Postoperative cerebellar mutism syndrome is an acquired Autism-like network disturbance.

BACKGROUND: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumour surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates. METHODS: In this study, we analyzed post-operative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and paediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n=427). RESULTS: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the paediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviours. CONCLUSIONS: Our findings indicate that CMS-associated lesions result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.

A needs assessment of pediatric epilepsy surgery in Haiti.

OBJECTIVE: Epilepsy disproportionately affects low- and/or middle-income countries (LMICs). Surgical treatments for epilepsy are potentially curative and cost-effective and may improve quality of life and reduce social stigmas. In the current study, the authors estimate the potential need for a surgical epilepsy program in Haiti by applying contemporary epilepsy surgery referral guidelines to a population of children assessed at the Clinique d'Épilepsie de Port-au-Prince (CLIDEP). METHODS: The authors reviewed 812 pediatric patient records from the CLIDEP, the only pediatric epilepsy referral center in Haiti. Clinical covariates and seizure outcomes were extracted from digitized charts. Electroencephalography (EEG) and neuroimaging reports were further analyzed to determine the prevalence of focal epilepsy or surgically amenable syndromes and to assess the lesional causes of epilepsy in Haiti. Lastly, the toolsforepilepsy instrument was applied to determine the proportion of patients who met the criteria for epilepsy surgery referral. RESULTS: Two-thirds of the patients at CLIDEP (543/812) were determined to have epilepsy based on clinical and diagnostic evaluations. Most of them (82%, 444/543) had been evaluated with interictal EEG, 88% of whom (391/444) had abnormal findings. The most common finding was a unilateral focal abnormality (32%, 125/391). Neuroimaging, a prerequisite for applying the epilepsy surgery referral criteria, had been performed in only 58 patients in the entire CLIDEP cohort, 39 of whom were eventually diagnosed with epilepsy. Two-thirds (26/39) of those patients had abnormal findings on neuroimaging. Most patients (55%, 18/33) assessed with the toolsforepilepsy application met the criteria for epilepsy surgery referral. CONCLUSIONS: The authors' findings suggest that many children with epilepsy in Haiti could benefit from being evaluated at a center with the capacity to perform basic brain imaging and neurosurgical treatments.

A partial least squares analysis of functional status, disability, and quality of life after surgical decompression for degenerative cervical myelopathy.

Previous studies aimed at identifying predictors of clinical outcomes following surgical decompression for degenerative cervical myelopathy (DCM) are limited by multicollinearity among predictors, whereby the high degree of correlation between covariates precludes detection of potentially significant findings. We apply partial least squares (PLS), a data-driven approach, to model multi-dimensional variance and dissociate patient phenotypes associated with functional, disability, and quality of life (QOL) outcomes in DCM. This was a post-hoc analysis of DCM patients enrolled in the prospective, multi-center AOSpine CSM-NA/CSM-I studies. Baseline clinical covariates evaluated as predictors included demographic (e.g., age, sex), clinical presentation (e.g., signs and symptoms), and treatment (e.g., surgical approach) characteristics. Outcomes evaluated included change in functional status (∆mJOA), disability (∆NDI), and QOL (∆SF-36) at 2 years. PLS was used to derive latent variables (LVs) relating specific clinical covariates with specific outcomes. Statistical significance was estimated using bootstrapping. Four hundred and seventy-eight patients met eligibility criteria. PLS identified 3 significant LVs. LV1 indicated an association between presentation with hand muscle atrophy, treatment by an approach other than laminectomy alone, and greater improvement in physical health-related QOL outcomes (e.g., SF-36 Physical Component Summary). LV2 suggested the presence of comorbidities (respiratory, rheumatologic, psychological) was associated with lesser improvements in functional status post-operatively (i.e., mJOA score). Finally, LV3 reflected an association between more severe myelopathy presenting with gait impairment and poorer mental health-related QOL outcomes (e.g., SF-36 Mental Component Summary). Using PLS, this analysis uncovered several novel insights pertaining to patients undergoing surgical decompression for DCM that warrant further investigation: (1) comorbid status and frailty heavily impact functional outcome; (2) presentation with hand muscle atrophy is associated with better physical QOL outcomes; and (3) more severe myelopathy with gait impairment is associated with poorer mental QOL outcomes.

Assessment and treatment of childhood epilepsy in Haiti.

OBJECTIVE: The global burden of pediatric epilepsy is disproportionately concentrated in low- and middle-income countries (LMICs). However, little is known about the effectiveness of current treatment programs in this setting. We present the outcomes of children who were assessed and treated at the Clinique D'Épilepsie de Port-au-Prince (CLIDEP), the only pediatric epilepsy referral center in Haiti. METHODS: A 10-year retrospective review of children consecutively assessed and treated at CLIDEP was performed. The primary outcome was seizure control following treatment for epilepsy. The secondary outcome was an accurate determination of the diagnosis of epilepsy. A data-driven principle component regression (PCR) analysis was used to identify variables associated with outcomes of interest. RESULTS: Of the 812 children referred for evaluation, most children (82%) underwent electroencephalography to investigate a possible epilepsy diagnosis. Very few children (7%) underwent cranial imaging. Although many patients were lost to follow-up (24%), most children who returned to clinic had less frequent seizures (51%) and compliance with medication was relatively high (79%). Using PCR, we identified a patient phenotype that was strongly associated with poor seizure control which had strong contributions from abnormal neurological examination, higher number of antiepileptic drugs, comorbid diagnoses, epileptic encephalopathy or epilepsy syndrome, and developmental delay. Head circumference also contributed to epilepsy outcomes in Haiti with smaller head sizes being associated with a poor seizure outcome. A dissociable phenotype of febrile seizures, suspected structural abnormality, epileptic encephalopathy or epilepsy syndrome, and higher seizure frequency was associated with a diagnosis of epilepsy. SIGNIFICANCE: We describe the current landscape of childhood epilepsy in Haiti with an emphasis on diagnosis, treatment and outcomes. The findings provide evidence for the effectiveness of programs aimed at the diagnosis and management of epilepsy in LMICs and may inform the allocation of resources and create more effective referral structures.

Connectomic Profiling Identifies Responders to Vagus Nerve Stimulation.

OBJECTIVE: Vagus nerve stimulation (VNS) is a common treatment for medically intractable epilepsy, but response rates are highly variable, with no preoperative means of identifying good candidates. This study aimed to predict VNS response using structural and functional connectomic profiling. METHODS: Fifty-six children, comprising discovery (n = 38) and validation (n = 18) cohorts, were recruited from 3 separate institutions. Diffusion tensor imaging was used to identify group differences in white matter microstructure, which in turn informed beamforming of resting-state magnetoencephalography recordings. The results were used to generate a support vector machine learning classifier, which was independently validated. This algorithm was compared to a second classifier generated using 31 clinical covariates. RESULTS: Treatment responders demonstrated greater fractional anisotropy in left thalamocortical, limbic, and association fibers, as well as greater connectivity in a functional network encompassing left thalamic, insular, and temporal nodes (p < 0.05). The resulting classifier demonstrated 89.5% accuracy and area under the receiver operating characteristic (ROC) curve of 0.93 on 10-fold cross-validation. In the external validation cohort, this model demonstrated an accuracy of 83.3%, with a sensitivity of 85.7% and specificity of 75.0%. This was significantly superior to predictions using clinical covariates alone, which exhibited an area under the ROC curve of 0.57 (p < 0.008). INTERPRETATION: This study provides the first multi-institutional, multimodal connectomic prediction algorithm for VNS, and provides new insights into its mechanism of action. Reliable identification of VNS responders is critical to mitigate surgical risks for children who may not benefit, and to ensure cost-effective allocation of health care resources. ANN NEUROL 2019;86:743-753.

Clinical phenotypes associated with outcomes following deep brain stimulation for childhood dystonia.

OBJECTIVE: Although deep brain stimulation (DBS) is an accepted treatment for childhood dystonia, there is significant heterogeneity in treatment response and few data are available to identify ideal surgical candidates. METHODS: Data were derived from a systematic review and individual patient data meta-analysis of DBS for dystonia in children that was previously published. Outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale for movement (BFMDRS-M) and for disability (BFMDRS-D). The authors used partial least squares, bootstrapping, and permutation statistics to extract patterns of contributions of specific preoperative characteristics to relationship with distinct outcomes, in all patients and in patients with primary and secondary dystonia separately. RESULTS: Of 301 children undergoing DBS for dystonia, 167 had primary dystonia, 125 secondary dystonia, and 9 myoclonus dystonia. Three dissociable preoperative phenotypes (latent variables) were identified and associated with the following: 1) BFMDRS-M at last follow-up; 2) relative change in BFMDRS-M score; and 3) relative change in BFMDRS-D score. The phenotype of patients with secondary dystonia, with a high BFMDRS-M score and truncal involvement, undergoing DBS at a younger age, was associated with a worse postoperative BFMDRS-M score. Children with primary dystonia involving the trunk had greater improvement in BFMDRS-M and -D scores. Those with primary dystonia of shorter duration and proportion of life with disease, undergoing globus pallidus DBS, had greater improvements in BFMDRS-D scores at long-term follow-up. CONCLUSIONS: In a comprehensive, data-driven, multivariate analysis of DBS for childhood dystonia, the authors identified novel and dissociable patient phenotypes associated with distinct outcomes. The findings of this report may inform surgical candidacy for DBS.

White matter microstructural differences identified using multi-shell diffusion imaging in six-year-old children born very preterm.

INTRODUCTION: The underlying microstructural properties of white matter differences in children born very preterm (<32 weeks gestational age) can be investigated in depth using multi-shell diffusion imaging. The present study compared white matter across the whole brain using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics in children born very preterm and full-term children at six years of age. We also investigated associations between white matter microstructure with early brain injury and developmental outcomes. METHOD: Multi-shell diffusion imaging, T1-weighted anatomical MR images and developmental assessments were acquired in 23 children born very preterm (16 males; mean scan age: 6.57 ±â€¯0.34 years) and 24 full-term controls (10 males, mean scan age: 6.62 ±â€¯0.37 years). DTI metrics were obtained and neurite orientation dispersion index (ODI) and density index (NDI) were estimated using the NODDI diffusion model. FSL's tract-based spatial statistics were performed on traditional DTI metrics and NODDI metrics. Voxel-wise comparisons were performed to test between-group differences and within-group associations with developmental outcomes (intelligence and visual motor abilities) as well as early white matter injury and germinal matrix/intraventricular haemorrhage (GMH/IVH). RESULTS: In comparison to term-born children, the children born very preterm exhibited lower fractional anisotropy (FA) across many white matter regions as well as higher mean diffusivity (MD), radial diffusivity (RD), and ODI. Within-group analyses of the children born very preterm revealed associations between higher FA and NDI with higher IQ and VMI. Lower ODI was found within the corona radiata in those with a history of white matter injury. Within the full-term group, associations were found between higher NDI and ODI with lower IQ. CONCLUSION: Children born very preterm exhibit lower FA and higher ODI than full-term children. NODDI metrics provide more biologically specific information beyond DTI metrics as well as additional information of the impact of prematurity and white matter microstructure on cognitive outcomes at six years of age.

Characterization of Autism Spectrum Disorder across the Age Span by Intrinsic Network Patterns.

Autism spectrum disorder (ASD) is characterized by abnormal functional organization of brain networks, which may underlie the cognitive and social impairments observed in affected individuals. The present study characterizes unique intrinsic connectivity within- and between- neural networks in children through to adults with ASD, relative to controls. Resting state fMRI data were analyzed in 204 subjects, 102 with ASD and 102 age- and sex-matched controls (ages 7-40 years), acquired on a single scanner. ASD was assessed using the autism diagnostic observation schedule (ADOS). BOLD correlations were calculated between 47 regions of interest, spanning seven resting state brain networks. Partial least squares (PLS) analyses evaluated the association between connectivity patterns and ASD diagnosis as well as ASD severity scores. PLS demonstrated dissociable connectivity patterns in those with ASD, relative to controls. Similar patterns were observed in the whole cohort and in a subgroup analysis of subjects under 18 years of age. Greater inter-network connectivity was seen in ASD with greater intra-network connectivity in controls. In conclusion, stronger inter-network and weaker intra-network resting state-fMRI BOLD correlations characterize ASD and may differentiate control and ASD cohorts. These findings are relevant to understanding ASD as a disruption of network topology.

Functional changes during visuo-spatial working memory in autism spectrum disorder: 2-year longitudinal functional magnetic resonance imaging study.

This study examined functional changes longitudinally over 2 years in neural correlates associated with working memory in youth with and without autism spectrum disorder, and the impact of increasing cognitive load. We used functional magnetic resonance imaging and a visuo-spatial 1-back task with four levels of difficulty. A total of 14 children with autism spectrum disorder and 15 typically developing children (ages 7-13) were included at baseline and followed up approximately 2 years later. Despite similar task performance between groups, differences were evident in the developmental trajectories of neural responses. Typically developing children showed greater load-dependent activation which intensified over time in the frontal, parietal and occipital lobes and the right fusiform gyrus, compared to those with autism spectrum disorder. Children with autism spectrum disorder showed minimal age-related changes in load-dependent activation, but greater longitudinal load-dependent deactivation in default mode network compared to typically developing children. Results suggest inadequate modulation of neural activity with increasing cognitive demands in children with autism spectrum disorder, which does not mature into adolescence, unlike their typically developing peers. Diminished ability for children with autism spectrum disorder to modulate neural activity during this period of maturation suggests that they may be more vulnerable to the increasing complexity of social and academic demands as they progress through adolescence than their peers.

Presurgical hyperconnectivity of the ablation volume is associated with seizure-freedom after magnetic resonance-guided laser interstitial thermal therapy.

PURPOSE: Magnetic Resonance-guided Laser Interstitial Thermal Therapy (MRgLITT) is an emerging minimally-invasive alternative to resective surgery for medically-intractable epilepsy. The precise lesioning effect produced by MRgLITT supplies opportunities to glean insights into epileptogenic regions and their interactions with functional brain networks. In this exploratory analysis, we sought to characterize associations between MRgLITT ablation zones and large-scale brain networks that portended seizure outcome using resting-state fMRI. METHODS: Presurgical fMRI and intraoperatively volumetric structural imaging were obtained, from which the ablation volume was segmented. The network properties of the ablation volume within the brain's large-scale brain networks were characterized using graph theory and compared between children who were and were not rendered seizure-free. RESULTS: Of the seventeen included children, five achieved seizure freedom following MRgLITT. Greater functional connectivity of the ablation volume to canonical resting-state networks was associated with seizure-freedom (p < 0.05, FDR-corrected). The ablated volume in children who subsequently became seizure-free following MRgLITT had significantly greater strength, and eigenvector centrality within the large-scale brain network. CONCLUSIONS: These findings provide novel insights into the interaction between epileptogenic cortex and large-scale brain networks. The association between ablation volume and resting-state networks may supply novel avenues for presurgical planning and patient stratification.

Load matters: neural correlates of verbal working memory in children with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterised by diminished social reciprocity and communication skills and the presence of stereotyped and restricted behaviours. Executive functioning deficits, such as working memory, are associated with core ASD symptoms. Working memory allows for temporary storage and manipulation of information and relies heavily on frontal-parietal networks of the brain. There are few reports on the neural correlates of working memory in youth with ASD. The current study identified the neural systems underlying verbal working memory capacity in youth with and without ASD using functional magnetic resonance imaging (fMRI). METHODS: Fifty-seven youth, 27 with ASD and 30 sex- and age-matched typically developing (TD) controls (9-16 years), completed a one-back letter matching task (LMT) with four levels of difficulty (i.e. cognitive load) while fMRI data were recorded. Linear trend analyses were conducted to examine brain regions that were recruited as a function of increasing cognitive load. RESULTS: We found similar behavioural performance on the LMT in terms of reaction times, but in the two higher load conditions, the ASD youth had lower accuracy than the TD group. Neural patterns of activations differed significantly between TD and ASD groups. In TD youth, areas classically used for working memory, including the lateral and medial frontal, as well as superior parietal brain regions, increased in activation with increasing task difficulty, while areas related to the default mode network (DMN) showed decreasing activation (i.e., deactivation). The youth with ASD did not appear to use this opposing cognitive processing system; they showed little recruitment of frontal and parietal regions across the load but did show similar modulation of the DMN. CONCLUSIONS: In a working memory task, where the load was manipulated without changing executive demands, TD youth showed increasing recruitment with increasing load of the classic fronto-parietal brain areas and decreasing involvement in default mode regions. In contrast, although they modulated the default mode network, youth with ASD did not show the modulation of increasing brain activation with increasing load, suggesting that they may be unable to manage increasing verbal information. Impaired verbal working memory in ASD would interfere with the youths' success academically and socially. Thus, determining the nature of atypical neural processing could help establish or monitor working memory interventions for ASD.

Altered white matter development in children born very preterm.

Children born very preterm (VPT) at less than 32 weeks' gestational age (GA) are prone to disrupted white matter maturation and impaired cognitive development. The aims of the present study were to identify differences in white matter microstructure and connectivity of children born VPT compared to term-born children, as well as relations between white matter measures with cognitive outcomes and early brain injury. Diffusion images and T1-weighted anatomical MR images were acquired along with developmental assessments in 31 VPT children (mean GA: 28.76 weeks) and 28 term-born children at 4 years of age. FSL's tract-based spatial statistics was used to create a cohort-specific template and mean fractional anisotropy (FA) skeleton that was applied to each child's DTI data. Whole brain deterministic tractography was performed and graph theoretical measures of connectivity were calculated based on the number of streamlines between cortical and subcortical nodes derived from the Desikan-Killiany atlas. Between-group analyses included FSL Randomise for voxel-wise statistics and permutation testing for connectivity analyses. Within-group analyses between FA values and graph measures with IQ, language and visual-motor scores as well as history of white matter injury (WMI) and germinal matrix/intraventricular haemorrhage (GMH/IVH) were performed. In the children born VPT, FA values within major white matter tracts were reduced compared to term-born children. Reduced measures of local strength, clustering coefficient, local and global efficiency were present in the children born VPT within nodes in the lateral frontal, middle and superior temporal, cingulate, precuneus and lateral occipital regions. Within-group analyses revealed associations in term-born children between FA, Verbal IQ, Performance IQ and Full scale IQ within regions of the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, forceps minor and forceps major. No associations with outcome were found in the VPT group. Global efficiency was reduced in the children born VPT with a history of WMI and GMH/IVH. These findings are evidence for under-developed and less connected white matter in children born VPT, contributing to our understanding of white matter development within this population.

Phase-amplitude coupling within the anterior thalamic nuclei during seizures.

Cross-frequency phase-amplitude coupling (cfPAC) subserves an integral role in the hierarchical organization of interregional neuronal communication and is also expressed by epileptogenic cortex during seizures. Here, we sought to characterize patterns of cfPAC expression in the anterior thalamic nuclei during seizures by studying extra-operative recordings in patients implanted with deep brain stimulation electrodes for intractable epilepsy. Nine seizures from two patients were analyzed in the peri-ictal period. CfPAC was calculated using the modulation index and interregional functional connectivity was indexed using the phase-locking value. Statistical analysis was performed within subjects on the basis of nonparametric permutation and corrected with Gaussian field theory. Five of the nine analyzed seizures demonstrated significant cfPAC. Significant cfPAC occurred during the pre-ictal and ictal periods in three seizures, as well as the postictal windows in four seizures. The preferred phase at which cfPAC occurred differed 1) in space, between the thalami of the epileptogenic and nonepileptogenic hemispheres; and 2) in time, at seizure termination. The anterior thalamic nucleus of the epileptogenic hemisphere also exhibited altered interregional phase-locking synchrony concurrent with the expression of cfPAC. By analyzing extraoperative recordings from the anterior thalamic nuclei, we show that cfPAC associated with altered interregional phase synchrony is lateralized to the thalamus of the epileptogenic hemisphere during seizures. Electrophysiological differences in cfPAC, including preferred phase of oscillatory interactions may be further investigated as putative targets for individualized neuromodulation paradigms in patients with drug-resistant epilepsy. NEW & NOTEWORTHY The association between fast brain activity and slower oscillations is an integral mechanism for hierarchical neuronal communication, which is also manifested in epileptogenic cortex. Our data suggest that the same phenomenon occurs in the anterior thalamic nuclei during seizures. Further, the preferred phase of modulation shows differences in space, between the epileptogenic and nonepileptogenic hemispheres and time, as seizures terminate. Our data encourage the study of cross-frequency coupling for targeted, individualized closed-loop stimulation paradigms.

Presurgical thalamocortical connectivity is associated with response to vagus nerve stimulation in children with intractable epilepsy.

Although chronic vagus nerve stimulation (VNS) is an established treatment for medically-intractable childhood epilepsy, there is considerable heterogeneity in seizure response and little data are available to pre-operatively identify patients who may benefit from treatment. Since the therapeutic effect of VNS may be mediated by afferent projections to the thalamus, we tested the hypothesis that intrinsic thalamocortical connectivity is associated with seizure response following chronic VNS in children with epilepsy. Twenty-one children (ages 5-21 years) with medically-intractable epilepsy underwent resting-state fMRI prior to implantation of VNS. Ten received sedation, while 11 did not. Whole brain connectivity to thalamic regions of interest was performed. Multivariate generalized linear models were used to correlate resting-state data with seizure outcomes, while adjusting for age and sedation status. A supervised support vector machine (SVM) algorithm was used to classify response to chronic VNS on the basis of intrinsic connectivity. Of the 21 subjects, 11 (52%) had 50% or greater improvement in seizure control after VNS. Enhanced connectivity of the thalami to the anterior cingulate cortex (ACC) and left insula was associated with greater VNS efficacy. Within our test cohort, SVM correctly classified response to chronic VNS with 86% accuracy. In an external cohort of 8 children, the predictive model correctly classified the seizure response with 88% accuracy. We find that enhanced intrinsic connectivity within thalamocortical circuitry is associated with seizure response following VNS. These results encourage the study of intrinsic connectivity to inform neural network-based, personalized treatment decisions for children with intractable epilepsy.

Brain biomarkers and pre-injury cognition are associated with long-term cognitive outcome in children with traumatic brain injury.

BACKGROUND: Children with traumatic brain injury (TBI) are frequently at risk of long-term impairments of attention and executive functioning but these problems are difficult to predict. Although deficits have been reported to vary with injury severity, age at injury and sex, prognostication of outcome remains imperfect at a patient-specific level. The objective of this proof of principle study was to evaluate a variety of patient variables, along with six brain-specific and inflammatory serum protein biomarkers, as predictors of long-term cognitive outcome following paediatric TBI. METHOD: Outcome was assessed in 23 patients via parent-rated questionnaires related to attention deficit hyperactivity disorder (ADHD) and executive functioning, using the Conners 3rd Edition Rating Scales (Conners-3) and Behaviour Rating Inventory of Executive Function (BRIEF) at a mean time since injury of 3.1 years. Partial least squares (PLS) analyses were performed to identify factors measured at the time of injury that were most closely associated with outcome on (1) the Conners-3 and (2) the Behavioural Regulation Index (BRI) and (3) Metacognition Index (MI) of the BRIEF. RESULTS: Higher levels of neuron specific enolase (NSE) and lower levels of soluble neuron cell adhesion molecule (sNCAM) were associated with higher scores on the inattention, hyperactivity/impulsivity and executive functioning scales of the Conners-3, as well as working memory and initiate scales of the MI from the BRIEF. Higher levels of NSE only were associated with higher scores on the inhibit scale of the BRI. CONCLUSIONS: NSE and sNCAM show promise as reliable, early predictors of long-term attention-related and executive functioning problems following paediatric TBI.

Longitudinal Study of White Matter Development and Outcomes in Children Born Very Preterm.

Identifying trajectories of early white matter development is important for understanding atypical brain development and impaired functional outcomes in children born very preterm (<32 weeks gestational age [GA]). In this study, 161 diffusion images were acquired in children born very preterm (median GA: 29 weeks) shortly following birth (75), term-equivalent (39), 2 years (18), and 4 years of age (29). Diffusion tensors were computed to obtain measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), which were aligned and averaged. A paediatric atlas was applied to obtain diffusion metrics within 12 white matter tracts. Developmental trajectories across time points demonstrated age-related changes which plateaued between term-equivalent and 2 years of age in the majority of posterior tracts and between 2 and 4 years of age in anterior tracts. Between preterm and term-equivalent scans, FA rates of change were slower in anterior than posterior tracts. Partial least squares analyses revealed associations between slower MD and RD rates of change within the external and internal capsule with lower intelligence quotients and language scores at 4 years of age. These results uniquely demonstrate early white matter development and its linkage to cognitive functions.

Mapping the Network of Neuropsychological Impairment in Children with Autism Spectrum Disorder: A Graph Theoretical Analysis.

Children with autism spectrum disorder (ASD) exhibit social-communicative impairments. Less is known about the neuropsychological profile of ASD, although cognitive and neuropsychological deficits are evident. We modelled neuropsychological function in 20 children with ASD and 20 sex, age and IQ matched typically-developing controls (ages 7-14) as a network of interacting parameters. Graph theoretical analysis was applied to identify critical topographic regions within this network. Two areas were significantly stronger hubs in typically-developing children, the ability to shift attention (p < 0.001) and overall executive function (p < 0.001). Planning/organization was a stronger hub in the cognitive networks of children with ASD (p = 0.001). We show that ASD is not only characterized by impairments in various neurocognitive domains, but also alterations in their interaction.

Longitudinal cerebellar growth following very preterm birth.

PURPOSE: To measure cerebellar growth in a longitudinal cohort of very preterm infants to identify early predictors of subsequent brain growth. Although the cerebellum grows rapidly during late gestation, the rate and variability of growth following premature birth, and the effects of associated injury, are largely unknown. MATERIALS AND METHODS: In all, 105 very-preterm born infants (24-32 weeks GA) were imaged using magnetic resonance imaging (MRI) at birth, term-equivalent, 2, and 4 years of age. Cerebellar and total cerebral volumes were estimated from 1 mm isotropic T1 -weighted scans acquired at 1.5T and 3T, using an atlas-based approach. Linear models were used to analyze cerebellar volume as cross-sectional and longitudinal functions of age, clinical, and radiological correlates. Linear models were also used to test for associations between volume and cognitive outcome. RESULTS: Cerebellar volume increased rapidly with age-at-scan during both the preterm (0.7 mL/wk, P < 0.001) and term periods (1.8 mL/wk, P < 0.001). Infants with grade 3 or 4 germinal matrix hemorrhage (GMH) had smaller cerebellar volumes as a percentage of total brain volume starting at birth and continuing to 4 years of age (-0.43%, -0.57%, -1.09% at preterm, term, and 4 years, respectively, P < 0.01). Irrespective of age-at-scan, early cerebellar volume was predictive of volume at 4 years of age (slope = 1.3, P < 0.001). Cerebellar volumes were not found to predict cognitive outcome at 4 years of age; P < 0.2. CONCLUSION: High-grade GMH and small perinatal cerebellar size is predictive of cerebellar development up to 4 years of age. These findings suggest that it is possible to identify individuals at high risk of reduced cerebellar volumes at an early age. J. Magn. Reson. Imaging 2016;43:1462-1473.

Diffusion tensor imaging-based assessment of white matter tracts and visual-motor outcomes in very preterm neonates.

INTRODUCTION: The purpose of this study was to assess the impact of brain injury on white matter development and long-term outcomes in very preterm (VPT) neonates. METHODS: Eighty-five VPT neonates (born <32/40 weeks gestational age (GA)) scanned within 2 weeks of birth were divided into three groups based on the presence of perinatal cerebral injury: (i) no injury, (ii) mild/moderate injury and (iii) severe injury. Diffusion tensor imaging (DTI) was acquired for each neonate and fractional anisotropy (FA), and diffusivity measures were calculated in the posterior limb of the internal capsule (PLIC) and optic radiation (OR). At 2 and 4 years of age, 41 and 44 children were assessed for motor and visual-motor abilities. Analyses determined the relation between GA and DTI measures, injury groups and DTI measures as well as developmental assessments. RESULTS: GA was related to all DTI measures within the PLIC bilaterally, FA in the OR bilaterally and AD in the left OR. The severely injured group had significantly different DTI measures in the left PLIC compared to the other two groups, independent of lateralization of lesions. Group differences in the left OR were also found, due to higher incidence of the white matter injury in the left hemisphere. No differences were found between groups and outcome measures at 2 and 4 years, with the exception of destructive periventricular venous haemorrhagic infarction (PVHI). CONCLUSIONS: DTI measures of the PLIC and OR were affected by injury in VPT neonates. These findings seen shortly after birth did not always translate into long-term motor and visual-motor impairments suggesting compensatory mechanisms.

Associations of Perinatal Clinical and Magnetic Resonance Imaging Measures with Developmental Outcomes in Children Born Very Preterm.

OBJECTIVE: To identify perinatal risk factors associated with long-term neurocognitive and behavioral impairments in children born very preterm using a multivariate, partial least squares approach. STUDY DESIGN: Twenty-seven perinatal clinical and magnetic resonance imaging measures were collected at birth and during the neonatal intensive care stay for 105 neonates born very preterm (≤ 32 weeks gestational age). One-half of the children returned for neuropsychological assessments at 2 and 4 years of age. Parent-reported behavioral measures were also obtained at 4 years of age. Three partial least squares analyses were performed to determine associations between clinical and radiologic measures with cognitive outcomes at 2 and 4 years of age, as well as with behavioral measures at 4 years of age. RESULTS: Within the first components of each analysis, only intrauterine growth restriction, male sex, and absence of antenatal corticosteroid use were associated with poorer cognitive and language ability at 2 and 4 years of age, accounting for 79.6% and 71.4% of the total variance, respectively. In addition, white matter injury at term-equivalent age contributed to more problematic internalizing behaviors, behavioral symptoms, and impaired executive function at 4 years of age, accounting for 67.9% of the total variance. CONCLUSIONS: Using this data-driven multivariate approach, specific measures in prenatal and early postnatal life are shown to be selectively and significantly associated with cognitive and behavioral outcomes in children born very preterm. Early detection of risk factors can help inform prognoses of children at greatest risk of long-term impairments.