Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial.

OBJECTIVE: To examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE). DESIGN: Double-blind pilot randomised controlled trial. SETTING: Eight neonatal units in South Asia. PATIENTS: Neonates (≥36 weeks) with moderate or severe HIE admitted between 31 December 2022 and 3 May 2023. INTERVENTIONS: Erythropoietin (500 U/kg daily) or to the placebo (sham injections using a screen) within 6 hours of birth and continued for 9 days. MRI at 2 weeks of age. MAIN OUTCOMES AND MEASURES: Feasibility of randomisation, drug administration and assessment of brain injury using MRI. RESULTS: Of the 154 neonates screened, 56 were eligible; 6 declined consent and 50 were recruited; 43 (86%) were inborn. Mean (SD) age at first dose was 4.4 (1.2) hours in erythropoietin and 4.1 (1.0) hours in placebo. Overall mortality at hospital discharge occurred in 5 (19%) vs 11 (46%) (p=0.06), and 3 (13%) vs 9 (40.9%) (p=0.04) among those with moderate encephalopathy in the erythropoietin and placebo groups. Moderate or severe injury to basal ganglia, white matter and cortex occurred in 5 (25%) vs 5 (38.5%); 14 (70%) vs 11 (85%); and 6 (30%) vs 2 (15.4%) in the erythropoietin and placebo group, respectively. Sinus venous thrombosis was seen in two (10%) neonates in the erythropoietin group and none in the control group. CONCLUSIONS: Brain injury and mortality after moderate or severe HIE are high in South Asia. Evaluation of erythropoietin monotherapy using MRI to examine treatment effects is feasible in these settings. TRIAL REGISTRATION NUMBER: NCT05395195.

Interictal EEG source connectivity to localize the epileptogenic zone in patients with drug-resistant epilepsy: A machine learning approach.

OBJECTIVE: To deconstruct the epileptogenic networks of patients with drug-resistant epilepsy (DRE) using source functional connectivity (FC) analysis; unveil the FC biomarkers of the epileptogenic zone (EZ); and develop machine learning (ML) models to estimate the EZ using brief interictal electroencephalography (EEG) data. METHODS: We analyzed scalp EEG from 50 patients with DRE who had surgery. We reconstructed the activity (electrical source imaging [ESI]) of virtual sensors (VSs) across the whole cortex and computed FC separately for epileptiform and non-epileptiform EEG epochs (with or without spikes). In patients with good outcome (Engel 1a), four cortical regions were defined: EZ (resection) and three non-epileptogenic zones (NEZs) in the same and opposite hemispheres. Region-specific FC features in six frequency bands and three spatial ranges (long, short, inner) were compared between regions (Wilcoxon sign-rank). We developed ML classifiers to identify the VSs in the EZ using VS-specific FC features. Cross-validation was performed using good outcome data. Performance was compared with poor outcomes and interictal spike localization. RESULTS: FC differed between EZ and NEZs (p < .05) during non-epileptiform and epileptiform epochs, showing higher FC in the EZ than its homotopic contralateral NEZ. During epileptiform epochs, the NEZ in the epileptogenic hemisphere showed higher FC than its contralateral NEZ. In good outcome patients, the ML classifiers reached 75% accuracy to the resection (91% sensitivity; 74% specificity; distance from EZ: 38 mm) using epileptiform epochs (gamma and beta frequency bands) and 62% accuracy using broadband non-epileptiform epochs, both outperforming spike localization (accuracy = 47%; p < .05; distance from EZ: 57 mm). Lower performance was seen in poor outcomes. SIGNIFICANCE: We present an FC approach to extract EZ biomarkers from brief EEG data. Increased FC in various frequencies characterized the EZ during epileptiform and non-epileptiform epochs. FC-based ML models identified the resection better in good than poor outcome patients, demonstrating their potential for presurgical use in pediatric DRE.

Linking maternal disrupted interaction and infant limbic volumes: The role of infant cortisol output.

Despite a large animal literature documenting the role of low maternal nurturance and elevated glucocorticoid production on offspring limbic development, these pathways have not yet been assessed during human infancy. Informed by animal models, the present study examined whether 1) maternal disrupted interaction is related to infant cortisol levels, 2) infant cortisol levels are associated with infant limbic volumes, and 3) infant cortisol levels mediate associations between maternal disrupted interaction and infant limbic volumes. Participants included 57 mother-infant dyads. Infant saliva was measured at one time point before and two time points after the Still-Face Paradigm (SFP) at age 4 months. Five aspects of maternal disrupted interaction were coded during the SFP reunion episode. Between 4 and 25 months (M age = 11.74 months, SD = 6.12), under natural sleep, infants completed an MRI. Amygdala and hippocampal volumes were calculated via automated segmentation. Results indicated that 1) maternal disrupted interaction, and specifically disoriented interaction, with the infant was associated with higher infant salivary cortisol (AUCg) levels during the SFP, 2) higher infant AUCg was related to enlarged bilateral amygdala and hippocampal volumes, and 3) infant AUCg mediated the relation between maternal disrupted interaction and infant amygdala and hippocampal volumes. Findings are consistent with controlled animal studies and provide evidence of a link between increased cortisol levels and enlarged limbic volumes in human infants. Results further suggest that established interventions to decrease maternal disrupted interaction could impact both infant cortisol levels and infant limbic volumes.

Maternal Childhood Abuse Versus Neglect Associated with Differential Patterns of Infant Brain Development.

Severity of maternal childhood maltreatment has been associated with lower infant grey matter volume and amygdala volume during the first two years of life. A developing literature argues that effects of threat (abuse) and of deprivation (neglect) should be assessed separately because these distinct aspects of adversity may have different impacts on developmental outcomes. However, distinct effects of threat versus deprivation have not been assessed in relation to intergenerational effects of child maltreatment. The objective of this study was to separately assess the links of maternal childhood abuse and neglect with infant grey matter volume (GMV), white matter volume (WMV), amygdala and hippocampal volume. Participants included 57 mother-infant dyads. Mothers were assessed for childhood abuse and neglect using the Adverse Childhood Experiences (ACE) questionnaire in a sample enriched for childhood maltreatment. Between 4 and 24 months (M age = 12.28 months, SD = 5.99), under natural sleep, infants completed an MRI using a 3.0 T Siemens scanner. GMV, WMV, amygdala and hippocampal volumes were extracted via automated segmentation. Maternal history of neglect, but not abuse, was associated with lower infant GMV. Maternal history of abuse, but not neglect, interacted with age such that abuse was associated with smaller infant amygdala volume at older ages. Results are consistent with a threat versus deprivation framework, in which threat impacts limbic regions central to the stress response, whereas deprivation impacts areas more central to cognitive function. Further studies are needed to identify mechanisms contributing to these differential intergenerational associations of threat versus deprivation.

Comprehensive quantitative analyses of fetal magnetic resonance imaging in isolated cerebral ventriculomegaly.

Isolated cerebral ventriculomegaly (IVM) is the most common prenatally diagnosed brain anomaly occurs in 0.2-1 % of pregnancies. However, knowledge of fetal brain development in IVM is limited. There is no prenatal predictor for IVM to estimate individual risk of neurodevelopmental disability occurs in 10 % of children. To characterize brain development in fetuses with IVM and delineate their individual neuroanatomical variances, we performed comprehensive post-acquisition quantitative analysis of fetal magnetic resonance imaging (MRI). In volumetric analysis, brain MRI of fetuses with IVM (n = 20, 27.0 ± 4.6 weeks of gestation, mean ± SD) had revealed significantly increased volume in the whole brain, cortical plate, subcortical parenchyma, and cerebrum compared to the typically developing fetuses (controls, n = 28, 26.3 ± 5.0). In the cerebral sulcal developmental pattern analysis, fetuses with IVM had altered sulcal positional (both hemispheres) development and combined features of sulcal positional, depth, basin area, in both hemispheres compared to the controls. When comparing distribution of similarity index of individual fetuses, IVM group had shifted toward to lower values compared to the control. About 30 % of fetuses with IVM had no overlap with the distribution of control fetuses. This proof-of-concept study shows that quantitative analysis of fetal MRI can detect emerging subtle neuroanatomical abnormalities in fetuses with IVM and their individual variations.

Fetal development of functional thalamocortical and cortico-cortical connectivity.

Measuring and understanding functional fetal brain development in utero is critical for the study of the developmental foundations of our cognitive abilities, possible early detection of disorders, and their prevention. Thalamocortical connections are an intricate component of shaping the cortical layout, but so far, only ex-vivo studies provide evidence of how axons enter the sub-plate and cortex during this highly dynamic phase. Evidence for normal in-utero development of the functional thalamocortical connectome in humans is missing. Here, we modeled fetal functional thalamocortical connectome development using in-utero functional magnetic resonance imaging in fetuses observed from 19th to 40th weeks of gestation (GW). We observed a peak increase of thalamocortical functional connectivity strength between 29th and 31st GW, right before axons establish synapses in the cortex. The cortico-cortical connectivity increases in a similar time window, and exhibits significant functional laterality in temporal-superior, -medial, and -inferior areas. Homologous regions exhibit overall similar mirrored connectivity profiles, but this similarity decreases during gestation giving way to a more diverse cortical interconnectedness. Our results complement the understanding of structural development of the human connectome and may serve as the basis for the investigation of disease and deviations from a normal developmental trajectory of connectivity development.

Regional brain development in fetuses with Dandy-Walker malformation: A volumetric fetal brain magnetic resonance imaging study.

Dandy-Walker malformation (DWM) is a common prenatally diagnosed cerebellar malformation, characterized by cystic dilatation of the fourth ventricle, upward rotation of the hypoplastic vermis, and posterior fossa enlargement with torcular elevation. DWM is associated with a broad spectrum of neurodevelopmental abnormalities such as cognitive, motor, and behavioral impairments, which cannot be explained solely by cerebellar malformations. Notably, the pathogenesis of these symptoms remains poorly understood. This study investigated whether fetal structural developmental abnormalities in DWM extended beyond the posterior fossa to the cerebrum even in fetuses without apparent cerebral anomalies. Post-acquisition volumetric fetal magnetic resonance imaging (MRI) analysis was performed in 12 fetuses with DWM and 14 control fetuses. Growth trajectories of the volumes of the cortical plate, subcortical parenchyma, cerebellar hemispheres, and vermis between 18 and 33 weeks of gestation were compared. The median (interquartile range) gestational ages at the time of MRI were 22.4 (19.4-24.0) and 23.9 (20.6-29.2) weeks in the DWM and control groups, respectively (p = 0.269). Eight of the 12 fetuses with DWM presented with associated cerebral anomalies, including hydrocephalus (n = 3), cerebral ventriculomegaly (n = 3), and complete (n = 2) and partial (n = 2) agenesis of the corpus callosum (ACC); 7 presented with extracerebral abnormalities. Chromosomal abnormalities were detected by microarray analysis in 4 of 11 fetuses with DWM, using amniocentesis. Volumetric analysis revealed that the cortical plate was significantly larger in fetuses with DWM than in controls (p = 0.040). Even without ACC, the subcortical parenchyma, whole cerebrum, cerebellar hemispheres, and whole brain were significantly larger in fetuses with DWM (n = 8) than in controls (p = 0.004, 0.025, 0.033, and 0.026, respectively). In conclusion, volumetric fetal MRI analysis demonstrated that the development of DWM extends throughout the brain during the fetal period, even without apparent cerebral anomalies.

Changes in the Functional Brain Network of Children Undergoing Repeated Epilepsy Surgery: An EEG Source Connectivity Study.

About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy surgery. Since epilepsy is increasingly conceptualized as a network disorder, understanding how brain regions interact may be critical for planning re-operation in these patients. We aimed to estimate functional brain connectivity using scalp EEG and its evolution over time in patients who had repeated surgery (RS-group, n = 9) and patients who had one successful surgery (seizure-free, SF-group, n = 12). We analyzed EEGs without epileptiform activity at varying time points (before and after each surgery). We estimated functional connectivity between cortical regions and their relative centrality within the network. We compared the pre- and post-surgical centrality of all the non-resected (untouched) regions (far or adjacent to resection) for each group (using the Wilcoxon signed rank test). In alpha, theta, and beta frequency bands, the post-surgical centrality of the untouched cortical regions increased in the SF group (p < 0.001) whereas they decreased (p < 0.05) or did not change (p > 0.05) in the RS group after failed surgeries; when re-operation was successful, the post-surgical centrality of far regions increased (p < 0.05). Our data suggest that removal of the epileptogenic focus in children with DRE leads to a gain in the network centrality of the untouched areas. In contrast, unaltered or decreased connectivity is seen when seizures persist after surgery.

Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.

Fetal Pose Estimation in Volumetric MRI using a 3D Convolution Neural Network.

The performance and diagnostic utility of magnetic resonance imaging (MRI) in pregnancy is fundamentally constrained by fetal motion. Motion of the fetus, which is unpredictable and rapid on the scale of conventional imaging times, limits the set of viable acquisition techniques to single-shot imaging with severe compromises in signal-to-noise ratio and diagnostic contrast, and frequently results in unacceptable image quality. Surprisingly little is known about the characteristics of fetal motion during MRI and here we propose and demonstrate methods that exploit a growing repository of MRI observations of the gravid abdomen that are acquired at low spatial resolution but relatively high temporal resolution and over long durations (10-30 minutes). We estimate fetal pose per frame in MRI volumes of the pregnant abdomen via deep learning algorithms that detect key fetal landmarks. Evaluation of the proposed method shows that our framework achieves quantitatively an average error of 4.47 mm and 96.4% accuracy (with error less than 10 mm). Fetal pose estimation in MRI time series yields novel means of quantifying fetal movements in health and disease, and enables the learning of kinematic models that may enhance prospective mitigation of fetal motion artifacts during MRI acquisition.

De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy.

KIF26B is a member of the kinesin superfamily with evolutionarily conserved functions in controlling aspects of embryogenesis, including the development of the nervous system, though its function is incompletely understood. We describe an infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. We performed whole exome sequencing on the trio and identified a de novo KIF26B missense variant, p.Gly546Ser, in the proband. This variant alters a highly conserved amino acid residue that is part of the phosphate-binding loop motif and motor-like domain and is deemed pathogenic by several in silico methods. Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Overall, KIF26B may play a critical role in the brain development and, when mutated, cause pontocerebellar hypoplasia with arthrogryposis.

Heavy Prenatal Alcohol Exposure is Related to Smaller Corpus Callosum in Newborn MRI Scans.

BACKGROUND: Magnetic resonance imaging (MRI) studies have consistently demonstrated disproportionately smaller corpus callosa in individuals with a history of prenatal alcohol exposure (PAE) but have not previously examined the feasibility of detecting this effect in infants. Tissue segmentation of the newborn brain is challenging because analysis techniques developed for the adult brain are not directly transferable, and segmentation for cerebral morphometry is difficult in neonates, due to the latter's incomplete myelination. This study is the first to use volumetric structural MRI to investigate PAE effects in newborns using manual tracing and to examine the cross-sectional area of the corpus callosum (CC). METHODS: Forty-three nonsedated infants born to 32 Cape Coloured heavy drinkers and 11 controls recruited prospectively during pregnancy were scanned using a custom-designed birdcage coil for infants, which increases signal-to-noise ratio almost 2-fold compared to the standard head coil. Alcohol use was ascertained prospectively during pregnancy, and fetal alcohol spectrum disorders diagnosis was conducted by expert dysmorphologists. Data were acquired using a multi-echo FLASH protocol adapted for newborns, and a knowledge-based procedure was used to hand-segment the neonatal brains. RESULTS: CC was disproportionately smaller in alcohol-exposed neonates than controls after controlling for intracranial volume. By contrast, CC area was unrelated to infant sex, gestational age, age at scan, or maternal smoking, marijuana, or methamphetamine use during pregnancy. CONCLUSIONS: Given that midline craniofacial anomalies have been recognized as a hallmark of fetal alcohol syndrome in humans and animal models since this syndrome was first identified, the CC deficit identified here in newborns may support early identification of a range of midline structural impairments. Smaller CC during the newborn period may provide an early indicator of fetal alcohol-related cognitive deficits that have been linked to this critically important brain structure in childhood and adolescence.

BabyMEG: A whole-head pediatric magnetoencephalography system for human brain development research.

We developed a 375-channel, whole-head magnetoencephalography (MEG) system ("BabyMEG") for studying the electrophysiological development of human brain during the first years of life. The helmet accommodates heads up to 95% of 36-month old boys in the USA. The unique two-layer sensor array consists of: (1) 270 magnetometers (10 mm diameter, ∼15 mm coil-to-coil spacing) in the inner layer, (2) thirty-five three-axis magnetometers (20 mm × 20 mm) in the outer layer 4 cm away from the inner layer. Additionally, there are three three-axis reference magnetometers. With the help of a remotely operated position adjustment mechanism, the sensor array can be positioned to provide a uniform short spacing (mean 8.5 mm) between the sensor array and room temperature surface of the dewar. The sensors are connected to superconducting quantum interference devices (SQUIDs) operating at 4.2 K with median sensitivity levels of 7.5 fT/√Hz for the inner and 4 fT/√Hz for the outer layer sensors. SQUID outputs are digitized by a 24-bit acquisition system. A closed-cycle helium recycler provides maintenance-free continuous operation, eliminating the need for helium, with no interruption needed during MEG measurements. BabyMEG with the recycler has been fully operational from March, 2015. Ongoing spontaneous brain activity can be monitored in real time without interference from external magnetic noise sources including the recycler, using a combination of a lightly shielded two-layer magnetically shielded room, an external active shielding, a signal-space projection method, and a synthetic gradiometer approach. Evoked responses in the cortex can be clearly detected without averaging. These new design features and capabilities represent several advances in MEG, increasing the utility of this technique in basic neuroscience as well as in clinical research and patient studies.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.

IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI.

Gamma-aminobutyric acid (GABA) and glutamate (Glu) are the major neurotransmitters in the brain. They are crucial for the functioning of healthy brain and their alteration is a major mechanism in the pathophysiology of many neuro-psychiatric disorders. Magnetic resonance spectroscopy (MRS) is the only way to measure GABA and Glu non-invasively in vivo. GABA detection is particularly challenging and requires special MRS techniques. The most popular is MEscher-GArwood (MEGA) difference editing with single-voxel Point RESolved Spectroscopy (PRESS) localization. This technique has three major limitations: a) MEGA editing is a subtraction technique, hence is very sensitive to scanner instabilities and motion artifacts. b) PRESS is prone to localization errors at high fields (≥3T) that compromise accurate quantification. c) Single-voxel spectroscopy can (similar to a biopsy) only probe steady GABA and Glu levels in a single location at a time. To mitigate these problems, we implemented a 3D MEGA-editing MRS imaging sequence with the following three features: a) Real-time motion correction, dynamic shim updates, and selective reacquisition to eliminate subtraction artifacts due to scanner instabilities and subject motion. b) Localization by Adiabatic SElective Refocusing (LASER) to improve the localization accuracy and signal-to-noise ratio. c) K-space encoding via a weighted stack of spirals provides 3D metabolic mapping with flexible scan times. Simulations, phantom and in vivo experiments prove that our MEGA-LASER sequence enables 3D mapping of GABA+ and Glx (Glutamate+Gluatmine), by providing 1.66 times larger signal for the 3.02ppm multiplet of GABA+ compared to MEGA-PRESS, leading to clinically feasible scan times for 3D brain imaging. Hence, our sequence allows accurate and robust 3D-mapping of brain GABA+ and Glx levels to be performed at clinical 3T MR scanners for use in neuroscience and clinical applications.