Where once doctors and researchers sought answers to brain disease mainly by looking for places in the brain where the damage occurs, such as the "speech-production" area described by Pierre-Paul Broca in 1861, they now are looking at its wiring as well.
"In the last twenty years, our thinking has changed to this idea of circuits," said Dr. Guy McKhann, professor of neurology and neuroscience at the Johns Hopkins School of Medicine and panelists during a session on circuits at the Dana Center in Washington, DC, this week.
Researchers have found, using ever-better brain imaging and listening devices, that circuits—the minuscule electrical and chemical pathways between parts of the brain—are a large part of how we process vision, how we carry out movement , how we feel our moods. Some circuits affect your heart rate and other maintenance work. Some might somehow fail, and signal the start of a cascade of bad connections that could lead up to an epileptic seizure, or a mood disorder, or Parkinson’s disease.
"Ultimately, we’re going to have to understand circuits to cure disease," said Dr. Mahlon Delong, director of the Comprehensive Neuroscience Center at Emory University. DeLong was the first to identify and describe a single type of circuit within the brain—"basal ganglia-thalamocortical" circuits, helping to explain the variety of ways those structures affect motor, cognitive and emotional functions.
New technology, new ideas
DeLong’s and others’ work has been translated into surgical success for some people who have Parkinson’s disease and have not responded well to medicines and other treatments. While earlier surgical treatments for such patients was hit or miss (but worth it because nothing else was working), surgery that aims to disrupt a certain pathway in the subthalamic nucleus, deep inside the brain, works consistently well, DeLong said. "It’s kind of standard fare" now, he said.
The surgery, called deep brain stimulation, involves implanting electrodes in target brain areas and connecting them to a neurostimulator device placed under the skin of the torso. The neurostimulator does for neurons what a pacemaker does for the heart muscle—disrupts the rhythm of the electrical impulses, changing the circuit.
Dr. Helen Mayberg, a professor of psychiatry and neurology at Emory, is experimenting using the same style of surgery for people who have such severe depression that multiple drugs and therapies have not helped them. Mayberg and her colleagues at the University of Toronto spent years studying the brain scans and other data of people who did and did not respond to various treatments for low mood, and found a handful of brain regions that seemed to consistently be involved.
In 2003, they started testing the effects of stimulating one region, called cingulate area 25. In some patients, it had an immediate effect, unlike drugs and therapy, which can take weeks to ease symptoms. Patients are conscious during the surgery, describing how they feel so the surgeons can be sure to get the placement and electrical dosage correct, and some felt in real-time a lifting of their spirits, as if a giant weight had fallen away. In addition, the other brain regions in the circuit improved, though they weren’t being directly stimulated.
"You exploit the availability of tools that you have," Mayberg said. With functional magnetic resonance and other forms of brain imaging, and people such as DeLong showing how it could be used, she has been able to connect the disparate evidence of chemical changes and slight physical changes in the brain to specific actions and activities in living people. "If we hadn’t had those, nothing … would have been possible. It would have really been reckless" to try such a procedure. But imaging allowed them to actually articulate the nodes in the circuit, to see the changes in real-time, albeit in a much grosser and much less elegant way than they would wish, she said.
Dr. Brian Litt, an assistant professor of neurology and bioengineering at the University of Pennsylvania, is pushing the envelope of scanning technologies to try to help people with severe forms of epilepsy. He also is in the very early stages of testing a device that works much like a pacemaker, monitoring signals and interrupting ones that might cascade into an episode. Through careful listening and studying the electrical results statistically, they found patterns of energy bursts hours before seizures and different patterns minutes before.
"In retrospect, our scanning has been crude," he said, citing EEG machines that now are digital but still offer only readings that were set by how fast the pencil attached to the old-style machines could write and electrodes that were designed when transistors were big. “We’re looking in wider frequencies and using micro-electrodes” now. Other researchers are doing the same, at other frequency levels and in various areas of the brain.
Willing volunteers
The scientists are greatly aided by the very people they wish to help, Litt and others said.
"Epilepsy and its surgery and evaluation provide a window and access to understanding cortical function like no other," Litt said. "At virtually every major center where there’s good surgery going on, there’s good research going on, and these patients allow us to record from their brains, from electrodes placed in the brain, to stimulate, record, try to understand and interrogate the networks that are involved in generating their seizures."
DeLong agrees. "We have greater access to the brain, in the course of these procedures that we carry out for sort of routine things like Parkinson’s and other disorders now," he said. "We’re able to use almost every operation as an experiment, gaining information that would have been impossible before."
Culture change
This sort of cross-sectional research requires more than just a neurological approach, the panelists agreed.
"We need a culture that encourages cross-talk among disciplines," DeLong said, including voices from therapists through moody poets and patients.
To do his research, for example, Litt works with statisticians and mathematicians, researchers and doctors, engineers and manufacturers. But "in my field, the centers have different equipment, they have different data formats, they have different protocols that are all based upon tradition" that may be out-of date, such as the slow EEG machines. "We have to get some organization, some standardization," he said, and share information so they can work on problems together.
These sorts of studies are in very early days, Mayberg said, proving in principle that these methods may work. And they are definitely not for everyone. "If you can get better through therapy, you should have it. If you can get better with drug A, drug B, you should have it."
"We’re now at the beginning of an era where it’s possible for the first time to understand the brain and by so doing to understand ourselves," said panelist Dr. William Mobley, director of the Neuroscience Institute at Stanford University. "This is immensely exciting. The technology is in hand or nearly there that will allow us to understand for the first time how our brain actually works.
"What we learn by studying the brain will change fundamentally every aspect of our existence. We will change who we are, as a society, as a result of our science."