HARVARD GAZETTE ARCHIVES

Emad Eskandar (right) discusses with neurosurgeon Ziv Williams and researcher Ramin Amirnovin (left foreground) how to determine the function of a brain area before it is removed by surgery. (Staff photo Jon Chase/Harvard News Office)

Researchers at Harvard Medical School and Massachusetts General Hospital in Boston came across five such cases and took advantage of the situation to study how people come to appreciate a loss and then do something about it.

A committee of psychiatrists, surgeons, ethicists, and others decided that the only course left for five people with otherwise untreatable mental disorders was to cut out a certain area of their brains. The region sits near the middle of the brain tucked between regions that have to do with thinking and emotion. It is known as the dorsal anterior cingulate cortex (ACC). In seldom-used surgery, the ACC is removed to relieve conditions such as major depression and obsessive-compulsive disorder, when every other treatment has failed.

A research team lead by Emad Eskandar, an assistant professor of surgery at Harvard and director of functional neurosurgery at Massachusetts General Hospital (MGH), saw this as a rare opportunity to reach a new level of understanding about this complex and somewhat mysterious part of the brain.

The five patients played computer video games during and after their surgeries. The circumstances of playing, however, were not the kind most people ever experience. During the surgery, two small holes were drilled into their brains. Microelectrodes were gently lowered into those holes, and they recorded activity in this part of the brain as the players decided what moves to make with a joystick. Such recordings are a standard part of this delicate and complex procedure.

The shaded part of the brain, called the anterior cingulate cortex, plays a role in how a person perceives a loss and how that perception changes behavior.

Brain game

Signals on the video screen instructed the five patients to move a joystick in one direction and they would receive a $5 reward. Then, periodically, they received one of two cues to move the stick in the opposite direction, an action that gave them either $5 or $3 if done correctly.

What was going through their minds at these times? Upon analyzing the recordings, Eskandar and neurosurgeon Ziv Williams discovered that their brain cells showed the greatest activity when patients realized that there was a monetary loss. That response clearly indicated that this part of the brain is where a person becomes aware of a reward or loss. Either way, those brain signals guided their hand to the right decision. When the researchers saw this cerebral activity, they could accurately predict the patient would make the right move.

If no brain activity occurred, for whatever reason, a player was likely to make the wrong choice. Therefore, this area of the brain was dedicated to perceiving the possibility of a monetary loss and sending commands to other parts of the brain to take appropriate actions.

After removal of the ACC area, the patients played the game again. As predicted, without the activity of the ACC, they made significantly more mistakes. An error rate of about 5 percent with that part of the brain intact jumped to about 60 percent when it was lost.

As long as they could continue to move the joystick in the same direction and be rewarded, their performance was near normal. But when cues came up to change direction, they moved the joystick in the wrong direction most of the time.

"Everything else remains intact as the patients recover, but they are now specifically impaired in their capacity to appreciate a loss and then act upon it," Eskandar says. The group's experiments are described in detail in the December issue of Nature Neuroscience.

Surprise results

"We were surprised not only that we got clear, useful information, but by the fact that we were able to do the experiment at all," exclaims Eskandar. "This is all new territory in a sense."

But would they have gotten the same results in people without mental disorders? Eskandar believes so. Studies of normal people, using noninvasive brain imaging, support this conclusion.

"We see quiet activity from this part of the brain when a normal person or animal is behaving in a way that is productive and fruitful," he notes. "Then as things change for the worse, activity increases, as if the brain was saying, 'Let's stop doing this and try something else.' The difference is that now we can see this change in detail that was never available before, on a brain cell-by-brain cell basis."

Researchers see similar results when they do such invasive studies of the ACC in normal animals like monkeys.

"Our feeling is that this exists in all people," Eskandar continues. "The only difference may be a matter of degree." For example, someone who is depressed might show a greater response to a perceived loss than a mentally stable person. Someone with a gambling addiction might exhibit a milder reaction.

Eskander believes that looking at such differences in responses in different mental disorders will be an intellectually profitable area for further research. If a person is relatively insensitive to perceived losses, he or she may be a big risk taker. Such brain chemistry might play a role in something like a gambling addiction. On the other hand, someone unduly sensitive to risk might take minor loses particularly hard.

But such applications are speculative, Eskandar admits. "At this point, the great value of this research is to compare the rare invasive experiments with data from noninvasive brain imaging to reach a deeper understanding of what this part of the brain does. It gives us a capability to answer new questions and advance our knowledge of our own brains."