fMRI of the Responses to Vibratory Stimulation of Digit Tips

NeuroImage 11, 188–202 (2000) doi:10.1006/nimg.2000.0541, available online at http://www.idealibrary.com on

fMRI of the Responses to Vibratory Stimulation of Digit Tips S. T. Francis,* E. F. Kelly,† R. Bowtell,* W. J. R. Dunseath,† S. E. Folger,† and F. McGlone‡ *Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, NG7 2RD United Kingdom; †Dental Research Centre, University of North Carolina, North Carolina; and ‡Unilever Research, Port Sunlight Laboratory, Wirral, L63 3JW United Kingdom Received August 24, 1999

Three studies were carried out to assess the applicability of fMRI at 3.0 T to analysis of vibrotaction in humans. A novel piezoelectric device provided clean sinusoidal stimulation at 80 Hz, which was initially applied in separate runs within a scanning session to digits 2 and 5 of the left hand in eight subjects, using a birdcage RF (volume) coil. Significant clusters of activation were found in the primary somatosensory cortex (SI), the secondary somatosensory cortex (SII), subcentral gyrus, the precentral gyrus, posterior insula, posterior parietal regions (area 5), and the posterior cingulate. Digit separation in SI was possible in all subjects and the activation sites reflected the known lateral position of the representation of digit 2 relative to that of digit 5. A second study carried out in six additional subjects using a surface coil, replicated the main contralateral activation patterns detected in study one and further improved the discrimination of the digits in SI. Significant digit separation was also found in SII and in the posterior insula. A third study to investigate the frequency dependence of the response focused on the effect of an increase in vibrotactile frequency from 30 to 80 Hz, with both frequencies applied to digit 2 during the same scanning session in four new subjects. A significant increase in the number of pixels activated within both SII and the posterior insula was found, while the number of pixels activated in SI declined. No significant change in signal intensity with frequencies was found in any of the activated areas. r 2000 Academic Press

INTRODUCTION As fMRI approaches maturity as a human functional neuroimaging modality, it will need to make increasingly close contact with well-developed areas of sensory neurophysiology and cognitive neuroscience, in which fMRI studies can both be guided by existing knowledge and contribute to the further development of that knowledge. One such area is vibrotaction, the sensory response to sinusoidal vertical-displacement stimuli applied to 1053-8119/00 $35.00 Copyright r 2000 by Academic Press All rights of reproduction in any form reserved.

the skin. Several decades of scientific effort have generated a wealth of information about the responses of single neurons and small neuron clusters at levels ranging from skin mechanoreceptive afferents to the cortical entry stage, and there is a large psychophysical literature related to judgements by humans and other primates of the presence, magnitude, and frequency of vibrotactile stimuli (e.g., Bolanowski et al., 1988; Goff, 1967; Hagbarth et al., 1970; Johansson et al., 1982; Johnson, 1974; LaMotte and Mountcastle, 1975; Mountcastle et al., 1990; O’Mara et al., 1988; Talbot et al., 1968; Verillo, 1968). Nevertheless, significant gaps in understanding remain, especially in regard to relationships between large-scale cortical neuronal population responses (and the spatiotemporal dynamics of these responses) and the resulting psychophysical effects (e.g., Hollins et al., 1990; Goble and Hollins, 1993, 1994; Kelly and Folger, 1999; Whitsel et al., 1989, 1991). We believe that fMRI studies can contribute importantly to this area (Lin et al., 1996; Sakai et al., 1995), following the development of appropriate methodological foundations. The first requirement is adequate control of the stimulus and its interface with the skin. Most of the prior work cited above utilized specialpurpose servocontrolled stimulators capable of delivering clean constant-amplitude sinusoidal stimuli over a wide range of frequencies and amplitudes. Unfortunately, these mechanical devices are typically unsuitable for use in fMRI studies due to their interaction with high static fields. To address this problem we have developed a new piezoelectric stimulator that reproduces most of the required performance and is compatible with a 3.0 T imaging system (Mansfield et al., 1993). The first purpose of the present study was therefore to determine whether this device also generates measurable haemodynamic responses under ‘‘typical’’ vibrotactile stimulus conditions and if so to determine the overall distribution of these responses within the brain. A second purpose was to benchmark and evaluate our imaging with respect to an independently known organizational feature of primary somatosensory cortex (SI). To this end, we focused on the single best estab-

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lished such feature, namely the mediolateral ordering of the digit representations from little finger to thumb along the postcentral gyrus. This feature was first established using evoked potentials in animal studies by Woolsey et al. (1942) and in human SI using both direct electrical stimulation (Penfield and Boldrey, 1937) and recording (Woolsey et al., 1979) from surgically exposed cortex. Somatotopic organization has also been detected, with varying degrees of success, in a considerable number of EEG, MEG (Suk et al., 1991; Baumgartner et al., 1991; Hari et al., 1993), PET (Fox et al., 1987), and more recently fMRI (Gelnar et al., 1998; Sakai et al., 1995; Moore et al., 1997; Puce et al., 1995; Harrington et al., 1998; McGonigle et al., 1998; Disbrow et al., 1998; Catalan et al., 1998) studies. We believe that fMRI must first demonstrate the capability of capturing this basic property of SI anatomical and functional organization before more subtle aspects of somatosensory neurophysiology can be studied. Accordingly, for the purposes of this paper we have studied the issue of SI somatotopic organization in terms of a simplified experimental model which embodies most of the difficulty of the mapping problem—specifically this involves applying vibrotactile stimuli to the tips of digits 2 and 5. In recently published work, Maldjian et al. (1999b) have demonstrated a sensory somatotopic map of the hand by using a similar vibrotactile stimulator to that described here (Maldjian et al., 1999a) in fMRI experiments carried out at 4.0 T. A third and related purpose of our investigation was to examine the improvement in digit discrimination that results from using a small surface RF coil instead of a standard whole head RF coil in fMRI experiments. Finally, we have also taken a first look at the possible frequency-dependence of the response. Vibrotaction has traditionally been regarded as at least partially separable both psychophysically and neurophysiologically into two major subdomains—i.e., ‘‘flutter’’ (roughly 10–50 Hz) and ‘‘vibration’’ (roughly 50–300 Hz) (e.g., Talbot et al., 1968; Verillo, 1968). To investigate whether the associated patterns of differential cortical distribution and response are also reflected in hemodynamic responses, we have carried out a small study designed specifically to contrast the responses to suprathreshold 30 vs 80 Hz stimulation. MATERIALS AND METHODS Stimulator and Stimulation Procedures Piezoelectric bender elements (T220-H4-503 Standard Brass Shim Bending Element, Piezo Systems, Inc., Cambridge, MA) were used to deliver the mechanical stimulus. Mechanical contact to the skin was made via a plastic tip, which electrically insulated the body from the driving voltage of the bender, typically 60–100 V pk. A static surround limited the stimulation to a

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region just under the contactor (Bolanowski et al., 1988). All stimuli took the form of sinusoidal waveforms produced by ICL-8038CCPD (Harris Semiconductor Corp.) precision waveform generators. These were externally triggered and the generators were capable of delivering frequencies from 30–300 Hz, the signal always starting at the zero-crossing of the positive slope. The bender was capable of delivering approximately 25 g peak force at 400 µm peak deflection with a 100 V peak drive. Measurements of the vibration amplitude with the bender loaded by the finger were made outside the magnet using a vibration meter (VM120 Monitran Ltd). Electrical connection of the driving voltage to the bender was made using 50 feet of shielded, twisted pair, tinned copper wires. No MR image degradation was found to result from using the piezoelectric stimulator in the scanner. The stimulator was controlled by a PC, which was interfaced to the scanner so as to allow precise synchronization of stimulus presentation and image acquisition. Experiments were approved by the local ethical committee and informed written consent was obtained from all subjects. Throughout all experiments the subject’s head was immobilized using inflatable cushions to minimize movement artefacts. Study 1 Imaging was performed on 8 healthy, right-handed subjects (5 males and 3 females, aged 25–40 years) using a purpose built 3.0 T echo planar imaging (EPI) scanner (Mansfield et al., 1993), incorporating a 27-cm diameter, bird-cage, RF (volume) coil. T *2-weighted coronal images with 128 3 64 matrix size, 3-mm in-plane resolution, and 8-mm slice thickness were acquired using MBEST (Modulus Blipped Echo-planar Singlepulse Technique; Ordidge et al., 1988) with a 35-ms echo time (TE) and 1.9 kHz gradient switching frequency. Ten contiguous 8-mm coronal slices extending from the anterior cingulate gyrus to the occipital lobe were acquired every 2 s (TR 5 2 s). Anatomical localization was achieved using multislice inversion recovery echoplanar data sets of the whole brain, acquired immediately after each fMRI data set. These scans were obtained with grey matter (TI 5 1200 ms) nulled and isotropic 3 mm resolution (64 slices). Since these images displayed identical distortions to those acquired in the functional imaging experiments, functional and anatomical images could easily be coregistered. The frequency of the bender was initially set to 80 Hz and a peak to peak amplitude of approximately 50–150 µm. Stimuli were applied to the tips of digits 2 and 5 of the left hand, in separate runs within a single scanning session. For each digit the vibrotactile stimulus was applied for an ‘‘ON’’ period of 8 s, followed by a resting ‘‘OFF’’ period of 24 s. The bender remained in contact

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with the finger during the OFF period. This procedure was repeated for a total of 20 cycles, resulting in a total experimental duration, including the time needed to gather the anatomical scans of approximately 30 min. Subjects were instructed to attend to the vibrotactile stimulus. Study 2 A second study on a new group of six right-handed subjects (4 males and 2 females, aged 20–30 years) utilized a 14-cm-diameter surface coil to yield improved spatial resolution and signal to noise, thus allowing a more detailed analysis of the contralateral somatotopical response. Ten contiguous 4-mm-thick sagittal slices, with 3 mm in-plane resolution, were acquired every 2 s, with the above stimulation paradigm again being run for digits 2 and 5. To eliminate passive subject movements and to ensure that the surface area of each finger pad in contact with the vibrotactile stimulus remained constant throughout the study, a vacuum cast was used to immobilize the arm and the fingers were gently taped to the stimulator. As in Study 1 subjects were instructed to attend to the stimulus. Anatomical localization was achieved via isotropic 3-mm resolution multislice inversion recovery echoplanar data sets with gray matter nulled, which were subsequently coregistered to 1-mm isotropic resolution, MPRAGE (Mugler and Brookeman, 1990) images. To explore the possible effect of stimulation frequency, experiments using the surface coil were repeated on digit 2 for a new subject group (four righthanded males subjects, aged 20–30 years), using both 80 Hz stimulation and the lower stimulus frequency of 30 Hz. An experimental run of the form used in Study 1 (20 cycles, 8 s ON, 24 s OFF) was performed, at each stimulus frequency. To address the reproducibility of the measured somatotopy, one randomly selected subject from each study was scanned twice in two identical sessions, spaced 1 month apart, in which digit 2 only was stimulated. Image Analysis Prior to analysis, all images were corrected for motion using a least sum of squares registration algorithm (Dr. A. Martel, Department of Medical Physics, University of Nottingham, Nottingham) and globally normalized. The initial analysis, directed toward evaluating the hemodynamic response function, was based on the use of a serial t test (Humberstone et al., 1997) in which signal levels at varying times were compared with the average value during a baseline period running from 16–22 s after the stimulus was switched off. The time courses of areas showing a significant change at any time during the cycle at a P value of 0.05 were examined and used to define the optimum waveform for use in subsequent correlation analysis. The waveform

thus chosen was formed from the convolution of the stimulus waveform and a Poisson function with a l-value of 6 s. To reduce high frequency noise, image data was temporally smoothed by convolving the fMRI time series with a Gaussian of 3 s full width at half maximum. The data was also high pass filtered to 0.01 Hz to remove any low-frequency drift before implementing the correlation analysis (Friston et al., 1994). No spatial filtering was applied. Statistical parametric maps with a corrected probability of P , 0.01, calculated using the method of Gaussian random fields (Friston et al., 1995), were viewed on the isotropic anatomical gray matter nulled images. The improved signal-to-noise-ratio (SNR) provided by the surface coil allowed thresholding of the data sets acquired in Study 2 at a lower corrected probability of P , 0.005. To allow anatomical localization of the relevant sulci and gyri and to aid in the identification of activated areas, T*2-weighted surface coil images were registered to MPRAGE images for each individual subject of Study 2. Activation sites for both digits 2 and 5 were then overlaid onto the MPRAGE images using MEDx (Sensor Systems Inc.). Overlaid image data sets were then volume rendered. Registration to MPRAGE images also allowed better identification of the anterior and posterior commissures for subsequent transformation of activation site coordinates to Talairach coordinates. For the purposes of this initial investigation, SI was then approximately separated into cortical subregions (Brodmann areas 3a, 3b, 1, and 2) by following the practices of previous investigators (Gelnar et al., 1998). This meant using the anatomy of the major sulci and gyri to provide the following operational descriptors. Area 1 was defined as occupying most of the crown of the postcentral gyrus, flanked by areas 2 and 3b located on its posterior and anterior walls, respectively. Brodmann’s area 3a was defined as occupying the fundus of the central sulcus. These anatomical divisions were established for each subject prior to examination of his/her fMRI results. Each of the clusters of activated pixels was then classified as falling within areas 3a, 3b, 1, or 2 as defined above. Any clusters falling on a border were counted for both areas. To detect spatial shifts in the location of activation for stimulation of digits 2 and 5, the separation of the center of mass of clusters in image space within each of the anatomically defined subregions was measured in each of the three dimensions (medial/lateral, anterior/ posterior, superior/inferior). To facilitate comparison with the results of other investigators, the coordinates of the center of mass of each of the clusters of activated pixels measured in image space were also transformed into the proportional coordinates of the atlas of Talairach and Tournoux (1988). This was done using a linear algorithm, which uses the anterior and posterior com-

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missures and the left, right, anterior, posterior, superior, and inferior borders of the brain, as key landmarks. The mean Talairach location of the activation sites within each of the defined subregions was computed for digits 2 and 5, along with the mean Euclidean separation in Talairach space. The cluster size and percentage change in the signal, computed using the ratio of the average of the maximum three points in the time course relative to the minimum three, were also calculated. The secondary somatosensory cortex (SII) was defined as an area located on the most inferior aspect of the postcentral gyrus and in the superior bank of the lateral sulcus (parietal operculum) (Affifi and Bergman, 1998). The posterior parietal region was defined to include the somesthetic association areas posterior to the postcentral gyrus encompassing Brodmann’s area 5 of the superior parietal lobe, while the precentral gyrus was defined to include areas 4 and 6. The posterior insula was defined to occupy the posterior third of the medial wall of the lateral sulcus. The mean image space and Talairach location of the activation sites of all cortical areas was computed for stimulation of digits 2 and 5, along with the mean Euclidean separation in image and Talairach space, cluster size, and percentage change as defined above. RESULTS Study 1 Significant foci of activation due to vibrotactile stimulation were found in the contralateral primary somatosensory cortex (SI), bilateral secondary somatosensory cortex (SII), the subcentral gyrus, the posterior insula, the posterior parietal region (Brodmann’s area 5), the precentral gyrus, and the posterior cingulate. Table 1 lists those regions showing significant contralateral activation (corrected P value of less than 0.01)

and details the mean cluster size and percentage change in signal in each region, for the 8 subjects scanned using the volume RF coil. Table 2 provides the same information about areas showing significant ipsilateral activation. The percentage change in signal was significantly greater for contralateral activation compared to ipsilateral in all areas (P , 0.05) except the secondary somatosensory cortex and the precentral gyrus, where there was no significant difference. The number of activated pixels was also significantly greater for contralateral activation in all areas (P , 0.05), except again in the secondary somatosensory cortex, and area 43. Figure 1 shows activation sites within a representative subject as a result of vibrotactile stimulation of digit 2. Data was acquired using the volume coil, and activation thresholded at a P value of less than 0.01 (corrected for multiple comparisons). Multiple foci of significant activity were found within the primary somatosensory (SI) cortex, and each such focus assigned to a subregion (area 3a, 3b, 1, or 2) as described above. Table 3 summarizes the frequencies with which significant activity was found within each of these subregions across the 8 subjects scanned. In all cases either a single cluster or no cluster of activated pixels was found in each area. The frequency of occurrence of clusters can be seen to be greatest within areas 1 and 3b. Ipsilateral activation in areas 1 and 3b due to stimulation of both digits 2 and 5 was found in 2 of the 8 subjects investigated in Study 1, in agreement with previous fMRI (Kurth et al., 1998) and MEG (Korvenoja et al., 1995) studies of the primary sensorimotor cortex. Table 3 shows that the most significant separation of digit representation was found in area 1, with a significant difference in location in the mediolateral plane (P 5 0.02), although no evidence of significant separation in the anterior-posterior or superior-inferior plane (paired t test of combined differences) was found. The

TABLE 1 Study 1: Contralateral Activation Found Using the Volume RF Coil

Digit 2 Frequency No. pixels Percentage change Digit 5 Frequency No. pixels Percentage change Both digits Frequency No. pixels Percentage change

SI

SII

Subcentral gyrus

Precentral gyrus

Insula

Posterior parietal

8 6.6 6 3.6 2.3 6 0.4

8 9.6 6 2.5 1.6 6 0.1

7 3.7 6 0.6 2.3 6 0.5

7 6.2 6 2.3 1.7 6 0.6

7 3.1 6 1.5 1.6 6 0.3

6 4.5 6 2.5 1.6 6 0.4

8 3.8 6 1.5 1.9 6 0.4

8 11.9 6 3.3 1.9 6 0.3

5 2.1 6 0.3 1.2 6 0.3

6 3.4 6 1.2 1.0 6 0.4

6 3.4 6 1.4 1.5 6 0.3

5 3.5 6 0.3 1.7 6 0.3

8 5.2 6 1.8 2.1 6 0.4

8 10.8 6 2.0 1.8 6 0.2

5 2.9 6 0.5 1.6 6 0.4

6 4.8 6 1.2 1.4 6 0.5

6 3.3 6 1.0 1.5 6 0.2

5 4.0 6 0.9 1.6 6 0.3

Note. Significant areas of contralateral activation found using the volume RF coil (data thresholded at P , 0.01 corrected for multiple comparisons) in eight subjects. The mean cluster size and percentage change in activated regions are also quoted.

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TABLE 2 Study 1: Ipsilateral Activation Found Using the Head RF Coil

Digit 2 Frequency No. pixels Percentage change Digit 5 Frequency No. pixels Percentage change Both digits Frequency No. pixels Percentage change

SI

SII

Subcentral gyrus

Precentral gyrus

Insula

Posterior parietal

3 1.5 6 0.7 0.9 6 0.8

7 8.8 6 2.1 1.6 6 0.2

5 3.5 6 1.7 1.5 6 0.8

2 2.5 6 0.8 0.9 6 0.3

4 1.2 6 0.7 0.6 6 0.3

1 0.3 6 0.3 0.2 6 0.2

4 1.1 6 0.6 0.5 6 0.3

7 11.1 6 3.0 1.6 6 0.1

3 1.75 6 1.4 1.0 6 0.2

1 0.75 6 0.4 0.4 6 0.2

1 0.6 6 0.3 0.3 6 0.2

1 0.2 6 0.2 0.2 6 0.3

2 1.3 6 0.5 0.7 6 0.3

7 9.9 6 2.1 1.6 6 0.1

3 2.5 6 1.4 1.2 6 0.6

1 1.6 6 0.6 0.6 6 0.2

1 0.7 6 0.3 0.4 6 0.2

1 0.2 6 0.2 0.3 6 0.2

Note. Significant areas of ipsilateral activation found using the volume RF coil (data thresholded at P , 0.01 corrected for multiple comparisons) in eight subjects. The mean cluster size and percentage change in activated regions are also quoted.

mean Euclidean separation between areas activated by stimulation of digits 2 and 5 was 6.0 6 1.3 mm (mean 6 standard error (sterr), n 5 8) (P 5 0.06, MANOVA, analysis of digit 2 versus digit 5 with differences in three directions as the dependent variables) in image coordinates and (6.7 6 1.1 mm) (mean 6 sterr, n 5 8) (P 5 0.02, MANOVA, analysis of digit 2 versus digit 5 with differences in three directions as the dependent variables) in Talairach coordinates. The limited separation between digits in the anterior-posterior and superior-inferior planes may be a result of either overlapping brain areas or poor spatial resolution and partial volume effects in the anterior-posterior plane. No significant digit separation was found in Study 1 in any other cortical region.

TABLE 3 Study 1: Activation Sites within Subregions of the Contralateral Somatosensory Cortex

Study 2 The increased spatial resolution (3 3 3 3 4-mm3 voxel size) and improved signal to noise in Study 2 allowed us to improve upon the measurement of the separation of activated areas made in Study 1. Table 4 shows the frequency of contralateral activation in SI, SII, the precentral gyrus, the middle/posterior insula, posterior parietal regions, and subcentral gyrus, due to 80 Hz vibrotactile stimulation for the six subjects scanned in Study 2. Figure 2 shows areas of significant activation in the postcentral gyrus, precentral gyrus, secondary somatosensory cortex, posterior parietal cortex, and subcentral gyrus (digit 2 activation being shown in yellow and digit 5 in blue, overlapping areas in green) overlaid onto MPRAGE images and subsequently volume rendered, for one representative subject. Activation maps are thresholded at P , 0.005, corrected for multiple comparisons. Multiple clusters of activity within the primary somatosensory (SI) cortex were again seen and each such cluster was assigned to a

Subregion

TABLE 4 3a

3b

1

Digit 2 3 6 8 Digit 5 1 3 8 Both digits 0 3 8 Mean difference in N.S. 4.4 6 1.3 6.0 6 1.3 position in image space (mm) Significance of sepa- N.S. (M/L 0.1, A/P .0.2, (M/L 0.02, A/P 0.1, ration in three S/I .0.2) S/I .0.2) coordinates of image space

2 5 2 1 1.5

N.S.

Note. Numbers given are results of those eight subjects scanned. The three-dimensional separation in image space and the measured significance of separation in each of the planes (M/L, A/P, S/I) in image space are also quoted.

Study 2: Numbers of Subjects in Which Significant Areas of Contralateral Activation Were Found Using the Surface Coil (Six Subjects Scanned)

Digit 2 Digit 5 Both digits

SI

SII

Subcentral gyrus

Precentral gyrus

Insula

Posterior parietal

6 6 6

6 6 6

4 3 3

6 6 6

5 3 3

6 5 5

Note. Significant areas of contralateral activation found using the surface RF coil (data thresholded at P , 0.005, corrected for multiple comparisons) in six subjects. Note that the drop-off in sensitivity of the surface coil meant that detection of activity in the cingulate and all ipsilateral cortical areas was not possible.

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TABLE 5 Study 2: Activation Sites within the Subregions of the Contralateral Primary Somatosensory Cortex Measured Using the Surface Coil Subregion 3a

3b

1

2

Digit 2 3 5 6 4 Digit 5 1 3 6 2 Both digits 1 3 6 2 Mean difference 0 462 11 6 1 362 in position in image space Significance of N.S. (M/L 0.12, A/P (M/L 0.003, A/P (M/L 0.18, A/P separation in .0.2, S/I 0.014, S/I .0.2, S/I three coordi0.18) .0.2) .0.2) nates of image space Note. Numbers given are results of those six subjects scanned. The three-dimensional separation in image space and the measured significance of separation in each of the planes (M/L, A/P, S/I) in image space are also quoted.

subregion (area 3a, 3b, 1, or 2) as described previously. As in Study 1 the number of clusters observed in any subregion never exceeded one. Table 5 summarizes the relative frequency of activity within each of the subregions for the six subjects scanned and also shows the mean difference in position of the centre of mass of the activated clusters for stimulation of digits 2 and 5 in each subregion in image space. Table 6 shows the Talairach coordinates of the activated cluster in area 1 and the mean Euclidean separation of clusters in this area in both Talairach and image coordinates for each of the six subjects. The frequency of activation within area 3a was again found to be the lowest, while the highest occurrence of activation was in the primary cutaneous areas 1 and 3b.

As in Study 1, the most significant separation of the digits was found in area 1, as shown in Fig 3, and since significance of separation was substantially improved in the anterior/posterior and superior/inferior directions, this suggests that localization was previously limited by the spatial resolution and signal to noise available using the head coil. The significance of separation of activated areas in area 1 in image space due to stimulation of digits 2 and 5 was P 5 0.003 in the mediolateral plane, and P 5 0.014 in the anteriorposterior plane on comparison over all subjects (combined difference of pairs), digit 5 activation being more medial and posterior. No significant separation was found in the superior-inferior plane. The mean Talairach coordinates for activation of area 1 following digit 2 stimulation were (249, 219, 44) 6 (1, 1, 1) versus (242, 225, 48) 6 (1, 1, 1) for digit 5. The mean Euclidean separation of activation in area 1 due to digits 2 and 5 was 12 6 1 mm in Talairach coordinates (P 5 0.001, MANOVA, analysis of digit 2 versus digit 5 with differences in three directions as the dependent variables) and 11 6 1 mm in image coordinates (P 5 0.001, MANOVA, analysis of digit 2 versus digit 5 with differences in three directions as the dependent variables) (Table 5). Area 1 of the primary somatosensory cortex (SI) was also found to be the subregion with both the largest signal change and greatest number of pixels activated, following 80 Hz stimulation of either digit. A significant increase in the number of pixels activated due to stimulation of digit 2 (n 5 8.3 6 0.6) compared with digit 5 (n 5 4.5 6 0.2) was found in area 1 (P 5 0.02, paired t test), consistent with the expectation that digit 2 has a larger representation within area 1 of the postcentral gyrus than digit 5. A significant increase in the percentage change of activation due to stimulation of digit 2 (3.3 6 0.2%) compared with digit 5 (1.9 6 0.2%) was also found (P 5 0.03, paired t test).

TABLE 6 Study 2: The Mean Talairach Coordinates of the Center of Mass of the Activated Cluster in Area 1 for Stimulation of Both Digits 2 and 5, for Six Subjects Three dimensional separation Digit 2

Digit 5

Subject

M/L

A/P

S/I

M/L

A/P

S/I

Talairach coordinates (mm)

Image space (mm)

1 2 3 4 5 6 Mean

248.2 250.8 247.9 251.0 246.9 247.3 248.7

216.9 218.0 220.6 220.4 223.5 217.2 219.4

43.5 40.3 44.7 44.6 46.3 47.4 44.5

243.8 242.5 240.7 243.0 238.8 242.1 241.8

224.9 223.1 225.0 227.6 227.2 225.4 225.5

52.5 52.2 49.8 50.0 43.3 41.9 48.3

12.8 15.4 9.9 12.1 9.4 11.3 11.8

11.6 15.1 7.2 9.8 12.8 10.4 11.2

Note. The Euclidean separation of sites is also given in image and Talairach coordinates (M/L, medial/lateral; A/P, anterior/posterior; S/I, superior/inferior).

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FIG. 1. Activation sites in a representative subject due to vibrotactile stimulation of digit 2 measured using the volume RF coil. Areas of contralateral activation can clearly be seen in SI (areas 1 and 3b), the secondary somatosensory cortex (SII), and the posterior parietal regions (areas 5). FIG. 2. Activation sites in a representative subject due to vibrotactile stimulation of digits 2 and 5 measured using the surface coil (Study 2–Subject 5). Data is overlaid upon volume rendered 1-mm isotropic resolution MPRAGE images.

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FIG. 3. Activation sites in one representative subject in area 1 due to vibrotactile stimulation of digits 2 and 5 measured using the surface coil (Study 2–Subject 5).

Even with the improved resolution of the second study, no significant separation of digits 2 and 5 was found within areas 3a, 3b (Fig. 4), or 2. A significant increase in number of pixels (P 5 0.03) and percentage change (P 5 0.04) was, however, found in area 3b due to stimulation of digit 2 compared with digit 5 (Digit 2 (D2): n 5 2.0 6 0.4, 2 6 0.5%; Digit 5 (D5): n 5 0.6 6 0.2, 0.65 6 0.2%). Figure 4 also shows that the foci of activation within area 3b are located well down the posterior wall of the central sulcus, approaching the 3a border as expected from previous receptive field (RF) mapping studies (Pons et al., 1987). No significant differences in cluster size or percentage change were found for areas 3a and 2. Study 1 revealed bilateral activation in the upper bank of the Sylvian fissure (contralateral . ipsilateral) as a result of stimulation of both digits 2 and 5, as indicated in Fig. 1 and Tables 1 and 2. Figure 5, which depicts data from Study 2, also clearly shows contralateral activation within the upper bank of the Sylvian fissure. Previous PET and fMRI studies have also shown activation of this portion of the parietal operculum in response to relatively intense vibrotactile stimulation (Burton et al., 1991, 1993; Gelnar et al., 1998). Although no significant separation between digits was found in this area in Study 1, Study 2 revealed a significant separation in the anterior-posterior plane, with the area activated by the stimulation of digit 5

being more posterior than that resulting from digit 2 stimulation (P 5 0.05; paired t test with unequal variances) in accord with previous RF mapping studies (Burton and Carlson, 1986). The activation measured in SII in this study was also found to be spatially extensive, running laterally from 246 to 254, and from 218 to 225 in the anterior-posterior direction (Talairach coordinates). A significant increase in cluster size for digit 2 (n 5 9.7 6 0.4) compared with digit 5 (n 5 6.8 6 0.8) (P 5 0.025) was also found, but there was no significant difference in percentage change. In both studies, a cluster of activated pixels was also found in the subcentral gyrus of the majority of subjects. The average Talairach coordinates of the center of mass of this cluster (254 6 2, 27 6 3, 17 6 2) correspond to the location of Brodmann’s Area 43 (Talairach and Tournoux, 1988), which is thought to represent gustatory function (Duvernoy, 1999). It is, however, more likely that this cluster actually falls in the most anterior region of secondary somatosensory cortex (Harrington et al., 1998). No somatotopic organization was found in this area in either study. Posterior parietal activation (Brodmann’s area 5 was found in the majority of subjects of Study 2, as in Study 1 (Tables 1 and 4). No somatotopic organization was found in either study. Data from Study 2 did, however, show significant increases in both the number of pixels (P 5 0.05) (D2: 8.4 6 1.3 D5: 4.2 6 1.5) and percentage

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change (P 5 0.05) (D2: 2.9 6 0.4%, D5: 1.7 6 0.3%) activated in this region for stimulation of digit 2 compared to digit 5. Several other recent functional imaging studies have reported activation in this region following vibrotactile stimulation (e.g., Gelnar et al., 1998). In three of the six subjects scanned in Study 2, as well as six of the eight subjects scanned in Study 1, significant activation was found in the posterior insula on stimulation of both digits 2 and 5. Pooled comparison over all six subjects suggested a possible shift between digit 2 and 5 in the anterior-posterior direction, with digit 5 activity being located more posterior (P 5 0.09 on intersubject comparison, paired t test with unequal variances). Other investigators using PET (Burton et al., 1997) and fMRI (Gelnar et al., 1998) have also reported activation of this region during digit stimulation. In all the subjects scanned in Study 2, as well as six of the eight subjects in Study 1, significant activation of the precentral gyrus (areas 4 and 6, the locus of the primary motor cortex) was found for both digits. The extent of activation within the precentral gyrus was significantly larger for stimulation of digit 2 compared with digit 5 (P 5 0.05) (D2: 7.4 6 1.3, D5: 5.0 6 1.0) in Study 2. This may partly reflect subthreshold muscle contractions of those digits undergoing stimulation (Goodwin et al., 1972), as well as direct somatosensory input to this cortical region. No significant separation of digit representations was found in this region. Repeatability of Measured Acitvation in SI Highly reproducible patterns of activation resulting from stimulation of digit 2 were found in the two subjects that were scanned on repeated occasions. The mean absolute error (i.e., the absolute value of test/ retest trial difference) in location of the center of mass of activation in area 1 in image space was: for Study 1, mediolateral 3 mm, anterio-posterior 3.0 mm, and superior-inferior 1.1 mm, giving a Euclidean separation of 4.4 mm; and for Study 2, mediolateral 1.5 mm, anterio-posterior 0.6 mm, and superior-inferior 1.2 mm, giving a Euclidean separation of 2 mm. The residual errors may reflect in substantial part the effect of changes in subjects’ head positioning or movement of the hand between studies, despite fixation using a vacuum pad. The response localization thus appears to be consistent on the length scale of the image spatial resolution across repeated trials within subjects. There was also no significant difference in the number of pixels or percentage change in activation induced by the repeated stimuli. This confirms the robust nature of the stimulus and its ability to allow meaningful comparisons between scanning sessions.

Frequency Dependence Investigating the effect of the vibrotactile frequency revealed that for digit 2, a decrease in stimulus frequency from 80 to 30 Hz led to a reduction in the number of activated pixels, within both SII (P 5 0.009) and the posterior insula (P 5 0.02). There was, however, no significant difference in percentage change. Conversely, a smaller number of activated pixels was found within SI at the higher frequency (80 Hz) (P 5 0.006). Table 7 details the number of activated pixels and percentage change in signal within each of these areas for stimulation at the two different frequencies. Figure 6 shows the effect of frequency difference on activation sites for stimulation of digit 2 in one representative subject. DISCUSSION The reported studies represent substantial progress toward the four objectives set forth in the Introduction: 1. The new piezoelectric stimulator proved capable of generating robust cortical activation, the gross morphology of which was generally similar to patterns reported by previous investigators (e.g., Burton et al., 1997; Gelnar et al., 1998; Kurth et al., 1998; Lin et al., 1996) and consistent with neurophysiological expectations. This is encouraging, because in contrast with the very large and sometimes harmonically complex mechanical or electrical stimuli used in previous functional imaging studies of responses to periodic digit stimulation, the stimuli we delivered were pure mechanical sinusoids with amplitude and frequency characteristics falling well within the range of the main body of previous neurophysiological and psychophysical studies of vibrotaction (see Introduction). Further development work is currently underway to improve the calibration of stimulus amplitude and force, but even in its current form the device provides—when used in conjunction with careful attention to the control of arm and finger position—a reasonably good approximation to functional properties of the much more complex electroTABLE 7 Study 2: The Mean Cluster Size and Percentage Change in Signal in Activated Regions for Stimulation of Digit 2 at 30 and 80 Hz 30 Hz

SI SII Insula

80 Hz

No. pixels

Percentage change

No. pixels

Percentage change

11.7 6 0.5 6.0 6 0.4 2.0 6 0.4

3.1 6 0.7 2.2 6 0.2 1.7 6 0.1

7.0 6 0.9 10.5 6 0.9 4.5 6 0.6

2.6 6 0.2 2.2 6 0.3 1.9 6 0.2

Note. Numbers given are results of those four subjects scanned.

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mechanical stimulators conventionally used in vibrotaction research. 2. Stimulus quality may also have contributed to our success in the second task—i.e., benchmarking our imaging and image analysis techniques with respect to the known spatial arrangement of the digit representations along the postcentral gyrus. Specifically, stimulation of digit 2 reliably led to activation of contralateral SI cortex at 3-D locations lateral and anterior to those activated by stimulation of digit 5. The separation was readily measured in image space, using subject-specific anatomy, and it was robust enough to survive transformation of individual cluster coordinates into Talairach space prior to statistical analysis. The latter is perhaps especially surprising, in view of the original observations of Penfield and Boldrey (1937), who showed that the regularity of the mapping of the human hand attaches primarily to the mediolateral ordering, and not to the absolute locations, of the digit representations. Although the M-L dimension of SI somatotopic organization was the primary focus of our benchmarking effort, its success encourages us to comment at least in a preliminary way on the more contentious subject of possible additional SI organization in the A-P direction. As noted above, we followed the practices of previous investigators in subdividing SI approximately into four Brodmann subareas using anatomical criteria, and cataloging the occurrence of significant clusters of activation with respect to the cortical territories so identified. The fact that ‘‘hot-spots’’ appeared in all SI subareas may be construed by some readers—as it has by a number of previous investigators including Burton et al. (1997), Gelnar et al. (1998), Kurth et al. (1998), and Lin et al. (1996)—as evidence consistent with, and possibly supportive of, the ‘‘multiple-representations’’ view of SI somatotopic organization (e.g., Kaas et al., 1979), according to which the cytoarchitectonic subdivisions of SI contain complete and functionally independent body representations. Without dwelling upon the numerous and complex details relevant to these claims, we urge that this interpretation of the available functional imaging data in general, and our data in particular, is at best premature: first, it must be recognized that the precision with which areal borders can be identified using surface anatomical criteria is limited (Geyer et al., 1999). Indeed, ambiguities can remain even when the analysis is guided not only by cytoarchitecture, but by information about receptor densities, myeloarchitecture, and connectivity patterns (e.g., Zilles et al., 1995). Hence, it is often unclear with what confidence a given cluster can be assigned to a specific subarea. In our case, a further related problem was that two of the clusters found in SI in study 2 analyzed fell on putative areal boundaries, and in these instances we incremented the counts for both areas

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although there was really only one cluster. In the case of digit-tip vibratory stimulation, moreover, the multiple-representations doctrine predicts more than simply the occurrence of spots in areas 3b, 1, and 2. For example, it claims that the digit representations in areas 3b and 1 point in opposite directions, joined at the digit base at the areal boundary. Thus for a digit-tip stimulus there should be one discrete spot deep in area 3b near the 3a border, and another near the posterior edge of area 1. Although we cannot really test such a detailed prediction, given the uncertainty of areal identification, some of the results seem inconsistent with it. For example, both of the clusters that fell on areal boundaries actually fell on the border between areas 3b and 1. We also note that although area 3a (which is supposed to deal exclusively with proprioceptive, deep receptor, and perhaps nociceptive input) was consistently lowest in the amount of activity observed (Tables 3 and 5), substantial activity in response to our innocuous cutaneous stimuli was observed there. Generally, the identified clusters may simply represent loci of peak activity falling within much larger territories of activation that typically extend more or less continuously across SI and especially across the core tactile areas 3b and 1. Such a view is consistent, for example, with receptive field-mapping observations in unanesthetized or lightly anesthetized animals (McKenna et al., 1982), with metabolic labeling and optical imaging results in lightly anesthetized animals (Juliano and Whitsel, 1985; Tommerdahl and Whitsel, 1996), and with observations on somatosensory evoked potentials recorded from arrays of intracranial electrodes in both human and monkey subjects (Allison et al., 1989, 1991). It should also be pointed out in this connection that the multiplerepresentations view arose primarily in the context of multiunit receptive field-mapping studies carried out under profound levels of ketamine anesthesia. This agent has been shown to reduce single unit responsivity and receptive field size (Duncan, 1982), and correspondingly to reduce both the spatial extent and the intensity of SI cortical activation observed with nearinfrared optical imaging in response to identical vibrotactile stimuli (Tommerdahl and Whitsel, 1996); these effects, moreover, are predictable from the fact that ketamine selectively antagonizes the NMDA receptor system of the upper cortical layers and thus impairs long-distance tangential interactions within the cortex. Although our observations to date certainly cannot resolve any issues related to the A/P dimension of SI organization, they do indicate that this topic (among others) is amenable to further study using fMRI methods. To this end, some specific refinements of the procedures introduced here could be particularly advantageous. First an experimental refinement: if it is the case, as suggested above, that the response to a ‘‘punc-

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FIG. 4. Activation sites in area 3b of one representative subject due to vibrotactile stimulation of digits 2 and 5 measured using the surface coil (Study 2–Subject 5). FIG. 5. Representative activation sites in the secondary somatosensory cortex (SII) of one representative subject due to vibrotactile stimulation of digits 2 and 5 measured using the surface coil (Study 2–Subject 5).

tate’’ digit stimulus is spatially extensive and includes neural territories responsive to multiple digits, as well as territories selectively responsive to the actual site of stimulation, the spatial contrast between digits could be accentuated by defining the responses as difference

patterns after the manner of Kleinschmidt et al. (1997) in their study of somatotopic organization in primary motor cortex. This was difficult to do in the present study because the digits were stimulated in separate runs. In future work it would therefore be desirable to

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FIG. 6. Effect of frequency of stimulation in one representative subject. Areas activated due to 80 Hz shown in yellow, 30 Hz in blue, and overlapping regions in green. Activation in area 1 and the secondary somatosensory cortex (SII) is shown.

interleave or randomly schedule stimulation of the targeted fingers. Many of the practical problems in fMRI arise from the notoriously high between-subject and even betweenhemisphere variability in the curving trajectory followed by the cortical mantle in its passage through the rigid 3-D geometry imposed by the scanning protocol. Rather than routinely transforming individual subjects’ data into the coordinates of any ‘‘standard’’ or common brain geometry, we think future work along the lines initiated here will be more successful if it deals with these between-subject differences in a more decisive way. Specifically, we think the optimal approach to more detailed analysis of SI functional organization would be to follow conventional somatosensory neurophysiological practice by mapping the measured activations onto unfolded and flattened 2D representations of each subject’s SI cortical anatomy. This will be especially important for studies of the A-P dimension, since a large fraction of the A-P extent of human SI lies within the central and postcentral sulci (The depth of the human CS in the vicinity of the hand area, for example, is on the order of 1.8 cm—Allison et al., 1989). Software for this purpose is gradually becoming more widely available (e.g., Carman et al., 1995). 3. The increased spatial resolution (3 3 3 3 4-mm3 voxel size) and higher signal to noise provided by the surface coil in Study 2 clearly allowed us to improve upon the digit discrimination achieved in Study 1 using the head coil (though at the cost of reduced sensitivity

to ipsilateral and more distant contralateral components of the activation pattern). Using midvolume slices from the images themselves, we determined that the surface coil increased signal to noise by a factor of 1.8 despite the twofold reduction in voxel volume, while the variation in intensity due to the nonuniform B1 field of the coil was an acceptable factor of 0.8 over the ten sagittal slices. 4. Finally, our results on the changes in activation produced by switching from 80 to 30 Hz vibratory stimulation of the same skin site, while preliminary, strongly suggest that the frequency parameter deserves more systematic attention than it has received in previous human functional imaging studies of responses to vibration. Most of the few relevant studies, it should be pointed out, used stimuli which were high in both amplitude and frequency—typically over 1000 µm at 130 Hz or higher. Even the stimulus of Gelnar et al. (1998), while nominally at 50 Hz, contained multiple higher harmonics. Other studies which manipulated the frequency of repetitive somatic stimuli have operated entirely in the range below 30 Hz (Iba´n˜ez et al., 1995; Puce et al., 1995; Fox et al., 1987). Ours is the first study, we believe, to sample across the neurophysiologically and psychophysically significant contrast between ‘‘flutter’’ (10–50 Hz) and ‘‘vibration’’ (50–300 Hz or more) using pure sinusoidal mechanical stimuli of small to moderate intensity. Briefly, flutter stimuli produce sharply localized skinsurface sensations that are widely believed to be sub-

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served primarily by rapidly adapting type one (Meissner) mechanoreceptive afferents. These terminate in the dermal ridges, are reliably entrained by flutter stimuli, and project securely to the core tactile areas 3b and 1 of SI (e.g., Mountcastle, 1984). Vibration stimuli, by contrast, produce relatively poorly localized and deeper sensations of higher ‘‘pitch’’ that are thought to reflect predominantly the activity of rapidly adapting type two mechanoreceptive afferents. These terminate in Pacinian corpuscles and project to both SI and SII, but are known to produce better entrainment responses in SII (Mountcastle, 1984; Ferrington and Rowe, 1980). Recently, Tommerdahl et al. (1999a, 1999b) have extended this picture by using near-infrared optical imaging to study the temporal dynamics of cortical responses to prolonged 25 vs 200 Hz vibratory stimuli applied to the same skin site in cats and squirrel monkeys. As expected, flutter stimuli engaged topographically appropriate regions of both SI and SII, the latter in strongly bilateral fashion, and activation quickly reached a steady state that was maintained for the duration of stimulation. The high-frequency stimulus activated SII in similar fashion, but even more strongly (again as expected), but its effects on SI were unexpected: specifically, the high-frequency stimulus initially produced activation in the same SI locus responsive to same-site flutter stimulation, but this activation was quickly extinguished and replaced by a spatially much larger area of deactivation, suggesting the possibility of inhibitory influences flowing in a time-dependent manner from some other cortical locus, possibly SII. Our initial frequency results are potentially consistent with this extended picture of the cortical response to vibration, and merit follow-up in this light. ACKNOWLEDGMENTS This work was supplied by Unilever, MRC Special Project Grant G9302591, and Program Project DE07509 from NIH.

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