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Introducing Neuropsychiatrist Christine Konradi - Pushing Ahead One of the Last Big Frontiers of Science

bridges vol. 23, October 2009 / News from the Network: Austrian Researchers Abroad

 

By Bianca Haderer

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Since the time of ancient Egypt, societies have struggled to understand mental illness and to care for those affected by it. It was only in the mid-twentieth century that several medical breakthroughs led to the understanding that mental illnesses are diseases of the brain. Since then, a set of systematic criteria for diagnosis has been developed, and together with pharmaceutical and psychological therapies they are still central to modern psychiatry.

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Christine Konradi in her laboratory.

One of the scientists searching for new breakthroughs in the field of neuropsychiatry is Christine Konradi.  Konradi studied biology in Vienna, where she was awarded a Ph. D. in 1987.  In addition to her core biology courses and in accordance with her personal interests, Konradi was always eager to attend as many courses as possible at the Medical University of Vienna. Shortly after her graduation, Konradi accepted a postdoctoral fellowship in neurochemistry in the Department of Psychiatry at the University of Würzburg, Germany. Although she describes her time in the laboratory in Würzburg as interesting and challenging, Konradi never lost sight of her dream about being a scientist in the US: "I took a six week trip to the US in order to visit different laboratories and find out which laboratory was the best fit for me professionally and personally."  She remembers her careful preparations before the big relocation from Europe to the United States.

 

 


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Due to her excellent academic performance, her experience in the laboratory, and the many papers she had already published, doors were wide open to the Austrian scientist. Konradi began her career in the US with a postdoctoral fellowship in neuropharmacology in the Neurology Department at the University of Medicine and Dentistry of New Jersey, followed by a fellowship in neurogenetics as well as in molecular neurobiology at Massachusetts General Hospital, a teaching hospital of Harvard Medical School. After finishing her postdocs, Konradi stayed at Harvard Medical School as an instructor in psychiatry, became assistant professor of psychiatry, and later, in 2001, associate professor of psychiatry.  After almost two decades, Konradi left Harvard Medical School in 2006 to accept a professorship in psychiatry and pharmacology at Vanderbilt University Medical Center, where she also heads her own research lab.
 

Unwrapping the mysteries of neuropsychiatry
 

nature_figure_causes_of_disability_worldwide_small.jpgDespite decades of research by dedicated researchers like Konradi, the systematic study of neuropsychiatric diseases still puzzles scientists around the globe.  In its Global Burden of Disease analysis, the World Health Organization (WHO) assessed mortality and loss of health due to diseases, injuries, and risk factors for all regions of the world. According to the WHO analysis, neuropsychiatric disorders, especially mood disorders like depression or bipolar disorder, are the leading risk factors for suicide; but the major effect of these illnesses on disease burden is the disability they create. WHO uses the "disability-adjusted life year" (DALY) - a time-based measure that combines years of life lost due to premature mortality and years of life lost due to time lived in states of less than full health - to assess the overall burden of a disease.   For the year 2000, the WHO estimated that neuropsychiatric disorders were responsible for 12 percent of all DALYs  worldwide and 31 percent of all years lived with disability.For North America and Europe, where infectious disease and malnutrition are far less prevalent than in the developing world, neuropsychiatric disorders were responsible for a striking 43 percent of all years lived with disability.
 
According to Konradi, there are many reasons for the slow progress in understanding neuropsychiatric disorders over the past decades. "Since the personality of every patient is different and psychiatric disorders are superimposed by the personality of a patient, every patient develops different behaviors," Konradi explains. "Thus it is a demanding challenge to delineate the neurobiology of higher cognition, emotion regulation, and executive function. Yet these are precisely the functions impaired in neuropsychiatric disorders."

In addition, it has been difficult to produce convincing and useful animal models of human cognitive, social, and emotional functions and their dysfunctions. Konradi explains how researchers hope to gain information from animal research by drawing a comparison to a puzzle:  "Like a puzzle is composed of many different pieces, psychiatric diseases cause many different behaviors and symptoms. In animal research, we scientists focus on one particular behavior, one piece of the puzzle, and put it into an animal model.  The aim of this model is to learn how this behavior can be affected and altered, to teach us about possible disease processes in the psychiatric disorders we investigate.  However, this information gained from animal models can never be put one-to-one into human beings. Even if the findings prove to be relevant for humans, the challenge remains of where to put this piece of information within the whole picture.  In other words, in order to understand a psychiatric disease and its various aspects, it is necessary to examine every little piece of the puzzle and eventually put the puzzle together to understand the whole picture."

Another obstacle to brain research lies in the very nature of its study object: The brain is well protected from the eyes and instruments of investigators by its bony skull, and for both practical and ethical reasons, human experimental neurobiology is mostly limited to indirect, noninvasive methods of investigation.  Newer technologies such a functional magnetic resonance imaging are capable of examining the brain at work, but there is still much to be worked out with the technology.  A major issue psychiatry research faces is that we do not know exactly where to look for the abnormalities that cause psychiatric diseases. Konradi explains that abnormalities causing psychiatric disorders seem to appear in very different parts of the human brain. "In other fields of neurology, for example in movement disorders research, we are able to define an exact area where the disorder develops and can focus our study on that area. In psychiatric disorders research, we have to start with 10 billion neurons of the human brain, which are inter-connected.  If this "wiring" is not set up correctly, brain malfunctions and disorders develop.  Although there are some ‘usual suspects', it is difficult to even determine which brain area to start with"

Another challenge faced by neuropsychiatric researchers is the fact that, although it has long been clear that neuropsychiatric disorders are highly influenced by genes, the identities of these genes have proved elusive. Last but not least, there are no well-validated objective biological markers that delimit precise phenotypes to use in genetics, or any other type of neuropsychiatric research. In other words, there is no characteristic or trait of an organism, such as its morphology, development, biochemical or physiological properties, or behavior that can be directly observed. The lack of objective tests has meant that diagnosis in neuropsychiatry is made on the basis of phenomenological criteria (symptoms, signs, and course of illness), which are selected by expert consensus.

In spite of all the challenges, however, there is some cause for optimism. Recent advances in genomic technology and large-scale studies are helping to identify genetic variants associated with diseases.

 
Entering the Konradi Lab
 
Konradi's laboratory focuses on the molecular correlates of typical and atypical brain function. "We want to show how environment and experience influence the molecular properties of the brain and brain development, thus being able at some point to define the molecular events associated with learning, behavioral adaptation, and brain disorders. Our research is geared toward understanding pathological conditions such as bipolar disorders, schizophrenia, and Parkinson's' disease; the therapeutic action of drugs in the developing and adult brain; and drug abuse and its effect on the developing and adult brain."

"We believe that psychotic disorders result from a combination of environmental and multiple genetic factors," Konradi continues. "When we look at schizophrenia for example, there might be 100 genes involved in the disease, and if any 20 of those 100 come together in a certain combination, the affected person might develop the disorder.  To complicate matters, the genetic factors might only lead to a vulnerability that leads to a full-blown disease after certain environmental impacts such as stress, drug abuse, viral infections or unknown others."  To give you an example: An environmental influence that might have a negative effect on the brain with respect to psychiatric disorders could be the fact that a patient's mother had the flu at a particular time during pregnancy."

 
Keeping the faith
 
According to Konradi, neuropsychiatric research is one of "the last big frontiers" in medical research. She encourages the best students and researchers to enter the field of neuropsychiatric research. However, she believes that "neuropsychiatry suffers from a stigma that discourages scientists from going into neuropsychiatric research." In her opinion, society not only lacks acceptance for neuropsychiatric diseases but also lacks appreciation for the scientists working in neuropsychiatric research. "You know, young researchers are naturally eager to achieve results and earn recognition," she says. "But many promising students are discouraged from going into neuropsychiatry because they are afraid that they might spend all of their research life without ever being able to make a major breakthrough."

 

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This article is based on an interview conducted by the author, Bianca Haderer, with Dr. Christine Konradi, professor of psychiatry and pharmacology and director of the Konradi Lab at Vanderbilt University Medical Center.
  

 

References & Sources:

-       Hyman, S. (2008) ‘A glimmer of light for neuropsychiatric disorders', in Nature Insight, Online Edition (accessed 17 August 2009)
http://www.nature.com/nature/journal/v455/n7215/full/nature07454.html

-       Chou, I. ; Chouard, T. (2008) ‘Neuropsychiatric Disease', in Nature Insight, Online Edition (accessed 17 August 2009)
http://www.nature.com/nature/journal/v455/n7215/full/455889a.html

-       http://www.who.int/healthinfo/global_burden_disease/en/index.html

-       http://en.wikipedia.org/wiki/Phenotype

-       http://kc.vanderbilt.edu/site/people/11388/konradi-christine.aspx

-       http://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml

-       http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml

-       http://www.nimh.nih.gov/health/topics/depression/index.shtml

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