By Kenda Freeman
While leadership and coordination for the Global Brain Disorders Research program is facilitated primarily by NIH FIC, funding is provided by multiple NIH institutes, including NIEHS, the National Institute on Aging, the National Institute of Mental Health, and others.
This program allows global collaborations to take place between researchers, where institutions in the U.S. and upper-middle income countries can partner with institutions in other countries, including LMICs.
In collaboration with NIH Fogarty International Center (FIC), NIEHS is supporting innovative global research to understand and reduce the effects of environmental factors on brain health. Through the Global Brain Disorders Research program, NIEHS funds collaborative research projects on brain and nervous system disorders that occur throughout life. The program is unique, providing a mechanism to build research capacity in low- and middle-income countries (LMICs) to address environmental factors and reduce the incidence of brain and nervous system disorders.
Many environmental and dietary exposures are known to impact the nervous system across the human lifespan, from before conception, through pregnancy, and into adulthood, thereby raising the risk for various brain and nervous system disorders. These disorders are a public health issue of global concern, especially for people in LMICs who may face additional vulnerabilities related to health care access, water security, burden of environmental pollutants, or pre-existing diseases.
With program coordination through NIH FIC, NIEHS funds projects addressing brain disorders in countries such as Thailand, Egypt, and the Democratic Republic of Congo (DR Congo). Investigators at U.S. institutions work to build the research capacity of institutions in LMICs, and to introduce or develop interventions to reduce exposures associated with brain and nervous system disorders in young children or adolescents.
Examining Prenatal Pesticide Exposure and Child Neurodevelopmental Outcomes in Thailand
For a project in Thailand, investigators are exploring the impact of prenatal pesticide exposure on children’s birth outcomes, such as birthweight and head circumference, as well as neurodevelopmental effects through life. To carry out their investigations, they are following a cohort of pregnant agricultural workers and their children in northern Thailand.
Dana Barr, Ph.D., professor in the Department of Environmental Health in the Rollins School of Public Health at Emory University, and Nancy Fiedler, Ph.D., professor in the Department of Environmental and Occupational Health at Rutgers School of Public Health, are partnering with investigators at Chulalongkorn University and Chiang Mai University to conduct the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE).
As one of the world’s leading food exporters, Thailand relies heavily on pesticides, such as herbicides and insecticides, to protect crops and increase yields. In recent years, the use of agricultural pesticides has increased exponentially in Thailand; however, infrastructure to effectively manage and control pesticide use is lacking.
In Thailand, it is not uncommon to find women working in the agricultural industry. “Pregnant agricultural workers and their children are especially vulnerable to the harmful effects of toxic pesticides, such as organophosphates and pyrethroids,” said Barr.
The research team is expanding the initial SAWASDEE cohort to 300 mother-infant pairs. The mothers are orchard workers and rice farmers from two sites in northern Thailand. “These two worker populations experience very different exposure scenarios,” Barr said. “Orchard workers have one growing season per year and experience high levels of pesticide exposure over a short period of time, whereas rice farmers have two growing seasons per year, and experience low levels of pesticide exposure over a long period of time. Studying these populations gives us an opportunity to better understand the relationship between prenatal pesticide exposure and adverse birth and neurological outcomes in children.”
To document pesticide exposure over time, the research team will measure organophosphate (OP) and pyrethroid (PYR) metabolites in urine and blood samples collected during each trimester of pregnancy, as well as from umbilical cord blood samples collected from newborns. They will then follow infants from birth to age 3 and perform a battery of neurodevelopmental tests to assess outcomes such as visual attention, regulation of emotion, memory, and inhibitory control.
“The funding and support from NIEHS and Fogarty for this project has been invaluable,” Barr stated. “This particular NIH funding mechanism has enabled us to not only successfully partner with Thai investigators, but to also impart knowledge and provide research experience so they can conduct their own studies independently in the future.”
Exploring the Vulnerability of the Adolescent Brain to Pesticides in Egypt
Another research project is taking place in Egypt, where the impact of pesticide exposure on adolescent field workers is a major public health concern. Diane Rohlman, Ph.D., professor of occupational and environmental health at the University of Iowa, is working with investigators from Menoufia University in Egypt and other partners to examine the effects of pesticide exposure on the developing adolescent brain.
In Egypt, adolescents are traditionally involved in the agricultural industry as field workers. “Teenagers are usually hired by the Ministry of Agriculture to work during the summer months, but they face significant risks to the harmful effects of pesticides,” said Rohlman.
In one exploratory research study, Rohlman and her research team followed a cohort of adolescent, male Egyptian field workers over a period of 10 months to examine the impact of exposure to chlorpyrifos, an OP pesticide, on neurobehavioral performance. They evaluated pesticide exposure and neurobehavioral performance data at 35 different time points before, during, and after the pesticide application season for adolescents hired to apply pesticides and adolescents from the same communities, but who were never hired as pesticide applicators. Cumulative levels of a urinary biomarker of chlorpyrifos exposure were used to classify study participants into low and high exposure groups.
“We found that adolescents in the high exposure group showed neurobehavioral deficits, and these deficits persisted and worsened, even months after the pesticide application season ended,” Rohlman stated.
“The funding and support from NIEHS and Fogarty have allowed us to build capacity among researchers in Egypt – to give them the training, resources, and experience – that are needed to carry out comprehensive exposure assessments and analyze subtle changes in neurological performance among study participants.” – Diane Rohlman, Ph.D.
Based on these findings, Rohlman and her team initiated a longitudinal study in Egypt of adolescent field workers. Over a five-year period, they will examine how the developing adolescent nervous system responds to varying levels of pesticides. Through this study, they aim to determine if repeated exposures produce progressive deficits in neurological and behavioral functions, and if these deficits are reversible after exposure ends. They are also working with the Ministry of Agriculture to implement a training and intervention program for the adolescent field workers on ways to reduce pesticide exposure through practical methods such as hygiene, work place policies and practices, and use of personal protective equipment. The impact of the training program will be evaluated by assessing workers’ reactions, behavior and work practice changes, and knowledge retained.
Addressing Harmful Dietary Exposures Linked With Neurological Deficits in the Democratic Republic of Congo
Daniel Tshala-Katumbay, M.D., Ph.D., associate professor of neurology at Oregon Health and Science University, is working with a multidisciplinary team of investigators at the Congo National Institute of Biomedical Research and other institutions to explore the neurological effects associated with cassava consumption in children, and to explore the effectiveness of a novel intervention in reducing cassava toxicity.
Cassava is a subsistence crop for more than 600 million people around the globe, especially those who live in poverty or remote areas where food security is lacking. Most countries in sub-Saharan Africa, such as the DR Congo, rely on cassava as a staple food source. The cassava varieties that grow in these regions contain high amounts of a toxic compound called linamarin, which is metabolized into poisonous cyanide following human consumption of cassava that has not been properly processed or detoxified. The consumption of improperly processed cassava is associated with developmental disabilities in children, including konzo, a severe and irreversible neurological disease that causes selective paralysis to the legs.
In a recent study, Tshala-Katumbay and his team demonstrated the value of measuring urinary thiocyanate, a biomarker of cyanide exposure, as a method to identify children at risk for neurological impairment before symptoms occur. They examined cognitive and motor performance in children with and without konzo who live in the district of Kahemba, DR Congo, and measured levels of thiocyanate in the children’s urine. Results showed that poorly processed cassava was associated with impaired cognitive and motor performance in the children over time, and these impairments were more pronounced in boys compared to girls. Furthermore, children with konzo showed impaired motor skills at least four years after follow-up, and boys without konzo performed better on cognitive tests than boys with konzo. These findings suggest the overall burden of cassava toxicity has been underestimated; therefore, there is an urgent need for interventions that ensure improved processing of cassava to remove cyanogenic content.
Traditional cassava processing includes soaking cassava in water, drying it out, and pounding it into flour. A novel wetting method (WTM), developed by Howard Bradbury, Ph.D., includes an additional step, where the flour is put into water, and dried for a second time. According to Tshala-Katumbay, the WTM has been shown to significantly reduce the cyanogenic content in cassava by 90 percent.
“The main challenge with the wetting method is that it increases the time to process cassava by incorporating an additional step to the traditional method,” said Tshala-Katumbay. “But we know changing a community’s food-processing habits is not always easy.” During a pilot project, Tshala-Katumbay and colleagues found that the WTM was accepted by rural women in the DR Congo. Now, they are working to implement the WTM as an intervention component in a larger longitudinal study.
The longitudinal study comprises a cohort of 400 mothers and their children, at ages 5 to 12 years, who live in the district of Kahemba, DR Congo. Enrolled children include those who have been diagnosed with konzo, as well as their siblings without konzo. The investigators will compare the effectiveness of a peer-led intervention, where women train other women in the WTM, to an intervention led by community health specialists. Investigators will assess the level of cassava cyanogenic content produced by the mothers from both groups and will measure levels of thiocyanate in the urine of her konzo and non-konzo children. They will also perform neuropsychological tests to measure subsequent changes in child cognitive and motor performance over time. These findings will help determine whether post-intervention reductions in cassava cyanogenic content are associated with improved neuropsychological performance in children over time.
“The funding and support from NIEHS and Fogarty has provided us with the resources to form a multidisciplinary team of experts in disciplines such as, neurology, psychology, nutrition, biology, toxicology, and epidemiology,” Tshala-Katumbay said. “This team not only focuses on addressing the issue of cassava toxicity, but also works to build the research capacity of local faculty and train the next generation of scientists in the Congo.”
Moving forward, Tshala-Katumbay and colleagues plan to conduct field studies to explore how factors such as climate, water availability, and soil composition directly contribute to the level of cassava toxicity. They will also explore the neurological impacts of cassava toxicity on younger children under 5 years old using funds from a separate grant awarded by Michigan State University.