Impulsive Personality Predicts Dopamine-Dependent Changes in Frontostriatal Activity during Component Processes of Working Memory

University of Cambridge, Cambridge, England, United Kingdom
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2007; 27(20):5506-14. DOI: 10.1523/JNEUROSCI.0601-07.2007
Source: PubMed
ABSTRACT
Dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks. Paradoxical effects are observed, by which the same drug causes cognitive enhancing as well as adverse effects. Here, we demonstrate that individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity. We observed that the dopamine D2 receptor agonist bromocriptine improved the flexible updating (switching) of relevant information in working memory in high-impulsive subjects, but not in low-impulsive subjects. These behavioral effects in high-impulsive subjects accompanied dissociable effects on frontostriatal activity. Bromocriptine modulated the striatum during switching but not during distraction from relevant information in working memory. Conversely, the lateral frontal cortex was modulated by bromocriptine during distraction but not during switching. The present results provide a key link between dopamine D2 receptor function, impulsivity, and frontostriatal activity during component processes of working memory.

Full-text

Available from: Emily G Jacobs, Aug 13, 2014
Behavioral/Systems/Cognitive
Impulsive Personality Predicts Dopamine-Dependent
Changes in Frontostriatal Activity during Component
Processes of Working Memory
Roshan Cools,
1,2
Margaret Sheridan,
1
Emily Jacobs,
1
and Mark D’Esposito
1
1
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720-3190, and
2
Behavioural and Clinical Neuroscience
Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom
Dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks.
Paradoxical effects are observed, by which the same drug causes cognitive enhancing as well as adverse effects. Here, we demonstrate that
individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and
associated frontostriatal activity. We observed that the dopamine D
2
receptor agonist bromocriptine improved the flexible updating
(switching) of relevant information in working memory in high-impulsive subjects, but not in low-impulsive subjects. These behavioral
effects in high-impulsive subjects accompanied dissociable effects on frontostriatal activity. Bromocriptine modulated the striatum
during switching but not during distraction from relevant information in working memory. Conversely, the lateral frontal cortex was
modulated by bromocriptine during distraction but not during switching. The present results provide a key link between dopamine D
2
receptor function, impulsivity, and frontostriatal activity during component processes of working memory.
Key words: dopamine; working memory; prefrontal cortex; basal ganglia; fMRI; impulsivity
Introduction
The mesocorticolimbic dopamine (DA) system is implicated in
working memory (Brozoski et al., 1979; Sawaguchi and
Goldman-Rakic, 1991). However, the effects of dopaminergic
drugs are complex and depend on task demands and associated
neural systems (Cools and Robbins, 2004). Recent work suggests
that DA may have opposite effects depending on the neural site of
modulation [prefrontal cortex (PFC) vs striatum] (Crofts et al.,
2001; Frank et al., 2001; Gruber et al., 2006). DA in the PFC is
thought to stabilize representations by reducing susceptibility to
distraction (Durstewitz et al., 2000; Seamans and Yang, 2004).
Conversely, DA in the striatum may rapidly update representa-
tions in a task-relevant manner (Frank et al., 2001; Gruber et al.,
2006). In the current study, we aimed to test the hypothesis that
DA modulates the striatum and frontal cortex during the flexible
updating and stable maintenance of representations, respec-
tively, by examining the effects of the D
2
receptor agonist bro
-
mocriptine with functional magnetic resonance imaging (fMRI).
Dopaminergic drug effects vary not only across task demands
but also across individuals (Cools and Robbins, 2004). Paradox-
ical effects are observed, by which drugs improve performance in
individuals with suboptimal DA and poor performance but im-
pair performance in individuals with already optimized DA and
good performance (Kimberg et al., 1997; Arnsten, 1998; Mattay
et al., 2003; Phillips et al., 2004). Here, we demonstrate that do-
paminergic drug effects can also be predicted from trait impul-
sivity. We observed differential effects of bromocriptine in high-
and low-impulsive subjects, who were preselected based on self-
report trait impulsivity. The rationale for impulsivity-based sub-
ject selection was threefold. First, impulsivity is the primary trait
thought to mediate vulnerability to impulse-control disorders,
such as drug addiction (Dawe and Loxton, 2004), and is associ-
ated with enhanced sensitivity to dopaminergic drug effects (Boi-
leau et al., 2006). Second, trait impulsivity is associated with low
baseline D
2
/D
3
receptor binding (Dalley et al., 2007). Third, im
-
pulsive disorders are characterized by working memory impair-
ment and abnormalities in frontostriatal circuits (Jentsch and
Taylor, 1999; Schweitzer et al., 2000; Castellanos and Tannock,
2002; Willcutt et al., 2005), and impulsive personality correlates
with low baseline cognitive performance (Keilp et al., 2005). Ac-
cordingly, we stratified our effects by trait impulsivity and pre-
dicted that high-impulsive individuals would be particularly sen-
sitive to the effects of bromocriptine on working memory.
In keeping with this prediction is recent evidence that dopa-
minergic medication in patients with attention-deficit/hyperac-
tivity disorder (ADHD) remediates difficulty with the flexible
updating and stable maintenance of task-relevant information in
working memory (Frank et al., 2007). Our study extends this
work by assessing drug effects on striatal and frontal activity dur-
ing these component processes in working memory in high- and
Received Feb. 11, 2007; revised April 17, 2007; accepted April 18, 2007.
This work was supported by National Institutes of Health Grants MH63901, NS40813, and DA02060 and the
VeteransAdministrationResearchService.WearegratefultoLeeAltamiranoandElizabethKelleyforassistancewith
data acquisition and analysis.
Correspondence should be addressed to Roshan Cools, Behavioural and Clinical Neuroscience Institute, Depart-
ment of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK. E-mail:
roshan.cools@gmail.com.
DOI:10.1523/JNEUROSCI.0601-07.2007
Copyright © 2007 Society for Neuroscience 0270-6474/07/275506-09$15.00/0
5506 The Journal of Neuroscience, May 16, 2007 27(20):5506–5514
Page 1
low-impulsive subjects. Subjects performed a delayed match-to-
sample paradigm that enabled the separate assessment of switch-
ing and resistance to distraction in working memory. We pre-
dicted that bromocriptine would improve switching and
resistance to distraction in high-impulsive subjects but that it
would impair these processes in low-impulsive subjects. More-
over, we predicted that these effects would be accompanied by
modulation of the striatum and frontal cortex, respectively.
Materials and Methods
Subjects
Twenty-eight healthy right-handed volunteers participated in this exper-
iment. The study was approved by the University of California, Berkeley
Committee for the Protection of Human Subjects and performed in
accordance with the Declaration of Helsinki. All volunteers gave written
informed consent and were paid for participation ($250 after
completion).
A large sample (n 1118) of young college undergraduates were
prescreened on the self-report Barratt Impulsiveness Scale (BIS-11) (Pat-
ton et al., 1995) as part of the Research Participation Program organized
by the Haas School of Business at the University of California, Berkeley.
We selected two groups of subjects from the tail ends (i.e., the top and
bottom 15th percentiles) of the normal distribution of total BIS scores
(mean score, 64.4; median score, 64; range, 39 –99; SD, 9.7). Fourteen
healthy high-impulsive subjects were recruited from the top 15th percen-
tile (n 163; scores 75; mean score, 80.0; median score, 79; SD, 4.8).
Similarly, 14 low-impulsive subjects were recruited from the bottom
15th percentile (n 168; scores 54; mean score, 50.1; median score, 51;
SD, 3.3). Six subjects had to be excluded because of excessive movement
and other reasons (supplemental material, available at www.jneuro-
sci.org). Data are reported from 12 low-impulsive subjects (mean age
SD, 19.6 1.6; range, 18 –22) and 10 high-impulsive subjects (mean
age SD, 20.8 2.1; range, 18 –26).
Exclusion criteria were an episode of loss of consciousness, use of
psychotropic drugs, sleeping pills, heavy marijuana use (10 times), and
any history of medical, neurological, or psychiatric disorder.
General procedure
All subjects were invited to visit the Helen Wills Neuroscience Institute
on three occasions: on the first occasion, which lasted 2.5 h, they were
interviewed for suitability, administered background neuropsychologi-
cal tests, and explained the procedure. On the second and third occa-
sions, subjects were scanned, after intake of a lactose placebo or an oral
dose of the DA D
2
receptor agonist bromocriptine [1.25 mg, a dose
commonly used in psychopharmacological studies and well tolerated by
subjects (Gibbs and D’Esposito, 2005a,b)], according to a double-blind,
placebo-controlled crossover design.
After arrival at the institute [time 0 (T0)], subjects performed their
first minibattery (described below), and their blood pressure was taken.
Twenty minutes after arrival (T20), subjects in-
gested a placebo or a bromocriptine capsule,
with a glass of soymilk. The minibatteries were
repeated at T50 and T80, after which the sub-
jects were prepared for their scan and taken to
the scanner. They entered the scanner at T110
(90 min after drug intake). After completion of
the scan, subjects were administered a fourth
minibattery (at T225), and their blood pres-
sure was measured again. Subjects were guided
back to the testing room, where they completed
a series of neuropsychological tests (results re-
ported elsewhere). The testing session ended
with a final minibattery at T335.
Subjects were instructed to avoid eating large
meals on the day of and before their visit but to
have a light meal 1 h before arrival. They were
asked to refrain from caffeine and cigarettes on
the days of the scan. Light snacks were provided
after drug intake and after scanning, before the
final neuropsychological testing session.
Background neuropsychology
Neuropsychological profile at baseline. During the preliminary testing ses-
sion, subjects completed a neuropsychological battery, which included
(1) the Daneman and Carpenter reading span (Daneman and Carpenter,
1980) (supplemental material, available at www.jneurosci.org); (2) the
North American Adult Reading Test (Nelson, 1982); (3) the Beck De-
pression Inventory (Beck et al., 1961); (4) the forward digit span; (5) the
forward and backward spatial span (Corsi Block-Tapping test) (Milner,
1971); (6) the Wisconsin Card Sorting Test (Grant and Berg, 1948); (7) a
paper-and-pen version of the Stroop task (Stroop, 1935); (8) letter and
semantic fluency tasks (Benton, 1968); (9) a six-trial practice block of the
experimental task to be performed in the scanner; and (10) the Montreal
Cognitive Assessment (Nasreddine et al., 2005) (to assess mild cognitive
impairment; analogous to the Mini Mental State Examination).
Performance on background cognitive tests on the scanning days. On each
scanning day, subjects performed a minibattery on five occasions. This
minibattery included the backwards digit span, visual analog scales (anx-
ious, happy, sad, nauseous, drowsy, jittery, fatigue, and dizzy) and a
motor tapping test.
Experimental design
During scanning, subjects performed a delayed match-to-sample task,
which consisted of four blocks with 32 trials per block (13 min/block).
Before entering the scanner, subjects were reminded of the instructions
by referring to the six-trial practice session they had performed on the
preliminary testing session.
On each trial, subjects were presented four pictures: two novel faces
and two novel scenes, which were arranged around a colored fixation
cross (location randomized). They had to encode, maintain, and retrieve
either the faces or the scenes, depending on the color of the fixation cross,
which thus served as an instruction cue. Subjects were instructed to
memorize the faces when the fixation cross was blue and to memorize the
scenes when the cross was green. The encoding period (duration, 1000
ms) was followed by an 8000 ms delay period during which the stimuli
were removed from the screen, and only the colored fixation cross was
presented. After this first delay period, a distractor was presented (dura-
tion, 2000 ms), which subjects were instructed to ignore. This distractor
allowed us to test the hypothesis that DA-dependent frontal mechanisms
are involved in maintaining relevant representations despite similar, but
irrelevant, stimuli. The distractor was followed by a second delay period
(duration, 8000 ms; colored fixation cross present), after which subjects
were probed to respond with the right or left finger depending on
whether or not the probe matched one of the two task-relevant encoding
stimuli (Fig. 1).
The order of blue-face and green-scene trials was pseudorandomized
and unpredictable, enabling the measurement of switching (from attend-
ing to faces to attending to scenes and vice versa) against a background of
Figure 1. Example trial from the experimental paradigm. In this trial, a blue fixation cross instructed subjects to attend to the
faces and ignore the scenes. The encoding period (1000 ms) was followed by an 8000 ms delay period, after which a scrambled
distractor was presented. After a second delay (8000 ms), subjects were probed to make a left/right button press depending on
whether or not the probe face matched one of the two encoding faces.
Cools et al. Dopaminergic Modulation of Frontostriatal Function J. Neurosci., May 16, 2007 27(20):5506 –5514 5507
Page 2
nonswitching (face to face or scene to scene; the minimum/maximum
number of consecutive nonswitch trials was 1/3). We also manipulated
the type of distractor that subjects encountered during the delay. On
some trials, subjects viewed a scrambled face or scene; on other trials, the
distractor was a nonscrambled, novel face or scene. The stimulus modal-
ity of this nonscrambled distractor (face or scene) was always congruent
with the task-relevant stimulus modality. Based on previous work from
our group (Yoon et al., 2006), we predicted that the performance at probe
would be impaired after the congruent novel distractor relative to the
scrambled distractor. Consistent with previous and predicted findings,
pilot data from 16 young healthy volunteers had indeed revealed slower
responses at probe after the nonscrambled than the scrambled distractor,
for faces (F
(1,15)
2.2; p 0.04). Moreover, reaction times were signif
-
icantly prolonged on switch trials compared with RTs on nonswitch
trials, regardless of stimulus modality (i.e., faces or scenes; F
(1,15)
19.1;
p 0.001). The effect of face distraction was replicated in 13 older
healthy volunteers (F
(1,12)
7.4; p 0.02), although an adaptation of the
paradigm for testing in patients rendered the task insensitive to switching
in that study (data reported elsewhere).
Distractors on switch trials were always nonscrambled, so that, in all,
there were three trial types: (1) switch trials with nonscrambled distrac-
tors (n 56), (2) nonswitch trials with nonscrambled distractors (n
36), and (3) nonswitch trials with scrambled distractors (n 36). Stim-
ulus modality and match/nonmatch status were counterbalanced be-
tween these trial types. There were two critical performance measures.
The calculation of the switch cost was restricted to the nonscrambled
distractor trials and performed by subtracting error rates and reaction
times (RTs) at probe on nonswitch trials from error rates and RTs at
probe on switch trials. The calculation of the distractor cost was restricted
to nonswitch trials and performed by subtracting performance after
scrambled distractors from that after nonscrambled distractors.
Behavioral analyses
Accuracy and RT data were submitted to two repeated-measures ANO-
VAs. The first ANOVA addressed the effects on attentional switching and
included the between-subjects factor group and the within-subject fac-
tors drug and switch. The second ANOVA addressed the effects on dis-
traction, and the within-subject factor distractor replaced the factor
switch. The behavioral analysis included the two high-impulsive subjects
who were excluded from the fMRI analysis because of excessive move-
ment. Exclusion of these subjects did not change the results. Data from
the bromocriptine session of one high-impulsive subject was missing
because of equipment (e-prime-recording) failure.
Image acquisition
Imaging data were collected using a Varian (Palo Alto, CA) INOVA 4T
scanner equipped with a transverse electromagnetic send-and-receive
radio frequency head coil. Functional data were obtained using a two-
shot T2*-weighted echo-planar imaging sequence sensitive to blood ox-
ygenation level-dependent contrast (repetition time, 2000 ms; echo time,
28 ms; field of view, 22.4 cm
2
; matrix size, 64 64; in-plane resolution,
3.5 3.5 mm). Each functional volume consisted of 18 5-mm-thick
axial-oblique slices separated by a 0.5 mm interslice gap and provided
nearly whole-brain coverage. Two T1-weighted anatomical scans were
also acquired [a gradient-echo multislice and a magnetization-prepared
fast low-angle shot (MP-FLASH) three-dimensional sequence].
Image analyses
After acquisition, MRI data were converted to Analyze format, corrected
for slice acquisition time and interpolated to 1 s temporal resolution
(one-half of the total repetition time). Subsequent processing was per-
formed using SPM2 (Wellcome Department of Cognitive Neurology,
London, UK; http://www.fil.ion.ucl.ac.uk) run under Matlab6.5 (The
MathWorks, Natick, MA). Functional data were realigned to the first
volume acquired, spatially normalized, and spatially smoothed using a
Gaussian kernel (10 mm full-width at half-maximum). For spatial nor-
malization, the individual subject’s MP-FLASH was skull stripped [using
the brain extraction tool (Smith, 2002)], coregistered to the mean func-
tional image, and subsequently normalized to the Montreal Neurological
Institute (MNI) skull-stripped structural template. The obtained nor-
malization parameter set was then written to the functional images. Time
series were high-pass filtered (128 s cutoff).
A canonical hemodynamic response function was used as a covariate
in a general linear model. The hemodynamic response function was
modeled to the onset of each event with independent regressors for each
stage and each trial type (supplemental material, available at www.
jneurosci.org). We concentrate on the following contrasts of interest: (1)
encoding-related activity during switch trials minus encoding-related
activity during nonswitch trials and (2) distractor-related activity during
nonscrambled stimuli minus distractor-related activity during scram-
bled, novel stimuli (collapsed across stimulus modality). We collapsed
data across correct and incorrect trials, because supplementary analyses
revealed that our effects of interest (of group, drug, and group drug)
did not differ between correct and incorrect trials (either as a function of
switching or distraction). Inclusion of both correct and incorrect trials
considerably enhanced the statistical power of the analyses.
To calculate whole-brain maps for the critical three-way group
drug trial type interactions, each individual’s placebo session’s con-
trast was subtracted from the corresponding bromocriptine session’s
contrast. These difference contrasts were taken to a second-level group
two-sample t test, allowing a direct comparison between the drug effects
in high-impulsive subjects with those in low-impulsive subjects. Data
from whole-brain maps are presented in Figures 5 and 7.
Regions of interest
The specific predictions allowed us to concentrate on region of interest
(ROI) analyses. The striatal ROIs were selected directly from the Auto-
mated Anatomical Labeling interface with SPM, which was developed by
Tzourio-Mazoyer et al. (2002), based on an anatomical parcellation of
the spatially normalized single-subject high-resolution T1 volume pro-
vided by the MNI. From this interface, we selected the right and left
putamen and the right and left caudate nucleus for ROI analysis. Al-
though there is considerable agreement about the anatomical boundaries
of and within striatal regions, a clear definition of both anatomical and
functional subregions within the lateral frontal cortex is lacking. There-
fore, lateral frontal ROIs were derived from the data themselves. To
obtain task-related frontal activation clusters that were orthogonal to our
comparisons of interest (between drug session and groups), contrasts
depicting encoding-related activity were calculated across the two treat-
ment sessions and across all subjects (n 22). We chose to select frontal
ROIs from the encoding contrast (reflecting activity correlating with the
mean of all encoding regressors vs the mean of all other regressors) (Fig.
2), because this was hypothesized to be the most sensitive contrast for
detecting changes as a function of switching (which occurred during the
encoding period). This encoding contrast revealed activation in large
parts of the posterior and frontal cortex.
A thresholded map (at p
FWE
0.00001; this threshold was the lowest
threshold to reveal discrete clusters in the frontal cortex) revealed three
discrete lateral frontal clusters in (1) the right middle frontal gyrus
(MFG); (2) the superior and posterior portion of the right inferior frontal
gyrus (IFG), extending into the right precentral gyrus (PCG) and the
rostral cingulate zone; and (3) the superior and posterior portion of the
Figure 2. Encoding-related suprathreshold clusters ( p
FWE
0.00001). Left, Right hemi
-
sphere (R); right, left hemisphere (L). Note that the small clusters that appear to be located in
the posterior/inferior portions of the inferior frontal gyrus were in fact located in the insulae/
superior temporal gyri.
5508 J. Neurosci., May 16, 2007 27(20):5506 –5514 Cools et al. Dopaminergic Modulation of Frontostriatal Function
Page 3
left IFG, extending into the left PCG (for peak loci, cluster sizes, and t
values, see Fig. 2, Table 1).
To select discrete lateral frontal clusters that did not extend into the
PCG or the medial PFC, we masked the encoding map with the right and
left IFG, as defined by Tzourio-Mazoyer et al. (2002). This resulted in
three ROIs: the right IFG, the left IFG, and the right MFG.
The statistical models described above were reapplied to the average
signal within the ROIs for each subject’s session, using the MarsBar tool
for SPM2 (Brett et al., 2002). Data from each of these ROIs were extracted
and transformed into percentage signal change (for details, see http://
marsbar.sourceforge.net/faq.html#percent_signal). These data were
submitted to two types of repeated-measures ANOVAs (in SPSS 11.0;
SPSS, Chicago, IL). The first type of ANOVA addressed our primary
hypothesis that bromocriptine has different effects on switch-related ac-
tivity in the striatum depending on trait impulsivity. In particular, we
predicted that the drug would modulate activity in the putamen during
switching. This hypothesis was based on our previous work in patients
with Parkinson’s disease (who suffer DA depletion primarily in the pu-
tamen) (Cools et al., 2001a,b, 2003) and patients with focal lesions in the
putamen (Cools et al., 2006) and an fMRI study that revealed putamen
activity during switching (Cools et al., 2004). Thus, the first analyses were
performed on switch-related activity in each of the striatal ROIs sepa-
rately (right/left putamen and right/left caudate nucleus) and included
the between-subjects factor group and the within-subject factor drug.
Switch-related activity was calculated by subtracting encoding-related
activity on nonswitch trials from encoding-related activity on switch
trials. The second set of ANOVAs tested our second hypothesis, that
these effects on striatal activity during switching differed from effects on
lateral frontal activity during distraction. For these analyses, we collapsed
the four sub-ROIs in the striatum (to render the second set of analyses
orthogonal to the first analysis set and to approximately match the size of
the striatal and frontal ROIs) and compared activity in this striatal meta-
ROI with a meta-ROI in the lateral frontal cortex (data collapsed across
the three frontal sub-ROIs described above). It was performed with
group as the between-subjects factor and ROI (striatum vs lateral frontal
cortex), process (switch-related activity vs distractor-related activity),
and drug as within-subject factors. Supplementary analyses explored ef-
fects in each lateral frontal cortex ROI separately. Finally, we report
results from the striatum (the putamen and caudate nucleus) and the
lateral frontal cortex [Talairach coordinates, y 0 and x ⬎⫹16 or x
16, with the x-coordinates based on Owen et al. (1999)] as revealed by
whole-brain analyses of the critical group by drug trial type interac-
tions (thresholded at p 0.001, uncorrected for multiple comparisons).
Other regions of no interest, for which we had no a priori predictions,
were explored at a higher threshold of p 0.05, corrected for multiple
comparisons according to the familywise error rate.
Results
Background neuropsychology
The drug effects that we report below were not attributable to
nonspecific effects on global cognitive or motor function. There
were no drug effects on our background neuropsychological tests
(see supplemental material, available at www.jneurosci.org)
other than a significant effect of drug on motor tapping speed in
both the high- and the low-impulsive subjects (drug time in-
teraction, F
(1,20)
5.0; p 0.04). This profile enabled us to
evaluate the drug effects of interest on working memory against a
background of unaltered basic cognitive abilities and subjective
effects.
As would be expected, the high-impulsive subjects performed
more poorly than the low-impulsive subjects on the interference
condition of the Stroop test (F
(1,20)
7.8; p 0.01). In addition,
they had a significantly lower reading span, as measured with the
listening version of the Daneman and Carpenter Read Span test
(F
(1,20)
5.4; p 0.03).
Performance effects
We first investigated performance effects (measured at probe) of
bromocriptine as a function of switching with an ANOVA with
the between-subjects factor group and the within-subject factors
drug and switch (switch vs nonswitch). In Figure 3, we present
the mean error switch costs for the high- and low-impulsive sub-
jects separately as a function of drug (for data as a function of trial
type, see Table 2). The drug effect on switching depended on trait
impulsivity, as indicated by a significant group drug switch
interaction (F
(1,21)
7.1; p 0.01). This three-way interaction
explained why the main effect of switching did not reach signifi-
cance (F
(1,21)
2.7; p 0.1) and indicates that switching in the
present paradigm depended on both trait impulsivity and drug
session.
These observations were confirmed by additional statistical
analyses. Although the switch cost at baseline did not differ sig-
nificantly between the two groups (F
(1,21)
1.3), bromocriptine
had different effects on switching in the high- and low-impulsive
subjects. Thus, bromocriptine significantly attenuated the switch
cost in high-impulsive subjects (F
(1,10)
5.5; p 0.04) but did
not affect the switch cost in low-impulsive subjects (F
(1,11)
1.3;
p 0.3). Simple interaction effects analyses confirmed that the
high-impulsive subjects exhibited significantly more errors on
switch trials than on nonswitch trials, when tested on placebo
(F
(1,11)
5.1; p 0.05). Bromocriptine abolished this switch cost
(F
(1,10)
0.04; p 0.8). Although inspection of Table 2 reveals
that bromocriptine altered performance primarily on switch tri-
als but not on nonswitch trials, the effects of bromocriptine did
not reach significance when switch and nonswitch trials were
analyzed separately ( p 0.2).
There was no significant distractor cost (error rate after the
nonscrambled distractor minus error rate after the scrambled
distractor) across all sessions and subjects (F
(1,21)
0.4), and
there were no effects of group or drug as a function of distraction
(group drug distractor, F
(1,21)
0.4; drug distractor,
F
(1,21)
0.2; group distractor, F
(1,21)
0.9).
No drug or group effects were found on RTs (group drug
Table 1. Encoding-related suprathreshold clusters at Talairach y > 0(p
FWE
<
0.00001)
Label
Talairach coordinates (x, y, z)
of peak locus t Cluster size (voxels)
Right IFG/PCG 46, 8, 32 16.65 3967
Left IFG/PCG 46, 0, 54 13.47 1528
Right MFG 36, 46, 32 10.06 76
Figure 3. Behavioral switch costs as a function of trait impulsivity and drug. Switch costs
represent themean proportion of errors on switchtrials minus the mean proportionof errors on
nonswitch trials. Error bars represent SEs of the difference between treatment sessions.
Cools et al. Dopaminergic Modulation of Frontostriatal Function J. Neurosci., May 16, 2007 27(20):5506 –5514 5509
Page 4
switch, F
(1,21)
1.5, p 0.2; drug
switch, F
(1,21)
0.4, p 0.5; group
drug distractor, F
(1,21)
0.07, p 0.8;
drug distractor, F
(1,21)
0.3, p 0.6).
There was no main effect of switching
(F
(1,21)
1.0) or distraction (F
(1,21)
0.8)
in terms of RT, even if face- and scene-
relevant trials were analyzed separately
from the placebo session only (switching
faces, F
(1,21)
0.3; switching scenes, F
(1,21)
0.2; distraction faces, F
(1,21)
0.8; dis
-
traction scenes, F
(1,21)
0.6). This con
-
trasted with previous pilot data from
young and older volunteers who showed a significant RT switch
cost as well as a significant RT distractor cost (see Materials and
Methods). This difference between the previous behavioral study
and the present fMRI study may reflect adoption of different
performance strategy in the scanner environment. Indeed, the
mean RT in the previous study was much faster (1017 ms; SEM,
74 ms) than the mean RT in the current study (1273.8 ms; SEM,
63 ms). Thus, it is possible that the predicted RT effects did not
surface because subjects did not sufficiently emphasize speed.
Perhaps the longer RTs and long delays enabled them to retrieve
information from long-term memory, circumventing distractor-
disrupted working memory.
In sum, the behavioral effects of bromocriptine depended on
trait impulsivity. The drug improved performance on switch tri-
als relative to nonswitch trials in the high-impulsive subjects but
not in the low-impulsive subjects. There were no effects as a
function of distraction.
Neural activity in the striatum
First we conducted hypothesis-driven ROI analyses in a priori
defined ROIs to test whether the drug modulated activity in spe-
cific subregions of the striatum during switching. In particular,
we predicted that the drug would modulate activity in the puta-
men during switching. This hypothesis was based on our previ-
ous work in patients with Parkinson’s disease [who suffer DA
depletion primarily in the putamen (Cools et al., 2001a,b, 2003)]
and patients with focal lesions in the putamen (Cools et al., 2006)
and an fMRI study that revealed putamen activity during switch-
ing (Cools et al., 2004). In keeping with this a priori hypothesis,
we found that the performance effects on switching were paral-
leled by effects on activity in the putamen during switching. In
Figure 4, we present the drug effects on switch-related activity in
the putamen for the high- and low-impulsive subjects separately.
We observed that the effects of bromocriptine depended on trait
impulsivity, as indicated by a significant group drug interac-
tion (bilateral putamen, F
(1,20)
6.5, p 0.02; the right puta
-
men, F
(1,20)
7.6, p 0.01; the left putamen, F
(1,20)
2.6, p
0.1; bilateral caudate nucleus, F
(1,20)
0.5) (Fig. 5
). Bromocrip-
tine modulated switch-related activity in the right putamen of
high-impulsive subjects (F
(1,9)
11.9; p 0.007) but did not
affect switch-related activity in the right putamen of low-
impulsive subjects (F
(1,11)
0.2). Simple effects analyses revealed
that the high-impulsive subjects on bromocriptine exhibited sig-
nificantly greater activity in the right putamen on switch trials
than on nonswitch trials (F
(1,9)
7.2; p 0.03). Conversely,
when they were on placebo, there was a trend toward greater right
putamen activity on nonswitch trials than on switch trials
(F
(1,9)
3.9; p 0.08).
To assess this drug effect further, we analyzed whether the
effect on switch-related activity in the right putamen was attrib-
utable to modulation of encoding-related activity during switch
trials or nonswitch trials. Bromocriptine significantly attenuated
activity on nonswitch trials (F
(1,9)
12.5; p 0.006), whereas it
left unaltered activity on switch trials (F
(1,9)
0.2) (Table 3
). It
may be noted that these latter simple main effects of bromocrip-
tine are difficult to interpret given likely global or vascular effects
that may differ between distinct brain regions (Krimer et al.,
1998). We emphasize that drug effects on fMRI contrasts between
comparable trial types (e.g., those between encoding on switch
trials and encoding on nonswitch trials, as reported above) are
more meaningful than simple main drug effects, because the
former but not the latter control for global drug effects.
Neural effects in the lateral frontal cortex
We performed a second set of hypothesis-driven ROI analyses to
test whether the drug effect on striatal activity during switching
differed from that on lateral frontal activity during distraction.
We conducted a repeated-measures ANOVA with group as the
between-subjects factor and ROI (striatum vs lateral frontal cor-
tex; see Materials and Methods for definition), process (switching
vs distraction), and drug (bromocriptine vs placebo) as within-
subject factors. This ANOVA revealed that the drug differentially
affected the striatum and the lateral frontal cortex during switch-
ing and distraction respectively, as evidenced by a significant
ROI process drug interaction (F
(1,20)
4.4; p 0.05).
Additional analyses revealed that the ROI process drug in-
teraction was significant only in the high-impulsive subjects
(F
(1,9)
8.0; p 0.02) (Fig. 6
) but not in the low-impulsive
subjects (ROI process drug, F
(1,11)
0.1). There were no
other effects of drug in the low-impulsive subjects, and we did not
analyze these data further (main effect of drug, F
(1,11)
0.3;
process drug, F
(1,11)
0.02; ROI drug, F
(1,11)
1.6).
To further analyze the drug effects on activity in the lateral
Figure 4. Signal change during switch trials minus nonswitch trials in the putamen. Data
represent mean percentage signal change and are collapsed across the right and left putamen.
Error bars represent SEs of the difference between treatment sessions.
Table 2. Behavioral data separated by trial type, group, and drug
Placebo Bromocriptine
Accuracy RT Accuracy RT
High-impulsive subjects
Nonswitch/nonscrambled distractor 0.68 (0.03) 1262 (89) 0.69 (0.03) 1255 (89)
Nonswitch/scrambled distractor 0.67 (0.02) 1271 (98) 0.67 (0.02) 1257 (98)
Switch/scrambled distractor 0.64 (0.03) 1272 (94) 0.67 (0.02) 1253 (98)
Low-impulsive subjects
Nonswitch/nonscrambled distractor 0.67 (0.03) 1277 (85) 0.68 (0.03) 1268 (85)
Nonswitch/scrambled distractor 0.65 (0.02) 1312 (94) 0.69 (0.02) 1281 (93)
Switch/scrambled distractor 0.65 (0.02) 1295 (90) 0.67 (0.02) 1283 (94)
Accuracy, Mean proportion of correct responses; RT, mean reaction time in milliseconds. Values in parentheses represent SEM.
5510 J. Neurosci., May 16, 2007 27(20):5506 –5514 Cools et al. Dopaminergic Modulation of Frontostriatal Function
Page 5
frontal cortex, we conducted additional simple effects analyses of
the data from the high-impulsive subjects. These analyses re-
vealed a significant drug effect on distractor-related activity in the
lateral frontal cortex (F
(1,9)
5.1; p 0.05) (Fig. 7
) but not in the
striatum (F
(1,9)
0.02). Conversely, the drug did not affect ac
-
tivity in the lateral frontal cortex during switching (F
(1,9)
0.3).
Thus, bromocriptine modulated activity in the lateral frontal cor-
tex during distraction, whereas it modulated the putamen during
switching (see above). It may be noted that the drug effect on
switch-related activity in the larger striatal meta-ROI only tended
toward significance (F
(1,9)
3.4; p 0.1), suggesting that the
effects were specific to the putamen.
Next, we analyzed the spatial specificity of the drug effects in
the lateral frontal cortex by looking at each sub-ROI separately in
the high-impulsive subjects. The drug effect on distractor-related
activity was attributable to effects on the left IFG (F
(1,9)
5.9; p
0.04), in which the drug potentiated activity during the non-
scrambled distractor (F
(1,9)
8.0; p 0.02), while not affecting
activity during the scrambled distractor (F
(1,9)
1.4) (Table 4).
There were no effects on distractor-related activity in the right
IFG (F
(1,9)
1.8) or the left MFG (F
(1,9)
2.0)
.
Supplementary analyses confirmed that there were no effects
on switch-related activity in the lateral frontal cortex, even when
the larger meta-ROI was broken down into sub-ROIs [the left
IFG (F
(1,9)
1.4), the right IFG (F
(1,9)
0.5), or the left MFG
(F
(1,9)
0.005)]. Similar ANOVAs showed that there were no
effects on distractor-related activity in the right putamen (F
(1,9)
0.001), left putamen (F
(1,9)
1.5), right caudate nucleus (F
(1,9)
0.005), or left caudate nucleus (F
(1,9)
1.8).
Finally, whole-brain analyses confirmed a significant drug
group effect on switch-related activity in the striatum [activity
peak centered on the right putamen at Talairach coordinates 24,
4, 2 (x, y, z); p 0.001] but not the lateral frontal cortex. Con-
versely, there was a drug group effect on distractor-related
activity in the lateral frontal cortex [activity peak centered on the
inferior frontal junction (Brass et al., 2005) (i.e., the border of the
left IFG and the left inferior PCG) at coordinates 46, 4, 28 (x, y, z);
p 0.001] but not the striatum (Figs. 5, 7).
There were no significant correlations between the drug-
induced change in performance and drug-induced changes in
neural activity.
Summary of main results
Bromocriptine improved attentional switching in high- but not
low-impulsive subjects. This drug-induced improvement was ac-
companied by a drug-induced modulation of activity in the pu-
tamen, whereas lateral frontal activity was unaltered as a function
of switching. Conversely, lateral frontal activity but not striatal
activity was modulated by bromocriptine during distraction.
This finding that bromocriptine had doubly dissociable effects in
Figure 5. Effect of bromocriptine during switching as a function of trait impulsivity. Statis-
tical parametric map superimposed on five axial sections [numbers below sections represent
MNI z-coordinates (millimeters from the anterior commissure)] from the MNI template brain
(theaverage of27 scansfrom 1subject tocreate theimage knownas “colin27”)for thegroup
drug switch interaction contrast. A significant peak was observed in the right putamen [at
coordinates 24, 4, 2 (x, y, z); all t values 2.5 are shown]. L, Left; R, right.
Table 3. Encoding- and distractor-related percentage signal change from the right
putamen
Placebo Bromocriptine
High-impulsive
Nonswitch 0.13 (0.05) 0.02 (0.05)
Switch 0.06 (0.05) 0.08 (0.04)
Nonscrambled distractor 0.11 (0.07) 0.06 (0.05)
Scrambled distractor 0.09 (0.07) 0.04 (0.04)
Low-impulsive
Nonswitch 0.10 (0.05) 0.10 (0.04)
Switch 0.11 (0.05) 0.07 (0.04)
Nonscrambled distractor 0.07 (0.04) 0.005 (0.03)
Scrambled distractor 0.04 (0.04) 0.01 (0.05)
Values represent mean percentage signal change; values in parentheses represent SEM.
Figure 6. Signal changeas a function ofprocess, drug, and regionof interest. Data represent
mean percentage signal change in the striatum (collapsed across the four subregions) and the
lateral frontal cortex (collapsed across the three subregions) for the high-impulsive subjects.
Error bars represent SEs of the difference between drug sessions.
Cools et al. Dopaminergic Modulation of Frontostriatal Function J. Neurosci., May 16, 2007 27(20):5506 –5514 5511
Page 6
the striatum and the lateral frontal cortex as a function of trait
impulsivity and component process was supported by both
whole-brain and ROI analyses.
Discussion
We demonstrate that impulsive personality predicts DA-
dependent changes in frontostriatal activity during component
processes of working memory. These results reveal the impor-
tance of taking into account individual variation in personality
traits when predicting drug efficacy. In addition, they provide a
key link between D
2
receptor function, impulsivity, and fronto
-
striatal activity during working memory.
The finding that trait impulsivity predicted effects on working
memory concurs with previous studies showing that impulse-
control disorders are accompanied not only by response control
failures and abnormal reward processing (Jentsch and Taylor,
1999; Sonuga-Barke, 2002) but also by working memory impair-
ment (Evenden, 1999; Schweitzer et al., 2000; Castellanos and
Tannock, 2002; Willcutt et al., 2005). Indeed, a key characteristic
of impulsive behavior is inappropriate attention to irrelevant in-
formation. DA dysfunction in frontostriatal systems may pro-
mote impulsivity by impairing the flexible updating of task rele-
vance and inducing susceptibility to distraction in working
memory (Frank et al., 2007).
We observed that bromocriptine improved switching, but
only in high-impulsive subjects who had low baseline working
memory capacity as measured with the reading span test. This
finding is consistent with recent observations that the D
2
receptor
agonist cabergoline improved the flexible updating of informa-
tion in working memory in healthy volunteers with low reading
spans (Frank and O’Reilly, 2006). In addition, it concurs with
results suggesting that dopaminergic medication improves the
updating of information in working memory in patients with
ADHD (Frank et al., 2007).
The present study revealed that the drug-induced improve-
ment in switching was accompanied by a drug-induced modula-
tion of putamen activity, again only in high-impulsive subjects.
On placebo, poor performance on switch trials (relative to non-
switch trials) was accompanied by reduced putamen activity.
This concurs with the hypothesis that striatal activity reflects the
extent to which newly relevant information is gated into (i.e.,
allowed to update) working memory. Thus, on placebo, high-
impulsive subjects were more proficient in updating working
memory (and activating the striatum) on nonswitch trials than
on switch trials. After bromocriptine, better performance on
switch trials was accompanied by greater switch-related striatal
activity. This is consistent with recent theorizing that DA opens
the gate to working memory and renders the system more re-
sponsive to newly relevant inputs by acting at D
2
receptors (Sea
-
mans and Yang, 2004) in the striatum (Frank et al., 2001). Ac-
cording to this account, bromocriptine attenuated the switch cost
by allowing newly relevant information access to working
memory.
Similar contrasting effects of DA have previously been ob-
served as a function of individual genotypic variation in baseline
DA. For example, the catechol O-methyltransferase Val
158
-Met
genotype, which is known to be associated with variation in base-
line DA, accounts for considerable variability in the effects of
amphetamine (Mattay et al., 2003). Trait impulsivity has been
associated with low baseline DA D
2
/D
3
receptor binding, as re
-
vealed by reduced uptake of the radioligand [
18
F] fallypride in the
striatum (Dalley et al., 2007). [
18
F] Fallypride has high affinity for
the DA D
2
/D
3
receptor and thus, reduced uptake of this radioli
-
Table 4. Encoding- and distractor-related percentage signal change from the left
IFG
Placebo Bromocriptine
High-impulsive
Nonswitch 0.21 (0.07) 0.19 (0.06)
Switch 0.21 (0.07) 0.18 (0.06)
Nonscrambled distractor 0.17 (0.05) 0.21 (0.07)
Scrambled distractor 0.19 (0.06) 0.20 (0.06)
Low-impulsive
Nonswitch 0.12 (0.04) 0.19 (0.05)
Switch 0.17 (0.05) 0.27 (0.08)
Nonscrambled distractor 0.27 (0.08) 0.32 (0.09)
Scrambled distractor 0.19 (0.05) 0.27 (0.08)
Values represent mean percentage signal change; values in parentheses represent SEM.
Figure 7. Effect of bromocriptine during distraction as a function of trait impulsivity. Statis-
tical parametric map superimposed on five axial sections [numbers below sections represent
MNI z-coordinates (millimeters from the anterior commissure)] from the MNI template brain
(theaverage of27 scansfrom 1subject tocreate theimage knownas “colin27”)for thegroup
drug distractor interaction contrast. A significant peak was observed in the inferior frontal
junction[i.e., theborder ofthe left inferiorfrontal gyrusand leftprecentral gyrus;at coordinates
46, 4, 28 (x, y, z); all t-values 3.0 are shown]. L, Left; R, right.
5512 J. Neurosci., May 16, 2007 27(20):5506 –5514 Cools et al. Dopaminergic Modulation of Frontostriatal Function
Page 7
gand likely indicates reduced dopamine D
2
/D
3
receptor availabil
-
ity. The hypothesis that high-impulsive subjects exhibit low DA
function is strengthened by the finding that, relative to low-
impulsive subjects, high-impulsive subjects exhibited signifi-
cantly lower working memory capacity (reading span), which has
been hypothesized to reflect baseline DA (Kimberg et al., 1997).
Indeed contrasting effects of DA D
2
receptor agonists depending
on reading span have previously been observed on switching and
susceptibility to distraction (Kimberg et al., 1997; Frank and
O’Reilly, 2006).
In keeping with previous suggestions (Frank et al., 2007), our
findings suggest that effects on striatal activity during flexible
updating in working memory may mediate the link between DA
and impulsivity. The observation that the switch cost of high- and
low-impulsive subjects did not significantly differ at baseline
does not undermine this conclusion. It has been proposed that an
“inverted U”-shaped relationship exists between DA and perfor-
mance (Williams and Goldman-Rakic, 1995; Zahrt et al., 1997;
Vijayraghavan et al., 2007), so that both too little and too much
DA impairs performance. Our high- and low-impulsive subjects
may be positioned on the left and right arm of the inverted U,
respectively, at approximately similar distances from the opti-
mum. This would account for both the opposite effects of bro-
mocriptine and the lack of a significant difference at baseline.
Bromocriptine is an agonist, assumed to mimic DA, and its
effects are frequently interpreted to reflect action at postsynaptic
receptors. Our observation that bromocriptine potentiated mo-
tor tapping speed in both high- and low-impulsive subjects sug-
gests that the drug acted postsynaptically in both groups, at least
in systems underlying motor tapping. However, work with exper-
imental animals has shown that low doses of bromocriptine act
primarily at presynaptic D
2
receptors, thereby paradoxically re
-
ducing DA release (Skirboll et al., 1979; Frank and O’Reilly,
2006). Therefore, it is possible that the beneficial effects of bro-
mocriptine in high-impulsive subjects reflect a reduction of en-
dogenous DA. This remains an outstanding issue to be addressed
in future research.
It is recognized that the behavioral effects were modest. This is
not surprising given that the effect reflected switching at encod-
ing but was measured at probe. The significance of the behavioral
effects is particularly meaningful given that they were accompa-
nied by neural effects. The effects during switching were seen
primarily in the putamen. This concurs with a recent study in
which we observed that selective lesions in the putamen impaired
cognitive switching (Cools et al., 2006) on a task that was previ-
ously shown to activate the putamen in healthy volunteers (Cools
et al., 2004). Thus, the putamen plays a role in cognitive control as
well as motor control.
The drug effects on striatal activity are unlikely to reflect non-
specific, global effects on the fMRI signal, because there was no
effect during switching on task-responsive regions in the lateral
frontal cortex. The null effects in the lateral frontal cortex do not
reflect a lack of statistical power, because activity in the same
region was significantly modulated during distraction. A role for
the striatum in the dopaminergic modulation of flexibility con-
curs with recent theoretical work highlighting the importance of
striatal DA in the flexible updating of currently active represen-
tations when change is required (Frank et al., 2001; Goto and
Grace, 2005; Gruber et al., 2006). Furthermore, it concurs with a
growing body of evidence for DA-dependent task-switching and
working memory-updating deficits in patients with Parkinson’s
disease, which is characterized by striatal DA depletion (Cools et
al., 2001a, 2006). The question of whether the effects observed
here on the flexible updating of working memory extend to clas-
sic task switching is currently under investigation.
The finding that bromocriptine did not modulate the frontal
cortex during switching is not to say that the frontal cortex does
not contribute to flexibility. There is much evidence indicating a
key role for the frontal cortex in task switching and set shifting
(Dias et al., 1996; Sohn et al., 2000; Aron et al., 2004; Brass et al.,
2005). However, DA may act at the level of the striatum to bias
flexibility that itself depends on frontostriatal interactions. In-
deed, Goto and Grace (2005) observed that injection of a D
2
receptor agonist and antagonist into the striatum respectively
attenuated and facilitated striatal responses that were invoked by
stimulation of the frontal cortex. Moreover, they showed that
injection of a D
2
receptor agonist in the striatum of the rat im
-
paired set shifting but only after inactivation of the (contralat-
eral) frontal cortex. These data suggest that DA in the striatum
serves attentional switching by mediating PFC-evoked input to
the striatum.
Distractor-related activity was modulated by bromocriptine
in the lateral frontal cortex and not in the striatum. This is con-
sistent with the prediction that D
2
receptor activation affects the
impact of currently irrelevant inputs on the lateral frontal cortex
(Seamans and Yang, 2004). Specifically, bromocriptine enhanced
activity during the scrambled relative to the nonscrambled dis-
tractor in the lateral frontal cortex. The drug-induced increase in
frontal activity may reflect enhanced recruitment of active main-
tenance processes to overcome distractibility, which concurs with
the previous observation that DA-enhancing medication reduced
susceptibility to distractors in patients with impulsive disorder
(ADHD) (Frank et al., 2007). Alternatively, the activity increase
may reflect greater impact of distractors and thus enhanced dis-
tractor susceptibility. Such enhanced distractibility was previ-
ously reported after administration of cabergoline in subjects
with low reading span (Frank and O’Reilly, 2006). It is difficult to
distinguish between these alternatives, because, despite the drug-
induced changes in the lateral frontal cortex, we did not observe a
drug-induced change in the behavioral distractor cost. Indeed,
the lack of distractor cost on placebo is a weakness of this study
and suggests that the task was not sufficiently sensitive to detect
behavioral distractibility, possibly because subjects did not em-
phasize speed during responding at probe. We recognize that the
modulation of lateral frontal activity during distraction may re-
flect processes other than maintenance in the face of distraction,
such as response inhibition. This does not undermine the main
conclusion that the striatum and frontal cortex mediate the do-
paminergic modulation of distinct component processes of
working memory.
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J. Neurosci., May 16, 2007 27(20):5506–5514 Cools et al. Dopaminergic Modulation of Frontostriatal Function
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    • "The increased flexibility with positive affect, as indicated by relatively few AY errors, may be explained by the modulatory effect of DA in the striatum. DA increases in the striatum are involved in some forms of cognitive flexibility (i.e., switching between relevant stimulus information), as substantiated by pharmacological fMRI studies with healthy controls and Parkinsonʼs patients on and off medication (Cools, Sheridan, Jacobs, & DʼEsposito, 2007; Cools, Barker, Sahakian, & Robbins, 2001). These studies indicated that a DA enhancement in the striatum improves the efficacy of using incoming response-relevant stimulus information to control behavior. "
    Full-text · Dataset · Mar 2016
    • "Such baseline differences (see also Gianotti et al., 2012; Eisenegger et al., 2010) may explain why Pine et al. (2010) found that L-dopa increased temporal impulsivity. In healthy young participants, administering L-dopa may result in overdosing of frontostriatal circuits depending on individual differences in baseline dopamine levels (Kayser et al., 2012; Clatworthy et al., 2009; Cools, Sheridan, Jacobs, & D'Esposito, 2007). In this study, medication dosage is titrated to each individual's need, perhaps allowing the enhanced patience often seen with moderate increases in dopamine levels. "
    [Show abstract] [Hide abstract] ABSTRACT: Choosing between sooner smaller rewards and larger later rewards is a common choice problem, and studies widely agree that frontostriatal circuits heavily innervated by dopamine are centrally involved. Understanding how dopamine modulates intertemporal choice has important implications for neurobiological models and for understanding the mechanisms underlying maladaptive decision-making. However, the specific role of dopamine in intertemporal decisions is not well understood. Dopamine may play a role in multiple aspects of intertemporal choices-the valuation of choice outcomes and sensitivity to reward delays. To assess the role of dopamine in intertemporal decisions, we tested Parkinson's disease patients who suffer from dopamine depletion in the striatum, in either high (on medication, PDON) or low (off medication, PDOFF) dopaminergic states. Compared with both PDOFF and healthy controls, PDON made more farsighted choices and reduced their valuations less as a function of increasing time to reward. Furthermore, reduced discounting in the high dopaminergic state was robust across multiple measures, providing new evidence for dopamine's role in making decisions about the future.
    No preview · Article · Feb 2016 · Journal of Cognitive Neuroscience
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    • "Second, acoustic noise may have enhanced a different facet of working memory, than the one specifically required here. Depending on target site, dopamine has been implicated in different component processes of cognitive control and working memory: while stability and maintenance of information have been argued to be mediated by prefrontal dopamine receptors, flexibility and updating of working memory representations are likely controlled by striatal dopamine receptors (Cools et al., 2007; Cools and D'Esposito, 2011). The precise effect of dopamine on gating mechanisms in the striatum, however, remained debated: opening (Braver and Cohen, 2000; Badre, 2012; D'Ardenne et al., 2012) as well as locking (Gruber et al., 2006) the gate to working memory has been suggested as a consequence of phasic dopamine release from the SN/VTA. "
    [Show abstract] [Hide abstract] ABSTRACT: Beneficial effects of noise on higher cognition have recently attracted attention. Hypothesizing an involvement of the mesolimbic dopamine system and its functional interactions with cortical areas, the current study aimed to demonstrate a facilitation of dopamine-dependent attentional and mnemonic functions by externally applying white noise in five behavioral experiments including a total sample of 167 healthy human subjects. During working memory, acoustic white noise impaired accuracy when presented during the maintenance period (Experiments 1–3). In a reward based long-term memory task, white noise accelerated perceptual judgments for scene images during encoding but left subsequent recognition memory unaffected (Experiment 4). In a modified Posner task (Experiment 5), the benefit due to white noise in attentional orienting correlated weakly with reward dependence, a personality trait that has been associated with the dopaminergic system. These results suggest that white noise has no general effect on cognitive functions. Instead, they indicate differential effects on perception and cognition depending on a variety of factors such as task demands and timing of white noise presentation.
    Full-text · Article · Nov 2015 · Frontiers in Psychology
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