In 2013, with a grant from the National Institute of Mental Health (NIMH), UCI established the Conte Center to explore how early-life experiences influence brain programming, which can in turn affect mental resilience or vulnerability. The original five-year award funded a series of projects focused on the connection between childhood adversity (in particular, fragmented and unpredictable signals from caretakers) and adolescent emotional and cognitive outcomes. The Conte Center includes two research cores — one for neuroimaging and one for biostatistics, computation and data management (BCDM) — that develop innovative methods and support the research projects.
“The computational core helps the projects with their study design and data analysis needs, and also develops novel statistical methods to assist with the analyses,” says Chancellor’s Professor of Statistics Hal Stern, who heads the BCDM core. With the recent announcement that the center has secured $15M through another five-year NIMH award, Stern is eager to build on the center’s preliminary findings.
The center’s initial projects focused on the effects of early-life maternal signals to the infant and child on mental and cognitive outcomes in the developing child. The projects involved both controlled experiments in rodents and observational studies of two human cohorts — one recruited and followed during the last five years and the other a previously recruited cohort of children who reached adolescence during the recent funding period.
“Our main contribution in the first round of the Conte Center was the development of a measure of unpredictability of a mother’s behaviors toward her child that would work with both rodents and humans,” says Stern. He and his group created the measure based on videos from the projects — some showed mothers playing with their infants and others showed mother rats and their offspring interacting in environments with and without sufficient resources. While watching the videos, undergraduate and graduate students recorded various behaviors. The computational group then used these observations to create a measure, known as the entropy rate, that assesses the unpredictability of the mother’s behavior. The key finding of the center is that greater unpredictability (higher entropy) was associated with weaker cognitive outcomes and greater vulnerability to emotional challenges.
“It is still a bit surprising to me that this measure of unpredictability, based on a 10-minute video of mothers playing with their children, correlates with important outcomes, like the child’s memory at seven years of age,” says Stern. “It’s not deterministic,” he emphasizes. “You can have an unpredictable mother and still have a great memory, but there’s an association that’s pretty strong.” A strength of the Conte Center is the use of the rodent model to help provide insight about the mechanisms that might explain the associations being observed.
Validating a Recall-Based Approach
The renewal of the Conte Center adds an additional project that is a collaboration with the department of psychiatry at UCSD involving a study of Marines immediately before and after deployment, and again six months after deployment ends with the aim of identifying Marines vulnerable to post-traumatic stress disorder (PTSD).
The Conte Center collaboration is investigating the role of early-life experiences in determining vulnerability to PTSD. However, as Stern points out, “we don’t have videos of the Marines playing with their mothers, so we need alternative measures of early-life experience.” The BCDM group worked with Conte Center psychologists to develop a recall-based approach to assessing their childhood experiences. “Part of what we did at the tail end of the initial Conte Center grant was to develop a questionnaire.” It asks questions such as “did your parents generally pick you up from school on time” and “did you regularly have dinner together?” Stern and his group used the cohort of adolescents for which they had earlier videos of mother-child interaction (from prior studies conducted at UCI) to validate the effectiveness of the questionnaire. The questionnaire was recently published in a peer-reviewed journal and is being used by other researchers outside the Conte Center.
While the center’s imaging core focuses on helping to elucidate the neurobiological factors associated with early-life unpredictability, Stern and neurobiology collaborators are exploring the role of epigenetics. “Where your genetic code is not changeable,” says Stern, “experiences do modify the genes that are regulated by the code through a number of epigenetic processes, including one called methylation.” During this process, the letters of the code don’t change, but changes occur that impact the way the genes express themselves.
A recent paper that Stern coauthored discusses a small study conducted with rodents that looked at the epigenetic methylation profile both at birth and after exposure to unpredictability. Results indicate that changes occurred in the epigenetic profile. “Now we have collected samples from the children at birth and after their first year of life to explore their epigenetics,” he says. “Epigenetic changes may serve as a biological marker of whether you were exposed to unpredictability and potentially could identify those at risk for mental illness.” He hopes this research can help with future strategies for mitigation.
Developing Novel Tools
Over the next five years, using his $750,000 portion of the grant, Stern will collaborate with graduate students in statistics as well as with UCI’s Center for Statistical Consulting to “elucidate the mechanism by which unpredictable maternal behavior turns out to have these cognitive and emotional consequences.”
At the same time, his work will help advance the field of statistics and support other projects in need of statistical analyses. As outlined in a message from Tallie Z. Baram, director of the Conte Center, in addition to understanding how unpredictable signals influence the developing brain, “we develop novel and useful tools for other people around the world [including] ways to mathematically quantify parental care signals, to easily assess unpredictability via questionnaires, to image and analyze brain organization in a powerful manner and across both humans and rodents, and to analyze and parse the big data that these studies generate.”
— Shani Murray