According to his two brothers, my uncle Glenn had always been a little odd. He was a quiet kid, and when he spoke—he talked at you, not to you. If he got excited, he might splay his fingers incongruously or his body would abruptly quiver. Never physically aggressive or mean, Glenn had friends—but not many. He was not what most people would consider fun. Later, Glenn developed schizophrenia, a disabling disorder in which patients lose contact with reality, develop hallucinations (seeing or hearing things that are not really there) and delusions (false beliefs). In retrospect, my Dad and my uncle Warren wondered whether they might have seen that coming. But, of course, they could not have.

Certainly no one foresaw the far more destructive path forged by 22-year-old Jared Lee Loughner, the man accused of wounding Congresswoman Gabrielle Giffords and killing six in a shooting rampage in Arizona. Loughner, too, suffers from delusions and random thoughts. In late May, he was deemed mentally unfit to stand trial, after two experts diagnosed him with schizophrenia. (Violent behavior is not characteristic of this disorder, however. See “Deranged and Dangerous,” By Hal Arkowitz and Scott O. Lilienfeld, Scientific American Mind, July/Aug 2011.)

In my uncle's case, as with most, the destruction was internal: unremitting anxiety, fear and mental chaos. And although his early symptoms hardly forecast that fate, his brain—if anyone could have looked at it back then—seemingly would have. Scientists have been searching for ways to accurately diagnose psychosis in its earliest stages, because intervening early appears to boost the odds of preventing or recovering more fully from schizophrenia. Now it seems that the brains of adolescents destined to develop psychosis do change in telltale ways in anticipation of the illness. These findings, among others that shed new light on the roots of the emotional and social difficulties of schizophrenics (see part II of this blog, to post next week), were presented in May at the Association for Psychological Science (APS) Annual Convention in Washington, D.C. Together, these results can help us better predict, even before symptoms appear, who to target for treatment. They may also tell us more precisely how to treat or prevent the illness, perhaps by aborting or stemming the neural processes that push the brain toward psychosis.

Cerebral shrinky dinks

Scientists looking for the roots of schizophrenia have for decades trained their eyes on genes that may tweak the brain in untoward ways, even back in the womb. Some people who later developed schizophrenia displayed characteristic oddities very early—delays in walking or talking, for instance. Yet the disorder does not afflict babies. Any early behavioral oddities crystallize into psychotic symptoms only much later, at the average age of 18 for males and 25 for females, according to Tyrone Cannon, a neuroscientist at the UCLA School of Medicine. What is more, in some young adults, symptoms pop up out of the blue. A popular A-student may, for example, suddenly withdraw into his or her own world. As a result, Cannon and other experts are shifting their efforts to examine the brain during this final ramp up to full psychosis.

Several years ago Cannon and his colleagues began scanning the brains of adolescents at high risk of psychosis, either because they showed subtle signs of it or had a family history of the illness combined with recent problems at school or work. The researchers watched how the brain changed over time, pinpointing regions of the brain's cerebral cortex, which covers its surface, that contract or expand, as well as what kind of brain matter was vanishing. (In particular, they measured gray matter, which contains the bodies of neurons and their short branches.) They wanted to see those volume changes, because previous studies have shown that people with full-blown schizophrenia have a distinct lack of nerve cell tissue in certain brain areas.

In 2009 Cannon and his colleagues reported that of 35 high-risk young people (ages 12 to 25), the 12 adolescents who became psychotic within a year had much greater contraction, particularly in their prefrontal cortex, than did the 23 who did not become sick. For the past three years, Cannon's team has expanded its efforts as part of the North American Prodrome Longitudinal Study (NAPLS), in which a consortium of research teams from eight universities are examining emerging psychosis. As Cannon reported at the APS convention, he and his colleagues have scanned the brains of 400 adolescents so far, about two-thirds of them high-risk. Compared to the healthy kids, the team found that the youth in danger lost much more gray matter with age in the prefrontal and temporal (side) cortex. And when they looked at surface contraction, the same pattern was found.

In addition, those whose symptoms worsened over 12 months showed much greater shrinkage than the kids who got better. “Those who became psychotic show steeper surface contraction in the prefrontal region plus parts of temporal cortex governing auditory processing,” a change that could be responsible for auditory hallucinations, Cannon says.

The shrinkage Cannon is measuring probably reflects an exaggeration of normal brain development, he says. In adolescence and early adulthood, the brain trims neural connections at an astounding rate. This paring is particularly fastidious in the brain's pre-frontal cortex, the center for decision-making, planning and impulse control, and undoubtedly underlies a teen's transformation into a more reasonable, risk-averse adult. In the case of psychosis, Cannon says, something seems to send this cellular pruning into overdrive, leading to an even faster loss of connections—including some that apparently keep us sane.

Lack of connections

But the spot-slashing of gray matter is not the only early anatomical sign of the disorder. Diagnosed schizophrenics also lack white matter, material that consists of an insulating sheath called myelin wrapped around long nerve fibers that connect distant brain regions. As gray matter shrinks in adolescence, the brain's white matter expands. Now, Cannon's team has found, in the NAPLS subjects, that as the disease develops early on, white matter fails to develop. Compared to normal brains, in which white matter grew steadily from age 12 to 25, that growth was far less obvious in the high-risk group, Cannon announced at the conference. And among the youth who deteriorated over time, the change over the teenage years was imperceptible.

The lack of white matter seems to cripple a key brain circuit involved in controlling emotions. Cannon and his colleagues also asked at-risk individuals and healthy controls to judge emotional content of faces inside the scanner. Although these individuals could perform the task perfectly well, their brains reacted abnormally in response. Compared to low-risk individuals, these kids in jeopardy showed depressed activity in the prefrontal cortex, whose job is largely to inhibit other brain regions, and accompanying increased activity in the amygdala, a hub of feelings. This and other work suggests that the brain circuit that puts a brake on emotions is not maturing properly in these individuals. “In patients, the amygdala is left unsupervised,” Cannon says.

Cannon hopes that these new findings will help not only better explain the disorder, but enable clinicians to accurately predict who will get it by producing anatomical profile of their brains. Machine-learning algorithms that analyze these profiles may someday help humans flag the youth at the greatest risk so that they can be helped. A growing body of data suggests that the earlier the illness is identified and treated, the better patients fare. Down the road, these results may provide clues to the best molecular targets for drugs that could put the development of the brain's gray and white matter back on track, stemming the slide into psychosis before kids hit bottom.

If such early diagnosis—and treatment—had been available when my uncle was a teenager, decades ago, they might have stemmed his lifelong struggle with schizophrenia. The disorder ultimately cost him his job and made establishing close relationships extremely difficult for him. But findings such as Cannon's provide fresh hope that those so tragically afflicted in the future will find life easier to traverse than it was for Glenn.