Disposed to Distraction: Genetic Variation in the - 麻省理工学院人工智能研究专业

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

Anne S. Berry1, Elise Demeter2, Surya Sabhapathy3, Brett A. English4,
Randy D. Blakely4, Martin Sarter1, and Cindy Lustig1

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抽象的

■ Both the passage of time and external distraction make it
difficult to keep attention on the task at hand. We tested the
hypothesis that time-on-task and external distraction pose
independent challenges to attention and that the brainʼs cho-
linergic system selectively modulates our ability to resist dis-
牵引力. Participants with a polymorphism limiting cholinergic
容量 (Ile89Val variant [rs1013940] of the choline transporter
gene SLC5A7) and matched controls completed self-report
measures of attention and a laboratory task that measured
decrements in sustained attention with and without distrac-
的. We found evidence that distraction and time-on-task

effects are independent and that the cholinergic system is
strongly linked to greater vulnerability to distraction. Ile89Val
participants reported more distraction during everyday life
than controls, and their task performance was more severely
impacted by the presence of an ecologically valid video dis-
tractor (similar to a television playing in the background).
These results are the first to demonstrate a specific impair-
ment in cognitive control associated with the Ile89Val poly-
morphism and add to behavioral and cognitive neuroscience
studies indicating the cholinergic systemʼs critical role in over-
coming distraction. ■

介绍
“Pay attention!” You may have given yourself this exhor-
tation during a long, boring drive as you realized both
your mind and your car were drifting off the road or
received it from your conversation partner when they
noticed your eyes wandering toward an attractive stimu-
lus walking by. Both extended task periods and external
distractors challenge our ability to remain focused on the
task at hand, and individuals with psychiatric disorders
such as schizophrenia and attention deficit hyperactivity
紊乱 (ADHD) may be especially vulnerable to such
挑战. Effective treatment of these vulnerabilities
will require a better understanding of whether they reflect
general declines in cognitive control or more specific pro-
cessing deficits and of the underlying neural systems that
may be targets for pharmaceutical intervention. Here we
present evidence that performance declines caused by
time-on-task demands and external distraction are inde-
pendent and that the cholinergic system plays an especially
important role in resisting external distraction.

直观地, one might expect that any demand on
cognitive control, regardless of its source, would reduce
表现, and that compounding such demands
would have an especially detrimental effect. 那是,

1密歇根大学, 2杜克大学, 3University of Michi-
gan Medical School, 4Vanderbilt University School of Medicine

external distractors might be especially tempting when
one is already having difficulty maintaining attention on
an attended task. 反过来, competition from external dis-
tractors may make it especially difficult to maintain focus,
causing steeper time-on-task declines. 然而, the reality
is much more complex. Vulnerability to external distraction
is typically increased by cognitive load but decreased by
perceptual load (Lavie, 2010; Lavie, Hirst, de Fockert, &
Viding, 2004). Time-on-task performance declines have
been attributed by some to overloads of attention and by
others to underloads of attention (see discussion by Pattyn,
Neyt, Heridericlcx, & Soetens, 2008), suggesting opposite
predictions for the effects of adding an additional cognitive
load in the form of external distraction.

Previous attempts to test potential interactions between
distraction and time-on-task effects have yielded ambigu-
ous results. Rosenberg, Noonan, DeGutis, and Esterman
(2013) used a continuous performance test (detect female
target faces vs. male nontarget faces) that showed sig-
nificant declines in both accuracy and RT stability over
a 12-min period and manipulated whether or not the
background consisted of distracting scenes. This manip-
ulation did not affect performance overall or the slope of
time-on-task declines, but did alter individual differences
因素: Only in the distraction condition did mind-
fulness scores predict time-on-task declines. In another
学习, Breckel, Giessing, and Thiel (2011) added motion
distractors (moving vs. stationary dots) to a simple signal

认知神经科学杂志 26:9, PP. 1981–1991
土井:10.1162/jocn_a_00607

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检测任务. 然而, these “distractors” did not affect
time-on-task declines on the minute scale and para-
doxically alleviated performance declines associated with
long intertarget intervals on no distractor (stationary)
试验. The distraction manipulation also had no effect on
brain activity (measured using fMRI) related to time-on-
task effects and intertarget interval. Looking in the other
方向, activity related to processing the motion dis-
tractors was not affected by time-on-task, and there were
mixed results in regions involved in motion processing
(some areas increasing, others decreasing) as a function
of intertarget interval.

简而言之, the bulk of the evidence from these studies
suggests that time-on-task and external distractor effects
are independent. 然而, the lack of an overall perfor-
mance decrement as a result of the nominal distractor
manipulations in these studies reduces the support for
this conclusion. 那是, without a reliable main effect
of distraction, it is hard to know whether distractor effects
might interact with time-on-task effects. The neuro-
imaging data are also somewhat ambiguous, as it is hard
to distinguish which changes represent the engagement
of cognitive control to inhibit distractor processing from
those that may represent increased distractor process-
ing because such inhibition has failed (see also Demeter,
Hernandez-Garcia, Sarter, & Lustig, 2011).

We therefore took a different approach, applying a
manipulation that creates robust distractor effects to a
task with rapid time-on-task performance declines and
asked whether time-on-task and distractor effects might
be related to different neuromodulatory systems. 这
approach also has a translational advantage: Developing
effective drug treatments for specific aspects of atten-
tional function will require understanding their links to
the neuromodulator systems targeted by such treatments.
Time-on-task effects have been linked to genetic variation
in the dopaminergic system (Lim et al., 2012); here we
asked whether distraction effects might be linked to
genetic variation in the cholinergic system.

The basal forebrain cholinergic system projects through-
out neocortex and modulates several neurocognitive func-
系统蒸发散, including both perceptual and goal-driven aspects of
注意力 (例如, Rokem, Landau, Garg, Prinzmetal, & Silver,
2010; Silver, Shenhav, & DʼEsposito, 2008; see Demeter &
Sarter, 2013, for a recent review). Although the cholinergic
system has been traditionally described as a diffuse neuro-
modulatory system contributing to arousal, plasticity, 和
improved signal-to-noise ratio (see Picciotto, Higley, &
Mineur, 2012, for a recent review of this evidence), current
models suggest that acetylcholine is also capable of medi-
ating specific cognitive operations through spatially re-
stricted signaling (Hasselmo & Sarter, 2011).

尤其, rodent studies indicate that right-lateralized
frontoparietal cholinergic circuitry mediates the ability to
resist distraction (英石. Peters, Demeter, Lustig, Bruno, &
Sarter, 2011; Broussard, Karelina, Sarter, & Givens, 2009;
Gill, Sarter, & Givens, 2000). When humans are tested in

the same paradigm, they show increased right prefron-
tal activation during the distraction condition, parallel-
ing rodentsʼ increase in right prefrontal acetylcholine
级别. Translational studies using human clinical popu-
lations (例如, Demeter, 格思里, 泰勒, Sarter, & Lustig,
2013; Pa et al., 2013) and animal models (see reviews by
Lustig, Kozak, Sarter, Young, & Robbins, 2012; Sarter,
Martinez, & Kozak, 2009) also suggest that cholinergic
pathways play a critical role in the increased vulnerabil-
ity to distraction seen in neurological disorders includ-
ing schizophrenia and mild cognitive impairment.

We tested the hypothesis that increased vulnerability
to distraction would be associated with genetic variation
affecting the high-affinity choline transporter (CHT),
which is responsible for transporting choline into the
nerve terminal for the synthesis of acetylcholine (ACh).
Mice with reduced CHT expression have normal ACh
release and choline clearance at baseline but are impaired
on both these measures in response to task demands
(Parikh, 英石. Peters, Blakely, & Sarter, 2013). 在人类中,
the Ile89Val variant (rs1013940) of the CHT gene SLC5A7
reduces the rate of choline transport by approximately
40–60% compared with the major allele (Okuda, Okamura,
Kaitsuka, Haga, & Gurwitz, 2002). The frequency of
the Ile89Val variant in normal White participants in the
美国, ∼6% (English et al., 2009), is equivalent to
a prevalence of over 10 million individuals. This variant
occurs more often in ADHD patients than controls and
has been linked to greater symptom severity in depressed
患者 (English et al., 2009; Hahn et al., 2008).

The link to depression suggests that individuals with
the Ile89Val allele might be more likely to engage in
rumination and mind-wandering but based on previous
human and animal data linking the cholinergic system
to distraction, we expected an increased susceptibility
to distraction to be their major difference from control
participants without the allele. To preview our results,
Ile89Val participants showed an increased vulnerability
to distraction on both self-report measures and labora-
tory task performance but were spared on other mea-
sures of attentional control, including those involved in
maintaining performance over time. These results indi-
cate that time-on-task demands and external distraction
tax at least partially dissociable components of cognitive
control and that the cholinergic system plays a particu-
larly important role in resisting distraction.

EXPERIMENT 1

方法

参加者

Six hundred seventeen individuals recruited from the
greater Ann Arbor community completed the Poor Atten-
tional Control questionnaire (Huba, 歌手, Aneshensel,
& Antrobus, 1982; see description below) and contrib-
uted saliva samples for genotyping. From this larger pool,

1982

认知神经科学杂志

体积 26, 数字 9

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67 Ile89Val heterozygotes were identified and compared
with age, 性别, and education-matched controls. 看
桌子 1 for demographics.

have reasonable discriminant validity (average correlation
between subscale total and items not in that subscale all
r < .49 compared with items in that subscale all r > .72).

Genotyping Methods

Results and Discussion

CHT SNP genotyping was carried out using the proce-
dures described in English et al. (2009). Briefly, DNA was
extracted from saliva samples using a commercial DNA
isolation kit (Gentra Systems, 明尼阿波利斯, 明尼苏达州) as pre-
viously described (Mazei-Robinson, Couch, Shelton,
斯坦因, & Blakely, 2005). An allelic discrimination assay
was performed in the Vanderbilt Center for Human
Genetics Research DNA Resources Core using TaqMan
SNP Genotyping Assay reagents (Applied Biosystems,
公司, Foster City, CA). Four nanograms of DNA were used
as template in reactions containing 1× TaqMan Universal
PCR Master Mix and 900 nM forward (50-TGTACCAGGT-
TATGGCCTAGCTT-30) and reverse (50-ACTGAGATTTGC-
ACTTTCACTTACCT-30) amplification primers, 200 nM VIC
(50-CAGGCACCAATTGGATA-30) and FAM (50-AGGCACC-
AGTTGGATA-30) dye-labeled probes. Thermal cycling
(95°C for 10 min, 其次是 50 cycles of 92°C for 15 秒
and 60°C for 1 min) and product detection were accom-
plished using the ABI 7900HT Real-Time PCR System
(ABI). Quality control analyses showed that the results
were consistent with recommended guidelines (例如,
Edenberg & 刘, 2009). The call rate (rate of at which
samples could be successfully assigned a genotype) 在
our sample was >95% with TaqMan, 和 100% consis-
tency when TaqMan was compared with gel-based geno-
typing. No-call TaqMan samples were reanalyzed using
gel-based genotyping.

Attention Questionnaire Measure

Trait attention. Participants completed 36 items from
the Imaginal Processes Inventory (歌手 & Antrobus,
1970). Each item consisted of a statement about cog-
nitive function in everyday life (例如. “I find it difficult to
concentrate when the TV or radio is on”), and partici-
pants rated the degree to which they identified with each
statement on a scale from 1 到 5. Our analyses focus on
这 15 items that make up the Poor Attentional Control
(PAC) subscale identified in a later factor analysis (Huba
等人。, 1982).

The PAC has good internal consistency (coefficient
alpha = .83) and test–retest reliability (r = .73; see also
Tanaka & Huba, 1985/1986). It can be subdivided into
subscales (five questions each) of distractibility, 头脑-
wandering, and boredom. Although Huba et al. (1982)
do not provide psychometric data on these subscales,
analyses of a large data set from our laboratory (N=
510; see Berry, 李, 林, & Lustig, 2014) indicate good
internal consistency within subscales (mind-wandering
coefficient alpha = .84, distraction coefficient alpha =
.79, boredom coefficient alpha = .77). The subscales also

As illustrated in Table 1, Ile89Val participants reported
experiencing more distractibility and mind-wandering in
everyday life than did controls, but not more boredom.
The groupsʼ equivalence on boredom is important, as it
indicates that Ile89Val participants were not simply inter-
preting the scale differently and marking all items higher
than controls.

The Ile89Val participantsʼ higher ratings for distraction
were in line with our predictions based on the cholin-
ergic systemʼs role in resisting distraction as described in
the Introduction. The higher ratings for mind-wandering
were somewhat less expected. 然而, in everyday life,
it may be difficult to disentangle the subjective experi-
ences of mind-wandering and distraction. 例如,
in factor analyses “I notice all the other things around
me I could be doing” groups with the distraction fac-
tor and involves external distractors whereas “thoughts
unrelated to my work always creep in” groups with the
mind-wandering factor and involves only internal experi-
恩塞斯. Despite these distinctions on a principled basis
(external vs. 内部的) and in large-scale factor analyses,
it is easy to see how they might overlap or become con-
fused in individual participantsʼ self-reports.

桌子 1. Demographics and Self-reported Everyday Attention
Function (PAC Measures; Huba et al., 1982) for Ile89Val
Participants and Controls

控制

Ile89Val

t Test

Effect Size
(Cohenʼs d)

年龄 (年)

中号
标清

Edu (年)

中号
标清

42.49
17.20

16.08
2.50

Distractibility

中号
标清

13.43
4.04

Mind-wandering

中号
标清

Boredom

中号
标清

12.93
3.46

12.64
3.26

42.33
17.33

16.50
3.49

15.16
4.43

14.45
4.77

12.97
4.12

t < 1 p = .96 t < 1 p = .43 t = 2.36 p = .02* t = 2.16 p = .05* t < 1 p = .61 d = .01 d = .14 d = .41 d = .36 d = .09 Each group included 67 participants (41 women, 26 men). *Significant difference between groups. Berry et al. 1983 D o w n l o a d e d f r o m l l / / / / j t t f / i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j . f / t u s e r o n 1 7 M a y 2 0 2 1 We therefore conducted a second experiment with a clearer operationalization of external distraction versus other, presumably internal challenges to attentional control and performance, including those that result from extended time on task. In particular, when asked about distractibility, Experiment 1 participants regardless of genotype gave high ratings to items such as “Faced with a tedious job, I notice all the other things around me I could be doing” and “I find it difficult to concentrate when the TV or radio is on.” These responses guided the design of the experimental task we used in Experiment 2. Specifically, we added an external distractor to the Continuous Temporal Expectancy Test (CTET; OʼConnell et al., 2009) and examined its effect on overall perfor- mance and time-on-task declines. The CTET is a duration judgment task: On most trials, a grid pattern rotates after a standard duration (800 msec), but on target trials it takes slightly longer (1070 msec). Because the grid pattern is the same for target and nontarget trials, there is no bottom–up perceptual change signaling the pre- sence of a target. Instead, duration judgments require continuous, focused attention to time and are exqui- sitely sensitive to fluctuations in attention; in some cases, performance declines may occur in as few as four trials (Lustig & Meck, 2005; Penney, Gibbon, & Meck, 2000; Zakay & Block, 1997). OʼConnell et al. found that the ability to detect the target declined linearly over 3 min and that failures to detect the target were predicted up to 20 sec beforehand by trends in alpha-band activity (measured using EEG) thought to index mind-wandering. The CTET thus constituted the “tedious task” described in the self-report data. To mimic the distraction caused by the TV or radio, next to the main task computer, we placed a laptop playing a series of distracting video clips. This compelling distractor, similar to the situa- tions that participants described as most distracting in everyday life, allowed us to test for potential inter- actions between distraction and time-on-task demands with greater sensitivity than previous studies that did not find overall distractor effects. To preview our results, we found that both distraction and time-on-task had robust but independent effects on performance and that Ile89Val participants were especially susceptible to distraction. EXPERIMENT 2 Methods Participants Thirty-two Ile89Val heterozygotes agreed to return for additional testing including the CTET with distractor and more questionnaire measures. The control group consisted of 32 individuals homozygous for the major allele and matched with the heterozygotes on age, gen- der, education, and PAC scores (Table 2). We matched participants on PAC score to reduce potential concerns that a finding of increased distractibility by Ile89Val par- ticipants on the laboratory task might be an artifact of selection bias. That is, if we had not matched the samples for this experiment on PAC score, there might have been concerns that we happened to pick low- distractibility participants from the control population and high-distractibility participants from the Ile89Val population and thereby inflated our chances of finding a group difference on the laboratory task. Instead, by matching the groups on PAC score, we conducted a conservative test, as any selection bias created using this method would be against our preferred hypothesis (i.e., we have likely picked control participants relatively high in the distractibility distribution for their pop- ulation and Ile89Val participants relatively low in the distractibility distribution for their population). Our re- sults may thus underestimate the size of the group dif- ference in the distraction effect. Ile89Val has been associated with ADHD and depression, so to maintain sample size, we matched participants as closely as pos- sible on history of diagnosis rather than excluding on this basis. (Analyses excluding these participants gave similar results with slightly reduced power.) Additional Screening Measures Depression. Hahn et al. (2008) found that Ile89Val was associated with depression severity (though not inci- dence) in a clinical population. We therefore matched participants on depression ratings using the Patient Health Questionnaire-9 (PHQ-9; Kroenke, Spitzer, & Williams, 2001). Participants respond to each of the nine symptom questions using a scale of 0–3. Possible scores range from 0 to 27, with 0 indicating no self-reported experience of depression and 27 reflecting severe de- pression symptoms. Sleep and other health measures. Because the choli- nergic system is also involved in the sleep/wake cycle and sleep quality can affect attention, we wanted to en- sure that our groups were also matched on this front. The Pittsburgh Sleep Quality Index (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) consists of 10 multi- component questions. Scores range from 0 to 21, with 0 indicating the best sleep quality. The Berlin Sleep Questionnaire (Netzer, Stoohs, Netzer, Clark, & Strohl, 1999) consists of 10 questions relating to snoring, sleep problems, and blood pressure, as well as age and body mass index. Participants are considered at high risk for sleep apnea if they have a positive score (more than 2 points) in two categories. Participants also completed the standard health, demographics, and screening form used in our laboratory, which asks questions about med- ications and medical or psychiatric conditions that could affect performance. 1984 Journal of Cognitive Neuroscience Volume 26, Number 9 D o w n l o a d e d f r o m l l / / / / j t t f / i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j . f / t u s e r o n 1 7 M a y 2 0 2 1 Table 2. Demographic and PAC Questionnaire Measures for Participants Completing the CTET with Distraction Task Control Ile89Val t Test Effect Size (Cohenʼs d) Demographic and Health Measures Age (years) M SD Education (years) M SD History of ADHD/depression/anxiety (n) Psychotropic medications (n) PHQ-9 depression score M SD Pittsburgh Sleep Quality Index M SD Self-report Everyday Attention Measures (PAC) Distractibility M SD Mind-wandering M SD Boredom M SD 45.13 16.85 16.73 2.57 6 6 3.50 3.97 5.91 4.32 13.50 4.21 12.91 3.77 12.94 3.30 44.66 16.99 16.53 3.59 7 5 3.47 4.12 4.75 3.54 14.59 4.45 13.38 4.47 12.25 4.21 t < 1 p = .91 t < 1 p = .80 – – t < 1 p = .98 t = 1.17 p = .25 t = 1.01 p = .32 t < 1 p = .65 t < 1 p = .47 d = .03 d = .06 – – d = .01 d = .29 d = .25 d = .11 d = .18 t test and Cohenʼs d refer to the comparison between control and lle89Val participants. Each group included 19 women and 13 men, for a total n = 32 per group. CTET with Video Distractor CTET procedures generally followed those used by OʼConnell et al. (2009), with some modifications (e.g., target and standard durations, response window) based on pilot testing to make it feasible for participants with a wide range of ability. The task was presented on a Dell PC using Presentation software (Neurobehavioral Systems, Inc., Berkeley, CA). On each trial, participants were presented with a black and white 10 × 10 grid of square tiles (15 mm2 each) divided diagonally into black and white halves. On standard trials, the grid randomly changed rotation (90°, 180°, or 270°) after 800 msec; on target trials it rotated after 1070 msec (Figure 1). Participants were instructed to press the spacebar as soon as they detected the target. The distraction manipulation was implemented using a laptop oriented 32° to the left of the CTET task and 65 cm from the participant. In the No Distractor condition, the laptop was silent and displayed a gray screen. In the Dis- tractor condition, the laptop played a series of 30-sec video clips from various sources (e.g., cartoons, movies, sports) with sound presented via headphones. None of the videos contained music or other obviously rhythmic content or overtly violent or sexual content. Responses were recorded as correct (hits) up to 1.5 sec following target offset. Responses outside this window were coded as false alarms (FAs). Participants received feedback at the end of each run. Before beginning the experiment, participants were given six practice runs that contained three targets each. For the first practice run, the duration difference between target and standard trials was exaggerated to ensure participants understood the task rules (standard: 800 msec; target: 1600 msec). Par- ticipants were informed that the timing parameters of Berry et al. 1985 D o w n l o a d e d f r o m l l / / / / j f / t t i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j t f . / u s e r o n 1 7 M a y 2 0 2 1 Figure 1. CTET with video distractor. As shown in (A) each trial consisted of a black and white grid made up of squares divided into triangles. At the end of the trial, the triangles rotated (90°, 180°, or 270°, chosen randomly) to start the next trial. The participantʼs task was to press the spacebar when they realized that the grid had taken longer than usual (1070 msec rather than the standard 800 msec) to rotate. (B) The distractor manipulation was implemented using a laptop oriented 32° to the left of the main task computer. In the No Distractor condition, the laptop was silent and displayed a gray screen. In the Distractor condition, it played video clips with sound. the subsequent five practice runs would be more challeng- ing and identical to the test runs (standard: 800 msec; target: 1070 msec). To ensure participants were able to discriminate between standard and target durations, they were required to continue practice until they achieved 100% (3/3 targets detected) if they had not already reached this criterion in the mandated five practice runs. Participants then performed nine task runs (4 min each) with 24 targets per run.1 Stimuli were pseudo- randomly intermixed, with four to eight target trials pre- sented per minute and 7–14 standard duration stimuli presented between each target. Participants took a 1-min break between each experimental run. For each par- ticipant, four runs were presented in the No Distractor condition, and four runs were presented in the Distrac- tor condition. Distractor and No Distractor runs alter- nated, and their order was counterbalanced across participants. Participants completed one additional “Boring Distractor” run for piloting purposes that is not included in the present analysis. The single Boring Distractor run was inserted as either the first, third, sixth, or ninth run. Post Experiment Questionnaire Distractor video content. After the CTET, participants completed a surprise 15-item multiple-choice quiz assess- ing memory for the video content. Similar procedures have revealed relationships between memory for the distracting stimuli and the impact of distraction on per- formance, as well as experimental group differences (Berry et al., 2014; Biss, Ngo, Hasher, Campbell, & Rowe, 2013; Clapp & Gazzaley, 2012; Gazzaley, Cooney, Rissman, & DʼEsposito, 2005). the level of distractibility, mind-wandering, and bore- dom they experienced during the task. These questions were intended to be similar in form and content to items from the PAC trait attention measure. Participants were given five statements and asked to rate the degree to which they identified with each statement on a scale from 1 to 5 (see Table 3). Questions 1, 2, and 4 measured mind-wandering, Question 3 measured boredom, and Question 5 measured distractibility. We emphasized mind-wandering (three questions) when constructing the questionnaire as that had been the focus of the orig- inal OʼConnell et al. (2009) article. However, subsequent analyses pooling across CTET experiments in our labora- tory show that Question 4 consistently shows the highest correlations with the PAC mind-wandering score and with CTET performance. For that reason and so that an equal number of items are used for the mind-wandering, distractibility, and boredom scores, as in prior work (Berry et al., 2014), we focus on Question 4 as the “state” measure of mind-wandering. Results and Discussion Consistent with previous articles (Berry et al., 2014; OʼConnell et al., 2009), analyses of CTET performance focused on hits (correct target detections); analyses of 0 measures yield similar results. Greenhouse–Geisser d sphericity correction was applied as needed for reporting p values, but degrees of freedom are reported as integers in the text for easier reading. Effect sizes are reported using η2 G (Bakeman, 2005), which gives smaller values than the frequently used η2 P but is preferable as it reduces error when comparing across studies (Fritz, Morris, & Richler, 2012). State attention. After completing the CTET and the quiz for memory of the distractors, participants rated As seen in Figure 2, external distraction and time-on- task effects were independent, and heterozygotes showed 1986 Journal of Cognitive Neuroscience Volume 26, Number 9 D o w n l o a d e d f r o m l l / / / / j f / t t i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j . / f t u s e r o n 1 7 M a y 2 0 2 1 Table 3. Post Experiment Questionnaire Measures for Participants Completing the CTET with Distraction Task 1. At times of this task, it was hard for me to keep my mind from wandering. M SD 2.63 1.21 3.53 1.19 t = 3.02 p = .004* d = .75 2. (Reverse scored) During the task, my thoughts seldom shifted from the subject in front of me. M SD 2.81 1.12 3.31 1.23 t = 1.7 p = .09 3. I was easily bored during this task. M SD 2.47 1.19 2.63 1.43 t < 1 p = .64 d = .43 d = .12 4. I had difficulty in keeping my attention focused on this long, tedious task. M SD 2.59 0.98 3.09 1.28 t = 1.76 p = .08 d = .44 5. No matter how hard I tried to concentrate, I felt easily dis- tracted by the videos playing. M SD 2.47 1.16 3.09 1.20 t = 2.11 p = .04* d = .53 Recognition memory for distractor content (% correct) M SD 0.60 0.26 0.71 0.22 t = 0.193 p = .06 d = .46 t test and Cohenʼs d refer to the comparison between control and lle89Val participants. *Significant difference between groups. a specific sensitivity to distraction. ANOVA results with within-participant factors Distraction (No Distractor, Dis- tractor), Time (Minutes 1, 2, 3, 4), and between-participant factor Genotype (Control, Ile89Val) revealed main effects of Distraction, F(1, 62) = 59.27, p < .0005, η2 G = .07, and Time-on-task, F(3, 186) = 21.35, p < .0005, η2 G = .03, that did not interact, F < 1 (Figure 2). Of primary interest, heterozygotes were more sensitive than controls to distraction, F(1, 62) = 11.65, p = .001, η2 G = .01, but not time-on-task, F < 1.2 The three-way interaction between Distraction, Time-on-task, and Genotype did not approach significance, F < 1. Although groups were matched on PAC distractibility, the CTET with distraction was sensitive to group differences in distractor vulnerabil- ity, suggesting that the PAC and laboratory performance measures captured at least partially distinct aspects of distractibility. FA rates were low and did not differ across groups. An ANOVA with within-participant factors Distraction (No Distractor, Distractor) and Time (Minutes 1, 2, 3, 4) and between-participant factor Genotype (Control, Ile89Val) revealed only a main effect of Distraction, F(1, 62) = 5.10, p = .03, η2 G < 0.01, such that FA rates were higher during distraction (No Distractor M = 0.94%, SD = 1.7; Distractor M = 1.15%, SD = 2.04). There was no effect of Time or Genotype and no interactions (all Fs < 1). Post experiment ratings of subjective experience gener- ally followed the patterns seen for ratings of everyday at- tentional function (PAC scores) in Experiment 1: Ile89Val participants tended to give higher ratings for items concerning mind-wandering and distractibility, but not boredom (Table 3). Although these effects are small, they are notable given that, in selecting our participants, we had matched Ile89Val and control participants as closely as possibly in their PAC subjective ratings of everyday attention. Thus, although the Ile89Val participants tested in this experiment were selected to give similar ratings as con- trols for attentional function in everyday life, they still tended to show an increased subjective as well as objec- tive susceptibility to distraction during the experimental task. In addition, Ile89Val participants tended to have bet- ter memory for the video contents. Together with the CTET performance data, these patterns suggest that Ile89Val individuals are more susceptible to distraction but may benefit from better memory for nominally irrel- evant information. To determine how task performance related to subjec- tive measures of attention, we examined how CTET per- formance correlated with the self-report measures of attention in everyday life and state of attention during the task. To reduce the number of comparisons and ensure replication across data sets, unless otherwise noted we restrict our analyses to those of theoretical interest and also examined in a previous experiment using an undergraduate sample (Berry et al., 2014). D o w n l o a d e d f r o m l l / / / / j f / t t i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j / t f . u s e r o n 1 7 M a y 2 0 2 1 Figure 2. CTET performance with and without video distractor. Markers represent mean proportion of hits for each minute; error bars represent SEM. Both groups exhibit time-on-task and distraction effects that do not interact, and the distractor effect is larger for IIeVal89 participants. Berry et al. 1987 In the text, we note the consistencies and discrepan- cies compared with Berry et al. so that the reader can weigh results accordingly. Full correlation tables for the combined group and each subgroup are available upon request. We first asked how performance correlated with the PAC “trait” measures of attention, with particular interest in those measures related to distraction (Figure 3). Across both groups, there was a small-to-moderate correlation such that participants who reported more distractibility in everyday life also showed a greater distractor-related drop in performance on the CTET, r = .25, p = .05. In a pre- vious experiment using an undergraduate sample (Berry et al., 2014), this correlation was in the same direction but did not reach significance. The greater variance in the distraction effect in this study (due to Ile89Val par- ticipantsʼ distractor vulnerability) may have contributed to this difference. In our undergraduate sample, self- reported mind-wandering negatively correlated with over- all performance in the No Distractor condition, but this relationship did not reach significance in the current sam- ple (r = −.19, p = .13). Thus, across studies, correlations between performance and self-reported everyday atten- tional function are of modest size but in the expected direction. Likewise consistent with the Berry et al. (2014) under- graduate sample, in this community sample stronger cor- relations were found between task performance and post experiment ratings (Table 3; Figure 3). Target detection in the No Distractor condition was negatively related to difficulty keeping attention focused (r = −.40, p = .001). Greater performance declines as a result of the video distractor correlated with greater self-rated distraction by the videos, r = .27, p = .03, and to better memory for the videosʼ content, r = .33, p = .008. A reviewer noted that the mean group differences in the size of the distractor effect on performance might have inflated the size of the cross-group correlations with this effect. To examine this possibility, we calculated the correlations with this factor for each group. For the cor- relation with trait distractibility as measured by the PAC subscale, the difference between the groups was rela- tively small (r = .16 for controls, r = .27 for Ile89Val par- ticipants), perhaps because we had matched the groups on PAC scores. However, for both self-rated distraction (r = −.01 for controls, r = .34 for Ile89Val participants) and memory for the videosʼ content (r = −.004 for con- trols, r = .53 for Ile89Val participants), correlations with the distractor effect on performance were largely driven by Ile89Val participants. In other words, in addition to being more vulnerable to distractionʼs detrimental effects on performance, Ile89Val participants were also more sen- sitive to its subjective effects and its potential benefits to later memory. GENERAL DISCUSSION The present results reveal three major findings. First, although both distraction and time-on-task reduce per- formance, their effects are independent. This seems inconsistent with simple “underload” or “overload” re- source explanations of vigilance decrements. Instead, these different types of demand appear to tap disso- ciable attention control processes. Although neuro- imaging studies suggest a core network involved in stable task control (e.g., Dosenbach et al., 2006), recent studies focused on time-on-task or fatigue effects show substantial variance in the neural correlates of such effects indicating fatigue of specific task-dependent processes (e.g., Persson, Larsson, & Reuter-Lorenz, 2013; Lim et al., 2010). The task used here may provide a useful tool for examining these processes in clinical and indivi- dual differences research. Second, in a community-based sample, genetic varia- tion in cholinergic function was related to self-reported everyday (trait) distractibility and mind-wandering, but not boredom. There are legitimate concerns about the degree to which a single nucleotide polymorphism (SNP) can be linked to cognitive processes, as genes are not D o w n l o a d e d f r o m l l / / / / j f / t t i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j t . f / Figure 3. Correlations between distractor-related performance declines in the CTET, self-rated “trait” distractibility measured using the PAC, self-rated “state” distractibility measured using the post experiment questionnaire and performance on the post experiment quiz for memory of the content of the distracting videos. Larger numbers indicate greater distractibility. If the data from the control participant in the lower left corner are excluded, the correlations remain in the same direction as indicated in the main text at reduced effect size (r = .20 for trait distraction, r = .22 for state distraction, and r = .29 for distractor memory). u s e r o n 1 7 M a y 2 0 2 1 1988 Journal of Cognitive Neuroscience Volume 26, Number 9 solitary mediators of behavior. Instead, gene–behavior relationships likely take the form of complex interactions that include other genes and the environment (Thomas, 2010). However, the pattern found here, especially in- creased distractibility, was predicted a priori from prior research and can be interpreted in the context of evi- dence about its neurobiological impact. When first describ- ing the Ile89Val SNP, Okuda et al. (2002) noted that the effects of reduced choline transport might be especially evident under demanding conditions, consistent with rodent studies that show that responding to the demands imposed by distraction depends critically on the right basal forebrain cholinergic system (St. Peters et al., 2011; Gill et al., 2000). These findings, as well as parallel human neuroimaging studies showing increased right prefrontal activation in the same conditions that produce increased right prefrontal ACh in rodents, converge to predict the present association between Ile89Val and distractibility. Third, even after matching participants on self-report measures of distraction in everyday life, Ile89Val partici- pants showed a specific vulnerability to distraction on a laboratory task (the CTET). A distraction score of 12% discriminated the groups with 63% sensitivity and 72% specificity. Conceptually replicating the group differences on the trait measures, when asked about their attentional state during the task, Ile89Val participants gave higher ratings on items concerning distractibility and mind- wandering, but not boredom. The equivalent state and trait boredom scores, No Distractor task performance, and time-on-task declines, as well as superior perfor- mance on the memory test, indicate that Ile89Val par- ticipants are not generally impaired but have a particular vulnerability to distraction. To summarize, the association between Ile89Val and distractibility is predicted from molecular, systems, and cognitive neuroscience and replicates across self-report measures of everyday attention, laboratory task perfor- mance, and self-report ratings of attention during the task. In contrast, the link to mind-wandering is more ten- uous. It is not clear how mind-wandering relates to the mechanism (attenuated cholinergic response to high task demands) indicated by molecular and cellular studies, and although Ile89Val participants consistently indicated higher rates of mind-wandering on the self-report mea- sures, they did not show worse task performance overall or steeper time-on-task declines. A potential reason for the discrepancy between the self-report and performance measures is that, although the former ask about off-track thoughts, those thoughts may not always disrupt per- formance. Esterman, Noonan, Rosenberg, and DeGutis (2013) recently reported different neural correlates and timescales for vigilance declines, off-track thought, and performance lapses. Of particular interest, default net- work activity putatively related to off-track thought had a nonlinear relationship to performance lapses depend- ing on the stability of goal-directed attention. Future investigations using experience-sampling techniques and neural measures with Ile89Val participants may resolve this issue. The more robust link between Ile89Val and distract- ibility found here is to our knowledge the first evidence linking this polymorphism to a specific cognitive process and the first indicating its role in normal cognitive varia- tion beyond clinical conditions such as ADHD. Besides their vulnerability to the distractorʼs detrimental effects, Ile89Val participantsʼ better memory for the distractor is reminiscent of findings from older adults showing that increased processing of nominally irrelevant information provides an advantage if that information becomes use- ful later on (Biss et al., 2013; Clapp & Gazzaley, 2012; Gazzaley et al., 2005). Increased processing of irrelevant information has been linked to creativity in ADHD (White & Shah, 2011); an interesting question for future studies is whether this advantage extends to Ile89Val. As noted above, understanding the role that any SNP, including Ile89Val, plays in normal cognition and cogni- tive disorders requires consideration of its interaction with other genetic and environmental factors. For exam- ple, variation at a nearby SNP (G to T substitution at CHT 30 UTR) has been linked to corticolimbic reactivity (Neumann et al., 2006), and this variation paired with Ile89Val was especially common in the combined subtype of ADHD (English et al., 2009). Recent evidence from a mouse model suggests that reduced CHT function in combination with dopamine depletion may explain why some Parkinsonʼs patients show pronounced cognitive declines (Zurkovsky et al., 2013) and links between the amyloid precursor protein and CHT indicate a potential role in Alzheimerʼs disease (Wang, Yang, Wang, & Zheng, 2007). The present results suggest that the cholinergic system plays an important and specific role in susceptibility to distraction in everyday life (Experiment 1) and on a laboratory task (Experiment 2). They add to a growing body of research that integrates findings from several areas of psychology and neuroscience to clarify links be- tween cognitive functions and the neural systems that underlie them (see also Howe et al., 2013). This integ- rative approach holds promise for improving our under- standing of how genes influence cognition and behavior and for developing more effective, precisely targeted treatments when these processes are disordered (Insel et al., 2010). Acknowledgments We thank Mina Raj for assistance in creating the stimuli for Experiment 2, Patricia J. Deldin for advising on depression and sleep screening measures and serving as a clinical contact for the depression screen, and John Jonides for comments on the manuscript. We are also grateful to the participants, espe- cially those who returned for Experiment 2, and the many research assistants who facilitated data collection. The study was funded by NIH Grant 1R01MH086530. A. B. and E. D. were both funded by National Science Foundation Graduate Fellowships. Berry et al. 1989 D o w n l o a d e d f r o m l l / / / / j t t f / i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 6 / 9 2 6 1 / 9 9 8 / 1 1 1 9 9 8 4 1 7 / 5 1 7 7 9 8 o 1 c 5 n 9 _ 2 a / _ j 0 o 0 c 6 n 0 7 _ a p _ d 0 0 b 6 y 0 g 7 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j f t . / u s e r o n 1 7 M a y 2 0 2 1 Reprint requests should be sent to Cindy Lustig, Psychology Department, Neuroscience Program, University of Michigan, 4016 East Hall, 530 Church Street, Ann Arbor, MI 49109-1043, or via e-mail: clustig@umich.edu. Notes 1. 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