Departments of 1Psychiatry, 2Diagnostic Imaging and Therapeutics, 3Neurology, and 4Program in Functional NeuroImaging, University of Connecticut Health Center, Farmington, Connecticut 06030-2017
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ABSTRACT |
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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.
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INTRODUCTION |
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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, 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 event-related 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.
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METHODS |
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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 presentation 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.
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RESULTS |
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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 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).
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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.
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DISCUSSION |
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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
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 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 occipital-temporal 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
).
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 populations 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
occipital-temporal 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 include the processing of behaviorally
relevant nonaversive stimuli as well.
Clinical applications of fMRI studies using the three-stimulus oddball task
The task used here was based on that used by Bauer (1997) for
patients recovering from cocaine dependency. Bauer's study found that
the P3b component evoked by the target stimulus was significantly smaller shortly after the cessation of cocaine use and that it then
returned to normal after two months of abstinence. One possible explanation for this finding is that there is an overlap between brain
regions found to respond to the target stimulus in the present study
and those that were found to bind cocaine (Telang et al. 1999
). These regions include the thalamus, cingulate gyri,
insulae, calcarine cortex, precentral gyrus, lateral frontal cortex,
and cerebellum. These regions could experience the residual
effects of cocaine use that reduce P3b amplitude, only to normalize
during sustained abstinence. Bauer also showed that the amplitude of the P3a component evoked by the rare distractor stimulus identified 71% of the cocaine-dependent individuals who later relapsed to cocaine
use. This P3a amplitude reduction predicted relapse with a higher
degree of accuracy than any other variable tested in the study. The
present findings suggest that this effect may involve the medial and
inferior prefrontal cortices and/or the posterior regions found in the
present study.
Because a variety of cognitive processes are required for the
oddball task to be accurately performed, it has proven to be useful in
assessing neural and cognitive function in patients with CNS disease.
The present results show that in healthy subjects a variety of brain
regions respond to target and distractor stimuli in this task.
Obtaining similar fMRI data from clinical populations could be useful
for the diagnosis of CNS disease, especially in its early stages.
Cognitive deficits resulting from CNS illnesses might be associated
with different neurophysiological responses in the brain regions that
support these cognitive processes. Obtaining fMRI data may also prove
useful in identifying patient subgroups, such as was accomplished
previously using P300 ERPs in cocaine dependence (Bauer
1997) and schizophrenia (Turetsky et al. 1998
). Using fMRI would allow such subgroups to be identified with greater anatomic precision. Such information would be useful for evaluating the
effectiveness of different treatment methods among patient subgroups
identified in this manner.
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ACKNOWLEDGMENTS |
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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.
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FOOTNOTES |
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Address for reprint requests: V. P. Clark, Dept. of Psychiatry, MC2017, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06032.
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 (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.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 August 1999; accepted in final form 11 January 2000.
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REFERENCES |
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