A Time to Kill

A runaway trolley is about to kill five railroad workers. The only way to stop it is to shove a huge man next to you onto the tracks. Would you kill that man to save five?

That is one of the standard moral dilemmas that scientists are using to study how people decide between right and wrong. But is it the best example? When was the last time you faced a runaway trolley?

 

Trolleyology. People find it difficult to take actions that kill people, even if it saves more lives.

To see how people deal with more realistic choices, Joshua Greene, a psychologist at Harvard University, and his undergraduate student Katie Ransohoff, turned to medicine and public health. They recruited 84 medical doctors and 69 public health professionals—people who manage health resources such as Medicare or plan vaccination campaigns but don’t treat patients—and posed the sort of moral dilemmas that can crop up in their professions. For example: To save the lives of several patients who need brief access to life support, you need to pull the plug on a more gravely ill patient and redistribute the limited supply of machines in a hospital. In another example, you must decide between saving a few lives now with very expensive treatments or preventing many more deaths with thousands of cheap diagnostic tests. The researchers also posed the standard series of dilemmas involving the runaway trolley. As a control, they also quizzed 110 people from unrelated professions.

The doctors’ decisions in both the trolley and the medical dilemmas were not statistically different from the control group, Greene reported last weekend at the annual meeting of the Association for Psychological Science in Washington, D.C. Only 12% of doctors were willing to kill a man to save the five railroad workers, for example. But there was a wide gap between doctors and their administrators: 21% of the public health professionals said that killing the man was the morally correct action to take. The same trend held for medical decisions. Nearly half of public health professionals were willing to pull the plug on a patient’s life support to save others, compared with less than a third of doctors.

The results make sense in light of doctors’ oath to “do no harm,” Greene says. He points out that some problems, such as the overprescription of antibiotics that leads to widespread resistance among bacteria, do require doctors to sacrifice the interests of their patients for the greater good—and yet doctors continue to overprescribe. The trolley dilemmas may seem artificial, Greene says, but they represent extreme versions of moral decisions “we make in our everyday lives.”

The next step would be a study that tracks public health professionals before and after their training, says Daniel Wikler, a bioethicist at Harvard School of Public Health in Boston, who helped Ransohoff design the medical dilemmas. Does an education in public health make people more willing to sacrifice an individual for the greater good, he wonders, or do such people gravitate to this field in the first place? People clearly differ in their moral reasoning, but whether those differences are due to nature or nurture remains to be seen.

Why Ketamine Makes You Happy

When psychiatrists write a prescription for a typical antidepressant such as Zoloft or Paxil, they don’t expect their patients to show much improvement for a few weeks. Clinical trials, however, have shown that low doses of a drug known as ketamine, which is used at higher doses as an anesthetic and is taken recreationally as a hallucinogen (sometimes called “Special K”), can ease the symptoms of depression within hours. Now, scientists have figured out how ketamine works in the brain. In the process, they’ve uncovered a new molecular pathway involved in clinical depression.

 

Happy drug? Ketamine helps combat depression.

Neuroscientist Lisa Monteggia and her colleagues at the University of Texas Southwestern Medical Center in Dallas began their work on ketamine by verifying what other scientists have shown: 30 minutes after receiving a dose of ketamine, mice prone to depression show an easing of their symptoms. When put in a tub of water, mice considered depressed quickly give up escape attempts and instead float motionless. After receiving ketamine treatment, such mice swim for a longer period of time in the water.

Monteggia’s team then moved toward understanding how the drug affects the brain. Scientists already knew that ketamine binds to, and blocks, a receptor in the brain called NMDAR, which triggers its anesthetic effects, so Monteggia’s group used other compounds to block NMDARs in mice. As the water test revealed, the animals depression once again lessened, so the researchers knew that ketamine’s antidepressant effects also depended on NMDAR. Next, the team studied how levels of certain proteins in the brain changed when mice were given ketamine. Blocking NMDARs with other compounds turns off production of some proteins, but ketamine causes the neurons to make more of a protein called BDNF (brain-derived neurotrophic factor), the researchers report online today in Nature. The findings suggest a new set of molecules that ketamine and NMDAR affects, and that means a new set of molecules involved in depression.

“There was no precedent for this,” Monteggia says. “We had no idea why blocking an NMDAR would produce protein.” There are two ways of activating NMDARs. Some turn on when the specific neurons fire to accomplish a task—be it learning, memorizing, or thinking. But other NMDARs are activated simply as background noise in the brain. Ketamine, the researchers showed, doesn’t block the brain from activating NMDARs when it’s using them to send a specific message. But it does block them from creating that background noise. Although scientists have long known about the brain’s spontaneous level of background nerve firing, Monteggia’s study is the first to suggest a link between such background noise and depression.

“What we’re suggesting is that this background activity is important,” Monteggia says. She says that the link between spontaneous nerve firing and depression could also explain why electroconvulsive therapy (also known as “electroshock therapy”) eases depression–perhaps ECT and ketamine reset the background brain activity. Furthermore, Monteggia’s group identified a new molecule that carries out NMDARs’ effects on spontaneous brain activity. When the researchers activate this protein, called eEF2, in mice, they see the same fast-acting antidepressant action. A drug that targets eEF2 instead of NMDARs could treat depression, Monteggia says.

Carlos Zarate, a psychiatrist at the National Institute of Mental Health, in Bethesda, Maryland, who led many of the initials studies of ketamine as an antidepressant, says that the study goes far in uncovering a new pathway involved in depression. “It brings about a new series of targets for drugs that has not been pursued at all.”

Although ketamine is used for short-term depression treatment in humans, its potential for abuse keeps doctors from prescribing it for the long term. A drug that targets the ketamine pathway in another way could offer antidepressants without the same potential for abuse. The next questions, Zarate says, are whether eEF2 is a safe drug target in humans and what other pathways are involved in depression.

The Mental Hazards of City Living

City dwellers worldwide enjoy several advantages over their rural compatriots, including, on average, better job prospects and better access to food and health care (not to mention nightlife). At the same time, city living can be stressful, and studies have found that mental health problems, such as schizophrenia, depression, and anxiety disorders, are more common in urbanites. Now, researchers have taken a crack at understanding this connection by looking for differences in how the brains of people from urban and rural environments react to certain kinds of stress.

Worlds apart. New research suggests living in a rural or urban environment can shape the way the brain responds to social stress.

Psychiatrist Andreas Meyer-Lindenberg and collaborators at the Central Institute of Mental Health and the University of Heidelberg Medical Faculty in Mannheim, Germany, have previously used brain-imaging methods to search for abnormalities in the brains of people with genetic risk factors for mental illness. In the new study, Meyer-Lindenberg says, the group wanted to apply the same approach to environmental risk factors, which can be even more powerful than genetic factors. “Urbanicity … has a much higher associated risk than any gene,” he says. “The idea was to take people with that risk factor and see if there’s anything different in their brains.”

In an initial study, the researchers placed ads in local newspapers to recruit 32 healthy German adults from cities (with more than 100,000 inhabitants), towns (with more than 10,000 inhabitants), or rural areas. Inside a functional magnetic resonance imaging (fMRI) scanner, which monitors brain activity, a subject worked on difficult arithmetic problems while a fake “performance monitor” indicated a dismal success rate compared with other subjects. Then the researchers ramped up the stress. Meyer-Lindenberg explains: “We would call them in between runs and say, ‘We notice this seems to be very hard for you, but please understand these experiments are very expensive, so if you could just try to at least be above the bottom quarter, we’d really appreciate it.’ ” Measurements of the subjects’ heart rates, blood pressure, and stress hormone levels indicated that the stress was indeed getting to them.

The fMRI scans showed that volunteers who currently lived in a city exhibited greater activation in the amygdala than did rural denizens during social stress. Previous studies have suggested that the amygdala, among other roles, evaluates social threats and is overactive in people with anxiety disorders. People who’d been raised in a city, regardless of their current home, showed a different pattern: more activation in the perigenual anterior cingulate cortex (pACC), another region thought to be involved in emotion and social processing, and implicated in some studies on schizophrenia. To Meyer-Lindenberg, the findings suggest that the pACC may be susceptible to lasting effects from the environment early in life, whereas the amygdala is more sensitive to one’s current situation.

Two follow-up experiments with new groups of volunteers and different tasks inside the scanner reinforced these findings, suggesting that the bigger the city someone currently lives in, the more amygdala activity he or she exhibits during social stress. And the more time spent in a city as a child, the more the pACC revs up, the team reports online today in Nature.

Meyer-Lindenberg suspects that city living actually causes these differences in brain activity. He acknowledges that the data so far can’t prove that, but he notes that his team found no correlations between brain activity and several measures of subjects’ mood and personality, or with demographic factors, such as education and income.

“I like the idea of going from population studies into the lab to test mechanisms,” says John Cacioppo, a social neuroscientist at the University of Chicago in Illinois. He’s not yet convinced that the German team has ruled out alternative explanations for their findings, but he thinks the idea that city living increases the risk of mental illness by altering the brain’s sensitivity to social stress is worth following up on. Cacioppo says he’d like to see future studies delve into specifically what kinds of social stress in urban environments are potentially harmful. Being mocked by a scientist isn’t a daily occurrence for many city dwellers, he notes, but feelings of loneliness and exclusion (or on the other hand, overcrowding), or perceptions of discrimination, powerlessness, or low status, might be.