Disposed to Distraction: Genetic Variation in the Cholinergic System Influences Distractibility But Not Time-on-Task Effects

Berry, Anne S.; Demeter, Elise; Sabhapathy, Surya; English, Brett A.; Blakely, Randy D.; Sarter, Martin; Lustig, Cindy

doi:10.1162/jocn_a_00607

Cited by 66 publications

(95 citation statements)

References 53 publications

(73 reference statements)

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“…This SNP, when expressed in a human cell line, reduced choline uptake by about 40% (Okuda et al, 2002) that, given the rate-limiting nature of the CHT for ACh synthesis and release, would be expected to limit elevations of cholinergic neuromodulation. We found that I89V humans self-report greater vulnerability for distractors and dramatically exhibit such vulnerability when tested in a continuous attention task in the presence of content-rich distractors, and they fail to activate right frontal regions in the presence of a distractor (Berry, Blakely, Sarter, & Lustig, 2015; Berry et al, 2014). As is the case in rats that are STs, the cognitive performance of humans expressing the I89V CHT subcapacity variant is consistent with a bias away from top-down attentional control and toward bottom-up, cue-driven performance (Sarter, Lustig, Blakely, & Koshy Cherian, 2016).…”

Section: Sts and Gts As Models For Research On Opponent Cognitive-motmentioning

confidence: 81%

“…Poor attentional control is characterized by relatively unstable task performance, poor task compliance, and a limited capacity for restoring performance after exposure to distractors or other detrimental manipulations (Berry et al, 2014; Demeter & Woldorff, 2016; St. Peters, Demeter, Lustig, Bruno, & Sarter, 2011).…”

Section: Attention-associated Levels Of Cholinergic Neuromodulation Imentioning

confidence: 99%

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The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

Sarter

Phillips

2018

Behavioral Neuroscience

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Cognitive-motivational styles describe predominant patterns of processing or biases that broadly influence human cognition and performance. Here we focus on the impact of cognitive-motivational styles on the response to cues predicting the availability of food or addictive drugs. An individual may preferably conduct an analysis of the motivational significance of reward cues, with the result that such cues per se are perceived as rewarding and worth approaching and working for. Alternatively, a propensity for a “cold” analysis of the behavioral utility of a reward cue may yield search behavior for food or drugs but not involve cue approach. Animal models for studying the neuronal mechanisms mediating such styles have originated from research concerning behavioral indices that predict differential vulnerability to addiction-like behaviors. Rats classified as sign- or goal-trackers (STs, GTs) were found to have opposed attentional biases (bottom-up or cue-driven attention vs. top-down or goal-driven attentional control) that are mediated primarily via relatively unresponsive versus elevated levels of cholinergic neuromodulation in the cortex. The capacity for cholinergic neuromodulation in STs is limited by a neuronal choline transporter (CHT) that fails to support increases in cholinergic activity. Moreover, in contrast to STs, the frontal dopamine system in GTs does not respond to the presence of drug cues and, thus, biases against cue-oriented behavior. The opponent cognitive-motivational styles that are indexed by sign- and goal-tracking bestow different cognitive–behavioral vulnerabilities that may contribute to the manifestation of a wide range of neuropsychiatric disorders.

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Section: Sts and Gts As Models For Research On Opponent Cognitive-motmentioning

confidence: 81%

Section: Attention-associated Levels Of Cholinergic Neuromodulation Imentioning

confidence: 99%

The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

Sarter

Phillips

2018

Behavioral Neuroscience

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“…However, concerns about reliability may be mitigated by the clear shift in the distributions seen when examining the individual subject data (i.e., effects are not driven by outliers; see especially Figure 3) and the consistency of findings across multiple analysis methods, including the use of an a priori BA 9 ROI drawn from an independent dataset. Furthermore, our primary hypothesis, Ile89Val hypoactivation of the right BA 9 response to attentional challenge, was grounded in findings bridging cognitive (Berry et al, 2014; Berry et al, in prep; Demeter et al, 2011; English et al, 2009; Kim et al, 2006), systems (Gill et al, 2000; Parikh et al, 2013; St Peters et al, 2011), and molecular (Okuda et al, 2002) neuroscience. Examining how the BA 9 response to attentional challenge was affected by cholinergic genetic variation was a logical next step in integrating these multidisciplinary findings, and there were strong a priori reasons to hypothesize the present results.…”

Section: Discussionmentioning

confidence: 97%

“…Participants contributed saliva samples for genotyping as previously described (Berry et al, 2014). In total, 67 Ile89Val heterozygotes were identified from this sample.…”

Section: Methodsmentioning

confidence: 99%

Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics

et al. 2015

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In rodent studies, elevated cholinergic neurotransmission in right prefrontal cortex (PFC) is essential for maintaining attentional performance, especially in challenging conditions. Apparently paralleling the rises in acetylcholine seen in rodent studies, fMRI studies in humans reveal right PFC activation at or near Brodmann’s area 9 (BA 9) increases in response to elevated attentional demand. In the present study, we leveraged human genetic variability in the cholinergic system to test the hypothesis that the cholinergic system contributes to the BA 9 response to attentional demand. Specifically, we scanned (BOLD fMRI) participants with a polymorphism of the choline transporter gene that is thought to limit choline transport capacity (Ile89Val variant of the choline transporter gene SLC5A7, rs1013940) and matched controls while they completed a task previously used to demonstrate demand-related increases in right PFC cholinergic transmission in rats and right PFC activation in humans. As hypothesized, we found that although controls showed the typical pattern of robust BA 9 responses to increased attentional demand, Ile89Val participants did not. Further, pattern analysis of activation within this region significantly predicted participant genotype. Additional exploratory pattern classification analyses suggested that Ile89Val participants differentially recruited orbitofrontal cortex and parahippocampal gyrus to maintain attentional performance to the level of controls. These results contribute to a growing body of translational research clarifying the role of cholinergic signaling in human attention and functional neural measures, and begin to outline the risk and resiliency factors associated with potentially suboptimal cholinergic function with implications for disorders characterized by cholinergic dysregulation.

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“…Also of potential relevance to these findings of individual differences in response to CDP-choline is the choline uptake transporter (CHT), which imports choline from extracellular space to presynaptic terminals for use in normal acetylcholine synthesis/cholinergic transmission (Sarter and Parikh 2005). As CHT capacity has been associated with variability in cognitive functioning (Sarter and Parikh 2009), and as human CHT gene polymorphisms have been associated with individual differences in cortico-limbic activation (Neumann et al 2006) and attentional processing (Berry et al 2014), genetic differences in CHT capacity may underly some of the inter-individual variability in acoustic change detection response to CDP-choline.…”

Section: Discussionmentioning

confidence: 99%

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

Knott

Impey

Choueiry

et al. 2015

Neuropsychiatr Electrophysiol

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Background: Alpha 7 nicotinic acetylcholine receptors (α7 nAChR) are prioritized molecular targets for the development of new pharmacological treatments for impaired cognition in schizophrenia. The use of schizophrenia-associated biomarkers both as endpoints and for segmentation of homogeneous populations for early detection of cognitive enhancing agents has been advanced to enhance the drug discovery process. Methods: In this study, the mismatch negativity (MMN) event-related brain potential (ERP), considered one of the few fully developed biomarkers in schizophrenia, was employed: a) to stratify 24 healthy volunteers into subgroups exhibiting low, medium, or high auditory sensory discrimination based on pre-attentive detection of deviant auditory features, and b) to assess their acute response to a low (500 mg) and moderate dose (1000 mg) of CDP-choline, a dietary supplement with selective agonist actions at α7 nAChRs.

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Disposed to Distraction: Genetic Variation in the Cholinergic System Influences Distractibility But Not Time-on-Task Effects

Cited by 66 publications

References 53 publications

The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

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