by Ekaterina Dobryakova
In preparation for this year’s Annual Meeting, we spoke to one of the keynote speakers, Dr. Claudia Buss. Claudia is an Associate Professor at the University of California, Irvine and a Professor of Medical Psychology at the Charité University Medicine in Berlin. In a virtual meeting, I sat down with Dr. Buss to discuss her captivating research in the field of developmental programming and newborn infant neuroimaging.
Ekatarina Dobryakova (ED): Dr. Buss, thank you for dedicating your time for this interview. Before we get into more specific questions, I was wondering whether you mind sharing a bit about how you came to do the work that you're doing, and what got you to follow this passion in research.
Claudia Buss (CB): Since I started studying psychology, I have always been very interested in the interface of the mind and the brain. Specifically, in how stress can affect the brain, and then, consequently, health and disease, specifically psychiatric disease. My mentor during my doctoral training was Dirk Hellhammer, who unfortunately recently passed away. He was really the one who stimulated my interest in stress biology and fetal programming of health and disease. He also taught me that if you want to understand the origins for disease susceptibility, you have to go back to the very early period of life, when an individual develops. The brain is highly plastic at that time and therefore can integrate information about the environment during development. Dirk introduced me to the concept of developmental programming.
The origins for basically all common complex disorders, including psychiatric disorders, can be traced back to very early life, when the susceptibility for these disorders is laid. I'm particularly very interested in the developing brain, because there is no other organ that develops over such a protracted period of time. More specifically, I am interested in how cues about maternal stress during and before pregnancy, and even during mothers’ own development, can affect the developing fetal brain. I investigate which biological signals provide information to the fetus about maternal stress.
ED: This is fascinating. What are the challenges of this research area given that you want to study individuals in their prenatal stage.
CB: Gaining information about the fetal origins of risk for psychiatric disorders in humans is best achieved by prospective longitudinal studies. These start during pregnancy and, ideally, follow up the offspring during critical developmental periods from fetal to infant to child to adolescence, with serial measures of brain, cognitive, and affective development. This ideally requires large study samples, which we usually don't have. However, our studies to date have provided a first proof of principle that there are associations between variation in the prenatal environment and alterations in the neonatal brain. At this point, postnatal events will have had minimal influence. Longer term changes and risks for psychiatric disorders have to be studied in large samples. Therefore, multicenter studies such as, the HEALthy Brain and Child Development Study and the Lifespan Baby Connectome Study are extremely valuable.
Further, to gain information about prenatal origins of susceptibility for psychiatric disorders, it is crucial to record many aspects of the prenatal environment and then serially assess the brain during the period of most rapid development. This is especially important during the first two years of life.
It is very important to have a neonatal baseline measure and then characterize the developmental trajectory from this point. Because we acquire MRI scans from neonates and young infants during natural sleep (so we never sedate the children), scan acquisition is extremely laborious and requires very, very committed and patient staff, as well as the cooperation of parents, because sometimes children take a long time to fall asleep and scans need to be repeated. We often discuss this amongst our collaborators, that study sites are only successful if there are people who are committed to this being done. It needs to be a priority because it's so laborious.
In terms of other challenges, the developing and immature brain is very different from an adult brain. Common data processing tools that have been developed and optimized for adult scans cannot be used. I'm very fortunate to collaborate with leading experts in the field, specifically Damien Fair from OHSU and Martin Styner from UNC, who have greatly contributed to developing methods that address these specific challenges.
Of course, another challenge common to all observational human studies is that inferences about causality cannot be drawn. This is why animal models that allow experimental manipulation is a very crucial complementation to the human observational studies on fetal programming.
ED: It’s obvious that there are a lot of layers to your research. Longitudinal studies by themselves present a lot of challenges, without adding a layer of scanning such a young pediatric population and having additional layers of technological challenges. So you already touched upon this before, but when you just started in this area of research, what was the most inspiring or motivating scientific work that sparked your interest even more aside from the inspiration you got from your mentors?
CB: The field received a lot of attention when the first papers on fetal programming of health and disease came out from David Barker’s lab. They showed that there were associations between lower birth weight and risk for cardiovascular disease in later life. Then, more and more epidemiological studies found associations between adverse birth outcomes, such as lower birth weight and shorter length of gestation, and basically all common complex disorders, including psychiatric disorders.
The idea was that it's not the low birth weight per se that's increasing the risk for later disease. Lower birth weight was found to be an indicator of an adverse prenatal environment which affects later disease susceptibility. So people started thinking: what kind of environmental conditions (i.e., nutrition, smoking, stress) during fetal life can program the organism in a way to predispose that individual for later disease? Through which pathways do these risk factors affect the developing fetus?
Another study that was really interesting to me was a study by Gilbertson et al. published in Nature Neuroscience in 2002. In a very elegant study design they found that a smaller hippocampal volume is a risk factor for developing Post Traumatic Stress Disorder (PTSD) after combat trauma exposure. Before that, it wasn't really clear whether the smaller hippocampal volume resulted from the trauma and due to the neurotoxicity of stress, or whether these patients had a smaller hippocampal volume to begin with, predisposing them to developing PTSD after trauma exposure. This study actually showed that it was smaller hippocampal volume predisposing them to PTSD. This made me want to find out what might be the origins of smaller hippocampal volumes.
I was pretty sure that genetics wouldn't explain hippocampal volumes, but that it rather would be an interaction with the environment and environmental factors, especially in early life and especially during critical periods of brain development. The Gilbertson paper made me want to study what might lead to these neuro-phenotypes that then increase vulnerability and susceptibility for psychiatric disorders.
ED: So are you seeing lower hippocampal volumes in pediatric populations, given the environmental factors during fetal development later in life.
CB: Yes, there are associations between adverse birth outcomes and smaller hippocampal volume, and lower birth weight and shorter length of gestation. Also, something we haven't published yet but we're just about to publish, is an association between maternal stress during pregnancy and smaller hippocampal volumes in newborns. Other groups have shown this as well. There's quite a bit of work now on alterations of the limbic system in association with prenatal stress.
ED: Stress is a hot topic now. When you're talking about stress, how do you define it in your research? Is it more chronic stress or a particular type of stress? One can say that even exercise is a stress to your body, for example.
CB: That's a very good question. I mainly define stress as an increase in stress-sensitive biological markers, specifically endocrine markers like cortisol or immune markers like proinflammatory cytokines, but also metabolic markers. What we know is that there are many different stressors, like stress at work, anxiety, depressive symptoms, death and sickness of someone close, lack of social support. All these factors have the potential to alter maternal biology. And the fetus needs to receive a biological cue to be able to adapt its development. The fetus doesn't care whether the mother is stressed because her boss is stressing her out, because she has conflicts with her partner, or because someone is sick. The fetus cannot interpret that; the fetus only gets biological cues through the placenta. Thus, stress of the mother has to translate into a biological signal, so that the fetus can respond to it.
Whether stress-associated biological changes occur depends on many things in the maternal constitution, such as maternal genetic makeup, social support, coping strategies, all these will determine whether the mothers’ stress that she experiences actually translates into a biological signal that the fetus can then receive. This is why I would refrain from calling certain stressors more harmful than others. There are some colleagues who think there's some evidence for that, but I don't think there is strong evidence. What is pretty clear is that acute stress and alterations in biological mediators of stress are very unlikely to alter fetal development. So it would have to be chronic stress exposure and chronic elevations of these stress mediators. I would even go as far as saying that maternal acute stress, from time to time, is good because the fetus gets exposed to certain variation in stress-sensitive biological mediators, which prepares him for extrauterine life.
Even when talking about the long-term neurodevelopmental consequences of chronic stress, you may view these as harmful because they increase risk for mental health disorders but you could also look at them from an evolutionary perspective and consider them adaptive because the changes may increase chances of survival in a more stressful environment (for example altered neural circuitry that supports high vigilance may on the one hand increase risk for anxiety disorders but may also serve an important purpose in a dangerous environment).
ED: Is there any research where you follow the kids who were exposed to chronic stress and how they fare later in life, even when they do develop psychiatric disorders?
CB: The studies that we have done mainly characterized newborn neuro-phenotypes based on MRI studies in association with different types of stressors. We have looked at elevated cortisol concentrations, and then also inflammation during pregnancy. There, we do see associations with newborn brain anatomy and also connectivity, and these neuro-phenotypes predict behavior at the age of two years. We have followed up these kids again at five years. But it's a rather small sample size; our sample size wasn't that big to begin with. We started out with about 120 mother-child pairs, where we had complete data during pregnancy of three time points during pregnancy and then the newborns. So by the age of five, the sample size was quite small: around 70. But in early childhood we also see associations between chronic systemic maternal inflammation during pregnancy and neuro-cognitive function, for example. We are now participating in the ECHO initiative, which may better allow answering questions about prenatal origins of psychiatric disorders because ECHO integrates many prospective longitudinal US studies into a common research protocol to answer questions related to developmental programming of health and disease.
ED: This is so interesting, and again, shows how multilayered your research is. What would you say are the most pressing methodological issues in your field of research?
CB: Improving processing pipelines for neonatal MRI data is a pressing issue. As I said, my collaborators are at the forefront of working on this and great advances have already been made in the context of the developing Human Connectome Project and the Baby Connectome Project. When I started this work 10 years ago there were very few groups who actually did newborn infant neuroimaging. Now, more and more people have become interested in this field and there are big consortia focusing on MRI-based characterization of early brain development. So a lot of progress has been made compared to 10 years ago. But I think there's still a lot of work ahead of us to be at a comparable state as we are for adult image processing.
Then, I think there is still room for optimizing acquisition protocols based on recent experiences. Weighing resolution and signal-to-noise ratio to scan time is important, as we always have to be very cognizant that, usually, newborns sleep pretty well for about 40 minutes and then after that, they start waking up. My experience, if you can keep the protocols below 40 or 45 minutes, you're good. Thus, my recommendation is to stay below 45 minutes and if you want to scan different modalities, you really have to weigh what is important to you.
I think what is also a pressing issue is to harmonize measures of the prenatal environment because, as you are pointing out, what people mean when they refer to stress and the way they define stress may differ a lot. Further, evaluating the quality of biological assays is very important. I'm not sure that this receives enough attention. I think there is this notion that biological measurements are more objective and valid than psychological self-report measures. However, there are problems and inaccuracies associated with biological assays as well, which deserve attention to obtain reliable and comparable study results. Right now, there is a lot of heterogeneity in the way prenatal stress is being defined in studies studying its neurodevelopmental consequences and it's therefore hard to say whether there is one study that specifically replicates what another study has found, as there are all these nuances between how the prenatal environment was characterized and then what aspects of the offspring brain was looked at. That really complicates the picture and I think there we can definitely improve.
ED: Absolutely. Hopefully such initiatives like OHBM’s Replication Award will start the wave of researchers trying to replicate previous findings and remove the barriers for replication studies. Another topic I would like to talk about is mentorship. What do you think are the most important things to do as a mentor?
CB: I feel that continuous communication and support for my students and regular meetings are crucial. Only if you're constantly communicating, you can monitor progress and detect barriers to progress. I also think it's crucial to foster intrinsic motivation for students’ work because I feel it is important to burn for what you are doing and what you're researching. Only then can you conduct these laborious studies and stay on top of things and stay motivated. I think one way of keeping students motivated is a very early introduction to international experts in the field, having research exchanges, visiting international laboratories and conferences, and being able to present one’s own work to peers.
What I also learned from my mentor, Pathik Wadhwa at UCI, is that having a well-grounded conceptual framework in the context of which research questions are being developed is very crucial. This is why I like to begin the training of my students by developing concept and perspectives papers in the respective fields that they are working on. I think that helps them get established in the field and provides a good basis and conceptual framework for doing their own empirical studies and developing their own research questions.
ED: Indeed, intrinsic motivation is very important. To round out our conversation, I was wondering whether you have thoughts about the OHBM conference going virtual in 2020. What are the silver linings given the current situation that hopefully will improve?
CB: Well, with the OHBM conference going virtual, potentially even more people can attend the conference because it will be more accessible, it doesn’t include traveling, which is good from an environmental perspective and also saves time. I think it could also be an advantage to take the time and listen in more detail to presentations that you're really interested in, and being able to go back and listen to them again. What we will be missing, of course, is the Q&A after the talks and interacting with peers during coffee breaks that's also really important at conferences. But I would assume that if there are specific questions, the speakers can be contacted, so I don't see too much of a downside. We just have to make the best of the situation that we're in. And I think having a virtual meeting is definitely better than not having a meeting and not hearing about the advancements in our field.
ED: Absolutely. The conference should still be very interesting and engaging. Thank you so much for your time.