Project 3

Project 3

Project Leader: Elysia Davis, PhD

SIGNIFICANCE: One out of 17 Americans will suffer from a severe mental illness during his/her lifetime. The origins of mental illness predominantly begin early in life. Over half of mentally ill adults exhibit symptoms before the age of 14. Intervention requires identification of at-risk individuals, evaluation of underlying mechanisms and development of targeted interventions. Achieving these goals requires research that assesses development during the fetal, infant and child periods. We will examine prenatal and postnatal influences that contribute to the development of mental illness during adolescence.

Our novel approach considers the joint role of fetal and infant experiences in determining the emergence of mental illness. Brain development is more rapid during the fetal and infant periods as compared to any stage of the life span. For example, during the fetal period, neurogenesis (the birth of new neurons) proceeds at a rate of 250,000 cells per minute. Because of the enormous changes during these periods, experiences can dramatically influence development. Collaborative animal research from this Center has identified fragmentation of maternal signals as a key influence that exerts lifelong consequences.

We will evaluate the role of fragmented maternal signals for human development. There are several novel questions that we will ask in the context of this Center.

  1. Does fragmentation of maternal behavior increase risk for mental illness in humans?
  2. Do the fragmented maternal signals during the fetal and infant periods jointly determine risk for mental disease?
  3. Are there sex differences in fetal and infant responses to fragmented maternal signals? Do these sex differences contribute to sex differences in risk for mental illness?

To answer these questions we will examine the influence of maternal mood (e.g., anxiety and depression) and maternal behavior on the fetus and infant. We will evaluate how these early experiences influence infant and child development. Further, we will determine whether these early experiences influence mental health during the transition to adolescence.

Mental disorders affect 15 to 20% of the US population, primarily originate early in life, have a peak onset of disease during adolescence, and vulnerabilities are sex dependent. Project 3 will test specific hypotheses about how prenatal and early postnatal maternal signals, experienced during transitional periods of rapid changes in brain and behavior, determine risk for cognitive and emotional vulnerabilities to mental illness. The long term consequences of exposure to fragmented maternal signals during fetal and early postnatal life will be tested with a prospective longitudinal investigation of two cohorts followed from early in gestation and assessed during infancy/toddlerhood (new cohort) and childhood/adolescence (existing cohort).

Project 3 will be guided by findings from Project 1 and will interact with Project 2 and Project 4 to accomplish the following aims:

Aim 1 tests the hypothesis that exposure to fragmented maternal care during the early postnatal period increases risk for mental illness.

Maternal behavior exerts profound and lasting influences on the developing brain. Our concept of abnormal, and especially fragmented, patterns of maternal behavior as a key component of maternal care that is responsible for these persisting effects is based on experimental animal work (Project 1). Fragmentation of maternal care will be evaluated throughout the first two postnatal years. Maternal behavior will be observed in both play and care-giving contexts and, with the Computational Core, will be characterized using linear and nonlinear analyses. The association between early exposure to disrupted patterns of maternal behavior and infant, child and adolescent emotional vulnerabilities (anxiety) and cognitive functions (executive function and memory) will be determined in two cohorts (new cohort-prospectively followed to 1 year) and childhood/adolescence (existing cohort: proposed assessments at 9, 11 and 13). Underlying neural mechanisms will be evaluated with Project 4 and the imaging core.

Aim 2 tests the hypothesis that prenatal and postnatal fragmented maternal signals jointly contribute to susceptibility to emotional and cognitive dysfunction during infancy and childhood.

The pre- and postnatal environments play crucial roles in the determination of risk for cognitive and emotional impairments yet few prospective human studies have jointly considered these two critical developmental periods. Consideration of fragmentation of maternal signals in both the pre- and the postnatal periods will determine if and how the prenatal environment influences vulnerability to fragmented postnatal maternal signals.

Aim 3 evaluates the hypothesis that adolescent vulnerability to mental illness will be predicted by infant and child behavior resulting from exposure to prenatal and postnatal fragmentation.

Using the existing cohort and with Project 2, infant and child indicators of cognitive vulnerability will be evaluated in conjunction with exposure to pre and postnatal fragmentation to predict risk for mental illness during adolescence. The resulting data will be incorporated with the imaging data of Project 4 to identify neuroanatomical and functional systems underlying these vulnerabilities.

Aim 4 tests the hypothesis that there are sex dependent consequences of fragmented early life experiences.

There are robust sex differences in mental illness and in responses to early adversity. Sex dependent vulnerability to mental illness may begin early in life and become amplified with the onset of puberty. It is not known how fragmented early life experiences differentially influence males and females.

This project will provide new information on the existing and new cohorts provide a unique opportunity to determine the role of two crucial periods for sexual differentiation (prenatal and adolescence) in the determination of sex dependent vulnerability to mental illness. We will test if and how sex moderates the hypotheses tested in the first 3 aims. In collaboration with Project 4, hypotheses about neuroanatomical and functional connectivity bases of sexually dimorphic vulnerabilities will be tested. These combined studies will yield major and groundbreaking insight into the contribution of pre-and postnatal experiences to the origin of cognitive and emotional disease.

Project Publications
  • Is there a viability-vulnerability tradeoff? Sex differences in fetal programming. Sandman CA, Glynn LM, Davis EP. J Psychosom Res. 2013 Oct;75(4):327-35.
  • Stout SA, Espel EV, Sandman CA, Glynn LM & Davis EP. Fetal programming of children’s obesity risk. Psychoneuroendocrinology. 2015; 53:29-39.
  • Sandman CA, Buss C, Head K, Davis EP. Fetal exposure to maternal depressive symptoms is associated with cortical thickness in late childhood. Biol. Psychiatry. 2014; 77:324-334.
  • Espel EV, Glynn LM, Sandman CA, & Davis EP. Longer gestation among children born full term influences cognitive and motor development. PLoS One. 2014; 9:e113758.
  • Sandman CA, Glynn LM, Davis EP. Is there a viability-vulnerability trade off? Sex differences in fetal programming.  Psychosom Res. 2013; 75:327-35.
  • Baram TZ, Davis EP, Obenaus A, Sandman CA, Small SL, Solodkin A, Stern H. Fragmentation and Unpredictability of Early-Life Experience in Mental Disorders. Am J Psychiatry. 2012; 169:907-15.

You can read the Project 3 Summary for a non-technical explanation.