The Multi-Source Interference Task: validation study with fMRI in individual subjects

Abstract

Dorsal anterior cingulate cortex (dACC) plays critical roles in cognitive processing, but group-averaging techniques have generally been required to obtain significant dACC activation in functional neuroimaging studies. Development of a task that reliably and robustly activates dACC within individuals is needed to improve imaging studies of neuropsychiatric disorders and localization of dACC in normal volunteers. By combining sources of cognitive interference (Stroop, Eriksen and Simon) with factors known to increase dACC activity, the Multi-Source Interference Task (MSIT) maximally taxes dACC, making it possible to reliably activate dACC within individuals using functional magnetic resonance imaging (fMRI). In this study, eight normal adult volunteers performed the MSIT during fMRI. We compared fMRI responses and performance data between interference and control trials. Significant dACC activation (P<1.7×10−4) was observed in all eight individuals and in the group-averaged fMRI data. In addition to dACC activation, group data also showed activation of presumably networked regions including dorsolateral prefrontal, premotor, and parietal cortices. The MSIT's reaction time interference effect (overall mean 312±61 ms) was up to 10 times greater than that of its component predecessors and temporally stable over hundreds of trials. The robustness, reliability and stability of the neuroimaging and performance data should make the MSIT a useful task with which to study normal human cognition and psychiatric pathophysiology.

Introduction

Abnormalities of different anterior cingulate cortex (ACC) subdivisions have been implicated in the pathophysiology of many neuropsychiatric disorders such as attention deficit/hyperactivity disorder,1,2 depression,3,4,5 schizophrenia,6,7 Alzheimer's disease,8 anxiety disorders,9,10,11 obsessive compulsive disorder12,13 and post-traumatic stress disorder.14,15 However, ACC is not a homogeneous region, and future progress in elucidating the neural substrates of psychiatric disorders will require refined understanding of these cognitive, motor, and emotional cingulate subdivisions. While appreciating the existence of these functional subdivisions can improve psychiatric research efforts, this alone will not be sufficient to push forward to the next levels, such as the development of functional imaging-based diagnostic tests for neuropsychiatric disorders. To accomplish this, we must develop standardized tasks with sufficient power to reliably and robustly activate ACC subdivisions within individual subjects. Cognitive activation paradigms used with functional magnetic resonance imaging (fMRI) to date, however, generally have not produced robust dorsal ACC (dACC) activation in individuals, and instead have had to rely on group-averaging techniques. The present study details the development and validation of the Multi-Source Interference Task (MSIT)—an fMRI task designed to specifically activate and assess the functional integrity of the ACC subdivision in selected neuropsychiatric disorders. The MSIT combines multiple dimensions of cognitive interference (ie Stroop,16 Eriksen,17 and Simon18) with decision-making and other factors known to activate dACC (target detection, novelty detection, error detection, response selection, stimulus/response competition, and task difficulty)19—thereby maximally recruiting dACC neurons and providing a robust fMRI response within this cortical area in individual subjects.

Convergent evidence from anatomical, connectionist, electrophysiological, and functional neuroimaging sources has established that dACC plays critical roles in complex cognitive and motor processing20,21,22,23,24,25 and reward-based decision-making.19 Reviews and meta-analyses have differentiated dACC from other cingulate subdivisions, including perigenual anterior cingulate cortex (pACC), which is involved in emotional processing,3,10,21,26,27,28,29,30 and the caudal cingulate motor area (cCMA), which assists with simple motor movements.22,29,31,32 Furthermore, task-dependent reciprocal responses have been repeatedly observed in dACC and pACC, (that is, complex cognitive tasks produce increased dACC activity and decreased pACC activity, while tasks involving emotion conversely produce decreased dACC activity and increased pACC activity.3,21,23,33,34

The MSIT's design was hypothesis-driven, emerging from the conceptualization of dACC as an admixture of heterogeneous neurons that variously anticipate and detect targets, indicate novelty, influence motor response selection, signal rewards and detect errors.19 This ‘dACC heterogeneity model’ is built upon a large body of monkey single unit recording studies that have established that dACC encompasses such heterogeneous neuron types,35,36,37,38,39 and was supported by the results from a recent human fMRI study using a reward-based decision-making task.19 In a related manner, human functional imaging studies of anticipation,40,41 target detection,42 novelty detection,43,44 response selection,20,22,45,46,47,48,49,50,51 reward,52,53 and error detection44,54,55,56,57 have all independently activated dACC, supporting the heterogeneity conceptualization.

Cognitive interference tasks, in which the processing of one stimulus feature impedes the simultaneous processing of a second stimulus attribute, have also activated dACC in group-averaged functional neuroimaging studies. These would include Stroop and Stroop-like tasks,1,20,46,49,58,59,60,61,62,63,64,65,66 Eriksen Flanker-type tasks,67,68,69 and Simon effect task variants.20 This is not surprising, as such tasks place high demands on target detection, response selection, and performance monitoring circuits. Interestingly, a recent study by Grachev et al70 went beyond the traditional forms of functional imaging and, using the Color Stroop and in vivo proton magnetic resonance spectroscopy, found biochemical differences in dACC that were correlated with the degree of cognitive interference (ie N-acetyl aspartate levels in the right dACC were significantly lower in subjects showing greater cognitive interference as measured by the Stroop reaction time interference effect).

While full descriptions of the cognitive interference tasks that the MSIT was derived from are beyond the scope of this paper, brief descriptions are given here. The essence of the prototypical cognitive interference task, the Color Stroop,16,59 is that subjects take longer to name the color of the ink that color words are written in when the ink color and color word are incongruent (eg the word red written in blue ink, correct answer ‘blue’) than when they do match (blue written in blue ink) or when the word is a noncolor word (house written in blue ink). In the Eriksen Flanker Task17 subjects take longer to identify a centrally located target letter (and make more errors) when the target letter is flanked by incongruent distractor letters (eg DDTDD) than when it is flanked by the same letter (eg TTTTT). The Simon Effect18 denotes the cognitive interference produced by spatial incongruence between the target and response (eg given a two-button response pad, it takes longer for subjects to respond using the left button when the target appears on the right [and vice versa] than when the stimulus and response positions correspond).

An ideal functional neuroimaging-based diagnostic test to be used in assessing the functional integrity of dACC or any other cortical structure(s) in neuropsychiatric disorders should possess the following characteristics: (1) It must produce reliable and robust activation of the cortical region(s)-of-interest (ROI) within healthy individuals. (2) It should be hypothesis-driven, (that is, pre-existing evidence should support a mechanism explaining why the task would be expected to recruit the RO). (3) It should include collection of concomitant imaging and performance data (reaction times and accuracy). (4) Testing procedures must be standardized. (5) The task instructions should be easy to learn and retain so that the task can be performed by subjects with impaired cognition (eg schizophrenia) and by subjects across a wide age spectrum (to enable developmental studies in children and studies of elderly subjects). (6) It should not require an excessive time commitment as children and elderly subjects tend to tire more easily than young adults. (7) It should not be language-specific (in order to allow cross-cultural studies). (8) Performance data should vary within a relatively narrow range in healthy volunteers. (9) Imaging and performance data should be related. (10) Imaging and performance data should show temporal stability (ie it should display sufficient test–retest reliability to permit longitudinal and treatment studies). (11) Imaging and performance data should be sensitive to changes with successful treatment. (12) Results should be disorder specific.

The MSIT was designed with attention to these characteristics. Our primary objective in this validation study was to show that the interference minus control comparison would produce reliable and robust dACC activation within individual subjects. Based on the available evidence cited above, we also predicted that in contrast to dACC activation, performance of the MSIT would yield decreased pACC activity and no significant difference in cCMA activity. Finally, we predicted that reaction times would be longer during interference trials than during control trials.

Materials and methods

Subjects

Informed consent was obtained following the established guidelines of the Massachusetts General Hospital Subcommittee on Human Subjects. All eight subjects (four males, four females, mean age 30.4 years [s.d. 5.6 years]) were strongly right-handed as per the Edinburgh Handedness Inventory.71 All had normal or corrected-to-normal vision. No subject had a history of neurological, major medical, or psychiatric disorder, nor did any have a history of serious head injury. None were taking medication.

Task description

For the MSIT (see Figure 1), subjects were given a button-press and instructed that the keypad buttons represented one, two, and three from left to right. They were told to use the index, middle and ring fingers of the right hand to respond. They were instructed that sets of three numbers (1and/or 2 and/or 3) and/or letters (x) would appear in the center of the screen every 1.75 s, and that one number would always be different from the other two (matching distractor) numbers or letters. Subjects were asked to report, via button-press, the identity of the number that was different from the other two items.

Figure 1
figure1

MSIT trial examples. Examples of single trials of the two types of stimuli are shown. Subjects are asked to report, via button-press, the identity of the number that differs from the other two items. During ‘control’ trials, the distractors were always the letter ‘x’, target numbers were always large and placed congruently with their position on the button box. During ‘interference’ trials, the distractors were other numbers (either 1, 2, or 3), target numbers could be large or small and they were never placed congruently with their position on the button box. In both top examples, the correct answer would be to press button ‘1’, and in both bottom examples, the correct answer would be to press button ‘2’.

Subjects were informed that scans would begin and end with fixation of a white dot for 30 s, and that between these times there would be two trial types that would appear in alternating 42 s long blocks. In trials with numbers and letters (control trials), the target number would always match its position on the button-press (eg the number ‘1’ would appear in the first [leftmost] position). In contrast, during the trials involving all numbers (interference trials), the target would never match its position. It was then emphasized that they were to ‘report what the target number was regardless of its position’. Further, subjects were informed that in the numbers and letters (control) condition, the target number would always be large, while in the numbers only (interference) condition the target number would sometimes be large and sometimes be small (in actuality, unbeknownst to subjects, the number of large target trials and small target interference trials were equal). For all trials, subjects were instructed to answer as quickly as possible but to make sure that they gave the right answer.

After instructions were reviewed, and just prior to entering the scanner, subjects completed a 1 min long computerized practice version of the task (20 control trials followed by 20 interference trials). Subjects completed four scans each of the MSIT, with each scan lasting 6 min and 36 s. RTs for erroneous or null responses were discarded.

Subjects completed 24 trials during each (control/interference) block, 96 trials of each type during a single scan, and 384 total trials of each type during the four-scan session (except for one subject who, due to technical problems, only had three scans). The order of presentation, regarding the control and interference blocks, was fixed within runs (ie it was always FCICICICIF). Four pseudorandom sequences were used—these were counterbalanced across subjects. Within each block each stimulus appeared an equivalent number of times (ie each of the three control stimuli 1xx, x2x, xx3 appeared eight times in each block, while each of the 24 different interference stimuli combinations appeared once in each block). Eye movements were not monitored.

fMRI procedures

fMRI was performed in a Siemens 3 T Allegra high-speed echo-planar imaging device (Munich, Germany) using a quadrature head coil (see Bush et al19 and Sperling et al72). Subjects lay on a padded scanner couch in a dimly illuminated room, and wore foam earplugs. Foam padding stabilized the head. Stimuli were generated via MacStim 2.2.1 (West Melbourne, Australia) on a Macintosh 250 MHz Powerbook™ (Cupertino, CA,USA) and projected onto a screen secured to the head coil. Subjects viewed images on a tilted mirror placed in front of their eyes. Stimuli subtended approximately 1° of the visual angle vertically.

High-resolution structural images (1.0×1.0×1.3 mm,3 magnetization-prepared rapid acquisition with gradient echoes (MP-RAGE), 128 slices, 2562 matrix, echo time (TE)=3.3 ms; repetition time (TR)=30 ms; flip=40°) were collected for 3-D reconstruction either during the functional scanning session or in a separate session. Functional sessions began with an initial sagittal localizer scan, followed by a set of high-resolution (22 coronal slices, perpendicular to the anterior commissure–posterior commissure line and extending posterior from a point approximately y=60 mm, 1.5 mm2 in-plane resolution (ipr) × 5 mm thick, skip 1 mm) inversion time T1-weighted echo-planar images (inversion time (TI)/TE/TR=1200/29/6000 ms; number of excitations (NEX)= 4) and T2 conventional anatomical scans (2562 matrix, TI/TE/TR=1200/104/11 ms, NEX=2). The co-registered functional series (TE/TR=30/1500 ms, 264 images/slice, flip=90°, FOV=20 cm2, 642 matrix, ipr=3.125 mm2) lasted 6 min and 36 s. Subjects completed four functional scans for a total of 1056 total images per subject. Data sets were motion-corrected using AFNI (Milwaukee, WI, USA) and normalized to represent percent signal change from the mean signal during the fixation condition.

A voxel-wise t-test was employed to test if greater activation occurred in dACC during interference trials vs control trials. The dACC ROI was defined based on a modification of a meta-analysis of 64 imaging studies that reported ACC activation during cognitively demanding tasks.19,21 The modification (added to better assess homology, based on the monkey electrophysiology studies and anatomical work in humans) was that only ACC cortex superior to the corpus callosum between y=0 and +30 mm and within the cingulate sulcus (or between the cingulate and paracingulate sulci inclusive in cases displaying double parallel cingulate sulci) was considered.19 It refers to the same cortical region that has been called the anterior cingulate cognitive division (ACcd),21 rostral cingulate zone,22 or midcingulate cortex.8 This was done for each subject on his/her anatomical scan (see Figure 2). For this a priori defined dACC region encompassing 250 voxels, statistical significance (of P<0.05 Bonferroni-corrected for multiple comparisons) was defined as P<1.7×10−4. Resultant statistical maps were displayed in pseudocolor, scaled according to significance, projected onto the high-resolution anatomical scan slices in native and Talairach space.73

Figure 2
figure2

Scan and reaction time data: group-averaged and individuals. Top: Group-averaged fMRI and RT results are shown in the larger top panels. Scan data are displayed on group-averaged slices in radiological convention (coronal slice at y=17 mm [left] and axial slice at z=24 mm [right]). On the coronal slice, the aqua box represents the group-averaged ROI. The gray box indicates the approximate borders of the enlarged areas shown for individuals (below). The axial slice highlights activity in other presumably networked regions such as dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex (PPC)—other regions that are commonly activated by Stroop-like tasks (for a full listing of activated regions, please refer to Table 2). At right, mean RTs are shown for the 16 interference–neutral word block pairs collected while subjects were being scanned. Black bars represent interference trials, gray bars control trials, and the thick black line represents the difference between the two. Error bars indicate standard errors of the mean. Bottom: In the eight panels below, fMRI and RT data are shown for each of the individuals. Aqua lines indicate the dACC ROI for that slice for each individual. Significance (color) scales are identical for all scan data in this figure.

We also conducted group-averaged analyses in Talairach atlas space using voxel-wise t-tests to test if greater activation occurred in dACC during interference trials vs control trials. This analysis was conducted for all interference minus control blocks both overall (all scans from all subjects) and on a scan-by-scan basis for the first three scans from all subjects (since one subject only completed three scans). For these group evaluations, the dACC ROI was defined as in past group studies, that is, anterior cingulate cortex anterior to y=0 mm, posterior to y=+30 mm, and within 15 mm of the midline.1 For completeness, while our main interest lies in evaluating dACC response, loci of activation in other regions meeting the same threshold are reported (although these post hoc identified regions should be independently and prospectively confirmed).

To quantify the degree to which the locations of individual dACC activations matched that of the group-averaged data, we calculated the mean distance (and SD) of each individual maximum from the ipsilateral group average (for the left hemisphere we measured the distances from individual maxima to a point midway between the two left-sided dACC maxima, which were found in close proximity to one another).

Results

Behavioral results

Figure 2 displays the robust and reliable RT data and illustrates how the performance data (and scan data) of the individuals closely matches that of the group as a whole. Planned comparisons revealed that, as a group, subjects showed a highly significant overall mean increase in RT of 312 ms (±61 ms, s.d.) during interference condition as compared to the control condition (t=13.6, df=6, P<0.001). In fact, this RT increase during the interference condition was highly significant for each scan individually: Scan 1 (t=11.0, df=6, P<0.001), Scan 2 (t=13.3, df=6, P<0.001), Scan 3 (t=10.8, df=6, P<0.001), and Scan 4 (t=18.6, df=6, P<0.001). Thus, the RT interference effect remains significant throughout the entire experiment (Figure 2, Table 1). Subjects showed a significant increase in errors during interference trials as compared to control trials ( Table 1, paired two-tailed Student's t-test, P<0.01).

Table 1 Performance data. Group-averaged reaction time and accuracy data during different trial types are shown

The effects of target characteristics on RT and accuracy within interference trials were examined ( Table 1). Target size did not have an appreciable effect on either RT or accuracy. A repeated-measures ANOVA revealed that RTs varied across target position (F=5.6, df =2,14, P<0.02). Follow-up t-tests revealed that RTs were significantly greater when the target was in position 1 vs position 2 (t=3.3, df=7, P<0.02) and marginally greater when the target was in position 1 vs position 3 (t=2.1, df=7, P<0.07). RTs for targets in positions 2 and 3 did not differ from each other (t=0.6, df=7, P<0.55). Error rates did not differ across target positions (F=0.6, df=2,14, P<0.58).

fMRI results

As illustrated in Figures 2 and 3, dACC was significantly activated (P<1.7×10−4) in eight out of eight single subjects (and in the group average) when comparing all interference blocks with all control blocks (ie 16 block-pairs per subject). These figures show the tight spatial correlation between the individual and group data (the mean distance of individual dACC activations from the group average was only 8.5 mm [SD 6.1 mm]). Additionally, the group data also showed temporal stability in that significant dACC activation (P<10−4) was observed when comparing interference blocks with control blocks within each of the first three scans.

Figure 3
figure3

MSIT: comparison to meta-analysis. This figure plots the group (aqua stars) and individual (small aqua squares) fMRI activation data observed during the MSIT atop the results from a previous meta-analysis of cognitive and emotional neuroimaging studies.21 The dACC is activated by cognitively challenging tasks (red dots, yellow, and orange triangles) such as Stroop and Stroop-like tasks, divided attention tasks, and complex response selection tasks. The pACC is activated by tasks that relate to affective or emotional content, or symptom provocation (blue dots and blue diamond). As predicted, the MSIT activated dACC, and the individual data clustered tightly around the group-averaged maxima. Also, the MSIT activations overlapped those observed in this same group of subjects when performing a reward-based decision-making task (the purple triangle indicates group maxima, and the purple rectangle indicates the limited spatial extent of the activations within individuals)—see Bush et al.19 Abbreviation: CC, corpus callosum.

As expected, prospective analysis revealed significant (P<1.7×10−4) bilateral signal decreases in the pACC (2 foci: x/y/z of 7/45/9 and −2/45/3) during the interference blocks (relative to the control blocks). Also as predicted, we did not observe significant activation in cingulate cortex caudal to dACC in the interference minus control contrast.

While our focus was on dACC, group-averaged fMRI data also showed that the MSIT coactivated other brain regions involved in cognition, target detection, response selection, motor planning, and motor output. These areas included dorsolateral prefrontal cortex, premotor cortex, and parietal cortex (see Table 2). These group effects are likely veridical, as these same areas were significantly activated in at least 75% of the individuals.

Table 2 Regions activated by the MSIT

Discussion

There were three principal findings:

(1) The MSIT produced reliable and robust fMRI activation of dACC within individual subjects. Activation observed in dACC within single subjects was tightly clustered around the dACC foci identified by group averaging of data.

(2) Predictably, in contrast to dACC activation during the interference minus control comparison, fMRI signal decreased in pACC, and did not increase significantly in either the caudal cingulate motor zone or posterior cingulate cortex. Together, the findings support the existence of functional subdivisions of cingulate cortex.

(3) The MSIT successfully produced a state of cognitive interference, as indicated by prolonged reaction times and increased errors during interference blocks as compared to control blocks. As with the fMRI data, the individuals’ performance data closely paralleled the group data.

Issues for studies of clinical populations

The MSIT possesses many of the qualities deemed desirable in a functional neuroimaging-based diagnostic test: (1) It reliably and robustly activates dACC within individuals. (2) Mechanistically, it is hypothesis-driven. (3) It permits collection of concomitant imaging and performance data. (4) Testing procedures are standardized. (5) The task instructions are easy to learn and retain so that the task can be performed by subjects with impaired cognition and by subjects across a wide age spectrum. (6) It can be completed in a short period of time. (7) It is not language-specific, which can facilitate cross-cultural studies (ie at least across those cultures that use Arabic numerals). (8) Performance data varied within a relatively narrow range. (9) Imaging and performance data were related (ie increased RT was associated with higher fMRI signal). (10) Imaging and performance data showed temporal stability. Thus, it appears that the MSIT can be a useful task in studies of neuropsychiatric patients and normal volunteers.

Many of the characteristics that make the MSIT a good candidate for a clinical task would appear to represent substantive advancements over previous tasks. Although many tasks (such as the Color and Counting Stroops, go/no-go tasks, and divided attention tasks) activate dACC reliably,21 these studies have historically relied on group averaging rather than analyses in single subjects. While reward-based decision-making19 and verb generation tasks74 have produced reliable fMRI activation in single subjects and provided valuable information with respect to dACC mechanisms, both present drawbacks in terms of clinical use. The reward-based decision-making task must be run in event-related format, and due to design issues such as infrequent target presentation, requires extensive averaging and nearly 2 h of dedicated scanning time. In contrast, the MSIT took less than an hour and potentially could be completed in about 20 min. The verb generation task has variable and nonstandardized output (making it difficult to quantify and compare performance) and, as Raichle et al75 showed, is extremely sensitive to minimal practice. Practice-related decrements in dACC activation, also observed within the first few minutes of the Counting Stroop62 were desirable in terms of understanding learning-related activity in dACC—but this type of temporal instability is an undesirable trait for a clinical test. In contrast, the MSIT yields temporally stable performance and imaging data, making it useful in treatment and other types of longitudinal studies.

It is important to note, however, that a number of imaging parameters were chosen to specifically maximize individual activation, and these alone (rather than factors specific to the MSIT) could conceivably have led to the enhanced ability to detect activation within individuals. For example, the current study used a high field strength 3 T Siemens magnet, and averaged four runs per individual, whereas most previous tasks have been run on 1.5 T magnets and averaged only two runs. Prior to developing the MSIT, we did conduct pilot studies of Color and Counting Stroops, go/no-go tasks, and other response override tasks (using up to four runs on a different high field General Electric Signa 3 T magnet [Milwaukee, WI, USA]) and these did not produce consistent single subject dACC activation, but this does not conclusively demonstrate that the MSIT is a ‘superior’ task, nor should one conclude that the other tasks are incapable of producing single subject activation with equivalent scanning parameters. Future comparative studies of the different tasks using the identical subjects, scan parameters and analysis methods might produce interesting results.

The RT interference effect (mean 312 ms) was extremely robust. It was much larger than has typically been seen in imaging studies of the Color Stroop (mean=142 ms, range=97–235 ms),58,60,64,65,76,77 the Counting Stroop (mean=38 ms, range=29–46 ms),1,62 Eriksen Flanker-type tasks (mean=102 ms, range 19–267 ms),67,68,69 or Simon effect task variants (39 ms in Hazeltine et al,78 and approximately 10–30 ms in Barch et al20). The fact that the MSIT's mean RT interference was at least double those of these other tasks indicates that the strategy of combining tasks to maximize cognitive interference was successful.

The ability to produce activation within individuals is particularly valuable to patient-based studies. Better localization will improve power to detect differences in future studies. This can help studies of normal function of dACC as well as patient/group studies. It can also help future patient studies by permitting the elimination of a potential confound (ie apparent ‘relative hypofunction’ of a brain region in a patient group (compared to the control group) could be spuriously caused not by actual hypofunction within the individuals with the disorder, but rather by greater spatial heterogeneity of the location of a normally functioning brain region in the patient group). Of course, while we stress the value of the individual study, group-averaged MSIT data can also be used with the advantages of greater power, fewer subjects, and higher confidence.

In addition to combining Stroop, Eriksen, and Simon interference effects, the MSIT was designed to recruit as many dACC neurons as possible (anticipation, target detection, novelty detection, error detection, response selection) in order to maximally activate dACC. Interference blocks (in block format) were expected to induce greater anticipation and designed to maximally tax response selection. Also, target detection and novelty detection requirements were greater during interference blocks, since these included 24 different stimulus combinations, as compared to three control task stimuli. Errors were significantly higher during the interference condition. It should be noted that while no specific single cell representations have been shown to exist within dACC for stimulus and/or response competition detection56 and task difficulty,79 these are factors that the ‘heterogeneity model of dACC’ predicts would, if differentially present between parts of a task, lead to increased dACC activation.19

Admittedly, the interference and control portions of the task were not perfectly matched in all characteristics save one, as is the goal in traditional psychology experiments. However, it must be emphasized that this was by design, since the goal here was not to study some aspect of dACC function in isolation, but rather to develop an adequately controlled task that would robustly activate dACC. The interference and control blocks did have virtually identical visual and motor requirements—beyond that, task design decisions were made to maximize dACC activity. Future work should be done using different permutations of the MSIT in order to study the effects of changing different task characteristics, such as target size, position, novelty, etc. For example, one could examine the effects of instructing subjects to report the position of the target stimulus rather than its identity.

Dorsal ACC activation in individuals—implications for studies of normal cognition

The MSIT advances our understanding of the localization of dACC in normal humans. Figure 3 shows that it activated the same area that has been activated repeatedly by other cognitively demanding tasks,21 as well as by the reward-based decision-making task that was performed by the same subjects in a different session.19 Both the MSIT and the reward-based decision-making task yielded bilateral activation in the majority of these individuals, even though the button-press responses were performed solely with the right hand in both studies, tacitly arguing in favor of a more generalized cognitive integration function rather than a lateralized, solely motor function for dACC.

Different functions have been ascribed to dACC, including attention-for-action/target selection,80,81 motivational valence assignment,63,82,83 motor response selection,47,50,51,79 error detection/performance monitoring,57,84 competition monitoring,56,67 anticipation40,63 working memory,85 novelty detection,43,44,63 reward assessment,52,53 and reward-based decision-making.19 Monkey single-unit recording studies have established that dACC is comprised of an admixture of heterogeneous cell types that anticipate and detect targets, encode novelty, influence motor preparation and execution, evaluate rewards, and signal errors,35,36,37,38,39 and fMRI results in humans indicate that a similar architecture exists in humans.19 While much work needs to be done to validate such a heterogeneity-based ‘local intracortical network model of dACC’, the heterogeneity conceptualization has the capacity to be refined into a unifying, neurobiologically plausible model that can explain the diverse results from neuroimaging and electrophysiological studies.19,21 It should be noted that the construction of the MSIT task was based on, but not dependent on, this heterogeneity concept. Thus, while the data are consistent with the heterogeneity concept, they do not rule out other proposed dACC mechanisms.

The results support the existence of separable dorsal (dACC) ‘cognitive’ and perigenual (pACC) ‘emotional’ subdivisions of ACC. The MSIT activated dACC, but not pACC. Similar dACC activity has been obtained in response to cognitively challenging tasks, and can be contrasted with activity seen in pACC (rostral/subgenual areas 24/25/32/33) during processing of emotional stimuli.21 Notably, in companion studies run in the same group of subjects during the same scanning session, the cognitive Counting Stroop activated dACC,62 while the emotional Counting Stroop activated pACC.10 The current data also are consistent with meta-analyses of ACC activations that showed reciprocal deactivations (ie decreases in the ‘cognitive’ dACC during emotional tasks and decreases in the ‘emotional’ pACC during ‘cognitive’ tasks,3,21,23 as the MSIT produced significantly less fMRI signal in pACC during the interference blocks than during the control blocks. Obviously, the terms ‘cognitive’ and ‘emotional’ are gross over-simplifications, and the actual relevance of ‘deactivations’ in imaging studies must be elucidated, but the MSIT data are consistent with previous findings supporting functional subdivisions of ACC.

No significant activation was observed in the caudal cingulate motor zone, which many conclude is involved in the execution of simple motor acts,22,29 or posterior cingulate cortex, which is involved in visuospatial processing.29,86 Together with the dACC and pACC data, these findings also support the conclusion that cingulate cortex contains functional subdivisions that differentially subserve cognitive, motor, and emotional processing.

Other brain regions

Although the current study focused on dACC, it should be emphasized that this in no way implies that dACC is the only region responsible for processing cognitive interference tasks. The MSIT also recruited many other brain regions including dorsolateral prefrontal cortex, premotor areas, and parietal cortex. This was expected, as many researchers have concluded that these structures subserve cognitive processing in parallel-distributed fashion.82,87,88 DLPFC has often been reported to be coactivated with dACC during cognitive tasks,24,89,90,91 premotor cortex is responsible for planning and execution of nonautomatic tasks,92,93 and parietal cortex has been shown to be activated during target detection tasks94,95 and Stroop tasks.1,58,62,64,96 Furthermore, interesting recent work by different groups utilizing combined transcranial magnetic stimulation (TMS) and neuroimaging has shown that TMS of lateral prefrontal cortex can modulate ACC activity97,98 indicating the strong inter-regional connectivity and suggesting another possible direction for research (ie technique refinements may produce dACC activation via remote TMS stimulation). While the precise roles these structures play in such tasks remain to be determined, the convergent data argue that they interact as a network, and the challenge ahead is to determine the role of the individual components of these distributed brain circuits.

Conclusions

The MSIT produced reliable and robust activation of dACC in individuals and this closely matched the group-averaged data. Coupled with the reliable and robust performance data, the MSIT displayed many of the characteristics desired in a neuroimaging-based diagnostic test. As such, it can be expected to serve as a useful fMRI probe in searching for the neural substrates of various neuropsychiatric disorders such as attention deficit disorder, schizophrenia, obsessive–compulsive disorder, and depression. Future studies can also use task manipulations to help us to better understand mechanisms of attention, response selection, and cognition.

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Acknowledgements

The authors wish to thank Mary T Foley, Larry White, Larry Wald, Meghan Searl, Kerry Carley-Bush, Jordan Alexander, Taryn Brandon, and our subjects for their patience and assistance. Support for this work was provided by NIMH (Scientist Development Award 01611), NARSAD and the Forrest C Lattner Foundation.

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Correspondence to G Bush.

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Bush, G., Shin, L., Holmes, J. et al. The Multi-Source Interference Task: validation study with fMRI in individual subjects. Mol Psychiatry 8, 60–70 (2003). https://doi.org/10.1038/sj.mp.4001217

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Keywords

  • cingulate
  • Stroop
  • Eriksen
  • Simon
  • cognition
  • interference
  • oddball
  • attention
  • clinical
  • diagnostic

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