Brain Imaging Correlates of Developmental Coordination Disorder and Associated Impairments

Developmental Coordination Disorder (DCD) is a common developmental disorder characterised by an inability to learn age appropriate complex motor skills. The first aim of this thesis was to characterise additional cognitive impairments and their relationship with motor difficulties in school aged children with DCD. The second aim was to investigate grey and white matter neuroimaging correlates of motor and cognitive deficits identified. Thirty six children aged 8-10 years who met DSM-5 criteria for DCD and an age-matched typically developing group (N=17) underwent standardised assessments of motor, intellectual, attention, speech and language skills as well as structural and diffusion-weighted MRI scans. Grey matter correlates of impairments were identified using subcortical volumetrics and surface-based analyses of cortical morphology. White matter correlates were examined using tractography and fixel-based fibre morphology of the pyramidal tracts, corpus callosum and cerebellar peduncles. Alongside impaired motor skills, children with DCD performed poorer than controls on several domains of executive function (attention and processing speed) and speech motor control. Motor skills did not correlate with impairments in other domains. Cortical thickness was significantly reduced in the left central sulcus in children with DCD compared to controls. Poor motor skills correlated with measures in left sensorimotor circuitry, posterior cingulate cortex and anterior insula. Poor speech motor control was associated with measures in the thalamus and corticobulbar tract. Poor sustained attention was linked to measures in the right superior cerebellar peduncle. Lower processing speed was associated with reduced mean cortical surface area. Children with DCD show co-occurring impairments in attention and speech motor control. DCD is associated with sensorimotor circuits as well as regions that form part of the default mode and salience networks. Disruption of subcortical circuits may underlie additional impairments. This study provides novel evidence of the neural correlates of DCD

Attention and motor profiles in children with developmental coordination disorder: A neuropsychological and neuroimaging investigation

AIM: This study aimed to (1) quantify attention and executive functioning in children with developmental coordination disorder (DCD), (2) assess whether some children with DCD are more likely to show attention difficulties, and (3) characterize brain correlates of motor and attention deficits. METHOD: Fifty-three children (36 with DCD and 17 without) aged 8 to 10 years underwent T1-weighted and diffusion-weighted magnetic resonance imaging, and standardized attention and motor assessments. Parents completed questionnaires of executive functioning and symptoms of inattention and hyperactivity. We assessed regional cortical thickness and surface area, and cerebellar, callosal, and primary motor tract structure. RESULTS: Analyses of covariance and one-sample t-tests identified impaired attention, non-motor processing speed, and executive functioning in children with DCD, yet partial Spearman's rank correlation coefficients revealed these were unrelated to one another or the type or severity of the motor deficit. Robust regression analyses revealed that cortical morphology in the posterior cingulate was associated with both gross motor skills and inattentive symptoms in children with DCD, while gross motor skills were also associated with left corticospinal tract (CST) morphology. INTERPRETATION: Children with DCD may benefit from routine attention and hyperactivity assessments. Alterations in the posterior cingulate and CST may be linked to impaired forward modelling during movements in children with DCD. Overall, alterations in these regions may explain the high rate of non-motor impairments in children with DCD

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease:A European Collaboration

Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. METHODS: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. RESULTS: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06–4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23–5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20–21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05–1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58–67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20–6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28–95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08–13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07–1.36]) also increased the risk of new cerebral sinus venous thrombosis. CONCLUSIONS: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors

Risk Factors for Perioperative Brain Lesions in Infants With Congenital Heart Disease: A European Collaboration

Background: Infants with congenital heart disease are at risk of brain injury and impaired neurodevelopment. The aim was to investigate risk factors for perioperative brain lesions in infants with congenital heart disease. Methods: Infants with transposition of the great arteries, single ventricle physiology, and left ventricular outflow tract and/or aortic arch obstruction undergoing cardiac surgery <6 weeks after birth from 3 European cohorts (Utrecht, Zurich, and London) were combined. Brain lesions were scored on preoperative (transposition of the great arteries N=104; single ventricle physiology N=35; and left ventricular outflow tract and/or aortic arch obstruction N=41) and postoperative (transposition of the great arteries N=88; single ventricle physiology N=28; and left ventricular outflow tract and/or aortic arch obstruction N=30) magnetic resonance imaging for risk factor analysis of arterial ischemic stroke, cerebral sinus venous thrombosis, and white matter injury. Results: Preoperatively, induced vaginal delivery (odds ratio [OR], 2.23 [95% CI, 1.06-4.70]) was associated with white matter injury and balloon atrial septostomy increased the risk of white matter injury (OR, 2.51 [95% CI, 1.23-5.20]) and arterial ischemic stroke (OR, 4.49 [95% CI, 1.20-21.49]). Postoperatively, younger postnatal age at surgery (OR, 1.18 [95% CI, 1.05-1.33]) and selective cerebral perfusion, particularly at ≤20 °C (OR, 13.46 [95% CI, 3.58-67.10]), were associated with new arterial ischemic stroke. Single ventricle physiology was associated with new white matter injury (OR, 2.88 [95% CI, 1.20-6.95]) and transposition of the great arteries with new cerebral sinus venous thrombosis (OR, 13.47 [95% CI, 2.28-95.66]). Delayed sternal closure (OR, 3.47 [95% CI, 1.08-13.06]) and lower intraoperative temperatures (OR, 1.22 [95% CI, 1.07-1.36]) also increased the risk of new cerebral sinus venous thrombosis. Conclusions: Delivery planning and surgery timing may be modifiable risk factors that allow personalized treatment to minimize the risk of perioperative brain injury in severe congenital heart disease. Further research is needed to optimize cerebral perfusion techniques for neonatal surgery and to confirm the relationship between cerebral sinus venous thrombosis and perioperative risk factors. Keywords: heart diseases; ischemic stroke; magnetic resonance imaging; pedatrics; risk factors; venous thrombosis; white matter

MRI studies of brain size and growth in individuals with congenital heart disease

Congenital heart disease (CHD) is the most frequent congenital abnormality. Most infants born with CHD now survive. However, survivors of CHD are at increased risk of neurodevelopmental impairment, which may be due to impaired brain development in the fetal and neonatal period. Magnetic resonance imaging (MRI) provides objective measures of brain volume and growth. Here, we review MRI studies assessing brain volume and growth in individuals with CHD from the fetus to adolescence. Smaller brain volumes compared to healthy controls are evident from around 30 weeks gestation in fetuses with CHD and are accompanied by increased extracerebral cerebrospinal fluid. This impaired brain growth persists after birth and throughout childhood to adolescence. Risk factors for impaired brain growth include reduced cerebral oxygen delivery in utero, longer time to surgery and increased hospital stay. There is increasing evidence that smaller total and regional brain volumes in this group are associated with adverse neurodevelopmental outcome. However, to date, few studies have assessed the association between early measures of cerebral volume and neurodevelopmental outcome in later childhood. Large prospective multicentre studies are required to better characterise the relationship between brain volume and growth, clinical risk factors and subsequent cognitive, motor, and behavioural impairments in this at-risk population

Recent advances in diffusion neuroimaging: applications in the developing preterm brain [version 1; referees: 2 approved]

Measures obtained from diffusion-weighted imaging provide objective indices of white matter development and injury in the developing preterm brain. To date, diffusion tensor imaging (DTI) has been used widely, highlighting differences in fractional anisotropy (FA) and mean diffusivity (MD) between preterm infants at term and healthy term controls; altered white matter development associated with a number of perinatal risk factors; and correlations between FA values in the white matter in the neonatal period and subsequent neurodevelopmental outcome. Recent developments, including neurite orientation dispersion and density imaging (NODDI) and fixel-based analysis (FBA), enable white matter microstructure to be assessed in detail. Constrained spherical deconvolution (CSD) enables multiple fibre populations in an imaging voxel to be resolved and allows delineation of fibres that traverse regions of fibre-crossings, such as the arcuate fasciculus and cerebellar–cortical pathways. This review summarises DTI findings in the preterm brain and discusses initial findings in this population using CSD, NODDI, and FBA

Maternal depressive symptoms, neonatal white matter, and toddler social-emotional development

Maternal prenatal depression is associated with increased likelihood of neurodevelopmental and psychiatric conditions in offspring. The relationship between maternal depression and offspring outcome may be mediated by in-utero changes in brain development. Recent advances in magnetic resonance imaging (MRI) have enabled in vivo investigations of neonatal brains, minimising the effect of postnatal influences. The aim of this study was to examine associations between maternal prenatal depressive symptoms, infant white matter, and toddler behaviour. 413 mother-infant dyads enrolled in the developing Human Connectome Project. Mothers completed the Edinburgh Postnatal Depression Scale (median = 5, range = 0–28, n = 52 scores ≥ 11). Infants (n = 223 male) (median gestational age at birth = 40 weeks, range 32.14–42.29) underwent MRI (median postmenstrual age at scan = 41.29 weeks, range 36.57–44.71). Fixel-based fibre metrics (mean fibre density, fibre cross-section, and fibre density modulated by cross-section) were calculated from diffusion imaging data in the left and right uncinate fasciculi and cingulum bundle. For n = 311, internalising and externalising behaviour, and social-emotional abilities were reported at a median corrected age of 18 months (range 17–24). Statistical analysis used multiple linear regression and mediation analysis with bootstrapping. Maternal depressive symptoms were positively associated with infant fibre density in the left (B = 0.0005, p = 0.003, q = 0.027) and right (B = 0.0006, p = 0.003, q = 0.027) uncinate fasciculus, with left uncinate fasciculus fibre density, in turn, positively associated with social-emotional abilities in toddlerhood (B = 105.70, p = 0.0007, q = 0.004). In a mediation analysis, higher maternal depressive symptoms predicted toddler social-emotional difficulties (B = 0.342, t(307) = 3.003, p = 0.003), but this relationship was not mediated by fibre density in the left uncinate fasciculus (Sobel test p = 0.143, bootstrapped indirect effect = 0.035, SE = 0.02, 95% CI: [−0.01, 0.08]). There was no evidence of an association between maternal depressive and cingulum fibre properties. These findings suggest that maternal perinatal depressive symptoms are associated with neonatal uncinate fasciculi microstructure, but not fibre bundle size, and toddler behaviour

Attentional development is altered in toddlers with congenital heart disease

Publication status: PublishedFunder: FP7 Ideas: European Research Council; doi: http://dx.doi.org/10.13039/100011199; Grant(s): FP7/20072013AbstractBackgroundCongenital Heart Disease (CHD) is the most common congenital abnormality. Survival rates are over 90%, however infants with CHD remain at high risk of attention and executive function impairments. These abilities are difficult to assess in toddlers because clinical assessments rely on language abilities which are commonly delayed in CHD. Our aim was to characterise visual attention in toddlers with CHD compared to controls and identify associations with parent‐rated effortful control.MethodsThirty toddlers with CHD (19 male, median (IQR) age at assessment 22.2 (22–23.1) months) and 66 controls from the developing human connectome project (36 male, age at assessment 22 (21.5–23.8) months) using eye‐tracking tasks designed to assess multiple components of visual attention. Analyses of co‐variance and regressions were used to identify differences between groups and relationships between gaze behaviours and parent‐rated effortful control.ResultsToddlers with CHD were less accurate when switching behaviours (set‐shifting) [median (IQR) 79%, (28–100)] compared to controls [100% (86–100), pFDR = 0.032], with worse accuracy associated with lower parent‐rated effortful control in CHD but not controls (interaction pFDR = 0.028). Reaction times were slower during selective [CHD 1243 ms (986–1786), controls 1065 ms (0851–1397), pFDR&lt;0.001] and exogenous attention tasks [CHD 312 ms (279–358), control 289 (249–331), (pFDR = 0.032) and endogenous attention was less mature (prolonged looks at facial stimuli CHD 670 ms (518–885), control 500 ms (250–625), (pFDR = 0.006). These results were unrelated to differences in cognition or socioeconomic status. In contrast, the allocation of attentional resources was preserved in CHD.ConclusionsWe identified a profile of altered attention and early executive functioning development in CHD. Eye‐tracking may provide clinically feasible, early objective measures of attention and executive function development in CHD.</jats:sec