The University of Tuebingen and the University of Uppsala are carrying out a study in which especially maternal and fetal changes during pregnancy and the infants’ development after birth are investigated. This will shed light on a sensitive phase where all of our life started.

Pregnancy is a crucial period for women and is associated with behavioral and neuronal adaptations presumably preparing them for the protecting and nurturing demands of motherhood. Moreover, the origins of altered brain anatomies associated with major mental disorders are assumed to already take place during the intrauterine phase. Thus, it is important to not only address the impact of pregnancy on the expecting mothers, but on fetal development, child behavior and mother-child interaction. It is necessary to shed more light on this critical period in a woman’s life that not only shapes her (and her brain) but also lays the foundation for her child’s health.

Most women undergo pregnancy at least once in their lives. While data on how pregnancy and associated fluctuations in sex hormone levels affect brain function and structure in animals has been collected throughout the last decades, evidence on the impact of human pregnancy on behavioral – but more interestingly – neuronal adaptations is scarce [1]. Sex hormones are known to act as an important regulator of neuronal morphology. Not surprisingly, other endocrine events involving less extreme and rapid fluctuations in hormone levels than pregnancy are known to render structural and functional alterations in the human brain. The production of gonadal sex hormones during puberty for example regulates an extensive reorganization of the brain [2].

Moreover, neural alterations have also been observed in response to even subtle changes in endogenous or exogenous sex hormone levels later in life [3]. Growing evidence has accumulated that the origins of structural alterations characterizing mental and neurodevelopmental disorders can be traced back to the intrauterine period of life. During this period the developing fetus (and its brain) is influenced by environmental conditions during sensitive periods of cellular proliferation, differentiation, and maturation to produce structural and functional changes in brain and peripheral systems i.e. fetal programming [4]. Human brain development begins early in gestation, occurs over a protracted period and follows a rapid, orchestrated chain of partially overlapping ontogenic events. It is highly likely that the intrauterine milieu can influence neurodevelopmental trajectories. These effects may independently, or in conjunction with other factors, impact subsequent long-term susceptibility for various neuropsychiatric disorders.

The Neuronal Emotion Regulation Network in Pregnancy

While the influence of fluctuating hormonal levels, such as during the menstrual cycle, are known to render structural and functional alterations in the human brain, knowledge of changes during pregnancy are surprisingly scarce [5]. However, recently a study has shown long lasting changes in brains of mothers in which reductions of grey matter were still visible 18 months after they had given birth [6]. Thereby, they were able to predict which of the women that took part in their study were pregnant with up to 95.6 % accuracy. Interestingly, reductions of brain matter lay in areas important for social processing and emotion regulation. This may shed some light on the transition women go through in order to adapt and prepare them-selves for looking after a baby. While women often report a subjective decline in certain cognitive functions such as memory deficits or decreased processing speed, evolutionarily this may actually support a theory of a reallocation of cognitive resources focusing on upcoming demands of protecting and caring for a baby [7].

Female sex hormones such as estradiol or progesterone play a crucial role during this process with an enormous increase up to 100 fold in late pregnancy. This change in hormonal concentrations influences women not only physically but also in their perception of the world around them. Accordingly, estradiol seems to influence emotion processing leading to an increase of the accuracy to encode emotional expressions signaling threat or harm [8].

Therefore in this subproject we will investigate the neural underpinnings of emotion regulation in pregnant and non-pregnant women and will further investigate the pregnant women 18 months after giving birth. Thereby we will be able to examine the impact of pregnancy vs. motherhood on emotion regulation success.

Preventing stress in pregnancy – the relaxed fetus

Especially the hormone cortisoI, known as the “stress hormone” is one major factor for stress regulation. Additionally in pregnancy, the mother has to deal with many changes and concerns about the fetus. This way an increased cortisol level can lead to metabolic or psychological changes in the mother. Therefore, it is important to prevent stress and to improve the mothers’ well-being during pregnancy. Regarding fetal development, the factor ‘stress’ in pregnancy may lead to the overall question, if stress or relaxation in pregnancy has any impact on the fetal nervous system. Over the last decades there is growing evidence that increased maternal stress levels lead to an adverse effect on the physiological, metabolic and neuronal development of the fetus during gestation with possible long-lasting effects.

At the University of Tuebingen we have the unique and rare possibility of measuring fetal brain and heart activity with fetal magnetencephalography (fMEG). Fetal Magnetoencephalography allows the recording of event-related responses (ER) to auditory [10] and visual stimuli [11] in fetuses. The latency of the ERs is an indicator for neurological development [12]. This measurement method allows insights into fetal brain development and helps to add knowledge about fetal development.

To investigate the role of relaxation on fetal activity, we will measure fetal development between 29 weeks of gestation and birth. Changes in heart activity and brain signals will be investigated under induced maternal relaxation.

 

Pregnancy and psychiatric comorbidity – Prediction of maternal mental health.

Especially from an obstetric point of view, mental health problems, together with obesity, are the two most common health problems encountered in pregnant women.

They are stressors for the women and even for the fetus. Clearly, psychiatric hospitalizations, post-partum depression or psychoses, self-harm or suicides, child neglect, abuse, and even infanticide during or shortly after pregnancy all represent severe adverse outcomes of psychiatric comorbidity, where the health care system has a responsibility to minimize the burden of adversity by early identification and adequate treatment of pregnant women with mental disorders. As mentioned before, there are several biological (e.g., hormones, immune/inflammatory, genetic) and psychosocial (e.g., stress, support) risk factors, however, up to now, rarely have neuronal, physiological and psychosocial factors been combined and consequently tested about their prediction value regarding maternal mental health. Therefore, we are particularly interested in whether resting-state functional connectivity in concert with other factors may contribute to predicting maternal mental health status.

The passenger in the womb – maternal distress and offspring development

In this context, it is necessary to identify key early-life epigenetic signatures in order to predict children’s cognitive and psycho-emotional development. Taking advantage of a population-based longitudinal study in Uppsala which includes extensive phenotyping of mothers and infants, together with a biobanking program, will help to identify novel high-quality umbilical cord blood and salivary epigenetic biomarkers that are associated with maternal stress. Additionally, this might help to predict the risk for internalizing problems after birth, to replicate and validate the above epigenetic markers and to take perinatal factors (i.e. maternal depression and stressful life events during pregnancy, use of antidepressants, maternal smoking) and early-life factors into account. To put it in a nutshell, in Tübingen, there will be special emphasis on characterizing infant development according to developmental “milestones” via a milestone diary to further infer associations between maternal and infant well-being/development and mother-child bonding. These relationships are essential for getting a deeper understanding of the origins and risk factors of developmental problems that later may lead to the development of various psychological disorders.

In our fourth project, we will investigate child development using milestones and standardized tests as well as investigate mother-child bonding and social interaction.

All in all, pregnancy as a vulnerable period influences not only the mother but has long lasting effects on the baby with growing evidence showing that the origins of structural alterations, characterizing mental and neurodevelopmental disorders may date back to the early intrauterine period. In our working group, we will therefore investigate the impact of sex hormones and pregnancy on socio-cognitive processes, brain structure and function. Women will undergo an fMRI emotion regulation task, structural and resting state measures as well as psychological and physiological measures and fMEG measurements. The measurements are planned to start around the 21st-23rd week of pregnancy and last until 18 months after the birth of their child.

We would like to thank the Center for Integrative Neuroscience, Tuebingen (CIN), for funding this Mini Research Training Group (DFG EXC 307).

Elisa Rehbein is a PhD student of the Centre of Integrative Neuroscience (CIN) in the working group of Prof. Birgit Derntl in Tübingen.


Ilena Bauer is a PhD student of the Graduate Training Center of Neuroscience. She is doing her PhD in the working group of Prof.  Hubert Preißl at the fMEG Center in Tübingen.

References:

[1] Brunton, P. J., Arunachalam, S., & Russel, J. A. (2008). Control of neurohypophysial hormone secretion, blood osmolality and volume in pregnancy. J Physiol Pharmacol, 59, 27-45.

 [2] Sisk, C. L., & Foster, D. L. (2004). The neural basis of puberty and adolescence. Nature Neuroscience, 7, 1040.

[3] Toffoletto, S., Lanzenberger, R., Gingnell, M., Sundström-Poromaa, I., & Comasco, E. (2014). Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review. Psychoneuroendocrinology, 50, 28-52.

 [4] Gluckman, P. D., & Hanson, M. A. (2004). Living with the past: evolution, development, and pat-terns of disease. Science, 305, 1733-1736.

[5] Lisofsky, N., Mårtensson, J., Eckert, A., Lindenberger, U., Gallinat, J., & Kühn, S. (2015). Hippocampal volume and functional connectivity changes during the female menstrual cycle. Neuroimage, 118, 154-162.

[6] Hoekzema, E., Barba-Müller, E., Pozzobon, C., Picado, M., Lucco, F., García-García, D., & … Vilarroya, O. (2017). Pregnancy leads to long-lasting changes in human brain structure. Nature Neuroscience, 20, 287-296.

[7] Anderson, M. V., & Rutherford, M. D. (2011). Recognition of novel faces after single expo-sure is enhanced during pregnancy. Evolutionary Psychology, 9, 147470491100900107.

[8] Pearson, R. M., Lightman, S. L., & Evans, J. (2009). Emotional sensitivity for motherhood: late pregnancy is associated with enhanced accuracy to encode emotional faces. Hormones and Behavior, 56, 557-563.

[9] John, O. P., & Gross, J. J. (2004). Healthy and unhealthy emotion regulation: Personality process-es, individual differences, and life span development. Journal of Personality, 72, 1301-1334.

[10] Schneider, U., Arnscheidt, C., Schwab, M., Haueisen, J., Seewald, H. J., & Schleussner, E. (2011). Steroids that induce lung maturation acutely affect higher cortical function: a fetal magnetoencephalography study. Reproductive Sciences, 18, 99-106.

 [11] Eswaran, H., Lowery, C. L., Wilson, J. D., Murphy, P., & Preissl, H. (2004). Functional development of the visual system in human fetus using magnetoencephalography. Experimental Neurology, 190, 52-58.

 [12] Kiefer, I., Siegel, E., Preissl, H., Ware, M., Schauf, B., Lowery, C., & Eswaran, H. (2008). Delayed maturation of auditory-evoked responses in growth-restricted fetuses revealed by magnetoencephalographic recordings. American Journal of Obstetrics & Gynecology, 199, 503-e1.


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