Unraveling the neurobiology of stress

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Do you remember what you were doing on 9/11? It is likely that you still remember. But do you also remember what you were doing on September 11 last year? Probably not. This shows that emotional events are better remembered than non-emotional events. This may well help us to better detect potential threats in the future. One of the main reasons why we have memory at all is that it equips us with a way to make predictions about what's happening around us: Where is there food? What's dangerous here? Who is a potential partner? And making better predictions increases our chances of survival.

I want to disentangle anxiety in such a way that doctors can know which patient needs which treatment

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We investigate the interaction between anxiety, memory and genes in an interdisciplinary context, combining cognitive neuroimaging with genetics, pharmacology and a range of clinical disciplines. The brain is not only the most complex and variable, but also the most individual organ of the human body. If you want to answer the question why one person is more vulnerable to stress or anxiety than another person, you need to do more than understand the general principles of the human brain. You need to understand the causes and effects of individual differences in the brain. And to understand individual brain differences, it's important to identify the underlying genetic differences and environmental differences throughout life.

Together with Prof. Barbara Franke, I  setup the brain-imaging-genetics project in order to answer the question as to how early life stress affects the brain and what role is played by the specific genetic makeup of an individual. More than two thousand subjects took part in this study. On the basis of their saliva, their genes are analyzed. They make brain scans and get the participants to answer questionnaires about their life experiences. This is one of the new ways in which individual differences can be studied more and more in detail.

When the brain perceives a dangerous situation, it's the amygdala that rings like an alarm bell. Together with the amygdala the brain makes a coordinated response to the threat: the body's motor response is activated so that it's ready for action, memory is up-regulated and vigilance is increased. All of this happens within seconds. We aim to unravel the precise biochemical pathways behind this response. Last year we discovered that it's not the stress hormone cortisol that is the driving force behind the stress response, as previously thought, but another stress hormone: noradrenaline. Noradrenaline up-regulates the brain response to threat, whereas cortisol actually brings this response down.

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We also showed that the amygdala response becomes unselective in threatening situations. In a generally safe situation the amygdala responds strongly to seeing fearful and angry faces, but not to seeing happy faces. However, in a generally threatening situation, the amygdala response becomes unselective. Suddenly it responds not only strongly when people see fearful or angry faces but also when they see happy faces. In other words: the amygdala becomes hypersensitive. It would be too risky for the survival of the individual if it would respond too selective. We also showed that a certain genetic makeup modulates this noradrenaline-driven response and the associated vigilance.

We also apply this fundamental work in a clinical setting. Our team investigated the stress response of Dutch soldiers before and after their mission to Afghanistan. And in a new study we are is going to study a population of parents who have a child with cancer. The idea is that the influence of a severely stressful situation - such as having a child with cancer - might lead to a higher risk in developing a post-traumatic stress disorder (PTSD).  The question is whether we can predict PTSD better on the basis of brain data than with traditional questionnaires and clinical interviews.

Why is this so important

By getting a better understanding of the brain's stress response we hope to develop better clinical predictions and treatments. How can we more effectively help patients with an anxiety disorder? Fifty percent of anxiety patients respond well to cognitive therapy, but fifty percent do not. Here we have to realize that there are at least two basic processes that regulate anxiety and fear: one based on a mainly automatic and another one based on a mainly cognitive process. The automatic process is mediated by the brain stem, which up-regulates the amygdala, whereas cognitive process is mediated by the prefrontal cortex, which can reduce the amygdala response via a cognitive control process. With pharmacology we can influence the automatic process in the brain stem. But the brain stem does respond to cognitive therapy. In contrast, people whose cognitive control system is impaired may optimally respond to cognitive therapy.

Biography

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Prof. Guillén Fernández is a professor for cognitive neuroscience at the Radboud University Nijmegen. He studies the brain basis of memory, emotion, and their interaction. He applies an interdisciplinary approach integrating cognitive neuroimaging, genetics, pharmacology and diverse clinical disciplines. His research is fundamental in nature, but with an explicit aim to improve education by neuroscientific insight in learning processes and to enable personalized care in psychiatry by providing mechanistic insight in stress-related pathophysiology. Guillén Fernández is elected member of the Academia Europaea and the Memory Disorder Research Society.

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My dream for this project

My vision is to disentangle anxiety in such a way that doctors can know which patient needs which treatment: cognitive therapy or a specific medicine. Psychiatry is the last clinical field where all diseases, definitions and treatments are based only on symptoms and not on underlying pathophysiology. I hope - and believe- that we will soon be able to base psychiatry to a large extent on underlying mechanisms by using an interdisciplinary approach.

My expertise

Brain, cognition, neuroscience, behaviour, neurobiology, stress