At McLean Hospital in Belmont, Mass., brain researchers have hit upon what could become a new way to treat depression--blocking a brain chemical called dynorphin, the "evil cousin" of endorphin, which triggers the "runner's high."
At UCLA, psychiatrists have modified the standard EEG (or electroencephalogram) to predict which depressed patients will get better with drugs and which won't--weeks before the patients can detect any changes in mood.
At the University of Toronto, scientists are tracing the specific components of depression--sadness, distorted thinking, disturbed sleep--to separate, but linked, regions of the brain. In the process, they've found one key region in the "emotional brain," area 24a. If that's overactive, depressed people improve with drug therapy; if it's not, they won't.
At Beth Israel Deaconess Medical Center in Boston, researchers are trying yet another approach--transcranial magnetic stimulation--that uses magnets placed on the scalp to stimulate the prefrontal lobes of the brain, which are often sluggish in depression.
Depression, in other words, is no longer believed to be a mere deficiency of key brain chemicals--norepinephrine, dopamine and, perhaps most important, serotonin. Today, brain researchers view this common illness, which strikes about 19 million Americans, as a malfunction of particular circuits. Those circuits connect the limbic system, or "emotional brain," with the prefrontal cortex, or "thinking brain," and the brain stem and hypothalamus, which control basic functions such as sleep, appetite and libido.
In truth, there never was much proof that depression was merely a serotonin deficiency. That was an inference from data showing that people who are aggressive or suicidal often have low serotonin, says Dr. Peter Whybrow, director of the neuropsychiatric institute at UCLA. And from data showing that if researchers deprived people of tryptophan, a substance from which the body makes serotonin, they quickly got very depressed.
But now, despite the obvious efficacy of serotonin-boosting drugs such as Prozac, Zoloft and Paxil, it's clear that when a person is depressed, there's a lot more going wrong in specific areas of the brain than just low levels of serotonin.
The Human Brain's Electrical Signals
The brain works by chemical and electrical signals. When an electric current passes through one cell, the cell releases a neurotransmitter, which floats to the next cell, causing it to "fire up electrically." This process, repeated cell after cell, activates whole circuits in the brain, says Dr. Alvaro Pascual-Leone, director of the transcranial magnetic stimulation lab at Beth Israel.
While most drug developers have focused on the chemical side of the equation, he says, depression can also be treated by getting the electrical circuits back to normal. One way to do this is ECT, or electroconvulsive "shock" therapy, which causes a brain-wide seizure. ECT is effective, but it can cause confusion and memory loss.
A potentially better though still experimental approach, Pascual-Leone says, is transcranial magnetic stimulation, or TMS, which uses a magnetic field to kick-start just the prefrontal lobes. That, in turn, may affect the limbic system, potentially easing depression without brain-wide seizures and memory loss.
The hallmark of depression, brain mapping shows, is too little activity in the right and left prefrontal lobes (behind the eyes) and the right and left parietal lobes (on the side of the brain, toward the top), and too much activity in the limbic system, or emotional brain.
But the limbic system and prefrontal lobes, which govern thinking, are actually wired together through specific neural circuits, says Dr. Helen Mayberg, a professor of neurology and psychiatry at the University of Toronto. She uses PET scans to measure blood flow and map "depression circuits" in the brain.
The close links between the limbic system and prefrontal lobes probably explain why depressed people not only feel bad emotionally but also have trouble thinking. "For many people, yes, they are sad," she says. "But what brings a lot of people to the doctor is the fact that they can't think straight."
In addition to the abnormal activity in the entire limbic system and prefrontal lobes, scientists are finding changes in specific subregions when people are depressed. The hippocampus, for instance, a center for learning and memory, is often shrunk in depression, perhaps because it is damaged by the stress hormone, cortisol. Some scientists also think the amygdala, a fear processing center, may be involved.
