Early changes in brain structure correlate with language outcomes in children with neonatal encephalopathy.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6 months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6 months, and assessed neurodevelopmental outcomes at 30 months. All subjects underwent T1-weighted imaging at 3 T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30 months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6 months are correlated with language outcome at 30 months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes

Midbrain–hindbrain malformations in patients with malformations of cortical development and epilepsy: A series of 220 patients

SummaryMidbrain–hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features.Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20–44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high-resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain–hindbrain structures were visually assessed by three independent raters.MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p=0.004) in three categories of MCD (category I – to abnormal neuronal proliferation; category II – to abnormal neuronal migration; and category III – due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p=0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p<0.001) and hippocampal abnormalities (52% vs. 27%; p<0.001). Patients wMHM were younger (median 25 years vs. 30 years; p=0.010) at the time of assessment and had seizure onset at an earlier age (median 5 years vs. 12 years; p=0.043) compared to those w/oMHM. Patients wMHM had higher rates of learning disability (71% vs. 38%; p<0.001), delayed developmental milestones (68% vs. 35%; p<0.001) and neurological deficits (66% vs. 47%; p=0.049) compared to those w/oMHM.The groups (wMHM and w/oMHM) did not differ in their response to antiepileptic treatment, seizure outcome, seizure types, EEG abnormalities and rate of status epilepticus. Presence of MHM in patients with MCD and epilepsy is associated with severe morphological and clinical phenotypes

A tract-specific approach to assessing white matter in preterm infants.

Diffusion-weighted imaging (DWI) is becoming an increasingly important tool for studying brain development. DWI analyses relying on manually-drawn regions of interest and tractography using manually-placed waypoints are considered to provide the most accurate characterisation of the underlying brain structure. However, these methods are labour-intensive and become impractical for studies with large cohorts and numerous white matter (WM) tracts. Tract-specific analysis (TSA) is an alternative WM analysis method applicable to large-scale studies that offers potential benefits. TSA produces a skeleton representation of WM tracts and projects the group's diffusion data onto the skeleton for statistical analysis. In this work we evaluate the performance of TSA in analysing preterm infant data against results obtained from native space tractography and tract-based spatial statistics. We evaluate TSA's registration accuracy of WM tracts and assess the agreement between native space data and template space data projected onto WM skeletons, in 12 tracts across 48 preterm neonates. We show that TSA registration provides better WM tract alignment than a previous protocol optimised for neonatal spatial normalisation, and that TSA projects FA values that match well with values derived from native space tractography. We apply TSA for the first time to a preterm neonatal population to study the effects of age at scan on WM tracts around term equivalent age. We demonstrate the effects of age at scan on DTI metrics in commissural, projection and association fibres. We demonstrate the potential of TSA for WM analysis and its suitability for infant studies involving multiple tracts

Molecular Genetic Approaches to Disease of Neural Development

This study utilized novel genetic techniques in order to find causative gene mutations that underlie diseases of neural development. Our laboratory has collected 175 cases of malformations of cortical development (MCD) from the United States and Europe. Four of these cases are the focus of this manuscript: two familial cases of infantile neuroaxonal dystrophy (INAD), a familial case of hereditary spastic paraparesis (HSP), and a sporadic case of Greig cephalopolysyndactyly (GCPS) and cerebral cavernous malformations (CCMs). The techniques utilized to study the affected patients include microarray-based single nucleotide polymorphism (SNP) genotyping and copy number variation (CNV) analysis, both of which are powerful tools in the hunt for disease-causing gene mutations. In the familial cases of INAD, we report two novel mutations in the PLA2G6 gene, previously shown to cause INAD when mutated. In the familial case of HSP, we demonstrate linkage to the SPG11 locus on chromosome 15q. Finally, in the sporadic case of GCPS and CCM, we published the first report on this novel syndrome along with a genetic analysis that demonstrates a microdeletion on chromosome 7p, resulting in heterozygous loss of both the GLI3 and CCM2 genes. The three studies presented in this manuscript demonstrate the utility of SNP genotyping and CNV analysis in revealing the genetic mutations that underlie diseases of neural development

Molecular Genetic Approaches to Disease of Neural Development

This study utilized novel genetic techniques in order to find causative gene mutations that underlie diseases of neural development. Our laboratory has collected 175 cases of malformations of cortical development (MCD) from the United States and Europe. Four of these cases are the focus of this manuscript: two familial cases of infantile neuroaxonal dystrophy (INAD), a familial case of hereditary spastic paraparesis (HSP), and a sporadic case of Greig cephalopolysyndactyly (GCPS) and cerebral cavernous malformations (CCMs). The techniques utilized to study the affected patients include microarray-based single nucleotide polymorphism (SNP) genotyping and copy number variation (CNV) analysis, both of which are powerful tools in the hunt for disease-causing gene mutations. In the familial cases of INAD, we report two novel mutations in the PLA2G6 gene, previously shown to cause INAD when mutated. In the familial case of HSP, we demonstrate linkage to the SPG11 locus on chromosome 15q. Finally, in the sporadic case of GCPS and CCM, we published the first report on this novel syndrome along with a genetic analysis that demonstrates a microdeletion on chromosome 7p, resulting in heterozygous loss of both the GLI3 and CCM2 genes. The three studies presented in this manuscript demonstrate the utility of SNP genotyping and CNV analysis in revealing the genetic mutations that underlie diseases of neural development

Age and interhemispheric transfer time: A failure to replicate.

In a recent study with the Poffenberger paradigm, Brizzolara et al. reported longer estimates of interhemispheric transfer time (IHTT) for children aged 7 years than for adults. They interpreted this finding as evidence for incomplete functional maturity of the corpus callosum in young children. The present study was we were unable to replicate the age effect reported by Brizzolara et al. A closer look at the original study revealed that only 80 observations per child had been collected, which makes it probable that the larger IHTTs in 7-year-olds were caused by stimulus-response compatibility rather than by the lower efficiency of the corpus callosum during childhood years

White matter injury predicts disrupted functional connectivity and microstructure in very preterm born neonates

© 2018 The Authors Objective: To determine whether the spatial extent and location of early-identified punctate white matter injury (WMI) is associated with regionally-specific disruptions in thalamocortical-connectivity in very-preterm born neonates. Methods: 37 very-preterm born neonates (median gestational age: 28.1 weeks; interquartile range [IQR]: 27–30) underwent early MRI (median age 32.9 weeks; IQR: 32–35), and WMI was identified in 13 (35%) neonates. Structural T1-weighted, resting-state functional Magnetic Resonance Imaging (rs-fMRI, n = 34) and Diffusion Tensor Imaging (DTI, n = 31) sequences were acquired using 3 T-MRI. A probabilistic map of WMI was developed for the 13 neonates demonstrating brain injury. A neonatal atlas was applied to the WMI maps, rs-fMRI and DTI analyses to extract volumetric, functional and microstructural data from regionally-specific brain areas. Associations of thalamocortical-network strength and alterations in fractional anisotropy (FA, a measure of white-matter microstructure) with WMI volume were assessed in general linear models, adjusting for age at scan and cerebral volumes. Results: WMI volume in the superior (β = −0.007; p =.02) and posterior corona radiata (β = −0.01; p =.01), posterior thalamic radiations (β = −0.01; p =.005) and superior longitudinal fasciculus (β = −0.02; p =.001) was associated with reduced connectivity strength between thalamus and parietal resting-state networks. WMI volume in the left (β = −0.02; p =.02) and right superior corona radiata (β = −0.03; p =.008), left posterior corona radiata (β = −0.03; p =.01), corpus callosum (β = −0.11; p \u3c.0001) and right superior longitudinal fasciculus (β = −0.02; p =.02) was associated with functional connectivity strength between thalamic and sensorimotor networks. Increased WMI volume was also associated with decreased FA values in the corpus callosum (β = −0.004, p =.015). Conclusions: Regionally-specific alterations in early functional and structural network complexity resulting from WMI may underlie impaired outcomes

Structural subnetwork evolution across the life-span: rich-club, feeder, seeder

The impact of developmental and aging processes on brain connectivity and the connectome has been widely studied. Network theoretical measures and certain topological principles are computed from the entire brain, however there is a need to separate and understand the underlying subnetworks which contribute towards these observed holistic connectomic alterations. One organizational principle is the rich-club - a core subnetwork of brain regions that are strongly connected, forming a high-cost, high-capacity backbone that is critical for effective communication in the network. Investigations primarily focus on its alterations with disease and age. Here, we present a systematic analysis of not only the rich-club, but also other subnetworks derived from this backbone - namely feeder and seeder subnetworks. Our analysis is applied to structural connectomes in a normal cohort from a large, publicly available lifespan study. We demonstrate changes in rich-club membership with age alongside a shift in importance from 'peripheral' seeder to feeder subnetworks. Our results show a refinement within the rich-club structure (increase in transitivity and betweenness centrality), as well as increased efficiency in the feeder subnetwork and decreased measures of network integration and segregation in the seeder subnetwork. These results demonstrate the different developmental patterns when analyzing the connectome stratified according to its rich-club and the potential of utilizing this subnetwork analysis to reveal the evolution of brain architectural alterations across the life-span

In-depth characterization of neuroradiological findings in a large sample of individuals with autism spectrum disorder and controls

Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with quantitative differences in cortical and subcortical brain morphometry. Qualitative assessment of brain morphology provides complementary information on the possible underlying neurobiology. Studies of neuroradiological findings in ASD have rendered mixed results, and await robust replication in a sizable and independent sample. Methods: We systematically and comprehensively assessed neuroradiological findings in a large cohort of participants with ASD and age-matched controls (total N = 620, 348 ASD and 272 controls), including 70 participants with intellectual disability (47 ASD, 23 controls). We developed a comprehensive scoring system, augmented by standardized biometric measures. Results: There was a higher incidence of neuroradiological findings in individuals with ASD (89.4 %) compared to controls (83.8 %, p = .042). Certain findings were also more common in ASD, in particular opercular abnormalities (OR 1.9, 95 % CI 1.3–3.6) and mega cisterna magna (OR 2.4, 95 % CI 1.4–4.0) reached significance when using FDR, whereas increases in macrocephaly (OR 2.0, 95 % CI 1.2–3.2), cranial deformities (OR 2.4, 95 % CI: 1.0–5.8), calvarian / dural thickening (OR 1.5, 95 % CI 1.0–2.3), ventriculomegaly (OR 3.4, 95 % CI 1.3–9.2), and hypoplasia of the corpus callosum (OR 2.7, 95 % CI 1.1–6.3) did not survive this correction. Furthermore, neuroradiological findings were more likely to occur in isolation in controls, whereas they clustered more frequently in ASD. The incidence of neuroradiological findings was higher in individuals with mild intellectual disability (95.7 %), irrespective of ASD diagnosis. Conclusion: There was a subtly higher prevalence of neuroradiological findings in ASD, which did not appear to be specific to the condition. Individual findings or clusters of findings may point towards the neurodevelopmental mechanisms involved in individual cases. As such, clinical MRI assessments may be useful to guide further etiopathological (genetic) investigations, and are potentially valuable to fundamental ASD research

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder