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Wired for Emotion

Now that we're getting closer to a root cause of depression (psst—it may come from your left prefrontal cortex), can we figure out how to fix it?

By Jeff Sciortino and Jim Robbins
Apr 1, 2000 12:00 AMMay 21, 2019 5:48 PM


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A woman in her early twenties sits alone in a small, windowless room at the University of Wisconsin's Health Emotions Research Institute in Madison. A bundle of spaghetti-thin wires draped over her head contains sensors that register the electrical activity of 128 brain sites as she watches photographic images flash by on a computer screen. A plump mushroom pops up for a few seconds, followed by a mangled body in a wrecked car and then a blooming rose.

Meanwhile, in a separate room, grad student Chris Larson watches the woman on a video screen and records the shifting pattern of electrical impulses in her brain. When a photo of a naked man and woman prompts a noticeable blip, Larson smiles. "Erotic pictures are the best," she says, for eliciting strong positive responses.

The electric charges Larson is most closely observing come from the woman’s prefrontal cortex, just behind her forehead. This palm-sized section of gray matter determines both our general outlook on life and whether we respond positively or negatively to events and experiences. “Animals do a lot of things instinctively,” says psychiatrist Ned Kalin, director of the institute. “But people—and probably monkeys—have the ability to think 20 steps into the future: ‘In the end I’m going to feel great, because I worked hard to get there,’ or ‘I’m going to get a lot of credit for this.’ It’s the prefrontal cortex that brings those emotions into play and guides us in our behavior. If we didn’t have a sense of what would be wonderful or awful in the future, we would behave very haphazardly.”

Brain imaging has revealed that positive and negative emotions are polarized on opposite sides of the prefrontal cortex. The right side governs a physiological loop that produces negative, inhibiting feelings, while the left commands a loop for positive, outward-reaching emotions. Research now suggests that a person’s natural temperament—optimistic, pessimistic, extroverted, or introverted—may depend on which side of the prefrontal cortex is more active. In one study of 10-month-old infants who were briefly separated from their mothers, researchers found that babies who cried had a dominant right prefrontal cortex, and that those who calmly explored the area where they had been abandoned had a more active left cortex.

Some asymmetry in the prefrontal cortex is normal, but in people who are depressed, the balance tips way over to the dark right side. Initially, scientists figured the system goes out of whack because of an overactive right cortex. Now some suggest the problem also stems from an underpowered left cortex. The deficit appears to be twofold. The left cortex seems to falter in mustering and maintaining positive feelings in response to outside stimuli as well as in dampening the outpouring of negative feelings in response to negative stimuli that are generated by another part of the brain: the amygdala. This almond-shaped structure behind the ear is Fear Central, the neural processing station that sends out warnings of perceived danger and threat. Scientists suspect that the left cortex normally shuts down the amygdala’s alarm signal, firing off a sort of “message received.”  Without a robust left cortex, they theorize, the amygdala runs unchecked, flooding a person with fear that leads to helplessness and despair.

The primary purpose of Larson’s blitz of images is to test how long it takes the young woman viewing the photos to tamp down her fear. As she looks at a bloody photo, she is also subjected to a brief burst of loud white noise delivered through a pair of earphones. Startled, she blinks rapidly for a half second or so—a normal startle response. “People who are still having eye blinks two-and-a-half seconds after the picture goes off are more right frontal,” Larson says. They apparently lack the biological wattage to shut down their startle response, and they are more prone to depression. She theorizes that the same individuals may have trouble managing other negative emotions, such as anger, fear, or sadness. Ultimately, an inability to rein in negative mental responses could aggravate physical problems like high blood pressure and heart disease.

University of Wisconsin researchers are in the vanguard of exploring the uncharted frontier that neuroscientist Richard Davidson has dubbed affective neuroscience—the study of how emotion is generated by the brain. “Emotion is the glue that holds a personality together,” says Davidson, a principal investigator at the institute. “Yet until now it’s been relegated to second-tier status as a subject of scientific study because it has been hard to measure.” Extraordinary improvements in brain-imaging technology during the past five years are the key. Davidson and Kalin use magnetic resonance imaging (mri), positron emission tomography (pet), and electrical sensing techniques to scour pockets of the brain where emotions dwell, then develop detailed schematics of the neural circuitry among them. By mapping how the brain generates and processes emotions, they hope to discover ways people might use the power of their own minds to overcome the crippling impact of fear or depression, and maybe even improve their physical health as well.

“This is the Holy Grail of human health research,” says Kalin.

Sustained emotional stress is known to damage the brain, and scientists wonder how it might affect the right and left prefrontal cortex, particularly in young children whose brains are still developing. “Severe stress affects the size of the structures in the brain, causes cell death, and affects the number of connections between brain cells,” observes Kalin. “Early in life the brain is much more vulnerable to these insults.” Studies with young rats, monkeys, and other mammals reveal that emotionally stressful events can flood the brain with cortisol, which Kalin calls “the master stress hormone. In low doses it alerts us and organizes our behavior so we make sure we protect ourselves.” But in high doses, “it leaves us stressed out, inattentive, disorganized, and depressed.” Early sustained cortisol exposure also damages the hippocampus, a part of the brain that regulates mood and memory.

And what kind of stress causes the most damage? “A car wreck is bad,” Kalin says, “but it’s not as bad as being neglected, isolated, or ostracized by your peers. Deprivation—lack of love, comfort, security—can have big-time effects.” Research from the University of Minnesota has shown that children age 2 and up who lack secure attachments to their mothers have higher rushes of cortisol during even mildly stressful events, such as getting a vaccination shot, than do youngsters with strong parental bonds.

People can’t always be protected from severe stress or trauma, so Kalin and Davidson are determined to find ways to insulate the brain from overexposure to stress chemicals. One idea is to develop drugs that block them from damaging brain tissues. Several scientists at the institute are experimenting with a peptide called alpha helical corticotropin releasing factor. When injected into the brains of rats, it plays a version of musical chairs, occupying receptor sites usually filled by an anxiety-inducing chemical. Blocking receptors dramatically increases the rats’ ability to deal with stress. Rats freeze (a classic stress response) for about 15 minutes when zapped by three low-intensity electric shocks—“the equivalent of touching a light socket and getting a zing,” says Vaishali Bakshi, a postdoctoral fellow at the institute. But rats injected with the blocker take much longer to stiffen and begin moving again in just half the time.

Davidson and Kalin also hope to discover ways to repair or reverse damage to neural circuitry without using drugs. That idea would have been scoffed at just a few years ago: The brain is malleable in the early years, so the thinking went, but by adulthood the only change possible is deterioration. The brain, however, turns out to be in constant flux, with cells both born and dying all the time. “Our notion of plasticity is changing incredibly,” Davidson says.

Magnetic stimulation is an example of one means that might mend damaged neural circuitry. At more than 20 medical institutions around the world, physicians have been experimentally treating patients diagnosed with recurrent depression by bombarding their left cortices with magnetic fields. “Our results have fit exceedingly well with Davidson’s findings,” says Alvaro Pascual-Leone, a behavioral neurologist at Harvard Medical School. He was skeptical at first because he thought pointing to an underpowered left cortex as a source of depression was simplistic: “But when you apply stimulation to the left side, patients indeed get better.”

In the half-hour treatment, a Ping-Pong paddle-sized instrument that generates magnetic energy is held against the patient’s left forehead. “It feels like someone is tapping on your head,” says Pascual-Leone. The sessions continue for 10 days. Presumably, the magnetic stimulation induces a current in the brain’s neurons, thus making them more active. Results among the several hundred patients treated worldwide so far indicate that this magnetic therapy outperforms a placebo treatment. As many as half the patients in some studies experienced significant relief from depression; all had failed to improve with previous therapies. Pascual-Leone emphasizes that magnetic stimulation is not a cure. But it does appear to check depression for a number of months.

Researchers at Northwestern University in Evanston, Illinois, are trying another unusual therapy called neurofeedback. A patient with depression sits in a quiet room with electrodes attached to both sides of the head. The electrodes register alpha brainwaves in the left and right frontal cortex. Alpha brainwaves are inversely related to brain activity. Depressed patients have “high alpha” on the left side, indicating that this region of the brain is too inactive.

In neurofeedback, as the patient increases alpha brainwaves on the right (calming the right cortex) and decreases them on the left (upping activity in the left cortex), he is rewarded with the sound of a flute playing at an ever higher pitch. After 20 to 40 half-hour sessions, tracings show the left cortex activity overtaking the right. So far, more than 20 people, from adolescents to a 65-year-old, have been treated with the technique. Except for those with bipolar depression, all patients reported feeling better, says psychologist J. Peter Rosenfeld, who developed the method.

Other techniques might yield equally dramatic results. For example, the left cortex produces positive feelings when a person sets goals and attains them. So Davidson suggests simple exercises could be developed that play into that response. “The goal for someone who is severely depressed might be very basic—getting out of the house before nine in the morning,” he says. “But the person would be mindful of how he or she feels in achieving that goal.”

Ultimately, a better understanding of what constitutes good and bad brain hygiene could be a powerful tool to help people stave off emotional disorders before they become crippling. Davidson suggests that evolving brain research will change the field of psychology drastically. “In 50 years,” he says, “psychology will be taught as a life science.” Kalin foresees mri brain scans becoming a common diagnostic tool. “At 6 years of age, everybody goes in for a little brain scan,” he says. “You show them a picture of something positive and something negative, and see how their brain activates. If nothing is happening on the positive side, you design an intervention.” That might be as simple, he says, as counseling parents to be more positive, or teaching a child to break a pattern of negative thoughts.

Other scientists imagine a more entertaining future scenario: Eight-year-old Sammy has been moping around the house, bored and listless. He picks at his food, argues with his sister, and ignores Ripley, his yellow Lab. His schoolteacher says he has become inattentive. His worried parents take him to the family doctor, who orders up a scan of Sam’s brain as the boy watches a series of pictures flash by. The diagnosis: depression. The doctor prescribes not a pill but a video game. Seated in front of a computer screen, Sammy steers his race car around a track with a joystick. But the joystick lacks a speed control. Instead, Sammy is told he has to rely on brainpower. As he learns to control certain brain waves while playing the game, his race car speeds up. After several sessions of play, Sammy heads home, cheerful, eager to see his pals, and ready to romp with Ripley.

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