Attention: Anti-sleep Pill Offers Insight Into Concentration Area of Brain

by Aalok Mehta

February 18, 2009

Using brain imaging to look directly at the effects of a drug in real time, scientists have zeroed in on areas responsible for attention and concentration, a finding that may improve drug design for conditions such as attention-deficit/hyperactivity disorder, Parkinson’s disease and depression.

Employing functional magnetic resonance imaging (fMRI) with volunteers under the influence of the stimulant drug modafinil, Michael Minzenberg, a professor of clinical psychiatry at the University of California, Davis, and his co-workers observed altered activity in the part of the brain stem known as the locus ceruleus.

This activity caused the prefrontal cortex to assume a more attentive state, shown by the volunteers’ improved scores on a battery of psychological tests, Minzenberg says.

From studies on monkeys, scientists have long suspected a link between cognitive control and the locus ceruleus, which also is associated with responses to stress and anxiety, he says. The new study is the first to confirm this connection in people.

Interest—both good and bad—in modafinil, also known as Provigil or Alertec, continues to increase.

Approved by the U.S. Food and Drug Administration to treat narcolepsy, shift-work sleep disorder and obstructive sleep apnea, the drug also has shown potential in preliminary research for treating Parkinson’s disease, depression, drug abuse, coma and other conditions. But modafinil also has inspired controversial uses: Many people take the drug recreationally to suppress the need for sleep, and some healthy people, such as students and their professors, say they use it as a cognitive enhancement tool.

Minzenberg’s work provides new insights into modafinil, which is known to affect many neurotransmitters but has remained somewhat mysterious. The drug can block the reuptake of norepinephrine, for example. Because the locus ceruleus is particularly rich in norepinephrine receptors, the findings suggest that the neurotransmitter plays a vital role in the drug’s attention-boosting properties.

“This study is novel for a number of reasons,” Minzenberg says. “It uses functional imaging to study the effects of medication, it shows how drugs affect neural cognition and behavior, we believe it’s the first to find this kind of altered pattern in the locus ceruleus and it reveals a mechanism that potentially could affect how pro-cognitive drugs are designed in the future.”

The new study appears in the December 12 issue of the journal Science.

‘Booming’ area of investigation

According to Rajeev Raizada, a professor of computational science at Dartmouth College, it’s not unusual for uncertainties to remain about how exactly a drug affects the brain, because of the sheer complexity of the interactions.

In fact, the new Science paper is a just one example of a booming area of investigation in which researchers are using sophisticated new drugs to tease out information about the brain in real time, he says.

“The idea of the locus ceruleus having different phases of activity—it’s very interesting,” he adds.

Such studies draw more-modest conclusions than do fMRI studies claiming to explain complex behavior such as political preference, which have generated a substantial backlash in recent months.

And Raizada warns that investigations of drugs’ real-time effects need to be carried out with caution. Just as modafinil affects the brain’s dopamine and histamine as well its norepinephrine receptors, “there are very few drugs that act only upon one system,” he says. “It is hard to pull mechanisms apart.”

Future studies could incorporate additional types of brain imaging, such as positron emission tomography and diffusion tensor imaging, to supplement and validate data provided by fMRI, he adds.

“Pharmacological fMRI is a very active area,” Raizada says. “I have seen a lot of interesting moves in that direction.”