Low-dose methylphenidate appears to help patients with attention deficit hyperactivity disorder by increasing sensitivity of neurons in the prefrontal cortex

Research with rats strongly suggests that low-dose methylphenidate helps patients with attention deficit hyperactivity disorder by increasing the sensitivity of neurons in the prefrontal cortex while producing little effect elsewhere in the brain, according to an article published online June 26 by Biological Psychiatry.

"It's the higher doses of these drugs that are normally associated with their effects as stimulants, those that increase locomotor activity, impair cognition and target neurotransmitters all over the brain," said psychologist Craig Berridge, coauthor of the paper. "These lower doses are diametrically opposed to that. Instead, they help the PFC better do what it's supposed to do."

In 2006, University of Wisconsin-Madison psychology researchers David Devilbiss and Craig Berridge reported that therapeutic doses of methylphenidate boosted neurotransmitter levels primarily in the prefrontal cortex, suggesting a selective targeting of this region of the brain. Since then, the researchers have focused on how methylphenidate acts on prefrontal neurons to enhance cognition.

In the current work, the researchers studied prefrontal neurons in rats under a variety of doses, including one that improved the animals' performance in a working memory task of the type that patients clinically have trouble completing. Using a sophisticated new system for monitoring many neurons at once through a set of microelectrodes, the scientists observed both the random, spontaneous firings of these neurons and their response to stimulation of the hippocampus.

When the researchers recorded electrical output from individual neurons, they found that while cognition-enhancing doses had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, prefrontal neurons stopped responding to incoming information.

"This suggests that the therapeutic effects of Ritalin [methylphenidate] likely stem from this fine-tuning of prefrontal cortex sensitivity," said Berridge. "You're improving the ability of these neurons to respond to behaviorally relevant signals, and that translates into better cognition, attention and working memory." Higher doses associated with drug abuse and cognitive impairment, in contrast, impair functioning of the prefrontal cortex.

More intriguing still were the results that came from tuning into the entire region of neurons at once. When groups of neurons were firing together strongly, methylphenidate reinforced the coordinated activity. At the same time, the drug weakened activity that was not well coordinated at baseline. These findings suggest that methylphenidate strengthens dominant and important signals within the cortex, while lessening weaker signals that may act as distractors.

"These results show a new level of action for cognition-enhancing doses of methylphenidate that couldn't have been predicted from single neuron analyses," he Berridge said. "So, if you're searching for drugs that might replace it, this is one effect you could potentially look for."

The researchers hope the current findings will help clarify how neurons encode complex behavior and cognition.


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