions. While DTI studies have found that adults with antisocial behaviour have reduced white matter organisation in the UF (Craig et al., 2009; Hoppenbrouwers et al., 2013; Sundram et al., 2012), and additional association pathways including the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and fornix (Bolhuis et al., 2019; Hoppenbrouwers et al., 2013; Karlsgodt et al., 2015; Lindner et al., 2016; Sethi et al., 2015; Sundram et al., 2012), studies investigating conduct problems in children and adolescents have produced mixed findings. There is evidence for greater white matter microstructural organisation in adolescents with conduct difficulties across association tracts (Breeden, Cardinale, Lozier, VanMeter, & Marsh, 2015; Decety, Yoder, & Lahey, 2015; Haney-Caron, Caprihan, & Stevens, 2014; Li, Mathews, Wang, Dunn, & Kronenberger, 2005), while other studies have reported lower microstructural organisation (Grazioplene et al., 2020; Passamonti et al., 2012; Peper, De Reus, Van Den Heuvel, & Schutter, 2015; Sarkar et al., 2013; Zhang, Zhu, et al., 2014) or no difference compared to adolescents without conduct problems (Decety et al., 2015; Finger et al., 2012; Hummer, Wang, Kronenberger, Dunn, & Mathews, 2015; Passamonti et al., 2012; Puzzo et al., 2018; Sarkar et al., 2013; Zhang, Gao, et al., 2014; Zhang, Zhu, et al., 2014).
Many of these studies recruited youths with wide age ranges, which may have contributed to the inconsistent findings given that white matter microstructure develops in a time-dependent fashion within major white-matter tracts (Lebel & Beaulieu, 2011; Lebel, Walker, Leemans, Phillips, & Beaulieu, 2008). In addition, the effects of cooccurring forms of psychopathology could influence white matter microstructure given the comorbidity of conduct problems with alternative externalising and internalising difficulties (Lahey et al., 2008; Patalay et al., 2015), which may have contributed to the inconsistent literature. It is therefore important to examine the effect of conduct problems alongside additional forms of psychopathology to investigate the specificity of altered white matter microstructure.
One further potential reason for the contrasting results observed in children and adolescents may be due to the metrics previously used in DTI studies to index white matter microstructure. Measures such as FA and MD are relatively non-specific at distinguishing between specific fibre properties, such as axon density, crossing fibres and myelination, which are separate physio-anatomical white matter properties important for understanding developmental changes (Beaulieu, 2014). Recent developments in diffusion MRI analysis techniques provide the means and opportunity to uncover more specific tissue properties compared with the diffusion tensor model. Analysis approaches such as Neurite Orientation Dispersion and Density Imaging (NODDI; Zhang, Schneider, Wheeler-Kingshott, & Alexander, 2012) and fixel-based analysis (FBA; Raffelt et al., 2012, 2017) have been shown to be more sensitive to age-related development of specific microstructural properties such as axon density (Lynch, Cabeen, Toga, & Clark, 2020; Genc et al., 2020). FBA is a framework of particular interest for group-wise and longitudinal analyses, enabling fibre level comparisons. FBA produces metrics that index fibre density (FD), which represents the intra-axonal volume fraction of white matter fibres, fibre cross-section (FC), which refers to the cross-sectional area of voxels that a fibre occupies, as well as the combined effect of fibre density and cross-section (FDC) (Raffelt et al., 2017). These indices aim to quantify and disentangle fibre-specific white matter properties more accurately compared to more traditional DTI metrics such as FA (Kelley, Plass, Bender, & Polk, 2019).
Grazioplene et al. (2020) is the only study to date to have used fixel-based analysis to examine childhood conduct problems and white matter microstructure. Using a cross-sectional design, a group of 70 children with parent-rated aggressive behaviour were compared to matched controls aged 8 – 16 years old for FD across a range white matter tracts. Children showing aggression demonstrated lower FD in a cluster of limbic and cortical pathways including the IFOF and fornix relative to controls, higher FD in the corpus callosum, and dimensional analysis revealed an association between aggression and reduced FD in the cingulum bundle. The current study intended to build upon this study and previous research to investigate childhood conduct problems in relation to fibre density and morphology as both measures are sensitive to changes during development (Genc et al., 2018), and to examine these relationships within a longitudinal design to study the effects of conduct problems on white matter microstructural development.
Section snippets
Current Study
We investigated conduct problems and white matter microstructure in a large community-based sample of children aged 9-13 years across two time-points. We implemented FBA to investigate tract-specific fibre density and morphology within the fornix, IFOF, ILF, SLF and UF, which are all implicated within socio-emotional processing systems (Ameis & Catani, 2015) and have been linked with antisociality (Waller, Dotterer, Murray, Maxwell, & Hyde, 2017). Importantly, the age-ranges were narrow at each
Participants
Participants were recruited as part of the Neuroimaging of the Children's Attention Project (NICAP; Silk et al., 2016), an Australian longitudinal multimodal neuroimaging study of community-based cohort of children with and without Attention Deficit Hyperactivity Disorder (ADHD). This longitudinal study was approved by The Royal Children's Hospital Melbourne Human Research Ethics Committee (HREC #34071). Written informed consent was obtained from the parent/guardian of all children enrolled in
Results
Table 1 details the demographic characteristics of the adolescent sample across time-points. The sample included showed a range of conduct problem scores including 27.7% of children who were rated as high or very high risk of conduct problems at time-point 1 and 24.7% at time-point. Figure 1A and 1B illustrate the age and conduct problems scores for the sample at each time-point. Mean FBA metrics for each white-matter tract are included across time-points in Table 2. Each FBA metric correlated
General Discussion
In this longitudinal study of children aged 9-13 years, we used fixel-based analyses to determine whether conduct problems were related to specific microstructural alterations within several white matter tracts both cross-sectionally and longitudinally. We identified that greater conduct problems were related to lower fibre density in the fornix at both time-points, as well as in the ILF at the second time-point. Longitudinally, the change in conduct difficulties did not predict the development
Author statement Contributors
Author T.J.S. acquired the funding and supervised the running of the study. Author S.G. contributed to data collection and imaging processing. D.T.B and T.J.S conceived of the focus of the manuscript. D.T.B and S.G. conducted the data analysis. D.T.B. wrote the manuscript, which was reviewed and edited by S.G. and T.J.S.
Role of the Funding Source
The Children's Attention Project was funded by the National Medical Health and Research Council of Australia (NHMRC; project grants #1008522 and #1065895). The data was collected within the Developmental Imaging research group, Murdoch Children's Research Institute and the Children's MRI Centre, The Royal Children's Hospital. It was supported by the Murdoch Children's Research Institute, The Royal Children's Hospital, The Royal Children's Hospital Foundation, Department of Paediatrics at The
Declaration of competing interest
The authors report no conflicts of interest.
Acknowledgements
We thank the RCH Medical Imaging staff for their assistance and expertise in the collection of the MRI data, and we thank all of the children and families for their participation.
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