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The Journal of Neuroscience, December 15, 1999, 19(24):10869-10876
Amygdala-Hippocampal Involvement in Human Aversive Trace
Conditioning Revealed through Event-Related Functional Magnetic
Resonance Imaging
Christian
Büchel1,
Raymond J.
Dolan1, 2,
Jorge
L.
Armony1, 3, and
Karl J.
Friston1
1 The Wellcome Department of Cognitive Neurology,
Institute of Neurology, London, UK WC1N 3BG, 2 The Royal
Free School of Medicine, London, UK NW3 2QG, and
3 Institute of Cognitive Neuroscience, University College
London, UK WC1E 6BT
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ABSTRACT |
Previous functional neuroimaging studies have characterized brain
systems mediating associative learning using classical delay conditioning paradigms. In the present study, we used event-related functional magnetic resonance imaging to characterize neuronal responses mediating aversive trace conditioning. During conditioning, neutral auditory tones were paired with an aversive sound
[unconditioned stimulus (US)]. We compared neuronal responses evoked
by conditioned (CS+) and nonconditioned (CS ) stimuli in which a 50%
pairing of CS+ and the US enabled us to limit our analysis to responses evoked by the CS+ alone. Differential responses (CS+ vs CS), related
to conditioning, were observed in anterior cingulate and anterior
insula, regions previously implicated in delay fear conditioning. Differential responses were also observed in the amygdala and hippocampus that were best characterized with a time × stimulus interaction, indicating rapid adaptation of
CS+-specific responses in medial temporal lobe. These results are
strikingly similar to those obtained with a previous delay conditioning
experiment and are in accord with a preferential role for medial
temporal lobe structures during the early phase of conditioning.
However, an additional activation of anterior hippocampus in the
present experiment supports a view that its role in trace conditioning is to maintain a memory trace between the offset of the CS+ and the
delayed onset of the US to enable associative learning in trace conditioning.
Key words:
associative learning; fear; medial temporal lobe; memory; functional neuroimaging; emotional learning
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INTRODUCTION |
In classical conditioning paradigms,
a previously neutral stimulus [conditioned stimulus (CS)] comes to
elicit a behavioral response through temporal pairing with an
unconditioned stimulus (US). In fear conditioning, the US is aversive,
and the behavioral response can be measured in terms of changes in skin
conductance responses (SCR) (Esteves et al., 1994 ). Hence, classical
conditioning is a form of associative learning involving linkage
between a neutral stimulus and a stimulus with innate behavioral significance.
The two most commonly used types of classical conditioning paradigms,
namely trace and delay conditioning, differ in the temporal relationship between the CS and the US. In delay conditioning, the US
is presented at the end of the CS so that they overlap temporally. In
trace conditioning, there is a gap between the offset of a CS and onset
of a US. The term trace conditioning stems from the idea that a
"memory trace" is necessary to "bridge the gap" between CS and
US so that associative learning can take place (Pavlov, 1927).
Lesion studies suggest a critical role for medial temporal lobe
structures, especially the amygdala, in the acquisition of conditioned
fear responses (Bechara et al., 1995; LaBar et al., 1995; LeDoux,
1996). However, the hippocampus also seems to play a key role in
classical conditioning if the CS is not immediately followed by the US,
as exemplified in trace conditioning paradigms. In eyeblink
conditioning, midbrain and cerebellar structures are sufficient for
associative learning to occur if CS and US are presented together
(i.e., delay conditioning). If a delay between CS and US is introduced
(i.e., trace conditioning), then data from animal studies (Solomon et
al., 1986; Moyer et al., 1990; Kim et al., 1995; McEchron et al., 1998)
and studies of amnesic patients (McGlinchey-Berroth et al., 1997; Clark
and Squire, 1998) indicate a crucial role for the hippocampus.
Event-related (mixed-single trial) functional magnetic resonance
imaging (fMRI) provides the optimal context for studying the
neurobiology of classical conditioning in humans, using functional neuroimaging (Buckner et al., 1996; Josephs et al., 1997; Büchel et al., 1998). In simple terms, this technique resembles those used to
record event-related potentials in electrophysiology in which different
stimuli are presented and sampled repeatedly over time. This approach
enabled us to investigate the neuronal basis of trace fear conditioning
in humans using a partial reinforcement discrimination-conditioning paradigm.
To identify the neuronal correlates of rapidly learned association, we
tested for differential responses between nonconditioned (CS) and
conditioned (CS+) stimuli over the whole experiment. Responses of this
type were expected in cortical regions. On the basis of previous
studies, we also anticipated responses in medial temporal lobe
structures implicated in emotional learning that would only be
expressed during acquisition. These were tested for with time × stimulus interactions to identify regions that responded more to the
CS+ in the early phases of the experiment. Acquisition-specific
responses to CS+ were expected in (1) the amygdala, given its central
role in all forms of emotional learning and (2) the hippocampus, which
could be specifically associated with trace conditioning.
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MATERIALS AND METHODS |
Paradigm. We studied 11 healthy volunteers (six male
and five female). Written informed consent was obtained before the
experiment. Two neutral tones (400 and 1600 Hz) with a duration of 3 sec were used as CS. During conditioning, one of the two CS was paired with a loud unpleasant tone (1 kHz) and consequently became CS+. The
amplitude of the US was set to 10% above each subject's aversive threshold [~100 dB(A); estimated by self-report during MR
scanning]. The 500 msec aversive tone (US) followed the offset of the
CS after a trace period of 1000 msec (Fig.
1). The assignment of the low (400 Hz) or
high (1600 Hz) frequency tone to either CS+ or CS was randomized
across subjects. The volume of both tones was adjusted to produce
identical subjective loudness levels. We used a 50% partial
reinforcement strategy (i.e., only half of the presentations of the CS+
were paired with the US [CS+paired]) to allow
us to assess evoked hemodynamic responses to the CS+ in the absence of
the US. In total, we presented 104 CS over 21 min. Fifty-two
were CS, 26 were CS+ paired with noise
(CS+paired), and 26 were unpaired CS+
(CS+unpaired). Figure 1A shows
an example of the scanning protocol. Computer-generated auditory
stimuli were delivered through plastic tubes, sealed by foam ear
inserts. To further decrease the influence of the gradient switching
noise from the scanner, the sound delivery system was shielded by
plastic ear defenders. Subjects were familiarized with the US and CS
during a 10 min preconditioning scanning session.
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Figure 1.
Illustration of the experimental design.
A, According to a 50% partial reinforcement, only
one-half of the presentations were followed by the US (i.e.,
CS+paired). Dotted and
dash-dotted vertical lines indicate the onset of the CS
and US, respectively. The three plots show the modeled hemodynamic
responses. Temporal and dispersion derivatives are omitted for clarity.
Responses are time-locked to the offset of the CS (CS,
CS+unpaired, and CS+paired). The
dashed line in the last row is an example
for a hypothetical response evoked by the US. Note the overlap in time
of hemodynamic responses for the paired CS+ and the US. The time scale
indicates that the ITI was randomized to introduce a phase shift
between sampling and stimulus onset (see Materials and Methods for
details). Thin vertical lines in the second
row demonstrate the relationship between the acquisition of
fMRI volumes and the presentation of stimuli. B, Details
of the temporal relationship between CS+ and US. Note that, because of
the partial reinforcement scheme, only 50% of the CS+ were actually
followed by a US.
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Functional imaging. Data were acquired with a 2 Tesla
Magnetom VISION whole-body MRI system (Siemens, Erlangen, Germany)
equipped with a head volume coil. Contiguous multi-slice
T2*-weighted echoplanar images [echo time, 40 msec; 80.7 msec/image; 64 × 64 pixels (19.2 × 19.2 cm)] were obtained
in an axial orientation. This sequence enhances blood oxygenation
level-dependent contrast (Kwong et al., 1992). The volume
acquired covered the whole brain (32 slices; slice thickness of 3 mm,
giving a 14.4 cm vertical field of view). The effective repetition time
(TR) was 3.2 sec/vol. To minimize head motion, subjects were restrained
with bitemporal pressure pads. Four hundred image volumes were acquired
for each subject over 21 min.
Skin conductance responses. On-line SCRs were
successfully measured in all subjects during fMRI scanning. SCR Ag/AgCl
electrodes were placed on the proximal phalanx of the index and middle
finger of the left hand. The signal was amplified and sampled at 100 Hz. Further off-line processing was performed with MatLab (The Mathworks, Natick, MA). Data were detrended and temporally smoothed (gaussian kernel with full-width at half maximum of 2000 msec) to
remove MRI scanning artifacts. Finally, the time-series were resampled
at 10 Hz. For quantitative analysis of SCRs, evoked SCRs were
characterized by the maximum of the SCR signal in the 8 sec interval
after stimulus onset. Extending this window beyond the onset of the US
(after 4 sec) was possible because only CS and
CS+unpaired were analyzed (Büchel et al.,
1998). This value was then subtracted from a baseline, the mean of the
SCR in the second before the onset of the CS, to account for residual
baseline fluctuations. For statistical analysis, the differences were
normalized to zero mean and SD of unity. The significance of SCR
differences for CS and CS+unpaired was assessed
separately for the first and second half of the experiment. This
allowed us to test for time × conditioning interactions.
Imaging data analysis. Image processing and statistical
analysis were performed using SPM97 (Friston et al., 1995b; Worsley and
Friston, 1995). All volumes were realigned to the first volume (Friston
et al., 1995a). Residual motion effects were eliminated by regressing
the time course of each voxel on a periodic function of the estimated
movement parameters. To account for the different sampling times of
different slices, voxel time-series were interpolated using Sinc
interpolation and resampled using the slice at the anterior-posterior
commissural line as the reference. A mean image was created using the
realigned volumes. An anatomical MRI, acquired using a MPRAGE
three-dimensional (3D) T1-weighted sequence (1 × 1 × 1.5 mm
voxel size), was coregistered to this mean (T2*) image. This ensured
that the functional and structural images were spatially aligned.
Finally, the functional images were spatially normalized (Friston et
al., 1995a) to a standard T2* template (Talairach and Tournoux, 1988;
Evans et al., 1994), using nonlinear basis functions. This
transformation was also applied to the structural T1 volume. Functional
data were smoothed using a 6 mm (full-width at half maximum) isotropic
gaussian kernel to compensate for residual variability after spatial
normalization and to permit application of gaussian random field theory
to provide for corrected statistical inference (Friston et al.,
1995b).
In contrast to evoked responses in electrophysiology, the sampling rate
(i.e., TR) in event-related fMRI is restricted. To characterize
hemodynamic responses after an indexed stimulus, it is necessary to
sample data points after the onset of many stimuli at different
peristimulus time points. We achieved this through a random jitter
between the intertrial interval (ITI) and TR, leading to an equal
distribution of data points after each event type. The intertrial
interval was randomized in the range of 4 ± 0.5 TR, leading to
ITIs between 11.2 and 14.4 sec. The example in Figure
1A (second row) illustrates the
relationship between fMRI volume acquisition and trials. For example,
scans took place 3, 6.2, and 9.4 sec after the first
CS+unpaired stimulus onset. After the second
CS+unpaired trial, volumes were acquired 2, 5.2, and 8.4 sec after the onset of the stimulus. The data were analyzed by
modeling the evoked hemodynamic responses for different stimuli as
delta functions convolved with a synthetic hemodynamic response
function (HRF), its temporal and dispersion derivative, in the context
of the general linear model as used by SPM97 (Josephs et al., 1997).
Using both derivatives in addition to the canonical HRF allowed us to
characterize HRFs with late onset or longer duration. Because of our
interest in the time period after the offset of the CS, all events were
time-locked to the offset of the CS. An additional analysis in which
events were modeled earlier (i.e., at the onset of the CS) did not
reveal additional activations. We defined three different event types: (1) CS, (2) CS+ paired (CS+paired), and (3) CS+
unpaired (CS+unpaired) (Fig. 1). Differential
effects were tested by applying appropriate linear contrasts to the
parameter estimates for the canonical HRF regressor of each event,
resulting in a t statistic for every voxel.
These t statistics (transformed to Z statistics)
constitute a statistical parametric map (SPM). The contrast used in the
main analysis tested for greater responses evoked by
CS+unpaired stimuli relative to CS.
In addition to the main analysis, we defined three new regressors
representing time × event interactions. These three additional regressors were created by multiplying the amplitude regressors for
CS, CS+paired, and
CS+unpaired with a zero mean exponential function
with a time constant of one-fourth of the session length (320 sec).
Based on our previous study, we hypothesized an overall negative
difference for regions showing decreased activation over time. We
therefore tested for a mean negative difference masked with a contrast
coding the differential decrease between the CS and
CS+unpaired. The masking threshold was set to
p < 0.1. We analyzed the group as a whole and all
subjects individually.
Ensuing SPMs were interpreted by referring to the probabilistic
behavior of gaussian random fields. Functional imaging data were only
analyzed for those seven subjects who showed successful conditioning.
Evoked responses were modeled in a subject-specific way. In the case of
the amygdala, the anterior cingulate, and anterior insula in which we
had a regional-specific hypothesis correction for multiple comparisons
was based on the volume of interest (Filipek et al., 1994) and the
smoothness of the underlying SPM (Worsley et al., 1996). For other
brain regions, the correction was for the entire volume analyzed (i.e.,
whole brain). Thus, in all cases, the threshold was set to
p < 0.05 (corrected).
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RESULTS |
Skin conductance responses
The SCR time series showed that 7 of 11 subjects acquired
conditioned autonomic responses to the CS+ (Fig.
2A). Figure
2B shows an example of the time course of the SCR
signal for one subject during MR scanning over the first 7 min of the
experiment. Statistical analysis revealed significant differences
(p < 0.05) between SCR for CS compared with
CS+ trials for all subjects during the first half of the conditioning
phase, indicating that these subjects were successfully conditioned
during fMRI. During the second half of the conditioning phase, the
difference between CS+ and CS evoked SCRs was much smaller (only
subject 6 showed a significant difference) (Fig. 2A).
As with the fMRI analysis, we only analyzed unpaired CS+ trials.
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Figure 2.
A, Average SCRs for all
seven subjects that showed conditioned responses during the experiment.
Each graph represents the SCR data from an individual subject. The
first two bars represent the mean SCR responses during
the first half of the experiment for CS and CS+unpaired
trials, respectively. The third and fourth
bars show the SCR data for CS and CS+unpaired for
the second half of the experiment. For all but subject 6, it is obvious
that the significant difference between CS and CS+ SCRs decreased
during the second half of the experiment. B, Recorded
SCR data for subject 6. + indicates the onset of a CS+ stimulus.  indicates the onset of a CS stimulus. x indicates the onset of the
aversive tone (US) after 50% of CS+ (). Stronger SCR responses are
evoked by CS+ trials (+), even in the absence of the US (x).
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Functional neuroimaging
In a CS+paired trial, the peak of the
response evoked by the CS+ could occur after delivery of the US (Fig.
1A, first event in the third
row). This can give rise to interaction effects in regions that
respond to both the US and the CS+ (Friston et al., 1998). To fully
disambiguate the effects of CS+ and US, we only compared responses
evoked by the conditioned tone when it was not followed by the US
(CS+unpaired). Consequently, the comparison of
interest in this experiment was that between the
CS+unpaired evoked responses and those evoked by
the CS. This comparison revealed differential activation of bilateral
anterior cingulate gyri and anterior insulae (Fig.
3). Further differential responses were
detected in the right medial thalamus, bilateral dorsolateral prefrontal cortex, bilateral ventral putamen, and posterior
peri-auditory cortex. The coordinates and significance of these
activations are summarized in Table
1.
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Figure 3.
Significant differential visual evoked responses
for CS+ versus CS tones in the anterior cingulate cortex and the
right and left insulae for two individual subjects (subject 5 in
A and subject 6 in B). The coronal slice
of the subject's individual T1-weighted MRI shows the location of
differential responses. Images are thresholded at p < 0.001 uncorrected for visualization. The significance for individual
activations are given in Table 1. The peristimulus time plots are shown
for all three regions. The fitted response and the adjusted data
(±SEM) are plotted for 2 sec time bins. Although responses are shown
for CS+paired, CS+unpaired, and CS,
the statistical inference is based on the difference between
CS+unpaired and CS.
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Table 1.
Differential activations comparing visual evoked responses
for conditioned stimuli in the absence of an unconditioned stimulus
(CS+unpaired) and CS
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Figure 3 shows the location of the anterior cingulate activation for
two subjects overlaid on their individual T1-weighted MRI. The coronal
slice also shows activation in bilateral insulae. To best characterize
the data, we plotted the responses evoked by the CS
(green ± SE), the response evoked by the
CS+paired (red ± SE), and the
response evoked by the CS+unpaired
(blue ± SE). As expected, the curves for CS+
paired and CS+ unpaired are almost identical, highlighting the fact that the evoked responses in
these regions are not related to processing of the US. Note that the
statistical comparison is based on the difference between CS+unpaired and the CS alone.
Decreases of amygdala responses over time in the context of classical
conditioning have been demonstrated in animal (Quirk et al., 1997) and
human studies of classical conditioning (Büchel et al., 1998;
LaBar et al., 1998). Furthermore, hippocampal activations have been
shown to follow a similar temporal pattern during learning (Strange et al., 1999). Such temporal effects would be disguised in a
simple categorical comparison of the CS+unpaired
and CS. We therefore explicitly tested for the presence of a
time × event type interaction in an additional analysis. This
analysis tests for areas in which neuronal responses evoked by
CS+unpaired decrease over time, and at the same
time this pattern is significantly different from the pattern for the
responses evoked by the CS. In effect, this analysis shows voxels
with a differential adaptation for the
CS+unpaired relative to the CS. In this
analysis, amygdala and anterior hippocampal activations were
significant bilaterally at p < 0.05. The exact
coordinates and statistics of the activations are given in Table 1.
Figure 4 shows significant voxels for the
group analysis in bilateral amygdalas and hippocampi on a coronal
section of the mean T1 MRI for the group. To unequivocally attribute
the activations to the amygdala and the anterior hippocampus, we
exploited the spatial and temporal resolution of fMRI and analyzed
single-subject data separately. Figure 5
shows medial temporal lobe activations revealed by the same analysis as
in the group for subjects 3 and 5. Each subplot shows the activation
overlaid on the subject's T1-weighted MRI and the time course of
responses evoked by CS+unpaired. The 3D graph
shows how evoked responses change over time as learning progresses (see
figure legend for details). Both amygdala and hippocampus exhibited
rapid decreases of their responses. This is in accord with our SCR data
showing a significant time × condition interaction.
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Figure 4.
Medial temporal lobe activations revealed by the
group analysis. Medial temporal lobe activation comprised an anterior
activation in the amygdala and a posterior activation in the anterior
hippocampus. As can be seen on the transverse section, the activation
of the hippocampus cannot be explained by the spatial smoothing of 6 mm
(full-width at half maximum).
Figure 5.
Medial temporal lobe activations (amygdala and
hippocampus) in two individual subjects. Each individual subplot shows
the localization of the activation on the subject's individual
T1-weighted MR scan together with a 3D plot of the activation pattern
over time. All activation maps are thresholded at p < 0.05 for display purposes. This plot shows evoked hemodynamic
responses to CS+unpaired stimuli in relation to the
stimulus [Peri-stimulus time (s) vs % Signal
change]. The additional third dimension (scans)
illustrates how this evoked response changes throughout the experiment.
All four regions show significant decreases of evoked responses,
indicated by smaller or negative amplitudes toward the end of the
experiment.
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DISCUSSION |
In summary, our results showed enduring conditioning-related
activations in cortical regions reflecting the acquired association. In
contrast, other regions showed differential responses that were
time-limited. Specifically, medial temporal lobe regions, amygdala, and
hippocampus showed rapid decreases in differential response implying
effects related to acquisition per se. Activation of the hippocampus in
trace, but not in delay, conditioning suggests a specific involvement
in this form of associative learning, i.e., by bridging the temporal
gap between CS and US.
Differential cortical responses
This analysis highlights cortical regions showing differential
activity associated with CS+ and CS trials. Note that the analysis
did not explicitly model time-dependent effects but represents a
sensitive approximation of rapidly evolving learning-related responses.
Such responses were expected in cortical regions highlighted previously
in the context of a classical delay conditioning paradigm (Büchel
et al., 1998).
The anterior cingulate plays a crucial role in assessing the
motivational content of internal and external stimuli and in regulating
context-dependent behaviors (Devinsky et al., 1995), such as approach
and avoidance learning (Freeman et al., 1996). Direct evidence for the
participation of the anterior cingulate in classical conditioning comes
from animal (Powell et al., 1996; Everitt and Robbins, 1997) and human
functional imaging studies (Büchel et al., 1998; LaBar et al.,
1998). Cingulo-thalamic neuronal plasticity may be crucial for the
acquisition of avoidance responses in the context of conditioning, and
it has been suggested that amygdala projections play an important role
in the modulation of these plastic changes (Poremba and Gabriel,
1997a,b). This is especially interesting because we also found
conditioning-related signal changes in the medial thalamus, in accord
with this hypothesis.
Several studies suggest a role for the anterior insula in processing
emotionally relevant contexts, such as disgust (Phillips et al., 1997)
and pain (Casey et al., 1995). This functional characterization fits
with insular projections to anterior cingulate, perirhinal, entorhinal,
and periamygdaloid cortices, and the amygdala (Mesulam and Mufson,
1982). This pattern of connectivity, together with neurophysiological
data, has led to a view of the insula as an area functionally
associated with emotional processing (Casey et al., 1995).
This profile of significant differential responses in the amygdala is
consistent with its proposed modulatory effect on cortical processing.
It has been shown that one role of the amygdala during conditioning is
in the early modulation of cingulo-thalamic connectivity (Poremba and
Gabriel, 1997a,b). Furthermore, differential posterior secondary
auditory cortex responses are in accord with the modulatory influence
the amygdala exerts over auditory cortex (Armony et al., 1998), leading
to learning-related plastic changes (Weinberger et al., 1993; Morris et
al., 1998). These observations suggest that, with time, mnemonic
representations of behaviorally salient contexts are expressed in
cortical regions other than medial temporal lobe structures (McGaugh et
al., 1996; Cahill and McGaugh, 1998). Proposed candidate structures,
including the anterior cingulate and insular cortices, were all
activated in our study (Everitt and Robbins, 1997).
Differential medial temporal lobe responses
Amygdala responses to CS+unpaired stimuli
decreased rapidly over time. This accords with results from other
neuroimaging studies showing similar decreases of amygdala responses in
the context of viewing emotionally expressive faces (Breiter et al.,
1996; Whalen et al., 1998) and classical delay conditioning
(Büchel et al., 1998; LaBar et al., 1998). This is also supported
by electrophysiological data showing decreasing amygdala single cell
responses during conditioning in the rat (Quirk et al., 1997) and
suggests a preferential role for the amygdala during the early phase of
aversive conditioning.
Another component of the decreases in amygdala responses might be
linked to negative feedback in classical conditioning (Fanselow, 1998).
In our experiment in which an aversive tone serves as US, engagement of
the stapedius reflex might decrease sound transmission at the level of
the middle ear and mediate negative feedback, which reduces the impact
of the US (Cacace et al., 1992). However, this is unlikely because the
SCR evoked by the US (i.e., CS+paired) did not
show a systematic decrease over time, as one would expect in the
presence of negative feedback. In fact, four of seven subjects, including subjects 3 and 5 (Fig. 5), showed a slight increase in SC
responses over time. Furthermore, the functional imaging data indicate
that amygdala responses exhibited significantly less decreases to the
CS+paired (i.e., US-associated) responses than to
the CS+unpaired. The amygdala voxels showing the
maximum difference in the time × condition interaction (i.e.,
decreases for CS+unpaired but no decrease for
CS+paired) were found in close vicinity to the
location reported in Table 1 (relevant coordinates: x = 24, y = 3, z = 21;
x = 18, y = 0, z = 24). A constant amygdala response to the US but decrease with respect
to the CS+ indicates that the observed time × condition
interaction in the amygdala is linked to learning rather than to
negative feedback.
Two previously conducted single-trial fMRI studies of aversive
conditioning showed activation of the amygdala but did not report
hippocampal activation (Büchel et al., 1998; LaBar et al., 1998).
Interestingly, both studies used a delay conditioning protocol. This is
consistent with animal studies showing that lesions of the hippocampus
do not interfere with delay fear conditioning (Schmaltz and Theios,
1972; Phillips and LeDoux, 1992; Clark and Squire, 1998). The
hippocampus is implicated in classical conditioning principally on the
basis of studies using nictitating membrane response conditioning. In
these studies, an intact hippocampus is necessary for learning when CS
and US presentations are separated in time (i.e., trace conditioning),
in line with a view that the hippocampus acts as an associator of
discontiguous events (Wallenstein et al., 1998). We note that it has
been reported recently that trace conditioning and other
hippocampus-dependent learning tasks have a trophic effect on
adult-generated hippocampal neurons (Gould et al., 1999).
Although the hippocampus is not essential for nictitating membrane
response conditioning, neurophysiological recordings in rabbits
(Disterhoft et al., 1986) and human positron emission tomography (PET)
studies (Molchan et al., 1994; Logan and Grafton, 1995; Blaxton et al.,
1996; Schreurs et al., 1997) have also reported hippocampal involvement
for delay eyeblink conditioning. The hippocampal signal changes as seen
in PET studies during delay conditioning might reflect a tonic
change in hippocampal activity. Such effects are not time-locked to
presentation of individual stimuli and were therefore beyond the scope
of single-trial designs as implemented in the present study. These
design differences may account for apparent discrepancies in findings
from studies using different experimental modalities.
In aversive conditioning, the involvement of the hippocampus has often
been attributed to context (Penick and Solomon, 1991; Phillips and
LeDoux, 1992; Rudy and Pugh, 1996). Context is referred to as the
ensemble of cues that coexist with a specific CS. Similar to the idea
that different cues need to be temporally and spatially integrated to
form a context, the introduction of a trace period leads to the
formation of a temporal context. This hypothesis explains the necessity
of an intact hippocampus for both, contextual fear and trace conditioning.
The similarity of hippocampal and amygdala temporal activation pattern
points to an important interaction during learning between these two
neighboring regions (McGaugh et al., 1996; Cahill and McGaugh, 1998;
Packard and Teather, 1998). In delay conditioning, the amygdala alone
is sufficient for the formation of associations (e.g., the modulation
of thalamo-cortical plasticity). In trace conditioning, with the
additional temporal discontiguity, the hippocampus might be involved in
bridging the temporal gap and allow an association to occur. Assuming
that the modulatory role of the amygdala is time-limited, this would
also imply a time-limited response for the hippocampus. This accords
with our data highlighting similar decreases of amygdala and
hippocampal responses.
Different time courses of cortical (anterior cingulate and insula) and
medial temporal lobe structures (amygdala and hippocampus) raise the
question of how these different regions and their time courses are
related. The fact that responses of medial temporal lobe structures
continued even after cortical structures have reached their maximal
response could reflect an early saturation of cortical responses,
implying a nonlinear temporal relationship between medial temporal lobe
and other cortical areas in associative learning.
Conclusions
The rapid decreases of amygdala responses fits well with
theoretical accounts of reinforcement and emotional learning, which suggest a role for the amygdala in modulating or enabling associative changes in synaptic efficacy through vicarious neuromodulatory mechanisms (Friston et al., 1994; Schultz et al., 1997). The hypothesis is that brain systems that mediate learning in which the amygdala plays
a central role do so by enabling or permitting associative plasticity
that encodes sensory contingencies being acquired. After acquisition,
the learned association will be expressed at a cortical level
reflecting changes in synaptic connection strengths (Alvarez and
Squire, 1994; McGaugh et al., 1996). However, once the association has
been learned, there is no need for further permissive modulation of
plasticity, and systems mediating it (e.g., the amygdala) disengage
(Quirk et al., 1997). Although this provides a sufficient account of
delay conditioning, trace conditioning-specific activation of anterior
hippocampus suggests an involvement in bridging the temporal gap
between CS+ and US and accords with its suggested role as an associator
of discontiguous events (Clark and Squire, 1998; Wallenstein et al.,
1998).
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FOOTNOTES |
Received July 8, 1999; revised Sept. 24, 1999; accepted Sept. 24, 1999.
This work was supported by the Wellcome Trust. We thank R. Frackowiak
for helpful comments. We would also like to thank the FIL physics group
and the radiographers for their support and help.
Correspondence should be addressed to Christian Büchel, Leopold
Müller Functional Imaging Laboratory, The Wellcome Department of
Cognitive Neurology, Institute of Neurology, 12 Queen Square, London
WC1N 3BG, UK. E-mail: cbuechel{at}fil.ion.ucl.ac.uk.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
