Holoprosencephaly

The application of AI in obstetric ultrasound includes three aspects: structure identification, automatic and standardized measurements, and classification diagnosis. Since obstetric ultrasound is time-consuming, the use of AI could also reduce examination time and improve workflow. Study design: this is a multicenter retrospective observational cohort study and subsequent prospective cohort study. The study design will be organized in two different phases. The first phase, the feasibility retrospective study, has the objective to develop and train AI-Algorithm with normal and abnormal images retrospectively acquired during second trimester ultrasound scan from various international fetal medicine centers. The second phase, a prospective clinical validation, has the objective to test the AI-Algorithm in the assessment of basic fetal brain anatomy in a real clinic setting with real patients from each of the participating fetal medicine centers. Setting: Three (3) fetal medicine centers. Participants: singleton pregnant population who underwent ultrasound examination between 19 - 22 weeks of gestation in the participating centers. Primary endpoint: to validate a novel AI-based technology for the automated assessment of the basic anatomy of the fetal brain which could potentially be used to support second trimester screening scan. Secondary endpoints: To improve the performance of the standard second trimester screening of fetal brain anatomy ensuring its reliable sonographic assessment within a shorter time of execution. To detect higher repeatability and reproducibility, allowing to implement the ultrasound screening also in terms of efficiency on a vast scale, optimizing healthcare resources In the first phase of the study, participating fetal medicine centers will search their electronic databases for images of singleton pregnant women who underwent ultrasound imaging at 19+0 - 22+6 weeks of gestation with any fetal brain anomaly. Normal images of the fetal brain at the same gestational age will be provided by the promoting centers - i.e., Fondazione Policlinico A. Gemelli, IRCCS and University of Parma. Clinical, ultrasound, prenatal and postnatal information of each case will be retrieved from patient's medical records and entered an electronic database collection file by the principal investigator from each participating center. The acquired images will be anonymized, saved as DICOM and shared through a dedicated cloud storage system which will be set up by the bioengineering team. Each center will be able to access the web system using a personal ID and password. In the second phase of the study, the algorithm will be prospectively tested and validated in a real clinical setting with real patients from each of the participating fetal medicine centers. Inclusion and exclusion criteria, imaging protocol and data collection will be the same carried out during the retrospective phase.

This Biobank is comprised of: 1) medical, social, obstetrical and ultrasonographic data, 2) human biological samples (maternal plasma, serum and buffy coat, maternal urine, cord blood) and 3) the results derived from these (biochemical or ultrasonographic markers, genetics, risk calculations ...)

Meditation has been linked to improved brain health and lower brain age. Brain age has been successfully estimated from structural MRI and more recently, EEG Sleep data using Brain Age Index (BAI) derived by machine learning algorithms. Patients with significant neurological or psychiatric disease exhibit a mean excess BAI of about 4 years. Higher BAI is a predictor of mortality. Long term meditation has been associated with lower Brain Age in MRI studies. However, the EEG sleep measure of Brain Age has not been reported in meditators. This project aims to quantify the progressive impact of meditation on brain age. If established objectively, meditation-based interventions could offer safe, affordable and accessible solutions to promote younger and healthier brains and will have invaluable health and financial implications. The goal of this project is twofold: 1. In alignment with the recent NCCIH emphasis, we propose this study to combine neuroimaging with other non-neural modalities to delineate the impact of meditation on brain health and overall physiology and to identify objective neural biomarkers to assess meditation-based interventions which could be further used in clinical applications. 2. It is estimated that by 2050, an unprecedented 18% of the world's population will be above 65 years of age. According to the National Institute on Aging (NIA), aging is the most significant risk factor of many chronic conditions including age-related neurodegenerative diseases, which severely impact the quality of life, healthcare and social costs. The total healthcare cost of Alzheimer's disease in 2020 was estimated at $305 billion and expected to rise to $1 trillion soon. NIA's 5 year strategy highlights the crucial need to better understand the aging brain and develop interventions to address age-related neurological conditions. The study intervention is a multi-component 21-minute meditation called Shambhavi Mahamudra Kriya. It is taught at the Inner Engineering program offered by non-profit Isha Foundation as online as well as in-person formats. It incorporates a combination of different breathing patterns and meditative components. The intervention training provides precise, step by step and easy to follow instructions on how to perform this practice. Performed in a seated posture, this is a simple, safe and accessible intervention that requires no previous experience of meditation. The intervention selected for this study was shown to significantly reduce perceived stress, enhance self-reported general well-being, improve positive emotions, mindfulness, sleep, engagement, relationships and may promote enhanced Heart Rate Variability and Sympathovagal balance. The control group will be selected to be age, gender and education level matched with the intervention group and will be asked to continue their daily routine.

The last months of pregnancy are particularly important for the development of the child's brain, and the consequences of premature birth on its development can be substantial. Prematurely born children are at higher risk of various cognitive impairments and exhibits more behavioral disorders than full-term born children. Thus early detection and management of at risk children are essential. There is growing evidence of significant volumetric abnormalities in subcortical structures of premature neonates, which may be associated to negative long-term neurodevelopmental outcomes. Understanding these abnormalities could help elucidate the underlying pathophysiology and enable early determination of at-risk patients, both of which would inform the design of novel treatment strategies. However, to date there is still a lack of sensitive, reliable, and accessible algorithms capable of characterizing the influence of prematurity on the anatomy of neonatal brain subcortical structures. In addition, few studies have looked directly at the long-term neurodevelopmental implications of these neonatal subcortical structures abnormalities. Predicting long-term neurodevelopmental outcomes early on - and preferably at neonatal ages - is likely to have a transformative effect on their outcome. Our preliminary data indicate significant morphological differences in the putamen, ventricles, corpus callosum, and thalamus between preterm and term neonates. Investigators propose to develop biomarkers of prematurity by statistically comparing the morphological and diffusion properties of subcortical structures between preterm and term neonates using brain MRI. These results will further be used in a sparse learning framework to predict long-term neurodevelopmental outcomes of prematurity. Hypotheses: By combining subcortical morphological and diffusion properties, we will be able to: (1) delineate specific correlative relationships between structures regionally and differentially affected by normal maturation and different patterns of white matter injury, and (2) improve the specificity of neuroimaging to predict neurodevelopmental outcomes earlier. Aim 1: Build a new toolbox for neonatal subcortical structures analyses that combine 1) a group lasso-based analysis of significant regions of shape changes, 2) a structural correlation network analysis, 3) a neonatal tractography, and 4) tensor-based analysis on tracts. Aim 2: Ascertain biomarkers of prematurity in neonates with different patterns of abnormalities. Aim 3: Assess the predictive potential of imaging and clinical features on neurodevelopmental outcomes among premature children at 9 and 18 months and 6-8 years of age. Impact: This application will provide the first complete subcortical network analysis in both term and preterm neonates. In the first study of its kind for prematurity, investigators will use sparse and multi-task learning to determine which of the biomarkers of prematurity at birth are the best predictors of long-term outcome. The expected findings could improve the ability to predict these outcomes and enable the design of early treatments - before years of pathological brain development and symptoms occur.

The MOBILE project is part of the dynamic European collaboration of the Human Brain Project (HBP). The overall aim of the project is to characterize brain structure and function in healthy subjects and patients with epilepsy, using a quantitative multimodal approach involving both neuroimaging (MRI, PET) and electrophysiology (EEG/MEG). The project is funded by the European HBP consortium, and the data acquired will ultimately be made available to the scientific community formed by this international collaboration. Several aspects of the project have already been initiated on the basis of extensions to previous authorizations, or as part of care activities. As part of this overall project, the present MOBILE-PET application concerns exclusively the performance of 18F-FDG PET (Positron Emission Tomography) imaging in the 30 healthy adult subjects in the protocol (aged 18 to 65, with inclusion parity for gender). This cerebral examination, performed at rest on a 45-minute 3D volume acquisition, enables quantitative measurement of the metabolic consumption of glucose underlying global synaptic activity, and to determine the associated connectivity. Around 1,500 examinations of this type are carried out each year in our department as part of care for patients with brain pathology, and over 10,000 for patients with cancer. This examination requires intravenous injection of a weakly radioactive tracer corresponding to a radiopharmaceutical which has been approved for marketing for over 20 years. We also carried out and finalized a similar project in 2007 on 60 healthy subjects, using a previous-generation PET camera (NCT00484523). The Nuclear Medicine Department holds clinical research authorizations for imaging in patients and healthy subjects (including early phase and first-in-man, although the present project does not fall into this research categarogy).

Epilepsy is responsible for tremendous long-term healthcare costs. Analysis of inherited epilepsy conditions has allowed for identification of several key genes active in the developing brain. Although many genetic abnormalities of the brain are rare and lethal, rapidly advancing knowledge of the structure of the human genome makes it a realistic goal to identify genes responsible for other epileptic conditions, related brain malformations and disorders of cognition. The purpose of this study is to identify genes responsible for epilepsy and disorders of human cognition (EDHC). The Walsh Laboratory at Boston Children's Hospital is looking for genes involved in brain development. Conditions that we study include brain malformations, such as polymicrogyria, lissencephaly, pachygyria, heterotopias, microcephaly and cerebellar hypoplasia, and inherited disorders of cognition, such as familial intellectual disability and familial autism. People with these conditions also often have epilepsy. The structural brain abnormalities are usually diagnosed by brain MRI or sometimes CT scans. Adults and children with these conditions, and their family members, are invited to participate in our study. By comparing the DNA of individuals or families that carry EDHC to the DNA of people in the general population, it may be possible to learn more about the genetic bases of certain forms of EDHC. Study participants must have a brain malformation or disorder of cognition, such as familial intellectual disability or autism, in order to take part in this research.

Study Description: This is a prospective natural history study of individuals who have MEHMO syndrome or eIF2-pathway related conditions, or who are carriers of EIF2S3-related conditions to generate hypotheses for further understanding of disease pathophysiology, diagnosis, prognosis, management, and treatment. The protocol aims to enroll and follow affected or carrier individuals longitudinally to establish a repository of concurrent evaluations and biomaterials, as well as to enroll unaffected individuals for collection of informative comparable data and samples. Objectives: Primary Objective: Characterize the presentation of MEHMO syndrome and eIF2 pathway related conditions. Secondary Objectives: 1. Identify disease-reflective fluid biomarkers 2. Develop a disease severity rating scale or classification algorithm 3. Assess tolerability and feasibility of study evaluations 4. Establish a repository of participant data and samples for future research Endpoints: Primary Endpoint: Frequency and time-to-event of signs and symptoms. Secondary Endpoints: 1. Mean difference of candidate fluid biomarkers level in affected versus carrier versus unaffected individuals 2. Correlation of rating scale or classification algorithm to age, genotype, or other variables 3. Frequency of completed evaluations and reasons for noncompletion

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by social communication/interaction impairments and restricted/repetitive behaviors. ASD associated with germline heterozygous PTEN mutations (PTEN ASD) is a genetically defined sub-group that, may be one of the more prevalent genetic disorders contributing to ASD (0.5-2%). The purpose of this research study is to carefully track the phenotypic and molecular characteristics of PTEN ASD and identify biomarkers for intervention studies. Individuals with PTEN ASD, with macrocephalic ASD without a PTEN mutation (macro-ASD), healthy controls, and individuals with PTEN mutations without ASD (PTEN no-ASD) will be asked to participate in this study if they are 18 months and older. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals' primary communicative language must be English. The study involves 3 on site visits over the course of two years. Study visits will vary in length from about 4 hours to 6 hours. Study visits involve a physical exam, medical history questions, neuropsychological assessments, and a blood draw done for laboratory studies. A subset of participants between the ages of 2 and 11 years old will take part in the EEG portion of the study. Individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.

Primary objective of the study is the evaluation of sleep-disordered breathing (SDB) in two distinct pediatric populations of patients with Chiari Malformation Type 1 (CM-I) and Chiari Malformation Type 2 (CM-II). Secondary objectives: Stratify the presence of SDB into central and obstructive origins in the two study populations. Assess the volume of posterior cranial fossae, airway volume, and area of cranial base foramina in both groups. Determine the relationships between SDB and morphological-quantitative anomalies associated with CM.

Primary Objective To provide fundamental information to better understand the mechanisms involved and to detect and treat or ameliorate adverse effects during pregnancy. Secondary Objectives The secondary objectives of this study are aimed at better understanding of normal processes during development and how maternal lifestyle and environment can affect it. The investigators' research will involve a wide range of laboratory, cell and tissue culture and xenografting as well as microscopic techniques to study chemicals, hormones, proteins, genes and DNA in the fetal tissues. The investigators have developed sophisticated approaches to minimise how much tissue is required to carry out as many different measurements as possible in the same sample. It should be noted that the proposed studies are collaborative with different research groups since no single research group could carry out all the studies in isolation. Furthermore, the proposed studies will inform back to animal and cell studies, enabling more accurate interpretation of their own findings in light of mechanisms and specific conditions actually at play in the human fetus. 1. Human fetal endocrine system The investigators aim to investigate how the different hormone systems in the fetus develop and are affected by adverse maternal factors such as cigarette smoking and obesity. These include the testis, ovary, adrenal gland, thyroid gland, kidney and the hypothalamus, pineal gland and pituitary gland in the brain. In addition, the investigators also aim to study the placenta, including its endocrine function, and how it is affected by maternal environment, since it is a key organ of pregnancy. Changes in programming that establishes the endocrine system can have lifelong consequences for health and wellbeing. 2. Human fetal reproductive and urogenital system The investigators aim to investigate how the ovary, testis, urogenital tract (including prostate gland, breast buds and uterus), genitalia and kidney develop in the human fetus. There is considerable evidence that maternal smoking and over the counter medicine use can have negative impacts on this system and we will investigate when such impacts begin and what mechanisms are involved. In addition, common cancers, such as testis cancer, may have fetal origins and certainly events in fetal life may predispose the resulting adult to develop cancers. In the case of testis, ovary, breast buds and prostate gland, an additional aim is to determine whether and how events between 7 and 20 weeks of gestation increase the likelihood of cancers in these organs in adulthood. 3. Mechanistic studies, Epilepsy and other brain disorders The investigators aim to investigate development of the fetal central nervous system, including the brain. The first study planned is to investigate changes in genes and the structure of DNA in the brain related to epilepsy and other neurodevelopmental disorders linked with maternal cigarette smoking during pregnancy. A second aim is to use the smoke-exposed fetuses to better understand the role vitamin A plays in normal fetal development, including development of the central nervous system. Similar concerns are expressed in the literature with respect to maternal alcohol consumption and by accessing data from the Fast Alcohol Screening Test alcohol questionnaire that is already collected at clinic, the investigators will be able to address this issue systematically with respect to all the studies, including fetal brain development. 4. Metabolism and liver disease The investigators aim to continue their studies (funded by the Medical Research Council) of the human fetal liver and other organs important for metabolism, including pancreas and fat cells and cells that will become fat cells (precursor cells). Programming of metabolism during life in the womb is important for adult health and better understanding of the development of the metabolic systems and how they are perturbed by factors such as maternal smoking and deprivation is an important basis of developing strategies for wellbeing post-natally. A critical disease of growing importance in these studies is non-alcoholic fatty liver disease, which is increasing in incidence, especially in obese individuals. Given that the human fetal liver is active and responding to maternal environment, some of the basis of this disease may be established in fetal life. In addition, the development of thyroid and adrenal glands is also essential in establishing normal metabolic processes. Cutting edge techniques, such as large-scale metabolomic and lipidomic studies, including analysis of a wide range of dietary metabolites, will also be used. 5. Heart and cardiovascular system The development of the heart and the major artery, the aorta, between 7 and 20 weeks of gestation will be characterised. The effects of adverse in-utero environment of the developmental processes will then be investigated. 6. Immune system development The thymus is critical and large organ in fetal development that is important to establish the immune system. The spleen manufactures antibodies and, in fetal life, red blood cells (as does the fetal liver) and recycles red blood cells. Both organs have important role in maintaining the immune system. The investigators aim to investigate whether adverse maternal lifestyle and/or environment can alter thymus and spleen development and function. 7. Bone, cartilage and joints Very little is known about normal bone and cartilage development in the human fetus. Importantly, it is not even know when the cells involved in bone, cartilage and joint development begin to alter their behaviour into a more "adult" format. The reason this is important is that in musculoskeletal disease in the elderly, especially osteoarthritis, early stages of disease is usually characterised by renewed tissue growth - i.e. a return to a more "fetal" pattern of cell behaviour. The role of cell programming during fetal life and better understanding of the correct development and maintenance of bone, cartilage and joints, and how programming is affected by the fetal environment, is therefore one of the investigators' aims. 8. The development of the placenta between 7 and 20 weeks of gestation A great deal is known about the term placenta because it is so easy to obtain and to relate directly to the accompanying new-born and its parents. However, the placenta is a dynamically developing organ that is vital for normal pregnancy and that is affected by maternal lifestyle (e.g. placental growth is reduced if the mother continues to smoke while pregnant). The investigators aim therefore to better understand how the placenta develops during this window in gestation and how it is affected by maternal environment. 9. Nerve repair Spinal cord injury is a massive health problem globally. Recently it has been shown that human fetal central nervous system cells or embryonic nerve stem cells have the potential to assist in novel treatment strategies to repair spinal cord injury. This final secondary objective is focussed on a proof of concept study to determine whether culturing severed nerves in the presence of human fetal nerve cells assists in correct and functional nerve regrowth and re-joining across the induced gap. Any further studies, if the proof of concept aim is realised in a satisfactory manner would require a separate ethic application. 10. Maternal emotional health and wellbeing effects on the fetus Maternal stress is a well-known negative influence on fetal development. The investigators' aim is to perform a pilot study relating indices of fetal development, such as morphology, endocrine status, to maternal records of emotional health and wellbeing and abuse. The principal outcome will be an indication as to whether maternal stress is affecting fetal development at a general level between 7 and 20 weeks of gestation. Placental biomarkers identified in other studies listed above will also be related to measures of maternal stress in order to establish whether there may be placental biomarkers of early fetal response to maternal stress. 11. Fetal lung While it is well known that the adverse effects of maternal smoking include increased incidences of respiratory problems, such as asthma. However, there are also data suggesting that the offspring exposed to cigarette smoke may be more likely to develop lung cancer. The investigators' aim is to determine whether maternal smoking disturbs fetal lung development early in pregnancy and if this includes signs of increased likelihood of cancer development, such as polycyclic aromatic hydrocarbon-DNA adducts in the fetal lungs. 12. Quantifying human fetal exposure to pollutants, drugs, pharmaceuticals and other chemicals It is simple to measure chemicals in the blood or urine of the mother, or in amniotic fluid collected during amniocentesis. However, amniocentesis is not performed for research purposes because of not inconsiderable risk to the fetus. This means reliance on animal studies of such chemicals getting to the fetus but this is rather inadequate due to major species differences. Therefore the investigators aim to measure chemicals and drugs of potential health concern (such as bisphenol A which is in plastics and over the counter drugs taken by mothers which may affect the fetus, such as paracetamol) in the fetal tissues, including blood and urine where available. This is the only way to accurately assess how much of these compounds actually get into the fetus itself. This is important since the fetus is considered much more vulnerable than the adult to toxic chemicals. In addition, the investigators aim to also measure these compounds in the placentas (and cord blood where available) from the same fetuses. Because the placenta is readily available at term, placental biomarkers of fetal exposure to adverse compounds (e.g. alcohol) that are detected in the second trimester fetal liver will be investigated in the term placenta. 13. Non-genetic programming of the fetus for adult life Epigenetic changes are changes that involve marks being put onto DNA that affects how genes are activated. Therefore, an epigenetic change can change, sometimes greatly, the link between the amount of a gene present in cell and its effect. This linkage can be quite large with a gene being practically silenced in terms of its effect, even though there may be plenty of the gene present in the cell. Conditions within the womb, such a maternal smoking, can have epigenetic effects. The investigators aim therefore to better understand how the environment experience by the fetus can affect development and programming of adult health and disease by epigenetic mechanisms.