Clinical decisions in fetal-neonatal neurology I. reproductive and pregnancy health influence the neural exposome over multiple generations.

Interdisciplinary fetal neonatal neurology (FNN) training requires integration of reproductive health factors into evaluations of the maternal-placental-fetal (MPF) triad, neonate, and child over the first 1000 days. Serial events that occur before one or multiple pregnancies impact successive generations. A maternal-child dyad history highlights this continuity of health risk, beginning with a maternal grandmother's pregnancy. Her daughter was born preterm and later experienced polycystic ovarian syndrome further complicated by cognitive and mental health disorders. Medical problems during her pregnancy contributed to MPF triad diseases that resulted in her son's extreme prematurity. Postpartum maternal death from the complications of diabetic ketoacidosis and her child's severe global neurodevelopmental delay were adverse mother-child outcomes. A horizontal/vertical diagnostic approach to reach shared clinical decisions during FNN training requires perspectives of a dynamic neural exposome. Career-long learning is then strengthened by continued interactions from al stakeholders. Developmental origins theory applied to neuroplasticity principles help interpret phenotypic expressions as dynamic gene-environment interactions across a person's lifetime. Debiasing strategies applied to the cognitive process reduce bias to preserve therapeutic and prognostic accuracy. Social determinants of health are essential components of this strategy to be initiated during FNN training. Reduction of the global burden of neurologic disorders requires applying the positive effects from reproductive and pregnancy exposomes that will benefit the neural exposome across the lifespan.

Clinical decisions in fetal-neonatal neurology II: Gene-environment expression over the first 1000 days presenting as "four great neurological syndromes".

Interdisciplinary fetal-neonatal neurology (FNN) training considers a woman's reproductive and pregnancy health histories when assessing the "four great neonatal neurological syndromes". This maternal-child dyad exemplifies the symptomatic neonatal minority, compared with the silent majority of healthy children who experience preclinical diseases with variable expressions over the first 1000 days. Healthy maternal reports with reassuring fetal surveillance testing preceded signs of fetal distress during parturition. An encephalopathic neonate with seizures later exhibited childhood autistic spectrum behaviors and intractable epilepsy correlated with identified genetic biomarkers. A systems biology approach to etiopathogenesis guides the diagnostic process to interpret phenotypic form and function. Evolving gene-environment interactions expressed by changing phenotypes reflect a dynamic neural exposome influenced by reproductive and pregnancy health. This strategy considers critical/sensitive periods of neuroplasticity beyond two years of life to encompass childhood and adolescence. Career-long FNN experiences reenforce earlier training to strengthen the cognitive process and minimize cognitive biases when assessing children or adults. Prioritizing social determinants of healthcare for persons with neurologic disorders will help mitigate the global burden of brain diseases for all women and children.

Treatable brain network biomarkers in children in coma using task and resting-state functional MRI: a case series.

The withdrawal of life-sustaining therapies is frequently considered for pediatric patients with severe acute brain injuries who are admitted to the intensive care unit. However, it is worth noting that some children with a resultant poor neurological status may ultimately survive and achieve a positive neurological outcome. Evidence suggests that adults with hidden consciousness may have a more favorable prognosis compared to those without it. Currently, no treatable network disorders have been identified in cases of severe acute brain injury, aside from seizures detectable through an electroencephalogram (EEG) and neurostimulation via amantadine. In this report, we present three cases in which multimodal brain network evaluation played a helpful role in patient care. This evaluation encompassed various assessments such as continuous video EEG, visual-evoked potentials, somatosensory-evoked potentials, auditory brainstem-evoked responses, resting-state functional MRI (rs-fMRI), and passive-based and command-based task-based fMRI. It is worth noting that the latter three evaluations are unique as they have not yet been established as part of the standard care protocol for assessing acute brain injuries in children with suppressed consciousness. The first patient underwent serial fMRIs after experiencing a coma induced by trauma. Subsequently, the patient displayed improvement following the administration of antiseizure medication to address abnormal signals. In the second case, a multimodal brain network evaluation uncovered covert consciousness, a previously undetected condition in a pediatric patient with acute brain injury. In both patients, this discovery potentially influenced decisions concerning the withdrawal of life support. Finally, the third patient serves as a comparative control case, demonstrating the absence of detectable networks. Notably, this patient underwent the first fMRI prior to experiencing brain death as a pediatric patient. Consequently, this case series illustrates the clinical feasibility of employing multimodal brain network evaluation in pediatric patients. This approach holds potential for clinical interventions and may significantly enhance prognostic capabilities beyond what can be achieved through standard testing methods alone.

Interdisciplinary fetal-neonatal neurology training applies neural exposome perspectives to neurology principles and practice.

An interdisciplinary fetal-neonatal neurology (FNN) program over the first 1,000 days teaches perspectives of the neural exposome that are applicable across the life span. This curriculum strengthens neonatal neurocritical care, pediatric, and adult neurology training objectives. Teaching at maternal-pediatric hospital centers optimally merges reproductive, pregnancy, and pediatric approaches to healthcare. Phenotype-genotype expressions of health or disease pathways represent a dynamic neural exposome over developmental time. The science of uncertainty applied to FNN training re-enforces the importance of shared clinical decisions that minimize bias and reduce cognitive errors. Trainees select mentoring committee participants that will maximize their learning experiences. Standardized questions and oral presentations monitor educational progress. Master or doctoral defense preparation and competitive research funding can be goals for specific individuals. FNN principles applied to practice offer an understanding of gene-environment interactions that recognizes the effects of reproductive health on the maternal-placental-fetal triad, neonate, child, and adult. Pre-conception and prenatal adversities potentially diminish life-course brain health. Endogenous and exogenous toxic stressor interplay (TSI) alters the neural exposome through maladaptive developmental neuroplasticity. Developmental disorders and epilepsy are primarily expressed during the first 1,000 days. Communicable and noncommunicable illnesses continue to interact with the neural exposome to express diverse neurologic disorders across the lifespan, particularly during the critical/sensitive time periods of adolescence and reproductive senescence. Anomalous or destructive fetal neuropathologic lesions change clinical expressions across this developmental-aging continuum. An integrated understanding of reproductive, pregnancy, placental, neonatal, childhood, and adult exposome effects offers a life-course perspective of the neural exposome. Exosome research promises improved disease monitoring and drug delivery starting during pregnancy. Developmental origins of health and disease principles applied to FNN practice anticipate neurologic diagnoses with interventions that can benefit successive generations. Addressing health care disparities in the Global South and high-income country medical deserts require constructive dialogue among stakeholders to achieve medical equity. Population health policies require a brain capital strategy that reduces the global burden of neurologic diseases by applying FNN principles and practice. This integrative neurologic care approach will prolong survival with an improved quality of life for persons across the lifespan confronted with neurological disorders.

A Bio-Social Model during the First 1000 Days Optimizes Healthcare for Children with Developmental Disabilities.

Most children with developmental disabilities (DD) live in resource-limited countries (LMIC) or high-income country medical deserts (HICMD). A social contract between healthcare providers and families advocates for accurate diagnoses and effective interventions to treat diseases and toxic stressors. This bio-social model emphasizes reproductive health of women with trimester-specific maternal and pediatric healthcare interactions. Lifelong neuronal connectivity is more likely established across 80% of brain circuitries during the first 1000 days. Maladaptive gene-environment (G x E) interactions begin before conception later presenting as maternal-placental-fetal (MPF) triad, neonatal, or childhood neurologic disorders. Synergy between obstetrical and pediatric healthcare providers can reduce neurologic morbidities. Partnerships between healthcare providers and families should begin during the first 1000 days to address diseases more effectively to moderate maternal and childhood adverse effects. This bio-social model lowers the incidence and lessens the severity of sequalae such as DD. Access to genetic-metabolomic, neurophysiologic and neuroimaging evaluations enhances clinical decision-making for more effective interventions before full expression of neurologic dysfunction. Diagnostic accuracy facilitates developmental interventions for effective preschool planning. A description of a mother-child pair in a HIC emphasizes the time-sensitive importance for early interventions that influenced brain health throughout childhood. Partnership by her parents with healthcare providers and educators provided effective healthcare and lessened adverse effects. Effective educational interventions were later offered through her high school graduation. Healthcare disparities in LMIC and HICMD require that this bio-social model of care begin before the first 1000 days to effectively treat the most vulnerable women and children. Prioritizing family planning followed by prenatal, neonatal and child healthcare improves wellness and brain health. Familiarity with educational neuroscience for teachers applies neurologic diagnoses for effective individual educational plans. Integrating diversity and inclusion into medical and educational services cross socioeconomic, ethnic, racial, and cultural barriers with life-course benefits. Families require knowledge to recognize risks for their children and motivation to sustain relationships with providers and educators for optimal outcomes. The WHO sustainable development goals promote brain health before conception through the first 1000 days. Improved education, employment, and social engagement for all persons will have intergenerational and transgenerational benefits for communities and nations.

Gene-Environment Interactions During the First Thousand Days Influence Childhood Neurological Diagnosis.

Gene-environment (G x E) interactions significantly influence neurologic outcomes. The maternal-placental-fetal (MPF) triad, neonate, or child less than 2 years may first exhibit significant brain disorders. Neuroplasticity during the first 1000 days will more likely result in life-long effects given critical periods of development. Developmental origins and life-course principles help recognize changing neurologic phenotypes across ages. Dual diagnostic approaches are discussed using representative case scenarios to highlight time-dependent G x E interactions that contribute to neurologic sequelae. Horizontal analyses identify clinically relevant phenotypic form and function at different ages. Vertical analyses integrate the approach using systems-biology from genetic through multi-organ system interactions during each developmental age to understand etiopathogenesis. The process of ontogenetic adaptation results in immediate or delayed positive and negative outcomes specific to the developmental niche, expressed either as a healthy child or one with neurologic sequelae. Maternal immune activation, ischemic placental disease, and fetal inflammatory response represent prenatal disease pathways that contribute to fetal brain injuries. These processes involve G x E interactions within the MPF triad, phenotypically expressed as fetal brain malformations or destructive injuries within the MPF triad. A neonatal minority express encephalopathy, seizures, stroke, and encephalopathy of prematurity as a continuum of trimester-specific G x E interactions. This group may later present with childhood sequelae. A healthy neonatal majority present at older ages with sequelae such as developmental disorders, epilepsy, mental health diseases, tumors, and neurodegenerative disease, often during the first 1000 days. Effective preventive, rescue, and reparative neuroprotective strategies require consideration of G x E interactions interplay over time. Addressing maternal and pediatric health disparities will maximize medical equity with positive global outcomes that reduce the burden of neurologic diseases across the lifespan.

Fetal-neonatal neurology program development: Continuum of care during the first 1000 days.

Global estimates show that 10-20% of persons express developmental disability. During critical and sensitive periods of developmental neuroplasticity over the first 1000 days, adverse gene-environment interactions are likely to contribute to permanent life-long disabilities and early mortality. This article describes fetal-neonatal neurology (FNN) program development that integrates vertical and horizontal diagnostic perspectives. Trimester-specific conditions to the maternal-placental-fetal triad begin at conception, followed by pediatric patient care over the first two years of life to address changing phenotypic form and function. While fetal and neonatal neurology trainees prepare to offer person-centric healthcare, population-based considerations address obstacles to optimal health relevant to resource-rich and poor nations. Maternal and pediatric care practices over the first 1000 days underscore equitable health policy. Global initiatives apply geographic distance, biosocial dynamics, and cultural differences to developmental origins and life-course theories, to more effectively reduce disease burden over the life continuum.

Neurologic Sequelae Associated with Hypertensive Disorders of Pregnancy.

Hypertensive disorders of pregnancy (HDP) contribute to adverse gene-environment interactions prior to conception and continue throughout pregnancy. Embryonic/fetal brain disorders occur from interactions between genetic susceptibilities interacting with acquired diseases or conditions affecting the maternal/placental fetal (MPF) triad. Trimester-specific pathophysiological mechanisms, such as maternal immune activation and ischemic placental syndrome, contribute to adverse peripartum, neonatal and childhood outcomes. Two diagnostic approaches provide timelier diagnoses over the first 1000 days from conception until two years of age. Horizontal analyses assess the maturation of the triad, neonate and child. Vertical analyses consider systems-biology from genetic, molecular, cellular, tissue through organ networks during each developmental niche. Disease expressions associated with HDP have cumulative adverse effects across the lifespan when subjected to subsequent adverse events. Critical/sensitive periods of developmental neuroplasticity over the first 1000 days are more likely to result in permanent sequelae. Novel diagnostic approaches, beginning during pre-conception, will facilitate the development of effective preventive, rescue and reparative neurotherapeutic strategies in response to HDP-related trimester-specific disease pathways. Public health policies require the inclusion of women's health advocacy during and beyond their reproductive years to reduce sequelae experienced by mothers and their offspring. A lower global burden of neurologic disease from HDP will benefit future generations.

"The First Thousand Days" Define a Fetal/Neonatal Neurology Program.

Gene-environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- and long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of brain maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the maternal/placental/fetal (MPF) triad, expressed as brain malformations and destructive lesions. Maladaptive MPF triad interactions impair progenitor neuronal/glial populations within transient embryonic/fetal brain structures by processes such as maternal immune activation. Destructive fetal brain lesions later in pregnancy result from ischemic placental syndromes associated with the great obstetrical syndromes. Trimester-specific MPF triad diseases may negatively impact labor and delivery outcomes. Neonatal neurocritical care addresses the symptomatic minority who express the great neonatal neurological syndromes: encephalopathy, seizures, stroke, and encephalopathy of prematurity. The asymptomatic majority present with neurologic disorders before 2 years of age without prior detection. The developmental principle of ontogenetic adaptation helps guide the diagnostic process during the first 1,000 days to identify more phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, and research agenda among multiple FNNP. Effective early-life diagnostic/therapeutic programs will help reduce neurologic disease burden across the lifespan and successive generations.

Neurologic outcome after fetal inflammatory response syndrome: Trimester-specific considerations.

Clinical signs and neuroimaging patterns associated with the fetal inflammatory response syndrome (FIRS) worsen or mimic the clinical repertoire after intrapartum hypoxic-ischemic encephalopathy (HIE) during labor and/or parturition. Diagnostic considerations expressed as neonatal encephalopathy (NE) must consider chronic as well as acute factors associated with FIRS. Trimester-specific factors adversely alter the interactions of the maternal/placental/fetal (MPF) triad and influence the postnatal phenotype of FIRS. Anticipatory guidance for families by clinicians caring for survivors with FIRS, as well as researchers, must consider acute and chronic effects that influence neurologic outcome. Novel neurotherapeutic interventions must include prenatal preventive as well as peripartum/postnatal rescue and repair strategies to effectively reduce the presence and severity of sequelae from FIRS.

Fetal neurology: Principles and practice with a life-course perspective.

Clinical service, educational, and research components of a fetal/neonatal neurology program are anchored by the disciplines of developmental origins of health and disease and life-course science as programmatic principles. Prenatal participation provides perspectives on maternal, fetal, and placental contributions to health or disease for fetal and subsequent neonatal neurology consultations. This program also provides an early-life diagnostic perspective for neurologic specialties concerned with brain health and disease throughout childhood and adulthood. Animal models and birth cohort studies have demonstrated how the science of epigenetics helps to understand gene-environment interactions to better predict brain health or disease. Fetal neurology consultations provide important diagnostic contributions during critical or sensitive periods of brain development when future neurotherapeutic interventions will maximize adaptive neuroplasticity. Age-specific normative neuroinformatics databases that employ computer-based strategies to integrate clinical/demographic, neuroimaging, neurophysiologic, and genetic datasets will more accurately identify either symptomatic patients or those at risk for brain disorders who would benefit from preventive, rescue, or reparative treatment choices throughout the life span.