Neurodevelopment Exam 3

Chaddock-Heyman et al., 2018

- 143 8- and 9-year-old children were divided up into intervention group and waitlist control group. - Intervention occurred for 2 hours each day after school for 150 days. - During intervention, participants spent approximately60 minutes at 70% or greater of max heart rate. - Measured white matter integrity in the corpus collosum before and after intervention. - Physical activity group showed increases in white matter integrity and myelination in corpus collosum but control group did not. - FA is measure of white matter microstructure:Higher FA = More tightly bundled, structurally compact white matter fibers with high integrity. - RD is marker of myelination. Lower RD = more myelination.

Physical Activity and BDNF Leckie et al., 2014

- 179 Older adult participants randomly assigned to walking exercise intervention or a stretching/toning control group - Exercise was supervised by a leader for all sessions. - Participants started by walking for 10 minutes and increased walking duration weekly by 5-minute increments until 40 minutes of walking was achieved at week 7. - Participants wore heart rate monitors with goal of keeping heart rate at 50-75% of max.Intervention was 3 days/week and lasted for one year. - Cognitive flexibility was assessed with a tax-switching paradigm

Cho et al., 2017

- 30 healthy 4th and 6th graders who were randomly assigned to control group or to take 16 weeks of TaeKwon Do, 5 days per week for 60 minutes. - Tested cognitive function with the stroop task. - Measured serum BDNF before and after intervention. - Only kids in intervention group saw increase in BDNF after intervention - Only kids in intervention group improved on stroop task - Effect of TKD on BDF increases - Effect of TKD on stroop score also increases

Barriers to Physical Activity

- 92% of Parks and Recreation agencies charge fees for all of their sports and activities programs - Low-Income Attitudes o I don't feel welcome - I don't have time due to family responisbilities - I don't have a way to get to games/practices - I don't know what sports are available in my community - Sports are too expensive

Malnutrition (poverty and lead exposure)

- A child with an empty stomach will absorb more lead into the blood - Diets high in iron, calcium, and vitamin C reduce lead absorption - High fat foods increase lead absorption

Physical Activity and Resilience Carlson et al., 2014

- Adolescence is a time of increased vulnerability to mental health problems - 1 in 5 adolescents experienced mental health problems - 50% of all lifetime psychological diagnoses are made before age 14 - Children from low SES backgrounds are 1-2 times more likely to development mental health problems than their peers - SES predicts age of onset, severity, and persistence of mental disorders

Does reduced EF/brain function cause obesity or does obesity cause reduced EF?

- Adult male rats were put on a high caloric diet for 90 days - During 90 days trained in Morris Water Maze and given test after the diet had ended - High calorie diet rats also performed more poorly in water maze task - Took longer to find the platform across every day of testing - entered quadrant of pool with platform significantly fewer times - High calorie diet rats experienced more neurodegeneration and had fewer undamaged neurons than rats fed a normal calorie diet - This was particularly true in the temporal cortex and in the hippocampus - High calorie diets leads to metabolic syndrome which can case dysfunction of the blood-brain barrier

Bellinger et al. 2008 Very low lead exposures and children's neurodevelopment

- Adverse outcomes, such as reduced intelligence quotient and academic deficits occur at low levels. Increased exposure is also associated with neuropsychiatric disorders such as ADHD and antisocial behavior - Lead remains the most important pediatric environmental health problem - No level of lead exposure appears to be safe and even the current low levels of exposure in children are associated with neurodevelopmental deficits - Primary prevention of exposure provides the best hope of mitigating the impact of this preventable disease - CDC will not reduce the screening guideline for lead because of the absence of effective clinical interventions to lower the blood lead levels for children or to reduce the risk for adverse developmental effects - Neurodevelopmental toxicity expression depends on... o neurotoxicants, nutritional status, genotype, and the characteristics of the home environment - Early lead exposure leads to o poorer academic success among children o increase the risk of behaviors linked to inattentive subtype of ADHD and aggression and explosive temper - Lead is implicated in o mitochondrial dysfunction o oxidativ e stress o deregulation of protein turnover o brain inflammation o decreased cellular energy metabolism o lipid peroxidation o altered activity of first and second messenger systems o abnormal neurotrophic factor expression o altered regulation of gene transcription - Lead levels affect hippocampal granule cell neurogenesis and morphology, and experience-dependent processes - Greater lead exposure in childhood had less activation in the left frontal cortex, and left middle gyrus in verb generation task - chelation is not a viable intervention for lead exposure - We have not yet reached the point where it is possible to cite a blood lead level that is "safe"

Air POllution

- Air Quality Index (AQI) is a measure of the degree of air pollution - In the US, 103 million people are exposed to PM above the standards - 123 million people are exposed to ozone above the standard

Taboada-Crispi et al. (2018) Undernutrition and Brain Development

- At age 5-11, malnourished children: • More power in theta bands in frontal, parietal, and motor cortex. • Higher theta band power is associated with learning and attentional disorders. • Similar to theta activity observed in children raised in institutions in Bucharest Early Intervention study. • Less power in alpha band in prefrontal cortex. • May be associated with delay in cortical white mater development.• May be a consequence of reduced myelination of prefrontal neurons resulting in inefficiency and reduced cognitive functioning

Early Life Stress and BDNF Perroud et al., 2013

- BDNF gene methylation (Gene silencing) in patients with borderline personality disorder is associated with the number of adverse childhood experiences - BDNF gene methylation is also associated with hopelessness and impulsivity in both patients and controls - Mothers completed the Traumatic Life Events Questionnaire. - Measured "lifetime trauma fear score" which is a total of fear ratings for each traumatic childhood event. - Then measured amount of methylation of BDNF gene at 2 CpG sites by collecting umbilical cord blood immediately after children's births. - Maternal lifetime fear was associated with increased BDNF methylation in male newborns and decreased BDNF gene expression in female newborns.

Overweight & Obesity

- Being overweight and obese are significantly prevalent among low-income families -Low-income communities tend to have fewer large supermarkets and more small grocery stores. •Small stores have fewer healthy alternatives like whole-grains, dairy, and fresh fruits and vegetables. •Food deserts, where 33% of residents live farther than one mile from a grocery store, are disproportionately in low-income neighborhoods. •Fast food restaurants and vending machines provide accessible ,affordable food in food deserts. •Fewer availability of outdoor space and recreational facilities. •Higher crime makes outside activities prohibitive.

BDNF

- Brain Derived Neurotropic Factor - A neurotropin, or growth factor, expressed in the brain - Regulates: synaptic plasticity, cell death, neural structure, increases neurogenesis and synaptogenesis - Especially expressed in hippocampus and amygdala - High levels in early childhood but reduced levels during adulthood are associated with aging related cell death - High levels of peripheral BDNF are associated with better memory and cognitive function - "Miracle grow for the brain"

Pollution and Neurodevelopment

- Children are especially vulnerable to air pollution: o higher breathing rate relative to body size o less developed natural barriers in lungs o Spend more time outside o less sanitary behaviors o Blood-brain barrier is more permeable in childhood than adulthood

BMI and Neurodevelopment

- Children who are overweight or have obesity tend to have poorer academic performance than non-overweight children - Why might this be the case? o Psychosocial factors such as poor self-esteem or difficulty with peer relationships o Cognitive factors such as decreased executive functioning - Studied 227 10- to 13-year-old children o Evaluated working memory, academic performance, and BMI - Being overweight or having obesity was associated with decreased academic performance - BMI was also associated with working memory performance - Working memory mediated the effects of BMI on academic performance

Study 1: Air pollution and brain abnormalities in children and dogs Calderón-Carcidueñas et al., 2008

- Children: o studied 55 children from Mexico City and 18 children from Polotitlán (control city) o Children were 9-10 years old o Children Completed IQ test and underwent MRI - Dogs o Studied 7 young dogs from Mexico City and 14 age-matched control dogs from Tlaxcala (control city) o Examined expression of IL-1B gene and COX2 gene (genes associated with cytokine expression or other inflammation related immune response) - ON IQ test, Mexico city children's performance age was significantly lower than their actual age o this was not true for children from Polotitlán - Using neuroimaging to measure "white matter hyperintensities" o WMH are areas of demyelinated neurons resulting from reduced blood flow potentially caused by inflammation o Negatively impact neurons' ability to synapse correctly, inhibiting neural communication o Associated with global cognitive deficits - Only one children form the control group had a single white matter lesion - Most children from Mexico city had white matter lesions. Several had many - Most of these lesions were subcortical in the prefrontal area - 3 Mexico city children were scanned 3-4. times over 11 months. All three showed increase in number of white matter lesions - 4/7 Mexico City dogs had white matter lesions. None were found in control dogs - Lesions were in regions similar to lesions in Mexico City children - Mexico City dogs had significantly higher IL_1B and Cox2 expression in frontal cortex - IL-1B and COX2 expression was significantly higher in regions with white matter lesions than in adjacent white matter

Undernutrition and Brain Development

- Critical period for the effect of nutrition on brain development is 2nd trimester of pregnancy to two years old (first 1000 days of life) - Malnutrition during this phase results in irreversible changes to cognition and behavior that persist even if period of malnutrition ends

Study 1: Air pollution and brain abnormalities in children dogs

- Dogs and children fro mMexico City had white matter hyper-intensities in frontal cortex - Dogs had increased expression of neuroinflmmatory genes - Neuroinflammation occurred near white matter intensities

Early Life Stress and BDNF Doherty et al., 2016

- Early life stress increases methylation of BDNF gene (particularly in the hippocampus and amygdala) leading to reduced expression in female rats - Methylation of BDNF gene in hippocampus of adolescent rats who were maltreated or received normal care during first week of life.

Malnutrition

- Entered 2022 with 828 million people worldwide suffering from malnutrition - Among those, 345 million were experiencing acute hunger - COVID added approximately 150 million hungry people to the world - The war in Ukraine increased the number of hungry people in the world by 25% in just three months - In 2020, 3.1 billion people worldwide could not afford a healthy diet - Every year approximately 5 million children in developing countries under 5 die of malnutrition - IN the U.S> nearly 20% of US households with children experience food insecurity, affecting approximately 15 million children - In developed countries, poverty is associated with obesity - In North America, 30% of children are overweight and 15% are considered obese

What are the effects of prenatal pollution exposure?

- Evaluated 267 mother-child pairs in BostonPrenatal exposure to pollutants was estimated by collecting daily pollution data where mother lived during time of pregnancy.At age 6.5 measured children's:•IQ•Attention•Response inhibition • Memory Chiu et al., 2016

Childhood Pollution Exposure and Cognition Sunyer et al., 2015

- Evaluated 2897 4- to 7-year-olds for one year from 39 different schools in Barcelona, Spain. - Children were assessed every three months for working memory and attention. - Also measured indoor and outdoor air pollution at each school. - Controlled for neighborhood SES - Children at high pollution schools showed significantly worse working memory than children at low-pollution schools - Also showed less improvement over the course of 4 evaluations - And these effects persisted even when controlling for age, sex, maternal education, neighborhood SES, and air pollution exposure at home

Lead and Cognitive Development Lanphear et al., 2005

- Even low concentration of lead have a detrimental impact on IQ - IQ scores drop on average 2-3 poitns for every additional 10 mg/dl of lead - But the effect is especially significant below 10 mg/dl, with an average 6.2 point decline between 0 and 10 mg/dl - Lead exposure both in early childhood and during later childhood (school age) can impact IQ

Physical Activity and BDNF

- Exercise increases BDNF expression in the brain, particularly in older adults - BDNF reduces cell death, promotes neuro/ synaptogenesis, and improves cognition and memory

Belcher et al. 2020 The roles of physical activity exercise and fitness in promoting resilience during adolescence--> Effects on Mental Well-Being and Brain Development

- Focuses on physical activity (PA), exercise, and fitness as modifiable resilience factors that may help promote self-regulation via strengthening of top-down control of bottom-up processes in the brain, thereby acting as a buffer against mental health problems during this period of vulnerability o Present how impairments in self-regulation, which involves top-down control to modulate bottom-up processes are common across a wide range of mental health disorders. o Use neuroimaging to highlight how neural systems underlying top-down control continue to develop across adolescence, and propose that PA, exercise, and aerobic fitness may facilitate resilience through strengthening individual brain regions and large-scale neural circuits to improve emotional and behavioral regulation -PA is defined as any bodily movement that increases energy expenditure above resting and encompasses occupational, sports, conditioning, and other activities (12). Exercise, a subset of PA, is defined as planned, structured, repetitive, and purposeful PA to improve or maintain physical fitness (12), which is a set of physiologic attributes (e.g., body composition, muscle strength, balance, cardiorespiratory effects) related to the ability to perform PA and exercise that have a relationship with good health (13,14). Aerobic fitness refers to maximal oxygen consumption (15), or the ability of circulatory and respiratory systems to deliver oxygen during activity, and is commonly interchanged with the term cardiorespiratory fitness file:///Users/criscus/Downloads/Belcher-2020-The%20roles%20of%20physical%20activity%20exercise%20and%20fitness%20in%20promoting%20resilience%20during%20adolescence%20Effects%20on%20mental%20well%20being%20and%20brain%20development.pdf

Poverty and Physical Activity

- High-Income o 75% played sports - Middle-Income o 50% played sports - Low-Income o 25% played sports - % of children participating in healthy levels of physical activity increases with annual family income

Lead and Cognitive Development Braun et al., 2006

- Higher lead levels have consistently been shown to be associated with symptoms of ADHD - Measures of blood lead concentrations in over 4,0000 4- to 15-year-old children - Kids in the highest 20th percentile of lead levels were 4 times more likely to be diagnosed with ADHD compared to the bottom 20th percentile

Lead and Cognitive Development

- In addition to water, lead exposure is most common through lead paint - The CDC recommends no more that lead levels of 10 mg/dl, however it has been recommended to reduce the threshold for "safe" lead levels to 2mg/dl - Lead levels in children's blood has declined significantly: o In the 1970s 88% of US preschool children had lead levels greater than 10mg/dl o Today the average has declined to 1.9 mg/dl and only 1.77% of children's lead levels are above 10 mg/dl - Non-white children and children from low-income households are significantly more likely to be exposed to lead o This is true both through water and paint

Air Pollution and Poverty

- In the US, low-income communities are consistently exposed to higher levels of pollutants than predominantly wealthier neighborhoods - In LA I-710 is a major source of pollution - Of the 20 neighborhoods the highway passes through, 70% are non-white and most are low-income - Across the US, white individuals are exposed to lower than average concentrations of emission from most sources - Four over 75% of different types of emissions, people of color experience greater than average exposure - Black, Asian, and Hispanic Americans have a higher incidence of premature death due to air pollution - Low-income individuals are particularly susceptible to the dangers of air pollution o low-income individuals are less likely to have health care - Low-income individuals are more likely to have additional health conditions - Low-income individuals are more likely to smoke and have less nutritious diets o Low-income indviduals have less access to other protective factors

Barbados Nutrition Study

- Initial participants recruited in the 1970s -Studied 108 children who experienced severe acute malnutrition in first year of life and 58 controls from same neighborhood and matched on age and sex. - Malnourished children participated in intervention program that insured healthy diet after first year as well as preschool, parental nutritional training, home visits, and medical care. -By age 12 had completely caught up to controls in terms of height and weight.Continue to be studied now that they are in their 50s. - At age 12, malnourished children had: o lower IQ scores o worse academic performance o attentional problems o behavioral problems - Attentional and behavioral problems persisted into adulthood - Had lower levels of educational and professional attainment - Undernourishment seems to particularly effect frontal cortex and salience and control networks - Consistent with other EEG and behavioral studies that find early undernourishment leads to IQ decrease and behavioral and attentional problems - Persistence of behavioral effects of undernourishment in first year suggests that effects on neural development are irreparable

Key Inflammatory cytokines related to air pollution

- Interlukin-1B - Tumor necrosis factor alpha - Human brain has specific receptors for these cytokines - Therefore, when there is an infection, the brain can mount its own immune response - Key cell in neural immune response are microglia (a macrophage) that patrols brain for damage or toxins and cleans up trash - Cytokines may also be able to cross the blood brain barrier or direct immune cells through the BBB o But generally stuff shouldn't be crossing the BBB - Pollutants may interact with immune cells (T and B cells) to allow them to damage endothelium and pass through the blood brain barrier - Because the brain also mounts its own immune response, the addition of additional immune cells causes a hyperactive immune response inside the brain o this leads to neuroinflammation o When brain is inflamed macrophages like microglia (the garbage collectors of the brain) can begin attacking healthy cells

Homeostatic Cytokines

- Involved in cell migration when there is no infection - Also bring the system back to baseline when immune response is no longer needed - E.g. some chemokines

Iron Deficiency and Neurodevelopment

- Iron aids in neural development, beginning prenatally - Pregnant rats fed iron-rich or iron-poor diets - Offspring whose mother had iron-deficient diets: o Had a 20% reduction in myelinated axon diameter in corpus collosum o Had reduction in peak action potential amplitude in corpus collosum o Reduced amplitude of action potentials in corpus collosum o Had 25% reduction in dendritic length in hippocampus o Had poorer performance in novel object recognition task - Iron aids in neural development, beginning prenatally - Pregnant rats fed iron-rich or iron-poor diets - Offspring whose mothers had iron-deficient diets: o Had 25% reduction in dendritic length in hippocampus o Had reduction in dendritic complexity in hippocampus o Failed to discriminate between novel and familiar objects

Iron

- Iron deficiency is the most common micronutrient deficiency worldwide - Affects approximately 1/2 of preschool-aged children and pregnant women

Poverty and Lead Exposure Bellinger et al., 1990

- Lead exposure interacts with poverty to have a greater effect on development in low-income children than high-income children - Measured children's cognitive functioning at 24 and 57 months - Low SES children showed decreases in cognitive functioning between 24 and 57 months, regardless of lead levels at birth - Hi SES children with low or medium levels of lead at birth showed no change in cognitive functioning between 24 and 57 months - High SES children with high levels of lead at birth showed large improvements in cognitive functioning - SES buffers the effect of lead on cognitive functioning

Co-exposure to other neurotoxicants Henn et al., 2012

- Manganese is another neurotoxicant metal that is found in soil, polluted air, and water - Co-administration of manganese and lead to rats triples brain lead levels - Lead has a greater effect on development for kids with the highest manganese levels

Galler et al. 2021 Neurodevelopmental effects of childhood malnutrition: a neuroimaging perspective

- Many children survive early intervention - However, many continue to exhibit neurodevelopmental deficits o low IQ o Poor school performance o Behavioral problems over their lifetimes - This article helps to assess brain structure and function (EEG/ERP/MRI/fNIRS) 1. Provide an overview of the impact of postnatal malnutrition on cognition and neurodevelopment 2. Identify evidence gaps in research studies of early childhood malnutrition and neurodevelopment 3. Advocate for the use of newer technologies in developing countries - Root causes of malnutrition are multi-dimension and include poverty, poor sanitation, crowding, infectious disease, maternal depression, and child abuse and neglect - Wasting: result of moderate-severe acute malnutrition associated with substantial weight loss or failure to gain weight - Stunting: results from inadequate nutritional intake, both in utero and early childhood, leading to potential and stunted children may never attain their full height potential even after intervention ---> brains may never develop to their full cognitive potential and often face learning difficulties and decreased earning capacities - Long-term effects of Protein-energy malnutrition (SAM) o EEG studies on SAM survivors indicate irreversible neurological damage when exposure occurred before the age of 2 (based on small sample size) o Decreased alpha activity, increased theta, alpha 2, and beta waves o Altered ERP activity was found to be associated with impaired executive functioning o Nutrition increases working memory - Gap in Research o longitudinal studies o studies of nutrition requirements to support brain development over the lifetime o All brain studies need to include both genders

Case Study: Mexico City

- Mexico City Metropolitian Area (MCMA): o largest urban area in North America o 20 million inhabitants (8 million children) o 40,000 industries and 4 million vehicles consume 10.5 million gallons of petroleum per year o Primary pollutants are a particulate matter (PM) and ozone

Lao et al. 2017 Mapping the basal ganglia alterations in children chronically exposed to manganese

- Mn can be toxic when the dose exceeds Mn homeostasis - Chronic Mn exposure is associated with neuro-motor and neuro-cognitive deficits from drinking water - Exposure to Mn enlarges many areas of the basal ganglia structures, preferentially affecting the putamen. o these areas showed significant correlations with fine motor performance, indicating a possible link between altered basal ganglia neurodevelopment and declined motor performance in high Mn exposed children - Basal Ganglia: intersection where action and cognition meet, due to its involvement in several motor and cognitive cortical-subcortical loops - Mn intoxication patients often show symptoms that resemble Parkinson's - This study applied a 3D surface-based morphometry analysis on 3 Basal ganglia structures (putamen, globus pallidus, and the caudate) - Observed significant hypointensities in the group of children with higher Mn exposure - This study may provide new biomarkers for Mn neurotoxicity and as neuro-substrates for the impaired motor performance associated with excessive Mn exposure. - Detected significant enlargement in the putamen and trends of enlargement in the left globus pallidus - Findings demonstrated significant regional enlargement in BG subnuclei of Mn exposed children - Mn likely disrupts downstream BG dopaminergic output pathways - Lmitiations o relied on Mn concentration in drinking water to define exposure groups o did not explore other contaminations in water o sample spans 9-15 years old

Inflammatory Cytokines

- Mobilize cells for the site of injury or infection and cause pain and inflammation - E.g. interlukons

Dennis et al., (2022) BMI and Neurodevelopment

- Neighborhood poverty strongly predicted BMI, cortical volume, and cognitive scores - There was also a relationship between BMI, cortical volume, cognitive scores, and parent education - Neighborhood poverty was specifically associated with reduced volume in prefrontal cortex 0 BMI mediated that effect of neighborhood poverty on cortical volume - This was true for measures of working memory and cognitive flexibility, but not cognitive control - Suggests that relationship between BMI and academic achievement may not be social or self-esteem related. Rather BMI may have some effect on brain development

BMI and Cognition

- Other research has found that higher BMI is associated with: o lower math and reading scores o Lower cortical volume in the OFC and reduced executive function o Reduced gray matter volume in medial temporal lobe and frontal lobes in men o Reduced cortical thickness in frontal lobes and decreases in executive function in 9- to 11-year-old children

Prenatal Pollution Exposure and Cognition

- Other studies on prenatal exposure have found:•Reduced non-verbal intelligence at age 5 (Edwardset al., 2010) • 3 times more likely to be developmentally delayed by age 3 than non exposed children (Perera et al.,2003). • Potentially delays in development of gross-motorskills by 6 months and fine-motor skills by 18 months(Lin et al., 2014)

Key Pollutants

- Particulate matter (PM) - Ozone (O3) - Carbon monoxide (CO) - Sulfur Dioxide (SO2) - Nitrogen oxide (NO) - Lead (Pb) - Most PM comes from mobile sources, residential fuel combustion, and industrial pollutants - All have been identified by EPA as hazardous to human health

Physical activity and Neurodevelopment Gunnell et al., 2019

- Physical activity can be beneficial for executive function, memory, brain development, and academic achievement - But results seem to depend on several factors: o Duration of intervention- longer interventions are more effective than acute bouts of exercise or short interventions - Level of exertion- PA should be aerobic or anaerobic (heart rate about 60% of max) - Duration and frequency of exercise- Exercise that lasts for 60 minutes and occurs multiple times a week is more effective - Age of participants- Exercise is more effective as an intervention with pre-adolescent participants

POVERTY, PHYSICAL ACTIVITY, AND THE BRAIN

- Poverty leads to reduction in BDNF expression - Poverty is associated with reduced access to PA - PA promotes BDNF expression - BDNF promotes neurogenesis/ synaptogenesis - PA relates changes in brain structure promote resilience, particularly in the face of poverty related stressors

Iodine

- Pregnancy involves higher demands for thyroid hormones - Iodine helps regulate the expression of thyroid hormones to maintain the appropriate balance during pregnancy - Thyroidal hormones are involved in nearly every key neurodevelopment processes - During first 20 weeks of gestation, fetal thyroid is inactive, so fetus is completely dependent on maternally produced thyroid hormones

Maternal Stress Cory-Slechta et al., 2004

- Pregnant rats are given high lead water or no lead during pregnancy through weening - Also exposed to restrain stress during pregnancy or not - Exposure to stress or lead caused increased cortisol levels in mothers - Lead (or lead + stress) also caused increased cortisol levels in offspring

Deprivation Guilarte et al., 2002

- Pregnant rats were fed high-lead or normal diets (controls) until they gave birth and were done nursing offspring - All offspring were the fed a normal diet but lived in either a normal cage or an enriched cage (had toys and activities) - Lead exposed rats raised in enrich environments experienced more BDNF expression in hippocampus than any other group - Lead exposed rats raised in enriched environments caught up to non-lead exposed rats in water maze learning

Iron deficiency and neurodevelopment Christian et al. 2010

- Pregnant women in Nepal were randomly assigned to receive daily: a) iron and folic acid b) iron, folic acid, and zinc c) a multi-vitamin containing many vitamins and minerals d) control: just vitamin A - At 7-9 years old 676 children were evaluated for executive and motor function - Children of women who received iron/folic acid supplement were only group that showed significant EF improvement over control group - Also the only group that showed improvement in movement and dexterity composite score

Dennis et al. 2022 Socioeconomic Status, BMI, and Brain Development

- Rates of childhood obesity are greater among low SES children and childhood obesity is also associated with cortical alterations and impaired neurocognition, specifically in the domain of executive functioning - Used Adolescent Brain Cognitive Development (ABCD) study to construct multiple linear regression models and conduct mediation analyses to investigate the influence of BMI on the relationships between SS and both neurocognition and brain morphology -SES was associated with lower BMI, greater total and prefrontal cortical volume, and better performance on assessments of executive functions - BMI had a significant indirect effect on associations between area deprivation and both total and prefrontal cortical volumes o BMI also played a mediating role in the association between area deprivation and composite neurocognitive scores, which were driven by performance on tasks of working memory and cognitive flexibility, but not cognitive control - These findings suggest that BMI should be considered in future studies investigating the relationship between low SES and poor neurodevelopmental outcomes - Indicated a significant association between SES and BMI, and positive association between SES and both neurocognition and cortical volumes - BMI had a significant indirect effect in the associations between ADI and various measures of brain structure and cognition - Sample sizes of the cited publications were limited in comparison to that of the ABCD dataset--> larger dataset allowed for more accurate representation of the relationship between parental education and cortical structure - Possible that ABCD participants who were obese might have had some level of insulin resistance, hypoglycemia, increases in inflammatory signals and/or cardiac disruption--> negatively impact brain development

Physical Activity and Resilience Beicher et al., 2020

- Remember: In adolescence, there is a lag in development of regions associated with top-down control/executive function relative to regions associated with emotion, rewards seeking, sensation seeking, etc. - This is also the time period of primary emergence of mental health problems. - And a significant decrease in physical activity.Belcher et al., 2020

Case Study: Mexico City Study 2: White matter hyperintensitities and brain growth

- Studied 3 groups of children for one year: o WMH+ groups: 10 children from Mexico City who have documented white matter hyperintensities o WMH- group: 10 children from Mexico City who do not have whtie matter hyperintensities o CTR: 10 children from outside of Mexico City without chronic exposure to pollution - All children were approximately 7 years old - Measured IQ, brain volume, and number of white matter hyper-intensities at baseline and one year later - Measured the expression of 3 proinflmmatory cytokines: o IL-12 o TNF-a o MCP-1 -And the expression of 2 cytokines associated with neural repair and rebuilding o CCL22: a "homeostatic" chemokine responsible for directing tissues to their appropriate location. May be associated with neural repair or neurogenesis o G-CSF: Neuotrophic factor that induces neurogenesis, counteracts apoptosis (cell death) and increases neuroplasticity - WMH+ group experience significantly more brain growth over the course of the year than the WMH- group.The WMH+ group did not differ in change in brain volume from the CTR group.Biggest differences in growth between WMH+ and WMH-groups were in frontal, parietal, and temporal cortices. - MCP-1 is involved in the recruitment of immune cells into the CNS and induces an increase in brain endothelial permeability. Increased TNF-α is a marker of brain disease in adults and associated with reduced brain volume. - Children who were exposed to pollution and showed WMH experienced more brain growth than those without WMH and equal brain growth to those not exposed to pollution. •Children without WMH had higher levels of inflammatory cytokines than children with WMH. •Children with WMH had higher levels of homeostatic cytokines, indicators of active immune response (monocytes and neutrophils),and cellular recovery. •Yet WMH are typically a risk-factor for neurodegeneration. - WMH may indicate temporary repair responses.•Mexico City children with WMH are those who are still able to mount an immune response to pollution •Increased grey matter volumes are associated with compensatory neuroplasticity: Damage to white matter leads to compensatory overdevelopment of relevant cortex •WMH may reflect increased blood flow to these rapidly developing areas. •WMH- children may be those who are no longer able to mount reparative immune response - Post-mortem evaluation of 20 children and 15young adults growing up in Mexico City and 8 individuals who grew up in non-polluted city. - Found evidence of both beta amyloid plaques and tau proteins in frontal lobes of individuals from Mexico City, but not in control individuals. - Observed other indicators of neuroinflammation. - Brains of children fromMexico City show many of the markers seen inAlzheimer's and Parkinson's Disease.

What are the barriers to physical activity for children from low-income households?

- TIme - Transportation - Feeling welcome and accepted - Availability of outdoor space, parks, fields, and programs - Less likely to have adequate PE in school

Leckie et al., 2014 Results

- The intervention increased the level of BDNF in blood for participants over 65 years old - For all participants BDNF levels mediated the effect of the intervention on cognitive flexibility - The intervention improved by cognitive flexibility but mediated by how much it restored or improved levels of BDNF

Iodine Deficiency and Neurodevelopment

- Thyroid hormone receptors are expressed both in neurons and glial cells. - When thyroid hormones bond to thyroid hormone receptors it activates patterns of genes involved in axonal and dendrite out growth, synapse formation, cell migration and proliferation. - Iodine deficiencies that disrupt maternal thyroid hormonal balance consequently disrupts neuronal migration processes. - Neurons will not reach their final destinations in the outer layers of cortex causing alternations in cortical structure. - Results in permanent lesions in cortex, hippocampus, and cerebellum. - Studied 8- to 9-year old children of mothers with low or normal iodine concentrations during pregnancy - Consequences of iodine deficiency during pregnancy: o Altered motor coordination o Language Delay o Behavioral problems o Higher incidence of ADHD

Prenatal Pollution Exposure and Cognition Chiu et al., 2016

- Timing of exposure and sex of the baby mattered!•Exposure in late pregnancy mattered for boys' IQ but not girls'. •Exposure also affected attention in boys but not in girls. •Early exposure affected memory in girls but not boys

Erickson et al., 2014

- Used similar intervention to Leckie et al. - Aerobic exercise increased hippocampal volumes compared to stretching/toning - Effect of exercise on hippocampal volume was additive. As the time in the intervention went longer, hippocampus grew larger - Greater increases in hippocampal volume were associated with 1. increased fitness 2. increased levels of peripheral BDNF 3. Increased memory performance - Usually see a decrease in hippocampal volume with age

Chiu et al. 2016 Prenatal particulate air pollution and neurodevelopment in urban children: Examining sensitive windows and sex specific and associations

- Wanted to identify sensitive windows for the associations between prenatal particulate matter with diameter <2.5 um and children's development - Mothers were primarily minorities - Increased PM exposure in specific prenatal windows may be associated with poorer function across memory and attention domains with variable associations based on sex. Refined determination of time window- and sex-specific associations may enhance insight into underlying mechanisms and identification of vulnerable sub group - Sex specific effects--> morphological, physiological and chemical differences between boys and girls in relation to neurodevelopment - Results o prenatal maternal particulate air pollution may be associated with IQ, attention, and memory - Pro-inflammatory environmental toxins may activate microglia altering production of cytokines and chemokines that disrupt neurodevelopment - Found the associations between prenatal PM2.5 and memory domains more evident in girls--> might be due to disruption in the development of hippocampal neurons - Study population consists of a lower-SES ethnically mixed inner-city cohort that may be more highly exposed to ambient pollution and also more likely to have poorer neurodevelopmental outcomes o Did not find significant interactions between sex and PM2.5

How might air pollution affect the developing brain?

- When toxins enter the body, an innate immune response is generated - Immune response is directed by cytokines: o small proteins that aid in cell-to-cell communication in immune response o stimulate the movement of immune cells to infection or truama o Cytokine levels are measurable in blood and cerebrospinal fluid - Many families of cytokines including interlukons, interferons, and chemokines

SNAP

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How might air pollution affect the developing brain? - List

1. Children are particularly susceptible to toxins in the air. 2. When toxins enter the body an immune response is generated. 3. This immune response is driven by inflammatory cytokines that direct immune cells to the site of the infection. 4. The brain mounts its own immune response, however, toxins may interact with T and B cells(immune cells) to damage endothelial cells and cross the blood brain barrier. 5. This causes a self-perpetuating cycle of increasing immune response in the brain leading to neuroinflammation. 6. When brain is inflamed and when inflammation is chronic, immune cells (like microglia) begin attacking healthy neural tissue and can destroy the myelin sheath.

Poverty interacts with lead to have detrimental effects on cognitive development. Why?

1. Co-exposure to other neurotoxicants 2. Deprivation 3. Malnutrition 4. Maternal Stress

Summary: Pollution Exposure and Poverty

1. Low-income individuals are more likely to be exposed to air pollutants, particularly from mobile sources. 2. Research on children growing up in Mexico City has found: a) Air pollution is associated with cytokinetic markers of neuroinflammation. b) Increased neuroinflammation is associated with white matter hyper intensities (white matter lesions). c) White matter hyper intensities may be associated with compensatory cortical growth. d) Children exposed to heavy pollution have neural markers typically seen in Alzheimer's disease. 3. Exposure to air pollution in utero can effect long-term cognitive development, but depends on the timing of the exposure and child's gender. 4. Childhood exposure to air pollution can have a detrimental affect IQ, working memory, motor responses, and attention.

BMI, SES, and Neurodevelopment

1. Obesity is associated with reduced cognitive function 2. SES is associated with reduced cognitive function and alterations in brain structure 3. SES is associated with increased risk for obesity - Collected data from ABC study from 7607 9- to 10-year-old children Evaluate o SES o Area deprivation index (neighborhood level poverty) o BMI o Executive funciton o Cortical volume

Overview of Physical Activity and Resilience Beicher et al., 2020

1. Physical Activity and Exercise 2. Strengthening of Brain Structure and Function 3. Resilience Effects & improved top-down control of bottom-up processes 4. Enhanced behavioral and emotional self-regulation 5. Decreased risk for mental health problems during adolescent development

Mechanisms of Neurodegenerative Disease

1. Tau proteins (which typically help to stabilize the internal structure of neurons) detach from their typical anchors and get stuck to other tau proteins. 2. This create neurofibrillary tangles of tau proteins inside neurons. 3. Beta amyloid (another protein) clumps into plaques between neurons. 4. The increase in beta amyloids leads to increased production of tau proteins. 5. When there is neuroinflammation, microglia and astrocytes (the brain's garbage collectors) cannot adequately remove plaques. 6. Likewise, microglia and astrocytes responding to beta amyloids increases neuroinflammation and can lead microglia to begin attacking healthy tissue.

Why might bMI affect brain development

1. The brain relies on cerebrovascular system to supply oxygen and glucose necessary for healthy neuronal function. Vascular dysfunction in the brain can lead to reduced cerebral perfusions and neuronal atrophy 2. Obesity may be related to insulin resistance which increases inflammation and may cause cardiac disruption affecting brain development 3. Childhood obesity is associated with endothelial disfunction (cells that line organs and cavities that control blood supply) leading to inadequate glucose supply in the brain 4. Obesity is associated with higher risk of sleep apnea which could negatively affect brain development and cognition

Malnutrition and Brain Development

1. Undernutrition - In the first 1000 days of life may irreversible damage, particularly to frontal cortex function 2. Micronutrient deficiencies - Can dramatically effect neurogenesis and migration in developing fetus 3. Overweight and obesity - Affects blood flow to the brain and may lead to cell death or reduced developmental of PFC, temporal cortex, and hippocampus - First 1000 days of life are critical period for nutritional effects on brain development - Damage caused by malnutrition at this stage may be irreversible, even if nutrition is improved - because obesity may lead to cell death, it may continue to affect brain health throughout the lifespan

Key Ideas for Class

Key Idea 1: Growing up in poverty is not deterministic for brain development or for psychological, behavioral, or life outcomes; individual experiences of childhood poverty differ. Key Idea 2: Adversity can be experienced by anyone, from any background, but poverty increases the likelihood of experiencing it. Key Idea 3: Poverty, race, and racism are inextricably linked in the United States.Key Idea 4: What appears to be a"deficit" may be an environmental adaptation, or hidden talent. Key Idea 5: The effect of developmental environment on neurodevelopment will differ depending on an individual's environmental susceptibility and this is true for both deficits and adaptations.

Note on Overweight & Obesity terminology

Overweight and obesity are terms used in the scientific literature to study the relationship between weight and cognitive/neural factors. - Overweight = BMI between 25 and 30 - Obesity = BMI greater than 30 - BMI is based on your weight given your height. - This terminology is problematic because: - BMI is an imperfect measure of what makes a healthy weight. - The terms overweight and obesity carry tremendous social stigma. - However, it is true that being less lean is associated with some poor health, cognitive, and neural outcomes. - Because this is the terminology used in the scientific literature, it is the terminology we are going to use in this class

Consequences of undernutrition

Wasting: Substantial weight loss or failure to gain weight due to severe acute malnutrition Stunting: when a child is too short for their age as due to malnutrition

Availability of parks and sports fields is determined by neighborhood income:

o Sampled 50 neighborhoods in large Southern California city o Identified concentration of poverty in each neighborhood - Average park acres and number of sports fields is highest in low poverty areas

Availability of PE in school depends on school income levels:

o Studied 97 elementary schools in two regions of the US o asked school principals to complete a yes/no questionnaire about PE accessibility - Low-income schools tend to provide less amount of PE, have more students in the classes, and fewer schools have PE teachers

Externalizing Disorder Conduct and oppositional defiant disorder; ADHD

• Affect 19% of adolescents. • May be a consequence of inability to exert "top-down"control over or regulation of impulsive or hyperactive behavior.

Internalizing Disorders:

• Anxiety and depression • Affect 14-32% of adolescents. • May be a consequence of an inability to exert "top-down"control over or regulation of emotional reactivity

Childhood exposure to pollution has also been found to be associated with

• Increased likelihood of producing low scores on tests for response-time, motor responses, and motor coordination (Wang et al., 2009). • Decreased intelligence at 8-11years old (Suglia et al., 2008). • Decreased attentional abilities at 7-14 years old (Chiu et al., 2013).