Effect of Dopamine Transporter Genotype on Intrinsic Functional Connectivity Depends on Cognitive State

Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Cerebral Cortex (Impact Factor: 8.67). 11/2011; 22(9):2182-96. DOI: 10.1093/cercor/bhr305
Source: PubMed


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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    • "However, this study is the first to have explored social WM related large-scale network connectivity. Similar to some classical WM findings (Newton et al., 2011; Gordon et al., 2012; Repovs and Barch, 2012), we observed increased competition between the FPC and DMN during social WM tasks. Yet, in opposition to the FPC-DMN anti-correlation, the FPC showed more cooperation with the DAN as the task performance and task load increased. "
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    ABSTRACT: An extensive body of literature has indicated that there is increased activity in the frontoparietal control network (FPC) and decreased activity in the default mode network (DMN) during working memory (WM) tasks. The FPC and DMN operate in a competitive relationship during tasks requiring externally-directed attention. However, the association between this FPC-DMN competition and performance in social WM tasks has rarely been reported in previous studies. To investigate this question, we measured FPC-DMN connectivity during resting-state and two emotional face recognition WM tasks using the 2-back paradigm. Thirty-four individuals were instructed to perform the tasks based on either the expression (EMO) or the identity (ID) of the same set of face stimuli. Consistent with previous studies, an increased anti-correlation between the FPC and DMN was observed during both tasks relative to the resting-state. Specifically, this anti-correlation during the EMO task was stronger than during the ID task, as the former has a higher social load. Intriguingly, individual differences in self-reported empathy were significantly correlated with the FPC-DMN anti-correlation in the EMO task. These results indicate that the top-down signals from the FPC suppress the DMN to support social WM and empathy. © The Author (2015). Published by Oxford University Press. For Permissions, please email:
    Full-text · Article · Aug 2015 · Social Cognitive and Affective Neuroscience
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    • "Specifically, functional connectivity was greater during working memory than rest between dlPFC and inferior parietal cortex (Gordon et al., 2012b). State-dependent changes are important to understand as they depend upon genetic factors (Gordon et al., 2012b) and can reflect consolidation associated with learning (Lewis et al., 2009). Further, task-free resting state, itself, is sensitive to individual variation in a variety of affective and behavioral traits (Vaidya and Gordon, 2013). "
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    ABSTRACT: Functional near-infrared spectroscopy (fNIRS) is an emerging low-cost noninvasive neuroimaging technique that measures cortical bloodflow. While fNIRS has gained interest as a potential alternative to fMRI for use with clinical and pediatric populations, it remains unclear whether fNIRS has the necessary sensitivity to serve as a replacement for fMRI. The present study set out to examine whether fNIRS has the sensitivity to detect linear changes in activation and functional connectivity in response to cognitive load, and functional connectivity changes when transitioning from a task-free resting state to a task. Sixteen young adult subjects were scanned with a continuous-wave fNIRS system during a 10-min resting-state scan followed by a letter n-back task with three load conditions. Five optical probes were placed over frontal and parietal cortices, covering bilateral dorsolateral PFC (dlPFC), bilateral ventrolateral PFC (vlPFC), frontopolar cortex (FP), and bilateral parietal cortex. Activation was found to scale linearly with working memory load in bilateral prefrontal cortex. Functional connectivity increased with increasing n-back loads for fronto-parietal, interhemispheric dlPFC, and local connections. Functional connectivity differed between the resting state scan and the n-back scan, with fronto-parietal connectivity greater during the n-back, and interhemispheric vlPFC connectivity greater during rest. These results demonstrate that fNIRS is sensitive to both cognitive load and state, suggesting that fNIRS is well-suited to explore the full complement of neuroimaging research questions and will serve as a viable alternative to fMRI.
    Full-text · Article · Feb 2014 · Frontiers in Human Neuroscience
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    • "Second, within-subjects' comparison showed that functional connectivity became stronger from resting to a task-evoked state selectively, in regions activated during the task such as auditory (Arfanakis et al., 2000), visual (Arfanakis et al., 2000; Hampson et al., 2004; Nir et al., 2006), or motor (Arfanakis et al., 2000; Jiang et al., 2004). Third, functional connectivity decreased across some networks during task performance relative to a resting state (Fransson, 2006; Gordon et al., 2012b), suggesting that specific networks became more segregated when subjects were in a cognitive state constrained by a task. Fourth, the extent to which functional connectivity changed from resting to task states, particularly across networks, varied across individuals based upon dopamine neurotransmitter function and traits of distractibility and impulsivity (Gordon et al., 2012b). "
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    ABSTRACT: We examined whether modulation of functional connectivity by cognitive state differed between pre-adolescent children with Autism Spectrum Disorders (ASD) and age and IQ-matched control children. Children underwent functional magnetic resonance imaging (fMRI) during two states, a resting state followed by a sustained attention task. A voxel-wise method was used to characterize functional connectivity at two levels, local (within a voxel's 14 mm neighborhood) and distant (outside of the voxel's 14 mm neighborhood to the rest of the brain) and regions exhibiting Group × State interaction were identified for both types of connectivity maps. Distant functional connectivity of regions in the left frontal lobe (dorsolateral [BA 11, 10]; supplementary motor area extending into dorsal anterior cingulate [BA 32/8]; and premotor [BA 6, 8, 9]), right parietal lobe (paracentral lobule [BA 6]; angular gyrus [BA 39/40]), and left posterior middle temporal cortex (BA 19/39) showed a Group × State interaction such that relative to the resting state, connectivity reduced (i.e., became focal) in control children but increased (i.e., became diffuse) in ASD children during the task state. Higher state-related increase in distant connectivity of left frontal and right angular gyrus predicted worse inattention in ASD children. Two graph theory measures (global efficiency and modularity) were also sensitive to Group × State differences, with the magnitude of state-related change predicting inattention in the ASD children. Our results indicate that as ASD children transition from an unconstrained to a sustained attentional state, functional connectivity of frontal and parietal regions with the rest of the brain becomes more widespread in a manner that may be maladaptive as it was associated with attention problems in everyday life.
    Full-text · Article · Aug 2013 · Frontiers in Human Neuroscience
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