Building a Brain

What’s needed to understand the brain is a parts list: a population of neurons, a close community of glial cells and a map of the neighborhoods that are hard hit in a variety of neurodegenerative diseases. Bring neurologist Bill Seeley these things and let him get under the hood: He will figure out why some brain regions are vulnerable to specific diseases and others are not.

Seeley has been interested in behavioral neurology since medical school. During his senior year at the University of California, San Francisco, he had a final elective and sought out Bruce Miller, who had just founded the Memory and Aging Center. Seeley—tall and intense and altogether cerebral—asked Miller if he could shadow him for a month. The year was 1999 and Miller had pretty much ignited the field of behavioral neurology with his idea that there were so many people with odd behaviors that had significant damage to the frontal and temporal parts of their brains. These patients had undergone shifts in their core personality. Seeley learned how to look for brain imaging changes that would explain this conversion of “self.”

During his neurology residency, he thought a lot about frontotemporal dementia patients and their brain scans. He knew he would return, which he did after residency—and he never left. For 14 years, he’s focused on the scans and the eventual pathology seen at autopsy. Seeley has made advances that have changed what is known about FTD, first with the identification of a population of neurons (von Economo neurons or VENs) hard hit in the disease, and then with detailed anatomical descriptions of FTD-related networks.

He and his team identified a network of brain regions associated with these conditions. They adapted a way to map signals with an fMRI that shows functional relationships between brain regions. They call it intrinsic connectivity network mapping. The method is helping them understand what brain regions work together in the healthy brain and become “disconnected” in FTD. Seeley’s team now studies network changes over time. These network approaches are used broadly to study other neurodegenerative and psychiatric conditions.

In 2011, he became a MacArthur Fellow, which many refer to as the “Genius Award.” The prize comes with money ($500,000 over five years) and prestige. Seeley is director of the UCSF Neurodegenerative Disease Brain Bank.

“This is the most mysterious illness I have ever encountered,” Seeley says of bvFTD. “If we could understand where and why these diseases start, we might gain a handle on how to prevent or reverse these processes.”

During my six-month fellowship at the MAC, I have been struck by how people with the same condition behave so differently. Everyone’s condition unfolds somewhat uniquely. He is working to understand why.

He sees behavioral variant FTD as a syndrome that can be caused by many diseases. The misfolded proteins in specific circuits define what the disease is called.

Getting back to his parts list to figure out these diseases: “Different brain regions have different parts lists. Find out what areas are most vulnerable in the disease,” he explains. “Where are they located? What are the personalities of the cell types there? Then, you can design a system to manipulate these characteristics and see whether they strengthen or weaken that vulnerability.”

Jamie Talan is an Atlantic Fellow in the Global Brain Health Institute, a collaborative program between UCSF and Trinity College in Dublin. She has spent six months at UCSF writing about the inner workings of the brain and giving voice to patients and the doctors, nurses, psychologists, geneticists and researchers involved in building the foundation for a whole body of non-Alzheimer dementias that are often missed, lost or ignored.