Conflict monitoring in early
C.E. Krueger, PhD
A.C. Bird, MS
M.E. Growdon, BA
J.Y. Jang, BA
B.L. Miller, MD
J.H. Kramer, PsyD
Background: Despite the extensive frontal atrophy and behavioral disinhibition that characterizes
behavioral variant frontotemporal dementia (bvFTD), many studies of early bvFTD suggest normal
executive functioning (EF). The current study examined cognitive control in patients with bvFTD
who otherwise seemed cognitively normal.
Methods: Subjects included 7 patients with bvFTD with normal neuropsychological test scores, 7
patients with bvFTD matched for Mini-Mental State Examination score but with impaired neuro-
psychological test scores, and 14 normal controls. A flanker paradigm and other measures of EF
were administered to participants. A semiautomated parcellation program was used to analyze
structural MRI scans.
Results: On the flanker task, multivariate analysis of variance revealed a significant condition X
diagnosis interaction. Both bvFTD groups showed a larger congruency effect than normal con-
trols, i.e., they displayed disproportionately reduced speed and accuracy on incongruent trials
relative to congruent trials. Imaging data illustrated significant orbitofrontal atrophy in patients
with early bvFTD as compared with controls.
Conclusions: Patients with behavioral variant frontotemporal dementia (bvFTD) who performed
within normal limits on clinical tests of executive functioning demonstrated a select impairment
on an experimental test of cognitive control, suggesting a subtle impairment in inhibiting attention
or response to the irrelevant stimuli. Measures of neuropsychological functioning sensitive to the
ventromedial prefrontal cortex may be useful in early diagnosis of patients with bvFTD. Our un-
derstanding of this syndrome may be increased by considering the efficiency of selective inhibi-
tion, a fundamental component of executive cognitive control. Neurology®2009;73:349–355
ANOVA ? analysis of variance; bvFTD ? behavioral variant frontotemporal dementia; CDR ? Clinical Dementia Rating; EF ?
executive functioning; FTLD ? frontotemporal lobar dementia; MANCOVA ? multivariate analysis of covariance; MCI ? mild
cognitive impairment; MMSE ? Mini-Mental State Examination; MP-RAGE ? magnetization-prepared rapid gradient echo;
MR ? magnetic resonance.
Frontotemporal lobar dementia (FTLD) is a devastating neurodegenerative disease found to be as
ral dementia (bvFTD) is the most common variant of FTLD and is characterized by profound
disturbances in personality, social function, judgment, and insight. Imaging studies have shown
early and disproportionate involvement of orbitofrontal cortex3and associated networks involving
the striatum, ventromedial prefrontal cortex, anterior cingulate cortex, and insula.4-6
Given the widespread frontal atrophy and behavioral disinhibition that characterizes bvFTD,
impairments in executive functioning have been surprisingly difficult to measure.7In fact, many
patients with early bvFTD perform within the normal range on traditional “frontal-executive” tests
measuring working memory, planning, mental flexibility, response inhibition, and concept forma-
tion.8One potential explanation for this lack of sensitivity of traditional tasks of executive control is
insensitive to the medial frontal involvement most affected in early bvFTD.10Recent studies from
From the Memory and Aging Center, UCSF Department of Neurology, San Francisco, CA.
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Casey E.
Krueger, 350 Parnassus Ave.,
Suite 905, San Francisco, CA
Copyright © 2009 by AAN Enterprises, Inc.
cognitive neuroscience suggest that conflict
Conflict monitoring is engaged during de-
cision making when it is necessary to override
prepotent responses or choose from a set of
equally permissible responses.11,12The flanker
test is a widely used conflict monitoring task
that requires subjects to indicate the direction
of a central arrow flanked by arrows pointing
in the same or opposite direction.
in patients with bvFTD who otherwise seemed
cognitively normal. We hypothesized that pa-
tients with bvFTD would show disproportion-
ate impairment on the incongruent trials of the
flanker task as compared with normal controls.
METHODS Subjects. All subjects were evaluated at the Uni-
versity of California, San Francisco Memory and Aging Center
by a team of experienced clinicians, including a behavioral neu-
rologist, a neuropsychologist, and a nurse. Every patient was
evaluated for capacity to consent, and then, once capacity was
assured, each patient signed a consent form to participate in this
research study. Institutional review board approval was received
to conduct this study. A research diagnosis of bvFTD was made
using Neary criteria.19From a larger cohort of patients with
bvFTD (n ? 18), we established a smaller cohort of high-
performing subjects with bvFTD by identifying all those who
scored within normal limits on a set shifting task (modified
Trails).20This search yielded 7 patients with bvFTD, who we
refer to as the high-scoring bvFTD group (bvFTD-high). Each
patient in this group was matched with 1 patient with bvFTD
who was impaired on the set shifting task (bvFTD-low) and 2
controls on the basis of age and sex (see table for demographic
information). The mean Mini-Mental State Examination
(MMSE) score of the bvFTD-high group was 27.9 (SD ? 1.7);
2 subjects had Clinical Dementia Rating (CDR) scores of 0.5,
and 5 subjects had CDR scores of 1.0. The mean MMSE of the
bvFTD-low group was 27.7 (SD ? 1.6); 4 subjects had CDR
scores of 1.0, and 3 subjects had CDR scores of 2.0. Age, educa-
tion, and sex did not significantly differ among the 3 diagnostic
groups. In addition to set shifting (modified Trails B: comple-
tion time), subjects were also administered other measures of
executive functioning, including verbal fluency (d-word genera-
tion: number correctly generated in 1 minute), response inhibi-
tion (Stroop Interference Test: total number correct), and
working memory (Digit Span Backwards).
Participants were given a computer-administered flanker task
and were asked to indicate the direction of a centrally presented
arrow as quickly and accurately as possible. The central arrow was
flanked on both sides by 2 arrows pointing in either the same direc-
400 to 1,600 ms. The fixation period was followed by a 100-ms
ulus (target arrow and flankers) appeared 1.06° above or below the
fixation point (figure 1). Subjects were given up to 3 practice set
trials of 16 (proceeding immediately to the test if they responded
correctly to 12 of the 16 trials and proceeding to the next practice
participants were administered 128 experimental trials (64 with a
200-ms cue-to-stimulus interval and then 64 with a 600-ms cue-to-
stimulus interval). The stimuli were presented until the subject
pressed a key (with a maximum exposure of 4 seconds). The inter-
stimulus interval was a random amount of time and varied between
1 and 3 seconds. Accuracy (percent correct) and reaction time were
measured for each trial.
MR image acquisition. MRI scans were acquired on a 1.5-T
Magnetom VISION system (Siemens Inc., Iselin, NJ) using a
standard quadrature head coil. Volumetric magnetization-
prepared rapid gradient echo (MP-RAGE) MRI (repetition
time/echo time/inversion time ? 10/4/300 ms) to obtain T1-
weighted structural images of the entire brain. The T1 images
were in a coronal orientation, with a 15° flip angle, 1.0 ? 1.0-
mm2in-plane resolution, and 1.5-mm slab thickness.
Image analysis. The T1 MP-RAGE structural magnetic reso-
nance (MR) images were analyzed using Freesurfer, which is
documented and freely available for download online (http://
surfer.nmr.mgh.harvard.edu/). Previous publications have de-
tailed and validated the software.21-24Freesurfer is a surface-based
structural MRI analysis tool that segments white matter and tes-
Table Demographic information and performance of subjects on
59.4 (5.7)59.3 (6.8)66.4 (8.7)
16.1 (2.0) 17.4 (1.0)17.4 (2.8)
27.9 (1.7)* 27.7 (1.6)*29.5 (0.7)
14.3 (7.4)11.3 (8.8) 17.4 (3.3)
43.4 (13.0)28.4 (8.2)*50.7 (9.1)
Digit Span Backwards
5.1 (1.1)4.4 (0.8)5.4 (1.1)
36.3 (17.6)61.6 (27.5)* 28.6 (11.5)
Flanker: Accuracy, %–Congruent
95.1 (7.9) 95.5 (3.0)‡99.4 (0.8)
Flanker: Accuracy, %–Incongruent
90.4 (12.2)*84.4 (17.9)†98.3 (1.8)
Flanker: Reaction time, ms–Congruent
759.1 (106.7)879.0 (165.1)† 678.2 (88.1)
Flanker: Reaction time, ms–Incongruent
978.7 (177.2)†1,094.3 (239.2)† 787.5 (103.8)
Standard deviations in parentheses.
*Differs from controls at p ? 0.05.
†Differs from controls at p ? 0.01.
‡Differs from controls at p ? 0.001.
bvFTD ? behavioral variant frontotemporal dementia; MMSE ? Mini-Mental State Exami-
nation; CDR ? Clinical Dementia Rating.
Figure 1Incongruent trial on flanker task
Illustration of an incongruent trial above the fixation point
on the flanker task.
Neurology 73August 4, 2009
sellates both grey and white matter surfaces. The procedure, in
brief, involves the removal of nonbrain tissue using a hybrid
watershed/surface deformation procedure21and intensity nor-
malization,25followed by automated Talairach transformation
and volumetric segmentation of cortical and subcortical gray and
white matter, subcortical limbic structures, basal ganglia and
ventricles, used to calculate total intracranial volume.26The sur-
facing algorithm uses intensity and continuity data, and corrects
topological defects to generate a continuous cortical ribbon used
to calculate gray matter volume and thickness,21,24a procedure
validated against histologic analysis27and manual measure-
ments.28This cortical surface is then inflated and registered to a
spherical atlas and parcellated into regions of interest based on
gyral and sulcal structure.23,29,30The current study examined the
orbitofrontal cortex and middle frontal gyrus cortical regions of
interest delineated by Desikan et al.30
Our study used the LONI Pipeline environment31(http://
pipeline.loni.ucla.edu), which was developed by LONI and used
to distribute Freesurfer processing tasks to an off-site central pro-
cessing unit cluster located at the UCLA- LONI.
Statistical analysis. Independentsamplesttestswereconducted
to examine group differences between bvFTD-high patients and
controls on measures of executive functioning (lexical fluency, re-
sponse inhibition, working memory, set shifting). An analysis of
variance (ANOVA) was used to examine differences between
bvFTD-high patients, bvFTD-low patients, and controls on tradi-
tional measures of executive functioning. Flanker accuracy and me-
covariance (MANCOVA) with diagnosis as the between-subjects
factor and condition (congruent vs incongruent) as the within-
subject factor. Although there were no group differences in age, the
included as covariates. These analyses were first completed in
bvFTD-high patients and controls to explore whether group differ-
ences existed early in the disease. Analyses were then conducted be-
tween bvFTD-low patients and controls to examine group
differences in more functionally impaired patients. bvFTD-high
and bvFTD-low patients were compared as well. Orbitofrontal cor-
tex and middle frontal gyrus volumes were analyzed with a
MANCOVA with diagnosis as the between-subjects factor and
brain region as the within-subject factor. Total intercranial volume
was included as a covariate.
RESULTS Neuropsychological functioning. Perfor-
mance on clinical neuropsychological tasks was first
compared using independent sample t tests to deter-
mine whether there was a significant difference in
performance between bvFTD-high patients and nor-
mal controls (table). There were no significant differ-
ences between the 2 groups’ performance on any of the
measures (verbal fluency, response inhibition, working
memory, and set shifting). ANOVA showed that
bvFTD-low patients differed from bvFTD-high pa-
tients and controls on set shifting and response inhibi-
tion tasks and performed comparably to the other
cohorts on verbal fluency and working memory tasks.
The MANCOVA for accuracy on the flanker in
bvFTD-high patients and controls yielded an insig-
nificant main effect for diagnosis and condition. The
diagnosis by condition interaction was also not sig-
nificant. The MANCOVA for accuracy on the
flanker in bvFTD-low patients and controls yielded
an insignificant main effect for condition and a sig-
nificant main effect for diagnosis [F(1,15) ? 9.5].
The diagnosis by condition interaction was signifi-
cant [F(1,15) ? 6.8], with bvFTD-low patients
showing a larger congruency effect than normal con-
trols (figure 2). Post hoc t tests revealed that bvFTD-
low patients performed less accurately than normal
controls on congruent (t ? 4.6, p ? 0.001) and in-
congruent (t ? 3.0, p ? 0.01) flanker trials.
No subject had a total accuracy rate less than 74%,
so all subjects were included in the reaction time analy-
ses. Main effects for diagnosis (bvFTD-high and con-
trols) and condition were not significant. However,
there was a significant diagnosis-by-condition interac-
tion on reaction time [F(1,17) ? 5.6], with bvFTD-
high patients showing a larger congruency effect than
normal controls (figure 3). Post hoc t tests revealed no
significant difference in reaction time between bvFTD-
Figure 2 Condition by diagnosis interaction
effect for accuracy
A condition by diagnosis interaction effect was found, dem-
onstrating that patients with behavioral variant frontotem-
poral dementia (FTD) showed a larger congruency effect on
accuracy than normal controls.
Figure 3Condition by diagnosis interaction
effect for reaction time
A condition by diagnosis interaction effect was found, dem-
onstrating that patients with behavioral variant frontotem-
poral dementia (FTD) showed a larger congruency effect on
reaction time than normal controls.
Neurology 73 August 4, 2009
high patients and normal controls on congruent trials,
but bvFTD-high patients had slower reaction times
than controls during incongruent flanker trials (t ?
?3.1, p ? 0.01). Normal controls showed a 16% in-
crease in reaction time on incongruent trials, whereas
bvFTD-high patients showed a 30% increase, almost
twice that of controls. The MANCOVA for reaction
yielded an insignificant main effect for condition, and a
significant main effect for diagnosis [F(1,15) ? 12.0].
The diagnosis by condition interaction was also signifi-
cant [F(1,15) ? 8.1], with bvFTD-low patients show-
ing a larger congruency effect than normal controls
(figure 3). Post hoc t tests revealed that bvFTD-low pa-
tients had slower reaction times than normal controls
on congruent (t ? ?3.7, p ? 0.01) and incongruent
(t ? ?4.2, p ? 0.01) flanker trials. bvFTD-low pa-
gruent trials as compared with congruent trials.
Of note, there were no significant differences be-
tween bvFTD-high and bvFTD-low patients on any
flanker accuracy or reaction time measures. Even
though bvFTD-high patients performed within nor-
mal limits on traditional neuropsychological mea-
sures, these patients displayed the same congruency
effect as neuropsychologically impaired bvFTD-low
patients when compared with normal controls.
Scatter plots depicting the individual scores of
bvFTD-high patients, bvFTD-low patients, and nor-
mal controls on the flanker tasks revealed a large degree
of overlap between the data, but the bvFTD groups
displayed more variability as compared with controls
(figure 4). This suggests that the flanker test may have
fairly high specificity but very low sensitivity for diag-
useful in diagnosing individual patients.
Imaging. The MANCOVA for region of interest brain
volumes in bvFTD-high patients and controls yielded
icant main effect for diagnosis [F(1,13) ? 5.5]. The
diagnosis by brain region interaction was not signifi-
cant. Post hoc t tests revealed a trend for differences in
middle frontal gyrus volumes and a significant differ-
high patients had significantly smaller orbitofrontal
cortex volumes (20.01 cm3) as compared with controls
(23.75 cm3). bvFTD-high patients showed somewhat
smaller middle frontal gyrus volumes (37.13 cm3) as
compared with controls (42.23 cm3).
Figure 4 Scatter plots of individual scores on flanker tasks
large degree of overlap among the 3 groups, but the behavioral variant frontotemporal dementia (FTD) groups displayed
greater variability in performance as compared with controls.
Neurology 73 August 4, 2009
DISCUSSION The main finding of this study is that
patients with very mild bvFTD who performed
within normal limits on clinical tests of executive
functioning demonstrated selective impairment in
conflict monitoring. On a flanker task, we found that
while bvFTD-high and controls responded with
comparable accuracy and speed on congruent trials,
reaction time data showed an interaction between
diagnosis and condition, whereby bvFTD-high
patients showed a larger congruency effect (i.e., dis-
proportionate slowing on incongruent trials) than
normal controls. These results demonstrate that
bvFTD is associated with deficits in executive cogni-
tive control, even very early in the disease when stan-
dard clinical neuropsychological test scores are
within normal limits. bvFTD-low patients also dis-
played a larger congruency effect than normal con-
trols, suggesting that selective impairment in conflict
monitoring continues as functional impairments
progress. Although the flanker test yielded group-
wise differences, it does not seem that this test can be
used for diagnosis in individual patients.
Research has proposed that the medial frontal lobes
tion processing.32A study examining the flanker inter-
ference effect as a function of the entire reaction time
(MCI) as compared with normal controls found evi-
dence that inefficient inhibition, rather than greater ac-
tivation of the response induced by incongruent
flankers, accounted for the enhanced interference effect
in MCI patients.33Accordingly, the greater interference
effect found in patients with bvFTD as compared with
normal controls is likely a function of inefficient re-
sponse inhibition. Patients with early bvFTD may have
subtle impairments in inhibiting their attention or re-
sponse to irrelevant stimuli.
Functional imaging studies have demonstrated the
role of the medial frontal circuits in response inhibition
during the flanker task.11-13,17Patients with diseases as-
sociated with impairment in these brain regions (e.g.,
Parkinson disease, MCI, attention-deficit hyperactivity
pared with healthy controls.33-37The strong activation
of medial frontal lobes, and specifically the rostral ante-
rior cingulate, during response conflict trials of the
flanker task in neurologic healthy controls suggests that
the observed findings of impairment in conflict moni-
toring in patients with bvFTD as compared with nor-
mal controls in the current study are a result of
dysfunction in this brain area and related anterior cin-
gulate circuit. Research has illustrated the intrinsic cor-
ticocortical connections within the orbital and medial
prefrontal cortex.38Imaging results in the current study
revealed significant orbitofrontal cortex atrophy in
bvFTD-high patients as compared with controls. More
lateral areas of the frontal lobes (middle frontal gyrus)
were not as profoundly affected. The orbitofrontal cor-
substrate for the observed suppression difficulties evi-
denced in patients with bvFTD.39
Patients with bvFTD and normal controls dif-
fered on an experimental cognitive measure of execu-
tive control but did not deviate on widely used
clinical measures of executive functioning. These re-
sults highlight the issue of task sensitivity in detect-
ing executive cognitive control deficits in patients
with bvFTD. Reaction time tasks may be more sensi-
tive to these deficits than standard clinical measures.
Current models of prefrontal function posit a disso-
ciation between ventromedial or orbitofrontal areas
that mediate behavioral control, and dorsolateral
structures that are more heavily involved in cogni-
tion. Clinical neuropsychological tests of executive
functioning sensitive to lateral prefrontal function
may fail to test the distinct and separate functions of
the areas of the prefrontal cortex that are predomi-
nantly affected in bvFTD.
One limitation to this study is the relatively small
sample size; however, the sample size was comparable
to other studies of this type, and statistically signifi-
cant differences were found indicating fairly large ef-
fect sizes. In addition, although not a significant
difference, controls were slightly older than subjects
with bvFTD. Nevertheless, one might expect that
the increased age in the controls would be associated
with greater likelihood of neuropsychological defi-
cits, if it had any effect at all.
Despite being a fairly common presenile neurode-
generative disease, bvFTD continues to be underdiag-
nosed and misdiagnosed.40Early and accurate diagnosis
remains essential to treat symptoms correctly and to
help patients and families plan for the future. Identify-
ing patients in the earliest stages of the disease not only
allows for effective patient management, but also may
interventions. Measures of neuropsychological func-
tioning sensitive to the ventromedial prefrontal cortex
may be useful in early diagnosis of patients with
bvFTD. Future research examining the efficiency of se-
lective inhibition, a fundamental component of execu-
tive cognitive control, may increase our understanding
of this syndrome.
Dr. Krueger conducted the statistical analysis.
Dr. Krueger reports no disclosures. Ms. Bird receives royalties from pub-
lishing Personality Disorders in Psychology: Contemporary Theory, Research,
and Issues, Lawrence Erlbaum, 2004. Mr. Growdon reports no disclo-
sures. Ms. Jang reports no disclosures. Dr. Miller serves on the speakers’
Neurology 73August 4, 2009
bureaus of Pfizer and Novartis Pharmaceuticals and is funded by NIH
grants 01-154-20 and P50-AG05142. Dr. Kramer is funded by NIH
grants AG22983 and HHSN-271200623661C. This study utilized the
LONI Pipeline environment, which was partially funded by NIH grants
P41 RR013642, R01 MH71940, and U54 RR021813.
Received January 13, 2009. Accepted in final form April 21, 2009.
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Editor’s Note to Authors and Readers: Levels of Evidence coming to Neurology®
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1. French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology 2008;71:1634–1638.
2. Gronseth G, French J. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology
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