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Responses to Rare Visual Target and Distractor Stimuli Using
Event-Related fMRI
VINCENT P. CLARK,1,4 SEAN FANNON,4 SONG LAI,2,4 RANDALL BENSON,3,4 AND LANCE BAUER1
Departments of 1Psychiatry, 2Diagnostic Imaging and Therapeutics, 3Neurology, and 4Program in Functional NeuroImaging,
University of Connecticut Health Center, Farmington, Connecticut 06030-2017
INTRODUCTION
The process of visual target detection in the presence of
interleaved distractor stimuli generates event-related potential
(ERP) components that have been found to be clinically useful
in the diagnosis and treatment of Alzheimer’s disease, schizophrenia, depression, closed head injury, and drug dependence,
among many other CNS disorders (Bauer 1997; Polich 1999).
Rare distractor stimuli that evoke the frontal P300 or P3a
subcomponent have proven especially useful in the study of
disorders thought to involve prefrontal and limbic cortex dysfunction (Bauer 1997; Knight and Nakada 1998). Although the
exact cause of the P3 component latency and amplitude differences found in these clinical populations is not fully understood, it is thought to involve deficits in arousal, attention,
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stimulus processing speed, and/or the memory operations required to perform these tasks (Polich and Kok 1995). Functional magnetic resonance imaging (fMRI) could provide an
improved measure of the specific neural fields that may be
involved in this response by virtue of the greater anatomic
specificity of fMRI when compared with ERPs. This in turn
would assist in the interpretation of these ERP effects in
clinical populations and may offer additional information useful for the diagnosis and treatment of CNS disorders.
Previous ERP studies suggested that the oddball task involves multiple neural fields that support the cognitive processes necessary for its performance. These include occipital,
temporal, parietal, frontal, thalamic, cerebellar, and limbic
regions that respond to rare target stimuli, and dorsolateral
prefrontal, medial prefrontal, parietal, and posterior hippocampal regions that respond to rare distractor stimuli (Baudena et
al. 1995; Courchesne et al. 1995; Halgren et al. 1998; Polich
and Kok 1995; Swick and Knight 1998). In contrast, previous
fMRI studies using similar stimuli found target-evoked activity
in a less extensive range of brain regions (McCarthy et al.
1997; Menon et al. 1997; Opitz et al. 1999) and few regions
that were identified for rare distractor stimuli (Kirino et al.
1997; Knight and Nakada 1998). This suggests that some
portion of the neural activity evoked by these stimuli is not
observed using fMRI.
In a previous study (Clark et al. 1998), we introduced a
method for performing event-related fMRI using multiple regression, which has shown greater sensitivity to task-related
signal change than other methods. In an effort to identify
additional target- and distractor-evoked activity using eventrelated fMRI, this method was adapted here to identify brain
regions that respond to a three-stimulus visual oddball task
based on Bauer (1997). Importantly, we hypothesized repetition-related changes in response amplitude such as might occur
with habituation or changes in response strategy, and which
were previously reported for the P300 ERP response (Knight
1984; Knight and Scabini 1998, Ravden and Polich 1998).
Using these methods, target- and distractor-evoked activity
was found in a wide range of brain regions.
METHODS
Stimuli were frequent standard (the letter “T,” P ⫽ 0.82), rare
distractor (the letter “C,” P ⫽ 0.09), and rare target (the letter “X,”
P ⫽ 0.09) single block-letter stimuli presented sequentially in pseudorandom order for 200 ms each with the interstimulus interval (ISI)
varied randomly from 550 to 2050 ms across trials. Subjects were
instructed to make a speeded button-press response upon each pre-
0022-3077/00 $5.00 Copyright © 2000 The American Physiological Society
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Clark, Vincent P., Sean Fannon, Song Lai, Randall Benson, and
Lance Bauer. Responses to rare visual target and distractor stimuli
using event-related fMRI. J. Neurophysiol. 83: 3133–3139, 2000.
Previous studies have found that the P300 or P3 event-related potential (ERP) component is useful in the diagnosis and treatment of many
disorders that influence CNS function. However, the anatomic locations of brain regions involved in this response are not precisely
known. In the present event-related functional magnetic resonance
imaging (fMRI) study, methods of stimulus presentation, data acquisition, and data analysis were optimized for the detection of brain
activity in response to stimuli presented in the three-stimulus oddball
task. This paradigm involves the interleaved, pseudorandom presentation of single block-letter target and distractor stimuli that previously were found to generate the P3b and P3a ERP subcomponents,
respectively, and frequent standard stimuli. Target stimuli evoked
fMRI signal increases in multiple brain regions including the thalamus, the bilateral cerebellum, and the occipital-temporal cortex as
well as bilateral superior, medial, inferior frontal, inferior parietal,
superior temporal, precentral, postcentral, cingulate, insular, left middle temporal, and right middle frontal gyri. Distractor stimuli evoked
an fMRI signal change bilaterally in inferior anterior cingulate, medial
frontal, inferior frontal, and right superior frontal gyri, with additional
activity in bilateral inferior parietal lobules, lateral cerebellar hemispheres and vermis, and left fusiform, middle occipital, and superior
temporal gyri. Significant variation in the amplitude and polarity of
distractor-evoked activity was observed across stimulus repetitions.
No overlap was observed between target- and distractor-evoked activity. These event-related fMRI results shed light on the anatomy of
responses to target and distractor stimuli that have proven useful in
many ERP studies of healthy and clinically impaired populations.
V. P. CLARK, S. FANNON, S. LAI, R. BENSON, AND L. BAUER
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FMRI
TABLE
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STUDY OF THREE-STIMULUS ODDBALL TASK
1. Areas with significant main effect of stimulus presentation
ROI Center (Brodmann Area)
Standard stimulus
Right superior temporal gyrus (38)
Cerebellum
Anterior cingulum (24)
Left middle occipital gyrus (18)
Target stimulus
Thalamus
Medial lingual gyrus (18)
Left fusiform gyrus (19, 37)
Right fusiform gyrus (19, 37)
Left superior temporal gyrus (22)
Left postcentral gyrus (1, 2, 3, 40)
Right inferior parietal lobule (7, 40)
Medial frontal gyrus (32, 6)
Left insula (13)
Left inferior frontal gyrus (9)
Right precentral gyrus (44)
Cuneus (17, 18)
Cerebellum, lingual gyrus (18), middle
occipital gyrus (18, 19, 37)
Cerebellum, middle occipital gyrus (18, 19, 37)
Inferior parietal lobule (40), middle temporal
gyrus (21), supramarginal gyrus (40)
Inferior parietal lobule (40)
Superior temporal gyrus (22), postcentral gyrus
(1, 2, 3, 5), supramarginal gyrus (40)
Inferior frontal gyrus (9), precentral gyrus (4,
6, 9)
Cingulate gyrus (24, 32), superior frontal gyrus
(6, 8)
Precentral gyrus (13, 44, 6), inferior frontal
gyrus (45, 47)
Inferior frontal gyrus (45, 47)
Volume
(cc)
Coordinates
(x,y,z)
1.12
1.42
1.03
1.54
34,20,⫺28
⫺18,⫺85,⫺44
⫺3,33,5
⫺36,⫺88,0
2.26
2.30
13.2
⫺1,⫺12,11
⫺1,⫺76,2
⫺38,⫺60,⫺16
5.68
3.60
15.5
13.4
6.34
14.2
29,⫺52,⫺14
⫺61,⫺45,21
⫺47,⫺24,53
48,⫺39,38
32,0,56
⫺3,10,46
4.71
⫺45,11,5
1.44
6.47
⫺64,19,15
44,17,6
ROI, region of interest.
sentation of the target letter. Subjects were further requested to maintain gaze. Direction of gaze was not monitored. The distractor letter
had the same presentation frequency as the target letter, but no
response was required. Each run was comprised of 90 stimuli. A
minimum of eight runs was acquired per subject. Stimulus sequence
development is described in detail in Clark et al. (1998). Briefly, a
large number of random stimulus sequences were generated. Sequences with a low correlation of predicted blood oxygen level–
dependent (BOLD) responses among the three stimulus types (¦r¦ ⬍
0.2) were used. This allowed the BOLD response evoked by each
stimulus type to be tested separately using multiple regression.
Six healthy right-handed volunteers (2 females, 4 males; mean age
32 yr, range 21– 44 yr) participated in this study. A gradient echo,
echo planar scanning sequence was used [single-shot, 20 oblique
slices 6-mm thick, no skip, repetition time (TR) ⫽ 2150 ms, echo time
(TE) ⫽ 40 ms, flip angle ⫽ 90°, field of view ⫽ 25.6 cm, matrix ⫽
64 ⫻ 64] on a 1.5 Tesla Vision magnetic resonance imaging (MRI)
scanner (Siemens, Erlangen, Germany). High-resolution three-dimensional inversion recovery MPRAGE volumes were also acquired in
the same orientation and field of view.
Movement correction and spatial normalization were performed
using SPM96b (Friston et al. 1995). A modified version of the
Talairach coordinate system (Talairach and Tournoux 1988) was used.
The significance of stimulus-evoked changes in MRI signal intensity
was evaluated using multiple regression (Haxby et al., in press). This
analysis was identical to that used in Clark et al. (1998) except that
regions of interest (ROIs) from group-averaged data were located by
identifying clusters of 10 or more contiguous voxels significant at P ⬍
0.001 (Friston et al. 1994). Additional analyses to detect the presence
of linear trends in response amplitude over stimulus repetitions were
performed using two additional regressors to test for linear trends. The
analyses were performed at a higher voxel-wise significance threshold
(P ⬍ 0.0001) to compensate for the use of additional comparisons. To
confirm the results of these statistical tests, stimulus onset time-locked
averages (analogous to the ERP) were obtained from detrended fMRI
data and averaged across voxels within individual ROIs.
RESULTS
The mean accuracy for detection of the target stimulus was
95% (reaction time ⫽ 466 ⫾ 110 ms, SD). Less than one false
alarm was made per subject on average. Standard and target
stimuli evoked a significantly increased BOLD signal in a total
FIG. 1. Areas of significant activation of spatially normalized data illustrate the anatomic regions of activity. All images are
displayed according to radiological convention. Numbers indicate positions of slices in the normalized z-axis dimension. The
group-averaged statistical map is superimposed over the high-resolution structural data of 1 representative subject. A: responses to
standard stimuli. ¦Z¦ ⬎ 3.09; region of interest (ROI), P ⬍ 0.005. B: response to target stimuli plotted as in A. C: regions with
significant trend in distractor response amplitude across successive distractor repetitions. ¦Z¦ ⬎ 4.0; ROI, P ⬍ 0.005. D: medial
frontal gyrus ROI for successive distractor repetitions. ¦Z¦ ⬎ 4.0; ROI, P ⬍ 0.005. Plotted in sagittal, coronal, and axial orientations.
E: superior frontal gyrus ROI for successive target repetitions plotted as in D.
FIG. 2. A: stimulus time locked averages shown for 5 ROIs from the group-averaged data that responded to the target stimulus.
From top to bottom, the plots were taken from ROIs centered in the thalamus (THAL), left occipitotemporal cortex/cerebellum
(LOTC), left inferior parietal gyrus (LIP), right middle frontal gyrus (RMF), and medial frontal/cingulate gyri (MFC). Amplitude
of percentage change relative to 6.45 s prestimulus baseline is shown. B: target stimulus time locked averages obtained from each
of the 6 subjects (S1–S6) plotted in red to purple for the same five ROIs shown in A. C: plots depicting changes in group mean
blood oxygen level– dependent signal intensity as a function of repeated stimulus presentations for the medial frontal gyrus ROI
shown in Fig. 1D. Values represent the peak percentage change of signal intensity from baseline per stimulus presentation.
Responses to distractor and target stimuli are shown in red and blue, respectively. D: plotted as in C for the ROI illustrated in
Fig. 1E.
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Right middle frontal gyrus (6, 9)
ROI Range (Brodmann Area)
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V. P. CLARK, S. FANNON, S. LAI, R. BENSON, AND L. BAUER
2. Areas with significant trend in response amplitude
across successive stimulus repetitions
TABLE
ROI Center
(Brodmann Area)
ROI Range
(Brodmann Area)
Volume
(cc)
Coordinates
(x,y,z)
Positive trend
Distractor stimulus
Medial frontal gyrus
(10)
Anterior cingulum (32)
Left inferior frontal
gyrus
Right inferior frontal
gyrus (47)
Right polar superior
frontal gyrus (10)
Left cerebellum
Right cerebellum
Cerebellar vermis
Left anterior fusiform
gyrus (20)
Left middle occipital
gyrus (18)
Left superior temporal
gyrus (22)
Left inferior parietal
lobule (40, 7)
Right inferior parietal
lobule (40, 7)
Target stimulus
Superior frontal gyrus
(32)
Medial frontal gyrus
(11, 12)
ROI, region of interest.
DISCUSSION
With careful attention to techniques of stimulus presentation, data acquisition, and data analysis, BOLD fMRI responses to target and distractor stimuli can be observed in brain
regions that overlap those reported previously using similar
statistical thresholds (Kirino et al. 1997; Knight and Nakada
1998; McCarthy et al. 1997; Opitz et al. 1999) and in additional
regions thought to be involved in the P3 ERP response for
similar stimuli (Baudena et al. 1995; Courchesne et al. 1995;
Halgren et al. 1998; Polich and Kok 1995; Swick and Knight
1998). Importantly, the use of multiple regression analysis in
the present study to examine higher-order BOLD fMRI responses led to the finding of significant distractor-evoked activity in widespread brain regions, including ventral-medial
prefrontal regions previously observed using depth-recorded
ERPs (Baudena et al. 1995) but not using fMRI.
Comparison with P300 ERP studies
3.73
⫺8,47,0
0.14
⫺34,33,⫺16
0.27
27,17,⫺22
0.82
0.58
0.28
0.34
9,70,10
⫺62,40,⫺46
29,⫺71,⫺53
0,⫺60,⫺46
0.15
⫺38,⫺13,⫺26
0.06
⫺47,⫺77,⫺8
0.10
⫺69,⫺39,16
0.15
⫺27,⫺63,31
0.26
24,⫺50,20
0.70
⫺16,52,⫺13
0.14
5,58,⫺16
Negative trend
Distractor stimulus
Right fusiform gyrus
(37)
Averaged BOLD time series showed that response amplitudes differed between stimulus types in a manner consistent
with the statistical analyses (Fig. 2A). The consistency of the
target response was examined across subjects (Fig. 2B), which
revealed activity for all subjects in all regions except the left
inferior frontal gyrus ROI, where two of the six subjects did
not show a response. A reversal from a negative response
evoked by the first stimulus in each run to a positive response
evoked near the end of the run was observed for ROIs with
significant positive trends (Fig. 2, C and D). The significant
linear trend in response amplitude across repetitions was found
to be stimulus specific within each ROI, showing that this
effect is not caused by nonspecific changes in response amplitude or baseline shift.
0.09
47,⫺33,⫺10
The presentation of rare target and nontarget distractor stimuli evokes a class of ERP components, collectively termed the
P300 or P3 component, that have been well studied since their
discovery (Sutton et al. 1965). Indeed, over 1,500 manuscripts
included in the Medline database since that time make specific
reference to this component in either their titles or abstracts.
The importance of this phenomenon is further illustrated by its
application in a wide range of clinical ERP studies, including
most CNS disorders (Polich 1999).
The P300 can be divided into at least two major subcomponents, the P3a and the P3b. The P3b is evoked by the presentation of target stimuli, to which subjects make a motor response or perform a mental instruction such as counting. This
component is largest near the temporal-parietal junction and is
thought to index the attention- and memory-related operations
involved in stimulus processing. The infrequent presentation of
distractor stimuli that interrupt the performance of the primary
task produces an earlier positive potential (the P3a) that is
largest over frontal and central scalp regions and that habituates rapidly (Comerchero and Polich 1998).1 This is believed
1
Various types of distractor stimuli were used in previous P300 ERP studies.
These may be differentiated depending on whether the distractor stimuli are
“novel” and differ categorically from the standard and target stimuli or,
instead, if they fall into the same stimulus category as the other stimuli, as in
the present study. Distractor stimuli may also be differentiated based on
whether individual instances of specific distractor stimuli are presented only
once or whether the same distractor stimulus is presented multiple times
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of 5 and 89 ml of brain tissue, respectively (Fig. 1, A and B;
Table 1). Target stimuli generated activity near the regions
identified in previous fMRI studies (McCarthy et al. 1997;
Menon et al. 1997; Opitz et al. 1999), including the thalamus,
bilateral inferior parietal lobules, cingulate, and right middle
frontal gyri. Additional activity was observed bilaterally in the
cerebellum; the middle occipital, lingual, and fusiform gyri; the
medial occipital cortex; the bilateral precentral, postcentral,
insular, medial frontal, polar superior frontal, and inferior
frontal gyri; and the left middle temporal gyrus. The larger
volume of target-evoked activity observed in the present study
compared with these previous studies may be caused by the
faster stimulus presentation rate, the larger imaging volume,
and the use of multiple regression as employed here; the
significance of target-evoked activity was not reduced by the
use of fewer subjects. No regions of significantly decreased
BOLD signal were observed, which is in agreement with
previous fMRI studies using the oddball task (McCarthy et al.
1997). No significant response was observed for the main
effect of distractor presentation. Instead, a significant positive
trend in signal intensity across distractor repetitions was found
in a total of 7 ml of tissue, with the largest volume of significant response located in the prefrontal cortex (Fig. 1, C and D;
Table 2). A smaller volume (0.84 ml) was observed for target
repetitions in the medial prefrontal cortex (Fig. 1E).
FMRI
STUDY OF THREE-STIMULUS ODDBALL TASK
Relationship between cognitive processes and associated
neural activity
Although the three-stimulus oddball task used here is relatively simple in design, many cognitive operations are required
for its accurate performance, including response inhibition,
preparation and execution, vigilance (or sustained attention),
object recognition, working memory, and long-term memory
(Polich and Kok 1995). Self-monitoring of response accuracy
and changes in mood and arousal (including the orienting
response) would also be expected to occur. Because most
perceptual and cognitive processes are neurally mediated by
multiple brain regions rather than by a single area (Posner and
Raichle 1993), the performance of this task in healthy popu(Knight 1984). Differences in the topography and latency of the P3 subcomponent evoked by these various types of distractor stimuli (Polich 1999) using
different sensory modalities (Swick and Knight 1998) have been observed.
However, most distractor stimuli have been found to generate a P3 subcomponent that peaks earlier and is situated more anteriorly than the target-evoked
P3b and that is generally referred to as the P3a subcomponent.
lations would be expected to generate activity within a diverse
set of brain regions that support these many cognitive operations.
Although the exact correspondence between the cognitive
operations required to perform this task and the specific brain
regions involved is beyond the scope of the present study, it
would generally be expected that response preparation and
execution would involve the somato-motor cortex and that
vigilance, response inhibition, and working memory would
involve the frontal and parietal cortices. Activity was observed
within these regions as expected. Additionally, the analysis of
letter identity would be expected to occur in the occipitaltemporal cortex for all stimulus types. The only region found to
have overlapping activity for the main effect of standard and
target stimulus presentation, as well as an adjacent linear trend
for distractor stimuli, was observed in the left middle occipital
gyrus (see slices located at z ⫽ 0 mm in Fig. 1, A, B, and D),
which is near regions observed in other studies using block
letter stimuli (Puce et al. 1996). However, no individual voxels
showed overlap among the three stimulus types at the statistical
thresholds used here, suggesting that once the target identification stage is completed, the neural and cognitive processes
invoked in response to this information diverge significantly.
This also indicates that neither stimulus frequency nor stimulus
response requirements alone can account for these results as
both distractor and target stimuli were presented with equal
frequency and both the distractor and standard stimuli did not
require a response. Instead, it is the combination of stimulus
frequency and task demands that determines which brain regions respond to these stimuli.
Interpretation of the present results can also be assisted by
making comparisons with the results of previous brain imaging
studies for anatomic similarity. For instance, distractor-evoked
activity was observed in medial prefrontal, inferior parietal,
and cerebellar regions in the present study; altered activity in
these regions was also observed in depressed patients (Bench et
al. 1992; Dolan et al. 1992; Mayberg et al. 1999) and in
patients experiencing induced sadness (George et al. 1995;
Mayberg et al. 1999). This suggests that the neural fields that
respond to distractor stimuli may be associated with variations
in mood related to the three-stimulus oddball task or with
cognitive processes that are shared by both changes in mood
and the detection of rare distractor stimuli. These medial and
inferior-lateral prefrontal regions are also near orbitofrontal
areas found to be involved in decision making (Bechara et al.
1998).
The anterior brain regions (anterior cingulate and insulae)
that responded to the target stimulus in the present study
overlap with regions consistently found in studies of pain
perception and aversive conditioning (Buchel et al. 1998;
Rainville et al. 1997). The anterior cingulate is involved in
attention, motivation, and behavioral regulation (Devinsky et
al. 1995). This region has reciprocal connections with the
anterior insula, which is involved in processing emotionally
relevant contexts (Fink et al. 1996), among other functions.
This network has been hypothesized to provide a mechanism
through which nociceptive inputs are integrated with memory
to allow appropriate responses to stimuli that predict future
adversities (Buchel et al. 1998). The present results suggest
that this combination of activity may not be uniquely specialized for the processing of aversive stimuli, but that it may
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to reflect an alerting or orienting response that may originate in
frontal cortex.
Finding distractor-evoked activity in a large portion of the
prefrontal cortex remained elusive in previous fMRI studies
but agrees with previous ERP findings of medial and inferior
lateral prefrontal activity that is evoked by rare distractor
stimuli (Baudena et al. 1995) and eliminated by lesions of the
prefrontal cortex (Knight 1984). The present results support the
hypothesis that distractor stimuli evoke activity in prefrontal
cortical regions and further indicate that additional brain regions are involved, including the medial and lateral cerebellum, bilateral inferior parietal lobules, and the left occipitaltemporal cortex. This suggests the possibility that reductions in
P3a amplitude observed in patients with CNS disease might be
caused by the dysfunction of brain regions outside the prefrontal and limbic cortices.
A significant linear trend was observed in the amplitude of
distractor-evoked activity, which reversed from negative to
positive on average (relative to the prestimulus baseline) during the course of each experimental run. This finding may be
caused by habituation of the neural response across stimulus
repetitions, as was described for the amygdala (Breiter et al.
1996; Buchel et al. 1998). However, this is in contrast to
typical ERP findings where the P3a component evoked by
similar distractor stimuli begins with a large positive amplitude
that diminishes toward zero over repeated stimulus presentations (Comerchero and Polich 1998). This discrepancy may be
caused by differences between the mechanisms of ERP and
BOLD fMRI signal generation, which have yet to be fully
described, or by neural activity that might possibly be recorded
using fMRI but is not observed in the typical ERP, such as
event-related desynchronization (Pfurtscheller and da Silva
1999). Such differences could lead to the sampling of activity
generated by different neural fields, thus resulting in a different
pattern of response. This finding could also reflect an alteration
in response strategy with repeated stimulus presentations, resulting in a concomitant change in metabolic demand. In
general, the present results point to the importance of examining higher-order response characteristics in neurophysiological
data (Friston et al. 1998).
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V. P. CLARK, S. FANNON, S. LAI, R. BENSON, AND L. BAUER
include the processing of behaviorally relevant nonaversive
stimuli as well.
Clinical applications of fMRI studies using the threestimulus oddball task
We are very grateful to J. Lackey, T. Wojtusik, Drs. S. Luck, J. Polich, J.
Townsend, D. Swick, and J. Nuetzel, and to the staff of the Dept. of Diagnostic
Imaging and Therapeutics at the University of Connecticut Health Center for
their assistance.
Address for reprint requests: V. P. Clark, Dept. of Psychiatry, MC2017,
University of Connecticut Health Center, 263 Farmington Ave., Farmington,
CT 06032.
Received 4 August 1999; accepted in final form 11 January 2000.
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