Mind Matters

I'm interested in what makes the brain unable to adapt, not able to bend and change, since every encounter changes how your brain is configured. That's what learning is. At the point that you're ill, it's a matter of failed adaptation. Depressed people who are very ruminative, very reactive, overthinking—that's a coping strategy at the brain level, although not a very effective one. Then there are people who clearly are off line: they're withdrawn, not sleeping, not eating, not taking care of their kids. Both types of people can meet all the criteria for a major depressive episode. What does that mean about what the brain is trying to do?

The brain is more shut down in a way?

That is reflected by patients who have low metabolism, low activity in their frontal lobe routinely, and at the most severe, have shut down major portions of the frontal lobe. But depression is not a cognitive disorder, it's an emotional disorder. You can be thinking about the meaning of words, but the question is how they make you feel. The cognitive effects are secondary. My experiments get into what happens to your brain when you are sad, because that's what's not being managed right.

What do the studies show?

There is a see-saw relationship between the limbic and cortical areas of the brain. When healthy persons are presented with a strong emotional stressor that takes them from a neutral mood to a sad mood, limbic areas such as the subgenual cingulate turn on. At the same time, the cortex turns off, the central executor in the frontal lobe, the thinking areas that direct your attention. When you get sad, your limbic system goes into gear, the cortex turns off and you can't think straight.

What happens to the recovered depressed?

We looked at women on maintenance antidepressants who have been totally well over a year. Like healthy women, they respond to the emotional provocation by getting sad. Certain areas of the brain change identically to what you see in healthy women—but not in the subgenual cingulate of the limbic region. In addition, they exhibit a change that is totally not seen in healthy women—a decrease in brain activity in midline frontal lobe regions. This area is responsible for directed attention or self-referential processing and reward. That area turns off when the recovered depressed women get sad. That pattern is identical to what we see in the most severely ill people who never get better.

When healthy women are emotionally stressed, they're tearful and their cognitive areas turn off but their self-reward areas don't even participate. The previously depressed women exhibit a brain correlate of what we know is going on all the time in them—increased emotional sensitivity. They're monitoring their environment as being self-referential all the time. It makes them sad, and it happens automatically.

What are the treatment implications of this vulnerability to emotional stress?

Cognitive-behavioral therapy teaches people to monitor the environment for the things that seem to set them off. Obviously they aren't even recognizing that they're becoming derailed by things until you call it to their attention. The very regions that do that kind of monitoring are turned off in these depressed patients when you acutely challenge them.

Obviously depression is about the imbalance between the outside world, your internal state, and how you see the relationships of those things to you. We have to be able to interact with our environment, learn from our experience and survive. If the choreography between brain areas that are monitoring the outside world, regulating internal state in reaction to the outside world, and learning with reference to self is not agile, that imbalance may be very important to why people get depressed and to why people don't stay well.

My studies show vulnerability in action. We don't know yet whether having been sick actually changed your brain's future response.

There's some evidence that the more depressive episodes you have…

…that your hippocampus changes. Sustained stress is probably not good for your brain. It can have long-term effects on the hippocampus.

But depression is not about your hippocampus. The hippocampus is very important for laying down new memories in response to novelty in the environment, including stress. Its connections to the frontal lobe are very important. The relationship between memory and reward and self are part of how emotions are processed. If the hippocampus is damaged by early stress, that system can be damaged in terms of how new learning is handled in the face of stress. It can make it difficult to manage later stress.