Madness: Price of a Big Brain?

A new study suggests that the debilitating disease schizophrenia may be a byproduct of the genetic changes that fueled the evolution of the expansive human brain. The idea, still preliminary, is that the massive energy demands of the brain may make it vulnerable to mutations in metabolism-related genes.

Up to 1% of people will eventually be diagnosed with schizophrenia, a disease that can cause delusions and hallucinations and severely impair a person’s ability to relate to others. Nobody knows what causes schizophrenia, although recent research implicates defective genes. Because schizophrenia affects "social cognition," a hallmark of human evolution, some researchers have hypothesized that the disease is caused by aberrations in genes key to the evolutionary expansion of the human brain.

To test this hypothesis, an international team led by evolutionary biologist Philipp Khaitovich of the Shanghai Institutes for Biological Sciences in China and the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, set out to see how many brain-related genes implicated in schizophrenia underwent positive natural selection since humans and chimpanzees diverged from a common ancestor between 5 million and 7 million years ago.

First, the researchers looked at published databases of positively selected brain genes, which have been classified into 22 categories according to their function. They found that six of the categories included a high proportion of genes also implicated in schizophrenia; the genes in these six categories relate to energy metabolism.

So the team focused its search on energy pathways in the brain. Using a technique called nuclear magnetic resonance spectroscopy, the researchers measured the concentrations of 21 metabolites key to nerve function in the brains of 10 deceased schizophrenia patients and 12 normal human controls. Specifically, they examined an area of the prefrontal cortex implicated in social cognition. Nine of the metabolites, such as lactate, choline, and acetate, showed significantly different concentrations--some higher, some lower--in schizophrenics and normal humans. That finding, the authors say, confirms previous studies that brain metabolism is "substantially altered" in schizophrenia.

The researchers then looked at whether those nine metabolites might be important in human brain evolution. When they measured the concentrations in the same area in chimp brains, the team found that the differences between chimps and normal humans were much greater for those nine than for the 12 metabolites not implicated in schizophrenia, suggesting that energy pathways implicated in schizophrenia were also altered by human evolution, the team reports this week in Genome Biology. And 40 genes involved in these nine schizophrenia-related pathways also differed much more between chimps and humans than genes associated with the other 12.

The authors suggest that the human brain, which uses 20% of the body's total energy supply compared with about 13% for nonhuman primates, runs "very close to the limit of its metabolic capabilities." So close, they say, that small changes in energy-related genes could fairly easily cause mental problems.

"Schizophrenia may be the price we pay for our big and complex brains," says Jonathan Burns, a psychiatrist at the Nelson R. Mandela School of Medicine in Durban, South Africa, who calls the findings "very exciting." But Daniel Geschwind, a neurogeneticist at the University of California, Los Angeles, cautions that it is too early to relate the changes in metabolism to "any specific human cognitive feature."