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1 Department of Neurology, University of Essen, 45122 Essen; 2 Department of Neuroradiology, University of Essen, 45122 Essen; 3 Institute of Physiology, University of Munich, 80336 Munich, Germany
Submitted 21 January 2003; accepted in final form 9 April 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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; Mauk et al. 2000; Thompson et al. 1997; Woodruff-Pak and Steinmetz 2000a,b; Yeo and Hesslow 1998). Other studies have examined involvement of the cerebellum in conditioning of the nociceptive limb withdrawal reflex (Apps and Lee 2002; Kolb et al. 1997; Timmann et al. 1996, 2000; Voneida 2000). To understand the role of the cerebellum in reflex conditioning knowledge about the cerebellar areas involved in control of the unconditioned responses has some relevance. First, lesion studies are likely to show the clearest deficits in learning if all areas involved in unconditioned reflex control are affected (Yeo and Hesslow 1998). Likewise, one possible reason for controversial results of lesion studies may be that cerebellar cortical areas involved in unconditioned reflex control are affected to various extents. In addition, demonstration of cerebellar areas involved in control of unconditioned reflexes raises the controversial issue of impaired motor performance (i.e., impaired unconditioned reflexes) and its possible relation to deficits in conditioning (pro: Harvey et al. 1993; Welsh and Harvey 1989; contra: Steinmetz et al. 1992).
Cerebellar areas involved in control of unconditioned eyeblink response have been investigated in detail in animals (Hesslow 1994a,b; Morcuende et al. 2002; Pellegrini and Evinger 1997) and humans (Dimitrova et al. 2002a). Knowledge about cerebellar areas involved in control of the nociceptive limb withdrawal reflex is less detailed. There is, however, experimental evidence that the cerebellum is involved in performance of the limb withdrawal reflex. Early animal studies report changes of limb withdrawal reflex after lesions and stimulation of the cerebellum (Chambers and Sprague 1955; Denny-Brown et al. 1929) and inferior olive (Rabacchi et al. 1986). More recent studies describe limb withdrawal reflex changes after lesions of the paravermal cortex (Yu 1972) and interposed nuclei (Kolb et al. 1997). Although involvement of the intermediate cerebellum has been shown in limb withdrawal reflex control, no attempts have been made to map the cerebellar cortical lobules involved.
The number of human studies examining the cerebellar role in nociceptive limb withdrawal reflex control is more limited. Impaired leg withdrawal reflexes have been reported in patients with Friedreich's ataxia (Shahani and Young 1971) and in a patient with a unilateral surgical cerebellar lesion (Timmann et al. 1998a). In a recent PET study by our group, changes of cerebellar activity evoked by nociceptive leg withdrawal reflex were observed within vermal regions primarily of the anterior lobe in healthy human subjects (Maschke et al. 2002a).
The aim of the present study was to use the high spatial and temporal resolution of event-related functional brain imaging (fMRI) to examine nociceptive leg withdrawal reflex–related cerebellar areas in humans. More detailed knowledge of unconditioned withdrawal reflex–related cerebellar areas are thought helpful to interprete data of limb withdrawal reflex conditioning studies both in cerebellar patients and in healthy human subjects using functional brain imaging.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Sixteen healthy adult subjects participated. Their average age was 30.8 ± 6.0 (range 22–41) years. Five subjects were female and 11 male. None of them had a history of neurological disease or revealed neurological signs based on neurological examination. All experiments were undertaken with the understanding and written consent of each subject. The local ethical committee of the University of Essen approved the study.
EMG recordings
Subjects were lying supine with the knee supported by a pillow and with their eyes closed. Nociceptive leg withdrawal reflexes were evoked by a train of bipolar current pulses (f = 100 Hz, pulse duration 0.65 ms) lasting for 100 ms applied through surface electrodes to the left tibial nerve behind the medial malleolus. The electrical stimulator (Elektrischer Stimulator ES, Jaeger Toennies, Hoechberg, Germany) was placed outside the MR scanning room. Before the recording session the sensory and motor thresholds were determined followed by successive increases of the current intensity until significant leg flexion responses were evoked. The mean sensory threshold was 1.2 mA (SD 0.5, range 0.4–1.5), mean motor threshold was 4.9 mA (SD 1.9, range 2–7), and mean leg withdrawal reflex stimulation strength was 14.3 mA (SD 7.5, range 6–30 mA).
An event-related fMRI paradigm (see following text) was applied with a total of 30 electrical stimuli being delivered pseudorandomly and with long intertrial intervals (range 28–56 s) during 500 consecutive MR scans. For each subject electrical stimuli were delivered at the end of MR scans 15, 35, 50, 67, 83, and 95, with the same order being repeated during the following 400 scans (115, 135, 150, 167, 183, 195, 215, 235, 250, etc.). Intervals of 600 ms were interposed between individual scans. Electrical stimulation occurred 186 ms after the beginning of the last of 22 slices of each scan and limb flexion reflexes were recorded within the interval without echo-planar imaging.
Electromyographic (EMG) activity was recorded from the left anterior tibial muscle (sampling rate 1,000 Hz). A pair of disposable surface carbon electrodes (ConMed), commonly used for ECG recording in the MR environment, was placed over the muscle belly. The overlying skin was cleaned with isopropyl alcohol (75%) and shaved if needed. A Velcro fastening ground strip was fixed between the site of stimulation and the recording site close to the ankle. The EMG signals were fed by carbon fiber cables (D120RL radiolucent cables, 3M Medica) to a battery-powered EMG amplifier (LWL-EXX-amplifier; Institut für Explorative Datenanalyse, Hamburg, Germany) custom-built for use in the MR environment (gain: 50–100, filter: 10 (2) Hz < f < 2,000 Hz). Electrical signals were transformed into optical signals and transmitted by fiber-optic cables to a fiber-optic receiver placed outside the scanning room. EMG signals were fully rectified, further filtered (100 Hz), and stored for off-line analysis.
EMG analysis
The EMG data were analyzed on a trial-by-trial basis using commercial software (AxoGraph 3.5, Axon Instruments, Union City, CA). Visual inspection of each trial allowed identification of trials without significant flexion reflex activity. Further analysis of leg withdrawal reflex was limited because of superimposed artifacts. The nociceptive leg withdrawal reflex consists commonly of an early (F1) and a late (F2) reflex component that are separated by a silent period (S) (Meinck et al. 1983; Shahani and Young 1971). Because onset of the early F1 component frequently overlapped with the stimulation artifact, onset of the F2 component only was determined. Onset was defined where EMG activity significantly increased from baseline activity. The end of the reflex response was frequently difficult to determine largely because of cable movement artifacts. Data inspection revealed that a fixed interval of 50 ms was free of artifacts in most cases. Therefore integrated EMG (IEMG) was quantified for a fixed interval of 50 ms (50 ms-IEMG). Mean EMG baseline activity was acquired in a 100 ms-interval before electrical stimulation. Mean baseline activity was subtracted from 50 ms-IEMG. To allow for comparison between subjects, leg withdrawal reflex amplitudes were normalized to the mean amplitudes across all 30 trials in each individual subject. Each withdrawal reflex amplitude was expressed as a percentage of this value.
Means and SDs of F2 onsets and fixed 50 ms-IEMGs were calculated. To quantify possible changes across time (i.e., habituation and sensitization effects) linear regression analyses with 50 ms-IEMG as a dependent factor were performed across trials for the group of all subjects and each individual subject.
Imaging
All fMRI scans were taken with a 1.5 T Siemens Sonata scanner (Dept. of Neuroradiology, University of Essen, Germany) with standard head coil. A multislice echo planar imaging sequence (EPI) was used to produce 22 continuous 3-mm-thick axial slices covering the volume of the cerebellum and adjacent brain stem with TR = 2.8 s, TE = 60 ms, flip angle = 90°, 64 x 64 matrix and voxel size = 3.59 x 3.59 x 3 mm3. An event-related fMRI paradigm was used for the experiment. An electronic triggering signal was used to achieve synchronization between the time of initiation of the active event (electrical stimulus) and the MR acquisition. Each series consisted of 500 scans with a total duration of 23.3 min. Structural images were acquired for each subject using a T1 3D sequence with TR = 11.1 ms, TE = 4.3 ms, flip angle = 15°, 136 partitions, effective thickness = 1.2 mm, and voxel size = 1 x 1 x 1.2 mm3.
Image analysis
The stereotaxical transformations and statistical analysis were carried out on a Sun Sparc Ultra 80 computer with statistical parametric mapping software (version SPM99; Wellcome Department of Cognitive Neurology, London, UK), implemented in MATLAB (Mathworks, Sherborn, MA). The functional images were first subjected to a slice time–alignment process. This correction procedure is necessary to minimize image intensity inhomogeneity arising from differences in slice image acquisition timing. All individual volumes were realigned after the 6 head-movement parameters were estimated (3 translations and 3 rotations) from rigid body transformations. The realignment procedure minimizes the displacement effects between each volume of the time series and the first. Images were then spatially normalized (Friston et al. 1995) into the reference system of Talairach and Tournoux (1988), using a representative standard EPI template from the Montreal Neurological Institute (MNI; Evans et al. 1994). The functional images were subsampled to a voxel size of 2 x 2 x 2 mm3 and smoothed using an isotropic Gaussian kernel of 6 mm.
The statistical analysis was performed for each time series after specifying the appropriate design matrix. The active event was modeled with hemodynamic response functions (HRF). The 6 head-movement parameters were included as trial-specific covariates in the design matrix to take into account effects of head movement–related changes after electrical stimulation of the foot. To minimize the effects of magnetization relaxation artifacts and to reduce the effects of accompanying startlelike reactions (see RESULTS, Nociceptive withdrawal reflex recordings), scans corresponding to the first two stimuli (i.e., the first 40 scans of each time series) were excluded from statistical analysis.
The significance of effects was assessed using Z statistics for every voxel from the brain, and these sets of Z values were used to create statistical parametric maps (SPMs). A high-pass filter was used to remove low-frequency drifts and fluctuations of the signal (Friston et al. 1996), and proportional scaling was applied to remove global changes in the signal.
Data were analyzed for each subject individually and for subjects as a group. Group effects were calculated using random effects models. Contrast images, one for each single subject, were taken to the second-level analysis and entered into the one-sample t-test model (Friston et al. 1999). The statistical test of variance of these single contrast images from subject to subject consists of contributions from both the between- and within-subject components of variance and can be used to extend the inference to population.
The specified contrasts compared the active event condition with rest. Only trials with significant EMG activity were used as active events in fMRI statistical analysis (see RESULTS, Nociceptive withdrawal reflex recordings). In 3 subjects no significant flexion reflexes were observed in EMG recordings. Data from these 3 subjects were excluded from statistical analysis. For the group study a threshold of P < 0.0001 (uncorrected; extended threshold 20 voxels) was adopted. Thresholds for statistical analysis of individual subjects were set as P < 0.001 (uncorrected; extended threshold 20 voxels). Anatomical localization of MNI coordinates were defined based on the 3D MRI atlas of the human cerebellum in proportional stereotaxical space developed by Schmahmann et al. (2000) and the 3D MRI atlas of the human cerebellar nuclei developed by Dimitrova et al. (2002b). The lateral extent of the vermis is difficult to define, particularly within the anterior lobe (Schmahmann et al. 2000). As an approximation, vermal activation was defined as activation within an x-range of –10 mm and 10 mm. Activation more laterally than 10 mm from the AC-PC line was defined as activation within the cerebellar hemispheres.
For localization of cerebral activation the Talairach and Tournoux atlas (1988) was used. To correct for a certain mismatch between MNI and Talairach and Tournoux space, MNI coordinates were transferred to the Talairach and Tournoux space using the algorithms described in http://www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Visual inspection of surface EMG recordings of the anterior tibial muscle revealed that leg withdrawal responses were present on average in 84% (SD 21%; range 50–100%) of the trials in 13 of the 16 subjects. In 3 subjects no significant limb flexion response activity was observed; these 3 subjects were excluded from fMRI analysis. Onsets and 50 ms-IEMGs of the limb flexion response were determined in 9 of the 13 subjects with provable withdrawal responses. In the remaining 4 subjects prominent artifacts prevented more detailed EMG analysis.
Individual, nonrectified EMG recordings of one subject (s-9 in Tables 1 and 2) are shown in Fig. 1A. The beginning of electrical stimulation within the MR scanning-free interval is indicated by a vertical line. The electrical stimulation is followed by EMG bursts in all 30 trials, with the first trial at the top and the last trial at the bottom. The beginning of subsequent MR scanning is indicated by the artifacts at the end of each trace. EMG responses were largest within the initial trials with no prominent change of response size in the remaining trials.
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Mean changes of response size (normalized 50 ms-IEMG) across trials in the group of all subjects are shown in Fig. 1B. Response reduction was most prominent within the first 3 trials. The largest response size of the first 2 trials suggested accompanying startlelike responses. Linear regression analysis of group data showed significant changes across trials (R = 0.63, P < 0.001). All but 2 of the individual subjects showed a tendency to decrease responses across trials (i.e., negative slope in individual linear regression analysis), which was significant in 4 subjects (P < 0.05; s-6, s-8, s-9, and s-13 in Tables 1 and 2). Because quantitative EMG data were not available in all subjects, the amount of EMG reductions across trials was not considered covariate in statistical fMRI analysis. The first 2 trials, however, were excluded from fMRI analysis to reduce effects of startlelike responses.
In the group of all subjects, the mean onset of leg withdrawal response (i.e., the F2 component) was 160 ms (SD 47 ms). Latencies were within the range described in the literature for nociceptive leg withdrawal reflex recordings without preinnervation of the anterior tibial muscle (e.g., Shahani and Young 1971; Torring et al. 1981).
fMRI data
SPM (t) maps of random model group analysis (P < 0.0001, uncorrected) are shown in Fig. 2. Nociceptive leg withdrawal reflex–related areas of cerebellar activations were present within the vermis, paravermal areas, and the lateral posterior hemispheres. Local maxima were found within the anterior vermis (lobules III/IV) and the posterior vermis (lobules VI and VIII). Activation extended into the fastigial nuclei. Paravermal areas were activated bilaterally within the anterior lobe (lobules III/IV) and posterior lobe (lobule VIII). Within the lateral posterior hemispheres local maxima were found within lobules VI and Crus I on the left and lobules V and VI on the right. Hemispheral activations were more prominent on the left.
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Group analysis revealed the largest cluster of activation (cluster size = 308) within the vermis with an absolute maximum in lobule VI [x, y, z coordinates in mm (–2, –64, –26; Z = 4.96)] extending into lobule V (–2, –64, –12; Z = 4.55). Additional local maxima were present within lobule III (–6, –44, –20; Z = 4.15), extending into lobule IV (–4, –48, –16; Z = 4.17), and lobule VIIIA (–2, –68, –42; Z = 4.75; –2, –66, –34; Z = 4.58), extending into lobule VIIIB (–2, –58, –30; Z = 4.77). Figure 3 illustrates that the cluster of activation included the fastigial nuclei. The statistical group data from the random model are displayed on MR templates taken from the 3D atlas of the human cerebellum nuclei developed by our group (Dimitrova et al. 2000b). An area of significant activation is seen in the roof of the fourth ventricle (2, –52, –28), which is consistent with the known location of the fastigial nuclei (Angevine et al. 1961; Duvernoy 1995). There was no significant activation of the interposed and dentate nuclei (I and D in Fig. 3). However, because the exact borders between fastigial and interposed nuclei are difficult to define, activation of parts of the interposed nuclei cannot be excluded.
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The second largest cluster of activation (cluster size = 121) was present in paravermis of the left anterior lobe with an absolute maximum in paravermal lobule IV (–22, –32, –36; Z = 4.85) and an additional maximum in lobule VI (–30, –44, –34; Z = 4.71). The third largest cluster (cluster size = 77) was located within left Crus I (–42, –64, –32; Z = 4.89). Smaller clusters of activations were present within right paravermal lobules III/IV (24, –34, –34; Z = 4.63), and hemispheral lobules V (28, –38, –28; Z = 4.12) and VI (28, –48, –32; Z = 4.87). In addition, small clusters of activation were located within left paravermal lobule VIIIA (–22, –72, –52; Z = 4.78) and right paravermal lobule VIIIB (24, –44, –56; Z = 4.67). On the group level, no significant extracerebellar activations (e.g., within the temporal lobes or brain stem) were found. The statistical group data from the random model are displayed on axial sections of a typical canonical MNI brain in Fig. 4. Table 1 summarizes the Z-scores and MNI coordinates for the vermal activation for the random model group analysis as well as for each single subject. Table 2 summarizes the data for the hemispheral activation.
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Analysis in individual subjects showed a similar pattern of activation within the vermis and cerebellar hemispheres. In 6 subjects (s-1–s-6) withdrawal reflex–related activation was present in vermal lobule III and/or IV. In 2 subjects vermal activation was present in lobules I/II (s-5, s-7). Vermal activation in the 7 subjects is displayed on sagittal sections of the individual normalized anatomical data sets in Fig. 5. Activation in vermal lobule VI was present in 9 subjects with additional activation in vermal lobule V in 2 subjects. Vermal activation in lobule VI is shown in 6 individual subjects in Fig. 5 (s-1, s-2, s-3, s-5, s-7, and s-10). Note that in s-2 the nearest local maximum was within vermal lobule VIIA and activation in VI is therefore not listed in Table 1. Vermal lobule VIIIA was activated in 5 subjects, with extension into lobule VIIIB in one subject. Vermal lobule VII was activated in 7 subjects. Activation of vermal lobules VII and/or VIII is shown in 7 of these subjects (s-1–s-7) in Fig. 5. Vermal activation extended into the region of the fastigial nuclei in 6 subjects. Activation overlapped with MNI coordinates of fastigial nuclei based on Dimitrova et al. (2002b) in 3 subjects (s-1, s-6, s-8 in Table 1) and was in close proximity in the other 3 subjects (s-2, s-3, s-7). Activation extending into the roof of the fourth ventricle is seen in 4 of the individual subjects in Fig. 5 (s-1, s-2, s-3, s-7). Activation overlapping with the location of the dentate or interposed nuclei was present in 5 subjects [s-2: right interposed (4, –68, –38; Z = 4.46); s-3: left interposed (–14, –56, –26; Z = 4.8); s-4: left dentate (–18, –66, –38; Z = 5.34); s-7: left dentate (–14, –58, –36; Z = 3.86); s-8: left interposed (–8, 52, –24; Z = 4.72)].
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Activation of paravermal lobules III/IV was present in one subject on the left, in 5 subjects bilaterally, and in 3 subjects on the right. Activation of paravermal lobules VIIIA/B was present in 4 subjects on the left, in 4 subjects bilaterally, and in one subject on the right. Two subjects showed activation in left lobule VII. Finally, activation of hemispheral lobule VI was present in 5 subjects on the left and in 4 subjects bilaterally. Activation of lobule Crus I was present in 3 subjects on the left, in 2 subjects bilaterally, and in 4 subjects on the right.
In 10 individual subjects additional activation was found within the temporal lobes. Temporal activation was on the left in 3 subjects and bilateral in 7 subjects. The location of activation within the temporal lobes varied between individual subjects. Locations included gyrus temporalis superior and medius, gyrus parahippocampalis, uncus, and amygdala.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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; Kugelberg et al. 1960; Sherrington 1910). The other areas within the posterior lobe (i.e., hemispheral lobules VI and Crus I, vermal lobule VI) may be related to other pain-related processes (e.g., pain-induced facial grimacing and/or fear; Craig 1984) and startlelike reactions (Bromm and Scharein 1982; Dowman 1992).
Findings confirm and extend results of our previous PET study of the nociceptive leg withdrawal response (Maschke et al. 2002a). Activations of the anterior vermis and more anterior parts of the posterior vermis (i.e., vermal lobules III–VI) were present in both studies. In the present fMRI study additional activations were observed in the posterior vermis and posterior cerebellar hemispheres. The more widespread cerebellar activation are likely a consequence of the better temporal and spatial resolution of event-related fMRI compared with PET.
Cerebellar activation related to the spinal nociceptive leg withdrawal reflex
Nociceptive leg withdrawal reflex–related areas within the vermal and paravermal areas of the anterior lobe (i.e., lobules III/IV) and the more posterior parts of the posterior lobe (i.e., lobule VIII) agree with the known cerebellar representation of the hindlimb and leg. Somatotopic representation in the cerebellum with two homunculi, one located upside down in the anterior lobe and a second one in the posterior lobe, was first decribed by Adrian (1943) and Snider and Stowell (1944). Although subsequent anatomical and electrophysiological studies have revealed a more complex spatial distribution of mossy and climbing fiber afferents, a rough somatotopical pattern appears to be present (Brodal 1975; Ekerot et al. 1991a,b; Oscarsson 1976; Welker 1987; for reviews see Bloedel and Courville 1974; Voogd and Glickstein 1998). Consistent with the present findings, climbing fiber hindlimb afferents have been found to the more rostral vermal and paravermal parts of the anterior lobe (Garwicz 1997) and to the more posterior vermal parts of the posterior lobe (i.e., vermal lobule VIII) (Atkins and Apps 1997).
More recent fMRI studies have confirmed the existence of a similar somatotopic representation in humans. In agreement with the present findings, representation of foot movements has been found both within the more anterior parts of the anterior lobe (i.e., in hemispheral lobules II–IV with extension into the vermis; Grodd et al. 2001; Nitschke et al. 1996; Rijntjes et al. 1999) and within the more posterior parts of the paravermal hemispheres (hemispheral lobules VII–VIII; Rijntjes et al. 1999) and vermis of the posterior lobe (Grodd et al. 2001; Rijntjes et al. 1999).
Paravermal activation was present bilaterally. Contralateral cerebellar activation may reflect movement of the contralateral limb and/or bilateral representation of sensory afferents. Electrical stimulation of one limb results in withdrawal of the stimulated limb and concomitant postural adjustments of the contralateral limb (e.g., extension during standing) (Hagbarth and Finer 1963; Kugelberg 1960; Sherrington 1910). In addition, cerebellar afferents have been shown to have a large ipsilateral and a smaller contralateral cerebellar representation (Bloedel and Courville 1974; Brodal 1981).
No voluntary foot movement and pure sensory stimulation conditions were performed in the present study. Therefore the present study does not allow differentiation if the reflex-related cerebellar activity reflects cerebellar modulation of the spinal reflex pathways, afferent input of the noxious stimulus, and/or afferent feedback of the limb withdrawal. It appears, however, likely that the afferent input is used to modulate the spinal nociceptive leg withdrawal reflex. As outlined in the INTRODUCTION changes of reflex amplitude have been found in a human case study (Timmann et al. 1998a) and animal lesion studies of the cerebellum (Chambers and Sprague 1955; Denny-Brown et al. 1929; Kolb et al. 1997; Yu 1972) and inferior olive (Rabacchi et al. 1986).
Findings of animal lesion studies, however, are not unequivocal. Despite clear deficits of classical conditioning, others have found no changes of the unconditioned limb withdrawal reflex after lesions of the interposed nucleus (Donegan et al. 1983), brachium conjunctivum (Voneida 2000), red nucleus (Smith 1970; Tsukahara et al. 1981), rubrospinal tract (Voneida 1999), and inferior olive (Voneida et al. 1990). Electrophysiological animal studies, on the other hand, provide detailed evidence that the spino-olivo-cerebellar system is involved in nociceptive limb withdrawal reflex control (Ekerot et al. 1991a,b; Garwitz et al. 1992, 2002; Kalliomäki et al. 1992; Oscarsson 1973; Schouenborg and Weng 1994; Schouenborg et al. 1994). The organization of cutaneous receptive fibers for spino-olivo-cerebellar pathways to cerebellar zones controlling detailed limb movements has been shown to resemble that of the nociceptive withdrawal reflexes (Ekerot et al. 1991a,b; Garwicz et al. 1992). Partial overlap of cerebellar areas activated during limb flexion reflex in the present fMRI study and during voluntary leg movements in previous fMRI studies is consistent with this finding. Overlap of cerebellar areas during voluntary and reflexive leg movement is further supported by the recent PET study of our group. Limb flexion reflex–related areas were found within the upper vermis of the anterior lobe including lobules III and IV. These areas partially overlapped with vermal activation areas in a voluntary foot movement condition (Maschke et al. 2002a). Similar cerebellar areas may be involved in control of reflexive and voluntary limb movements by modulating spinal neuronal networks that implement the withdrawal reflexes and also mediate signals from supraspinal motor centers involved in coordination of voluntary motor behavior (Jankowska 1992; Kalliomäki et al. 1992; Kolb et al. 1997; Lundberg 1982; Schomburg 1990; Schouenborg and Weng 1994). Future studies need to investigate possible impairment of performance of the nociceptive leg withdrawal reflex in a larger group of cerebellar patients.
Cerebellar activation related to other pain-related reactions
In addition to areas that overlap with the known cerebellar representation of the leg, nociceptive leg withdrawal reflex–related activation was present within the anterior parts of the posterior vermis (lobule VI), with extension into lobule V and the fastigial nuclei and the anterior parts of the posterior cerebellar hemispheres bilaterally (lobules VI/Crus I). Consistent with the present findings, withdrawal reflex–related activity extended into vermal lobules V and VI in our recent PET study (Maschke et al. 2002a). These areas may be related to functions other than the reflexive withdrawal of the leg. Electrical stimulation is accompanied by sensation of pain, facial expressions of pain, fear, and startlelike reactions (Craig 1984; Craig and Patrick 1985; Dowman 1992; Ploghaus et al. 1999). There is evidence from the animal and functional human brain imaging literature that the cerebellum may be involved in these pain-induced reactions.
First, painful stimuli are accompanied by facial actions including eye closing or blinking (Craig and Patrick 1985). Cerebellar somatotopic representation of facial afferents and movements are known to be within the posterior cerebellar lobe (i.e., vermal and paravermal lobules VI and VII) (Grodd et al. 2001; Hesslow 1994a,b; Nitschke et al. 1996; Snider and Stowell 1944). Likewise, a recent fMRI study of our group showed blink reflex–related areas within bilateral hemispheral lobules VI and Crus I with extension into the vermis (Dimitrova et al. 2002a). Reflex eyeblinking as part of startlelike responses may also account for at least part of activation in areas representing facial movements. Responses to the first two stimuli were excluded from analysis to minimize the effects of startlelike reactions. Whole body startle habituates within few trials. Startle-related eyeblinks, however, take a slower course of habituation and their occurrence cannot be excluded in later trials (Koch 1999; Maschke et al. 2000). Furthermore, the cerebellar vermis, particularly lobule VI, and adjacent parts of the hemispheres have been shown to be involved in modulation of the startle reflex (i.e., habituation and fear-induced potentiation) (Frings et al. 2002; Leaton and Supple 1991; Lopiano et al. 1990; Pissiota et al. 2002; Timmann et al. 1998b).
Thus cerebellar activation of the anterior part of the posterior cerebellum may reflect pain-induced facial movements (e.g., grimacing and/or startle-related eyeblinking). An increasing number of studies, however, suggest that the cerebellum is involved in nonmotor functions including affect and behavior (see Schmahmann 1997 for review). Areas within the neocerebellum, for example, the neovermis (i.e., lobules VI/VII) and the posterior cerebellar hemispheres (i.e., lobule VI and below), appear to be of particular importance (Akshoomoff and Courchesne 1994; Schmahmann and Sherman 1998; Thach 1998).
Likewise, cerebellar activation of the vermis and posterior cerebellar hemispheres have been demonstrated in fMRI studies of neural substrates involved in pain (Becerra et al. 1999; Coghill et al. 1999; Svensson et al. 1997). On the basis of Schmahmann et al.'s (2000) atlas of the human cerebellum, activations were found primarily within lobule VI. Ploghaus et al. (1999) showed that different areas in the cerebellum are involved in different aspects of pain processing. In their study painful stimuli of the hand evoked responses of the anterior cerebellum (i.e., within the known hand areal), whereas expectation of the same stimuli evoked activations within the posterior cerebellar hemisphere. Vermal and paravermal areas of the anterior lobe and more posterior parts of the posterior lobe (corresponding to the somatotopic representation of the stimulated limb) may be involved with integration of nociceptive information to other motor areas, whereas neocerebellar areas within the posterior hemispheres may be involved in other (e.g., affective or cognitive) dimensions of pain.
Finally, pain is frequently accompanied by fear. Both the cerebellar vermis and the posterior cerebellar hemispheres have been shown to be activated as a result of externally evoked emotions (Beauregard et al. 1998; Lane et al. 1997; Reiman et al. 1997). In most fMRI studies areas of activation were located within vermal lobules V/VI and in hemispheral lobules VI/Crus I (based on Schmahmann et al.'s atlas).
Cerebellar activations attributed to pain-related reactions other than the actual limb withdrawal are further supported by the likely activation of the fastigial nuclei. Fear is known to be accompanied by changes of autonomic functions (for review see LeDoux 1993; Maschke et al. 2002b). The fastigial nuclei have been shown to participate in emotions and autonomic functions (e.g., cardiovascular control), in addition to processing of vestibular signals (Heath et al. 1974; Holmes et al. 2002; for review see Schmahmann 2000).
Hemispheral activations on the group level were more prominent on the left. Although this may simply reflect effects of stimulation side, another explanation appears worth mentioning. The oldest model of emotion lateralization holds that the right cerebral hemisphere is dominant for emotional processing. An alternative view posits that the left cerebral hemisphere is preferentially involved in positive emotions and approach, whereas the right hemisphere is preferentially involved in negative emotions and withdrawal (Zald 2003). These models focus on the prefrontal cortex. Because of the known connections of the left cerebellum to the right prefrontal cortex (Middleton and Strick 1994), fear-related activation of the cerebellum may be expected on the left.
In conclusion, in addition to actual limb withdrawal, a variety of other motor and nonmotor reactions are induced by pain that appear able to induce changes of cerebellar activity in the posterior cerebellar lobe. Quantitative assessment of facial movements, startlelike reactions, and fear-induced autonomic changes (i.e., skin conductance response, heart rate) may be helpful to differentiate between the possibilities in future studies.
Different areas within the vermis and cerebellar hemispheres appear to be related to the nociceptive leg withdrawal reflex. Vermal and paravermal areas overlapping with the known representation of the leg are likely related to the leg withdrawal reflex in itself. Areas within the posterior lateral hemispheres and neovermis appear to be related to other pain-induced reactions. Studies of conditioning of the nociceptive limb withdrawal reflex should take these findings into consideration. Conditioning of the electrically evoked leg withdrawal reflex will induce conditioning of specific (i.e., the leg withdrawal) and nonspecific (e.g., fear, changes of heart rate) aversive reactions (Lavond et al. 1993). Accordingly, in fMRI studies in healthy human subjects different cerebellar areas are likely to be activated. Likewise, in patients with focal cerebellar lesions concomitant conditioning of specific and nonspecific aversive reactions is likely to be differentially affected depending on the side of the lesion.
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DISCLOSURES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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Address for reprint requests: D. Timmann, Department of Neurology, University of Essen, Hufelandstra
e 55, 45122 Essen, Germany (E-mail: Dagmar.Timmann{at}uni-essen.de).
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Akshoomooff NA and Courchesne E. ERP evidence for a shifting attention deficit in patients with damage to the cerebellum. J Cogn Neurosci 6: 388–399, 1994.[Web of Science]
Angevine JB, Mancall EL, and Yakovlev PI. The Human Cerebellum. An Atlas of Gross Topography in Serial Sections. Boston, MA: Little, Brown & Company, 1961.
Apps R and Lee S. Central regulation of cerebellar climbing fibre input during motor learning. J Physiol 541: 301–317, 2002.
Atkins MJ and Apps R. Somatotopical organisation within the climbing fibre projection to the paramedian lobule and copula pyramidis of the rat cerebellum. J Comp Neurol 389: 249–263, 1997.[Web of Science][Medline]
Beauregard M, Leroux J-M, Bergman S, Arzoumanian Y, Beaudoin G, Bourgouin P, and Stip E. The functional neuroanatomy of major depression: an fMRI study using an emotional activation paradigm. Neuroreport 9: 3253–3258, 1998.[Web of Science][Medline]
Becerra LR, Breiter HC, Stojanovic M, Fishman S, Edwards A, Comite AR, Gonzalez RG, and Borsook D. Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study. Magn Reson Med 41: 1044–1057, 1999.[Web of Science][Medline]
Bloedel JR and Bracha V. On the cerebellum, cutaneomuscular reflexes, movement control and the elusive engrams of memory. Behav Brain Res 68: 1–44, 1995.[Web of Science][Medline]
Bloedel JR and Courville J. Cerebellar afferent systems. In: Handbook of Physiology. The Nervous System. Baltimore, MD: Williams & Wilkins, 1981, sect. 1, vol. II, p. 735–829.
Brodal A. Neuroanatomical Anatomy in Relation to Clinical Medicine (3rd ed.). New York: Oxford University Press, 1981.
Brodal P. Demonstration of a somatotopically organized projection onto the paramedian lobule and the anterior lobe from the lateral reticular nucleus: an experimental study with horseradish peroxidase method. Brain Res 95: 221–239, 1975.[Web of Science][Medline]
Bromm B and Scharein E. Response plasticity of pain evoked reactions in man. Physiol Behav 28: 109–116, 1982.[Medline]
Chambers WW and Sprague JM. Functional localization in the cerebellum. II. Somatotopic organization in cortex and nuclei. Arch Neurol Psychiatr 75: 653–680, 1995.
Coghill RC, Sang CN, Maisog JM, and Iadarola MJ. Pain intensity processing within the human brain: a bilateral, distributed system. J Neurophysiol 82: 1934–1943, 1999.
Craig KD. Emotional aspects of pain. In: Textbook of Pain, edited by Wall PD and Melzack R. New York: Churchill Livingstone, 1984, p. 153–161.
Craig KD and Patrick CJ. Facial expression during induced pain. J Pers Soc Behav 48: 1080–1091, 1985.
Denny-Brown D, Eccles JC, and Liddell EGT. Observations on electrical stimulation of the cerebellar cortex. Proc R Soc Lond B Biol Sci 104: 518–536, 1929.
Dimitrova A, Weber J, Maschke M, Elles H-G, Kolb FP, Forsting M, Diener HC, and Timmann D. Eyeblink-related areas in human cerebellum as shown by fMRI. Hum Brain Mapp 17: 100–115, 2002a.[Web of Science][Medline]
Dimitrova A, Weber J, Redies C, Kindsvater K, Kolb FP, Maschke M, Forsting M, Diener HC, and Timmann D. MRI atlas of the human cerebellar nuclei. NeuroImage 17: 240–255, 2002b.[Web of Science][Medline]
Donegan NH, Lowry RW, and Thompson RF. Effects of lesioning cerebellar nuclei on conditioned leg-flexion responses. Soc Neurosci Abstr 9: 331, 1983.
Dowman R. Possible startle response contamination of spinal nociceptive withdrawal reflex. Pain 49: 187–197, 1992.[Web of Science][Medline]
Duvernoy HM. The Human Brain Stem and Cerebellum. Surface, Structure, Vascularization, and Three-Dimensional Sectional Anatomy with MRI. New York: Springer-Verlag, 1995.
Ekerot CF, Garwicz M, and Schouenborg J. Topography and nociceptive receptive fields of climbing fibres projecting to the anterior lobe in the cat. J Physiol 441: 257–274, 1991a.
Ekerot CF, Garwicz M, and Schouenborg J. The postsynaptic dorsal column pathway mediates cutaneous nociceptive information to cerebellar climbing fibres in the cat. J Physiol 441: 275–284, 1991b.
Evans AC, Kamber M, Collins DL, and MacDonald D. An MRI-based probabilistic atlas of neuroanatomy. In: Magnetic Resonance Scanning and Epilepsie, edited by Shorvon S, Fish D, Andermann F, Bydder GM, and Stefan H. New York: Plenum, 1994, p. 263–274.
Frings M, Maschke M, Erichsen M, Jentzen W, Müller S, Kolb FP, Diener HC, and Timmann D. Involvement of the human cerebellum in fear-conditioned potentiation of the acoustic startle reflex: a PET study. Neuroreport 13: 1275–1278, 2002.[Web of Science][Medline]
Friston KJ, Ashburner J, Poline JB, Frith CD, Heather JD, and Frackowiak RSJ. Spatial registration and normalization of images. Hum Brain Mapp 2: 165–189, 1995.
Friston KJ, Holmes A, Poline JB, Price CJ, and Frith CD. Detecting activations in PET and fMRI: levels of inference and power. NeuroImage 4: 223–235, 1996.[Web of Science][Medline]
Friston KJ, Holmes AP, Price CJ, Buchel C, and Worsley KJ. Multisubject fMRI studies and conjunction analyses. NeuroImage 10: 385–396, 1999.[Web of Science][Medline]
Garwicz M. Sagittal zonal organization of climbing fibre input to the cerebellar anterior lobe of the ferret. Exp Brain Res 117: 389–398, 1997.[Web of Science][Medline]
Garwicz M, Ekerot C-F, and Schouenborg J. Distribution of cutaneous nociceptive and tactile climbing fibre input to sagittal zones in cat cerebellar anterior cortex. Eur J Neurosci 4: 289–295, 1992.[Web of Science][Medline]
Garwicz M, Levinsson A, and Schouenborg J. Common principles of sensory encoding in spinal reflex modules and cerebellar climbing fibres. J Physiol 540: 1061–1069, 2002.
Grodd W, Hülsmann E, Lotze M, Wildgruber D, and Erb M. Sensorimotor mapping of the human cerebellum: fMRI evidence of somatotopic organization. Hum Brain Mapp 13: 55–73, 2001.[Web of Science][Medline]
Hagbarth KE and Finer B. The plasticity of human withdrawal reflexes to noxious stimuli in lower limb muscles. In: Brain Mechanisms, edited by Moruzzi G, Fessard A, and Jasper HH. Amsterdam: Elsevier, 1963, vol. I, p. 65–78.
Harvey JA, Welsh JP, Yeo CH, and Romano AG. Recoverable and nonrecoverable deficits in conditioned responses after cortical cerebellar lesions. J Neurosci 13: 1624–1635, 1993.[Abstract]
Heath RG, Cox AW, and Lustick LS. Brain activity during emotional states. Am J Psychiatry 131: 858–862, 1974.
Hesslow G. Correspondence between climbing fibre input and motor output in eyeblink-related areas in cat cerebellar cortex. J Physiol 476: 229–244, 1994a.
Hesslow G. Inhibition of classically conditioned eyeblink responses by stimulation of the cerebellar cortex in the decerebrate cat. J Physiol 476: 245–256, 1994b.
Holmes MJ, Cotter LA, Arendt HE, Cass SP, and Yates BJ. Effects of lesions of the caudal cerebellar vermis on cardiovascular regulation in awake cats. Brain Res 938: 62–72, 2002.[Web of Science][Medline]
Jankowska E. Interneuronal relay in spinal pathways from proprioceptors. Prog Neurobiol 38: 335–378, 1992.[Web of Science][Medline]
Kalliomäki J, Schouenborg J, and Dickenson AH. Differential effects of a distant noxious stimulus on hindlimb nociceptive withdrawal reflexes in the rat. Eur J Neurosci 4: 648–652, 1992.[Web of Science][Medline]
Koch M. The neurobiology of startle. Prog Neurobiol 59: 107–128, 1999.[Web of Science][Medline]
Kolb FP, Irwin KB, Bloedel JR, and Bracha V. Conditioned and unconditioned forelimb reflex systems in cat: involvement of the intermediate cerebellum. Exp Brain Res 114: 255–270, 1997.[Web of Science][Medline]
Kugelberg E, Eklund K, and Grimby L. An electromyographic study of nociceptive reflexes of the lower limb. Mechanisms of the plantar responses. Brain 83: 394–410, 1960.
Lane RD, Reiman EM, Ahern GL, Schwartz GE, and Davidson RJ. Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry 154: 926–933, 1997.[Abstract]
Lavond DG, Kim JJ, and Thompson RF. Mammalian brain substrates of aversive classical conditioning. Annu Rev Psychol 44: 317–342, 1993.[Web of Science][Medline]
Leaton RN and Supple WF Jr. Medial cerebellum and long-term habituation of acoustic startle in rats. Behav Neurosci 105: 804–816, 1991.[Web of Science][Medline]
LeDoux JE. Emotional memory: in search of systems and synapses. Ann N Y Acad Sci 702: 149–157, 1993.[Web of Science][Medline]
Lopiano L, DeSperati C, and Montarolo PG. Long-term habituation of the acoustic startle response: role of the cerebellar vermis. Neuroscience 35: 79–84, 1990.[Web of Science][Medline]
Lundberg A. Inhibitory control from the brain stem of transmission from primary afferents to motoneurons, primary afferent terminals and ascending pathways. In: Brain Stem Control of Spinal Mechanisms, edited by Sjölund BH, and Björklund A. Amsterdam: Elsevier Biomedical, 1982, p. 179–224.
Maschke M, Drepper J, Kindsvater K, Kolb FP, Diener HC, and Timmann D. Fear-conditioned potentiation of the acoustic blink reflex in cerebellar patients. J Neurol Neurosurg Psychiatry 68: 358–364, 2000.
Maschke M, Erichsen M, Drepper J, Jentzen W, Müller SP, Kolb FP, Diener HC, and Timmann D. Limb flexion reflex-related areas in human cerebellum. Neuroreport 13: 2325–2330, 2002a.[Web of Science][Medline]
Maschke M, Schugens M, Kindsvater K, Drepper J, Kolb FB, Diener HC, Daum I, and Timmann D. Fear-conditioned changes of heart rate in patients with medial cerebellar lesions. J Neurol Neurosurg Psychiatry 72: 116–118, 2002b.
Mauk MD, Medina JF, Nores WL, and Ohyama T. Cerebellar function: coordination, learning or timing? Curr Biol 10: R522–R525, 2000.[Web of Science][Medline]
Meinck HM, Benecke R, Küster S, and Conrad B. Cutaneomuscular (flexor) reflex organization in normal man and in patients with motor disorders. In: Motor Control Mechanisms in Health and Disease, edited by Desmedt JE. New York: Raven Press, 1983, p. 787–796.
Middleton FA and Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science 266: 458–461, 1994.
Morcuende S, Delgado-Garcia J-M, and Ugolini G. Neuronal premotor networks involved in eyeblink responses: retrograde transneuronal tracing with rabies virus from the orbicularis oculi muscle in the rat. J Neurosci 22: 8808–8818, 2002.
Nitschke MF, Kleinschmidt A, Wessel K, and Frahm J. Somatotopic motor representation in the human anterior cerebellum. A high-resolution functional MRI study. Brain 119: 1023–1029, 1996.
Oscarsson O. Functional organization of spinocerebellar paths. In: Handbook of Sensory Physiology: Somatosensory System, edited by Iggo A. Berlin: Springer-Verlag, 1973, vol. II, p. 339–380.
Oscarsson O. Spatial distribution of climbing and mossy fibre inputs into the cerebellar cortex. Exp Brain Res Suppl 1: 36–42, 1976.
Pellegrini JJ and Evinger C. Role of the cerebellum in adaptive modification of reflex blinks. Learn Mem 3: 77–87, 1997.
Pissiota A, Frans O, Fredrikson M, Langstrom B, and Flaten MA. The human startle response and pons activation: a regional cerebral blood flow study. Eur J Neurosci 15: 395–398, 2002.[Web of Science][Medline]
Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, and Rawlins JN. Dissociating pain from its anticipation in the human brain. Science 294: 1979–1981, 1999.
Rabacchi S, Rocca P, and Strata P. Influence of inferior olive on flexor reflex activity. Exp Brain Res 63: 191–196, 1986.[Web of Science][Medline]
Reiman ER, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, Yun L-S, and Chen K. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 154: 918–925, 1997.[Abstract]
Rijntjes M, Buechel C, Kiebel S, and Weiller C. Multiple somatotopic representations in the human cerebellum. Neuroreport 10: 3653–3658, 1999.[Web of Science][Medline]
Schmahmann JD. The Cerebellum and Cognition. San Diego, CA: Academic Press, 1997.
Schmahmann JD. The role of the cerebellum in affect and psychosis. J Neuroling 13: 189–214, 2000.
Schmahmann JD, Dojon J, Toga AW, Petrides M, and Evans AC. MRI Atlas of the Human Cerebellum. San Diego, CA: Academic Press, 2000.
Schmahmann JD and Sherman JC. The cerebellar cognitive affective syndrome. Brain 121: 561–579, 1998.
Schomburg ED. Spinal sensory motor systems and their supraspinal control. Neurosci Res 7: 265–340, 1990.[Web of Science][Medline]
Schouenborg J and Weng H-R. Sensorimotor transformation in a spinal motor system. Exp Brain Res 100: 170–174, 1994.[Web of Science][Medline]
Schouenborg J, Weng H-R, and Holmberg H. Modular organization of spinal reflexes: a new hypothesis. News Physiol Sci 9: 261–265, 1994.
Shahani BT and Young RR. Human flexor reflexes. J Neurol Neurosurg Psychiatry 34: 616–627, 1971.
Sherrington CS. Flexion-reflex of the limb, crossed extension-reflex and reflex stepping and standing. J Physiol 40: 28–121, 1910.
Smith AM. The effects of rubral lesions and stimulation on conditioned forelimb flexion responses in the cat. Physiol Behav 5: 1121–1126, 1970.[Medline]
Snider RS and Stowell A. Receiving areas of the tactile, auditory, and visual systems in the cerebellum. J Neurophysiol 7: 331–357, 1944.
Steinmetz JE, Lavond DG, Ivkovich D, Logan CG, and Thompson RF. Disruption of classical eyeblink conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit? J Neurosci 12: 4403–4426, 1992.[Abstract]
Svensson P, Minoshima S, Beydoun A, Morrow TJ, and Casey KL. Cerebral processing of acute skin and muscle pain in humans. J Neurophysiol 78: 450–460, 1997.
Talairach J and Tournoux P. Co-planar Stereotaxis Atlas of the Human Brain. New York: Georg Thieme Verlag, 1988.
Thach WT. What is the role of the cerebellum in motor learning and cognition? Trends Cogn Sci 2: 331–337, 1998.[Web of Science]
Thompson RF, Bao S, Chen L, Cipriano BD, Grethe JS, Kim JJ, Thompson JK, Tracy JA, Weninger MS, and Krupa DJ. Associative learning. Int Rev Neurobiol 41: 151–189, 1997.[Web of Science][Medline]
Timmann D, Baier C, Diener HC, and Kolb FP. Impaired acquisition of limb flexion reflex and eyeblink classical conditioning in a cerebellar patient. NeuroCase 4: 207–217, 1998a.[Web of Science]
Timmann D, Baier PC, Diener HC, and Kolb FP. Classically conditioned withdrawal reflex in cerebellar patients. 1. Impaired conditioned responses. Exp Brain Res 130: 453–470, 2000.[Web of Science][Medline]
Timmann D, Kolb FP, Baier C, Rijntjes M, Müller SP, Diener HC, and Weiller C. Cerebellar activation during classical conditioning of the human flexion reflex: a PET study. Neuroreport 7: 2056–2060, 1996.[Web of Science][Medline]
Timmann D, Musso C, Kolb FP, Rijntjes M, Jüptner M, Müller SP, Diener HC, and Weiller C. Involvement of the human cerebellum during habituation of the acoustic startle response: a PET study. J Neurol Neurosurg Psychiatry 65: 771–773, 1998b.
Torring J, Pedersen E, and Klemar B. Standardisation of the electrical elicitation of the human flexor reflex. J Neurol Neurosurg Psychiatry 44: 129–132, 1981.
Tsukahara N, Oda T, and Notsu T. Classical conditioning mediated by the red nucleus in the cat. J Neurosci 1: 72–79, 1981.[Abstract]
Voneida TJ. The effect of rubrospinal tractotomy on a conditioned limb response in the cat. Behav Brain Res 105: 152–162, 1999.
Voneida TJ. The effect of brachium conjunctivum transection on a conditioned limb response in the cat. Behav Brain Res 109: 167–175, 2000.[Web of Science][Medline]
Voneida TJ, Christie D, Bogdanski R, and Chopko B. Changes in instrumentally and classically conditioned limb-flexion responses following inferior olivary lesions and olivocerebellar tractotomy in the cat. J Neurosci 10: 3583–3593, 1990.[Abstract]
Voogd J and Glickstein M. The anatomy of the cerebellum. Trends Cogn Sci 2: 307–313, 1998.
Welker W. Comparative study of cerebellar somatosensory representations: the importance of micromapping and natural stimulation. In: Cerebellum and Neuronal Plasticity, edited by Glickstein M, Yeo C, and Stein J. New York: Plenum, 1987, p. 109–118.
Welsh JP and Harvey JA. Cerebellar lesions and the nictitating membrane reflex: performance deficits of the conditioned and unconditioned response. J Neurosci 9: 299–311, 1989.[Abstract]
Woodruff-Pak DS and Steinmetz JE. Eyeblink Classical Conditioning: Applications in Humans. Boston, MA: Kluwer Academic, 2000a, vol. I.
Woodruff-Pak DS and Steinmetz JE. Eyeblink Classical Conditioning: Animal Models. Boston, MA: Kluwer Academic, 2000b, vol. II.
Yeo CH and Hesslow G. Cerebellum and conditioned reflexes. Trends Cognit Sci 2: 322–330, 1998.[Web of Science]
Yu J. The pathway mediating ipsilateral limb hyperflexion after cerebellar paravermal cortical ablation or cooling in cats. Exp Neurol 36: 549–562, 1972.[Web of Science][Medline]
Zald DH. The human amygdala and the emotional evaluation of sensory stimuli. Brain Res Rev 41: 88–123, 2003.[Medline]
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