Costs of Underfunding Brain Development Open Access

Developmental disabilities have profound and lifelong consequences, affecting not only the individual but also their family and society as a whole. Despite their substantial impact, the true costs – both economic and social – are often overlooked, and comprehensive data remain scarce [1‒3]. Disorders such as attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and schizophrenia involve highly complex behavioral changes, yet their precise etiology, pathomechanisms, and affected neurological circuits remain poorly understood. Even subtle alterations in neuronal connectivity – often imperceptible under typical conditions – can significantly influence behavior when exposed to sunder special circumstances, e.g., if neuronal modulation is altered by environmental stimuli [4, 5]. A substantial body of research highlights the interplay between genetic and environmental influences on behavior, but the subtle modifications within neural circuits that drive these conditions are not yet fully elucidated. Key developmental processes – including neuronal induction, neurogenesis, migration, differentiation and synapse formation – are tightly regulated and interdependent. Disruptions at various stages, even arising from the same underlying condition, can produce different outcomes depending on timing and interacting factors [6‒8]. The relationship between slight variations in neural circuit organization and their effects on normal versus pathological brain function is shaped by both genetic predispositions and environmental exposures. In some cases, genetic factors alone can lead to subtle neural changes, which, when compounded across multiple circuits, may contribute to disease pathology even in the absence of external triggers. The combined effects of genetic and environmental insults during development are highly complex, varying across developmental stages and specific neural circuits. In this review, we aim to shed light on these complexities and emphasize the importance of deeper investigation into developmental mechanisms to inform effective early interventions.

The burden of developmental disabilities becomes apparent when we compare the cumulative number of years lost due to ill-health, disability or early death, which are collectively measured as disability-adjusted life years (DALYs). Neonatal conditions are No. 5 global cause of death and No. 1 global cause of DALYs, and congenital anomalies are No. 10 global cause of DALYs, according to the World Health Organization (WHO) data in 2019 (Fig. 1) [9]. DALYs is a sum of years of life lost and years lived with disability. While the proportion of death caused by noncommunicable diseases, such as ischemic heart disease and dementia, among all mortality are increasing, that caused by neonatal conditions is decreasing due mostly to advances in healthcare in low- and middle-income countries [10]. The leading cause of neonatal mortality is preterm birth (36%), followed by childbirth-related complications (e.g., birth asphyxia) (24%), infections, and birth defects in 2019 [11, 12]. DALYs caused by neonatal conditions may decrease along with the decrease of neonatal mortality, i.e., years of life losts. Environmental risks are not limited to direct exposures of the mother during pregnancy, they could include cumulative exposures of both parents to teratogenic agents that damage female and male gametes [13], and they can also include early life exposures of the newborn, infant, or child. All these environmental factors are relevant, and equally complex.

Neurodevelopmental disabilities are more prevalent than currently recognized. It is not just conditions such as cerebral palsy or spinal bifida which can be tracked to pre-birth. One in 100 in the population on average can develop childhood epilepsy, one in 100 can develop schizophrenia, one in 68 ASD, one in 30 ADHD, one in 10 is currently diagnosed with dyslexia. The early practices we experience during development are important in further development of our brain and to having a good QoL. Prenatal parental diets and other general health metrics may be useful points for prevention of fetal distress that can cause neurodevelopmental vulnerability. The development of the human brain is highly protracted on the evolutionary scale, even compared to our closest relatives [8]. The developmental timing is longer, probably because requires proper interactions with the environment through our sensory organs and early aberrations can manifest much later in more severe form. The developing brain is not just a smaller version of the adult brain; it has numerous transient circuits that are no longer present in the adult, but essential for development. Therefore, understanding the cellular arrangements, connectivity, activity patterns all require specific investigations of these developmental states.

Each individual cannot control those disadvantageous factors inflicted during fetal and neonatal periods by him- or herself. Society must prioritize improving maternal, fetal, and neonatal conditions to ensure optimal early life development for all individuals. Efforts should be made to maximize the likelihood of healthy births through public health interventions. This is not just an ethical and moral but also a health and economic issue. For instance, total economic burden of ADHD amongst adults, excluding burden during childhood, in the USA is estimated USD 123 billion (USD 14,000 per adult) [28]. The costs for healthcare services among the total cost are relatively small (12%), but the excess costs of unemployment comprise the largest proportion of the total cost (54%). While both neurodevelopmental and neurodegenerative disorders impose significant economic burdens, the timing and distribution of these costs differ. Neurodevelopmental disorders lead to prolonged expenses over the individual’s lifespan, whereas neurodegenerative diseases result in substantial costs concentrated in the final years of life. In neurodevelopmental disorders, the costs begin in early childhood and persist throughout the individual’s life, encompassing medical care, specialized education, therapeutic interventions, and indirect costs like lost productivity. In neurodegenerative diseases, the expenses are predominantly incurred in the later stages of life, especially during the end-of-life period, covering intensive medical care, long-term care facilities, and palliative services. The total healthcare costs for the treatment of Alzheimer disease in 2020 is estimated at USD 305 billion, which include home healthcare, informal caregiving, and decreased QoL [29]. The total economic burdens of neurodevelopmental disorders, which encompass ADHD, ASD, and learning disorder would exceed those of Alzheimer disease. People consider that Alzheimer disease is no doubt one of the biggest burdens for our society along with coronary heart diseases, stroke, and cancers, but neurodevelopmental disorders are just as big as, if not bigger than, those four diseases. As small vulnerable newborns are at higher risk for developing those neurodevelopmental disorders, reducing the number of small vulnerable newborns will results in reducing the number of individuals with neurodevelopmental disorders.

It is highly informative to compare the lifetime cost estimates per individual. ASD: lifetime costs per individual are estimated at USD 3.2 million, encompassing various direct and indirect expenses [30]. Total societal costs of caring for children aged 3–17 years in the USA were USD 11.5 billion in 2011 [31]. Another research group estimated that annual costs including productivity costs in the USA will be USD 461 billion (range USD 276–USD 1,011 billion; 0.982–3.600% of GDP) for 2025 [32]. ADHD: lifetime costs can vary widely, with significant expenses related to healthcare and lost productivity. The total annual societal excess costs attributable to ADHD in the USA are estimated at USD 19.4 billion among children (USD 6,799 per child), USD 13.8 billion among adolescents (USD 8,349 per adolescent), and USD 122.8 billion among (USD 14,092 per adult) [33]. The total social costs in Australia were estimated at AUD 20.42 billion including loss of wellbeing in 2019, which is AUD 15,747 per person with ADHD [34]. Schizophrenia: the economic burden in the USA was estimated at USD 343.2 billion in 2019, reflecting both direct and indirect costs [35]. Dementia and Alzheimer’s disease: the lifetime cost of care per individual is substantial, with significant expenses incurred during the end-of-life period. Total costs for healthcare for people aged 65 and older with dementia are estimated to be USD 360 billion in 2024, and that for unpaid caregiving is valued at USD 346.6 billion in 2023 [36]. For Parkinson’s disease, the total economic burden in the USA was estimated at USD 51.9 billion in 2017, including indirect costs (e.g., reduced employment) [37].

Although there are numerous causes for them (see Fig. 3 below), supplementation of balanced energy food and micronutrients (e.g., zinc, calcium) for pregnant women is by far the most effective measure to reduce the number of small vulnerable newborns [38]. Pre- and postnatal dietary changes can significantly impact brain development and cognitive abilities through multiple mechanistic pathways [39]. During fetal development, maternal nutrition influences neurogenesis, synaptogenesis, and myelination, with key nutrients such as omega-3 fatty acids, folate, choline, iron, and vitamin D playing crucial roles in neuronal structure and function [39‒41]. Deficiencies in these nutrients during pregnancy can lead to altered neurotransmitter systems, impaired synaptic plasticity, and increased neuroinflammation, potentially predisposing individuals to neurodevelopmental disorders such as ADHD and ASD [40].

Post-natally, early life nutrition continues to shape cognitive function and neural circuit maturation, with breast milk, essential fatty acids, and micronutrients supporting optimal brain development [40, 42]. Diets high in refined sugars and saturated fats have been linked to neuroinflammation, oxidative stress, and gut microbiota dysbiosis, all of which can negatively impact cognitive outcomes [43]. Conversely, diets rich in polyphenols, antioxidants, and essential amino acids promote synaptic plasticity, memory function, and executive processing. These findings suggest that nutritional interventions during critical periods of brain development could mitigate cognitive deficits and reduce the risk of neurodevelopmental disorders.

Nutrition supplementation is surprisingly effective even in developed countries. A study shows that pregnant women consuming two seafood meals (230–340 g) per week could provide their child with an additional 3.3 IQ points [44]. Unfortunately, society is stratified and sometimes families struggle to make ends meet. The Association of Special Supplemental Nutrition Program for women, infants, and children in the USA set up a program where USD 40.96/month support was given to 700,000 expectant mothers toward healthy diet. The support could only be spent on selected healthy food for the pregnant mother and the effect on birth outcome was assessed and investigated. The results are astonishing. The pregnant women who had received vouchers to purchase healthy food had nearly 40% less infant mortality among their offspring compared with those who had not received the vouchers [45]. The result of this investigation drew attention to the complex issue how maternal nutrition impacts infant mortality, how supporting pregnant women can prevent numerous conditions that would increase the burden of healthcare at later life.

Numerous factors during the neonatal and early infancy periods influence long-term developmental outcomes. For instance, breastfeeding affects infants’ future in many ways. A large, randomized control trial shows that children who were breastfed have 5.9 points higher IQ than those who were not at 6 years of age [46]. Another study shows that individuals who were breastfed for 12 months or more had significantly higher IQ scores and higher monthly incomes than those who were breastfed for less than 1 month at 30 years of age after adjusting for ten confounding variables including family income and maternal education [47].

Gut microbiota, i.e., the microbial flora residing within the gastrointestinal system, has now known to influence brain physiology and behavior; this association is known as the “gut-microbiome-brain axis.” An increasing number of studies show the association between gut microbiota and neurological/psychiatric diseases [48, 49]. Gut microbiota is formed during the first 1,000 days of life and would not change afterward substantially [50]. Factors affecting the formation of gut microbiota include mode of delivery (vaginal or C-section), maternal vaginal microbiota, breastfeeding/formula-feeding, diet during infancy, use of antibiotics [51]. Although it is not confirmed yet, studies show associations between altered gut microbiota and higher risks of ASD and ADHD [52, 53].

If a child had abovementioned beneficial two factors, i.e., a child’s mother consumed adequate amount of seafood during pregnancy and breastfed, the child’s IQ would be more than 9 points higher than those who have neither of those two factors. To this end, we need to raise public awareness on those issues. Although the Food and Drug Administration (FDA) in the USA recommended consumption of 340 g of fish per week during pregnancy to obtain maximum benefit for IQ in 2014, the average amount of fish eaten by pregnant women in the USA is 54 g per week [54]. The most common reason for the low fish consumption is lack of knowledge of such benefit, followed by the costs of fish and then the concern of mercury contained in fish [54]. The FDA recommendation reported that even if pregnant women eat significantly more than 340 g of fish, the predicted detrimental effect of mercury is negligible compared to the robust benefit of eating fish [54].

Some damages are caused to the unborn child through maternal abuse of alcohol or drugs. Alcohol abuse during pregnancy disrupts maternal micronutrient status by impairing the absorption and metabolism of essential nutrients such as folate, vitamin A, zinc, and iron, which are critical for fetal growth and brain development. Ethanol exposure also increases oxidative stress and inflammation, leading to placental insufficiency and impaired nutrient transfer, further exacerbating fetal malnutrition [55]. Direct effects on the fetus include neurotoxicity, altered brain structure, and disrupted neurotransmitter systems, contributing to fetal alcohol spectrum disorders, characterized by cognitive, behavioral, and neurodevelopmental deficits [56]. Chronic ethanol exposure interferes with DNA methylation and epigenetic regulation, leading to lifelong consequences for neurodevelopment and metabolic health [57].

The statistics are surprising on a condition that could be prevented with more public awareness. In the USA and Europe, depending on the location, one in 100 babies being born has fetal alcohol syndrome (FAS) and it has been estimated that up to thirty percent of pregnant women have taken alcohol during pregnancy [58]. FAS/effects (FAS/E) is a lifetime disability. It is not curable. A child does not “grow out of it.” However, early diagnosis and intensive, and appropriate, intervention can make an enormous difference in the prognosis for the child. There is a small window of opportunity, up to about age 10 or 12, to achieve the greatest potential for an alcohol affected child.

It is estimated that on average, each fetal alcohol spectrum disorder individual costs the taxpayer more than USD 3 million in his or her lifetime to cover the costs of health problems, special education, psychotherapy and counseling, welfare, crime, and the costs of the use of justice system (Tables 1, 2) [58]. It is also suggested that a considerable proportion of incarcerated prisoners are likely affected by alcohol in utero [58].

Genetic predisposition to low birthweight is influenced by variations in genes related to placental function, fetal metabolism, and maternal-fetal nutrient transport, such as IGF1, LEP, and ADIPOQ [59]. These genetic variants can impair insulin-like growth factor signaling, leading to reduced fetal growth efficiency and placental insufficiency [60]. Maternal dietary status interacts with these genetic factors, where deficiencies in key micronutrients like folate, iron, and omega-3 fatty acids exacerbate genetic susceptibilities, further restricting fetal growth [61]. Epigenetic modifications, such as DNA methylation changes in imprinted genes like H19/IGF2, have been linked to suboptimal intrauterine nutrition and LBW risk, reinforcing the interplay between genetics and diet [62]. Epidemiological studies show that maternal malnutrition in genetically susceptible populations amplifies the risk of fetal growth restriction, particularly in low-income and food-insecure settings [63]. These findings highlight the importance of nutritional interventions tailored to maternal genetic risk profiles to mitigate the adverse outcomes of low birthweight.

Providing emotional and structural support to mothers and women of reproductive age are essential in addressing disparities in child health outcomes, especially those in small vulnerable newborns. Mothers of low birthweight infants often experience self-blame. This phenomenon should be acknowledged and addressed through targeted psychological and social support interventions. Genetic predisposition is a major contributing factor to preterm birth and fetal growth restriction. However, genetic risk factors are not modifiable, emphasizing the importance of environmental and medical interventions [64]. Some mothers cannot breastfeed their child for reasons beyond their control even if they would love to do so. Mothers need clear guidance on diet and taking supplements based on solid experimental evidence. All we need to do are to give accurate updated information to general public and to support women with reproductive age from multiple angles, i.e., physically, mentally, medically, financially, and socially. Simple changes in diet or supplementation of nutrients can have great impact on disease prevalence, suggesting that relatively little and simple investment can make considerable changes in eliminating future issues.

Having sufficient iodine is essential for healthy brain development in the fetus and young child. Iodine is essential for thyroid hormone synthesis, which regulates neuronal proliferation, migration, differentiation, and myelination during fetal brain development [65, 66]. Maternal iodine deficiency impairs thyroid hormone availability, leading to reduced dendritic arborization, altered synaptic plasticity, and disruptions in cortical and hippocampal circuit formation, which are critical for memory and executive function [67]. Severe deficiency results in cretinism, characterized by intellectual disability, motor dysfunction, and auditory deficits, while mild-to-moderate deficiency has been linked to lower IQ and increased risk of attention deficits in childhood [68]. Iodine supplementation during pregnancy has been shown to support optimal neurodevelopmental outcomes, improving cognitive function and psychomotor skills in iodine-deficient populations [69].

A woman’s iodine requirements increase substantially during pregnancy to ensure adequate supply to the fetus during this defined period. Iodine sdeficiency leads to inadequate production of thyroid hormone, and congenital hypothyroidism is the most common cause of preventable intellectual disability globally [65]. To ensure that everyone has a sufficient intake of iodine, WHO and UNICEF recommend universal salt iodization as a global strategy [70]. However, in certain countries salt iodization may not be feasible in all regions. Evidence suggests that in settings where universal salt iodization is not fully implemented, pregnant and lactating women and children under 2 years of age may not be receiving adequate amounts of iodized salt. Recent data shows that 35 million newborns globally are estimated to be unprotected from adverse consequences of iodine deficiency [71]. WHO and UNICEF recommend iodine supplementation for pregnant and lactating women in countries where less than 20% of households have access to iodized salt, until the salt iodization programme is scaled up. Countries with a household access to iodized salt between 20 and 90% should make efforts to accelerate salt iodization or assess the feasibility of increasing iodine intake in the form of a supplement or iodine fortified foods by the most susceptible groups.

Folic acid and inositol play critical roles in neural tube closure, neuronal proliferation, and synaptic plasticity during fetal brain development [72]. Folic acid is essential for DNA methylation, nucleotide synthesis, and one-carbon metabolism, ensuring proper neuronal differentiation and axonal growth, while inositol regulates intracellular signaling pathways critical for neurogenesis and myelination [73]. Deficiencies in either nutrient increase the risk of neural tube defects (NTDs), impaired cortical layering, and disrupted hippocampal circuit formation, which can lead to cognitive impairments, ASDs, and motor dysfunction [74]. Maternal supplementation with folic acid and inositol has been shown to reduce NTD risk, support neurotransmitter balance, and promote healthy synaptic connectivity, improving long-term cognitive and behavioral outcomes [75].

NTDs, which include spina bifida, are common congenital disorders; the global prevalence is roughly 1/500 births, accounting to approximately 241,000–322,000 affected pregnancies globally [76]. Neuroal tube defects lead to neonatal death or lifelong morbidity, i.e., cerebral palsy and intellectual impairment. Strong evidence shows that folic acid supplementation before and during first trimester of pregnancy significantly decreases the incidence of NTDs [77]. The neural tube forms by 28 days after conception. Therefore, start taking folic acid supplement after recognition of pregnancy likely miss opportunity to prevent NTDs. That is why many countries have implemented mandatory folic acid fortification of staple food, so that every single woman in reproductive age can take adequate amount of folic acid. Nevertheless, many countries including developed countries have not implemented folic acid fortification program yet. Many European countries have not yet implemented the fortification, and the prevalence of spina bifida in Europe is roughly 50% more than that in the North America where the fortification has implemented [78]. In the USA, folic acid fortification costs USD 0.06 per person per year, while lifetime direct costs for a person with spina bifida is estimated to be USD 791,000 in 2014 [79]. Currently, approximately 60 countries are implementing mandatory folic acid fortification of staple food, which is preventing only a quarter of preventable NTD cases globally [76] (Fig. 4). Folic acid fortification can exert benefit on other health problems such as anemia [80]. Number of countries with mandatory food fortification legislation included: salt, wheat flour, vegetable oil, maize flour, sugar, and rice (Fig. 4) [81, 82].

Efforts should be made to maximize the likelihood of healthy births through public health interventions. Environmental exposures during early life (particularly the in utero period) can permanently influence health and vulnerability to disease in later life (Fig. 3). Better public understanding is needed on the Developmental Origins of Health and Disease (DOHaD) – which can have lifelong implications.

The developing fetal brain is uniquely vulnerable to disruptions in maternal health and nutrition, with profound and lasting consequences for neurodevelopmental outcomes. Genetic predisposition, micronutrient availability, and environmental exposures intricately shape critical processes such as neurogenesis, neuronal migration, differentiation, and circuit formation. Efforts should be made to enhance the likelihood of healthy fetal, neonatal, and infantile periods, but it is difficult to enforce this basic right due to social and economic disparities in environmental factors, nutrition, education, and different levels of public understanding. National healthcare policies, global initiatives, or governmental regulations are needed to tackle some conditions/disabilities. Deficiencies in iodine, folic acid, inositol, and other key nutrients impair essential pathways, leading to structural and functional deficits in cortical and hippocampal networks, increasing the risk for intellectual disabilities, ASD, schizophrenia, and other cognitive and behavioral impairments. Similarly, ethanol exposure and maternal alcohol abuse disrupt micronutrient absorption and epigenetic regulation, exacerbating neurodevelopmental vulnerability.

Ongoing research is crucial to unraveling the mechanistic underpinnings of neurodevelopmental disorders, with the potential to inform precision-based interventions that optimize maternal health and fetal brain development. Advances in genetic and epigenetic research highlight the interplay between inherited susceptibilities and modifiable environmental influences, reinforcing the urgent need for nutritional interventions and targeted therapeutic strategies. Investments in these areas not only deepen our understanding of brain development but also hold the promise of reducing the global burden of neurodevelopmental disorders through rational, evidence-based interventions. By bridging epidemiological findings with molecular insights, we can drive transformative progress toward improving neurodevelopmental outcomes and lifelong cognitive health. Study and manage developmental disabilities should be priority in all countries. Increasing general awareness on the importance of early development and investing into prevention could have very significant impact on public health.

The authors acknowledge the stimulating discussions with Molnár Laboratory members and with the Medical Tutors and Students of St. John’s College during tutorials over the years.

This review does not contain new original research. The details on ethics are described in the cited publications.

The authors have no conflicts of interest to declare.

The sabbatical visit of Professor Masahiro Tsuji was supported by St. John’s College, Oxford with temporary membership of the senior common room. The laboratory of Z.M. was supported by the following funding sources: BBSRC Project Grant (BB/X008711/1) – Brain mechanisms of sleep: top-down or bottom-up, with Vyazovskiy (PI) and Molnár (Co-PI), MRC Project Grant “Orexinergic projections to neocortex: potential role in arousal, stress and anxiety-related disorders.” Molnár (PI) and Mann (Co-PI) (MR/W029073/1), Einstein Stiftung Berlin with Prof Britta Eickholt at Charité-Universitätsmedizin Berlin, Germany as part of Z.M. being Einstein Fellow at Charité-Universitätsmedizin Berlin (2020–2026), Oxford Martin School Grant: repairing the brain with 3D-printed neural tissues (Bayley, Szele, Molnár). M.T. was supported by the following funding sources: JSPS Grant-in-Aid for Fund for the Promotion of Joint International Research (Fostering Joiny International Research [B]) 21KK0176 Tsuji (PI), JSPS Grant-in-Aid for Fund for Scientific Research (B), KAKENHI 24K02866, Kyoto Women’s University Institutional Funding.

M.T. and Z.M. contributed equally to conceptualization, writing, editing, and selecting illustrations for this review.