ENIGMA's simple seven: Recommendations to enhance the reproducibility of resting-state fMRI in traumatic brain injury.

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field.

Team functioning in Neurorehabilitation: a mixed methods study.

The objective of this study was to enhance understanding of team functioning in a neurorehabilitation team by identifying the factors that impede and facilitate effective interprofessional team collaboration. We focused on team identification, psychological safety, and team learning, and conducted the research at a neurorehabilitation center treating young patients with severe acquired brain injury in the Netherlands. A mixed-methods approach was employed, integrating quantitative data from questionnaires (N = 40) with qualitative insights from a focus group (n = 6) and in-depth interviews (n = 5) to provide a comprehensive perspective on team dynamics. Findings revealed strong team identification among participants, denoting a shared sense of belonging and commitment. However, limited psychological safety was observed, which negatively affected constructive conflict and team learning. Qualitative analysis further identified deficiencies in shared mental models, especially in shared decision-making and integrated care. These results highlight the crucial role of psychological safety in team learning and the development of shared mental models in neurorehabilitation settings. Although specific to neurorehabilitation, the insights gained may be applicable to enhancing team collaboration in various healthcare environments. The study forms a basis for future research to investigate the impact of improvements in team functioning on patient outcomes in similar settings.

Pharmacotherapy to Improve Cognitive Functioning After Acquired Brain Injury: A Meta-Analysis and Meta-Regression.

Cognitive impairments, common sequelae of acquired brain injury (ABI), significantly affect rehabilitation and quality of life. Currently, there is no solid evidence-base for pharmacotherapy to improve cognitive functioning after ABI, nevertheless off-label use is widely applied in clinical practice. This meta-analysis and meta-regression aims to quantitatively aggregate the available evidence for the effects of pharmacological agents used in the treatment of cognitive impairments following ABI. We conducted a comprehensive search of Embase, Medline Ovid, and Cochrane Controlled Trials Register databases for randomized controlled and crossover trials. Meta-analytic effects were calculated for each pharmaceutical agent and targeted neuromodulator system. Cognitive outcome measures were aggregated across cognitive domains. Of 8,216 articles, 41 studies (4,434 patients) were included. The noradrenergic agent methylphenidate showed a small, significant positive effect on cognitive functioning in patients with traumatic brain injury (TBI; k = 14, d = 0.34, 95% confidence interval: 0.12-0.56, P = 0.003). Specifically, methylphenidate was found to improve cognitive functions related to executive memory, baseline speed, inhibitory control, and variability in responding. The cholinergic drug donepezil demonstrated a large effect size, albeit based on a limited number of studies (k = 3, d = 1.68, P = 0.03). No significant effects were observed for other agents. Additionally, meta-regression analysis did not identify significant sources of heterogeneity in treatment response. Our meta-analysis supports the use of methylphenidate for enhancing cognitive functioning in patients with TBI. Although donepezil shows potential, it warrants further research. These results could guide clinical decision making, inform practice guidelines, and direct future pharmacotherapeutic research in ABI.

Effects of Bumetanide on Neurocognitive Functioning in Children with Autism Spectrum Disorder: Secondary Analysis of a Randomized Placebo-Controlled Trial.

We present the secondary-analysis of neurocognitive tests in the 'Bumetanide in Autism Medication and Biomarker' (BAMBI;EUDRA-CT-2014-001560-35) study, a randomized double-blind placebo-controlled (1:1) trial testing 3-months bumetanide treatment (≤ 1 mg twice-daily) in unmedicated children 7-15 years with ASD. Children with IQ ≥ 70 were analyzed for baseline deficits and treatment-effects on the intention-to-treat-population with generalized-linear-models, principal component analysis and network analysis. Ninety-two children were allocated to treatment and 83 eligible for analyses. Heterogeneous neurocognitive impairments were found that were unaffected by bumetanide treatment. Network analysis showed higher modularity after treatment (mean difference:-0.165, 95%CI:-0.317 to - 0.013,p = .034) and changes in the relative importance of response inhibition in the neurocognitive network (mean difference:-0.037, 95%CI:-0.073 to - 0.001,p = .042). This study offers perspectives to include neurocognitive tests in ASD trials.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

The mediating role of neurocognitive functions in the relation between physical competencies and academic achievement of primary school children.

Previous studies into associations between physical, neurocognitive and academic skills have reported inconsistent results. This study aimed to get more insight into these relations by examining all three domains simultaneously, testing a complete mediational model including measures of physical competencies (cardiovascular fitness and motor skills), neurocognitive skills (attention, information processing, and core executive functions), and academic achievement (reading, mathematics, and spelling). Dutch primary school students (n = 891, 440 boys, mean age 9.17 years) were assessed on the Shuttle Run Test (cardiovascular fitness), items of the Körperkoordinationstest für Kinder and Bruininks-Oseretsky Test-II (fundamental motor skills), computerized neurocognitive tests, and standardized academic achievement tests. A multilevel structural equation model showed that physical competencies were only indirectly related to academic achievement, via specific neurocognitive functions depending on the academic domain involved. Results provide important implications, highlighting the importance of well-developed physical competencies in children.

Risk factors for neurocognitive impairment and the relation with structural brain abnormality in children and young adults with severe chronic kidney disease.

BACKGROUND: Severe chronic kidney disease (CKD) in children and young adults has shown to be associated with abnormal brain development, which may contribute to neurocognitive impairments. We aimed to investigate risk factors for neurocognitive impairment and investigate the relation with structural brain abnormalities in young severe CKD patients. METHODS: This cross-sectional study includes 28 patients with severe CKD (eGFR < 30), aged 8-30 years (median 18.5 years), on different treatment modalities (pre-dialysis [n = 8], dialysis [n = 8], transplanted [n = 12]). We assessed neurocognitive functioning using a comprehensive test battery and brain structure by magnetic resonance imaging metrics of brain volume and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD] measured with diffusion tensor imaging). Multivariate regression and mediation analyses were performed between clinical CKD parameters, brain structure, and neurocognitive outcome. RESULTS: A combination of risk factors (e.g., longer time since kidney transplantation, longer dialysis duration and late CKD onset) was significantly associated with lower intelligence and/or worse processing speed and working memory. Lower FA in a cluster of white matter tracts was associated with lower intelligence and mediated the relation between clinical risk factors and lower intelligence. CONCLUSIONS: Young severe CKD patients with a prolonged duration of kidney replacement therapy, either dialysis or transplantation are at particular risk for impairments in intelligence, processing speed, and working memory. Disrupted white matter integrity may importantly contribute to these neurocognitive impairments. Prospective, longitudinal studies are needed to elucidate the mechanisms involved in CKD and treatment that affect white matter integrity and neurocognitive outcome in young patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Bronchopulmonary dysplasia is not related to neurofilament light for neuroaxonal damage in preterm infants.

BACKGROUND: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage. METHODS: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups. RESULTS: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time. CONCLUSIONS: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD. IMPACT: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH.

Prediction Models for Neurocognitive Outcome of Mild Traumatic Brain Injury in Children: A Systematic Review.

Mild traumatic brain injury (mTBI) is highly prevalent in children. Recent literature suggests that children with mTBI are at considerable risk of persisting neurocognitive deficits, threatening post-injury child development. Nevertheless, clinical tools for early identification of children at risk are currently not available. This systematic review aims to describe the available literature on neurocognitive outcome prediction models in children with mTBI. Findings are highly relevant for early identification of children at risk of persistent neurocognitive deficits, allowing targeted treatment of these children to optimize recovery. The electronic literature search was conducted in PubMed, EMBASE, CINAHL, Cochrane, PsychINFO and Web of Science on February 9, 2022. We included all studies with multi-variate models for neurocognitive outcome based on original data from only children (age <18 years) with mTBI. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two authors independently performed data extraction and risk of bias analysis using the Prediction model Risk of Bias Assessment Tool (PROBAST). This systematic review identified eight original studies (nine articles) reporting prediction models for neurocognitive outcome, representing a total of 1033 children diagnosed with mTBI (mean age at injury = 10.5 years, 37.6% girls). Neurocognitive outcome assessment took place between 1 month and 7 years post-injury. Models were identified with significant predictive value for the following outcomes: memory, working memory, inhibition, processing speed, and general neurocognitive functioning. Prediction performance of these models varied greatly between weak and substantial (R2 = 10.0%-54.7%). The best performing model was based on demographic and pre-morbid risk factors in conjunction with a subacute neurocognitive screening to predict the presence of a deficit in general neurocognitive functioning at 12 months post-injury. This systematic review reflects the absence of robust prediction models for neurocognitive outcome of children with mTBI. The findings indicate that demographic factors, pre-morbid factors as well as acute and subacute clinical factors have relevance for neurocognitive outcome. Based on the available evidence, evaluation of demographic and pre-morbid risk factors in conjunction with a subacute neurocognitive screening may have the best potential to predict neurocognitive outcome in children with mTBI. The findings underline the importance of future research contributing to early identification of children at risk of persisting neurocognitive deficits.

Towards PErsonalised PRognosis for children with traumatic brain injury: the PEPR study protocol.

INTRODUCTION: Traumatic brain injury (TBI) in children can be associated with poor outcome in crucial functional domains, including motor, neurocognitive and behavioural functioning. However, outcome varies between patients and is mediated by complex interplay between demographic factors, premorbid functioning and (sub)acute clinical characteristics. At present, methods to understand let alone predict outcome on the basis of these variables are lacking, which contributes to unnecessary follow-up as well as undetected impairments in children. Therefore, this study aims to develop prognostic models for the individual outcome of children with TBI in a range of important developmental domains. In addition, the potential added value of advanced neuroimaging data and the use of machine learning algorithms in the development of prognostic models will be assessed. METHODS AND ANALYSIS: 210 children aged 4-18 years diagnosed with mild-to-severe TBI will be prospectively recruited from a research network of Dutch hospitals. They will be matched 2:1 to a control group of neurologically healthy children (n=105). Predictors in the model will include demographic, premorbid and clinical measures prospectively registered from the TBI hospital admission onwards as well as MRI metrics assessed at 1 month post-injury. Outcome measures of the prognostic models are (1) motor functioning, (2) intelligence, (3) behavioural functioning and (4) school performance, all assessed at 6 months post-injury. ETHICS AND DISSEMINATION: Ethics has been obtained from the Medical Ethical Board of the Amsterdam UMC (location AMC). Findings of our multicentre prospective study will enable clinicians to identify TBI children at risk and aim towards a personalised prognosis. Lastly, findings will be submitted for publication in open access, international and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL71283.018.19 and NL9051.

Machine Learning Prediction Models for Neurodevelopmental Outcome After Preterm Birth: A Scoping Review and New Machine Learning Evaluation Framework.

BACKGROUND AND OBJECTIVES: Outcome prediction of preterm birth is important for neonatal care, yet prediction performance using conventional statistical models remains insufficient. Machine learning has a high potential for complex outcome prediction. In this scoping review, we provide an overview of the current applications of machine learning models in the prediction of neurodevelopmental outcomes in preterm infants, assess the quality of the developed models, and provide guidance for future application of machine learning models to predict neurodevelopmental outcomes of preterm infants. METHODS: A systematic search was performed using PubMed. Studies were included if they reported on neurodevelopmental outcome prediction in preterm infants using predictors from the neonatal period and applying machine learning techniques. Data extraction and quality assessment were independently performed by 2 reviewers. RESULTS: Fourteen studies were included, focusing mainly on very or extreme preterm infants, predicting neurodevelopmental outcome before age 3 years, and mostly assessing outcomes using the Bayley Scales of Infant Development. Predictors were most often based on MRI. The most prevalent machine learning techniques included linear regression and neural networks. None of the studies met all newly developed quality assessment criteria. Studies least prone to inflated performance showed promising results, with areas under the curve up to 0.86 for classification and R2 values up to 91% in continuous prediction. A limitation was that only 1 data source was used for the literature search. CONCLUSIONS: Studies least prone to inflated prediction results are the most promising. The provided evaluation framework may contribute to improved quality of future machine learning models.

Resting-state network organisation in children with traumatic brain injury.

Children with traumatic brain injury are at risk of neurocognitive and behavioural impairment. Although there is evidence for abnormal brain activity in resting-state networks after TBI, the role of resting-state network organisation in paediatric TBI outcome remains poorly understood. This study is the first to investigate the impact of paediatric TBI on resting-state network organisation using graph theory, and its relevance for functional outcome. Participants were 8-14 years and included children with (i) mild TBI and risk factors for complicated TBI (mildRF+, n = 20), (ii) moderate/severe TBI (n = 15), and (iii) trauma control injuries (n = 27). Children underwent resting-state functional magnetic resonance imaging (fMRI), neurocognitive testing, and behavioural assessment at 2.8 years post-injury. Graph theory was applied to fMRI timeseries to evaluate the impact of TBI on global and local organisation of the resting-state network, and relevance for neurocognitive and behavioural functioning. Children with TBI showed atypical global network organisation as compared to the trauma control group, reflected by lower modularity (mildRF + TBI and moderate/severe TBI), higher smallworldness (mildRF + TBI) and lower assortativity (moderate/severe TBI ps < .04, Cohen's ds: > .6). Regarding local network organisation, the relative importance of hub regions in the network did not differ between groups. Regression analyses showed relationships between global as well as local network parameters with neurocognitive functioning (i.e., working memory, memory encoding; R2 = 23.3 - 38.5%) and behavioural functioning (i.e., externalising problems, R2 = 36.1%). Findings indicate the impact of TBI on global functional network organisation, and the relevance of both global and local network organisation for long-term neurocognitive and behavioural outcome after paediatric TBI. The results suggest potential prognostic value of resting-state network organisation for outcome after paediatric TBI.

Resting state networks mediate the association between both cardiovascular fitness and gross motor skills with neurocognitive functioning.

Recent evidence suggests that cardiovascular fitness and gross motor skill performance are related to neurocognitive functioning by influencing brain structure and functioning. This study investigates the role of resting-state networks (RSNs) in the relation of cardiovascular fitness and gross motor skills with neurocognitive functioning in healthy 8- to 11-year-old children (n = 90, 45 girls, 10% migration background). Cardiovascular fitness and gross motor skills were related to brain activity in RSNs. Furthermore, brain activity in RSNs mediated the relation of both cardiovascular fitness (Frontoparietal network and Somatomotor network) and gross motor skills (Somatomotor network) with neurocognitive functioning. The results indicate that brain functioning may contribute to the relation between both cardiovascular fitness and gross motor skills with neurocognitive functioning.

Measurement Feedback System for Intensive Neurorehabilitation after Severe Acquired Brain Injury.

Outcome of acquired brain injury (ABI) and the potential for neurorehabilitation are subject to distinct heterogeneity between patients. Limited knowledge of the complex constellation of determinants at play interferes with the possibility to deploy precision medicine in neurorehabilitation. Measurement Feedback Systems (MFS) structure clinical data collection and deliver the measurement results as feedback to clinicians, thereby facilitating progress monitoring, promoting balanced patient-centered discussion and shared decision making. Accumulation of clinical data in the MFS also enables data-driven precision rehabilitation medicine. This article describes the development and implementation of a MFS for neurorehabilitation after ABI. The MFS consists of specialized measurement tracks which are developed together with representatives of each discipline in the multidisciplinary team. The MFS is built into a digital platform that automatically distributes measurements among clinicians, at predetermined time points during the inpatient treatment, outpatient treatment and follow-up. The results of all measurements are visualized in individual patient dashboards that are accessible for all clinicians involved in treatment. Since step-wise implementation, 124 patients have been registered on the MFS platform so far, providing an average of more than 200 new measurements per week. Currently, more than 15,000 clinical measurements are captured in the MFS. The current overall completion rate of measurements is 86,4%. This study shows that structured clinical assessment and feedback is feasible in the context of neurorehabilitation after severe ABI. The future directions are discussed for MFS data in our Health Intelligence Program, which aims at periodic care evaluation and the transition of neurorehabilitation care towards precision medicine.

Heading Exposure in Elite Football (Soccer): A Study in Adolescent, Young Adult, and Adult Male and Female Players.

PURPOSE: This study aims to quantify heading exposure in real-life elite football at the level of individual male and female adolescents, young adults, and adults. METHODS: Heading exposure was determined by video analysis in combination with a structured electronic registration tool and observation training, to comprehensively register heading characteristics. Characteristics of heading events were registered in 116 official matches (96 male, 20 female) of Dutch national teams. RESULTS: Mean exposure for male players based on full match participation was 4.2 headers, with maximum heading exposure at 10.6 headers. Mean heading exposure was higher in adult than adolescent players ( P = 0.049), whereas maximum heading exposure was higher for adult than for young adult players ( P = 0.045). Maximum heading exposure was higher in male than in female players ( P = 0.015). Defenders had the greatest mean and maximum heading exposure ( P < 0.001). Longer flight courses of the ball had greater contribution to mean and maximum heading exposure than shorter courses ( P < 0.01). Frontal headers had greater contribution to exposure than other points of contact on player's head ( P < 0.001), whereas linear headers had greater contribution than rotational headers ( P = 0.016). Defensive headers had greater contribution to exposure than other heading types ( P < 0.014). Unintentional head contacts in elite football players were, in most cases (80%), not related to heading situations. CONCLUSIONS: This study provides real-life quantifications of mean and maximum heading exposure in elite football, with strong relevance for policy makers and researchers. The results highlight the roles of player and heading characteristics in heading exposure, informing current discussions on the role of heading in football.

Effects of aerobic versus cognitively demanding exercise interventions on brain structure and function in healthy children-Results from a cluster randomized controlled trial.

The beneficial effects of physical activity on neurocognitive functioning in children are considered to be facilitated by physical activity-induced changes in brain structure and functioning. In this study, we examined the effects of two 14-week school-based exercise interventions in healthy children on white matter microstructure and brain activity in resting-state networks (RSNs) and whether changes in white matter microstructure and RSN activity mediate the effects of the exercise interventions on neurocognitive functioning. A total of 93 children were included in this study (51% girls, mean age 9.13 years). The exercise interventions consisted of four physical education lessons per week, focusing on either aerobic or cognitively demanding exercise and were compared with a control group that followed their regular physical education program of two lessons per week. White matter microstructure was assessed using diffusion tensor imaging in combination with tract-based spatial statistics. Independent component analysis was performed on resting-state data to identify RSNs. Furthermore, neurocognitive functioning (information processing and attention, working memory, motor response inhibition, interference control) was assessed by a set of computerized tasks. Results indicated no Group × Time effects on white matter microstructure or RSN activity, indicating no effects of the exercise interventions on these aspects of brain structure and function. Likewise, no Group × Time effects were found for neurocognitive performance. This study indicated that 14-week school-based interventions regarding neither aerobic exercise nor cognitive-demanding exercise interventions influence brain structure and brain function in healthy children. This study was registered in the Netherlands Trial Register (NTR5341).

Structural brain abnormalities in children and young adults with severe chronic kidney disease.

BACKGROUND: The pathophysiology of neurological dysfunction in severe chronic kidney disease (CKD) in children and young adults is largely unknown. We aimed to investigate brain volumes and white matter integrity in this population and explore brain structure under different treatment modalities. METHODS: This cross-sectional study includes 24 patients with severe CKD (eGFR < 30) aged 8-30 years (median = 18.5, range = 9.1-30.5) on different therapy modalities (pre-dialysis, n = 7; dialysis, n = 7; transplanted, n = 10) and 21 healthy controls matched for age, sex, and parental educational level. Neuroimaging targeted brain volume using volumetric analysis on T1 scans and white matter integrity with tract-based spatial statistics and voxel-wise regression on diffusion tensor imaging (DTI) data. RESULTS: CKD patients had lower white matter integrity in a widespread cluster of primarily distal white matter tracts compared to healthy controls. Furthermore, CKD patients had smaller volume of the nucleus accumbens relative to healthy controls, while no evidence was found for abnormal volumes of gray and white matter or other subcortical structures. Longer time since successful transplantation was related to lower white matter integrity. Exploratory analyses comparing treatment subgroups suggest lower white matter integrity and smaller volume of the nucleus accumbens in dialysis and transplanted patients relative to healthy controls. CONCLUSIONS: Young CKD patients seem at risk for widespread disruption of white matter integrity and to some extent smaller subcortical volume (i.e., nucleus accumbens). Especially patients on dialysis therapy and patients who received a kidney transplant may be at risk for disruption of white matter integrity and smaller volume of the nucleus accumbens.

Exploring the neurocognome: Neurocognitive network organization in healthy young adults.

Conventional neurocognitive assessment does not account for the complex interplay between neurocognitive functions that gives rise to (goal-directed) behavior. This study aims to explore the value of the application of network analysis to individual neurocognitive data, in order to investigate neurocognitive network organization (i.e., the neurocognome). Participants were healthy young adults (N = 51, average age: 26 years [range: 18-34], 49% female) that underwent a single comprehensive neurocognitive assessment. To allow implementation of network analysis, we developed a new measure of connectivity between neurocognitive functions that can be calculated on a single neurocognitive assessment. Connectivity values between all possible pairs of neurocognitive functions were used to reconstruct individual neurocognitive networks. Graph theory was applied to extract measures of global and local network organization from neurocognitive networks at the individual level. The results confirmed the expectation that neurocognitive connectivity values should be higher for connections between neurocognitive functions that are more closely related (i.e., within neurocognitive domains) than for connections between neurocognitive functions that are less closely related (i.e., across neurocognitive domains). The results further showed that reconstruction of the neurocognitive network at the individual level has considerable agreement with a group-based approach, providing preliminary evidence for the validity of our approach. The reconstructed neurocognitive network also showed considerable consistency among (randomly selected) independent subgroups, supporting the stability of our approach. Lastly, neurocognitive network parameters were related to intelligence and behavior problems, reflecting relevance of neurocognitive network organization for other important domains of functioning. Moreover, local network parameters (i.e., the relative importance of neurocognitive functions in the network) may have stronger relevance for behavioral functioning than conventional measures of neurocognitive functioning (i.e., z-scores reflecting performance on individual neurocognitive tests). Taken together, this study indicates that analysis of individual neurocognitive network organization has potential value for neurocognitive assessment in research and clinical practice.

Neurodevelopmental outcome of patients with congenital gastrointestinal malformations: a systematic review and meta-analysis.

AIM: Children with congenital gastrointestinal malformations may be at risk of neurodevelopmental impairment due to challenges to the developing brain, including perioperative haemodynamic changes, exposure to anaesthetics and postoperative inflammatory influences. This study aggregates existing evidence on neurodevelopmental outcome in these patients using meta-analysis. METHOD: PubMed, Embase and Web of Science were searched for peer-reviewed articles published until October 2019. Out of the 5316 unique articles that were identified, 47 studies met the inclusion criteria and were included. Standardised mean differences (Cohen's d) between cognitive, motor and language outcome of patients with congenital gastrointestinal malformations and normative data (39 studies) or the studies' control group (8 studies) were aggregated across studies using random-effects meta-analysis. The value of (clinical) moderators was studied using meta-regression and diagnostic subgroups were compared. RESULTS: The 47 included studies encompassed 62 cohorts, representing 2312 patients. Children with congenital gastrointestinal malformations had small-sized cognitive impairment (d=-0.435, p<0.001; 95% CI -0.567 to -0.302), medium-sized motor impairment (d=-0.610, p<0.001; 95% CI -0.769 to -0.451) and medium-sized language impairment (d=-0.670, p<0.001; 95% CI -0.914 to -0.425). Patients with short bowel syndrome had worse motor outcome. Neurodevelopmental outcome was related to the number of surgeries and length of total hospital stay, while no relations were observed with gestational age, birth weight, age and sex. INTERPRETATION: This study shows that children with congenital gastrointestinal malformations exhibit impairments in neurodevelopmental outcome, highlighting the need for routine screening of neurodevelopment during follow-up.

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes. METHODS: Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline. RESULTS: Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between d=-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027). CONCLUSIONS: WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically-meaningful patient subtypes.