A new device for tactile stimulation during fMRI

www.elsevier.com/locate/ynimg NeuroImage 39 (2008) 1094 – 1103

A new device for tactile stimulation during fMRI Christian Dresel,a, * Andreas Parzinger,a Christoph Rimpau,c Claus Zimmer,b Andres O. Ceballos-Baumann,d and Bernhard Haslingera a

Department of Neurology, Klinikum rechts der Isar, Technische Universitaet Muenchen, Ismaninger Str. 22, 81675 Muenchen, Germany Department of Neuroradiology, Klinikum rechts der Isar, Technische Universitaet Muenchen, Germany c Institute of Machine Tools and Industrial Management, Technische Universitaet Muenchen, Germany d Neurologisches Krankenhaus Muenchen, Germany b

Received 30 April 2007; revised 22 July 2007; accepted 14 September 2007 Available online 7 November 2007 Standardized somatosensory stimulation of the face during functional MRI is technically demanding due to the high magnetic field of the MRI scanner and the confined geometry of the head coil. We developed a new computer-controlled MR-compatible stimulation device for mapping somatosensory-evoked brain activations during fMRI. The device employs von Frey-filaments which are commonly used for quantitative sensory testing (QST) to deliver punctate tactile stimuli to the face and other body surfaces with a high spatiotemporal accuracy. Such stimuli were applied to the ipsilateral face and hand of eight volunteers during two different experimental designs to explore the feasibility of the new stimulator for somatosensory mapping. Tactile stimulation activated a distributed neural network including primary (S1) and secondary (S2) somatosensory areas as well as the premotor cortex and the thalamus. An event-related experimental design yielded S1 activation in all subjects despite a smaller total number of stimuli compared to a blocked design where S1 activation was not consistently found in three subjects. In individuals where S1 was significantly activated during both experimental conditions, the punctate tactile stimuli allowed discriminating the face and the hand representation in S1. We conclude that the novel stimulation device appears to be a valuable tool for mapping somatosensory representations. The data suggest that an event-related study design could be beneficial as it better controls for confounding factors such as anticipation, habituation and attention. © 2007 Elsevier Inc. All rights reserved. Keywords: fMRI; somatosensory cortex; face; device; MR-compatible

Abbreviations: QST, quantitative sensory testing; VFF, von Freyfilament; PVC, polyvinyl chloride; ON, stimulating channel on; OFF, stimulating channel off; F, face; H, hand; V1–3, trigeminal divisions; B, blockdesign fMRI; E, event-related fMRI; MNI, Montreal Neurological Institute; AS, analogue scale; S1/S2, primary/secondary somatosensory cortex; PMC, premotor cortex. * Corresponding author. Fax: +49 89 4140 4867. E-mail address: [email protected] (C. Dresel). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.09.033

Introduction The mapping of somatosensory representations using functional imaging requires the controlled application of standardized stimuli. In the past, cotton wool-tips, monofilaments or tailored surfaces have been administered manually for investigating fundamental aspects of tactile perception and somatosensory processing (Davis et al., 1998; Fox et al., 1987; Francis et al., 2000; Hagen and Pardo, 2002; Iannetti et al., 2003; Moore et al., 2000; Ruben et al., 2001; Yetkin et al., 1995). However, the manual application of stimuli introduces an examiner-dependent spatiotemporal variance into the statistical analysis of imaging data and is therefore problematic for group comparisons. Furthermore, there is an increasing need for new techniques which allow more detailed studies of the temporal and spatial dynamics of functional interactions within somatosensory areas (Porro et al., 2004). The automatic application of somatosensory stimuli during functional MRI (fMRI) results in a smaller variance of the BOLD time series data and increased sensitivity for brain activations (Graham et al., 2001). A variety of technical devices for somatosensory stimulation during fMRI have been presented. These stimulators include mechanical (Golaszewski et al., 2002a,b), magnetomechanical (Graham et al., 2001), piezoceramic (Francis et al., 2000; Gizewski et al., 2005; Harrington et al., 2000; Maldjian et al., 1999) or pneumatic (Briggs et al., 2004; Gelnar et al., 1998; Huang and Sereno, 2007; Servos et al., 1999; Stippich et al., 1999; Wienbruch et al., 2006; Zappe et al., 2004) devices which were fitted to the MR environment and provide vibrotactile, i.e. tactile or vibratory, stimuli. Other researchers have applied electrical stimulation techniques (Arthurs et al., 2004; Blankenburg et al., 2003; Del Gratta et al., 2002; Deuchert et al., 2002; Disbrow et al., 1998; Kampe et al., 2000; Krause et al., 2001; Kurth et al., 1998; Trulsson et al., 2001). For example, such stimulators can be used for presurgical mapping in patients with a brain tumour or for fMRI of cortical reorganization and plasticity in handicapped patients. Among them, the pneumatically-driven vibrotactile devices can apply stimuli to the face without causing imaging

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artefacts (Huang and Sereno, 2007; Schulz et al., 2004; Servos et al., 1999; Stippich et al., 1999). The automatic application of standardized stimuli to the face during fMRI is technically demanding due to the high magnetic field of the MRI scanner and the narrow geometry of the head coil. Stippich et al. (1999) attached pneumatically-powered plastic clips to the lip, finger and toe while Servos et al. (1999) and Huang and Sereno (2007) used a sequence of air puffs to stimulate the face. Other approaches include the application of balloon diaphragms (Schulz et al., 2004). However, most of these devices use unphysiologic modes of stimulation, and the relationship between the technical and the physiologic (e.g. force applied to the skin) parameters of the stimulation are not well defined. We developed a new stimulation device capable of applying standardized physiologic tactile stimuli to the face and other parts of the body in an experimenter-independent way. Similar to other devices, it will allow a systematic investigation of tactile perception. The intensity of the tactile stimuli is normalized and can be adjusted individually, both being a precondition for quantitative sensory testing (QST). In recent years, QST has become the gold standard in electrophysiological experiments of the somatosensory system (Rolke et al., 2006; Yarnitsky, 1997). The QST framework takes the intra- and interindividual variance of sensory perception thresholds and the psychophysical dimension of somatosensory perception into account (Porro et al., 2004; Romo et al., 2002). The aim of the present study was to demonstrate the safety and feasibility of the new stimulation device to map the cortical representation of the face and hand in eight volunteers. As previous studies had shown a top-down modulation of stimulus-induced activations by subject-inherent factors such as anticipation (Carlsson et al., 2000; Drevets et al., 1995; Porro et al., 2004), habituation (Becerra et al., 1999) and attention (Arthurs et al., 2004; Hamalainen et al., 2000; Hoechstetter et al., 2000; JohansenBerg et al., 2000; Meyer et al., 1991), we explored two different experimental paradigms, i.e. a blocked and an event-related fMRI design. We hypothesized, that both fMRI designs will yield robust

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activations in somatosensory areas, and that the punctate tactile stimuli will allow discriminating the face from the hand representation in the primary somatosensory cortex (S1). Materials and methods Tactile stimulation device The tactile stimulation device can apply von Frey-filaments (VFF) to the face or other parts of the subject's skin in order to deliver punctate, i.e. point-like, tactile stimuli in a precise spatiotemporal sequence. Von Frey-filaments (Optihair22-set, Marstock nervtest, Germany) are monofilaments (Fruhstorfer et al., 2001) which exert a constant, logarithmically-scaled force between 0.25 mN and 728 mN to a small area of the skin (≤1 mm2). They are widely used for testing tactile perception thresholds during quantitative sensory testing in neurophysiological experiments (Park et al., 2001; Rolke et al., 2006; Yarnitsky, 1997). Manually applied VFF have yielded robust activations in previous neuroimaging studies (Hagen and Pardo, 2002; Moore et al., 2000). The stimulation device is a modular assembly of six main components (Fig. 1): a control unit and a signal converter outside the magnetically shielded MRI scanner room; and a driving unit, multiple mediators (bowden wires), positioning units and applicators (von Frey-filaments) inside the scanner room. The driving unit contains electromagnetic valves and double action-pneumatic cylinders in an electrically-earthed aluminium case which serves as a Faraday cage and is positioned underneath the patient table, remote of the magnet bore (Fig. 2A). All other components of the device inside the scanner room and in the vicinty of the subject are nonmagnetic, i.e. have a low magnetic susceptibility (Schenck, 1996), in order to ensure correct functioning and to prevent the subject from potential hazards. The von Frey-filaments are made of acrylic glass, the bowden wires contain Nylon® and Teflon® while all other materials near the subject and the head coil consist of polyvinyl chloride (PVC). Due to the modular construction and the use of nonmagnetic materials, the stimulation device does not

Fig. 1. Schematic illustration of the tactile stimulation device. 5-V TTL pulses from the PC-based control unit are converted by the signal converter into 24-V actuation signals for the magnetic valves in the driving unit. The magnetic valves release the pressure from the pressurized air supply to the appropriate side of the double action-pneumatic cylinders which drive eight separate von Frey-filaments (applicators) by nonmagnetic bowden wires (mediators). Each von Freyfilament can be individually oriented by a positioning unit (see also Fig. 2B). The stimulus application is synchronized with the MR image acquisition by the MRI trigger signal.

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Fig. 2. (A) Optional setup with six positioning units mounted on the patient table alongside the two-channel Siemens head coil, e.g. for stimulating the three trigeminal divisions bilaterally, and the driving unit underneath the patient table. The bowden wires transmit the mechanical momentum of the pneumatic cylinders in the driving unit to movable pistons in the positioning units (see also B). Note that all materials in the vicinity of the subject and the head coil are nonmagnetic. (B) Drawing of a positioning unit with a von Frey-filament attached to the mobile piston. (C) Study setup with the eight-channel head coil and a von Frey-filament stimulating the right upper lip of a subject. (D) Study setup for stimulation of the (for better visibility) left hand with the subject inside the magnet bore.

interfere with MR image acquisition. To test for potential devicerelated imaging artefacts, we obtained series of T1-, T2- and T2*weighted images of a water phantom (i) without the stimulation device mounted, (ii) with the device mounted and (iii) with the device mounted and operating at various frequencies, e.g. during continuous 5 Hz-stimulation near the head coil. We subtracted corresponding images of the same and of different series from each other as such subtraction images are rather sensitive to image distortions and other imaging artefacts. We observed no differences in such image-by-image comparisons apart from the inherent scanner noise. The control unit is operated by a conventional Windows-based personal computer (PC). The software Presentation (http://www. neurobs.com) is used for synchronizing the temporal sequence of stimulation with the MR image acquisition. The parallel port of the PC generates 5-V TTL pulses which are converted into 24-V actuation signals by the signal converter. The actuation signals are transmitted through the filter panel (Siemens Erlangen, Germany) to the driving unit within the MRI scanner room by an electromagnetically shielded cable. The actuation signals operate the magnetic valves of the driving unit which release the pressure from a pressurized air supply to the appropriate side of the double action-pneumatic cylinders (ON vs. OFF), i.e. a pressure is constantly applied to either side of the cylinder. As the 24-V actuation signals supply the magnetic valves with electric power,

this electric circuitry cannot be replaced by an optical signalling pathway unless a separate electric power supply will be installed in the scanner room (including its limitations and disadvantages). The anchorages of the magnetic valves and the pneumatic cylinders within the aluminium case are damped as well as mechanically and acoustically decoupled. Additional measures of acoustic insulation were implemented to reduce the operating noise to a minimum. The pistons of the pneumatic cylinders are connected to bowden wires consisting of nylon leads with a Teflon® cladding. The nylon leads transmit the mechanical momentum of the cylinders to mobile pistons in the positioning units where different types of applicators can be mounted. In this study, von Freyfilaments were used as applicators (Fig. 2B). Each VFF is driven back and forth by moving the piston of the positioning unit. The device provides eight independent channels for controlling eight different VFF. Each VFF can be positioned individually within the magnet bore of the scanner as the piston of the positioning unit is attached to a gooseneck with multiple flexible elements. The bottom parts of the positioning units are fixed on mounting rails that are firmly connected to the patient table of the MRI scanner (Fig. 2). Due to its modular construction and the use of double action-cylinders in combination with bowden wires, the device allows positioning several applicators next to each other within the narrow head coil (Fig. 2A). It has been tested to apply punctate tactile stimuli with a maximum frequency of 10 Hz (50 ms ON vs.

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(second trigeminal division, V2) and the thenar eminence of the hand (H). According to the somatotopy of the primary somatosensory cortex, the cortical representation of the hand is located next to the face area (Huang and Sereno, 2007; Penfield and Rasmussen, 1952; Stippich et al., 1999). Since anticipation, habituation and attention cause a top-down modulation of touchinduced activations (see review by Porro et al., 2004), we explored two different experimental paradigms, i.e. a blocked (B) and an event-related (E) fMRI design. For both designs, the spatiotemporal sequence of stimulations was optimized with regard to these confounders. The location of stimulation (face or hand) was pseudorandomized, and the duration of runs and blocks were kept short. A post-fMRI questionnaire was announced pre-scanning to motivate the subjects for keeping their attention focussed on the stimuli during functional imaging. They were told that a conscious concentration on the stimuli would allow them to answer questions about the stimulation afterwards while they were left uninformed about the exact nature of these questions prior to the experiment. Although this way of monitoring the subject's attention and perception may be less reliable than online intensity ratings, e.g. by button press responses, we decided not to use the latter as this may have caused coactivation in sensorimotor areas and additional movement artefacts. The purpose of the study was explained to the subjects before scanning while they were left uninformed about the number and spatiotemporal sequence of stimuli. All participants performed two runs of a blocked and two runs of an event-related design in a pseudorandomized order without doubling of the same design at the beginning or at the end of the experiment in order to reduce a systematic effect of experiment duration, i.e. EEBB and BBEE were excluded. As some previous studies have investigated only one side of the body, four subjects (two females) were stimulated

50 ms OFF, pressure 4 bar, bowden length 3 m) and a full extension of the piston. Higher frequencies may be achieved with shorter bowden lengths and smaller stroke amplitudes. Subjects Written informed consent was obtained from eight healthy volunteers (age: 23–26, 4 females) who are right-handed according to the Edinburgh Handedness Inventory (Oldfield, 1971). The study protocol has been approved by the ethics board of the Klinikum rechts der Isar, Technische Universitaet (TU) Muenchen. Stimulation paradigm and experimental design The neurophysiologic investigation of the sensation of touch is non-trivial due to the large inter-individual variance of tactile perception threshold values (Park et al., 2001; Rolke et al., 2006). Prior to the fMRI experiment, sensory perception thresholds were determined for the face and hand of each subject at the planned stimulation sites by applying logarithmically-scaled VFF according to the method of limits which is commonly used in quantitative sensory testing (Yarnitsky, 1997). In order to account for the individual differences in thresholds and to evoke a genuine and distinct sensation of touch, we used individually adapted stimulus intensities for the face and hand, respectively, in each subject during fMRI (Table 1). These individual stimulation intensities were chosen well above the mechanical detection threshold but below the mechanical unpleasantness and pain thresholds in order to avoid unpleasant or painful sensations during repetitive punctate stimulation. Also, stimuli or intensities which evoked a sensation of itch, tingling, pricking or burning were excluded. During fMRI, two different areas were stimulated ipsilaterally: the face (F) about 2 cm paramedian and above the upper lip

Table 1 MNI coordinates of the local activation maxima in S1 during tactile stimulation of the face or hand for the two different study designs (Des) Stim

Subj (Gen/Seq)

Des

MNI coordinates Face

Left

CR (m/BEEB) FR (m/EBEB) MT (f/EBBE) SE (f/BEBE)

Right

BL (f/EBEB) CT (f/BEEB) JS (m/EBBE) TB (m/BEBE)

B E B E B E B E B E B E B E B E

Hand

Int

x

y

z

32

– 60 64 68

− 26 − 18 − 14

30 38 34

62 60 62 − 56 − 56 – 64 − 60 − 58 − 56 − 56

− 30 − 12 − 16 − 16 − 22

42 22 20 52 54

− 24 − 16 − 14 − 18 − 16

40 40 38 48 48

16 16 23 32 23 23 32

–

t-level – 7.76 7.21 6.77 – 5.05 8.23 4.66 12.93 10.47 – 5.50 14.73 10.20 5.32 6.10

(Area) (BA 40) (BA 3) (BA 3)

Int

x

y

z

t-level

(Area)

64

56 48 54 52 60 50 48 50 − 38 − 40 – 62 − 56 − 54 − 52 − 52

− 32 − 34 − 32 − 34 − 22 − 30 − 32 −36 − 36 − 36

58 62 62 58 56 60 64 60 70 68

(BA 2) (BA 2) (BA 2) (BA 2) (BA 1) (BA 2) (BA 1) (BA 40) (BA 3) (BA 2)

− 26 − 26 − 28 − 22 − 24

52 56 58 58 58

4.67 4.95 6.69 8.75 4.94 8.00 9.50 7.90 9.97 8.71 – 4.65 11.40 8.99 11.62 5.75

45 45

(BA 2) (BA 3) (BA 3) (BA 3) (BA 1)

45 64 64

(BA 1) (BA 4) (BA 4) (BA 1) (BA 3)

64 64

(BA 2) (BA 2) (BA 1) (BA 3) (BA 1)

Information is given on the side (Stim) and intensity of stimulation (Int), the sequence of runs (Seq) and the gender (Gen) for each subject. The Brodman areas (BA) were derived from the anatomic atlas of Talairach and Tournoux (1988). According to that atlas, the coordinates of the local activation maxima of subject JS corresponded to BA 4 (primary motor cortex) while the superposition of the activation cluster onto JS's normalized T1-weighted brain image revealed focal activation of the postcentral gyrus (S1). Note that no significant S1 activation was found for the blocked study design in two subjects during stimulation of the face and in another subject during stimulation of the face and the hand. m = male, f = female, B = blockdesign fMRI, E = event-related fMRI.

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on the left body side while the other four subjects were stimulated on the right side of the body. The side of stimulation was documented by photographs. The sequence of runs and the side of stimulation were randomized and balanced across the eight individuals (Table 1). Each run was about 7 min long (171 volumes) but the total number of stimuli applied differed between the two experimental designs. During the runs with a blocked design, tactile stimuli were applied continuously for 20 s with a frequency (f) of 4 Hz and the corresponding stimulating channel ON for 80 ms resulting in 80 stimuli per block and 400 stimuli per run and condition. As the device uses double action-cylinders instead of unidirectional cylinders with restoring springs which introduce unknown temporal latencies, switching the stimulating channel ON for 80 ms corresponds to about 80 ms of full intended pressure at the piston and approximately 80 ms stimulation time. Active blocks alternated with rest blocks of 20 s duration. During each run, five active blocks per condition (F or H) were completed in a pseudorandomized order with a maximum of two identical blocks in a row. During the runs with the event-related design, a series of eight consecutive stimuli (f = 4 Hz, ON for 80 ms) were applied in a pseudorandomized fashion allowing for a maximum of four consecutive trials with stimulating the same area (F or H). The onset of stimulation was jittered by an interstimulus interval between 7.5 s and 14.5 s. Each stimulation series, i.e. trial, was repeated 15 times for each condition yielding 120 stimuli per condition and run.

noise arising from the scanner equipment. The anatomical image was coregistered to the mean image of the functional series and spatially normalized to the T1-weighted MNI template conserving the initial resolution of 1.0 × 1.0 × 1.0 mm3. After preprocessing, the functional images of each individual were analysed by applying the general linear model as implemented in SPM2 (Friston et al., 1995b). Alternating periods of stimulation and rest during the blocked design were modeled by a boxcar vector while each short series of stimuli during the event-related design was modeled as a single trial by a stick function. Both onset functions were convolved with the canonic hemodynamic response function. Contrasts between the active condition, i.e. stimulation of the face or hand, and rest were created for both designs. One-sided t-tests were applied to these contrast images to define statistically significant activations during tactile stimulation of the face or hand. As single subjects were investigated, a statistical threshold of p b 0.001 uncorrected was considered to show significant activation during tactile stimulation. Furthermore, an extent threshold of five contiguous voxels was applied to reduce the number of false positive voxels. The thresholded activation maps were superimposed on each individual's normalized anatomical image to define the location of the local activation maxima. Additionally, the MNI coordinates of these activation maxima in S1 were converted into the space of Talairach and Tournoux (Talairach and Tournoux, 1988) applying procedures developed by Matthew Brett (http://www.mrc-cbu.cam. ac.uk/Imaging).

Functional imaging and data analysis Behavioral questionnaire Prior to the study, measurements on a water phantom and volunteers with the same set of sequence parameters were performed to test for any imaging artefacts arising from the tactile stimulation device as described above. For the fMRI experiment, the head and hand of the subject were fixed with foam pads in a relaxed and comfortable position in order to minimize involuntary motor activity (Figs. 2C/D). Subjects were instructed to keep their eyes closed during functional imaging to avoid activation of visual areas and irritation caused by watching the von Frey-filaments moving back and forth. T2*-weighted echoplanar images covering the whole brain were acquired on a 1.5 T-Siemens Symphony MRI scanner (Erlangen, Germany) using an 8-channel head coil (TR = 2.48 s, TE = 50 ms, 28 slices with 10% gap, FOV = 224 mm, flip angle 90°, matrix 64 × 64, voxel size 3.5 × 3.5 × 4.5 mm3). After the experiment, an anatomical T1-weighted image was obtained from each participant using a MPRAGE-sequence (TR = 1.52 s, TE = 3.93 ms, TI = 800 ms, flip angle 15°, matrix 256 × 256, FoV = 250 mm, 160 slices, voxel size 1 × 1 × 1 mm3). The functional images were analysed using SPM2 (Wellcome Institut of Imaging Neuroscience, London, UK, http://fil.ion.ucl.ac. uk/spm) and Matlab (The Mathworks Inc., Natick, USA). The first three images of each run were discarded from further analysis allowing the longitudinal magnetization to reach a steady state. The remaining images were realigned to the first image in order to compensate for head motion during functional imaging, and a mean image was created (Friston et al., 1995a). After normalization to the Montreal Neurological Institute (MNI) template, the functional images were spatially smoothed by an isotropic Gaussian kernel of 6 mm full-width-at-half-maximum to increase the signal-to-noise ratio (Friston et al., 1995b). A temporal highpass filter (cutoff 128 s) was applied to remove low-frequency

After the fMRI experiment, the participants had to answer a questionnaire as explained above and in order to find out whether the perceived intensity of stimulation changed significantly throughout the experiment. The questions mainly concerned the location and perceived intensity of stimulation on an 11-point analogue scale (AS: 0 = no touch; 10 = strongest non-painful touch), separately for the face and hand, and the incidence of irritating, unpleasant or painful sensations. Results Behavioral questionnaire The post-fMRI questionnaire confirmed that all participants perceived the automatically applied stimuli as genuine tactile stimuli without any sensation of itch, dysaesthesia or pain. The location of stimulation did not change during the experiment. None of the subjects reported a noticeable difference of stimulus intensity between the two different experimental designs. Six of eight participants had a strong perception of touch (ASF/H ≥ 8) during the face and hand stimulation while two individuals rated their perception with ASF/H = 4 at the beginning of the experiment. Four subjects reported no change of perceived intensity towards the end of the experiment while the remaining subjects reported a small change of one point up or down on the analogue scale. Most individuals rated the perceived intensity for face and hand stimulation identical. Only one individual reported different intensities for the stimulation of the face and hand at the beginning (ASF = 9, ASH = 10) and towards the end (ASF = 10, ASH = 8) of the experiment.

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Fig. 3. The somatosensory representation of the face (red) and hand (green) is shown for tactile stimulation of the right side. In this subject, an overlap (yellow) of the two representations is found also for S1. The activation maps are superimposed onto the individual's normalized T1-weighted anatomical image for a better anatomical localization of activations. The slice position is given in MNI coordinates. c = contralateral, i = ipsilateral, L = left, R = right.

Fig. 4. In contrast to Fig. 3, the activation maps which were generated from the blocked (red) and the event-related (green) runs are compared separately for the face (top) and the hand (bottom) representation of another subject. While there is a rather good overlap between the center of activation (particularly in cS1), the extent of activation differs between the two study designs. In this case, the event-related study design reveals a greater extent of cS2 activation within the Sylvian fissure than the blocked design.

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Tactile stimulation The punctate tactile stimulation of the upper lip and the thenar activated a spatially distributed neural network including the primary and secondary somatosensory cortex during both experimental designs. While activation of the primary sensory cortex was predominantly contralateral (Table 1), activation of the secondary somatosensory cortex (S2) extending into the posterior insular cortex was found bilaterally (Figs. 3 and 4). In a subgroup of subjects, the premotor cortex (PMC) was activated bilaterally (3 subj.) or contralaterally (1 subj.) during both experimental conditions irrespective of the study design while the thalamus was activated on the contralateral side in 2 subjects during the event-related study design. During the event-related runs, the face and the hand representation in S1 could be identified in all individuals (Table 1). In contrast, no significant S1 activation was detected during the block-wise stimulation of the face in two subjects and of the face and hand in another subject despite the greater number of stimuli (400 vs. 120). Latter subject (CT) showed an ipsilateral activation of S1 during event-like stimulation while all other individuals generally revealed stronger S1 activation on the contralateral side. It was assumed that this ipsilateral activation was due to a bilateral activation of S1 where only the ipsilateral cluster reached statistical significance. This assumption was corroborated by a trend for bilateral activation in S1 after reducing the statistical threshold to p b 0.01 uncorrected. In those individuals (5 subj.) where S1 was significantly activated during both experimental conditions and designs, it was possible to differentiate between the face and the hand representation in S1 (see the coordinates of the local activation maxima in Table 1). However, despite the punctate stimulation, an overlap between the two cortical representations can be found in some subjects as illustrated in Fig. 3. The short series of tactile stimuli during the event-related design yielded almost identical local maxima of activation in the primary somatosensory cortex as the continuous 4 Hz-stimulation during the blocked design. The Table 1 shows a good congruence between the coordinates of the peak activation for the two experimental designs, particularly with regard to the z-coordinate (see also Fig. 4). Discussion In this study, we present a new pneumatically-driven multichannel stimulation device for functional MRI. It uses logarithmically-scaled von Frey-filaments to apply standardized punctate tactile stimuli to the face and other locations of the body with a high temporal and spatial precision. Tactile stimulation of the ipsilateral face and hand yielded activation of the primary and secondary somatosensory cortex in all subjects. In a subgroup of subjects, the premotor cortex and the thalamus were activated. A block-wise tactile stimulation of the face and hand did not consistently generate significant S1 activation despite the greater number of stimuli compared to an event-like stimulation. In subjects where S1 was significantly activated during both stimulation conditions, either experimental design allowed discriminating the face from the hand representation in the primary somatosensory cortex. Tactile stimulation device The presented data show that the new tactile stimulation device appears to be a valuable tool for a detailed somatosensory mapping of the face and other body areas during functional MRI. It is safe to

operate, does not interfere with MR image acquisition and shows a high flexibility regarding the type and intensity as well as the location and temporal pattern of stimulation including the use of event-related stimulation paradigms. Transcutaneous electrical excitation of peripheral nerve endings or nerve fibres is another examiner-independent method of somatosensory stimulation during fMRI (Arthurs et al., 2004; Blankenburg et al., 2003; Del Gratta et al., 2002; Deuchert et al., 2002; Disbrow et al., 1998; Kampe et al., 2000; Krause et al., 2001; Kurth et al., 1998). It provides a tunable and spatiotemporally precise stimulation but induces a rather unspecific and unphysiologic excitation of neural afferents. Electrical stimulation may produce imaging and muscle artefacts, particularly when applied near the head coil or the face, and can be potentially hazardous for the subject. It shows a higher intrasubject variance of sensory thresholds (78%) compared to tactile (23%) or thermal stimulation (18%) (Park et al., 2001). In contrast to electrical stimulation techniques, mechanical or pneumatic vibrotactile devices selectively stimulate tactile afferents, i.e. touch-sensitive rapidly adapting cutaneous mechanoreceptors and large myelinated Aβ-afferents (Johansson and Vallbo, 1979; Park et al., 2001). For example, nonmagnetic piezoceramics achieve vibrational frequencies of 150 Hz and higher but they may be difficult to customize, and the vibrational amplitude is commonly small (Francis et al., 2000; Gizewski et al., 2005; Harrington et al., 2000; Maldjian et al., 1999). A piezoceramic transducer can cause discomfort in some subjects and the intensity of its stimulation can vary during the experiment (Harrington et al., 2000). Similar to magnetomechanical vibrotactile devices containing wire coils (Graham et al., 2001), piezoceramic stimulators require an electric driving current and usually cannot be used for a stimulation of the face. Compared to other pneumatic vibrotactile devices (Huang and Sereno, 2007; Schulz et al., 2004; Servos et al., 1999; Stippich et al., 1999; Zappe et al., 2004), the new tactile stimulator applies normalized tactile stimuli in form of von Frey-filaments which are commonly used for quantitative sensory testing (Rolke et al., 2006; Yarnitsky, 1997). The use of such stimuli will therefore allow a more quantitative investigation of the tactile somatosensory system and potentially better comparability between imaging and nonimaging experiments. Currently, an effort is made to establish the QST framework for the clinical routine (Rolke et al., 2006). From a technical point-of-view, the new stimulation device has a few advantages compared to other devices. The modular construction of the device avoids long pneumatic tubes and thereby reduces the temporal latency as well as increases the temporal accuracy of stimulation. The slim geometry of the positioning units allows directing different VFFs towards the same area of the skin and applying stimuli of varying intensity to the same spot. By changing the applicator, the new stimulation device may also be used for the application of other types of stimuli, e.g. pin-prick pain stimuli. Experimental design In order to find out which experimental paradigm might be applicable – or even favorable – for short punctate tactile stimulations, each participant performed two runs with a block-wise and two runs with an event-like stimulus application in a pseudorandomized order. Previous fMRI studies on somatosensory processing have often used a blocked design due to its robustness and efficiency while such a design is generally more susceptible to confounding effects of anticipation and habituation (for a discussion see Friston

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et al., 1999; Porro et al., 2004). Only few studies applied stimuli such as complex tactile patterns (Zappe et al., 2004) or single electrical pulses (Deuchert et al., 2002) in an event-like fashion. The present data show that both experimental designs yielded robust activations in most but not all of the participants (Table 1). A block-wise tactile stimulation failed to consistently activate the primary somatosensory cortex during both stimulation conditions (face or hand) in three individuals (CR, MT, CT) while an eventlike stimulus application yielded S1 activation in all subjects and conditions despite the smaller number of stimuli. In individuals where significant S1 activation was present during either condition, both study designs allowed discriminating the face and the hand representation in S1 reflecting the somatotopy of the primary somatosensory cortex (Fox et al., 1987; Hagen and Pardo, 2002; Penfield and Rasmussen, 1952; Stippich et al., 1999). Also, the blocked and the event-related experimental designs yielded consistent results with regard to the location of the local activation maxima (Table 1, Fig. 4) while the spatial extent of activations may differ (Fig. 4). The latter may be due to differences regarding the design efficiency and the modulatory effects of anticipation, habituation or attention (Friston et al., 1999; Porro et al., 2004). Our findings suggest that an event-related paradigm may be more sensitive for the detection of S1 activation in certain subjects as it is known to better control for such modulatory factors (Porro et al., 2004). However, these results do not support a general recommendation in favor of an event-related design due to the limited number of subjects in this study.

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The locations of the S1 face and hand representations in our study correspond well to previous data from Schulz et al. (2004) who used pneumatically-driven balloon diaphragms in combination with different imaging methods including fMRI to explore the somatosensory representation of the right lower lip and the digits 1 and 4 of the right hand. The mean z-coordinates of the activation peaks in S1 during lower lip (V3) stimulation were found between + 40 and + 45 mm while the activation maxima during stimulation of the digits were located about 10–15 mm more superior, in good congruence with our peak coordinates. A similar congruence was found between our data and the center-of-mass coordinates of the face, lip and finger representations of a single subject in a recent fMRI study by Huang and Sereno (2007). Further extending these results, Iannetti et al. (2003) revealed that stimulation of the first trigeminal division (V1) yielded a bilateral activation of S1 while a significant activation of S1 during stimulation of V3 was only found on the side contralateral to the stimulation. In our study, significant activation of S1 was also detected on the ipsilateral side during stimulation of the upper lip (V2) as well as during stimulation of the hand. Ipsilateral S1 activation had previously been described in magnetoencephalographic (Korvenoja et al., 1995), PET (Hagen and Pardo, 2002) and fMRI studies of the somatosensory system (Golaszewski et al., 2002a; Huang and Sereno, 2007). Further studies will therefore be needed to explore the role of ipsilateral activation in the primary somatosensory cortex. Activation of a distributed somatosensory network during tactile stimulation

The face representation in the primary somatosensory cortex The punctate tactile stimuli which were applied to the upper lip and thenar allowed the discrimination of the face and hand area in the primary somatosensory cortex (Table 1). The representation of the upper lip (second trigeminal division, V2) was found inferolaterally and close to the hand representation according to the somatopic organization of S1 (Penfield and Rasmussen, 1952). The results of the present study complement previous fMRI and positron emission tomography (PET) data on the somatosensory representation of the face using a manual or pneumatically-driven application of stimuli. While some of these studies convincingly demonstrated the somatotopy of the primary somatosensory cortex (Hagen and Pardo, 2002; Servos et al., 1999; Stippich et al., 1999), only a few provide anatomic coordinates of the activation cluster in S1 (Fox et al., 1987; Huang and Sereno, 2007; Iannetti et al., 2003; Schulz et al., 2004). The individual representations of the upper lip (V2) in our subjects were located close and slightly more superior to the grouprepresentations of the forehead (V1) and chin (V3) in a fMRI study on 14 healthy subjects (Iannetti et al., 2003) and the lip representations (V2/3, not further specified) of eight individuals investigated by PET (Fox et al., 1987). While Fox et al. used a 130 Hz-vibration stimulus, Iannetti and colleagues manually applied cotton–wool tips with a frequency of about 1 Hz. Iannetti et al. found a considerable overlap between the representations of the first and third trigeminal division in the inferior postcentral gyrus in proximity to the secondary somatosensory cortex. The discrete differences between our and these two studies may partly be due to the type of stimulation and the imaging modality as well as the inter-individual topographical variance of the three trigeminal representations in S1. Such an inter-individual variability of anatomical and functional representations has earlier been described by Penfield and Rasmussen (1952).

Apart from the primary somatosensory cortex discussed above, punctate tactile stimulation activated the secondary somatosensory cortex bilaterally in all eight participants similar to earlier studies (Davis et al., 1998; Francis et al., 2000; Gelnar et al., 1998; Golaszewski et al., 2002a; Graham et al., 2001; Hagen and Pardo, 2002; Hamalainen et al., 2000; Iannetti et al., 2003; Wienbruch et al., 2006). In a subgroup of subjects, also the thalamus was activated as part of a distributed somatosensory network as previously described by Davis et al. (1998). Additional clusters of activation were found in the contralateral premotor cortex during stimulation of the face and the hand in four individuals. Only few studies have so far reported activation of the premotor cortex (Golaszewski et al., 2002a; Huang and Sereno, 2007; Keysers et al., 2004) as previous reports have often focussed on the activation of primary and secondary somatosensory areas during sensory stimulation, sometimes by using a limited number of slices or a surface coil (Gelnar et al., 1998; Servos et al., 1999; Trulsson et al., 2001). Premotor activation is likely to arise from the intense anatomical connections between the premotor cortex and the primary and secondary somatosensory areas which were discovered in animal studies (see review by Romo et al., 2002). The ventral part of the PMC, which was activated during face stimulation in the present study, seems to play a major role for the sensorimotor integration of afferent sensory information during the coordination and control of orofacial movements (Dresel et al., 2005). Acknowledgments This study and the development of the new stimulation device were supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany, and the Kommision Klinische Forschung (KKF), Klinikum rechts der Isar, TU Muenchen, Germany. We thank the

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