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Previous Article | Next Article
Volume 16, Number 19, Issue of October 1, 1996 pp. 6219-6235
Copyright ©1996 Society for NeuroscienceFunctional Anatomic Studies of Memory Retrieval for Auditory Words and Visual Pictures
Randy L. Buckner1, 2, Marcus E. Raichle1, 2, 3, Francis M. Miezin1, and Steve E. Petersen1, 3, 4 1 Department of Neurology and Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, 2 Department of Radiology, Mallinckrodt Institute of Radiology, 3 Department of Anatomy and Neurobiology, and 4 Department of Psychology, Washington University, St. Louis, Missouri 63105
ABSTRACT
Functional neuroimaging with positron emission tomography was used to study brain areas activated during memory retrieval. Subjects (n = 15) recalled items from a recent study episode (episodic memory) during two paired-associate recall tasks. The tasks differed in that PICTURE RECALL required pictorial retrieval, whereas AUDITORY WORD RECALL required word retrieval. Word REPETITION and REST served as two reference tasks.
Comparing recall with repetition revealed the following observations. (1) Right anterior prefrontal activation (similar to that seen in several previous experiments), in addition to bilateral frontal-opercular and anterior cingulate activations. (2) An anterior subdivision of medial frontal cortex [pre-supplementary motor area (SMA)] was activated, which could be dissociated from a more posterior area (SMA proper). (3) Parietal areas were activated, including a posterior medial area near precuneus, that could be dissociated from an anterior parietal area that was deactivated. (4) Multiple medial and lateral cerebellar areas were activated. Comparing recall with rest revealed similar activations, except right prefrontal activation was minimal and activations related to motor and auditory demands became apparent (e.g., bilateral motor and temporal cortex). Directly comparing picture recall with auditory word recall revealed few notable activations.
Taken together, these findings suggest a pathway that is commonly used during the episodic retrieval of picture and word stimuli under these conditions. Many areas in this pathway overlap with areas previously activated by a different set of retrieval tasks using stem-cued recall, demonstrating their generality. Examination of activations within individual subjects in relation to structural magnetic resonance images provided anatomic information about the location of these activations. Such data, when combined with the dissociations between functional areas, provide an increasingly detailed picture of the brain pathways involved in episodic retrieval tasks.
Key words: memory; positron emission tomography; prefrontal cortex; episodic memory; precuneus; pictures
INTRODUCTION
Functional anatomic pathways involving prefrontal areas, anterior cingulate, and cerebellar areas have recently been implicated in long-term memory retrieval (Squire et al., 1992; Andreasen et al., 1995a
One of the most consistent findings is that specific prefrontal areas become activated during the recollection of information from temporally unique events, a form of memory commonly referred to as episodic memory. Episodic memory retrieval differs from other forms of retrieval in that the unique context associated with a learned episode is accessed as part of the retrieval event (Tulving, 1983
The finding that brain pathways involving certain prefrontal areas may be activated by episodic memory retrieval has appealed to many researchers (Tulving et al., 1994b
We too find this an appealing possibility (Buckner and Petersen, 1996
What is needed are further careful analyses of a large spectrum of episodic memory retrieval tasks, as well as retrieval tasks outside the domain of episodic memory. The brain pathways used during each of these tasks should be specified as completely as possible. Then, by comparing data across tasks, brain areas and pathways differentially involved in tasks relying on episodic retrieval will become apparent.
We present positron emission tomography (PET) neuroimaging data from two episodic retrieval tasks involving paired-associate recall. The data were examined thoroughly to reveal a detailed picture of the brain areas activated, as well as some of their locations in relation to structural magnetic resonance imaging (MRI) data.
MATERIALS AND METHODS
General design. Three goals were considered in constructing the tasks and methodology used in this study.First, the cognitive tasks were designed to expand findings from our previous studies of episodic retrieval (Squire et al., 1992
Second, the present study was designed to look at two slightly different kinds of episodic retrieval: recall of pictures and auditory words. This manipulation was done to address the question of whether episodic retrieval tasks use different areas to access specific types of information being retrieved. It seems quite possible that, in addition to brain areas recruited in common by episodic retrieval tasks, additional distinct brain areas may be activated to supply modality or content-specific information (for an example of this phenomenon in relation to semantic retrieval, see Martin et al., 1995
Finally, we used a procedure that allowed within-subject averaging in brain areas believed to be related to episodic retrieval. By combining such PET data with MRI data, we specified anatomic locations of brain activations related to episodic retrieval more precisely than has previously been possible.
Subjects. Fifteen participants (7 men, 8 women) were recruited from the local Washington University community. Subjects were ages 18-35 (mean = 24.1), strongly right-handed as measured by the Edinburgh handedness inventory (Raczkowski et al., 1974
Apparatus. Emission and transmission measurements were made using a Siemens 953B-CTI scanner (Spinks et al., 1992
During PET scans, ear plugs were inserted and a plastic face mask was molded to each subject's head to reduce movement (Fox et al., 1985
PET procedures. PET scanning activation methodology developed at Washington University was used (Fox et al., 1988
Subjects laid on a flat bed and were positioned within the tomograph so that they could comfortably view a computer monitor placed ~40 cm from their eyes. A lateral skull x-ray was taken to verify appropriate head alignment and identify markers to locate the position of the transverse plane intersecting the anterior and posterior commissures (AC-PC line) (Talairach and Tournoux, 1988
For the functional neuroimaging scans, O-15-labeled water (half-life 123 sec) was used as a blood-flow tracer and administered as an intravenous bolus injection. Ten 40 sec scans were performed sequentially on each subject with each scan spaced ~12 min apart to allow nearly complete decay of the O-15 between scans. Each scan was acquired while the subjects performed a behavioral task (for task descriptions, see Behavioral procedures). Because blood flow increases are known to be a linear function of radiation counts for scans of <1 min duration, measurements of arterial blood radioactivity after bolus injection were not made (Herscovitch et al., 1983
The 10 scans were acquired in two different scanning positions for each subject (5 scans in each position) so that the entire brain was sampled. Without this procedure, dorsal and ventral areas of the brain would not be imaged because of the limited axial sampling in the three-dimensional mode (~7 cm). The same set of five behavioral tasks was scanned in each position. This procedure, which we refer to as ``indexing,'' results in uneven sampling across the brain. Across indexing positions, the middle portion of the brain gets considerable sampling because both positions overlap in this region. We took advantage of this property and biased the positioning to allow redundant sampling to occur in frontal and occipital areas thought to be most interesting for this study.
Images were reconstructed using filtered back-projection with a Butterworth filter (order = 5, half frequency = 0.5 cycles/cm). This filter results in images smoothed to ~14 mm full width at half-maximum. All blood flow images were globally normalized by linear scaling to 1000 PET counts so that fluctuations in global flow and random variations in the amount of O-15 injected would not obscure local changes induced by task manipulations (Fox et al., 1987
To isolate local changes in blood flow, subtraction images were generated by subtracting blood flow data of one scan (REFERENCE TASK) from a second scan (TARGET TASK). Because the scans were done while different tasks were performed, the TARGET minus REFERENCE subtraction images reflected blood flow changes induced by the processing demands that differed between the two tasks. All subtraction pairs were screened for movement to reduce noise. Signal-to-noise properties of the subtraction images were increased by averaging data from several subjects together and/or by averaging within a single subject (Fox et al., 1984
Analysis of PET data: strict criteria. To identify activations and determine their reliability with a considerable degree of confidence, a replication approach was used (Corbetta et al., 1993
For each subtraction analyzed, data were divided into two separate sets. No image used as either the target or reference tasks overlapped between the two separate data sets. One of the two sets, referred to as the hypothesis-generating data set, was selected and analyzed first. The second, independent hypothesis-testing data set was placed aside for later analysis.
The hypothesis-generating data sets were examined to identify activations with the highest peak magnitudes (those >50 PET counts). Spherical regions (14 mm) were defined around each of these peak activations in the first data set and tested for replication in the second hypothesis-testing data set. A one-sample t test with a hypothesized mean of zero was used to assess the statistical significance in the second data set. This analysis was conducted to test across-data set reliability.
If an activation was found to replicate, an estimate of the location of that activation was determined using the combined data set. This is because the combined data set, rather than either of the subsets of data used in the replication analysis, provides the best estimate of the activation's true location.
Because a wide range of laboratories use methods based on thresholding approaches in single-summed data sets (often t- or Z- score criterion), we also computed such values. t values for the regions defined on the best estimates of the activation locations were determined using the entire data sample. Such t values differ from the kind computed to obtain the p values in the replication approach described above. The t values computed here use the entire data sample, as opposed to half of the data, but do not test whether the values replicate. Thus, such t values characterize the within-data set reliability (similar to the statistical parametric mapping approach) (Friston et al., 1991
Importantly, regions of activation that pass the across-data set reliability screen and have a high within-data set t value can be considered with a great deal of confidence.
Analysis of PET data: lenient criteria. So as not to make Type II errors by establishing too stringent criteria, we also report as ``tentative activation foci'' peaks with magnitude > 50 PET counts and t > 3.50. These activations pass thresholding criteria applied in most published papers and are likely to reflect true activations. However, because these activations were not replicated using the approach described above, they should be considered with a lesser degree of confidence.
Several of the tentative activation foci, especially those in poorly sampled regions of the cerebellum, could not be tested using replication because of data set limitations. That is, because of our sampling procedure, duplicate data often were not collected in the most inferior and superior brain regions. When this occurred, the number of separate images was too few to provide for independent hypothesis-generating and -testing data sets.
Analysis of PET data: regions across conditions. For a limited number of activations demonstrated to be reliable using the strict criteria, regional cerebral blood flow (rCBF) was tracked across multiple task subtraction images. This allowed behavior of these regions to be better characterized.
Analysis of visual areas previously activated during picture viewing. Specific analyses were conducted to examine possible visual cortex activations during PICTURE RECALL and AUDITORY RECALL. These analyses were based on a previous study in which we examined visual areas activated during picture viewing (Buckner et al., 1995c
Five visual regions were found to be differentially activated by picture viewing compared with word viewing (Buckner et al., 1995c
Analysis of PET data: within-subject analysis. Multiple subtraction pairs were generated within each subject for several of the task comparisons. This enabled the creation of averaged within-subject images with good signal-to-noise properties (Silbersweig et al., 1993
Using an automated procedure (similar to Hunton et al., in press), within-subject activations were identified if their peak magnitudes were at least 100 PET counts in magnitude and within 15 mm of the location observed in the averaged image. This criteria is conservative and may miss activations that are present at lower magnitudes (Type II error) or that represent extreme individual variability. However, the goal of this analysis was to localize predetermined activations within individual subject's anatomies. For this reason, it seemed appropriate to use conservative criteria to be certain of the activations that were identified, even if that meant failing to identify activations within several of the subjects.
MRI procedures. A Siemens MP RAGE three-dimensional scanning sequence was obtained to provide detailed anatomic information. In sagittal orientation, the TR was 10 msec, TE 4 msec, and the inversion time was 300 msec. Voxel size was 1 × 1 × 1.25 mm3.
The MRI images were fit into stereotaxic space by selecting multiple points (>150) along the surface of the MRI brains and matching the surface marking points to a template surface derived from the Talairach and Tournoux (1988)
Behavioral procedures. Activity during different behavioral tasks was imaged. Four of the tasks are relevant to the present report: PICTURE RECALL, AUDITORY WORD RECALL, REPETITION, and REST. The subjects closed their eyes during these four tasks but had their eyes open for memory study conditions that took place before some of these tasks. Each task was repeated twice in each subject (for an explanation, see PET procedures). A fifth FIXATION task also was included to be compared with the REST task, but it is not discussed in this report.
For both RECALL tasks, subjects studied item pairs (e.g., horse-mount) before the PET scan. Each pair was studied twice within a 16-pair list (4.5 sec between pairs). The last item pair was presented (on average) 4.5 min before the beginning of the PET scan. Then, during the RECALL PET scans, subjects heard the second members of the pairs and were instructed to verbally recall the first members. Subjects were instructed not to dwell on any single word cue and to go on to the next item if they felt they had made a mistake.
The two RECALL tasks differed in that for PICTURE RECALL, item pairs were picture-word pairs, whereas for AUDITORY WORD RECALL, the items were word-word pairs (Fig. 1).
Fig. 1. Diagrams illustrate the two different episodic memory retrieval tasks that were studied: PICTURE RECALL and AUDITORY WORD RECALL.
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Specifically, during study for PICTURE RECALL, which was not scanned, subjects were presented with line-drawn objects on the computer monitor (3.5 sec duration). After each picture was present for 1 sec, the auditory word was played. Subjects were instructed to remember what the pictures looked like and which words were paired with them, with a strong emphasis on remembering what the pictures looked like.
During study for AUDITORY RECALL, which also was not scanned, subjects heard a word and then, after a 1 sec delay, heard a second word. The instructions to the subjects paralleled PICTURE RECALL except subjects were told to pay careful attention to what each word sounded like.
During the test phase, which was scanned, subjects heard the second members of the pairs in both RECALL conditions (1 word every 3 sec). The test instructions differed slightly between the two RECALL tasks. For PICTURE RECALL, subjects were instructed to listen to the word cue and recall what the associated picture looked like and say aloud the name of that picture. For AUDITORY WORD RECALL, subjects were instructed to listen to the word cue and remember what the associated word sounded like and say aloud that word.
The reason for the particular design of the RECALL tasks was to create two recall situations, both of which involved identical stimulation and a common verbal response during the PET scans but differed with regard to the kind of information being retrieved.
Pilot data obtained from behavioral subjects (n = 8) suggested that performance on PICTURE RECALL would be ~81% correct recall, whereas performance on AUDITORY WORD RECALL would be slightly lower at 73% correct recall.
As a further behavioral measure, a forced-choice recognition test (8-item pairs) was given after the PICTURE RECALL scan task. Stimuli were two exemplars of the same object (Fig. 2), one of which overlapped with the particular exemplar the subjects studied. Subjects were instructed to indicate, with a key press, which exemplar was studied, a decision requiring knowledge of the visual form of the object (Tversky and Sherman, 1975
Fig. 2. An example of the stimuli used for the after-scan picture recognition task.
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The first reference task was REPETITION; subjects heard words and simply repeated the words aloud. This task involved the same stimulation as RECALL and similarly involved a common verbal output. REPETITION, however, did not require retrieval from episodic memory. A REST reference task, in which subjects rested with their eyes closed, also was included to serve as a low-level reference condition.
Between PET scans, a brief task was conducted to calibrate the EOG record. Subjects fixated and then moved their eyes back and forth between two locations.
Stimuli. Sixty-four line-drawn picture stimuli were selected from Snodgrass and Vanderwart (1980)
All picture stimuli were digitally scanned and stored as Macintosh ``PICT'' resources. Auditory words were recorded in a male voice using a unidirectional microphone (Realistic 33-1073a). The words were recorded as Macintosh ``snd'' resources and edited to all be perceptually about the same loudness using SoundEdit (Macromind).
Picture-word and word-word pairs were divided into four lists of 16-item pairs. Lists were balanced for word frequency of the picture name and verb frequency (Ku
era and Francis, 1967
if it exists
RESULTS
Behavioral results
Table 1 shows RECALL performance. Subjects performed well in both RECALL tasks, with slightly better performance in PICTURE RECALL compared with AUDITORY WORD RECALL. A slight decrement in performance was noted as the study progressed (for both RECALL conditions), perhaps reflecting minimal fatigue or interference from the preceding items. An ANOVA revealed that both main effects were significant: F(1,12) = 5.79 for recall condition and F(1,12) = 7.87 for order, both p < 0.05. The interaction was not significant (F < 1).
Table 1. Task performance
Task Order No. of responses No. correct % correct VOL PICTURE RECALL 1 14.5 14.3 89 851 2 13.8 13.6 85 843 AUDITORY WORD RECALL 1 13.6 12.8 80 850 2 13.1 12.5 78 989 Performance data obtained during PET scans. VOL, Voice onset latencies (mean value in msec). Voice onset latencies for RECALL indicated that responses in both PICTURE RECALL and AUDITORY WORD RECALL were significantly slower than during REPETITION (mean REPETITION latency was 539 msec for the first presentation and 508 msec for the second), presumably reflecting the additional processing that is necessary for RECALL. Both effects were significant (p < 0.0001). Response latencies between PICTURE RECALL and AUDITORY WORD RECALL did not significantly differ (Table 1) (p > 0.2).
Subjects correctly recognized 91% of the pictures in the after-scan picture recognition test, indicating that they had encoded and stored the visual attributes of the studied pictures.
PET results: activations identified based on strict criteria
Analyses were first performed to identify brain areas related to the general episodic retrieval demands of the two RECALL tasks compared with the multiple reference control tasks. rCBF changes were identified in the RECALL minus REPETITION task subtraction (collapsed across PICTURE RECALL and AUDITORY WORD RECALL tasks) and similarly for the RECALL minus REST task subtraction.The results of these two comparisons revealed many activations during RECALL (Tables 2 and 4; Fig. 3). Most consistent were: bilateral frontal-opercular cortex, in the anterior insula; anterior cingulate cortex, possibly including multiple areas; and an anterior region of the supplementary motor area (SMA). The location of the SMA activation shifted posteriorly when compared with REST (see section below).
Table 2. Identification of rCBF increases in RECALL minus REPETITION using strict criteria
Brain area Data from replication analysis (data set divided as described in text) Best estimate of location and t value (from combined data set) Data set No. 1 Data set No. 2 x y z Magnitude Significance x y z t value SMA 3
15 47 102 p < 0.05 13 50 7.12 Anterior cingulate 19 36 65 p < 0.01 17 34 5.55 Anterior cingulate 29 26 61 p < 0.05 31 22 6.32 Posterior medial parietal 38 53 p < 0.05 34 3.99 Anterior medial cerebellum 57 p < 0.05 2.01 Left anterior insular 15 6 60 p < 0.05 13 6 4.33 Left posterior parietal 42 86 p < 0.05 38 4.13 Right anterior insular 33 15 8 55 p < 0.05 31 15 2 3.81 Right anterior prefrontal 29 47 14 66 p < 0.01 27 49 16 5.14 Right anterior prefrontal 29 53 63 p = 0.09 29 59 6.46 Right prefrontal 41 21 26 52 p < 0.005 39 23 28 3.83 Right lateral parietal 33 40 52 p < 0.005 33 42 3.31 Legend to Tables 2-4. Activations determined to be reliable using replication criteria are listed along with the best estimate of their location from the combined data set (see text). BA, Approximate Brodmann area location. Stereotaxic locations are listed (x, y, z) in the space of Talairach and Tournoux (1988) 
Fig. 3. Horizontal sections show PET data from several of the subtraction images analyzed. All data are raw subtraction data displayed without threshold so that the quality of the image data can be observed. Brighter colors represent larger rCBF changes (peak = white). Activations in the cerebellum are not shown but are listed in Tables 2, 4, and 6. Top, rCBF increases are shown (scaled to 70 PET counts). Several areas, only some of which are labeled, were found to be activated in RECALL minus REPETITION including SMA (A), posterior medial parietal cortex (B), anterior cingulate (C), right anterior prefrontal cortex (D), and bilateral frontal-opercular cortex (E, F). RECALL minus REST (scaled to 100 PET counts) revealed many of the same activations with only minimal activation of right anterior prefrontal cortex (D) and robust activation of motor cortex (G, H) and auditory cortex (I, J). Bottom, rCBF decreases are shown for all of the tasks involving auditory stimulation (AUDITORY WORD RECALL, PICTURE RECALL, and REPETITION) compared with REST. Robust rCBF decreases in somatosensory cortex (A) (right > left) and visual cortex (B-F) are seen across all comparisons (scaled to
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Robust right anterior prefrontal activations were observed only in relation to REPETITION. When RECALL was compared with REST, the right anterior prefrontal activations were minimal (see section below). Several parietal activations including an area in posterior medial parietal cortex (near precuneus) showed activation (see section below). Finally, several cerebellar areas were activated across the comparisons, but most detected here likely are attributed to motor demands of the tasks, as they were not present in the RECALL minus REPETITION subtraction. However, a number of cerebellar areas were activated that appear to be related to the nonmotor aspects of the tasks, as was demonstrated using the lenient criteria.
Several areas were found to be deactivated during RECALL (i.e., more activated during the reference tasks than during the RECALL tasks; Tables 3 and 5). These included a medial orbital frontal area and a medial parietal area that was anterior to the increased activation described above (Fig. 4). In relation to REST, a number of highly robust decreases in visual areas were present, as were similarly robust decreases in somatosensory cortex (Fig. 3) (see section below).
Table 3. Identification of rCBF decreases in RECALL minus REPETITION using strict criteria
Brain area Data from replication analysis (data set divided as described in text) Best estimate of location and t value (from combined data set) Data set No. 1 Data set No. 2 x y z Magnitude Significance x y z t value Medial frontal 27 p < 0.001 29 3.71 Medial parietal 42 p = 0.09 40 2.66 Left posterior insular 6 p < 0.05 6 5.01 Left lateral parietal 20 p < 0.005 16 4.52 Left lateral parietal 38 p < 0.005 36 5.31 Left BA 4/6 30 p < 0.05 No peak Left BA 28/34 p = 0.09 3.78 Right BA 43 55 18 p < 0.05 53 20 4.28 Right posterior insular 43 16 p < 0.05 41 14 3.59 Right lateral parietal 45 22 p < 0.01 49 24 4.27 See legend to Table 2.
Table 4. Identification of rCBF increases in RECALL minus REST using strict criteria
Brain area Data from replication analysis (data set divided as described in text) Best estimate of location and t value (from combined data set) Data set No. 1 Data set No. 2 x y z Magnitude Significance x y z t value SMA 7 54 82 p < 0.001 7 52 6.97 Anterior cingulate 25 38 54 p < 0.01 23 38 4.73 Medial thalamus 1 0 95 p < 0.005 0 5.79 Medial cerebellum 83 p < 0.001 7.61 Posterior medial parietal 40 56 p = 0.05 40 2.59 Anterior medial cerebellum 73 p = 0.0.5 3.30 Left anterior insular 19 8 99 p < 0.005 19 4 5.21 Left prefrontal 15 26 59 p < 0.05 15 26 4.91 Left primary motor 40 67 p < 0.01 40 6.18 Left superior temporal gyrus 6 106 p < 0.005 10 6.91 Right anterior insular 33 19 8 60 p < 0.005 31 19 8 4.39 Right posterior thalamus 21 8 61 p < 0.05 19 8 3.05 Right cerebellum 17 87 p < 0.05 13 6.63 Right cerebellum 35 75 p < 0.05 29 4.31 Right lateral cerebellum 51 65 p < 0.01 49 4.35 Right posterior cerebellum 19 67 p = 0.05 No peak Right primary motor 55 38 54 p = 0.08 47 38 4.63 Right superior temporal gyrus 53 8 98 p < 0.005 53 10 5.02 See legend to Table 2.
Table 5. Identification of rCBF decreases in RECALL minus REST using strict criteria
Brain area Data from replication analysis (data set divided as described in text) Best estimate of location and t value (from combined data set) Data set No. 1 Data set No. 2 x y z Magnitude Significance x y z t value Medial prefrontal 57 0 90 p < 0.05 55 3.54 Medial prefrontal 1 43 0 78 p = 0.06 37 5.11 Left extrastriate (BA 18) 0 93 p < 0.005 0 4.88 Left extrastriate (BA 19) 18 80 p < 0.0005 20 7.22 Left parietal 46 67 p < 0.005 48 4.96 Left extrastriate (BA 19) 24 81 p < 0.005 No peak Left extrastriate (BA 19) 6 66 p < 0.005 2 6.89 Left prefrontal (BA 47) 39 64 p < 0.05 39 3.64 Left parietal 58 61 p < 0.05 58 4.85 Left parietal 28 52 p = 0.07 32 4.13 Right extrastriate (BA 19) 37 0 98 p < 0.005 41 0 7.65 Right somatosensory 47 38 87 p < 0.005 49 38 6.22 Right extrastriate (BA 18) 17 14 78 p < 0.0001 17 14 3.89 Right parietal 47 24 80 p < 0.05 45 22 5.67 Right inferior temporal 49 67 p < 0.05 49 4.43 Right parietal 29 46 60 p < 0.05 29 44 4.38 Right extrastriate (BA 19) 35 30 57 p < 0.05 No peak Right extrastriate (BA 18) 21 55 p < 0.05 27 6 5.49 Right extrastriate (BA 19) 25 52 p < 0.05 23 4.69 Medial parietal 17 22 50 p < 0.01 5 26 3.04 See legend to Table 2. 
Fig. 4. Horizontal sections show PET data as in Figure 3. Top, rCBF change for two distinct areas along medial frontal cortex are shown separately for two different sets of tasks. REPETITION minus REST reveals a posterior medial frontal activation in SMA (SMA PROPER). In addition to this activation, RECALL minus REPETITION reveals a second more anterior activation (PRE-SMA). The same separation between posterior and anterior divisions of medial frontal cortex is shown for READING minus FIXATION (SMA PROPER) and VERB GENERATION minus READING (PRE-SMA). Middle, Two separate medial parietal areas show rCBF change. A more posterior area shows an rCBF increase in RECALL compared with either REPETITION or REST, whereas a second more anterior area shows a reliable rCBF decrease in the same subtraction images. Bottom, A bilateral rCBF increase (right) is shown that appears to originate from somewhere within the eye muscles as demonstrated by comparison to an averaged MRI image (left).
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To determine brain areas that differed between PICTURE RECALL and AUDITORY WORD RECALL, the two tasks were directly compared. Surprisingly, almost no rCBF differences were noted between them (no activations reached the strict criteria). A few areas reached the lenient criteria as described below, but none of these was in visual cortex.
PET results: activations identified based on lenient criteria
Tables 6, 7, 8, and 9 show additional activations identified by the lenient criteria for the RECALL minus REPETITION, RECALL minus REST, and PICTURE RECALL minus AUDITORY WORD RECALL subtractions. Absence of a table for a given comparison means that no additional activations met the lenient criteria.
Table 6. Identification of rCBF increases in RECALL minus REPETITION using lenient criteria
Brain area Data from combined data set x y z Magnitude t value Posterior medial cerebellum 9 62 3.57 Left lateral cerebellum 60 10.25 BA 6 or cingulate 17 17 42 58 4.48 Near BA 31 3 28 51 4.21 Legend to Tables 6-9. Activations meeting the more lenient criteria (all t > 3.50 in combined data set) are listed along with their stereotaxic locations in x, y, z coordinates from the Talairach and Tournoux (1988)
Table 7. Identification of rCBF increases in RECALL minus REST using lenient criteria
Brain area Data from combined data set x y z Magnitude t value Medial thalamus 5 8 76 4.94 Left temporal (BA 21) 0 57 7.05 See legend to Table 6.
Table 8. Identification of rCBF decreases in RECALL minus REST using lenient criteria
Brain area Data from combined data set x y z Magnitude t value Left extrastriate (BA 18) 14 6.86 See legend to Table 6.
Table 9. Identification of rCBF increases in PICTURE RECALL minus AUDITORY WORD RECALL using lenient criteria
Brain area Data from combined data set x y z Magnitude t value Left temporal (BA 21/37) 52 3.58 Right lateral cerebellum 41 57 4.42 Putamen 27 0 56 5.69 See legend to Table 6. Behavior of right prefrontal cortex and comparison to other studies
A reliable right anterior prefrontal activation was observed in RECALL minus REPETITION (Fig. 3). Because this area was localized close to the right prefrontal activation noted in our earlier studies (Squire et al., 1992Behavior of medial-parietal cortex
RECALL compared with either reference task revealed rCBF increases in a posterior medial parietal area (Tables 2, 4) and rCBF decreases in an anterior medial parietal area [Table 3; a rCBF decrease was noted against REST at
Fig. 5. Regional activation magnitudes are displayed with SE bars. Each region was tracked across multiple subtraction pairs as listed on the x-axis. Left panel, Regional rCBF change for two separate parietal regions. The two regions, which show completely opposite behavior, change rCBF in relation to the RECALL task compared with either of the reference tasks, whereas both show no rCBF change when the two reference tasks are compared directly. Right panel, Regional rCBF change for two separate divisions of medial frontal cortex. One area (SMA proper), shown with lighter shading, increased rCBF for both RECALL and REPETITION compared with REST, whereas the second area (pre-SMA) showed an rCBF increase only during RECALL.
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The posterior region, near precuneus, showed rCBF increases for both RECALL tasks compared with either of the reference tasks, with no rCBF change between the two reference tasks. The second more anterior region showed the exact opposite behavior: rCBF was decreased in RECALL compared with either reference task.
Separation of pre-SMA and SMA
Activation of an anterior division of the medial frontal wall was noted in the RECALL minus REPETITION subtraction (Fig. 3, Table 2). This area, which might be termed pre-SMA (Picard and Strick, in press), was activated in addition to a more posterior area, possibly SMA proper, already activated by REPETITION (compared with REST). The behavior of these two areas (anterior pre-SMA location =The idea that multiple divisions of human SMA can be distinguished by activation studies has been suggested previously (Picard and Strick, in press). One possibility is that internally generated motor programs are facilitated by the additional recruitment of pre-SMA. This would explain the observed dissociation between RECALL, which required outputting a word from memory, and REPETITION, which required saying aloud a word presented to the subjects.
To further explore this possibility, previous data collected during a word reading task (Buckner et al., 1995c
Visual regions previously activated during picture viewing
Table 10 shows the locations of the five regions identified in our previous picture-viewing study (Buckner et al., 1995c
Table 10. Mean rCBF changes for visual extrastriate areas previously determined to be involved in picture processing
Location PICTURE RECALL minus AUD. WORD RECALL PICTURE RECALL minus REPETITION PICTURE RECALL minus REST AUD. WORD RECALL minus REPETITION AUD. WORD RECALL minus REST x y z Mean SE Mean SE Mean SE Mean SE Mean SE 18 10 11 15 11 15 0 12 13 11 15 12 13 20 13 0 12 14 3 15 8 33 15 13 18 17 11 41 4 12 9 14 13 14 Stereotaxic locations for the five regions found to be activated during picture viewing (Buckner et al., 1995c In contrast, the visual regions showed marked decreases in rCBF across several of the task comparisons. The most robust decreases were present when either of the RECALL tasks were compared with REST. Such rCBF decreases were also detected in the previous replication analyses and were among the most reliable activations determined in this study. These findings, although not predicted in the context of memory retrieval, parallel a phenomenon observed by Haxby and colleagues (Haxby et al., 1994
A post hoc examination of the REPETITION minus REST subtraction supports this idea because robust visual cortex rCBF decreases were again noted (Fig. 3). The REPETITION task also demanded the use of auditory information but did not require long-term episodic memory retrieval.
Moreover, rCBF decreases also were noted in somatosensory cortex for all of the tasks involving auditory stimulation compared with rest, suggesting that the effect is not specific to interactions between only visual and auditory cortices. This later finding is also consistent with the work of Haxby et al. (1994)
Bilateral frontal-opercular cortex
A surprising finding was that bilateral frontal-opercular areas were activated during the RECALL tasks compared with either of the references tasks. Such a finding suggests that these areas may play a role in episodic retrieval. However, these areas have not previously been reported as active during episodic retrieval tasks. To explore the possibility that such activations might have been missed during previous analyses, we reanalyzed data from our earlier set of experiments involving episodic retrieval using the stem-cued recall task (Buckner et al., 1995aReanalysis of stem-cued recall minus fixation using a formal procedure revealed that bilateral frontal-opercular activations were reliably present in that data set, but only at a relatively weak level (left =
Results of within-subject analysis
Of 11 subjects who had a sufficient data set for within-subject analyses, six demonstrated right anterior prefrontal activations and six demonstrated medial parietal activations that met identification criteria. Data from several of these subjects are presented in Figure 6. The presented data come from those subjects whose activations made the largest contributions to the group averaged image using a ``weighted mean,'' i.e., weighting distance from the averaged location and peak magnitude of the activation. In this way, the data displayed represent activations passing a conservative magnitude threshold and also represent those subjects who contributed most to the replicated group activations.
Fig. 6. Within-subject PET activation data are shown coregistered with structural MRI data. Three single subject activations for each of two areas are shown (see Results). The color sections are transverse PET images with raw subtracted PET data from each subject. Images are scaled near the slice maximum. Three separate MRI views of each subject are aligned to center on the peak activation identified in the PET image (see Materials and Methods). Red lines and square markings show corresponding locations across the different modality types and views.
[View Larger Version of this Image (97K GIF file)]
For the right anterior prefrontal activation, subjects P2503, P2518, and P2526 were the most certain activations with weighted magnitudes of 86, 83, and 73 PET counts, respectively; for the medial parietal activation, subjects P2539, P2526, and P2525 were with weighted means of 75, 61, and 55 PET counts, respectively.
Based on Damasio (1995)
The medial parietal activations (rCBF increases) localized remarkably well to the parieto-occipital sulcus (POS), which borders precuneus and cuneus. Identification of the POS was accomplished by marking multiple-point locations in a sagittal view and projecting these points onto the transverse sections similar to Damasio (1995)
These localizations should be interpreted conservatively because of the several sources of error (e.g., error induced by PET-MR coregistration, resolution of the 953B tomograph, and volume averaging errors that might bias peak activation location estimates toward denser gray matter regions).
EOG results
Each horizontal eye movement record was quantified to detect individual saccades (square-wave jerks), slow drifting eye movements (Fig. 7), and erratic movements (Fig. 7). There were few isolated square-wave jerk saccades (3 per scan condition, on average) during any of the task conditions. Considerable portions of the records, however, contained periods of erratic eye movements. These erratic eye movements are most likely the product of random frequent saccades that could not be individually isolated given our recording methods and are consistent with the experimental procedure that required subjects to close their eyes during the task conditions.
Fig. 7. Examples of slow drift and erratic movement as measured by the horizontal EOG for subject p2537. Vertical displacement on the record reflects horizontal eye movements. Time bar indicates scale of horizontal axis.
[View Larger Version of this Image (11K GIF file)]
Erratic eye movements were quantified in terms of the percentage of the task period that contained erratic movements. Erratic eye movements decreased as a function of the complexity of the scan task: 66% for RECALL, 43% for REPEAT, and 28% for REST. The difference between RECALL and REST was significant (t[13] = 3.36; p < 0.01), and the difference between RECALL and REPEAT showed a trend (t[13] = 1.78; p = 0.09). PICTURE RECALL and AUDITORY WORD RECALL were nearly identical (68 and 64%, respectively).
Slow drifting eye movements, which did not involve saccades, showed the exact opposite pattern: 2% for RECALL, 13% for REPEAT, and 42% for REST. The difference between RECALL and REST was significant (t[13] = 3.85; p < 0.01) as was the difference between REPEAT and REST (t[13] = 3.24; p < 0.01). The difference between RECALL and REPEAT showed only a trend for significance (t[13] = 1.88; p = 0.08).
The presence of substantial periods of slow drifting eye movements during REST may suggest that the REST condition involved a lesser level of arousal than any of the other more active task conditions.
Identification of a potential eye muscle artifact
After initial inspection of the data from the RECALL minus REST and RECALL minus REPEAT subtraction images, there appeared to be a bilateral activation in inferior orbital frontal cortex. However, when the images were viewed without a template masking the brain, the orbital frontal activations were found to originate from a source inferior to the brain. Coregistration with MRI suggested that the activation sources localized to the region of the eye muscles (Fig. 4). This finding is consistent with the observation that RECALL elicited more erratic eye movements than either REST or REPEAT. Thus, it seems that a blood flow response in the region of the eye muscles can be modulated by task demands and/or behavioral output. Moreover, this response can produce an artifact that appears within the brain
DISCUSSION
Two episodic memory retrieval tasks involving paired-associate recall were studied. One task relied on pictorial retrieval (PICTURE RECALL) and the second relied on auditory word retrieval (AUDITORY WORD RECALL). When the direct comparison between PICTURE RECALL and AUDITORY WORD RECALL was analyzed, few noteworthy activation differences were detected between the two tasks. Many robust and reliable activations were, however, detected across the two tasks. For this reason, the two tasks will be discussed collectively as RECALL. The commonalities will be discussed first.During the RECALL tasks, a distributed pathway of brain areas was activated. This pathway included areas in auditory cortex, bilateral frontal-opercular cortex, anterior cingulate, posterior medial parietal cortex, right anterior prefrontal cortex, two separable areas of medial frontal cortex (SMA proper and pre-SMA), motor cortex, and cerebellar areas. Components of this pathway, as they relate to other episodic retrieval tasks and nonepisodic retrieval tasks, can only be appreciated by comparing data from multiple studies.
To facilitate such a comparison, Figure 8 presents heuristic diagrams of tentative cortical pathways activated during four different tasks involving memory retrieval: (1) the paired-associate RECALL tasks discussed in this paper; (2) another set of episodic retrieval tasks based on stem-cued recall (Buckner et al., 1995a
Fig. 8. Heuristic diagrams illustrate current functional anatomic characterizations of four verbal tasks relying on long-term memory retrieval (see Discussion). These diagrams are tentative. The areas activated by each task are indicated by boxes, with similarly localized areas occurring in consistently positioned boxes across diagrams. In each diagram, the left-most boxes reflect left-lateralized brain areas and the right-most boxes reflect right-lateralized brain areas. Question marks are included in several of the boxes to indicate that there is some uncertainty over whether one or multiple areas are included. A set of areas (shown in thick outlined boxes) demonstrates activation during episodic memory retrieval and may reflect areas being recruited to guide processes selectively demanded by episodic retrieval tasks. SMA proper and pre-SMA are joined in stem-cued recall and stem completion to reflect the fact that the activations could not be separated in those studies. Subcortical structures, including consistently activated cerebellar areas, are not included in these diagrams for simplicity.
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Contrasting these tasks reveals a common set of areas that appears to underlie processes generally related to accessing and producing words. The common areas include left inferior prefrontal cortex in or near frontal-opercular cortex, anterior cingulate, and pre-SMA. Also shared in common were SMA proper and motor cortex, which probably play a relatively direct role in programming the motor aspect of speech (Petersen and Fiez, 1993
Right anterior prefrontal activation, at or near BA 10, has now been observed across several tasks involving episodic retrieval (for review, see Buckner and Petersen). The observation of activation in the present RECALL tasks establishes that such activation is not attributable to the alternation between task strategies, as was possible given earlier experimental confounds (Buckner et al., 1995a
As for the specific role this right anterior prefrontal area contributes to episodic memory, some have suggested that processes related to retrieval effort and search are the most likely candidates (Schacter et al., 1996
The second area emerging as a candidate for a prominent role in episodic retrieval is the posterior medial parietal cortex (near precuneus). Although we have observed this activation previously, its potential contribution to episodic memory was not appreciated because large, closely localized rCBF decreases were observed in another comparison not involving episodic retrieval (Buckner et al., 1995a
Fletcher et al. (1995a)
One hypothesis about the role this area plays in episodic retrieval is that it participates in imagery processes inherent to episodic retrieval (Fletcher et al., 1995a
Robust activations were observed in bilateral frontal-opercular cortex during RECALL. Although such activations have not previously been reported during episodic retrieval, a reanalysis of an older set of stem-cued recall tasks suggested that these areas may be activated more often then originally thought. The consistency of this bilateral activation across five episodic retrieval tasks [three tasks in Buckner et al. (1995a)
The most perplexing finding was the absence of large differences between PICTURE RECALL and AUDITORY WORD RECALL, especially in visual cortex. This is because PICTURE RECALL was designed to have an imagery component, and much recent data have supported the notion that visual extrastriate cortex and possibly earlier visual areas participate in such processes (Kosslyn et al., 1993
An activation was noted in left temporal cortex (see Table 9). Although this activation was not replicated by the strict analysis criteria, it is worthwhile to note that this activation falls within the vicinity of a region proposed to play a role in imagery demands based on neuropsychological findings (Farah, 1995
Comparisons of RECALL to REPETITION or REST also did not reveal any activations in visual cortex. Rather, the comparison to REST revealed robust rCBF decreases in several visual areas, which may reflect a form of crossmodal suppression (Haxby et al., 1994
In summary, detailed functional anatomic descriptions of two episodic retrieval tasks were presented. At present, it appears that a family of tasks activate a closely related set of brain areas. This common pathway may be used to access and maintain representations of words during their retrieval and production
The present data additionally offer insight into more detailed aspects of the pathways activated during such tasks. Human SMA is often discussed as one area. Our data provide evidence within a single set of studies for a distinction between two subdivisions of medial frontal cortex (SMA proper and pre-SMA), as suggested by Picard and Strick (in press). Two subdivisions of medial parietal cortex were also demonstrated with only one of the areas (near precuneus) showing increased rCBF during episodic retrieval.
FOOTNOTES
Received Feb. 29, 1996; revised July 9, 1996; accepted July 15, 1996.
This work was supported by National Institutes of Health Grants NS06833, EY08775, HL13851, and Grant AG08377, the Charles A. Dana Foundation, and the McDonnell Center for the Study of Higher Brain Function. We thank Dacia Hunton, Maurice Makram, Len Lich, John Hood, Tom Videen, and the staff of the Cyclotron Unit for technical assistance, and Avi Snyder for help with the MRI data.
Correspondence should be addressed to Dr. Randy L. Buckner, MGH-NMR Center, 13th Street Building 149, Room 2301, Charlestown, MA 02129.
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