Effect of dopamine transporter genotype on intrinsic functional connectivity depends on cognitive state.
ABSTRACT Functional connectivity between brain regions can define large-scale neural networks and provide information about relationships between those networks. We examined how relationships within and across intrinsic connectivity networks were 1) sensitive to individual differences in dopaminergic function, 2) modulated by cognitive state, and 3) associated with executive behavioral traits. We found that regardless of cognitive state, connections between frontal, parietal, and striatal nodes of Task-Positive networks (TPNs) and Task-Negative networks (TNNs) showed higher functional connectivity in 10/10 homozygotes of the dopamine transporter gene, a polymorphism influencing synaptic dopamine, than in 9/10 heterozygotes. However, performance of a working memory task (a state requiring dopamine release) modulated genotype differences selectively, such that cross-network connectivity between TPNs and TNNs was higher in 10/10 than 9/10 subjects during working memory but not during rest. This increased cross-network connectivity was associated with increased self-reported measures of impulsivity and inattention traits. By linking a gene regulating synaptic dopamine to a phenotype characterized by inefficient executive function, these findings validate cross-network connectivity as an endophenotype of executive dysfunction.
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ABSTRACT: Control regions in the brain are thought to provide signals that configure the brain's moment-to-moment information processing. Previously, we identified regions that carried signals related to task-control initiation, maintenance, and adjustment. Here we characterize the interactions of these regions by applying graph theory to resting state functional connectivity MRI data. In contrast to previous, more unitary models of control, this approach suggests the presence of two distinct task-control networks. A frontoparietal network included the dorsolateral prefrontal cortex and intraparietal sulcus. This network emphasized start-cue and error-related activity and may initiate and adapt control on a trial-by-trial basis. The second network included dorsal anterior cingulate/medial superior frontal cortex, anterior insula/frontal operculum, and anterior prefrontal cortex. Among other signals, these regions showed activity sustained across the entire task epoch, suggesting that this network may control goal-directed behavior through the stable maintenance of task sets. These two independent networks appear to operate on different time scales and affect downstream processing via dissociable mechanisms.Proceedings of the National Academy of Sciences 07/2007; 104(26):11073-8. · 9.74 Impact Factor
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ABSTRACT: Age-related deficits have been demonstrated in working memory performance and in the dopamine system thought to support it. We performed positron emission tomography (PET) scans on 12 younger (mean 22.7 years) and 19 older (mean 65.8 years) adults using the radiotracer 6-[(18)F]-fluoro-L-m-tyrosine (FMT), which measures dopamine synthesis capacity. Subjects also underwent functional magnetic resonance imaging (fMRI) while performing a delayed recognition working memory task. We evaluated age-related fMRI activity differences and examined how they related to FMT signal variations in dorsal caudate within each age group. In posterior cingulate cortex and precuneus (PCC/Pc), older adults showed diminished fMRI deactivations during memory recognition compared with younger adults. Greater task-induced deactivation (in younger adults only) was associated both with higher FMT signal and with worse memory performance. Our results suggest that dopamine synthesis helps modulate default network activity in younger adults and that alterations to the dopamine system may contribute to age-related changes in working memory function.Human Brain Mapping 06/2011; 32(6):947-61. · 6.88 Impact Factor
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ABSTRACT: A fundamental characteristic of working memory is that its capacity to handle information is limited. While there have been many brain mapping studies of working memory, the physiological basis of its capacity limitation has not been explained. We identified characteristics of working memory capacity using functional magnetic resonance imaging (fMRI) in healthy subjects. Working memory capacity was studied using a parametric ‘ n -back’ working memory task involving increasing cognitive load and ultimately decreasing task performance. Loci within dorsolateral prefrontal cortex (DLPFC) evinced exclusively an ‘inverted-U’ shaped neuro- physiological response from lowest to highest load, consistent with a capacity-constrained response. Regions outside of DLPFC, in contrast, were more heterogeneous in response and often showed early plateau or continuously increasing responses, which did not reflect capacity constraints. However, sporadic loci, including in the premotor cortex, thalamus and superior parietal lobule, also demon- strated putative capacity-constrained responses, perhaps arising as an upstream effect of DLPFC limitations or as part of a broader network-wide capacity limitation. These results demonstrate that regionally specific nodes within the working memory network are capacity-constrained in the physiological domain, providing a missing link in current explorations of the capacity characteristics of working memory.Cerebral Cortex 01/1999; · 6.83 Impact Factor