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Neurology Today:
doi: 10.1097/01.NT.0000399189.56651.e9
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Up&Coming: Tomo Tarui, MD, AAN Clinical Research Fellow: On Fighting Disease in the Earliest Developing Brain

Rukovets, Olga

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Tomo Tarui, MD, has always been fascinated by the intricacies of the human brain — from the initial stages of fetal development and the young brain's ability to heal itself to the elaborate processes that define human ethics. But it is his novel research on Twin-Twin Transfusion Syndrome (TTTS), a severe fetal disease that occurs from the second trimester of identical twin pregnancy, which has earned his selection as a 2011 AAN and AAN Foundation Clinical Research Training Fellow.

DR. TOMO TARUI There...
DR. TOMO TARUI There...
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Dr. Tarui will use his AAN Fellowship to study how systemic disease in the fetal period causes brain injury, and how this injury may affect neural development in the mother's womb.

After graduating from the Keio University School of Medicine in Tokyo, Japan, Dr. Tarui completed his residency in pediatrics at Keio University Hospital in Tokyo in 2000. Dr. Tarui then came to the US to do post-doctoral research in neurology at Massachusetts General Hospital. After completing his research, he did a clinical residency in pediatrics at Maimonides Medical Center of the Mount Sinai Medical School in 2004, followed by a pediatric neurology residency at Harvard Medical School in 2006. Currently, he is a Fetal-Neonatal Neurology Fellow at Children's Hospital Boston.

Neurology Today spoke with Dr. Tarui about how he found his way to fetal neurology, as well as what (and, more importantly, who) keeps him motivated.

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I UNDERSTAND YOU'RE FOCUSING YOUR RESEARCH ON BABIES WITH TWIN-TWIN TRANFUSION SYNDROME. CAN YOU TELL US ABOUT THE SYNDROME AND THE FOCUS FOR YOUR RESEARCH?

TTTS is believed to develop because of unbalanced placental sharing and blood transfusion between identical twins. One twin is deprived of the blood supply and the other twin receives too much blood, which creates an abnormal environment and physiology for both twins, and can cause direct injury or alter normal development.

TTTS occurs in 10 to 15 percent of identical twin pregnancy with varying severity, which means about 7,500 pairs of twins born annually in the US will be affected. Some TTTS resolves or shows minimal changes in utero. However, many cases of TTTS cause significant growth discordance and systemic disease, sometimes resulting in the intrauterine death of the affected twin. After birth, the twin who has received too much blood often suffers from heart disease that requires intensive cardio-respiratory management. TTTS babies are also usually born premature, creating additional challenges, and causing a heightened mortality rate through the neonatal period, as well.

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HOW DOES TTTS AFFECT THE BRAIN?

In TTTS we know that fetal and neonatal brain injuries (hypoxic injury, intraventricular hemorrhage, embolic stroke, etc.) can occur and have a significant impact on long-term neurodevelopmental disability. However, even without such gross brain injuries, there are often neurodevelopmental impairments. There is limited knowledge about these more subtle pathological processes in utero and their association with the baby's future neurological development. Our hypothesis is that the robust brain development that takes place in the second and third trimesters and after birth is affected by TTTS; causing abnormal formation of the brain that would add another risk of neurodevelopmental disability.

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WHAT IS THE FOCUS FOR YOUR RESEARCH?

There are two major questions we want to answer: How can we establish measurables for the fetal brain's development, and how can we more accurately detect early abnormalities in fetal brain development using quantitative fetal brain MRI analysis. We will be using four different parameters for measurement: biometric analysis, whole brain and regional volumetrics, gyral development (surface area, curvature and folding similarity measures), and brain tissue composition (using diffusion MRI).

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WHAT IS UNIQUE ABOUT YOUR TECHNIQUE?

Two things are novel in our methodology. This will be one of the first cortical surface analyses implemented for fetal brain analysis. It is also novel to use separate modes of measurement on TTTS fetuses or any fetal brain injury, especially in a chronological fashion — we will acquire the measures at three time points during the fetal period.

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WHY ARE YOU FOCUSING ON THE FETAL PERIOD?

A large proportion of neurodevelopmental disabilities and injuries are caused by the pathology in the fetal and perinatal periods. This is a big public health issue, and this study can provide new insight into the evolution of brain pathology, using TTTS as a model.

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WAS THERE A PARTICULAR CASE OR PATIENT THAT PROMPTED YOUR INTEREST IN TTTS RESEARCH?

Many patients have influenced me. In particular, there is a family who has a child now close to three years old. That boy's twin brother died in utero, from TTTS. The surviving boy is also suffering global developmental delay and may face vision impairment. I met this family after the twins' birth, so they had already gone through numerous storms when they came to my clinic. I was stunned by how strong and positive the parents can stay in the face of such adversity in the lives of their children. Even in very difficult moments (their baby having a severe seizure or showing slow progress in development), they are always hopeful. It has been a privilege to work with such a strong family.

This case just reminds me that we need to find a better way to prevent these injuries. And it reminds me that even the surviving children and their families can face difficulties.

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DO YOU FORESEE ANY CHALLENGES IN YOUR RESEARCH?

One challenge is the fact that my research patients are babies — fetuses. Their brains are so small. The fetal MRI has technical difficulties, especially because the technology is motion-sensitive and you cannot really ask a fetus to be still. This makes it challenging to do image analysis.

I also want to mention that my research needs a lot of technical support and it really is a team effort because it's a very high-tech analysis and methodology, and I could not do it by myself — there are a lot of computer scientists and PhDs who are collaborating with me as a team.

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HAVE YOU HAD ANY SURPRISING FINDINGS?

In the preliminary studies, we found that normal looking twins are likely not normal. When we reviewed our archived cases of Twin-Twin Transfusion fetal MRIs, about one-third had abnormalities. That is a pretty high occurrence.

For the remaining two-thirds of fetuses, who were ‘normal’ on visual inspection, I did a relatively simple quantitative analysis — biometric measurement of the brain. The analyses showed that babies who were called ‘normal’ also have abnormalities in brain growth (manuscript is in preparation).

Initially, I was only looking for an injury pattern, and I was surprised to find that even the fetuses without obvious injury had subtle abnormalities.

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HAVE YOU HAD A PARTICULAR MENTOR THAT HAS INFLUENCED YOU IN YOUR WORK OR IN YOUR RESEARCH SPECIFICALLY?

Yes, I have been fortunate to have many mentors. Dr. Ellen Grant, a pediatric neuroradiologist and developmental neuroscientist at Children's Hospital Boston, has been kindly mentoring me for this project. Dr. Verne Caviness at Massachusetts General Hospital was my first research mentor when I came to this country [from Japan]. I have had the privilege to work with Dr. Joseph Volpe at Children's Hospital Boston, who is essentially the founder of neonatal neurology. He has given me very valuable advice on this project. Dr. Omar Khwaja, a neurologist at Children's Hospital Boston, has been teaching me the in depth details of clinical fetal and infant neurology.

My mentors have all taught me to ask always the foundation or the reason behind any answer — to not use “established knowledge” in the place of investigation.

For example, Dr. Grant recommended that I read articles about the molecular biology and cellular biology of brain development when we were writing the manuscript on TTTS changes in order to interpret the observations in MRI imaging. Dr. Grant is a physicist by background, who thinks through every object to its most fundamental level. This is particularly important when studying the developing brain. She told me to think twice before applying any scientific knowledge about the mature brain to the developing brain.. First, we know less about fetal brain from every aspect compared to the adult brain. Second, the fetal brain is likely to be different from the matured brain structurally, chemically, and functionally. Therefore, we need to be prepared for the surprise that fetal brain physiology may follow totally different rules than the adult brain.

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CAN YOU LET US KNOW WHAT YOU ARE READING OR SOMETHING YOUR COLLEAGUES MIGHT FIND SURPRISING?

There's nothing too surprising about me…but the book I'm actually reading now is Michael Sandel's Justice. It is very inspiring. He's a professor at Harvard and he writes about ethical dilemmas — what is wrong and what is right — that we face in daily life in a very easy-to-read way, but in depth.

The book is so rich in insight... it led me to think about freedom and responsibility as a researcher. As a researcher (scientist), I have the freedom to choose what I want to study, but I am also restricted in the sense that it is my responsibility, as a scientist, to consider if the study is beneficial to others (society) and ethically “right” in its predicted impact. I think that it is good to question everything — even the research pursuits that I have already thought through very carefully.

AAN Clinical Research Training Fellowships are funded by the AAN, the AAN Foundation, and the AAN Foundation Corporate Roundtable, and provide $55,000 per year for two years, plus $10,000 per year for tuition to support formal education in clinical research methodology at the fellow's institution or elsewhere. Fourteen fellowships were awarded for 2011, and more than 70 training fellowships have been awarded through the program since its inception in 1996. For more information about the program, visit http://bit.ly/egrG8L.

©2011 American Academy of Neurology

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