Dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks.
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 D2receptor agonist bromocriptine improved the flexible updating
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
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
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
updating and stable maintenance of representations, respec-
tively, by examining the effects of the D2receptor agonist bro-
Dopaminergic drug effects vary not only across task demands
but also across individuals (Cools and Robbins, 2004). Paradox-
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-
leau et al., 2006). Second, trait impulsivity is associated with low
baseline D2/D3receptor 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-
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
working memory (Frank et al., 2007). Our study extends this
ing these component processes in working memory in high- and
This work was supported by National Institutes of Health Grants MH63901, NS40813, and DA02060 and the
ment of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK. E-mail:
5506 • TheJournalofNeuroscience,May16,2007 • 27(20):5506–5514
low-impulsive subjects. Subjects performed a delayed match-to-
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.
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
A large sample (n ? 1118) of young college undergraduates were
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
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
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
any history of medical, neurological, or psychiatric disorder.
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 D2receptor 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.
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
the scan, subjects were administered a fourth
minibattery (at ?T225), and their blood pres-
sure was measured again. Subjects were guided
a series of neuropsychological tests (results re-
ported elsewhere). The testing session ended
with a final minibattery at ?T335.
asked to refrain from caffeine and cigarettes on
after drug intake and after scanning, before the
final neuropsychological testing session.
sion, subjects completed a neuropsychological battery, which included
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,
paper-and-pen version of the Stroop task (Stroop, 1935); (8) letter and
Cognitive Assessment (Nasreddine et al., 2005) (to assess mild cognitive
impairment; analogous to the Mini Mental State Examination).
scanning day, subjects performed a minibattery on five occasions. This
ious, happy, sad, nauseous, drowsy, jittery, fatigue, and dizzy) and a
motor tapping test.
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
which thus served as an instruction cue. Subjects were instructed to
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
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
stimuli (Fig. 1).
The order of blue-face and green-scene trials was pseudorandomized
Coolsetal.•DopaminergicModulationofFrontostriatalFunction J.Neurosci.,May16,2007 • 27(20):5506–5514 • 5507
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
ity of this nonscrambled distractor (face or scene) was always congruent
with the task-relevant stimulus modality. Based on previous work from
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
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
p ? 0.001). The effect of face distraction was replicated in 13 older
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
to nonswitch trials and performed by subtracting performance after
scrambled distractors from that after nonscrambled distractors.
Accuracy and RT data were submitted to two repeated-measures ANO-
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
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.
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-
28 ms; field of view, 22.4 cm2; 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].
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-
the brain extraction tool (Smith, 2002)], coregistered to the mean func-
Institute (MNI) skull-stripped structural template. The obtained nor-
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.
encoding-related activity during switch trials minus encoding-related
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)
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-
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-
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
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 pFWE? 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
gyrus (IFG), extending into the right precentral gyrus (PCG) and the
rostral cingulate zone; and (3) the superior and posterior portion of the
Encoding-related suprathreshold clusters ( pFWE? 0.00001). Left, Right hemi-
5508 • J.Neurosci.,May16,2007 • 27(20):5506–5514 Coolsetal.•DopaminergicModulationofFrontostriatalFunction
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
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
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-
putamen (Cools et al., 2006) and an fMRI study that revealed putamen
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
the four sub-ROIs in the striatum (to render the second set of analyses
ROI with a meta-ROI in the lateral frontal cortex (data collapsed across
the three frontal sub-ROIs described above). It was performed with
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.
The drug effects that we report below were not attributable to
nonspecific effects on global cognitive or motor function. There
(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
background of unaltered basic cognitive abilities and subjective
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,
listening version of the Daneman and Carpenter Read Span test
(F(1,20)? 5.4; p ? 0.03).
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
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
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
cost in high-impulsive subjects (F(1,10)? 5.5; p ? 0.04) but did
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(1,10)? 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
(group ? drug ? distractor, F(1,21)? 0.4; drug ? distractor,
F(1,21)? 0.2; group ? distractor, F(1,21)? 0.9).
Behavioral switch costs as a function of trait impulsivity and drug. Switch costs
Coolsetal.•DopaminergicModulationofFrontostriatalFunctionJ.Neurosci.,May16,2007 • 27(20):5506–5514 • 5509
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
in terms of RT, even if face- and scene-
relevant trials were analyzed separately
from the placebo session only (switching
? 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
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
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.
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
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
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-
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,
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-
that may differ between distinct brain regions (Krimer et al.,
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.
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-
vs distraction), and drug (bromocriptine vs placebo) as within-
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
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
Signal change during switch trials minus nonswitch trials in the putamen. Data
5510 • J.Neurosci.,May16,2007 • 27(20):5506–5514Coolsetal.•DopaminergicModulationofFrontostriatalFunction
the data from the high-impulsive subjects. These analyses re-
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).
switching (see above). It may be noted that the drug effect on
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
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
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
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
Bromocriptine improved attentional switching in high- but not
companied by a drug-induced modulation of activity in the pu-
of switching. Conversely, lateral frontal activity but not striatal
activity was modulated by bromocriptine during distraction.
tical parametric map superimposed on five axial sections [numbers below sections represent
lateral frontal cortex (collapsed across the three subregions) for the high-impulsive subjects.
Coolsetal.•DopaminergicModulationofFrontostriatalFunctionJ.Neurosci.,May16,2007 • 27(20):5506–5514 • 5511
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.
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 D2receptor function, impulsivity, and fronto-
striatal activity during working memory.
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
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
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 D2receptors (Sea-
mans and Yang, 2004) in the striatum (Frank et al., 2001). Ac-
by allowing newly relevant information access to working
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 Val158-Met
line DA, accounts for considerable variability in the effects of
amphetamine (Mattay et al., 2003). Trait impulsivity has been
associated with low baseline DA D2/D3receptor binding, as re-
the DA D2/D3receptor and thus, reduced uptake of this radioli-
tical parametric map superimposed on five axial sections [numbers below sections represent
5512 • J.Neurosci.,May16,2007 • 27(20):5506–5514 Coolsetal.•DopaminergicModulationofFrontostriatalFunction
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-
been hypothesized to reflect baseline DA (Kimberg et al., 1997).
Indeed contrasting effects of DA D2receptor agonists depending
susceptibility to distraction (Kimberg et al., 1997; Frank and
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
low-impulsive subjects did not significantly differ at baseline
“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
imental animals has shown that low doses of bromocriptine act
primarily at presynaptic D2receptors, 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-
in future research.
not surprising given that the effect reflected switching at encod-
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
cognitive switching (Cools et al., 2006) on a task that was previ-
well as motor control.
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 D2
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 D2receptor 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
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 D2receptor activation affects the
impact of currently irrelevant inputs on the lateral frontal cortex
activity during the scrambled relative to the nonscrambled dis-
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
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-
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-
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