Deficits in Brain's Reward System Observed in ADHD Patients

A brain-imaging study conducted at Brookhaven National Laboratory provides the first definitive evidence that patients suffering from attention deficit hyperactivity disorder (ADHD) have lower-than-normal levels of certain proteins essential for experiencing reward
and motivation.

"These deficits in the brain's reward system may help explain clinical symptoms of ADHD, including inattention and reduced motivation, as well as the propensity for complications such as drug abuse and obesity among ADHD patients," says lead author Nora Volkow, director of the National Institute on Drug Abuse and a long-time collaborator on neuroimaging research at Brookhaven Lab.

The study, published in the September 9, 2009, issue of the Journal of the American Medical Association, also has important implications for treatment. "Finding ways to address the underlying reward-system deficit could improve the direct clinical outcome of ADHD, and potentially reduce the likelihood of other negative consequences of this condition," says study co-author Gene-Jack Wang, chair of Brookhaven's medical department.

Prior to this study, it was not clear whether people with ADHD had abnormalities in the brain's dopamine-mediated motivation/reward system. Previous studies were relatively small and may have been complicated by the fact that some ADHD patients had undergone treatments, or had a history of drug abuse or other conditions that can affect the dopamine system.

To strengthen the statistics and control for these factors, the current study looked at 53 adult ADHD patients who had never received treatment and 44 healthy control subjects -- all of whom had been carefully screened to eliminate potentially confounding variables.

The scientists used positron emission tomography (PET) to measure two markers of the dopamine system -- dopamine receptors, to which the chemical messenger binds to propagate the "reward" signal, and dopamine transporters, which take up and recycle excess dopamine after the signal is sent.

Lying in a PET scanner, each patient was injected with a minute amount of a "radiotracer" compound -- a chemical labeled with a radioactive form of carbon and designed to bind specifically to one of the targets. Different tracers were used for each target, and patients were scanned for each at separate times. By detecting the signal from the radiotracers, the PET machine can measure the receptor and transporter locations and concentrations in various parts of the brain.

The results clearly showed that, relative to the healthy control subjects, the ADHD patients had lower levels of dopamine receptors and transporters in the accumbens and midbrain -- two key regions of the brain directly involved in processing motivation and reward. In addition, the measurements of dopamine markers correlated with measures of behavior and clinical observations of ADHD symptoms, such as reduced levels of attention as measured by standard
psychological tests.

"Our findings imply that these deficits in the dopamine reward pathway play a role in the symptoms of inattention in ADHD and could underlie these patients' abnormal responses to reward," Volkow says.

"This pathway plays a key role in reinforcement, motivation, and in learning how to associate various stimuli with rewards," she adds. "Its involvement in ADHD supports the use of interventions to enhance the appeal and relevance of school and work tasks to improve performance.

"Our results also support the continued use of stimulant medications - the most common pharmacological treatment for ADHD -- which have been shown to increase attention to cognitive tasks by elevating brain dopamine," she says.

The findings may also help explain why ADHD patients are more likely than control subjects to develop drug-abuse disorders and conditions such as obesity.

Watch more breaking news now on our video feed:



Bookmark http://universeeverything.blogspot.com/ and drop back in sometime.

New Method Expands Tool Kit for Monitoring Body Chemistry, Disease

Scientists at the U.S. Department of Energy's Brookhaven National Laboratory have devised a simple, fast method for adding a radioactive "tag" to formaldehyde, a common organic chemical. Using this labeled formaldehyde, scientists can now synthesize a whole new class of radiotracers, compounds that can be tracked by positron emission tomography (PET) scanners to monitor the movement and interactions of a wide range of chemicals in the human body. A study describing the method was published online on July 4, by Angewandte Chemie International Edition.

"PET is an extremely valuable tool for understanding human physiology," says Brookhaven chemist Jacob Hooker, who led the research. PET studies and radiotracers developed at Brookhaven and elsewhere have greatly advanced scientists' understanding of diseases such as cancer and the neurochemistry of drug addiction.

"But many, if not most, molecules people are interested in studying with PET cannot be radiolabeled right now," Hooker says. "So there is a huge need for basic science to develop new strategies for making radiotracers. Our new method is part of that effort. It expands our tool kit of reagents and increases the number and types of compounds we can use to peer into the human body."

Like many existing methods for radiotracer synthesis, the new method incorporates a radioactive form of the element carbon, known as carbon-11 (for the total number of protons and neutrons in its nucleus), into the formaldehyde molecule. Carbon-11 atoms emit positrons -- particles similar to electrons but with a positive charge -- which can be tracked by a PET scanner. In many carbon-11 radiotracers, the radioactive tag is attached to "exterior" portions
of the molecule rather than the carbon chains that make up the backbone of biological molecules. Scientists have long sought ways to label this backbone, as it would greatly expand the kinds of tracers they could make.

Since formaldehyde is involved in many chemical reactions that lead to the synthesis of organic, carbon-chain molecules, it has been a natural target for labeling because it can then be used to make other labeled organic compounds that can be administered to humans as radiotracers.

Several groups have devised ways to label formaldehyde using other methods, but they are not routinely used, says Hooker. "While new methods often provide proof of principles, they are often not easily adapted by others to label radiotracers, because they require special equipment and reagents not readily available to all PET chemists," he says. "Our goal in designing a new route to carbon-11-labeled formaldehyde was to make it simple, efficient, and very easy
to repeat."

Quick reactions

Simple and efficient radiolabeling methodologies are important in carbon-11 chemistry because the radioactive element has a very short half-life -- a mere 20.4 minutes. That means the radioactive signal decays, or decreases in strength, by half every 20.4 minutes. So, the entire process has to be fast enough to generate carbon-11, incorporate it into formaldehyde, use that
formaldehyde to make a radiotracer, purify, formulate and inject the tracer compound into a research volunteer lying in a PET scanner -- all before the radioactive signal decays.

Testing a variety of approaches, the Brookhaven team devised a method using commercially available, inexpensive starting ingredients to produce carbon-11-labeled formaldehyde under mild conditions. The reactions require no special equipment and produce high yields after only a few minutes. "That leaves sufficient time to make useful radiotracers," Hooker says.

Some tracers Hooker envisions include new compounds to bind with types of brain-cell receptors that were previously "invisible" to PET. The team at Brookhaven is also investigating ways to use carbon-11 formaldehyde to produce radiotracers for monitoring drugs, proteins, and enzymes that affect gene expression in cells.

Watch more breaking news now on our video feed:



Bookmark http://universeeverything.blogspot.com/ and drop back in sometime.