San Diego - Neuroscientists at Georgetown University Medical Center (GUMC) say brain scans show that a gene nominally linked to attention deficit hyperactivity disorder (ADHD) leads to increased interference by brain regions associated with mind wandering during mental tasks.

Presented at the annual meeting of the Society for Neuroscience, these researchers believe their findings are the first to show, through brain scanning, the differences in brain network relationships between individuals with this particular form of gene and others with a different form.

"Our goal is to narrow down the function of candidate genes associated with ADHD, and in this study, we find this gene is tied to competition between brain networks. This could lead to increased inattention, but it likely has nothing to do with hyperactivity," says the study's lead author, Evan Gordon, a doctoral candidate in the Interdisciplinary Program in Neuroscience at GUMC. "This is just one gene, and it does not cause ADHD but likely contributes to it. The disorder is believed to be due to a myriad of genetic factors."

The gene in question is DAT1; its protein produces the dopamine transporter that helps regulate dopamine transmission between brain cells. The DAT1 gene comes in two alleles, or forms - DAT1 10 and DAT1 9. People who inherit two 10 alleles (10/10) are said to be at greater risk for developing ADHD than people who inherit 10/9 alleles. Rarely does someone inherit two 9 alleles, according to Gordon; he says, in fact, that the10 allele is slightly more common than the 9 allele.

The biological significance of inheriting a DAT1 10 allele is that the brain produces excess quantities of dopamine transporters, and that results in less dopamine signaling between neurons. Too many dopamine transporters quickly scoop up dopamine released by neurons, leaving fewer available to actually reach other neurons and pass on a signal. If there are fewer transporters, more dopamine stays in the synapse between neurons, triggering a reaction.

That is important, Gordon says, because dopamine is important for "gating" the transfer of information between brain regions - that is, allowing or preventing new information to come in. "The belief is that dopamine helps teach certain brain regions how and when to gate, and that 10/10 carriers are not gating as quickly or effectively as is possible."

That is exactly what the researchers found when they used functional MRI (fMRI) on a group of 38 participants. Half of the groups were 10/10 carriers and half were 10/9 carriers, and none of the participants were diagnosed with ADHD.

The researchers investigated the activity in two areas of the brain, the default mode network (DMN), which is associated with mind wandering or daydreaming and is active when the mind is at rest, and task-positive networks (TPNs), which are active during problem solving and other cognitive work. In this study, participants were asked to remember letters they saw on a screen inside the fMRI machine, and to recall them, thus activating TPNs.

Scanning demonstrated that in 10/10 carriers, the mind wandering areas tended to communicate with regions performing memory tasks more strongly than in did in 10/9 carriers. "Dopamine in the 10/10 carriers was not doing a good enough job in preventing the mind wandering regions from interfering with memory performance regions, resulting in less efficient cognition," Gordon says.

They also found no differences between genotype when the participants were at rest after their memory tasks.

"That tells us that the DAT1 genotype affects gating only when release of dopamine is high, such as during a memory task, and that less dopamine signaling leads to increased inattention," he says.

"Being a DAT1 10/10 carrier does not mean a person has ADHD; it is not a diagnostic marker," Gordon says. "It has been viewed as a contributing factor, and now we know one reason why."

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The study was funded by the National Institute of Mental Health.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Georgetown Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO). In fiscal year 2009-2010, GUMC accounted for 79 percent of Georgetown University's extramural research funding.

603.21/KKK65. Modulation of temporal relationships between default mode and task-positive networks by the dopamine transporter genotype during working memory and the resting state

*E. M. GORDON1, M. STOLLSTORFF1, C. J. VAIDYA1,2; 1Psychology, Georgetown, WASHINGTON, DC; 2Children's Natl. Med. Ctr., Washington, DC.

Human cognitive performance depends on competition between large-scale brain networks such as the default mode network (DMN), implicated in internally oriented cognition, and task-positive networks (TPNs), active during externally oriented cognition. These networks can be identified even in the task-free resting state, suggesting that they represent a stable functional architecture of the brain. Increased competition between networks is associated with more efficient cognition; however, the mechanisms which regulate this competition are unknown. The neurotransmitter dopamine (DA) may help stabilize networks by regulating network competition. We investigated this possibility by examining network relationships associated with natural variation in DA signaling due to polymorphism of the Dopamine Transporter gene (DAT1). Increased synaptic DA is associated with the 9-repeat allele; thus, 9/10 carriers have higher DA signaling than 10/10 carriers. DA differences due to DAT1 are further enhanced by increased DA release during cognitively demanding states (e.g., working memory (WM) performance). If DA signaling helps regulate DMN-TPN relationships, then those relationships should differ between 10/10 and 9/10 carriers during the resting state, and differ even more during WM. To test this possibility, 10/10 and 9/10 carriers underwent functional magnetic resonance imaging during rest and while they performed an N-back WM task. To identify DMN and TPN networks common across all subjects, we conducted a group Independent Components Analysis on the resting data. One resulting network matched the canonical DMN, while three matched canonical TPN regions: a cingulo-opercular (CO) network and right and left frontoparietal (FP) networks. Regions of interest were constructed from these four networks, and for each subject the timecourse of activity within each network was calculated for the rest scan and the WM scan. Temporal correlations between the DMN timecourse and each of the TPN timecourses were calculated and were entered into a Run (rest or WM) X TPN (CO, left FP, or right FP) X DAT (9/10 or 10/10) mixed ANOVA, revealing a significant Run X TPN X DAT interaction. Post-hoc tests showed that the DMN-FP temporal correlations were more positive for 10/10 than for 9/10 carriers during the WM scan, indicating that the 10/10 carriers, who have lower DA signaling, demonstrated less competition between networks, which has been linked to less efficient cognition. However, no network relationships differed by genotype during rest. Thus, DAT genotype affects network competition only when endogenous DA release is high, as in the WM condition.