A somato-cognitive action network alternates with effector regions in motor cortex.

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Functional parcellation of the neonatal cortical surface.

The cerebral cortex is organized into distinct but interconnected cortical areas, which can be defined by abrupt differences in patterns of resting state functional connectivity (FC) across the cortical surface. Such parcellations of the cortex have been derived in adults and older infants, but there is no widely used surface parcellation available for the neonatal brain. Here, we first demonstrate that existing parcellations, including surface-based parcels derived from older samples as well as volume-based neonatal parcels, are a poor fit for neonatal surface data. We next derive a set of 283 cortical surface parcels from a sample of n = 261 neonates. These parcels have highly homogenous FC patterns and are validated using three external neonatal datasets. The Infomap algorithm is used to assign functional network identities to each parcel, and derived networks are consistent with prior work in neonates. The proposed parcellation may represent neonatal cortical areas and provides a powerful tool for neonatal neuroimaging studies.

Prenatal exposure to maternal social disadvantage and psychosocial stress and neonatal white matter connectivity at birth.

Early life adversity (social disadvantage and psychosocial stressors) is associated with altered microstructure in fronto-limbic pathways important for socioemotional development. Understanding when these associations begin to emerge may inform the timing and design of preventative interventions. In this longitudinal study, 399 mothers were oversampled for low income and completed social background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent factors: social disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, and nutrition) and psychosocial stress (depression, stress, life events, and racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social disadvantage and psychosocial stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social disadvantage, but not psychosocial stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical morbidities and prenatal drug exposure. In moderation analysis, psychosocial stress was associated with lower MD in the left inferior CB among the lower-to-higher socioeconomic status (SES) (INR ≥ 200%) group, but not the extremely low SES (INR < 200%) group. Increasing access to social welfare programs that reduce the burden of social disadvantage and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways.

Mapping brain function in adults and young children during naturalistic viewing with high-density diffuse optical tomography.

Human studies of early brain development have been limited by extant neuroimaging methods. MRI scanners present logistical challenges for imaging young children, while alternative modalities like functional near-infrared spectroscopy have traditionally been limited by image quality due to sparse sampling. In addition, conventional tasks for brain mapping elicit low task engagement, high head motion, and considerable participant attrition in pediatric populations. As a result, typical and atypical developmental trajectories of processes such as language acquisition remain understudied during sensitive periods over the first years of life. We evaluate high-density diffuse optical tomography (HD-DOT) imaging combined with movie stimuli for high resolution optical neuroimaging in awake children ranging from 1 to 7 years of age. We built an HD-DOT system with design features geared towards enhancing both image quality and child comfort. Furthermore, we characterized a library of animated movie clips as a stimulus set for brain mapping and we optimized associated data analysis pipelines. Together, these tools could map cortical responses to movies and contained features such as speech in both adults and awake young children. This study lays the groundwork for future research to investigate response variability in larger pediatric samples and atypical trajectories of early brain development in clinical populations.

Sleep and circadian rhythms during pregnancy, social disadvantage, and alterations in brain development in neonates.

Pregnant women in poverty may be especially likely to experience sleep and circadian rhythm disturbances, which may have downstream effects on fetal neurodevelopment. However, the associations between sleep and circadian rhythm disturbances, social disadvantage during pregnancy, and neonatal brain structure remains poorly understood. The current study explored the association between maternal sleep and circadian rhythm disturbances during pregnancy and neonatal brain outcomes, examining sleep and circadian rhythm disturbances as a mediator of the effect of social disadvantage during pregnancy on infant structural brain outcomes. The study included 148 mother-infant dyads, recruited during early pregnancy, who had both actigraphy and neuroimaging data. Mothers' sleep was assessed throughout their pregnancy using actigraphy, and neonates underwent brain magnetic resonance imaging in the first weeks of life. Neonatal structural brain outcomes included cortical gray matter, subcortical gray matter, and white matter volumes along with a measure of the total surface area of the cortex. Neonates of mothers who experienced greater inter-daily deviations in sleep duration had smaller total cortical gray and white matter volumes and reduced cortical surface areas. Neonates of mothers who had higher levels of circadian misalignment and later sleep timing during pregnancy showed smaller subcortical gray matter volumes. Inter-daily deviations in sleep duration during pregnancy mediated the association between maternal social disadvantage and neonatal structural brain outcomes. Findings highlight the importance of regularity and rhythmicity in sleep schedules during pregnancy and bring to light the role of chronodisruption as a potential mechanism underlying the deleterious neurodevelopmental effects of prenatal adversity. RESEARCH HIGHLIGHTS: Social disadvantage was associated with sleep and circadian rhythm disturbances during pregnancy, including later sleep schedules, increased variability in sleep duration, circadian misalignment, and a higher proportion of the sleep period spent awake. Maternal sleep and circadian rhythm disturbances during pregnancy were associated with decreased brain volume and reduced cortical surface area in neonates. Maternal inter-daily deviations in sleep duration during pregnancy mediated the association between social disadvantage and neonatal brain volume and cortical surface area.

Network-specific selectivity of functional connections in the neonatal brain.

The adult human brain is organized into functional brain networks, groups of functionally connected segregated brain regions. A key feature of adult functional networks is long-range selectivity, the property that spatially distant regions from the same network have higher functional connectivity than spatially distant regions from different networks. Although it is critical to establish the status of functional networks and long-range selectivity during the neonatal period as a foundation for typical and atypical brain development, prior work in this area has been mixed. Although some studies report distributed adult-like networks, other studies suggest that neonatal networks are immature and consist primarily of spatially isolated regions. Using a large sample of neonates (n = 262), we demonstrate that neonates have long-range selective functional connections for the default mode, fronto-parietal, and dorsal attention networks. An adult-like pattern of functional brain networks is evident in neonates when network-detection algorithms are tuned to these long-range connections, when using surface-based registration (versus volume-based registration), and as per-subject data quantity increases. These results help clarify factors that have led to prior mixed results, establish that key adult-like functional network features are evident in neonates, and provide a foundation for studies of typical and atypical brain development.

Maturation of large-scale brain systems over the first month of life.

The period immediately after birth is a critical developmental window, capturing rapid maturation of brain structure and a child's earliest experiences. Large-scale brain systems are present at delivery, but how these brain systems mature during this narrow window (i.e. first weeks of life) marked by heightened neuroplasticity remains uncharted. Using multivariate pattern classification techniques and functional connectivity magnetic resonance imaging, we detected robust differences in brain systems related to age in newborns (n = 262; R2 = 0.51). Development over the first month of life occurred brain-wide, but differed and was more pronounced in brain systems previously characterized as developing early (i.e. sensorimotor networks) than in those characterized as developing late (i.e. association networks). The cingulo-opercular network was the only exception to this organizing principle, illuminating its early role in brain development. This study represents a step towards a normative brain "growth curve" that could be used to identify atypical brain maturation in infancy.

Socioeconomic disadvantage and parental mood/affective problems links negative parenting and executive dysfunction in children born very preterm.

Poverty increases the risk of poorer executive function (EF) in children born full-term (FT). Stressors associated with poverty, including variability in parenting behavior, may explain links between poverty and poorer EF, but this remains unclear for children born very preterm (VPT). We examine socioeconomic and parental psychosocial adversity on parenting behavior, and whether these factors independently or jointly influence EF in children born VPT. At age five years, 154 children (VPT = 88, FT = 66) completed parent-child interaction and EF tasks. Parental sensitivity, intrusiveness, cognitive stimulation, and positive and negative regard were coded with the Parent-Child Interaction Rating Scale. Socioeconomic adversity spanned maternal demographic stressors, Income-to-Needs ratio, and Area Deprivation Index. Parents completed measures of depression, anxiety, inattention/hyperactivity, parenting stress, and social-communication interaction (SCI) problems. Parental SCI problems were associated with parenting behavior in parents of children born VPT, whereas socioeconomic adversity was significant in parents of FT children. Negative parenting behaviors, but not positive parenting behaviors, were related to child EF. This association was explained by parental depression/anxiety symptoms and socioeconomic adversity. Results persisted after adjustment for parent and child IQ. Findings may inform research on dyadic interventions that embed treatment for parental mood/affective symptoms and SCI problems to improve childhood EF.

Predictive Utility of Irritability "In Context": Proof-of-Principle for an Early Childhood Mental Health Risk Calculator.

OBJECTIVE: We provide proof-of-principle for a mental health risk calculator advancing clinical utility of the irritability construct for identification of young children at high risk for common, early onsetting syndromes. METHOD: Data were harmonized from two longitudinal early childhood subsamples (total N = 403; 50.1% Male; 66.7% Nonwhite; Mage = 4.3 years). The independent subsamples were clinically enriched via disruptive behavior and violence (Subsample 1) and depression (Subsample 2). In longitudinal models, epidemiologic risk prediction methods for risk calculators were applied to test the utility of the transdiagnostic indicator, early childhood irritability, in the context of other developmental and social-ecological indicators to predict risk of internalizing/externalizing disorders at preadolescence (Mage = 9.9 years). Predictors were retained when they improved model discrimination (area under the receiver operating characteristic curve [AUC] and integrated discrimination index [IDI]) beyond the base demographic model. RESULTS: Compared to the base model, the addition of early childhood irritability and adverse childhood experiences significantly improved the AUC (0.765) and IDI slope (0.192). Overall, 23% of preschoolers went on to develop a preadolescent internalizing/externalizing disorder. For preschoolers with both elevated irritability and adverse childhood experiences, the likelihood of an internalizing/externalizing disorder was 39-66%. CONCLUSIONS: Predictive analytic tools enable personalized prediction of psychopathological risk for irritable young children, holding transformative potential for clinical translation.

Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry.

The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala-cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.

Associations Between Preterm Birth, Inhibitory Control-Implicated Brain Regions and Tracts, and Inhibitory Control Task Performance in Children: Consideration of Socioeconomic Context.

Preterm birth (PTB) is associated with increased risk for unfavorable outcomes such as deficits in attentional control and related brain structure alterations. Crucially, PTB is more likely to occur within the context of poverty. The current study examined associations between PTB and inhibitory control (IC) implicated brain regions/tracts and task performance, as well as the moderating role of early life poverty on the relation between PTB and IC-implicated regions/tracts/task performance. 2,899 children from the ABCD study were sampled for this study. Mixed effects models examined the relation between PTB and subsequent IC performance as well as prefrontal gray matter volume, white matter fractional anisotropy (FA), and mean diffusivity (MD). Household income was examined as a moderator. PTB was significantly associated with less improvement in IC task performance over time and decreased FA in left uncinate fasciculus (UF) and cingulum bundle (CB). Early life poverty moderated the relation between PTB and both CB FA and UF MD.

Synthesizing pseudo-T2w images to recapture missing data in neonatal neuroimaging with applications in rs-fMRI.

T1- and T2-weighted (T1w and T2w) images are essential for tissue classification and anatomical localization in Magnetic Resonance Imaging (MRI) analyses. However, these anatomical data can be challenging to acquire in non-sedated neonatal cohorts, which are prone to high amplitude movement and display lower tissue contrast than adults. As a result, one of these modalities may be missing or of such poor quality that they cannot be used for accurate image processing, resulting in subject loss. While recent literature attempts to overcome these issues in adult populations using synthetic imaging approaches, evaluation of the efficacy of these methods in pediatric populations and the impact of these techniques in conventional MR analyses has not been performed. In this work, we present two novel methods to generate pseudo-T2w images: the first is based in deep learning and expands upon previous models to 3D imaging without the requirement of paired data, the second is based in nonlinear multi-atlas registration providing a computationally lightweight alternative. We demonstrate the anatomical accuracy of pseudo-T2w images and their efficacy in existing MR processing pipelines in two independent neonatal cohorts. Critically, we show that implementing these pseudo-T2w methods in resting-state functional MRI analyses produces virtually identical functional connectivity results when compared to those resulting from T2w images, confirming their utility in infant MRI studies for salvaging otherwise lost subject data.

Filtering respiratory motion artifact from resting state fMRI data in infant and toddler populations.

The importance of motion correction when processing resting state functional magnetic resonance imaging (rs-fMRI) data is well-established in adult cohorts. This includes adjustments based on self-limited, large amplitude subject head motion, as well as factitious rhythmic motion induced by respiration. In adults, such respiration artifact can be effectively removed by applying a notch filter to the motion trace, resulting in higher amounts of data retained after frame censoring (e.g., "scrubbing") and more reliable correlation values. Due to the unique physiological and behavioral characteristics of infants and toddlers, rs-fMRI processing pipelines, including methods to identify and remove colored noise due to subject motion, must be appropriately modified to accurately reflect true neuronal signal. These younger cohorts are characterized by higher respiration rates and lower-amplitude head movements than adults; thus, the presence and significance of comparable respiratory artifact and the subsequent necessity of applying similar techniques remain unknown. Herein, we identify and characterize the consistent presence of respiratory artifact in rs-fMRI data collected during natural sleep in infants and toddlers across two independent cohorts (aged 8-24 months) analyzed using different pipelines. We further demonstrate how removing this artifact using an age-specific notch filter allows for both improved data quality and data retention in measured results. Importantly, this work reveals the critical need to identify and address respiratory-driven head motion in fMRI data acquired in young populations through the use of age-specific motion filters as a mechanism to optimize the accuracy of measured results in this population.

Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.

Biallelic pathogenic variants in the nuclear gene DARS2 (MIM# 610956), encoding the mitochondrial enzyme aspartyl-tRNA synthetase (MT-ASPRS) cause leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL) (MIM# 611105), a neurometabolic disorder characterized by progressive ataxia, spasticity, developmental arrest or regression and characteristic brain MRI findings. Most patients exhibit a slowly progressive disease course with motor deterirartion that begins in childhood or adolescence, but can also occasionaly occur in adulthood. More severe LBSL presentations with atypical brain MRI findings have been recently described. Baker's yeast orthologue of DARS2, MSD1, is required for growth on oxidative carbon sources. A yeast with MSD1 knockout (msd1Δ) demonstrated a complete lack of oxidative growth which could be rescued by wild-type MSD1 but not MSD1 with pathogenic variants. Here we reported two siblings who exhibited developmental regression and ataxia with different age of onset and phenotypic severity. Exome sequencing revealed 2 compound heterozygous missense variants in DARS2: c.473A>T (p.Glu158Val) and c.829G>A (p.Glu277Lys); this variant combination has not been previously reported. The msd1Δ yeast transformed with plasmids expressing p.Glu259Lys, equivalent to human p.Glu277Lys, showed complete loss of oxidative growth and oxygen consumption, while the strain carrying p.Gln137Val, equivalent to human p.Glu158Val, showed a significant reduction of oxidative growth, but a residual ability to grow was retained. Structural analysis indicated that p.Glu158Val may interfere with protein binding of tRNAAsp, while p.Glu277Lys may impact both homodimerization and catalysis of MT-ASPRS. Our data illustrate the utility of yeast model and in silico analysis to determine pathogenicity of DARS2 variants, expand the genotypic spectrum and suggest intrafamilial variability in LBSL.

Neonatal Intensive Care Unit Network Neurobehavioral Scale Profiles in Full-Term Infants: Associations with Maternal Adversity, Medical Risk, and Neonatal Outcomes.

OBJECTIVES: To examine healthy, full-term neonatal behavior using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) in relation to measures of maternal adversity, maternal medical risk, and infant brain volumes. STUDY DESIGN: This was a prospective, longitudinal, observational cohort study of pregnant mothers followed from the first trimester and their healthy, full-term infants. Infants underwent an NNNS assessment and high-quality magnetic resonance imaging 2-5 weeks after birth. A latent profile analysis of NNNS scores categorized infants into neurobehavioral profiles. Univariate and multivariate analyses compared differences in maternal factors (social advantage, psychosocial stress, and medical risk) and neonatal characteristics between profiles. RESULTS: The latent profile analysis of NNNS summary scales of 296 infants generated 3 profiles: regulated (46.6%), hypotonic (16.6%), and fussy (36.8%). Infants with a hypotonic profile were more likely to be male (χ2 = 8.601; P = .014). Fussy infants had smaller head circumferences (F = 3.871; P = .022) and smaller total brain (F = 3.522; P = .031) and cerebral white matter (F = 3.986; P = .020) volumes compared with infants with a hypotonic profile. There were no differences between profiles in prenatal maternal health, social advantage, or psychosocial stress. CONCLUSIONS: Three distinct neurobehavioral profiles were identified in healthy, full-term infants with hypotonic and fussy neurobehavioral features related to neonatal brain volumes and head circumference, but not prenatal exposure to socioeconomic or psychosocial adversity. Follow-up beyond the neonatal period will determine if identified profiles at birth are associated with subsequent clinical or developmental outcomes.

Geotemporal analysis of perinatal care changes and maternal mental health: an example from the COVID-19 pandemic.

Our primary objective was to document COVID-19 induced changes to perinatal care across the USA and examine the implication of these changes for maternal mental health. We performed an observational cross-sectional study with convenience sampling using direct patient reports from 1918 postpartum and 3868 pregnant individuals collected between April 2020 and December 2020 from 10 states across the USA. We leverage a subgroup of these participants who gave birth prior to March 2020 to estimate the pre-pandemic prevalence of specific birthing practices as a comparison. Our primary analyses describe the prevalence and timing of perinatal care changes, compare perinatal care changes depending on when and where individuals gave birth, and assess the linkage between perinatal care alterations and maternal anxiety and depressive symptoms. Seventy-eight percent of pregnant participants and 63% of postpartum participants reported at least one change to their perinatal care between March and August 2020. However, the prevalence and nature of specific perinatal care changes occurred unevenly over time and across geographic locations. The separation of infants and mothers immediately after birth and the cancelation of prenatal visits were associated with worsened depression and anxiety symptoms in mothers after controlling for sociodemographic factors, mental health history, number of pregnancy complications, and general stress about the COVID-19 pandemic. Our analyses reveal widespread changes to perinatal care across the US that fluctuated depending on where and when individuals gave birth. Disruptions to perinatal care may also exacerbate mental health concerns, so focused treatments that can mitigate the negative psychiatric sequelae of interrupted care are warranted.

Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease.

OBJECTIVE: Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. METHODS: We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. RESULTS: We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = -0.760 [95% CI = -1.297, -0.224]), default mode (p = 0.012, parameter estimate = -0.417 [95% CI = -0.731, -0.104]), and cingulo-opercular (p = 0.009, parameter estimate = -0.883 [95% CI = -1.517, -0.250]) networks decreased. INTERPRETATION: We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020;88:995-1008.

Surgery requiring general anesthesia in preterm infants is associated with altered brain volumes at term equivalent age and neurodevelopmental impairment.

BACKGROUND: The aim of the study was to describe and contrast the brain development and outcome among very preterm infants that were and were not exposed to surgery requiring general anesthesia prior to term equivalent age (TEA). METHODS: Preterm infants born ≤30 weeks' gestation who did (n = 25) and did not (n = 59) have surgery requiring general anesthesia during the preterm period were studied. At TEA, infants had MRI scans performed with measures of brain tissue volumes, cortical surface area, Gyrification Index, and white matter microstructure. Neurodevelopmental follow-up with the Bayley Scales of Infant and Toddler Development, Third Edition was undertaken at 2 years of corrected age. Multivariate models, adjusted for clinical and social risk factors, were used to compare the groups. RESULTS: After controlling for clinical and social variables, preterm infants exposed to surgical anesthesia demonstrated decreased relative white matter volumes at TEA and lower cognitive and motor composite scores at 2-year follow-up. Those with longer surgical exposure demonstrated the greatest decrease in white matter volumes and lower cognitive and motor outcomes at age 2 years. CONCLUSIONS: Very preterm infants who required surgery during the preterm period had lower white mater volumes at TEA and worse neurodevelopmental outcome at age 2 years. IMPACT: In very preterm infants, there is an association between surgery requiring general anesthesia during the preterm period and reduced white mater volume on MRI at TEA and lower cognitive and motor composite scores at age 2 years. It is known that the very preterm infant's brain undergoes rapid growth during the period corresponding to the third trimester. The current study suggests an association between surgery requiring general anesthesia during this period and worse outcomes.

Training in neonatal neurocritical care: a proposal for a hybrid model of competence by design and time-based methods.

BACKGROUND: Neonatal neurocritical care (NNCC) is a rapidly advancing field with limited fellowship training available in locally developed, non-accredited programs. A standardized survey aimed to understand the training backgrounds of individuals practicing NNCC, the structure of existing clinical NNCC services/training programs, and suggested clinical competencies for new graduates. METHODS: We developed an anonymous survey electronically sent to members of societies related to NNCC. Using the survey results as a guide, we discuss a competence by design (CBD) curriculum as a complementary approach to traditional time-based training. RESULTS: There were 82 responses to the survey from 30 countries; 95% of respondents were physicians. Thirty-one (42%) institutions reported having an NNCC service, 24 (29%) individuals reported formal NNCC training, 81% reported "significant variability" across NNCC training programs, and 88% were both in favor of standardizing training programs and pursuing formal accreditation for NNCC in the next 5 years. CONCLUSIONS: The survey results demonstrate international interest in standardizing NNCC training and development of an accreditation or certification process. We propose consideration of a CBD-type curriculum as a training approach to focus on the development of specific NNCC competencies, rather than assuming the acquisition of these competencies based on time as a surrogate. IMPACT: Continued growth and development in the field of NNCC has led to increasing need for training programs suited to meet the diverse needs of trainees from varied backgrounds. We present the results of an international survey that assessed the structure of existing training programs and the priority areas in which graduates must demonstrate competence, highlighting the combination of CBD and time-based training as one approach to address these recommendations. The survey results support interest in translating published training competencies, existing expertise, and infrastructure across centers into a standardized curriculum for NNCC including certification opportunities.