Source activity in the human secondary somatosensory cortex depends on the size of corpus callosum

Brain Research 936 (2002) 47–57 www.elsevier.com / locate / bres

Research report

Source activity in the human secondary somatosensory cortex depends on the size of corpus callosum a, b c a a Andrej Stancak *, Karsten Hoechstetter , Jaroslav Tintera , Jiri Vrana , Rosa Rachmanova , a b Jiri Kralik , Michael Scherg a

Department of Normal, Pathological and Clinical Physiology, Third Faculty of Medicine, Charles University Prague, Ke Karlovu 4, 120 00 Prague 2, Czech Republic b Section of Biomagnetism, Department of Neurology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany c Institute of Clinical and Experimental Medicine, Videnska 800, 140 00 Prague 4, Czech Republic Accepted 6 February 2002

Abstract If corpus callosum (CC) mediates the activation of the secondary somatosensory area (SII) ipsilateral to the side of stimulation, then the peak latencies of the contra- and ipsilateral SII activity as well as the amplitude of the ipsilateral SII activity should correlate with the size of CC. Innocuous electrical stimuli of five different intensities were applied to the ventral surface of the right index finger in 15 right-handed men. EEG was recorded using 82 closely spaced electrodes. The size of CC and of seven callosal regions was measured from the mid-sagittal slice of a high-resolution anatomical MRI. The activation in the contralateral and ipsilateral SII was evaluated using spatio-temporal source analysis. At the strongest stimulus intensity, the size of the intermediate part of the callosal truncus correlated negatively with the interpeak latency of the sources in ipsi- and contralateral SII (r520.83, P,0.01). Stepwise regression analysis showed that the large size of the intermediate truncus of CC was paralleled by a latency reduction of peak activity of the ipsilateral SII, whereas both contra- and ipsilateral peak latencies were positively correlated. The peak amplitude of the ipsilateral SII source correlated positively with the size of the intermediate truncus of CC, and with the peak amplitudes of sources in the primary somatosensory cortex (SI) and in the mesial frontal cortex. The results suggest that in right-handed neurologically normal men, the size of the intermediate callosal truncus contributes to the timing and amplitude of ipsilateral SII source activity.  2002 Elsevier Science B.V. All rights reserved. Theme: Somatosensory and visceral afferents Topic: Somatosensory cortex and thalamocortical relationships Keywords: Secondary somatosensory area; Corpus callosum; EEG; Dipole source analysis

1. Introduction The secondary somatosensory area is a small cortical area sized about 2 cm 2 and located in the upper bank of the Sylvian fissure [36,43,65]. Brief, phasic stimuli such as electrical stimulation of the median nerve [18– 20,26,27,41], air puff stimuli [19], tactile pressure pulses [28,29], and painful laser heat [10,23,37,61] or electrical stimuli [60] evoke specific neuromagnetic fields and electrical potentials in SII which can be studied using *Corresponding author. Tel.: 1420-2-2492-3241; fax: 1442-2-24923905. E-mail address: [email protected] (A. Stancak).

magnetoencephalography (MEG) or electroencephalography (EEG). The neuromagnetic fields generated from the contralateral SII show peak latencies from 80 to 100 ms [19,20,27,28,62]. The magnetic response in the ipsilateral SII follows the contralateral peak with a delay of |15 ms [27,28,62]. However, a large inter-individual variance in the time delay of the ipsilateral relative to the contralateral SII source peaks has been noted [62]. The latency of the SII peak response in EEG recordings ranges from 100 to 150 ms [24,60]. Since the late SII component (.100 ms) has rarely been observed in MEG studies, radial orientation of the underlying source activity can be suspected. A radial source in SII around 100–120 ms has been confirmed in intracortical recordings [6,7,22,23].

0006-8993 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0006-8993( 02 )02502-7

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The bilateral activation of SII areas following unilateral somatosensory stimuli and the time delay of the ipsilateral SII response relative to the contralateral SII activation suggest that the ipsilateral SII response might be related to the transcallosal connections of both SII areas. The transcallosal fibers connecting both SII areas are relatively dense [31,44–46]. Subjects with callosal transection show activation in response to a unilateral hand stimulation in the contralateral but not in the ipsilateral SII [17]. Besides homotopic callosal projections, heterotopic connections between SII and SI of the opposite hemisphere have been reported [31,35,38,39]. However, some ipsilateral SII activation was observed even after callosotomy in monkeys [46] suggesting additional extracallosal input to ipsilateral SII. The intermediate part of CC contains predominantly fibers of large diameter (.3 mm) [3]. The size of a particular callosal region is determined by the fibers composing that region [2]. It can be conjectured that a large number of thick axons may facilitate the speed and temporal summation of neuronal impulses transmitted from the contra- to ipsilateral SII. In this study, somatosensory evoked potentials were analyzed using spatio-temporal source analysis [48,49] to evaluate the dynamics of the ipsilateral and contralateral SII response to the innocuous electrocutaneous stimuli, and in vivo magnetic resonance imaging to measure the size of CC. We postulated that if CC plays a role in activation of the ipsilateral SII, then the strength of the ipsilateral SII source and the time delay of the ipsilateral relative to the contralateral SII peak would be a function of the callosal size, especially of the callosal body which is known to connect the sensorimotor areas [44,45]. The activation of SII is related to stimulus intensity [33,29,42]. Thus, we employed five stimulus intensities which covered a wide range of non-painful sensations and analyzed the correlations between the callosal parameters and the source activities of contralateral and ipsilateral SII at each stimulus intensity.

2. Methods

2.1. Subjects Fifteen healthy men aged 22.162.4 (mean6standard deviation) participated in the study. The use of men in our study was justified by sex differences in the size [4,53] and fiber composition [3] of CC. All subjects were righthanded according to the Hand-Dominanz Test [51]. The subjects gave their written consent prior to the experiment according to the declaration of Helsinki. The experimental procedure was approved by the Ethical Committee of the ´ ´ Vinohrady in Prague. Hospital Kralovske

2.1.1. Procedure The subjects were seated in a comfortable armchair with

their right hand resting on a platform. Surface electrocutaneous stimulation of the index finger was used in the present study to avoid overlap with long-latency motor evoked potentials elicited by median nerve stimulation. The electrical stimuli were applied to the ventral surface of the right index finger using two silver cup electrodes filled with electrode gel (Elefix, Nihon-Kohden Corp., Tokyo, Japan). The distal electrode (anode) was placed 0.5 cm from the tip of the finger. The proximal electrode (cathode) was placed on the second phalanx. The electrode to skin impedance was always below 10 kV. The duration of the monophasic constant current stimulus was 0.1 ms. In the beginning of recording, the sensory threshold was determined by applying the cutaneous stimuli in steps of 0.1–0.2 mA in ascending and descending directions. We then determined the highest stimulus intensity which the subjects indicated as painful or very unpleasant. The pain sensation was described as a prick or a hit with a solid object. Some of the subjects hesitated to use pain terms but indicated the intensity which they felt as very unpleasant. Using individual sensory and pain / unpleasantness thresholds, five stimulus intensities were computed according to the formula: stimulus intensity5d 3(unpleasantness2sensory threshold) 1sensory threshold

(1)

where d corresponded to one of five values: 0.20, 0.35, 0.50, 0.65 and 0.80. This procedure ensured that even the weak stimuli (d 5 0.20) were felt throughout the whole session in spite of the effects of habituation, and that the strong stimuli (d 5 0.80) were below the pain threshold. Five blocks of 130 stimuli interspersed with 5 min resting periods were presented during the experiment. The duration of each block was about 22 min. In each block, twenty-six stimuli of each intensity were presented in random inter-stimulus intervals ranging from 6 to 12 s. The order of the stimuli was also randomized. The subjective intensity was recorded using the visual analogue scale (VAS) after each of the five blocks of stimuli and prior to the first block. The VAS scale was a 100 mm horizontal line representing the continuum of subjective intensities ranging from ‘just perceived’ to ‘already painful’. For statistical analysis, the individual mean values computed from all six VAS presentations were used.

2.1.2. Recordings EEG was recorded using 82 Ag /AgCl (EEGCapings, Graz, Austria) electrodes in continuous mode on BrainScope equipment (M&I, Prague, Czech Republic). The electrodes covered the frontal, central, temporal and parietal areas of both hemispheres with an average inter-electrode distance of 2.5 cm. The electrode to skin impedance was kept below 5 kV. The reference electrode was mounted on the forehead. The diagonal electrooculogram was recorded bipolarly by placing one electrode above the

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eyebrow and the other to the lateral corner of the eye. EEG was recorded using a sampling frequency of 1024 Hz and a bandpass filter of 0.015–200 Hz. The 3-D electrode coordinates and about fifty surface points describing the head contour were measured at the end of each experiment using an Isotrak II digitizer (Polhemus Inc., Colchester, Vermont, USA). Structural MRI data of the whole brain were acquired on a 1.5-Tesla Magnetom Vision (Siemens, Erlangen, Germany) using a volume encoded, fast-low-angle-shot pulse sequence with parameters TR / TE / a525 ms / 6 ms / 208. The field of view was set to 2563256 mm 2 , the matrix size to 2563256 pixels and the slab of 180 mm thickness was divided into 180 partitions resulting in an isotropic voxel size of 1 mm 3 . The mid-sagittal slice yielding a clear view of fornix and anterior commissure was selected and the contrast was enhanced using the Paintshop5 program (JASC, Eden Prairie, Minnesota, USA). The CC was extracted using a magic wand procedure of the same program and the total cross-sectional area of CC as well as the areas of its seven regions (Fig. 1) were measured [53,63]. The division of CC into seven regions roughly corresponds to the rostrum, genu, rostral truncus, anterior intermediate truncus, posterior intermediate truncus, isthmus and splenium of the CC [63].

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stimulus) after band-pass filtering (1 Hz, 6dB / octave–50 Hz, 24dB / octave) and analyzed using the Brain Electrical Source Analysis (BESA) program (MEGIS Software, Munich, Germany). An ellipsoidal, four-shell conductor head model was employed. A source model of the EEG potentials was constructed from the grand average data (N515) (Fig. 2A) using the grand average of electrode positions and head diameters. To match the source locations to the individual brain anatomy, BrainVoyager (BrainInnovation B.V., Maastricht, Netherlands) was used. The fiducial surface points and the 3-D electrode positions were fitted to the skin surface to enable a coregistration of the EEG sources to the 3-D brain images. The MRI data were transformed into the Talairach coordinate system [56] and the Talairach coordinates of the EEG sources were

2.1.3. Data analysis For averaging, data epochs of 768-points with a total length of 0.75 s (0.25 s prestimulus and 0.5 s poststimulus time) were selected. Trials containing EMG artefacts or large EOG variations (.150 mV) were discarded from further analysis. Averaged EEG epochs were segmented to a total length of 400 ms (50 ms pre- to 350 ms post-

Fig. 1. Evaluation of the callosal parameters according to Witelson [63]. ACC and PCC correspond to the anteriormost and posteriormost border of corpus callosum (CC), respectively, and define the length of the CC. Point G represents the anteriormost point of the inner convexity of the anterior CC. The line perpendicular to the ACC–PCC line which crosses the point G defines regions 1 and 2. Regions 3–7 are delineated by the vertical lines corresponding to the halves, thirds and fifths of the ACC– PCC line. The seven regions roughly correspond to the rostrum (1), genu (2), rostral truncus (3), anterior intermediate truncus (4), posterior intermediate truncus (5), isthmus (6) and splenium (7) of the CC.

Fig. 2. (A) Locations, orientations (left panel) and source waveforms (x, y, and z components) of the four regional sources sources (right panel) derived from the grand average data. The largest of the three orthogonal components is always denoted as x. The left panel shows the locations of the regional sources (15SI, 25SIIc, 35SIIi, 45SMA) in the lateral, top and frontal views. The short lines originating in each square depict the orientation of the primary component of the respective regional source. The filled squares and the lengths of the orientation lines illustrate the source strengths at a latency of 130 ms for SIIc, SIIi and SMA sources, and at 45 ms for SI. (B) Three-dimensional localization of the EEG sources in one subject.

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evaluated for each subject. The source model developed from the grand average data was used to evaluate the dipole source waveforms in the individual recordings. The orientation of the primary component of each of the regional sources was determined from the individual average data (average waveforms from five recordings corresponding to five stimulus intensities) at the respective maxima of the source waveforms. The root mean square of the three orthogonal components of each regional source was computed and the peak latencies and amplitudes were measured for each stimulus intensity.

2.1.4. Statistical analysis Dipole source moment was evaluated as the root mean squared sum of the three orthogonal components (x, y and z) of each regional source. To approximate a Gaussian distribution, the decadic logarithm of the root mean square values was used in the statistical analyses. The effects of stimulus intensity on the dipole source moments was analyzed using analysis of variance (ANOVA) for repeated measures. The independent variables were stimulus intensity (five levels) and hemisphere (SIIc vs. SIIi). To overcome a violation of the sphericity assumption due to repeated measures, the Greenhouse–Geisser epsilon correction of degrees of freedom was used. The association between the size of each of seven callosal regions and of the total CC with peak amplitudes of SIIc and SIIi sources and with the SIIi–SIIc peak latency difference was analyzed using the Pearson product–moment correlations [9]. Each correlation was tested for the presence of extreme values using the k1 statistics of Dixon [16]. Stepwise regression analysis (NCSS program, Kaysville, Utah, USA) was computed to evaluate the contribution of a set of independent variables to a selected independent variable. A 95% confidence level was used throughout.

3. Results The mean individually adjusted stimulus intensities were 5.661.4 mA, 7.362.0 mA, 8.962.6 mA, 10.663.3 mA and 12.363.9 mA for the five intensity levels, respectively. The five stimulus intensities differed significantly from each other according to the ANOVA for repeated measures (F(4,56)585.2, P,0.0001). The mean sensory threshold in our subjects was 3.361.0 mA. Thus, the weakest and the strongest stimulus intensities were 1.7 times and 3.7 times stronger than the sensory threshold, respectively. The pain / unpleasantness threshold was 14.864.8 mA, and the lowest and highest individual values were 9.9 mA and 26.7 mA, respectively. The VAS intensity scores showed a linear increase paralleling the current intensity (F(4,56)5 72.3, P,0.0001). The mean VAS values for the five intensity levels were 8.968.3, 20.6613.2, 36.4615.4, 53.1618.3 and 69.8622.8, respectively.

3.1. Source model Using a sequential strategy, four regional sources [48,49] were fitted to describe the 3-dimensional source currents in the four regions contributing predominantly to the data (Fig. 2A and B). Regional source 1 was fitted in the time interval from 20 to 55 ms. The orientation of the primary of the three orthogonal components was determined at the maximum of the source strength in the selected time interval. Source 1 localized to the contralateral primary sensorimotor area and it is referred to as the SI source. The orientation of the primary component of this regional source was tangential and pointed posteriorly similar to the source of the P30 wave of the somatosensory evoked potential of area 3b [5]. Three additional regional sources could be fitted in the time interval from 100 to 150 ms. Regional source 2 peaked around 128 ms and localized to the contralateral hemisphere in the vicinity of the lateral cerebral fissure. The orientation of the primary orthogonal component of the 2nd regional source was close to radial (Fig. 2A). The location, orientation and latency suggested that source 2 corresponded to the activation of the contralateral SII area. The 3rd regional source fitted to the corresponding location in the ipsilateral, right hemisphere with a peak latency of 147 ms. The orientation of the primary component of this regional source was also predominantly radial. The location of source 3 and the 19 ms delay of its peak relative to the SIIc peak suggested origin in the ipsilateral SII. Hence, sources 2 and 3 are further denoted as SIIc and SIIi sources, respectively. Fitting the data using three sources (SI, SIIc and SIIi) over the whole epoch at this step showed that both SII sources tended to move towards midline and frontal areas. Inspection of the residual potential waveforms revealed unexplained negativity over the vertex peaking from 130 to 140 ms. Thus, a 4th regional source had to be incorporated into the model to obtain a stable localization of the SII sources bilaterally. The tangentially oriented source 4 fitted to the mesial frontal cortex and showed a peak latency of about 136 ms. Due to the anatomical location it is referred to hereafter as the supplementary-motor-area (SMA) source. The model was further improved by adding one spatial principal component [8,48] to remove slow drifts in the EEG data. In order to separate alpha rhythmic activity in individual subjects, one regional source was placed into the midline parieto-occipital area (unit sphere coordinates: x 5 0.0, y 5 0.42, z 5 0.54). Incorporation of the alpha source improved the readings of the source waveforms of SI and SII in individual recordings, especially at low stimulus intensity (d 50.20).

3.2. SI source Fig. 2B shows the 3-D localizations of the four regional sources in one subject. The individual and grand average source waveforms are presented in Fig. 3A and B, respec-

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Fig. 3. (A) Individual root mean square source waveforms in subject S04. The waveforms represent the root mean squared sum of the x, y and z orthogonal components of the respective regional source (SI, SIIc, SIIi, SMA). The rows correspond to different stimulus intensities ranging from weak (d 5 0.2) to strong (d 5 0.8). (B) Grand average source dipole moments of the four regional sources (SI, SIIc, SIIi, SMA). Average taken over all subjects. The thin lines around the mean waveforms correspond to the 95% confidence interval.

tively. The peak latency of the SI source was 45.3610.2 ms. The peak latency indicates a lack of a clear P30 component which is consistent with a small P30 component and absence of a clear polarity reversal over the frontal and parietal scalp electrodes during electrical stimulation of digits compared to median nerve stimulation [47]. The localization of the SI source (Talairach coordinates (mean6SEM) x5 237.361.3, y5 217.061.7, z5 52.16 0.8 mm) was in the anterior bank of the central sulcus rather than in the posterior bank as would be expected from the location of the Brodmann area 3b [5]. The slightly anterior location of the SI source might be due to localization errors of the spherical head model known to be in the order of 10–11 mm in EEG recordings [13,14], or due to the contribution of a radial source with latency

longer than 20 ms attributed to the precentral cortex [40], or due to both factors. Peak amplitude of the SI source was significantly influenced by stimulus intensity (F(4,56)5 10.3, P,0.0001). The effect of stimulus intensity on SI peak latency was not significant (F(4,56)50.3, P.0.05).

3.3. SII sources The SII sources were located in the upper bank of the Sylvian fissure (Fig. 2A and B), and the Talairach coordinates of the SII sources (SIIc: x 5 2 49.760.8, y 5 2 10.860.6, z 5 18.463.2 mm; SIIi: x 5 49.960.8, y 5 2 9.161.2, z 5 24.761.0 mm) were consistent with previous studies [23,28]. Fig. 3A and B illustrates the root mean square source waveforms of the SIIc and SIIi for each

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stimulus intensity. Analysis of variance for repeated measures using five intensities and hemisphere as independent variables revealed a significant effect of hemisphere (F(1,14)55.3, P50.04) and stimulus intensity (F(4,56)5 16.7, P,0.0001). In addition, we found a significant interaction between stimulus intensity and hemisphere (F(4,56)54.3, P50.008). The test of simple effects showed that the interaction was due to the significantly larger amplitude of SIIc as compared to SIIi under low and medium stimulus intensities (d 5 0.20, F(1,14)58.6, P5 0.01; d 5 0.35, F(1,14)59.8, P50.007; d 5 0.5, F(1,14)55.8, P50.03) but not under two strong stimulus intensities (d 5 0.65, F(1,14)53.3, P50.09; d 50.80, F(1,14)50.6, P50.56). The mean peak latencies of SIIc and SIIi sources were 128.8616.6 ms, and 146616.6 ms, respectively. Thus, the SIIi peak followed the SIIc peak with mean latency of 17.4611.4 ms. The SIIi–SIIc peak latency differences ranged from 0 to 34 ms indicating a large inter-individual variability. The two-way ANOVA for repeated measures using stimulus intensity and hemisphere as independent variables showed a significant difference between the contra- and ipsilateral SII peak latency (F(1,14)592.6, P,0.0001). The effect of stimulus intensity on the peak latencies of the SIIc and SIIi sources was not significant (P.0.05).

significant regression coefficients in the stepwise discriminant analysis (Table 1A). However, the relative increments of the standardized regression coefficients for these callosal region were small compared to the peak latency of SIIc source and the size of callosal region 4. Stepwise discriminant analysis with the peak amplitude of SIIi as dependent variable (Table 1B) showed positive relationships with the peak amplitude of the SI and SMA sources, and with the size of the callosal region 4, and a negative relationship with the size of callosal region 7. The regression coefficient of the SIIc peak amplitude was not significant (P.0.05). The relationship between the peak amplitude of the SIIi and SIIc sources and the size of callosal region 4 is illustrated in Fig. 4B. As far as the contralateral SII peak amplitude is concerned, stepwise regression analysis with this amplitude as a dependent variable revealed that only the peak amplitude of the SI source contributed to SIIc peak amplitude (standardized regression coefficient 0.65, T5 3.08, P,0.009). The pair-wise correlation coefficient between the peak amplitudes of SI and SIIc sources was r(14)50.57, P50.02. The peak latency of SIIc correlated significantly with the peak latency of SIIi (Table 1A) but not with the peak latency of the SI response (r(14)5 20.15, P50.61).

3.5. The mesio-frontal source 3.4. Corpus callosum and SIIi Pearson product–moment correlations were computed between the SIIi–SIIc peak latency difference and the callosal parameters for each stimulus intensity. A significant negative correlation was observed between the size of region 4 and the SIIi–SIIc peak latency difference for the strongest stimulus intensity (d 5 0.80, r(14) 5 2 0.83, P, 0.001) (Fig. 4A) but not for other stimulus intensities (P.0.05). To analyze which of the callosal and source parameters correlated with SIIi peak latency, a stepwise regression analysis was performed using the peak latency of the SIIi source as dependent variable and the peak latencies of the SIIc, SI and SMA sources, and the callosal parameters as independent variables. Since significant pairwise correlation coefficients between source and callosal parameters occurred only for the strongest stimulus intensity, the stepwise regression analysis was performed for the strong stimulus (d 5 0.8). The results of this analysis in the form of standardized regression coefficients, the increment of the squared regression coefficient representing the importance of each regression coefficient, T-statistics and probability levels for SIIi peak latency and amplitude are given in Table 1A and B. The peak latency of the SIIc source and the size of region 4 showed significant standardized regression coefficients with SIIi peak latency. The longer the peak latency of the SIIc source and the smaller the region 4, the greater was the SIIi peak latency. Besides region 4, the sizes of callosal regions 2, 5 and 7 showed

Source analysis revealed an additional source in the mesial frontal cortex (Fig. 2A and B) peaking at 135.8616.1 ms (Fig. 3A and B), i.e. intermediate between SIIc and SIIi peak latencies. The Talairach coordinates (x 5 2 1.561.2, y 5 2 0.162.1, z 5 63.360.8 mm) pointed to SMA as the generator area. The effects of the stimulus intensity on the SMA source were significant (F(4,56)510.8, P50.0005) according to the ANOVA for repeated measures. The peak latency of the SMA source was not influenced by stimulus intensity (P.0.05).

4. Discussion The involvement of the callosal fiber system in the activation of the ipsilateral SII can be inferred from the connectivity studies in non-human primates [31,35,38,39,46], and from the absence of ipsilateral SII activation in patients with callosotomy [17]. Using EEG source imaging and MRI recordings in neurologically healthy subjects, our data show for the first time that the size of corpus callosum contributes to the peak amplitude of the ipsilateral SII activation and to the time delay between the ipsilateral and contralateral SII peaks.

4.1. Source model The source model used in the present study yielded four

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Fig. 4. (A) Relationship between the size of callosal region 4 and the peak latency difference of the ipsi- and contralateral SII responses (SIIi–SIIc) at the strongest stimulus intensity (d 5 0.8). The waveforms of the primary component of the SIIc (bold line) and SIIi (thin line) regional sources in subjects having a small (S01) and a large (S12) region 4 of CC. The right panel shows the scatter-plot of individual values and the linear regression line illustrating the negative correlation between the size of region 4 (x-axis) and the interhemispheric peak latency difference SIIi–SIIc ( y-axis). (B) Relationship between the size of callosal region 4 and the peak amplitude of SIIi and SIIc sources at the strongest stimulus intensity (d 5 0.8). The SIIc (left upper panel) and SIIi (left lower panel) root mean square source waveforms in three subjects having small (dotted line), medium (thin solid line) and large (bold line) region 4 of corpus callosum are shown. MRI segments of individual corpora callosa are illustrated in the middle part of the figure. The scatter-plot of individual values illustrating the significant correlation coefficient between the size of region 4 and the peak amplitude of the SIIi source is shown in the right lower panel. The correlation coefficient between the peak amplitude of SIIc source and region 4 was not statistically significant (right upper panel).

interpretable cortical sources. The sources in SI, SIIc and SIIi are consistent with source models used in previous MEG [27,28,41,62] and EEG studies [60,61]. One distinction from the MEG studies was the longer latency and prevailing radial orientation of the SII sources. A radial source with a peak latency .100 ms [5,22,23] and the unequal habituation of various SII components [6] may account for this discrepancy. The SMA source in our model is fully consistent with localization of the N130 component in intracortical recordings [6,7] and with PET and fMRI studies reporting activation of SMA following innocuous somatosensory stimulation [15,50,57].

4.2. Stimulus intensity and SII activation The activity of all four EEG sources increased in parallel with stimulus intensity. For the weak and medium

stimuli (d 50.20, 0.35 and 0.50), the strength of the contralateral SII source was greater than the strength of the ipsilateral SII source consistent with previous MEG studies [28,33,42]. For the strong stimuli (d 50.65 and 0.80), SIIc and SIIi activations showed about equal strength. Comparison with other studies is difficult since they might not have covered a sufficient range of intensities. It is possible that the intensity of the strong pressure pulse stimulus in a previous study [28] did not exceed the equivalent of the medium stimulus intensity of the present study. The median nerve stimuli in previous studies elicited a finger movement [33,42] which might diminish the SII response to the somatosensory stimulus by gating the long-latency neuromagnetic fields. In support of this explanation, the SII source amplitudes in both hemispheres were equal for strong (twice the motor threshold) and medium stimuli (just above the motor threshold) [33].

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Table 1 Dependent variable: SIIi

Standardized regression coefficient

Increment of the standardized regression coefficient

A. Stepwise regression and analysis for the peak latency of the SIIi source SIIc peak latency 0.862 0.69 CC region 4 20.704 0.29 CC region 2 20.174 0.02 CC region 5 0.242 0.03 CC region 7 0.173 0.02 SI peak latency SMA peak latency CC region 1 CC region 3 CC region 6 Total CC area B. Stepwise regression analysis for the SIIi peak amplitude SI amplitude 0.520 SMA amplitude 0.552 CC region 4 0.322 CC region 7 20.388 SIIc amplitude CC region 1 CC region 2 CC region 3 CC region 5 CC region 6 Total CC area

4.3. Corpus callosum and SII The peak latency of the ipsilateral SII source follows the peak response of the contralateral SII source in neuromagnetic and EEG recordings with a time delay of about 10–20 ms which corresponds to the transmission time from the contra- to the ipsilateral SII as estimated in previous studies [10,22]. However, the individual variability in the peak latency was large both in the present and previous studies [28,62]. We even found a simultaneous onset of the ipsi- and the contralateral SII peak in one subject. The significant correlation between the peak latency difference of ipsi- and contralateral SII responses and the size of region 4 and the stepwise regression analysis support the view that CC contributes to the timing of the ipsilateral SII response. Our finding of a positive correlation between the size of callosal region 4 and the peak latency of the ipsilateral SII activation fits with electrophysiological studies demonstrating that the intermediate part of CC contains the callosal fibers connecting the sensorimotor areas of both hemispheres [44,45]. It is especially this intermediate truncus of CC which contains large-diameter fibers (.3 mm) [3]. Furthermore, the size of a particular callosal area correlates with the number of those fibers which constitute that callosal area [2]. Thus, we suggest that a large midbody of CC has an abundance of the large-diameter fibers which contribute to the short-

0.17 0.24 0.08 0.11

T-value

Probability level

19.38 212.4 23.16 3.94 3.32 0.49 0.32 1.80 1.39 1.41 1.32

0.0001 0.000 0.011 0.003 0.009 n.s. n.s. n.s. n.s. n.s. n.s.

4.53 5.34 3.02 23.56 0.09 0.49 0.14 0.22 1.49 0.68 0.14

0.001 0.0001 0.012 0.005 n.s. n.s. n.s. n.s. n.s. n.s. n.s.

ening of the callosal transmission time between both SII areas. In men, the size of the intermediate truncus correlates with the size of the Sylvian fissure and planum temporale [1]. A hemispheric assymetry of the horizontal ramus of the Sylvian fissure has also been reported [52,64]. Although the correlations between callosal parameters and source activation in the ipsilateral SII may also be associated with structural differences in the left and right SII, the impact of these hemispheric asymmetries, e.g. in the shape of the Sylvian fissure [52,64] cannot account for individual differences in the interpeak latency of SII sources in the range of tens of milliseconds. According to the velocities of neuronal transmission in callosal fibers [1,55] and the estimated 0.1 m distance between the right and left SII, the shortest possible peak difference between the left and right SII in subjects with large-diameter callosal fibers (.4.7 mm) would be 1.5 ms [1]. On the other hand, considering a prevalence of smalldiameter fibers (|0.4 mm) in subjects with the smallest size of callosal truncus, the estimated inter-hemispheric transmission would be .20 ms. [1]. Additional delay might arise from the interaction of the callosal and extracallosal inputs in the ipsilateral SII. In subjects having a large callosal midbody, various inputs might act in concert to provide a superior functional control of the ipsilateral SII area. The SIIi peak amplitude was mostly influenced by the peak amplitudes of the SI and the mesial frontal sources

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and by the size of the callosal region 4. The positive correlations between SIIi peak amplitude and both the SI peak amplitude and the size of callosal region 4 may be related to the heterotopic callosal connections between SII and SI of the opposite hemisphere which have been demonstrated in non-human primates [31,35,38,39]. SI exerts a facilitatory influence upon both SII areas consisting of adjustment of the background excitation of SII neurons [11,12,58,59,66]. An activation in SII paralleling the SI activation has been observed in one neuromagnetic study in the early post-stimulus period [34]. Fig. 3A and B of the present study and previous intracortical [7] and MEG [21] recordings showed that SI remains active for at least 150 ms period after stimulus onset. Since a modulation of the ipsilateral SII activity from the contralateral SI is mediated by the transcallosal fibers, the size of the callosal midbody is the limiting factor of the SI influence upon the ipsilateral SII. If the callosal midbody is large, the sum of the influences from the contralateral SI and SII may be strong enough to produce synchronous firing of neurons in the ipsilateral SII. Hence, in subjects with a large callosal midbody the peak response in the ipsilateral SII may occur earlier than the peak response in the contralateral SII. The concept of ipsilateral SII activation as the sum of the homotopic and heterotopic callosal influences outlined here may explain simultaneous SIIc and SIIi peaks in one subject in the present study, and earlier ipsilateral than contralateral SII peaks in a few subjects in one recent study [62]. The significant positive regression coefficient of the size of callosal region 4 and the negative regression coefficient of the size of region 7 for the amplitude of SIIi (Table 1B) can be explained by the relative proportions of the largediameter myelinated and small-diameter non-myelinated fibers. In men, the most rostral and caudal callosal parts are occupied by the small-diameter fibers and the intermediate truncus by the large-diameter fibers [1]. The stepwise regression analysis for the SIIi amplitude explained about 65% of variance of the dependent variable (Table 1B). The substantial portion of unexplained variance indicates a contribution of variables other than the size of CC which were not accounted for in our study. One likely source of influence may originate in the ventral posterolateral (ventrobasal) and ventral posteroinferior thalamic nuclei which radiate to SI and SII [30,32,54]. In the cat, both SI and SII send facilitatory fibers to the part of the thalamic ventral posterolateral nucleus [25] which may adjust the gain of thalamic nuclei, and possibly help to build up the activation in SII in the time interval between the maximum of SI and SII peak responses. Stroke patients with lesions in the peri-rolandic region show ipsilateral SII neuromagnetic fields in absence of a contralateral SI and SII source activation [21] indicating links between the ipsilateral SII and the peripheral somatosensory receptors bypassing both CC and SI. However, the callosal inputs to the ipsilateral SII in neurologically

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healthy subjects appear to dominate and contribute both to the amplitude and timing of the ipsilateral SII source activation. Significant correlations between the callosal parameters and the dipole source moments were only observed for the strongest (d 5 0.8) stimuli. The ipsilateral SII source showed an amplitude equal to that of the contralateral SII source only under the two strongest stimulus intensities suggesting that the manifestation of the callosal influences depends on sufficient neuronal input to the ipsilateral SII.

Acknowledgements This study was supported by the Grant Agency of the Czech Republic (309 / 98 / 1065 and 309 / 01 / 0665), IGA (NF 6377-3 / 2000), Research Directions of the Czech Republic (JS 0011112006) and a fellowship from the Land ¨ Baden-Wurtemberg to Dr. Stancak. K. Hoechstetter was supported by the ‘Pain Research Programme’ of the Medical Faculty of the University of Heidelberg.

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