Madness and Genius Revisited

I must have heard a thousand times that there’s a fine line between genius and insanity. I have talked before about the possible link between the two through schizotypal personality disorder. It is quite well known that there are two living Nobel Prize winners who have a diagnosis of schizophrenia and many more who have first-degree relatives with it.

There is some very interesting research in the current issue of the Journal of Clinical Investigation from a team of scientists at the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH).

In the latest installment of a story that has been unfolding over the last three decades, they report on their findings concerning a human gene for a master switch in the brain called DARPP-32. Most people inherit a version of a gene that optimizes their brain’s thinking circuitry, yet paradoxically also appears to increase risk for schizophrenia, an illness marked by impaired thinking. The main kinds of thinking involve reasoning, abstraction and creativity.

Over the last two decades, studies in animals, most notably by Nobel Laureate Paul Greengard at Rockefeller University, have established that DARPP-32 in the striatum switches streams of information coming from multiple brain chemical systems so that the cortex can process them. Both the neurotransmitter that DARPP-32 works through – dopamine – and the chromosomal site of the DARPP-32 gene have been implicated in schizophrenia.

The NIMH researchers in this new study have identified a common version of the gene and showed how it impacts the way in which two key brain regions exchange information, so affecting a range of functions from general intelligence to attention.

To understand DARPP-32’s role in the human brain, they used genetic, structural and functional magnetic resonance imaging and also post-mortem studies to identify the human gene’s variants and their functional consequences.

Seventy five percent of subjects had the most common version of the gene, which boosted the activity of circuits in the prefrontal cortex of the brain. This region is the major filter, controller and processor of cognitive information. When active, it increases structural and functional connections and our performance on tasks that involve thinking. It almost certainly does so by increasing gene expression. In 257 affected families, people with schizophrenia were also more likely to have this common version of the DARPP-32 gene.

DARPP-32 appears to shape and control a circuit running between the striatum and prefrontal cortex. The circuit affects key brain functions implicated in schizophrenia, such as motivation, working memory and reward-related learning.

The senior investigator is Daniel Weinberger, who had this to say,

"Our results raise the question of whether a gene variant favored by evolution, that would normally confer advantage, may translate into a disadvantage if the prefrontal cortex is impaired, as in schizophrenia. Normally, enhanced cortex connectivity with the striatum would provide increased flexibility, working memory capacity and executive control. But if other genes and environmental events conspire to render the cortex incapable of handling such information, it could backfire — resulting in the neural equivalent of a superhighway to a dead-end."

Although several groups of researchers have looked for the possible clinical relevance of DARPP-32, they have had much success. This study shows a strong connection between the molecule and human cognition and also, perhaps, with schizophrenia.

What is also interesting about this finding is that it helps provide us with a mechanism by which environmental stress could lead to cognitive problems.

Apart from the uninformed tirades of Tom Cruise, I see a lot of opinion pieces on websites and YouTube expressing the opinion that psychiatry is baseless, ostensibly because there is no science behind it. By anyone’s standards, this is high level science utilizing a series of state-of-the-art approaches. And another piece of evidence that psychiatry is becoming more science than art, linking the mind, the brain and the environment into one harmonious whole.