Infrequent Events Transiently Activate Human Prefrontal and Parietal Cortex as Measured by Functional MRI

Gregory McCarthy1, 2, 3, Marie Luby1, 2, John Gore4, and Patricia Goldman-Rakic5

1 Neuropsychology Laboratory, Veterans Affairs Medical Center, West Haven, 06516; and 2 Department of Neurosurgery, 3 Department of Neurology, 4 Department of Diagnostic Imaging, and 5 Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510

    ABSTRACT
Abstract
Introduction
Methods
Results
Discussion
References

McCarthy, Gregory, Marie Luby, John Gore, and Patricia Goldman-Rakic. Infrequent events transiently activate human prefrontal and parietal cortex as measured by functional MRI. J. Neurophysiol. 77: 1630-1634, 1997. P300 is an event-related potential elicited by infrequent target events whose amplitude is dependent on the context provided by the immediately preceding sequence of stimuli, suggesting its dependence on working memory. We employed magnetic resonance imaging sequences sensitive to blood oxygenation level to identify regional changes evoked by infrequent visual target stimuli presented in a task typically used to elicit P300. Targets evoked transient event-related activation bilaterally in the middle frontal gyrus, in the inferior parietal lobe, and near the inferior aspect of the posterior cingulate gyrus beginning within 1.5 s of target onset and peaking between 4.5 and 6 s. These regions have been identified in previous neuroimaging studies in humans, and in single-unit recordings in monkeys, as components of a neural system mediating working memory, which suggests that this system may be activated by the same events that evoke P300.

    INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References

Electrophysiological studies in humans in which noninvasive scalp recordings were used have investigated neural responses to infrequent task-relevant stimuli. Such stimuli elicit a reliable sequence of event-related potentials (ERPs), most prominently P300, which occurs ~300-500 ms after stimulus onset (Sutton et al. 1965). P300 has attracted widespread interest because, although it is insensitive to some stimulus characteristics such as modality, P300 amplitude is exquisitely sensitive to the attentional demands of the task and P300 latency varies with the time required to identify the experimentally designated, or rules-based, category to which an individual stimulus belongs (Donchin and Coles 1988). Of particular interest is the sensitivity of P300 to the category memberships of the preceding sequence of stimuli (Squires et al. 1976), which suggests that its elicitation is dependent on the contents of a transient memory buffer and that its appearance may reflect updating of working memory (Donchin and Coles 1988).

Physiological studies in monkeys have elucidated a neuronal system underlying cognitive operations involved in working memory (Baddeley 1992) that involves reciprocal interconnections between dorsolateral prefrontal cortex, inferior parietal cortex, hippocampus, and other structures (Goldman-Rakic 1987). Neuroimaging studies by our group and others (Cohen et al. 1994; McCarthy et al. 1994, 1996; Smith et al. 1995) have demonstrated activation of prefrontal and parietal cortex in the human brain during working memory tasks. If P300 reflects processes related to working memory, then the transient events that elicit P300 should also activate this same fundamental neuronal circuit. In the present study we employed a novel application of signal averaging to determine whether these same regions were transiently activated by the occurrence of infrequent target stimuli as typically used to elicit P300.

    METHODS
Abstract
Introduction
Methods
Results
Discussion
References

Subjects

Ten neurologically normal right-handed volunteers (5 males) participated. Subjects ranged in age between 19 and 42 yr with a mean age of 29 yr. All subjects were experienced in neuroimaging studies and provided informed consent.

Task

Visual stimuli were delivered by computer to an active matrix liquid crystal display panel and back-projected onto a translucent Plexiglas screen mounted on the patient gurney of the scanner. The subject viewed the stimuli through a mirror mounted in the head coil. The stimuli consisted of two letter strings (OOOOO and XXXXX) presented as white characters centered against a dark field. A run consisted of a series of 128 successive stimuli presented at a rate of one string per 1.5 s with a duration of 0.5 s. Most of the stimuli were OOOOO strings (standards); however, six to eight stimuli per run were XXXXX strings (targets). The latter were randomly intermixed into the series with the constraint that >= 12 standards occurred between successive targets. Subjects were required to count mentally the number of targets and report that number at the end of the run. Subjects were cautioned against blinks, changes in breathing patterns, or movements coincident with counting. There were eight experimental runs in each session, resulting in a total of 55-63 targets for each subject.

Imaging

Echoplanar magnetic resonance (MR) images were continuously acquired during task performance at a rate of one image every 1.5 s with the use of sequences sensitive to blood oxygenation level (Kwong et al. 1992; Ogawa et al. 1992; for review see Moseley and Glover 1995). A 1.5-T MR imaging (MRI) scanner (General Electric Signa, Milwaukee, WI) with a quadrature head coil and echoplanar capability (Instascan, ANMR Systems, Wilmington, MA) was used. The subject's head was immobilized with the use of a vacuum cushion and forehead strap. High-resolution sagittal scans were obtained (TR = 500 ms, TE = 11 ms, NEX = 1,FOV = 24 cm, slice thickness = 5 mm, skip = 2.5 mm, imaging matrix 256 × 192) to identify the anterior commissure (AC) and posterior commissure (PC). Four T1-weighted coronal scans(TR = 500 ms, TE = 11 ms, NEX = 2, FOV = 40 cm, skip = 0 mm, slice thickness = 7 mm, imaging matrix 256 × 192) were then acquired at distances measured along the AC-PC line. Two images were centered 40 mm anterior to the AC to investigate prefrontal cortex. An additional two images were centered 5 mm posterior to the PC; the more anterior to study the midbody of the hippocampus and the more posterior to study parietal cortex. Additional images were acquired of these same slices for anatomic reference with the use of an echoplanar sequence (TR = 3,000 ms, TE = 80 ms, NEX = 4, FOV = 40 × 20 cm, slice thickness = 7 mm, skip = 0, imaging matrix 128 × 64). Functional images were acquired with the use of a gradient-echo echoplanar image acquisition sequence (TR = 1,500 ms, TE = 45 ms, alpha  = 60°, NEX = 1, FOV = 40 × 20 cm, slice thickness = 7 mm,skip = 0, imaging matrix 128 × 64). Each 196-s run consisted of the acquisition of 128 images for each of the four coronal slices preceded by four radiofrequency excitations to achieve steady-state transverse magnetization. On the basis of prior electrophysiological (Goldman-Rakic 1987; McCarthy and Wood 1987; McCarthy et al. 1989) and neuroimaging studies (Cohen et al. 1994; McCarthy et al. 1994, 1996; Smith et al. 1995), slice selection focused on prefrontal cortex, parietal cortex, and hippocampus.


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FIG. 1. Average activations (P < 0.01) across all 10 subjects depicted on spatially normalized averaged magnetic resonance images for frontal (A and B) and posterior (C and D) anatomic slices. The activations shown occurred 6 s after target onset.


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FIG. 2. Group-average target-synchronized segment for prefrontal cortex showing activations that exceeded the mean signal intensity of the 6 pretarget images at P < 0.01. Top left image: target onset; each succeeding image depicts an increment of 1.5 s. The largest activations occurred at 4.5-7.5 s and declined thereafter. The 5 pretarget images showed no activation and are not shown.

Image analysis

Segments consisting of the six images preceding and the nine images following each target were excised from the eight runs comprising each subject's data. These images were then averaged maintaining the order of each image relative to target onset. Thus each averaged segment consisted of the average of the 55-63 segments for each of the 15 images making up the segment. Averaged segments were calculated for each of the four anatomic slices for each subject. The averaged segments were then standardized and deviations from the baseline were represented in SD units. The mean and SD were computed for each voxel over the six pretarget, or baseline, images of each averaged segment. Standardized segments were then created by subtracting the mean and dividing by the SD on a voxel-by-voxel basis for each image in the segment.

In addition to the computation of segments synchronized to the target stimuli, control image segments were computed that were randomly synchronized to an equal number of standards. These segments were computed in exactly the same manner as the target-synchronized segments, and thus provide a measure of unsystematic image intensity variation or noise.

To identify intersubject consistency in the pattern of activation, spatially normalized, group-averaged segments were computed for each anatomic slice. Mean anatomic images were first created by superimposing each subject's anatomic image over a common image and then manually translating and stretching the individual's image, taking particular care to align major sulci. These alignment procedures were performed by two experimenters without reference to activation results. The group-averaged standard segments were then computed and superimposed on the group-averaged anatomic images. Activated regions exceeding ±2.57 SD compared with baseline (corresponding to a probability of 0.01 for a z distribution) were then interrogated to reveal the time course of activation. Similar analyses were performed on anatomically defined regions of interest drawn by cursor, which were then interrogated in target-synchronized and randomly synchronized segments.

    RESULTS
Abstract
Introduction
Methods
Results
Discussion
References

Group-averaged images

The spatially normalized, group-averaged data corresponding to the mean activation pattern at 4.5 s after target onset are presented in Fig. 1. The middle frontal gyrus was activated bilaterally (Fig. 1, A and B), with a somewhat more extensive activation in the right hemisphere. Bilateral activation of the inferior parietal lobe was also clearly evident (Fig. 1D), primarily in the supramarginal gyrus and adjacent postcentral sulcus, a region corresponding to Brodmann's area 40. This parietal activation diminished in the more anterior slice (Fig. 1C), which encroached on somatosensory cortex. In both posterior slices, a discrete patch of activation was noted in the supracallosal region near the inferior aspect of the cingulate.

No differences were observed in the pattern of activation between males and females. No clusters were identified in which targets evoked a significant signal decrease. In contrast to the robust activation observed in the group-averaged data synchronized to targets, no activated clusters were observed in the group-averaged control images that were randomly synchronized to standards.

Activation time course

The time course of the evoked MR signal change can be seen in Fig. 2, in which group-averaged data for the prefrontal slice (corresponding to Fig. 1B) are shown. The top left image represents target onset (corresponding to the 6th image of the 15-image segment) and each succeeding image occurred at a 1.5-s increment. Activation exceeded threshold at 3 s in the left middle frontal gyrus and reached peak values at 4.5-6 s.

The clusters of activation observed in Fig. 1, A and B, for the middle frontal gyri were used to interrogate each image of the group-averaged data for both target-synchronized and randomly synchronized segments. Figure 3A shows a peak signal change of 0.32% at 6 s posttarget onset for the target-synchronized segment. By 1.5 s after target onset, the increase in signal well exceeded the noise level represented by the randomly synchronized segments. These averaged transient activations will be referred to as event-related activations (ERAs) by analogy with ERPs, which also use averaging to improve the signal-to-noise ratio of signals embedded in biological and nonbiological noise.


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FIG. 3. A: across-subjects mean activation time course for activated voxels from the left and right middle frontal gyrus is depicted by a solid line for the average time segment synchronized to the target event. The time course for these same voxels interrogated in the randomly sychronized control time segment is depicted by a dashed line and provides a measure of unsystematic noise. B: mean activation time course for activated voxels from the left and right supramarginal gyrus for target-synchronized (solid line) and randomly synchronized (dashed line) average control time segments.

Similar analyses were performed for the activated clusters in the inferior parietal lobe (Fig. 3B), which also showed an ERA within 1.5 s after target onset. The ERA peaked 1.5 s earlier in the parietal than the prefrontal region and reached a smaller overall level (0.21%) of signal change. The parietal ERA was also shorter in duration and declined to noise levels by 10 s after target onset.

The activation of the supracallosal region also showed a brisk onset, with peak activation at 4.5 s. The time course of activation for the supracallosal region was similar to that of parietal cortex but larger in magnitude, reaching a peak of 0.45%. The time courses and magnitudes of activation for all regions were similar when the activations were independently interrogated and compared for each hemisphere.

    DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References

These results reveal that detection of infrequent target stimuli elicited a small, transient MR signal increase that began within 1.5 s of target onset and peaked within 4.5-6 s. These activations were observed primarily in the middle frontal gyri and inferior parietal lobule, regions previously shown to be active in working memory tasks (Cohen et al. 1994; Goldman-Rakic 1987; McCarthy et al. 1994, 1996; Smith et al. 1995). P300 is readily elicited in scalp and intracranial recordings in humans and monkeys by the same infrequent targets as used here (e.g., Halgren et al. 1980; McCarthy et al. 1989; Paller et al. 1992; Puce et al. 1989). Thus the infrequent targets that elicit P300 also activate some of the same neural circuitry active in working memory tasks in both humans and monkeys.

A precise anatomic description of the activated region of supracallosal cortex is difficult to provide because it occurred at the junction of the cingulate and supracallosal gyri. This region gives rise to the cingulum bundle, a major afferent input to limbic regions including the hippocampus, and may thus play an important role in a circuit underlying working memory. However, this region also contains large blood vessels whose contribution to this activation cannot be excluded.

ERPs analogous to P300 have been recorded from widespread sites within the brain including the frontal and parietal lobes, posterior cingulate, and hippocampus (Baudena et al. 1995; Halgren et al. 1995a,b; McCarthy and Wood 1987; McCarthy et al. 1989; Paller et al. 1992; Puce et al. 1989). It is noteworthy that we did not observe consistent ERAs of the hippocampus in individual subject or group functional MRI (fMRI) data. Our failure to demonstrate hippocampal fMRI activation in a task in which electrophysiological activation is readily demonstrated may simply reflect the relative sensitivities of the two techniques. Alternatively, it may reflect a more complex mapping between activation measured by fMRI and electrophysiological events. The fMRI activations obtained in the present study may not reflect blood oxygenation changes caused by the brief synaptic activity associated with P300 per se, but rather the sustained activity of a neuronal system triggered by the target event. The target may evoke a more sustained activation in prefrontal and parietal cortex than that evoked in the hippocampus. Regardless of the resolution of this issue, the present study demonstrates that fMRI can provide a sensitive measure of cognitive processes engendered by brief and unpredictable stimuli.

    ACKNOWLEDGEMENTS

  We thank F. Favorini for programming assistance and Drs. T. Allison, A. Puce, and R. T. Knight for comments.

  This work was supported by the Department of Veterans Affairs and by National Institute of Mental Health Grants MH-44866 and MH-05286.

    FOOTNOTES

  Address for reprint requests: G. McCarthy, Neuropsychology Laboratory/116B1, VA Medical Center, West Haven, CT 06516.

  Received 14 March 1996; accepted in final form 1 November 1996.

    REFERENCES
Abstract
Introduction
Methods
Results
Discussion
References

0022-3077/97 $5.00 Copyright ©1997 The American Physiological Society