Q&A WITH COLLEAGUES

Dr. Tallie Z. Baram is well known to all members of the Child Neurology Society. As one of the foremost researchers in the world working on the developing brain, Dr. Baram regularly draws large crowds to her frequent presentations at CNS Annual Meetings, including the 2013 Bernard Sachs Lecture.

Dr. Baram was honored this past spring by the American Academy of Neurology, delivering the prestigious George C. Cotzias Lecture at the AAN Meeting in Los Angeles (“How Early-Life Experiences Sculpt Your Brain: From Molecules to Circuits”). Dr. Baram is the Danette Shepard Professor Neurological Sciences at the University of California Irvine where she also serves as Director of the Conte Center and as Executive Council Chair of the Epilepsy Research Center.

Question | How did you become interested in the effects of stress on the developing brain?

I have always been drawn to the brain, and specifically to the evolving, ever-changing developing brain. As child neurologists, we think of the brain in four rather than three dimensions, adding Time to the concept. I have often wondered how environmental and experiential forces sculpted brain development. Stress is clearly a powerful force from an evolutionary perspective. The ability of an individual to learn from adversity and adapt to it will strongly increase survival.

I was also intrigued by the complexity of the mechanisms the brain deploys to process and handle stress. The idea that the only players in this complexity are steroids simply didn’t make sense. I was interested in uncovering the non-steroid hormone mechanisms that might be specific to the brain as it faces stress, and especially neuropeptides.

Question | Your research has revealed that neonatal stress can impair future memory abilities, cognitive functions, and behavioral responses. Yet, it seems that stress is universal and that evolution would strongly favor individuals who can cope with stress without it causing such negative consequences. Are you surprised that early life stress can have such lasting negative consequences?

Of course! Rapid and long-lasting responses to stress are critical. This is why our brain is designed to respond to stress. Learning to associate the roar of the sabre-tooth tiger to the need to hop up the nearest tree is highly beneficial, and promotes stress-induced augmentation of memory decision making and other brain functions. However, the infant and child often do not face the quick, short roar of a sabre-tooth tiger. Rather, there are emotional challenges that derive from the most dominant experiential forces – the parents. And they are not instantaneous. Rather, they are long, ongoing and unpredictable. In these circumstances, the original mechanisms designed to enable stress-induced survival get co-opted in a disruptive way, leading to the adverse effects of early-life stress.

Two surprises: first, that physical stress is not as important in governing infants’ mental outcomes. It is the presumed ‘emotional’ aspects of disrupted maternal care that powerfully change how brain circuits develop. Second, that there is a novel dimension of parental signals to the infant that add significantly to optimal or poor brain development – the patterns of these signals and especially their predictability.

By the way, stress is such a vague and poorly defined entity. The more we understand this concept, the more tempted I am to discuss “adversity” rather than “stress” as a negative force that shapes the brain.

Question | One important model system that you use in your animal research of chronic early life stress is limited bedding and nesting material for rodents. This situation would stress the mothers as much as the newborns. How does your research sort out indirect effects of maternal stress from direct effects of stress on the infants?

Yes. The limited bedding and nesting paradigm stresses the mother directly. The mother’s behavior is changed. Specifically, it becomes fragmented and unpredictable compared to the typical predictable patterns of maternal care in normally-bedded cages. It is this altered maternal care that is the source of stress to the pups, and probably also the source of the altered brain development. There is little physical adversity that the pups perceive (temperature and total amount of care and nutrition are not altered). In summary, the profound effects of the paradigm on the development of many brain circuits seem to result from the stress of the mother, which leads to her disrupted behavior towards the pups. Notably, we have recently found that unpredictable patterns of maternal care influence cognitive development in (human) children.

Question | In your research regarding early stress, what has been your most surprising finding to date?

Two surprises: first, that physical stress is not as important in governing infants’ mental outcomes. It is the presumed ‘emotional’ aspects of disrupted maternal care that powerfully change how brain circuits develop. Second, that there is a novel dimension of parental signals to the infant that add significantly to optimal or poor brain development – the patterns of these signals and especially their predictability. In addition to known ‘quality’ of care, predictable patterns are key. We believe that there is an important principle here: light and light patterns are required to activate neurons in the visual circuit. This leads to strengthening of some synapses and pruning of others, building a functional visual circuit. Sound and sound patterns are required to build a tonotopic auditory system in an analogous manner. Predictable, consistent, tactile (in rodents) and multimodal (in humans) sensory signals from the mother/caretaker are required for the normal maturation of stress-sensitive as well as cognitive circuits.

Question | Does your research suggest any ways in which we should be taking care of babies differently?

Our findings highlight the importance of predictable and non-fragmented sequences of signals from the parent (and environment). The good news: quantity of care, within limits, doesn’t seem to have a major impact (To all my women colleagues: guilt about long hours of work and relatively little quality time with baby is not necessary). The more ominous news: we don’t have a clue about the consequences on children’s neurodevelopment of the most common and potent disruptor of predictable routine of care – the smartphone.

Question | What are the most important and interesting questions to address next?

1. There are lots.
2. First and foremost, to what degree are studies in experimental animals relevant to children?
3. Can we use neuroimaging to identify aberrant circuit maturation and predict risk?
4. Can we generate methylome signatures in an individual infant to predict risk?
5. What are the mechanisms, at molecular, cellular and circuit levels, that mediate the effects of early-life adversity on brain development?
6. And, finally – how do we intervene?

Here, we are excited that we were able to reverse anhedonia by gene manipulations in rodents. Now we need to get practical and identify methods that will work in children.