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The Journal of Neuroscience, October 15, 2000, 20(20):7776-7781
Functional Magnetic Resonance Imaging (fMRI) Activity in
the Hippocampal Region during Recognition Memory
Craig E. L.
Stark1 and
Larry R.
Squire1, 2
1 University of California, San Diego, California
92093, and 2 Veterans Affairs Medical Center, San
Diego, California 92161
 |
ABSTRACT |
Neuroimaging studies have often failed to observe activity in the
hippocampal region during memory retrieval. Recently, two functional
magnetic resonance imaging studies reported activity in the hippocampal
region associated with recollective success. In both, participants
studied pictures of objects and were given a recognition memory test
with words that either did or did not name the studied objects. The
recognition test was therefore cross-modal or associative in nature.
These findings raise the question of what circumstances are required to
observe activity in the hippocampal region during memory retrieval.
Here, we report that robust hippocampal activity for targets relative
to foils occurred during retrieval in a recognition memory task when
single words were used at both study and test, as well as when pictures
of single nameable objects were used at both study and test. The
hippocampal region is involved not just in overtly associative tasks
but more broadly in the recollection of recently occurring facts and events.
Key words:
recognition memory; fMRI; hippocampus; declarative
memory; amnesia; associations
| |
INTRODUCTION |
Lesion studies of humans and
experimental animals have identified a system of medial temporal lobe
(MTL) structures essential for the formation of declarative memory
(memory for facts and events) (Milner et al., 1998 ). The contributions
of the separate components of this system are not well understood.
Recently, neuroimaging techniques have provided additional evidence for
the importance of the MTL in learning and memory (for review, see
Lepage et al., 1998; Schacter and Wagner, 1999) and have begun
to examine the role of specific structures during encoding and
retrieval. For example, during encoding, MTL activity is lateralized
based on stimulus type. Activity is usually left unilateral during the encoding of words (Martin et al., 1997; Wagner et al., 1997; Kelly et
al., 1998) (but see Fernandez et al., 1998) and bilateral during the learning of objects or pictures (Gabrieli et al., 1997; Martin et
al., 1997; Brewer et al., 1998; Kelly et al., 1998). Furthermore, the
level of activity in the MTL during learning is positively correlated
with subsequent recognition memory accuracy (Wagner et al., 1997;
Brewer et al., 1998; Fernandez et al., 1998).
Neuroimaging has been used less often to study memory retrieval, no
doubt in part because of early failures to demonstrate activity in the
MTL during retrieval (Grasby et al., 1993; Kapur et al., 1994; Shallice
et al., 1994; Tulving et al., 1994; Buckner et al., 1995; Fletcher et
al., 1995; Haxby et al., 1996). More recently, however, a number of
studies have reported activity in the MTL during retrieval tasks (for
review, see Lepage et al., 1998; Schacter and Wagner, 1999). Some of
these studies contrasted activity during retrieval with activity during
a perceptual baseline (a broad contrast that includes many cognitive
functions, including the intention and effort to retrieve). Other
studies contrasted the activity associated with studied target items
with activity associated with unstudied foil items to identify brain
regions associated with recollective success. Of the studies that
compared targets with foils, most used positron emission tomography
(PET) to observe activity in the MTL during retrieval (Nyberg et al., 1995; Fujii et al., 1997; Schacter et al., 1997). However, with PET, the limited spatial resolution (1-2 cm) makes it difficult to
isolate the hippocampal region (the CA fields of the hippocampus, the
dentate gyrus, and the subiculum) from adjacent structures in the
parahippocampal gyrus.
Two studies have found bilateral activity in the hippocampal region at
retrieval for targets versus foils using the higher resolution
available with functional magnetic resonance imaging (fMRI) (Gabrieli
et al., 1997; Stark and Squire, 2000). In both studies, participants
studied pictures of objects and were tested with words that either did
or did not name the objects. This task requires the formation or use of
associations between objects and words. Whether such a cross-modal or
associative task is required to observe hippocampal activity has broad
theoretical implications for understanding the role of the hippocampus.
Indeed, it has been suggested that the hippocampus is essential for
forming and using associations and that simpler tasks of recognition
memory can be supported by the adjacent cortex (Henke et al., 1997,
1999; Murray and Mishkin, 1998; Aggleton and Brown, 1999). We now
report that robust hippocampal activity occurs during retrieval when single words are used at both study and test, as well as when single
nameable objects are used at both study and test. Because there have
been very few studies reporting hippocampal activity during recognition
memory testing, we conducted our experiments independently at two
different fMRI facilities to ensure the reliability of our results. The
same results were obtained at both facilities.
| |
MATERIALS AND METHODS |
The participants were 9 male and 13 female right-handed
volunteers (5 in each condition at site 1 and 6 in each condition at
site 2; mean age, 26 years; range, 18-38 years) who gave informed consent before the study. Participants first viewed 80 items, twice
each [duration, 2 sec; intertrial interval (ITI), 0.5 sec] outside the scanner with instructions to study the items for a later
test. For half the participants (n = 11), the stimuli
were line drawings of common nameable objects (Snodgrass and
Vanderwart, 1980). For the other half (n = 11), the
stimuli were words presented in capital letters that named the objects.
Approximately 30 min after this study phase, 160 items (80 studied
targets and 80 nonstudied foils) were presented on a screen located at
the participant's feet (duration, 1.5 sec; ITI, 0.5 sec) while fMRI
data were collected. Using their right hands, participants pressed one
button on a response box to indicate that the item was studied (target)
and another to indicate that it was not (foil). Which items served as
targets and foils were counterbalanced across participants. A variant
of the "boxcar" or blocked design was used in which test items were
presented in eight blocks of 20 items each (40 sec/block). Blocks
alternated between primarily targets (T; 18 targets and 2 foils) and
primarily foils (F; 18 foils and 2 targets). Additionally, at site 2, 40 sec "rest" periods (R) were placed at the beginning and end of
the recognition memory test (RTFTFTFTFTFR). The recognition test was
given twice to each participant (~3 min between tests 1 and 2). The
two tests were identical, except that the order of items was different
in each test.
Imaging parameters. At site 1, imaging was performed on a
General Electric (Milwaukee, WI) 1.5T Signa clinical MRI scanner fitted
with high-performance local head gradient and radio-frequency coils
(Wong et al., 1992a,b). Functional T2*-weighted images were acquired
using an echoplanar, single-shot pulse sequence with a matrix size of
64 × 64, echo time (TE) of 40 msec, flip angle of 90°, and
in-plane resolution of 3.75 × 3.75 mm. For each scanning run, 90 images were acquired for each of 21 sagittal 6 mm slices in an
interleaved fashion with a repetition time (TR) of 3.6 sec. The first
two images from each slice were discarded to assure that the MR signal
had reached equilibrium on each slice. At site 2, imaging was performed
on a Siemens (Erlangen, Germany) 1.5T Vision clinical MRI scanner
fitted with a large clinical "flex" coil and a bite bar. Functional
T2*-weighted images were acquired using an echoplanar, single-shot
pulse sequence with a matrix size of 64 × 64, TE of 43 msec, flip
angle of 90°, and in-plane resolution of 4 × 4 mm. For each
scanning run, 164 images were acquired for each of 16 4-mm-thick slices
aligned with the principal axis of the hippocampus in an interleaved
fashion with a TR of 2.475 sec. In Figures 1-3, the approximate area
covered by these slices at site 2 is indicated by a green
box. The first four images from each slice were discarded to
assure that the MR signal had reached equilibrium on each slice. At
both MRI sites, a high-resolution MP-RAGE structural scan was
acquired for anatomical localization.
Image analysis. Images from site 1 were first corrected for
distortion attributable to field inhomogeneity (Reber et al., 1998).
This capability was not available at site 2. At both sites, images were
then co-registered through time using a two-dimensional (2D)
registration algorithm (Cox, 1996). Each slice was spatially smoothed
using a 2D (in-plane) Gaussian kernel; full width half-maximum = two voxels. Within each run, voxels were eliminated if the signal magnitude changed >8% between two samples or if the mean signal level
was below a threshold defined by the inherent noise in the data
acquisition. Such voxels (none were located in the hippocampal region)
are likely to be contaminated by motion effects, venous effects, or
exceptionally poor signal-to-noise ratios and cannot contain reliable
data. Each participant's runs were then averaged and transformed
(Collins et al., 1994; Cox, 1996) to conform to the atlas of Talairach
and Tournoux (1988) using a nine-parameter transformation matrix with a
final voxel size of 2.5 mm3. Data from all
participants were then averaged.
Areas exhibiting activity selective for targets versus foils were
identified by cross-correlating the time course of activity in each
voxel against a set of seven time-shifted versions of an idealized
reference function derived from the eight alternating blocks of targets
and foils (Cox, 1996). An initial idealized reference function was
first constructed to reflect the lag (~6 sec) between neural activity
and hemodynamic response using a gamma function to model the response
to each event. Six additional versions of this reference function were
then constructed by shifting the idealized reference function both
forward and backward in time in three 1 sec steps. By cross-correlating
activity with multiple versions of the initial reference function, it
is possible to allow for potential subject- and voxel-wise variations
in the hemodynamic delay and for differences in the time of acquisition of each slice. Low-frequency noise was removed by including a third-order polynomial term in the cross-correlation procedure. The
resulting statistical maps were then thresholded at a two-tailed  level of 0.01 (site 1, r > 0.326; site 2 and the two
sites combined, r > 0.265). A clustering algorithm was
then applied to remove voxels that were not part of a cluster of at
least 125 mm3 of contiguous tissue (eight
resampled 2.5 mm3 voxels).
Combining data from the two MRI facilities. The fMRI data
from the two sites differed in their temporal resolution. At site 1, 88 samples of each voxel's activity (TR, 3.6 sec) were taken during each
5 min 17 sec test. At site 2, 128 samples of each voxel's activity
(TR, 2.475 sec) were taken during the same test along with 16 samples
before and after the test began. To combine the data from the two
sites, the fMRI data (averaged across participants) from each of the
conditions were transformed as follows. First, the 88 samples of the
activity of each voxel in the averaged data from site 1 (TR, 3.6 sec)
were linearly resampled into 128 samples (TR, 2.4675 sec). The two 128 sample data sets from the two sites were then averaged, and the
resulting data set was masked to include only voxels that contained
reliable data in both data sets.
Region of interest analysis. The fMRI data from site 2 included 40 sec rest periods immediately before and after each of the two recognition memory tests. Regions of interest (ROIs) were defined
by the clusters of activity observed in the fMRI data, averaged across
the two recognition memory tests. Within the left hippocampal region,
an 8-voxel ROI was present when participants were shown words at both
study and test, and a 90-voxel ROI was present when participants were
shown objects at both study and test. The fMRI data from the voxels
within each of these two ROIs were first averaged for tests 1 and 2 separately. Low-frequency drift within each ROI was then removed by a
third-order polynomial fit, and each of the 160 samples (2.475 sec/sample) was classified as falling within one of the three task
categories: rest, target, or foil. Because of the long rise and fall
times associated with the blood oxygen level-dependent (BOLD)
effect, samples that were acquired during a transition between blocks
were discarded when at least 85% of the activity could not be assigned
to one of the three task categories. The mean activity within the ROIs
associated with the rest periods was then used as a baseline to
calculate percent change associated with the presentation of targets
and foils. It should be noted that although the rest period can
provide a stable baseline across tests, it does not represent a measure of zero activity in the hippocampal region.
| |
RESULTS |
Using the statistical procedures described above, activation for
targets versus foils was observed in the hippocampal region when either
words or objects were being remembered (Fig.
1, combining across two MRI facilities
and two successive recognition tests). Activation occurred in the left
hippocampal region when participants saw words at both study and test
(Fig. 1a,b), and activation occurred bilaterally when
participants saw objects at both study and test (Fig. 1c,d).
Because the activation of the hippocampal region during retrieval has
been infrequently reported, the same experiments were conducted at two
different MRI sites to determine the reliability of the results. The
results were strikingly consistent at the two different MRI sites (Fig.
2, Site 1, Site 2, combining
across the two recognition tests that were given with words and across the two recognition tests that were given with objects). At each MRI
facility, activity was observed in the left hippocampal region when
either words or objects were being remembered, and the location of
activity within the hippocampal region was virtually identical at the
two facilities (Fig. 2, Words, posterior hippocampus;
Objects, middle of the left hippocampus and the full
anteroposterior extent of the right hippocampus). In the right
hippocampal region (data not shown), activity was observed at both
sites when objects were being remembered but reached significance only
at site 2.
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Figure 1.
Activity in the left and right hippocampal
regions. Shown are fMRI data from 11 participants who saw words at both
study and test (Words) and from 11 different
participants who saw pictures of nameable objects at both study and
test (Objects), averaged across two MRI facilities and
two recognition memory tests. Recognition memory accuracy was 80.2%
correct for words and 89.9% correct for pictures of objects. Areas of
significant fMRI signal change (targets vs foils) are shown in sagittal
sections as color overlays on the averaged structural
images [transformed to the atlas of Talairach and Tournoux (1988) at
29 left (L) and 29 right (R) (Words) and 27L and
27R (Objects)]. At site 1, whole-brain imaging was
performed, but at site 2, imaging data were obtained from sixteen 4 mm
slices aligned with the principle axis of the hippocampus. The
green box indicates the area in which reliable data were
available. When words were used at study and at test, activity was
observed in the left (a) but not in the right
(b) hippocampal region. When nameable objects
were used at study and at test, activity was observed in both the left
(c) and the right (d)
hippocampal regions.
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Figure 2.
Hippocampal region activity: sites 1 and 2. fMRI
data from participants in both the Words and
Objects conditions (two recognition tests for each
condition) were analyzed separately at each of the two MRI facilities
to assess the reliability of the findings (five participants in each
condition at Site 1 and six participants in each
condition at Site 2). Areas of significant fMRI signal
change (targets vs foils) in the left hippocampal region are shown in
sagittal sections as color overlays on the averaged
structural images [transformed to the atlas of Talairach and Tournoux
(1988) at 31L and 25L]. The green box indicates the
area in which reliable data were available from Site 2.
The findings were similar at the two sites. When participants saw words
at both study and test, activity was observed at test in the left
hippocampal region (a, b). When participants saw
nameable objects at both study and test, activity was also observed at
test in the left hippocampal region (c, d). For objects,
activity was also observed in the right hippocampal region at test
(data not shown) but reached significance only at Site
2.
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We also examined activity in the hippocampal region separately during
each of the two recognition memory tests (the same material was used in
each test). Combining across the two MRI facilities, activation of the
hippocampal region (targets vs foils) was observed (Fig.
3a-d) during the first of the
two word recognition tests (Test 1) and during the second of
two object recognition tests (Test 2). This same pattern of
results was observed in the data from each of the MRI facilities as
well (data not shown). Specifically, at each site, recognizing words
(vs foils) activated the left hippocampal region during test 1 but not
during test 2. Furthermore, at each site, recognizing objects (vs
foils) activated the hippocampal region bilaterally during test 2 but
not during test 1.
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Figure 3.
Hippocampal region activity: tests 1 and 2. fMRI
data from participants in both the Words
(n = 11) and Objects
(n = 11) conditions were analyzed separately for
each of the two recognition memory tests (Test 1, Test
2). The two tests were separated by ~3 min and presented the
same targets and foils but in different orders. Areas of significant
fMRI signal change in the left hippocampal region (targets vs foils)
are shown in sagittal sections as color overlays on the
averaged structural images [transformed to the atlas of Talairach and
Tournoux (1988) at 29L and 25L]. The green box
indicates the area in which reliable data were available from both MRI
facilities. When participants saw words at both study and test,
activity was observed in the left hippocampal region during the first
recognition memory test (a) but not the second
(b). When participants saw nameable objects at
both study and test, activity was observed in both the left and right
hippocampal regions (data not shown for the right side) during the
second recognition memory test (d) but not the
first (c). Reliable hippocampal activity during a
single recognition memory test (Words, Test 1;
Objects, Test 2) was observed not only when the data
were combined across the two MRI sites but also in the data from both
individual sites as well (data not shown). An ROI analysis of the
averaged fMRI data from site 2 indicated the likely source of the
words-objects × test 1-test 2 interaction. When participants
saw words at both study and test (e), left
hippocampal activity associated with presentation of foils (percent
signal change relative to baseline) was low in both Test
1 and Test 2, whereas activity associated with
the presentation of targets was high in Test 1 and low
in Test 2 (for a similar effect during encoding, see
Martin et al., 1997). When participants saw objects at both study and
test (f), activity associated with targets was
similar in Test 1 and Test 2 (also see
Martin et al., 1997). In contrast, the first presentation of the foils
(Test 1) resulted in considerably more activity than the
second presentation (Test 2), probably because the foils
were entirely novel during Test 1 but not during
Test 2. The enhanced activity in the hippocampal region
during Test 1 associated with the novel foils masked the
hippocampal activity associated with recognition of targets and reduced
the target versus foil difference. Error bars indicate SEM across the
60 fMRI samples in the averaged data that were associated with
presentation of either targets or foils.
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At site 2, fMRI data were also collected during 40 sec rest periods
immediately before and after each of the two recognition memory tests.
Hippocampal activity during these rest periods was then used as a
baseline against which to assess activity associated with both targets
and foils (Fig. 3e,f). When participants saw words at
both study and test (Fig. 3e), the first recognition memory
test revealed a large difference between targets and foils. This
difference was much reduced during the second recognition memory test,
because much less activity was associated with the targets. When
participants saw objects at both study and test, the results were
opposite (Fig. 3f). Only the second recognition test
revealed a large difference between targets and foils, because during
the first test the foils were associated with a relatively high level
of activity.
| |
DISCUSSION |
Activation was observed in the hippocampal region during
recognition memory testing when either words or pictures of nameable objects were used at both study and test. Activation was left unilateral for words and bilateral for objects, as has been reported previously in the case of memory encoding (Gabrieli et al., 1997; Martin et al., 1997; Wagner et al., 1997; Brewer et al., 1998; Kelly et
al., 1998). This pattern of activation was reliable, because it was
observed independently at two different MRI facilities. It should be
noted that activity associated with recollective success was not
consistently localized to either the more anterior or posterior region
of the hippocampus (for discussion, see Gabrieli et al., 1997; Lepage
et al., 1998; Schacter and Wagner, 1999).
There are at least two reasons why activity of the hippocampal region
during retrieval, in association with recollective success, has not
been commonly reported. First, the physical properties of the
hippocampal region (its small size and proximity to the sinus cavity)
make obtaining reliable data from the hippocampal region more difficult
than from other cortical areas. Second, the difference in activity
associated with targets and foils can often be reduced by activity
associated with the encoding of foils. Several studies have found
increased activity in the MTL associated with unfamiliar stimuli
(relative to familiar stimuli), even when participants are instructed
to view the stimuli passively (Stern et al., 1996; Lepage et al., 1998;
Schacter and Wagner, 1999). This relatively automatic activation of the
MTL associated with the encoding of unfamiliar stimuli works in
opposition to finding a target versus foil contrast during recognition
memory testing. Thus, the activity associated with the presentation of
foils was high in test 1 (Fig. 3f), largely masking
the difference in activity between targets and foils. In test 2, when
the foils were more familiar, the activity associated with foils
decreased substantially, revealing a large difference in activity
between targets and foils.
Interestingly, when words were used at both study and test (Fig.
3e), the activity associated with foils was low in both
recognition tests. Presumably because of their high preexperimental
familiarity, words have been shown to produce less activity in
association with encoding than do objects (Kelly et al., 1998). In both
tests 1 and 2, this factor may have contributed to the low level of activity for foil words. We also note that the activity associated with
target words was lower in test 2 than in test 1. We suggest that, for
both words and objects, each time the test is administered and the
targets and foils become more familiar, the activity associated with
targets and the foils will become more similar. One might therefore
expect that the level of activity in the hippocampal region associated
with targets and foils would eventually converge. At the beginning of
the present study, the words were more familiar than the pictures and
therefore exhibited a reduction in target activity sooner than the
pictures (i.e., from test 1 to test 2). It is possible that with more
than two repetitions of the test, activity associated with target
objects would also have diminished.
The experiments reported here used a variant of a blocked fMRI design
in which the presentation of stimuli alternates between primarily
targets and primarily foils. A purely blocked design represents one
extreme of a fundamental tradeoff between optimizing trial-to-trial
variability in stimulus presentation and the efficiency of the fMRI
design (Friston et al., 1999). In a purely blocked design, the stimulus
type to be presented on the next trial is easily predicted by the
current trial. However, a blocked design exploits the additive nature
of the BOLD response to multiple stimuli and produces a substantially
larger percent signal change between blocks than the percent signal
change between single events. Therefore, the efficiency of estimating
the difference in activity associated with the two stimulus types can
be several times higher in a blocked design than in an event-related
design (Friston et al., 1999). By including foil items in the blocks of
targets and by including target items in the blocks of foils, we
achieved an efficient fMRI design (similar to the "dynamic
stochastic" design of Friston et al., 1999) but also encouraged
participants to respond on the basis of their memory for the item
rather than on the basis of block structure.
To determine whether participants did respond primarily on the basis of
memory (rather than expectation), we compared recognition accuracy for
the minority items in each block (i.e., the two foil items in each
block of primarily target items and the two target items in each block
of primarily foil items) with recognition accuracy for the majority
items in each block. On average, participants scored 86% correct on
the majority items and 76% correct on the minority items. Thus, there
was only a small difference in recognition accuracy for majority
relative to minority items. Furthermore, the four participants who
demonstrated the largest differences were all at site 1 (average
difference at site 1, 13%); the average difference at site 2 was 6%.
Considering that the fMRI results at sites 1 and 2 were identical, it
seems unlikely that the blocked nature of the task affected the results
in any significant way.
The finding of robust hippocampal activation during retrieval of words
or objects shows that such activation occurs in traditional recognition
memory tasks and does not require tasks that are cross-modal, overtly
associative, or explicitly spatial (for another potential example, see
Henson et al., 1999). The data are consistent with lesion studies that
have demonstrated impaired visual recognition memory after damage
limited to the hippocampal region in humans and nonhuman primates (Reed
and Squire, 1997; Beason-Held et al., 1999; Zola et al., 2000). They
are also consistent with single-unit data of cells within the
hippocampus that indicate visual or olfactory recognition as an
abstract match-nonmatch signal, which sometimes occurs in conjunction
with other task features (Hampson et al., 1993, 1999; Fried et al.,
1997; Wiebe and Staubli, 1999; Wood et al., 1999; Suzuki and
Eichenbaum, 2000). Taken together, the available data indicate that the
hippocampal region is involved rather broadly during recognition memory performance.
It is also worth noting that the current findings are wholly consistent
with a role for the hippocampus in learning about relationships and
conjunctions among stimuli (Sutherland and Rudy, 1989; Eichenbaum et
al., 1994; Reed and Squire, 1999). In the recognition memory task
studied here, the item presented during the retention test must be
identified as what was presented during learning. Thus, at the time of
learning, an association must be made between a to-be-remembered item
and its context, and later this association must be retrieved. Indeed,
the use of this kind of association can be considered an example of the
process of rapidly forming conjunctions and retaining them across time
that is fundamental to declarative memory. The present findings
emphasize the fact that forming or retrieving an explicit association
between two stimuli (e.g., an object and a word) is not required to
engage the hippocampal region. It is sufficient simply to recognize the same stimulus that was presented at study. The question of how long
after learning hippocampal activity remains important for retrieval
(Milner et al., 1998; Bontempi et al., 1999; Stark and Squire, 2000) is
an important topic for future studies.
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FOOTNOTES |
Received May 4, 2000; revised Aug. 2, 2000; accepted Aug. 2, 2000.
This research was supported by the Medical Research Service of the
Department of Veterans Affairs, National Institute of Mental Health
Grants MH24600 and MH12278, the National Alliance for Research in
Schizophrenia and Depression, and the Metropolitan Life Foundation. We
thank Shauna Stark, Jennifer Frascino, Joyce Zouzounis, and Cecelia
Kemper for their assistance with data collection.
Correspondence should be addressed to Larry R. Squire, Veterans Affairs
Medical Center, 116-A, 3350 La Jolla Village Drive, San Diego, CA
92161. E-mail: lsquire{at}ucsd.edu.
| |
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ABSTRACT
INTRODUCTION
