Wellcome Department of Cognitive Neurology, Institute of Neurology, London WC1N 3BG, United Kingdom
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ABSTRACT |
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Ramnani, N.,
I. Toni,
O. Josephs,
J. Ashburner, and
R. E. Passingham.
Learning- and Expectation-Related Changes in the Human Brain
During Motor Learning.
J. Neurophysiol. 84: 3026-3035, 2000.
We have studied a simple form of motor learning
in the human brain so as to isolate activity related to motor learning
and the prediction of sensory events. Whole-brain, event-related
functional magnetic resonance imaging (fMRI) was used to record
activity during classical discriminative delay eyeblink conditioning.
Auditory conditioned stimulus (CS+) trials were presented either
with a corneal airpuff unconditioned stimulus (US,
paired), or without a US (unpaired). Auditory CS
trials were never reinforced with a US. Trials were presented
pseudorandomly, 66 times each. The subjects gradually produced
conditioned responses to CS+ trials, while increasingly differentiating
between CS+ and CS
trials. The increasing difference between
hemodynamic responses for unpaired CS+ and for CS
trials evolved
slowly during conditioning in the ipsilateral cerebellar cortex (Crus
I/Lobule HVI), contralateral motor cortex and hippocampus. To localize
changes that were related to sensory prediction, we compared trials on
which the expected airpuff US failed to occur (Unpaired CS+) with
trials on which it occurred as expected (Paired CS+). Error-related
signals in the contralateral cerebellum and somatosensory cortex were
seen to increase during learning as the sensory prediction became
stronger. The changes seen in the ipsilateral cerebellar cortex may be
due either to the violations of sensory predictions, or to
learning-related increases in the excitability of cerebellar neurons to
presentations of the CS+.
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INTRODUCTION |
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Eyeblink conditioning can be
used as simple model of associative motor learning in humans. In
classical delay eyeblink conditioning, an airpuff to the eye and the
surrounding skin (unconditioned stimulus, US) unconditionally elicits
an eyeblink reflex (unconditioned response, UR). If the airpuff is
repeatedly paired with a preceding auditory tone (conditioned stimulus,
CS), the initially neutral CS itself comes to elicit a well-timed,
conditioned eyeblink response (CR) after a sufficient number of
pairings (Gormezano 1966; Yeo and Hesslow
1998
). This process must depend on the ability of neuronal
circuitry to undergo plastic changes. However, the issue of where such
plasticity occurs in the brain is both controversial and unresolved
(Yeo 1991
). For brain areas to be identified as candidate sites, two important criteria must be met. The first is that
learning should not progress if lesions or inactivations functionally
compromise these areas. The second is that such areas must show
learning-specific changes in activity as learning occurs.
The rabbit model has been particularly useful for identifying the
pathways essential for the acquisition and expression of this
conditioned reflex. In rabbits, movements of the external eyelid and
the nictitating membrane (NM) are tightly coupled and highly correlated
(McCormick et al. 1982). During conditioning, CRs and URs are therefore composed of compound movements of both the NM
and external eyelid. Despite these behavioral similarities, the two
movements are driven by separate muscle groups, which are innervated by
different motor nuclei. The orbicularis oculi muscle is innervated by
the seventh nerve from the facial nucleus and closes the external
eyelid. The retractor bulbi muscle is innervated by the sixth nerve
from the accessory abducens nucleus and causes nictitating membrane
responses by eyeball retraction into the eye socket. It has been shown
that the cerebellum is essential for the conditioning of both the
external eyelid and the NM (Ivarsson et al. 2000
;
McCormick et al. 1981
) together with its efferent
connections with the red nucleus, the accessory abducens nucleus and
the facial nucleus (Krupa et al. 1996
; Rosenfield and Moore 1983
, 1995
; Rosenfield et al. 1985
).
Anatomically specific lesions have shown that the integrity of
cerebellar cortical lobule HVI and anterior parts of the
interpositus nucleus are essential for NM conditioning (Yeo et
al. 1985a
-c
, 1986
). Although permanent lesions impair the
expression of NM and eyeblink CRs, it is an important finding that
learning is prevented by reversible inactivations of the
cerebellar nuclei during conditioning, irrespective of effects on the expression of NM and eyeblink CRs
(Krupa et al. 1993
; Ramnani and Yeo
1996
). It has been claimed that inactivation of the efferent
fibers running in the brachium conjunctivum leaves learning intact
(Krupa and Thompson 1995
), and this finding has been
used to suggest that plasticity for this form of motor learning may
exist in cerebellar or precerebellar circuitry.
Areas in which there is plasticity for motor learning should show
neuronal activity that changes as a function of learning. Functional
brain imaging has the advantage that it records population activity for
a whole region, and more recent studies have therefore used this method
to study learning-related activity. There have been four positron
emission tomography (PET) studies in which subjects were
scanned during delay conditioning of the external eyelid
(Blaxton et al. 1996; Logan and Grafton
1995
; Molchan et al. 1994
; Schreurs et
al. 1997
). Typically, the subjects were first scanned during
"no-learning" blocks and then during "learning" blocks in which
CRs developed as a result of paired training. Stimulus presentations
were matched in the two conditions. All of these PET studies have
reported the presence of differential activity in the cerebellum and
have therefore provided evidence that the human cerebellum becomes
engaged during delay-eyeblink conditioning. The precise nature of this
engagement is not clear. It has recently been proposed that the
learning of relationships between sensory events is an important
component process in motor learning (Hikosaka et al.
1999
). In line with recent theories, it is possible that the
cerebellum is specifically engaged in learning the relationships
between sensory events (Bower 1997
). Such accounts
are supported by findings that violations of sensory predictions
activate the cerebellum (Blakemore et al. 1999
;
Tesch and Karhu 2000
).
Event-related functional magnetic resonance imaging (fMRI) permits the
analysis of activity at the level of a single trial, thus conferring
specific advantages on classical conditioning experiments. It is
possible, for example, to localize regions in which there are
trial-by-trial changes in learning-related activity.
Refinements in experimental design make it possible to interpolate
experimental events with control events, such that control and baseline
activity may be sampled simultaneously. This is particularly important
for detecting learning-specific changes, where nonspecific changes must
be discounted. It is also a strength of event-related fMRI that it is
able to reveal activity that occurs during unpredicted "oddball"
events (Josephs et al. 1997) such as that which occurs
when a US predicted by a preceding CS, fails to occur.
We have used whole-brain, event-related fMRI to scan during
discriminatory delay eyeblink conditioning. On one-third of
the trials, one tone (CS+) was paired with an airpuff (US) delivered to
the right eye (Paired CS+ trials). On one-third of the trials the same
tone was presented, but the airpuff was omitted (Unpaired CS+ trials).
On the remaining one-third of trials a different tone was presented but
never paired with the airpuff US (CS trials). Thus there was partial
reinforcement for the CS+. The three trial types were randomly
intermixed. The subjects increasingly learned to give conditioned
eyeblinks (CRs) to the CS+, and the CR frequency on CS
trials
decreased with conditioning. This design enabled us to analyze the data
in two ways. First, we could look for changes over time when comparing
Unpaired CS+ and CS
trials. No airpuff was given on either trial
type, but as learning occurred, CRs were increasingly produced on the
Unpaired CS+ trials. Second, we could look for changes over time which
were related to sensory prediction. This could be done by comparing
Unpaired CS+ trials with Paired CS+ trials. As learning occurred, the
subjects increasingly predicted the occurrence of the US on both trial
types, but on the Unpaired CS+ trials, there was an increasing mismatch
between the predicted sensory outcome and the actual events.
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METHODS |
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Subjects
The subjects were five, healthy right-handed male volunteers. Written informed consent was obtained prior to scanning.
Behavioral methods
STIMULI.
The US was an airpuff (5 psi at source; 100 ms) delivered through
tapered plastic tubing, the tip of which was positioned close to the
cornea of the right eye. The CSs were auditory tones (700 ms, 85 dBA)
that differed in frequency (600- and 1,400-Hz sine waves; see following
text). These frequencies were clearly audible above the noise of the
MRI scanner and are comparable with those reported in Moore
(1964) in which differential human eyeblink conditioning was
characterized in detail.
APPARATUS. Each subject lay supine in the MRI scanner with the head immobilized by padded restraints. Sound was delivered directly into the subjects' ears through MRI-compatible air-tubes. A self-fastening (Velcro) strap was wrapped securely around the forehead, on which a novel, light MRI compatible opto-mechanical low-torque transducer was affixed above the right eye. One arm of an articulated joint was coupled rigidly at a right angle to the freely rotating shaft of the transducer, and the other was a contacting arm, coupled to the base of the upper eyelid. This arrangement enabled eyelid movements to be transduced into voltage signal, without the need for restoring forces on the transducer. Eyelid movements were unimpeded by this arrangement. Stimulus delivery equipment was calibrated for accurate timing and intensity before the start of each conditioning session (see Data acquisition).
CONDITIONING.
A differential conditioning procedure was used (Moore
1964). There were three trial types: Paired CS+ trials (the
interstimulus interval between CS+ onset and US onset was 600 ms, and
the US coterminated with the CS+); Unpaired CS+ trials (the CS+ trials occurred in the absence of the US); and CS
trials (the CS occurred on
its own).
CONDITIONED RESPONSES. Eyeblink responses were scored as CRs on the basis of amplitude and latency based on criteria established in other studies. The same criteria were applied to all subjects. Eyeblinks were measured in reference to a stable, 100 ms pre-CS baseline.
Latency criterion. Short-latency "alpha" eyeblink responses (onset latency <250 ms) sometimes occur unconditionally in response to auditory stimuli and are not associative (see Gormezano 1966ACQUISITION OF BEHAVIORAL DATA. Behavioral data, scanner slice acquisition times, CS times, and US times were acquired simultaneously using an AD converter (1401 unit) and programmable signal amplifier (1902 unit) (Cambridge Electronic Design, Cambridge, UK). Eyelid movements were sampled at 1 kHz, and auditory stimuli were sampled at 3 kHz. US onset times and slice acquisition times were recorded as marker events. These data were acquired simultaneously from each subject during conditioning
ANALYSIS OF BEHAVIORAL DATA.
CR frequencies were expressed as percentages of CRs relative to the
number of trials presented, for each block of trials, for each trial
type. An ANOVA was conducted using SPSS for Windows 8.0 (SPSS) to
determine the effect of BLOCK (11 levels, 6-trial blocks) and the
effect of TRIAL TYPE (2 levels, unpaired CS+, CS). The BLOCK × TRIAL TYPE interaction determined the statistical significance of
differences between Unpaired CS+ and CS
trials that developed as a
function of training. Comparisons were not made with Paired CS+ trials
because the time interval for the assessment of CRs was different from
the other trial types (see CONDITIONED RESPONSES).
MRI imaging
The imaging methods were similar to those reported in
Buechel et al. (1998). Six hundred and fifteen EPI
images were acquired contiguously using a 2 Tesla Magnetom VISION
whole body MRI system (Siemens, Erlangen, Germany) and a head volume
coil. Images were T2*-weighted axial volumes (48 slices; TR, 4.73 s; TE = 40 ms; voxel size, 3 mm3; slice
dimensions, 64 × 64 pixels). The volumes acquired covered the
whole brain. After the experiment, structural images were acquired
using a T1 MPRAGE sequence (TE = 4 ms; TR = 9.5 s;
T1 = 600 ms; voxel size 1 × 1 × 1.5 mm). We sampled evoked
hemodynamic responses (EHRs) at an effective frequency that was
considerably higher than the TR (Josephs et al. 1997
) by
uniformly distributing random trial-to-trial variation in the interval
between scan onset and trial onset [from 14.l s (TR × 3) to
18.8 s (TR × 4)]. This determined the ITI.
Image processing methods
Image processing and analysis methods were carried out in SPM97
(Friston et al. 1995b) and performed on Sparc computers
(Sun Microsystems, Mountainview, CA). The following preprocessing
methods were applied for data from each subject. The experiment began after four volumes were collected. These four volumes were then discarded to minimize T1 relaxation artifacts; 611 volumes were analyzed for each subject. After inspection of image quality, six
head-movement parameters were estimated (3 translations and 3 rotations) from rigid body transformations that minimized the difference between each volume and the first (Friston et al.
1995b
). The parameters were subsequently used to realign the
time series. A mean T2*-weighted volume was computed from these
functional volumes, and the structural T1 image was coregistered it.
The functional and structural images were realigned and then spatially normalized into the reference system of Talairach and Tournoux (1988)
, using a representative reference brain from the
Montreal Neurological Institute series (Evans et al.
1994
) as a template. The functional images were subsampled to a
voxel size of 2 mm3, smoothed using an isotropic
Gaussian kernel of 6 mm, and so conformed to the multivariate Gaussian
assumptions of SPM97.
Image analysis method
MODELS.
To model EHRs for each of the three trial types, three covariates were
constructed to create a general linear model (GLM) that could be
estimated in SPM97. Delta functions derived from trial onset times for
each trial type were convolved with a synthetic "canonical"
hemodymic response function. The regressors (Paired CS+, Unpaired CS+,
and CS) were multiplied by a linear
trend and mean corrected to form three more covariates that modeled linearly changing event-specific EHRs (Paired
CS+T, Unpaired CS+T, and
CS
T). It should
be noted that these regressors were completely orthogonal to each other.
CONTRASTS.
Fixed effects analyses were performed using linear contrasts. The
following contrasts were employed to generate SPM{t} maps: auditory
(effect of unpaired CS+), Unpaired CS+;
somatic and motor (effect of US and UR), Paired
CS+ > Unpaired
CS+; effects of learning (time-dependent
effects), Unpaired
CS+T > CST; and effects
of prediction error, Unpaired
CS+T > Paired CS+T.
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RESULTS |
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Behavior
The subjects learned to produce well-timed CRs (Fig.
1B). The frequency of CRs
given on Unpaired CS+ trials increased markedly with training, reaching
an asymptote at the end of training (Fig. 1A). Initially,
the frequency of CRs on CS trials also increased, but as the subjects
started to differentiate between CS+ and CS
events, the CR frequency
for CS
trials declined to low levels.
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There were two factors: CS TYPE (2 levels, Unpaired CS+ and CS) and
BLOCK (11 levels, blocks 1-11). There was a significant effect of
BLOCK, indicating that there was an overall block-by-block change in CR
frequency [ANOVA, F(1,4) = 10.52; P < 0.05]. There was also a significant effect of CS TYPE, indicating that
overall, there were significantly more CRs for CS+ than for CS
[ANOVA, F(1,4) = 159.85; P < 0.05].
Most importantly, there was a significant BLOCK × CS TYPE
interaction [ANOVA, F(1,4) = 40.45; P < 0.05]. The CR frequency for CS+ and CS
became increasingly
different as a function of BLOCK.
During the fMRI imaging sessions, no CRs were produced at first,
and by the end of scanning, 93.33% CRs were produced to the CS+ trials
compared with 20% on CS trials. We have assessed the difference between CR frequencies for Unpaired CS+ and CS
for each of the 11 blocks using linear regression analysis. The
differential CR frequency for each block was pooled from the five
subjects (5 values for the 11 blocks). The analysis showed that for the group, there was a highly significant linear increase in the
differential over the 11 blocks [ANOVA, F(1,54) = 55.76, P < 0.0001]. To ensure that between-subjects
variation did not contribute significantly to this effect, the slopes
were calculated for each subject individually, and a t-test
was then performed on these values. The results of this analysis show
that there was a linear trend in each subject and that the slopes for
each subject were not significantly different from each other
[1-sample t-test, t(4) = 6.37, P < 0.005]. The behavioral data confirm that we
achieved our aims. Our behavioral results are consistent with other
studies (Clark and Squire 1998
; Moore
1964
) and justify the use of linear models to assess the time-effects in the event-related bold signal.
fMRI results
EFFECTS OF AUDITORY CSS.
The effects of presentation of the tones alone are shown by the effects
for Unpaired CS+. There were robust activations in the primary auditory
cortex (Fig. 2A) and auditory
association cortex in the temporal lobes (see 1st contrast in
Image analysis methods). In addition, activity was also
present in the cerebellum bilaterally at the borders of Crus I and
lobule HVI (P < 0.05; 26, 82, 24 and
24,
66,
22).
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EFFECTS OF US.
The effects of presentation of the airpuff are shown by the main effect
of Paired CS+ trials compared with Unpaired CS+ trials (2nd contrast).
We did not present isolated US trials because this is known to
significantly impair conditioning. There was an activation in the right
ventral somatosensory cortex ipsilateral to the US (Fig. 2B;
56, 2, 0; Z = 4.56). This lay at a dorsoventral level
corresponding to the face area of SI; however, we cannot exclude the
possibility that the activation lay in the anterior part of SII. There
was also a peak in a ventral motor area near the anterior bank of the
left central sulcus (58, 8, 2; Z = 4.56) contralateral to the US, which may relate to the execution of UR eyeblinks.
TIME-DEPENDENT EFFECTS OF UNPAIRED CS+ COMPARED
WITH CS.
Unpaired CS+T > CS
T.
This analysis looked for voxels at which there was a greater
increase over time in event-related bold activity for
unpaired CS+ trials compared with CS
trials. Significant effects are
reported in Table 1. There was a
learning-related increase to CS+ in an area of the cerebellar cortex
ipsilateral to the US, immediately above the horizontal fissure, but
well below the primary fissure. The activation overlapped a medial
portion of lobule HVI, but the maximally active voxel was located in an
adjacent area of Crus I (Fig.
3A). As shown by the plotted
best-fitting models (Fig. 3A, inset), hemodynamic responses
for the peak voxel typically increased sharply for CS+ events in
contrast to CS
events. No other cerebellar voxels were observed when
the threshold was lowered to P < 0.005, but weaker
activity was present in two small clusters in Lobule HVI of the
contralateral cerebellar cortex when the threshold was
lowered still further to P < 0.01 (
14,
62,
22 and
24,
64,
26).
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EFFECTS OF UNPAIRED CS+ COMPARED WITH PAIRED CS+ (TIME DEPENDENT).
The final comparison reveals the effects of expectancy. As subjects
learned, the predictive strength of the CS+ increased, and this
prediction was confirmed on presentations of the Paired CS+ trials.
However, on each Unpaired CS+ trial, the predicted airpuff US failed to
occur as expected. We looked for responses to this error that became
stronger with learning. EHRs to Unpaired CS+ compared with Paired CS+
trials increased over time in cerebellar lobule HVI contralateral to
the US (22,
56,
22; Z = 3.63; see Fig. 4 and
Table 2). There was also an effect at a
lower significance level (Z = 3.07) on the borders
between lobule HVI and Crus I in the ipsilateral cerebellar cortex
(22,
78, 26). There was also an effect in somatosensory cortex (64, 0, 4, Z = 3.63). It is not clear if this lay within in the
face area of SI or an anterior part of SII. Among other areas activated
in this comparison were the right lateral orbitofrontal cortex, left
frontal pole and the anterior cingulate cortex.
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DISCUSSION |
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Learning-related changes
Subjects gradually developed well-timed CRs but were unaware that
they had developed these adaptive responses to the CS+. The analysis
revealing time-dependent changes therefore reflected implicit
procedural learning. We looked for the areas involved in learning by
comparing Unpaired CS+ trials with CS trials. For both trial types,
there were tones and for neither trial type was an airpuff received;
but CRs were increasingly produced on Unpaired CS+ trials. We found
learning-related increases in the ipsilateral cerebellum and the
contralateral ventral motor/premotor cortex. A weaker effect was also
found in the hippocampus.
CEREBELLUM.
A learning-related change in activity was found in an area spanning
medial Crus I and the neighboring lobule HVI of Larsell, ipsilateral to
the US. This is consistent with the learning-related cerebellar
activations of previous PET studies (Blaxton et al. 1996; Logan and Grafton 1995
; Molchan et
al. 1994
; Schreurs et al. 1997
). However, the
present study differs from these in two crucial respects. The use of an
event-related experimental design has allowed us to interpolate
learning CS+ trials with no-learning CS
trials and thus control for
nonspecific time effects much more stringently. Second, in the present
study learning-related increases were revealed by comparing Unpaired
CS+ trials with CS
trials. We have been able to use this
event-related analysis to examine activity related to unexpected events
(the interpretation of our cerebellar increase is discussed in the
following text).
MOTOR/PREMOTOR CORTEX.
Comparing Unpaired CS+ with CS trials, there was also an increase in
the hemodynamic response in a region of ventral frontal cortex. The
peak lay on the border between the ventral premotor and motor cortex.
The same area was activated for the comparison of Paired CS+ > Unpaired CS+ trials, and this was presumably related to the fact that
there were URs on paired but not unpaired trials. Learning-related
increases have also been reported in motor cortex during implicit
learning of motor sequences (Hazletine et al. 1997
).
HIPPOCAMPUS.
A weak time-by-condition interaction was found in the left hippocampus
proper. But, while it is clear that hippocampal lesions disrupt
"trace" eyeblink conditioning (Moyer et al. 1990;
Solomon et al. 1986
), it is clear that standard delay
eyeblink conditioning and discriminative conditioning are not impaired
by such lesions (Akase et al. 1989
; Miller and
Steinmetz 1997
; Schmaltz and Theios 1972
). This finding makes it difficult to interpret the role
that the hippocampus might have in delay eyeblink conditioning. Despite this, it is of note that populations and single neurons in the hippocampus alter their activity in a conditioning-specific manner. These are consistent with three of the four PET studies of human eyeblink conditioning that reported conditioning-specific activity in
the hippocampal formation (Blaxton et al. 1996
;
Logan and Grafton 1995
; Schreurs et al.
1997
). Berger, Thompson and colleagues have shown that
as rabbits acquired CRs, the neuronal activity in hippocampal CA1 and
CA3 pyramidal cells showed responses that modeled the amplitude and
time course of behavioral CRs. Such responses increased at a rate
faster than behavioral acquisition from trial to trial (Berger
and Thompson 1978
; Thompson et al. 1980
). During
extinction, hippocampal unit responses decreases at a faster rate than
behavioral CRs (Berger and Thompson 1982
). A similar
pattern of activity in the hippocampus has also been observed during
discrimination and reversal conditioning (Miller and Steinmetz
1997
).
What does activity in unpaired CS+ trials reflect?
Our principle interest was the activity in Unpaired CS+ that changed as a function of learning. The following explanations may account for activity in Unpaired CS+ trials. First, it is possible that our predominantly ipsilateral cerebellar activity reflected the motor execution of CRs, irrespective of learning. Second, activity may reflect learning-related changes in excitability to CS+ trials. Neurons may become increasingly responsive to presentations of CS+ trials (such neurons have been found in the cerebellum and motor cortex in animals and are discussed in CEREBELLUM and MOTOR/PREMOTOR CORTEX). Third, it is possible that the changes in activity in Unpaired CS+ trials reflected an error signal. As learning progressed, the subjects came increasingly to predict the US on CS+ trials (since subjects increasingly produced CRs on CS+ trials). However, on unpaired trials the US failed to occur. Thus with learning there was an increasing mismatch between the predicted occurrence of the US and its failure to occur. These three possibilities are discussed in the following text.
There has been a controversy about whether cerebellar lesions affect
learning or simply the performance of learned motor responses (Llinas and Welsh 1993; Welsh and Harvey
1989
). To try to resolve this issue, two groups have
inactivated the anterior interpositus nucleus in rabbits during
acquisition of CRs of the nictitating membrane (Hardiman et al.
1996
; Krupa et al. 1993
). When the animals were
later tested without inactivation, they failed to show evidence of
having learned CRs. These studies indicate that cerebellar lesions
prevent the acquisition of CRs, irrespective of any effect on CR
execution. In human eyeblink conditioning, the CRs are given bilaterally. Others have therefore argued that one would expect cerebellar activity to be bilateral if it reflected the motor execution
of CRs (Logan and Grafton 1995
). Thus it is more likely that the time-dependent changes in the present study reflect learning effects.
Our effects in the ipsilateral cerebellum and contralateral
motor/premotor cortex were found by comparing the changes found during
Unpaired CS+ trials with changes found during CS trials. In this
comparison, the changes found in Unpaired CS+ trials may reflect not
only learning, but error signals associated with the failure of the
increasingly predicted US. Both were present in Unpaired CS+ trials,
but neither was present in the CS
trials, and it is possible that one
or both of these processes occurred in the ipsilateral cerebellar cortex.
Several groups have suggested that the olivo-cerebellar system is
engaged in learning "inverse" (controller) and "forward" (predictive) models. The predictive models are likely to be engaged in
detecting discrepancies between predicted and actual sensory feedback
arising from movements (Miall 1998; Wolpert et
al. 1998
). Flament et al. (1996)
reported
increases in the bold signal when subjects performed a visuomotor
tracking task and the gain was altered, leading to a discrepancy
between the predicted and actual movement of the cursor.
Blakemore et al. (1999)
have used imaging to show that
there is a correlation between activity in the cerebellum and the size
of the discrepancy between predicted and actual sensory feedback. Is it
possible that such processes are present during eyeblink/NM conditioning?
During extinction learning, unpaired CS trials are repeatedly presented
after subjects have acquired CRs. As the value of the CS as a predictor
of the US declines with each presentation of the unpaired CS, the
frequency and amplitude of CRs also declines. Extinction of NM CRs is
prevented by reversible inactivations of the cerebellum
(Ramnani and Yeo 1996), and sites within the cerebellum
that are essential for CR acquisition in NM conditioning are also
essential for their extinction (Hardiman et al. 1996
). Although our experiment did not repeatedly present Unpaired CS+ trials
in this way, it could be said that the patterns of activity in Unpaired
CS+ trials may reflect the early stages of extinction learning in which
there are initially violations of sensory predictions related to the CS
and US. Changes in excitability to the CS+ were present in both
Unpaired and Paired CS+ trials. However, only in the Unpaired CS+
trials were there error signals associated with the absence of an
increasingly predicted US (this prediction was not violated in the
Paired CS+ trial type). Comparing the activity in these trials would
therefore reveal areas that became increasingly responsive to the
absence of an increasingly predicted US, irrespective of excitability
changes in to the CS+. Such activity was found predominantly in the
contralateral cerebellar cortex (Lobule HVI), although there was an
effect ipsilaterally at a lower significance level. It is of note that
there were also activations in somatosensory cortex and visual cortex.
This BOLD response could reflect either activation or increased
inhibition. However, Raij et al. (1997)
have recorded in
a sensory area with magnetoencephalography when a signal that
is predicted fails to occur. They found that when predicted tones were
omitted, there was activity in the supratemporal auditory cortices. We
also found activity in the orbital and anterior cingulate cortex; and
activity has been reported in the orbitofrontal (Nobre et al.
1999
) and medial frontal cortex (Ploghaus et al. 1999
) when there are breaches of expectation.
There is strong evidence that the contralateral cerebellar cortex plays
an important role in eyeblink conditioning. Anatomical evidence shows
that the contralateral cerebellar cortex processes CS and US stimuli
that support conditioning. Auditory information distributes to the
cerebellum bilaterally through the pons from the auditory system and in
our experiment, the CS tones were presented binaurally. Auditory
information was therefore processed bilaterally. Although it is widely
known that US somatic information from the face is conveyed from the
contralateral inferior olive to ipsilateral lobule HVI, van Ham
and Yeo (1992) have also shown that inputs to face
areas of the inferior olive from the trigeminal system are bilateral.
There are also direct mossy fiber projections from the trigeminal
nuclei to lobule HVI, crus I, and crus II of the cerebellar cortex.
Thus it is possible for ipsilateral somatic stimulation of the face to
evoke activity in the contralateral cerebellar cortex. Indeed,
Miles and Weisendanger (1975a
,b
) have recorded climbing
fiber field potentials in both ipsilateral and contralateral lobule HVI and crus Ia during stimulation of
the facial skin. Electrical stimulation of the facial areas of the primary somatosensory cortex also resulted in climbing fiber potentials in the same sites of the cerebellar cortex.
Lesion evidence provides direct and compelling evidence that the
contralateral cerebellar cortex participates in eyeblink conditioning.
Animals with ipsilateral cerebellar lesions were initially impaired but
reacquired CRs after extended retraining, but bilateral
cerebellar lesions were effective in permanently abolishing CRs trained
ipsilaterally (Yeo et al. 1997). This suggests that the
contralateral cerebellum plays an important role in conditioning. To
test this specifically, Ivarsson et al. (1997)
unilaterally and reversibly blocked the outflow from the cerebellar
cortex is by micro-injections of lignocaine into the brachium
conjunctivum. Both the ipsilateral and contralateral eyeblink CRs were
abolished. In summary, the contralateral cerebellar cortex controls
ipsilateral and contralateral conditioned eyeblink and NM responses.
Finally, other groups who have studied eyeblink conditioning using PET
functional imaging have also reported the involvement of the
contralateral cerebellum in human eyeblink conditioning (Blaxton
et al. 1996; Logan and Grafton 1995
). To this
extent, their results are comparable with ours. As in our own study,
Logan and Grafton (1995)
reported strong contralateral
activity in the cerebellar cortex during human eyeblink conditioning.
Neuroimaging data therefore also suggest that the contralateral
cerebellar cortex plays an important role in human eyeblink conditioning.
Conclusion
The results present a simple picture. We have shown learning
related changes in two areas (cerebellar Crus I/lobule HVI and ventral
motor/premotor cortex) that have been shown in animal studies to be
essential for conditioning of the external eyelid. These may reflect
learning-related changes in neuronal excitability that may be essential
for eyeblink conditioning specifically and for motor learning more
generally. We also found a learning related decrease in activity in the
amygdaloid complex. In an event-related fMRI study with the same design
(Buechel et al. 1998), there was also a decrease in
activity in the amygdala during fear conditioning (unpaired CS+
trials). In that study, the US was a loud noise, whereas in our study
the US was a mildly aversive airpuff.
Our event-related design also enabled us to look for changes in unpaired CS+ trials that could be related to the mismatch between sensory prediction and actual outcomes. The only difference between these trials and the comparison paired CS+ trials lay in violations of the sensory predictions on the unpaired trials. There was an effect in contralateral cerebellar lobule HVI for this comparison. This encourages the view that this change in activity may reflect the operation of the cerebellum in predicting sensory events.
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ACKNOWLEDGMENTS |
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We thank the referees for helpful comments. We also thank Drs. J. W. Moore, C. Evinger, and B. Schreurs for advice on behavioral methods and Prof. Karl Friston for comments on earlier versions of the manuscript.
This work was supported by the Wellcome Trust.
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FOOTNOTES |
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Present address and address for reprint requests: N. Ramnani, University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, UK (E-mail: narender.ramnani{at}physiol.ox.ac.uk).
Received 19 April 2000; accepted in final form 17 August 2000.
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REFERENCES |
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