Maternal tadalafil treatment does not increase uterine artery blood flow or oxygen delivery in the pregnant ewe.

Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .

Magnetic resonance imaging of placental intralobule structure and function in a preclinical nonhuman primate model†.

Although the central role of adequate blood flow and oxygen delivery is known, the lack of optimized imaging modalities to study placental structure has impeded our understanding of its vascular function. Magnetic resonance imaging is increasingly being applied in this field, but gaps in knowledge remain, and further methodological developments are needed. In particular, the ability to distinguish maternal from fetal placental perfusion and the understanding of how individual placental lobules are functioning are lacking. The potential clinical benefits of developing noninvasive tools for the in vivo assessment of blood flow and oxygenation, two key determinants of placental function, are tremendous. Here, we summarize a number of structural and functional magnetic resonance imaging techniques that have been developed and applied in animal models and studies of human pregnancy over the past decade. We discuss the potential applications and limitations of these approaches. Their combination provides a novel source of contrast to allow analysis of placental structure and function at the level of the lobule. We outline the physiological mechanisms of placental T2 and T2* decay and devise a model of how tissue composition affects the observed relaxation properties. We apply this modeling to longitudinal magnetic resonance imaging data obtained from a preclinical pregnant nonhuman primate model to provide initial proof-of-concept data for this methodology, which quantifies oxygen transfer and placental structure across and between lobules. This method has the potential to improve our understanding and clinical management of placental insufficiency once validation in a larger nonhuman primate cohort is complete.

A Dempster-Shafer Approach to Trustworthy AI With Application to Fetal Brain MRI Segmentation.

Deep learning models for medical image segmentation can fail unexpectedly and spectacularly for pathological cases and images acquired at different centers than training images, with labeling errors that violate expert knowledge. Such errors undermine the trustworthiness of deep learning models for medical image segmentation. Mechanisms for detecting and correcting such failures are essential for safely translating this technology into clinics and are likely to be a requirement of future regulations on artificial intelligence (AI). In this work, we propose a trustworthy AI theoretical framework and a practical system that can augment any backbone AI system using a fallback method and a fail-safe mechanism based on Dempster-Shafer theory. Our approach relies on an actionable definition of trustworthy AI. Our method automatically discards the voxel-level labeling predicted by the backbone AI that violate expert knowledge and relies on a fallback for those voxels. We demonstrate the effectiveness of the proposed trustworthy AI approach on the largest reported annotated dataset of fetal MRI consisting of 540 manually annotated fetal brain 3D T2w MRIs from 13 centers. Our trustworthy AI method improves the robustness of four backbone AI models for fetal brain MRIs acquired across various centers and for fetuses with various brain abnormalities.

Multi-source multi-modal markers for Bayesian Networks: Application to the extremely preterm born brain.

The preterm phenotype results from the interplay of multiple disorders affecting the brain and cognitive outcomes. Accurately characterising these interactions can reveal prematurity markers. Bayesian Networks (BNs) are powerful tools to disentangle these relationships, as they inherently measure associations between variables while mitigating confounding factors. We present Modified PC-HC (MPC-HC), a Bayesian Network (BN) structural learning algorithm. MPC-HC employs statistical testing and search-and-score techniques to explore equivalent classes. We employ MPC-HC to estimate BNs for extremely preterm (EP) young adults and full-term controls. Using MRI measurements and cognitive performance markers, we investigate predictive relationships and mutual influences through predictions and sensitivity analysis. We assess the confidence in the estimated BN structures using bootstrapping. Furthermore, MPC-HC's validation involves assessing its ability to recover benchmark BN structures. MPC-HC achieves an average prediction accuracy of 72.5% compared to 62.5% of PC, 64.5% of MMHC, and 71.5% of HC, while it outperforms PC, MMHC, and HC algorithms in reconstructing the true structure of benchmark BNs. The sensitivity analysis shows that MRI measurements mainly affect EP cognitive scores. Our work has two key contributions: first, the introduction and validation of a new BN structure learning method. Second, demonstrating the potential of BNs in modelling variable relationships, predicting variables of interest, modelling uncertainty, and evaluating how variables impact each other. Finally, we demonstrate this by characterising complex phenotypes, such as preterm birth, and discovering results consistent with literature findings.

Longitudinal MRI in the context of in utero surgery for open spina bifida: A descriptive study.

INTRODUCTION: Fetal surgery for open spina bifida (OSB) requires comprehensive preoperative assessment using imaging for appropriate patient selection and to evaluate postoperative efficacy and complications. We explored patient access and conduct of fetal magnetic resonance imaging (MRI) for prenatal assessment of OSB patients eligible for fetal surgery. We compared imaging acquisition and reporting to the International Society of Ultrasound in Obstetrics and Gynecology MRI performance guidelines. MATERIAL AND METHODS: We surveyed access to fetal MRI for OSB in referring fetal medicine units (FMUs) in the UK and Ireland, and two NHS England specialist commissioned fetal surgery centers (FSCs) at University College London Hospital, and University Hospitals KU Leuven Belgium. To study MRI acquisition protocols, we retrospectively analyzed fetal MRI images before and after fetal surgery for OSB. RESULTS: MRI for fetal OSB was accessible with appropriate specialists available to supervise, perform, and report scans. The average time to arrange a fetal MRI appointment from request was 4 ± 3 days (range, 0-10), the average scan time available was 37 ± 16 min (range, 20-80 min), with 15 ± 11 min (range, 0-30 min) extra time to repeat sequences as required. Specific MRI acquisition protocols, and MRI reporting templates were available in only 32% and 18% of units, respectively. Satisfactory T2-weighted (T2W) brain imaging acquired in three orthogonal planes was achieved preoperatively in all centers, and 6 weeks postoperatively in 96% of FSCs and 78% of referring FMUs. However, for T2W spine image acquisition referring FMUs were less able to provide three orthogonal planes presurgery (98% FSC vs. 50% FMU, p < 0.001), and 6 weeks post-surgery (100% FSC vs. 48% FMU, p < 0.001). Other standard imaging recommendations such as T1-weighted (T1W), gradient echo (GE) or echoplanar fetal brain and spine imaging in one or two orthogonal planes were more likely available in FSCs compared to FMUs pre- and post-surgery (p < 0.001). CONCLUSIONS: There was timely access to supervised MRI for OSB fetal surgery assessment. However, the provision of images of the fetal brain and spine in sufficient orthogonal planes, which are required for determining eligibility and to determine the reversal of hindbrain herniation after fetal surgery, were less frequently acquired. Our evidence suggests the need for specific guidance in relation to fetal MRI for OSB. We propose an example guidance for MRI acquisition and reporting.

Myelination of preterm brain networks at adolescence.

Prematurity and preterm stressors severely affect the development of infants born before 37 weeks of gestation, with increasing effects seen at earlier gestations. Although preterm mortality rates have declined due to the advances in neonatal care, disability rates, especially in middle-income settings, continue to grow. With the advances in MR imaging technology, there has been a focus on safely imaging the preterm brain to better understand its development and discover the brain regions and networks affected by prematurity. Such studies aim to support interventions and improve the neurodevelopment of preterm infants and deliver accurate prognoses. Few studies, however, have focused on the fully developed brain of preterm born infants, especially in extremely preterm subjects. To assess the long-term effect of prematurity on the adult brain, myelin related biomarkers such as myelin water fraction and g-ratio are measured for a cohort of 19-year-old extremely preterm born subjects. Using multi-modal imaging techniques that combine T2 relaxometry and neurite density information, the results show that specific brain regions associated with white matter injuries due to preterm birth, such as the posterior limb of the internal capsule and corpus callosum, are still less myelinated in adulthood. Furthermore, a weak positive relationship between myelin water fraction values and Full-Scale Intelligence Quotient (FSIQ) scores was found in multiple brain regions previously defined as less myelinated in the Extremely Preterm (EPT) cohort. These findings might suggest altered connectivity in the adult preterm brain and explain differences in cognitive outcomes.

Use of super resolution reconstruction MRI for surgical planning in Placenta accreta spectrum disorder: Case series.

INTRODUCTION: Comprehensive imaging using ultrasound and MRI of placenta accreta spectrum (PAS) aims to prevent catastrophic haemorrhage and maternal death. Standard MRI of the placenta is limited by between-slice motion which can be mitigated by super-resolution reconstruction (SRR) MRI. We applied SRR in suspected PAS cases to determine its ability to enhance anatomical placental assessment and predict adverse maternal outcome. METHODS: Suspected PAS patients (n = 22) underwent MRI at a gestational age (weeks + days) of (32+3±3+2, range (27+1-38+6)). SRR of the placental-myometrial-bladder interface involving rigid motion correction of acquired MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume, was achieved in twelve. 2D MRI or SRR images alone, and paired data were assessed by four radiologists in three review rounds. All radiologists were blinded to results of the ultrasound, original MR image reports, case outcomes, and PAS diagnosis. A Random Forest Classification model was used to highlight the most predictive pathological MRI markers for major obstetric haemorrhage (MOH), bladder adherence (BA), and placental attachment depth (PAD). RESULTS: At delivery, four patients had placenta praevia with no abnormal attachment, two were clinically diagnosed with PAS, and six had histopathological PAS confirmation. Pathological MRI markers (T2-dark intraplacental bands, and loss of retroplacental T2-hypointense line) predicting MOH were more visible using SRR imaging (accuracy 0.73), in comparison to 2D MRI or paired imaging. Bladder wall interruption, predicting BA, was only easily detected by paired imaging (accuracy 0.72). Better detection of certain pathological markers predicting PAD was found using 2D MRI (placental bulge and myometrial thinning (accuracy 0.81)), and SRR (loss of retroplacental T2-hypointense line (accuracy 0.82)). DISCUSSION: The addition of SRR to 2D MRI potentially improved anatomical assessment of certain pathological MRI markers of abnormal placentation that predict maternal morbidity which may benefit surgical planning.

A review of feto-placental vasculature flow modelling.

The placenta provides the vital nutrients and removal of waste products required for fetal growth and development. Understanding and quantifying the differences in structure and function between a normally functioning placenta compared to an abnormal placenta is vital to provide insights into the aetiology and treatment options for fetal growth restriction and other placental disorders. Computational modelling of blood flow in the placenta allows a new understanding of the placental circulation to be obtained. This structured review discusses multiple recent methods for placental vascular model development including analysis of the appearance of the placental vasculature and how placental haemodynamics may be simulated at multiple length scales.

The effect of maternal position on placental blood flow and fetoplacental oxygenation in late gestation fetal growth restriction: a magnetic resonance imaging study.

Fetal growth restriction (FGR) and maternal supine going-to-sleep position are both risk factors for late stillbirth. This study aimed to use magnetic resonance imaging (MRI) to quantify the effect of maternal supine position on maternal-placental and fetoplacental blood flow, placental oxygen transfer and fetal oxygenation in FGR and healthy pregnancies. Twelve women with FGR and 27 women with healthy pregnancies at 34-38 weeks' gestation underwent MRI in both left lateral and supine positions. Phase-contrast MRI and a functional MRI technique (DECIDE) were used to measure blood flow in the maternal internal iliac arteries (IIAs) and umbilical vein (UV), placental oxygen transfer (placental flux), fetal oxygen saturation (FO2 ), and fetal oxygen delivery (delivery flux). The presence of FGR, compared to healthy pregnancies, was associated with a 7.8% lower FO2 (P = 0.02), reduced placental flux, and reduced delivery flux. Maternal supine positioning caused a 3.8% reduction in FO2 (P = 0.001), and significant reductions in total IIA flow, placental flux, UV flow and delivery flux compared to maternal left lateral position. The effect of maternal supine position on fetal oxygen delivery was independent of FGR pregnancy, meaning that supine positioning has an additive effect of reducing fetal oxygenation further in women with FGR, compared to women with appropriately grown for age pregnancies. Meanwhile, the effect of maternal supine positioning on placental oxygen transfer was not independent of the effect of FGR. Therefore, growth-restricted fetuses, which are chronically hypoxaemic, experience a relatively greater decline in oxygen transfer when mothers lie supine in late gestation compared to appropriately growing fetuses. KEY POINTS: Fetal growth restriction (FGR) is the most common risk factor associated with stillbirth, and early recognition and timely delivery is vital to reduce this risk. Maternal supine going-to-sleep position is found to increase the risk of late stillbirth but when combined with having a FGR pregnancy, maternal supine position leads to 15 times greater odds of stillbirth compared to supine sleeping with appropriately grown for age (AGA) pregnancies. Using MRI, this study quantifies the chronic hypoxaemia experienced by growth-restricted fetuses due to 13.5% lower placental oxygen transfer and 26% lower fetal oxygen delivery compared to AGA fetuses. With maternal supine positioning, there is a 23% reduction in maternal-placental blood flow and a further 14% reduction in fetal oxygen delivery for both FGR and AGA pregnancies, but this effect is proportionally greater for growth-restricted fetuses. This knowledge emphasises the importance of avoiding supine positioning in late pregnancy, particularly for vulnerable FGR pregnancies.

Developments in functional imaging of the placenta.

The placenta is both the literal and metaphorical black box of pregnancy. Measurement of the function of the placenta has the potential to enhance our understanding of this enigmatic organ and serve to support obstetric decision making. Advanced imaging techniques are key to support these measurements. This review summarises emerging imaging technology being used to measure the function of the placenta and new developments in the computational analysis of these data. We address three important examples where functional imaging is supporting our understanding of these conditions: fetal growth restriction, placenta accreta, and twin-twin transfusion syndrome.

Placental MRI Predicts Fetal Oxygenation and Growth Rates in Sheep and Human Pregnancy.

Magnetic resonance imaging (MRI) assessment of fetal blood oxygen saturation (SO2 ) can transform the clinical management of high-risk pregnancies affected by fetal growth restriction (FGR). Here, a novel MRI method assesses the feasibility of identifying normally grown and FGR fetuses in sheep and is then applied to humans. MRI scans are performed in pregnant ewes at 110 and 140 days (term = 150d) gestation and in pregnant women at 28+3  ± 2+5 weeks to measure feto-placental SO2 . Birth weight is collected and, in sheep, fetal blood SO2 is measured with a blood gas analyzer (BGA). Fetal arterial SO2 measured by BGA predicts fetal birth weight in sheep and distinguishes between fetuses that are normally grown, small for gestational age, and FGR. MRI feto-placental SO2 in late gestation is related to fetal blood SO2 measured by BGA and body weight. In sheep, MRI feto-placental SO2 in mid-gestation is related to fetal SO2 later in gestation. MRI feto-placental SO2 distinguishes between normally grown and FGR fetuses, as well as distinguishing FGR fetuses with and without normal Doppler in humans. Thus, a multi-compartment placental MRI model detects low placental SO2 and distinguishes between small hypoxemic fetuses and normally grown fetuses.

Emerging Treatments for Disorders of Consciousness in Paediatric Age.

The number of paediatric patients living with a prolonged Disorder of Consciousness (DoC) is growing in high-income countries, thanks to substantial improvement in intensive care. Life expectancy is extending due to the clinical and nursing management achievements of chronic phase needs, including infections. However, long-known pharmacological therapies such as amantadine and zolpidem, as well as novel instrumental approaches using direct current stimulation and, more recently, stem cell transplantation, are applied in the absence of large paediatric clinical trials and rigorous age-balanced and dose-escalated validations. With evidence building up mainly through case reports and observational studies, there is a need for well-designed paediatric clinical trials and specific research on 0-4-year-old children. At such an early age, assessing residual and recovered abilities is most challenging due to the early developmental stage, incompletely learnt motor and cognitive skills, and unreliable communication; treatment options are also less explored in early age. In middle-income countries, the lack of rehabilitation services and professionals focusing on paediatric age hampers the overall good assistance provision. Young and fast-evolving health insurance systems prevent universal access to chronic care in some countries. In low-income countries, rescue networks are often inadequate, and there is a lack of specialised and intensive care, difficulty in providing specific pharmaceuticals, and lower compliance to intensive care hygiene standards. Despite this, paediatric cases with DoC are reported, albeit in fewer numbers than in countries with better-resourced healthcare systems. For patients with a poor prospect of recovery, withdrawal of care is inhomogeneous across countries and still heavily conditioned by treatment costs as well as ethical and cultural factors, rather than reliant on protocols for assessment and standardised treatments. In summary, there is a strong call for multicentric, international, and global health initiatives on DoC to devote resources to the paediatric age, as there is now scope for funders to invest in themes specific to DoC affecting the early years of the life course.

What brain abnormalities can magnetic resonance imaging detect in foetal and early neonatal spina bifida: a systematic review.

PURPOSE: Open spina bifida (OSB) encompasses a wide spectrum of intracranial abnormalities. With foetal surgery as a new treatment option, robust intracranial imaging is important for comprehensive preoperative evaluation and prognostication. We aimed to determine the incidence of infratentorial and supratentorial findings detected by magnetic resonance imaging (MRI) alone and MRI compared to ultrasound. METHODS: Two systematic reviews comparing MRI to ultrasound and MRI alone were conducted on MEDLINE, EMBASE, and Cochrane databases identifying studies of foetal OSB from 2000 to 2020. Intracranial imaging findings were analysed at ≤ 26 or > 26 weeks gestation and neonates (≤ 28 days). Data was independently extracted by two reviewers and meta-analysis was performed where possible. RESULTS: Thirty-six studies reported brain abnormalities detected by MRI alone in patients who previously had an ultrasound. Callosal dysgenesis was identified in 4/29 cases (2 foetuses ≤ 26 weeks, 1 foetus under any gestation, and 1 neonate ≤ 28 days) (15.1%, CI:5.7-34.3%). Heterotopia was identified in 7/40 foetuses ≤ 26 weeks (19.8%, CI:7.7-42.2%), 9/36 foetuses > 26 weeks (25.3%, CI:13.7-41.9%), and 64/250 neonates ≤ 28 days (26.9%, CI:15.3-42.8%). Additional abnormalities included aberrant cortical folding and other Chiari II malformation findings such as lower cervicomedullary kink level, tectal beaking, and hypoplastic tentorium. Eight studies compared MRI directly to ultrasound, but due to reporting inconsistencies, it was not possible to meta-analyse. CONCLUSION: MRI is able to detect anomalies hitherto underestimated in foetal OSB which may be important for case selection. In view of increasing prenatal OSB surgery, further studies are required to assess developmental consequences of these findings.

Super-resolution Reconstruction MRI Application in Fetal Neck Masses and Congenital High Airway Obstruction Syndrome.

OBJECTIVE: Reliable airway patency diagnosis in fetal tracheolaryngeal obstruction is crucial to select and plan ex utero intrapartum treatment (EXIT) surgery. We compared the clinical utility of magnetic resonance imaging (MRI) super-resolution reconstruction (SRR) of the trachea, which can mitigate unpredictable fetal motion effects, with standard 2-dimensional (2D) MRI for airway patency diagnosis and assessment of fetal neck mass anatomy. STUDY DESIGN: A single-center case series of 7 consecutive singleton pregnancies with complex upper airway obstruction (2013-2019). SETTING: A tertiary fetal medicine unit performing EXIT surgery. METHODS: MRI SRR of the trachea was performed involving rigid motion correction of acquired 2D MRI slices combined with robust outlier detection to reconstruct an isotropic high-resolution volume. SRR, 2D MRI, and paired data were blindly assessed by 3 radiologists in 3 experimental rounds. RESULTS: Airway patency was correctly diagnosed in 4 of 7 cases (57%) with 2D MRI as compared with 2 of 7 cases (29%) with SRR alone or paired 2D MRI and SRR. Radiologists were more confident (P = .026) in airway patency diagnosis when using 2D MRI than SRR. Anatomic clarity was higher with SRR (P = .027) or paired data (P = .041) in comparison with 2D MRI alone. Radiologists detected further anatomic details by using paired images versus 2D MRI alone (P < .001). Cognitive load, as assessed by the NASA Task Load Index, was increased with paired or SRR data in comparison with 2D MRI. CONCLUSION: The addition of SRR to 2D MRI does not increase fetal airway patency diagnostic accuracy but does provide improved anatomic information, which may benefit surgical planning of EXIT procedures.

On the use of multicompartment models of diffusion and relaxation for placental imaging.

Multi-compartment models of diffusion and relaxation are ubiquitous in magnetic resonance research especially applied to neuroimaging applications. These models are increasingly making their way into the world of placental imaging. This review provides a framework for their motivation and implementation and describes some of the outstanding questions that need to be answered before they can be routinely adopted.

Multiscale and multimodal imaging of utero-placental anatomy and function in pregnancy.

Placental structures at the nano-, micro-, and macro scale each play important roles in contributing to its function. As such, quantifying the dynamic way in which placental structure evolves during pregnancy is critical to both clinical diagnosis of pregnancy disorders, and mechanistic understanding of their pathophysiology. Imaging the placenta, both exvivo and invivo, can provide a wealth of structural and/or functional information. This review outlines how imaging across modalities and spatial scales can ultimately come together to improve our understanding of normal and pathological pregnancies. We discuss how imaging technologies are evolving to provide new insights into placental physiology across disciplines, and how advanced computational algorithms can be used alongside state-of-the-art imaging to obtain a holistic view of placental structure and its associated functions to improve our understanding of placental function in health and disease.

Cortical spectral matching and shape and volume analysis of the fetal brain pre- and post-fetal surgery for spina bifida: a retrospective study.

PURPOSE: A retrospective study was performed to study the effect of fetal surgery on brain development measured by MRI in fetuses with myelomeningocele (MMC). METHODS: MRI scans of 12 MMC fetuses before and after surgery were compared to 24 age-matched controls without central nervous system abnormalities. An automated super-resolution reconstruction technique generated isotropic brain volumes to mitigate 2D MRI fetal motion artefact. Unmyelinated white matter, cerebellum and ventricles were automatically segmented, and cerebral volume, shape and cortical folding were thereafter quantified. Biometric measures were calculated for cerebellar herniation level (CHL), clivus-supraocciput angle (CSO), transverse cerebellar diameter (TCD) and ventricular width (VW). Shape index (SI), a mathematical marker of gyrification, was derived. We compared cerebral volume, surface area and SI before and after MMC fetal surgery versus controls. We additionally identified any relationship between these outcomes and biometric measurements. RESULTS: MMC ventricular volume/week (mm3/week) increased after fetal surgery (median: 3699, interquartile range (IQR): 1651-5395) compared to controls (median: 648, IQR: 371-896); P = 0.015. The MMC SI is higher pre-operatively in all cerebral lobes in comparison to that in controls. Change in SI/week in MMC fetuses was higher in the left temporal lobe (median: 0.039, IQR: 0.021-0.054), left parietal lobe (median: 0.032, IQR: 0.023-0.039) and right occipital lobe (median: 0.027, IQR: 0.019-0.040) versus controls (P = 0.002 to 0.005). Ventricular volume (mm3) and VW (mm) (r = 0.64), cerebellar volume and TCD (r = 0.56) were moderately correlated. CONCLUSIONS: Following fetal myelomeningocele repair, brain volume, shape and SI were significantly different from normal in most cerebral layers. Morphological brain changes after fetal surgery are not limited to hindbrain herniation reversal. These findings may have neurocognitive outcome implications and require further evaluation.

White matter analysis of the extremely preterm born adult brain.

The preterm brain has been analysed after birth by a large body of neuroimaging studies; however, few studies have focused on white matter alterations in preterm subjects beyond infancy, especially in individuals born at extremely low gestation age - before 28 completed weeks. Neuroimaging data of extremely preterm young adults are now available to investigate the long-term structural alterations of disrupted neurodevelopment. We examined white matter hierarchical organisation and microstructure in extremely preterm young adults. Specifically, we first identified the putative hubs and peripheral regions in 85 extremely preterm young adults and compared them with 53 socio-economically matched and full-term born peers. Moreover, we analysed Fractional Anisotropy (FA), Mean Diffusivity (MD), Neurite Density Index (NDI), and Orientation Dispersion Index (ODI) of white matter in hubs, peripheral regions, and over the whole brain. Our results suggest that the hierarchical organisation of the extremely preterm adult brain remains intact. However, there is evidence of significant alteration of white matter connectivity at both the macro- and microstructural level, with overall diminished connectivity, reduced FA and NDI, increased MD, and comparable ODI; suggesting that, although the spatial configuration of WM fibres is comparable, there are less WM fibres per voxel. These alterations are found throughout the brain and are more prevalent along the pathways between deep grey matter regions, frontal regions and cerebellum. This work provides evidence that white matter abnormalities associated with the premature exposure to the extrauterine environment not only are present at term equivalent age but persist into early adulthood.

Middle Frontal Gyrus and Area 55b: Perioperative Mapping and Language Outcomes.

Background: The simplistic approaches to language circuits are continuously challenged by new findings in brain structure and connectivity. The posterior middle frontal gyrus and area 55b (pFMG/area55b), in particular, has gained a renewed interest in the overall language network. Methods: This is a retrospective single-center cohort study of patients who have undergone awake craniotomy for tumor resection. Navigated transcranial magnetic simulation (nTMS), tractography, and intraoperative findings were correlated with language outcomes. Results: Sixty-five awake craniotomies were performed between 2012 and 2020, and 24 patients were included. nTMS elicited 42 positive responses, 76.2% in the inferior frontal gyrus (IFG), and hesitation was the most common error (71.4%). In the pMFG/area55b, there were seven positive errors (five hesitations and two phonemic errors). This area had the highest positive predictive value (43.0%), negative predictive value (98.3%), sensitivity (50.0%), and specificity (99.0%) among all the frontal gyri. Intraoperatively, there were 33 cortical positive responses-two (6.0%) in the superior frontal gyrus (SFG), 15 (45.5%) in the MFG, and 16 (48.5%) in the IFG. A total of 29 subcortical positive responses were elicited-21 in the deep IFG-MFG gyri and eight in the deep SFG-MFG gyri. The most common errors identified were speech arrest at the cortical level (20 responses-13 in the IFG and seven in the MFG) and anomia at the subcortical level (nine patients-eight in the deep IFG-MFG and one in the deep MFG-SFG). Moreover, 83.3% of patients had a transitory deterioration of language after surgery, mainly in the expressive component (p = 0.03). An increased number of gyri with intraoperative positive responses were related with better preoperative (p = 0.037) and worse postoperative (p = 0.029) outcomes. The involvement of the SFG-MFG subcortical area was related with worse language outcomes (p = 0.037). Positive nTMS mapping in the IFG was associated with a better preoperative language outcome (p = 0.017), relating to a better performance in the expressive component, while positive mapping in the MFG was related to a worse preoperative receptive component of language (p = 0.031). Conclusion: This case series suggests that the posterior middle frontal gyrus, including area 55b, is an important integration cortical hub for both dorsal and ventral streams of language.

Neuropsychiatric disease classification using functional connectomics - results of the connectomics in neuroimaging transfer learning challenge.

Large, open-source datasets, such as the Human Connectome Project and the Autism Brain Imaging Data Exchange, have spurred the development of new and increasingly powerful machine learning approaches for brain connectomics. However, one key question remains: are we capturing biologically relevant and generalizable information about the brain, or are we simply overfitting to the data? To answer this, we organized a scientific challenge, the Connectomics in NeuroImaging Transfer Learning Challenge (CNI-TLC), held in conjunction with MICCAI 2019. CNI-TLC included two classification tasks: (1) diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) within a pre-adolescent cohort; and (2) transference of the ADHD model to a related cohort of Autism Spectrum Disorder (ASD) patients with an ADHD comorbidity. In total, 240 resting-state fMRI (rsfMRI) time series averaged according to three standard parcellation atlases, along with clinical diagnosis, were released for training and validation (120 neurotypical controls and 120 ADHD). We also provided Challenge participants with demographic information of age, sex, IQ, and handedness. The second set of 100 subjects (50 neurotypical controls, 25 ADHD, and 25 ASD with ADHD comorbidity) was used for testing. Classification methodologies were submitted in a standardized format as containerized Docker images through ChRIS, an open-source image analysis platform. Utilizing an inclusive approach, we ranked the methods based on 16 metrics: accuracy, area under the curve, F1-score, false discovery rate, false negative rate, false omission rate, false positive rate, geometric mean, informedness, markedness, Matthew's correlation coefficient, negative predictive value, optimized precision, precision, sensitivity, and specificity. The final rank was calculated using the rank product for each participant across all measures. Furthermore, we assessed the calibration curves of each methodology. Five participants submitted their method for evaluation, with one outperforming all other methods in both ADHD and ASD classification. However, further improvements are still needed to reach the clinical translation of functional connectomics. We have kept the CNI-TLC open as a publicly available resource for developing and validating new classification methodologies in the field of connectomics.