Is madness the price of a big brain?

Today on Science's online news service, ScienceNOW, I report on a new paper in the open access journal Genome Biology suggesting that schizophrenia is a byproduct of the evolution of the human brain, and more specifically of the huge energy requirements that brain expansion on the human line required. The link is free for four weeks from publication, so I am providing the text below.

These news items are very short, so I was only able to give the gist of a series of very interesting experiments this research team--which also included famed ancient DNA researcher Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig--carried out to test this hypothesis. The full paper is available free at this link.

The notion of a specific link between schizophrenia and brain evolution was probably first put forward by University of Oxford psychiatrist Tim Crow, who saw schizophrenia as a consequence of a "speciation event" that led to Homo sapiens, language, and advanced cognition. I discussed some of Crow's research along these lines in the last section of a feature article in Science several years ago called "What Made Humans Modern?" (you can access it free at the link.) More recently, psychiatrist Jonathan Burns of the Nelson Mandela School of Medicine in Durban, South Africa, who is quoted below, has argued for what he calls the "social brain hypothesis" of schizophrenia, most notably in his book "The Descent of Madness"; indeed, many current theories about why we have big brains are related to the need to maintain our complex social relationships and organizations (see, for example, the ideas of Robin Dunbar and others.)

Madness: Price of a Big Brain?

By Michael Balter
ScienceNOW Daily News
5 August 2008

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."

Photo: Kevin Bird/Copyright ©2006