Increasing top-down suppression from prefrontal cortex facilitates tactile working memory

NeuroImage 49 (2010) 1091–1098

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NeuroImage j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n i m g

Increasing top-down suppression from prefrontal cortex facilitates tactile working memory Henri Hannula a,b,1, Tuomas Neuvonen a,b,g,1, Petri Savolainen a, Jaana Hiltunen c, Yuan-Ye Ma d, Hanne Antila a, Oili Salonen e, Synnöve Carlson a,c,f,⁎, Antti Pertovaara g,⁎ a

Neuroscience Unit, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland Nexstim Ltd., Helsinki, Finland Advanced Magnetic Imaging Center, Brain Research Unit, Helsinki University of Technology, Espoo, Finland d Kunming Institute of Zoology and Kunming Primate Center, Chinese Academy of Sciences, Kunming, Yunnan, P.R. China e Functional Brain Imaging Unit, Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland f Medical School, University of Tampere, Tampere, Finland g Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland b c

a r t i c l e

i n f o

Article history: Received 6 May 2009 Revised 20 July 2009 Accepted 21 July 2009 Available online 28 July 2009

a b s t r a c t Navigated transcranial magnetic stimulation (TMS) combined with diffusion-weighted magnetic resonance imaging (DW-MRI) and tractography allows investigating functional anatomy of the human brain with high precision. Here we demonstrate that working memory (WM) processing of tactile temporal information is facilitated by delivering a single TMS pulse to the middle frontal gyrus (MFG) during memory maintenance. Facilitation was obtained only with a TMS pulse applied to a location of the MFG with anatomical connectivity to the primary somatosensory cortex (S1). TMS improved tactile WM also when distractive tactile stimuli interfered with memory maintenance. Moreover, TMS to the same MFG site attenuated somatosensory evoked responses (SEPs). The results suggest that the TMS-induced memory improvement is explained by increased top-down suppression of interfering sensory processing in S1 via the MFG–S1 link. These results demonstrate an anatomical and functional network that is involved in maintenance of tactile temporal WM. © 2009 Elsevier Inc. All rights reserved.

Introduction Remembering the properties of a perceived tactile stimulus for several seconds or minutes involves tactile working memory (WM). Studies in primates and humans indicate that the S1 (Harris et al., 2002; Zhou and Fuster, 1996, 2000; however, Salinas et al., 2000), S2 (Romo et al., 2002), various regions of the prefrontal cortex (PFC; Gruber et al., 2000; Kaas et al., 2007; Kostopoulos et al., 2007; Numminen et al., 2004; Preuschhof et al., 2006; Romo and Salinas, 2003; Romo et al., 1999; Stoeckel et al., 2003) and the premotor cortex (Hernandéz et al., 2002; Romo et al., 2004) are associated with tactile

Abbreviations: DD, delayed discrimination; DW-MRI, diffusion-weighted magnetic resonance imaging; HS, hotspot; MFG, middle frontal gyrus; NHS, non-hotspot; PFC, prefrontal cortex; 1- or 2-w-rmANOVA, one- or two-way repeated-measured analysis of variance; S1, primary somatosensory cortex; SEP, somatosensory evoked potential; SFG/SFS, superior frontal gyrus/sulcus; SLF, superior longitudinal fasciculus; TMS, transcranial magnetic stimulation; WM, working memory. ⁎ Corresponding authors. Institute of Biomedicine/Physiology, POB 63, FIN-00014 University of Helsinki, Finland. Fax: +358 9 191 25302. E-mail addresses: [email protected].fi (S. Carlson), antti.pertovaara@helsinki.fi (A. Pertovaara). 1 These authors contributed equally to this study. 1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.07.049

WM. An important question for current science is: what are the specific functions that are supported by the PFC during WM task performance? The goal of the present set of experiments is to test one specific idea: that one contribution of the PFC to WM function is the gating of irrelevant sensory information so as to protect the contents of WM from interference (Chao and Knight, 1995, 1998; Gazzaley et al., 2005; Postle, 2005). A transcranial magnetic stimulus (TMS) pulse provides a possibility to assess the functional role of the stimulated cortical area in WM in human subjects. One obstacle for such a TMS study, particularly with single monophasic TMS pulses that allow spatially restricted stimulation, is finding a relevant stimulation site within the large human PFC. In the present study, we tested the hypothesis that an area within the PFC that is neurally connected to the S1 representation of the cutaneous test area might be involved in suppressing irrelevant information from interfering with WM processing, thus contributing to successful maintenance of tactile WM. In this study, the focus within the large PFC was in the middle frontal gyrus (MFG, Brodmann's area 46/6) that has been associated with WM-related activity in various types of WM tasks (Goldman-Rakic, 1987; Fuster, 1997). Since the superior frontal gyrus/sulcus (SFG/SFS) has been activated particularly during spatial WM tasks (Carlson et al., 1998; Courtney et al., 1998), we tested, for comparison, whether stimulation

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of an SFG/SFS site connected with S1 also influences maintenance of tactile temporal WM. Experiment 1 In the first experiment, we tested the hypotheses that activation of top-down control by a TMS pulse influences tactile WM maintenance, and that the top-down influence also varies with anatomical connectivity of the stimulated cortical region. We used navigated TMS with single monophasic pulses and tractography to investigate whether areas in the S1, MFG or SFG/SFS are involved in WM processing of tactile information. The S1 area corresponding to the cutaneous test site in the hand thenar (S1Hotspot (HS)) and the area in the MFG or SFG/SFS that had anatomical connectivity to the S1 thenar area (MFGHS or SFG/SFSHS, respectively) were among the cortical stimulation sites. First, we established the S1HS by determining the cortical site where the sensation of the cutaneous test stimulus could be blocked by navigated TMS (Hannula et al., 2005). We then investigated whether the S1HS and the MFGHS or SFG/SFSHS linked with it are involved in mnemonic processing of tactile temporal information. For this purpose, DW-MRI and probabilistic tractography were performed to determine connections between the S1HS and MFG or SFG/SFS. While the subjects performed a delayed discrimination WM task involving temporal discrimination of tactile signals, single TMS pulses were directed during the retention interval to the S1HS, a non-thenar area in S1 (S1Non-hotspot (NHS); 13.3 ± 3.0 mm lateral from S1HS), SFG/SFSHS, and to two tractographyguided areas of MFG, one with (MFGHS) and one without (MFGNHS) a link to the S1HS. Moreover, earlier evidence suggesting that the early retention period is more important for the consolidation of WM than the late period (Jolicoeur and Dell'Acqua, 1998; Vogel et al., 2006) raised the hypothesis that top-down control of WM maintenance varies during the retention period. This hypothesis was tested by assessing WM performance when a TMS pulse was applied to the cortical targets early (300 ms) or late (1200 ms) during the retention period. Materials and methods Participants Experiment 1 was performed with six healthy subjects (one female and five males; see Table 1 and Supplementary Fig. S1 for more details). The subjects gave their informed consent before participating in the experiment, and the experiments were approved by the ethical committee of the Helsinki University Central Hospital. The subjects were tested during a period of about 4 h. During the experiment, the subjects had earplugs to suppress noise.

Diffusion-weighted magnetic resonance imaging data acquisition A single MRI scan was performed on each participant using a 3.0 T scanner (Signa VH/I Excite II; GE Healthcare, Chalfont St. Giles, UK) equipped with an 8-channel High-Resolution Brain Array head coil (GE Signa Excite, GE Healthcare, Chalfont St. Giles, UK) at the Advanced Magnetic Imaging Centre (AMI Centre, Helsinki University of Technology, Espoo, Finland). The diffusion imaging scheme consisted of acquiring a set of 60 diffusion-weighted images with non-collinear diffusion gradients (1000 s/mm 2 , Δ = 30 ms, δ = 24 ms) and four non-diffusion-weighted images employing a single-shot diffusion-weighted echo-planar imaging sequence. The orientation of diffusion gradients was chosen to minimize the directional bias in the measurements (Jones et al., 1999). The configuration of diffusion gradients was obtained from a 60-electron repulsion scheme computed on the surface of a unit sphere. A set of 54 slices was acquired using a matrix of 128 × 128 and voxel dimensions of 1.875 × 1.875 × 3.0 mm, resulting in a rectangular field of view (FOV) of 240 mm. The echo time (TE) was 79 ms and the repetition time (TR) was 10,000 ms. A manually adjusted high order shim procedure was performed prior to acquisition of diffusion-weighted images. The images acquired axially covered the entire brain. The imaging was performed twice, resulting in a data set consisting of 128 volumes. T1-weighted 3D anatomical volume was also acquired using same field of view, matrix of 256 × 256, voxel dimensions of 0.9375 × 0.9375 × 1.0 mm (TE = 1.912 ms, TR= 9. 1 ms, IT = 300 ms, flip angle = 15°, NEX = 2). A total of 162 axial slices were collected covering the entire brain. Total imaging time was approximately 40 min. Post-processing of diffusion-weighted images The diffusion-weighted data set was corrected for subject motion and eddy currents with the FMRIB's linear registration tool (FLIRT) using the non-diffusion-weighted volume as reference. The data was prepared for probabilistic tractography by performing a Bayesian estimation of diffusion parameters with the BEDPOST tool in the FSL software package (www.fmrib.ox.ac.uk/analysis/; Behrens et al., 2003a,b). The non-diffusion-weighted volume was coregistered with the anatomical T1-weighted volume using the FLIRT tool in the FSL package (Jenkinson et al., 2002). In both of the images, the brain was extracted from skull and background voxels using the Brain extraction tool (BET, FMRIB, Oxford, UK; Smith, 2002). Navigated TMS The eXimia NBS system locates the TMS coil with an optical tracking system that can recognize the TMS tracking tools with a

Table 1 Numbers of subjects and TMS trials in different experimental conditions. Experiment

Subjectsf

WM task SEP recording WM task with distraction

5 M, 1 F 5 M, 1 F 4 M, 2 F

Number of TMS trials/subject in each target MFGHS

MFGNHS

SFG/SFSHS

S1HS

S1NHS

Sham

32a 100b 10d

32a 100b 10d

32a – –

32a – –

32a – –

32a –c –e

M = male, F = female. a In 16 of the trials/subject, TMS was presented early (at a delay of 300 ms) and in 16 trials/subject late (1200 ms) during the retention period. Additionally, there were 8 trials/ subject in which TMS was applied early (4×) or late (4×) during the retention period, but the pairs of cutaneous test stimuli were identical; these trials served as additional sham trials and were not included in the data analysis. b In SEP recordings, the modulatory effect of each TMS on the average SEP evoked by three cutaneous test pulses following the TMS pulse was compared with the average SEP evoked by three cutaneous tests applied before the TMS pulse; i.e., in each subject and in each of the four conditions (i. before TMS of MFGHS, ii. after TMS of MFGHS, iii. before TMS of MFGNHS, iv. after TMS of MFGNHS), 300 cutaneous test stimuli were presented to evoke the SEP. c Instead of sham TMS, comparisons were made between the TMS-induced modulation of the SEP evoked by cutaneous pulses applied before versus after the TMS pulse. Moreover, comparisons were made between the modulatory effects of TMS of the MFGHS versus MFGNHS. d Additionally, the session included 20 trials in which distractive tactile stimuli were presented during the memory maintenance period without an accompanying TMS pulse. Moreover, there were 20 baseline trials, in which neither distractive tactile stimuli nor TMS were delivered during the memory maintenance period. e Instead of sham TMS, the comparisons were made between the performance in the tactile distraction condition with versus without TMS. An additional comparison for the effect induced by TMS of MFGHS was provided by the result obtained by TMS of MFGNHS. f Total number of healthy subjects participating in this study was eight (age range 22–33 years). Four subjects participated in all three experiments, two subjects participated in two experiments, and two subjects participated in one experiment.

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precision of less than 1 mm (Hannula et al., 2005). The TMS coil is positioned and the stimulator output is adjusted according to the electric field display of NBS system to focus the stimulation. The eXimia NBS system takes into account the stimulator and coil parameters, and the individual head shape and size, coil location, tilting and orientation with respect to the head. The stimulation coil is modelled and the calculation of the intracranial electric field is based on the spherical model (Sarvas, 1987; Tarkiainen et al., 2003) matched to the individual magnetic resonance images (MRIs). M1HS location For standardization of the intensity of TMS across the subjects in the following blocking, WM and SEP experiments, the individual motor threshold (MT) in the thenar hand muscles was determined in all subjects. In this assessment, mapping of the M1 cortex determined the optimal coil position to produce a motor response of the relaxed abductor pollicis brevis (APB) muscle. Coil orientation was such that the induced electric field was aimed at the motor cortex, anterior to the central sulcus. First the area that produced the highest motor response was located, and the coil was rotated in 20° steps to determine the optimal coil orientation. This coil location was selected as target for determining the resting MT. Motor evoked potentials (MEP) were measured with continuous on-line surface electromyography (Mega Electronics Ltd, Kuopio, Finland). In all subjects the optimal cortical location for APB muscle stimulation (M1Hotspot (HS)) was at the lateral bend of the motor knob of the central sulcus. The maximum-likelihood threshold hunting procedure was used when assessing the MT (Awiszus, 2003). The lowest TMS intensity at which 5–9 out of 10 pulses to the optimal motor area resulted in a MEP of 50 μV (peak-to-peak) or greater was considered MT. The average motor threshold was 53.8 ± 7.3% of the maximal output of the stimulator. In the rest of the experiments, TMS was applied at 120% of MT. Cutaneous test stimulation Two Ag–AgCl skin electrodes (Ambu, Ballerup, Denmark) were fixed on the thenar area of the dominant hand and electrical stimuli were delivered via a Grass PSIU6 constant current stimulator (Grass Instruments, Quincy, MA) with a pulse duration of 0.2 ms. Tactile threshold for single pulses applied at a frequency of 0. 5 Hz was determined by the method of limits and it was defined as the stimulus intensity that was felt by the subject in at least 90% of the trials. The mean threshold intensity was 2.0 ± 0.4 mA (±SD). Determination of the S1HS An eXimia NBS Navigation system controlled eXimia TMS Stimulator (Nexstim Ltd., Helsinki, Finland) with the Focal Monopulse 8-coil was used for delivering TMS (Hannula et al., 2005). TMS was applied at 120% of the motor threshold (MT). When determining functionally the S1HS in a blocking experiment (Hannula et al., 2005), electrical test stimuli were delivered at threshold intensity to the thenar skin of the dominant hand using a constant current stimulator. To stimulate S1, TMS coil was rotated 180° so that the electric field was directed posterior to the central sulcus. TMS pulses and tactile stimuli were programmed with Presentation software (Neurobehavioral Systems, Albany, CA). Subjects were instructed to attend to the thenar test region and after each TMS pulse to answer “yes” if they felt a tactile stimulus, “no” if not, and “maybe” if they were uncertain. Initial mapping of the S1 area, with a TMS pulse intensity of 120% of MT and a time delay of 20 ms from the cutaneous stimulus, determined where the sensation block of the contralateral thenar could be achieved. The location and orientation of the coil were preserved once consistent blocking resulted from stimulation of a particular S1 location. S1HS was defined as the S1 site the stimulation of which produced at least 75% blocking of sensation of cutaneous test stimuli applied at threshold intensity.

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Tractography Connections between the S1HS and the MFG or SFG/SFS were probed with probabilistic tractography using FSL 4.0 software (FMRIB, Oxford, UK). After functional determination of the S1HS (see above), coordinates of the maximal estimated electric field produced by the stimulating coil at the S1HS were recorded. The coordinates were then transferred to anatomical T1 image, registered to diffusion space. A region with a diameter of approximately 10 mm was selected around the maximum E-field coordinate as a seed mask for tractography covering the area estimated to be activated by the stimulating pulse from the focal monophasic coil (Ruohonen and Ilmoniemi, 2002). Tracts were generated starting from the seed mask (step length = 0.5; number of steps = 2000; number of particles = 5000; curvature threshold = 0.2). Fig. 1 shows tractography results for one subject and Supplementary Figure S2 shows tractography results for seven other subjects. The probabilistic tractography algorithm produces a number of streamlines, some of which may be generated by noise in the data, motion or other sources of error (Behrens et al., 2003a). A number at each voxel represents a connectivity value, the number of streamlines passing through the voxel and the seed region. Only voxels with a connectivity value N100 were considered (Ciccarelli et al., 2006). Target selection for navigated TMS in the tactile working memory task In each target area stimulation was oriented in such a way that the stimulating current would be induced in the tissue in a direction perpendicularly with respect to the bank of the gyrus at the stimulation site (Mills et al., 1992). This coil orientation was noticed to produce the strongest and the most selective motor responses when stimulating the M1HS in the estimation of the motor threshold with the focal monophasic coil. Prefrontal regions with a connectivity to S1HS that was superior to threshold of 100 were considered as possible targets for transcranial magnetic stimulation. In each subject, two regions in the MFG (one with and one without connection to the S1HS that were defined as MFGHS and MFGNHS, respectively) and one in the SFG/SFS (with a connection to S1HS) were selected as targets for navigated TMS. In selection of MFGNHS, it was made sure that the site was in the MFG, the site had no anatomical connectivity with S1HS, and the distance MFGHS–MFGNHS was more than 13 mm to reduce the possibility that TMS of MFGNHS had a significant direct effect on MFGHS (Hannula et al., 2005). Moreover, the coil orientation in the MFGNHS condition was away from the MFGHS to reduce the possibility that MFGHS was stimulated in the MFGNHS condition. In the sham TMS condition, the TMS coil was kept about 5 cm above the head (vertex).

Fig. 1. Example of tractography in one subject. An example of a cortico-cortical connection between the MFGHS or the SFG/SFSHS and the S1HS. DW-MRI-based probabilistic tractography in one subject. Strength of connection: yellow N red. Tractography results for other seven subjects are shown in Supplementary Fig. S2.

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Studying the effect of TMS applied to various cortical areas on tactile WM Influence of TMS at five different cortical sites on tactile temporal WM maintenance was assessed in six subjects (one female and five males) using a delayed discrimination task. The five TMS targets in this WM experiment were: S1HS, S1NHS, MFGHS, MFGNHS, and SFG/ SFSHS. Additionally, sham TMS was the sixth experimental condition. In each WM session, 36 pairs of twin pulses were delivered to the thenar hand of the dominant hand. In one session, only one cortical stimulation site, or sham stimulation, was studied. The order of testing different TMS conditions (five cortical stimulation sites and sham stimulation condition) was varied between subjects so that no order of testing brain sites was used more than once. The order of presenting different stimulus conditions (such as TMS applied early versus late during the retention period) within a session was varied in a semirandom fashion. In the WM task, the subjects were presented pairs of twin pulses at a retention interval of 2 s, while real or sham TMS was applied at one of the two time points (300 ms or 1200 ms) during the retention interval (Fig. 2A). The subject's task was to determine in which one of the twin pulses the interstimulus interval (ISI) was longer by pressing a button as rapidly as possible. In the WM task, the ISI within each twin pulses varied in a semirandom fashion from 120 to 260 ms; our preceding study indicated that within this ISI range, the subjects can easily discriminate a twin pulse from a single pulse (Hannula et al., 2008). In the present study, the variability of the ISI duration applied both to the first (base) and second (comparison) twin stimuli of the task. In 32 of the 36 stimulus pair presentations, one of the twin pulses was 80 ms longer than the other one. Thus, if ISI of the first twin stimulus (base) was 120 ms, then ISI of the second twin stimulus

(comparison) was 200 ms. If ISI of the first twin stimulus was 240 ms, then ISI of the second twin stimulus was 160 ms. For control purpose, the ISI of the two twin stimuli was of same duration four times within each session; the data for this control condition (comparison of two identical twin stimuli) was excluded from the final data analysis. The subject indicated the longer twin pulse by pressing the button as rapidly as possible after presentation of the second pair of pulses. To reduce potential motor interference, the hand ipsilateral to TMS was used for pressing the mouse button. After indicating the longer twin pulse by pressing a button, the subject gave a verbal report about certainty of his assessment using a category scale: certain, uncertain, or a guess. For further analysis, the category scale was transformed into a numerical scale from 3 to 1. Statistics Statistical evaluation of the data was performed separately for each cortical region of interest using a two-way repeated-measures analysis of variance (2-w-rmANOVA) with main factors TMS (TMS of the region of interest versus sham TMS) and TMS delay during the retention period (300 ms versus 1200 ms). Post hoc testing was performed using Newman–Keuls test. P b 0.05 was considered to represent a significant difference. Results In the sham TMS condition, the mean response time (RT) in the tactile temporal WM task was 862 ms and its 95% confidence limits ranged from 708 ms to 1015 ms. When TMS was directed to MFGHS, the main effects of TMS (F1,5 = 0.56) or TMS delay (F1,5 = 0.94) on RT were not significant, while the interaction between these main factors (TMS and TMS delay) was significant (F1,5 = 17.20, P = 0.009). Post hoc testing indicated that TMS directed to MFGHS significantly reduced RT when TMS was applied at a delay of 300 ms but not at a delay of 1200 ms (Fig. 3A). TMS directed to other cortical targets (MFGNHS, SFG/SFSHS, S1HS, or S1NHS), independent of TMS delay, failed to have a significant effect on RT in the WM task (all Fs b 2.92, 2-way-rmANOVA; Fig. 3A). While the response certainty in the WM task was highest when TMS was directed to MFGHS at a delay of 300 ms (Fig. 3B), the main effects on response certainty by TMS of MFGHS (F1,5 = 0.385) or by TMS delay (F1,5 = 0.042) were not significant, nor did the interaction between TMS treatment and TMS delay reach significance in the MFGHS condition (F1,5 = 3.95, P = 0.10). TMS of MFGNHS, SFG/SFSHS, S1HS, or S1NHS also failed to produce significant effects on response certainty in the WM task (all Fs b 1.0, 2-way-rmANOVA; Fig. 3B). The lowest error rate in the WM task was observed when TMS was directed to MFGHS at a delay of 300 ms (Fig. 3C). However, the main effects on the error rate by TMS of MFGHS (F1,5 = 0.048) or by TMS delay (F1,5 = 0.782), or the interaction between main factors were not significant (F1,5 = 1.935, P = 0.22). TMS of MFGNHS, SFG/SFSHS, S1HS, or S1NHS had no significant effects on error rates in the WM task (2-way-rmANOVA; Fig. 3C). Discussion

Fig. 2. Experimental protocols for experiment 1 (A), experiment 2 (B) and experiment 3 (C). Vertical black lines = cutaneous test stimuli, red line = TMS, blue line = a distractive tactile stimulus.

Our results show that a single monophasic TMS pulse applied to the MFGHS site with a connection to the S1HS representing the tactile test stimulus facilitates performance in a tactile temporal WM task as shown by a significant decrease of the response latency. While motor facilitation might improve task performance, several aspects of the experimental design support the interpretation that the shortening of the response time was due to facilitation of a memory rather than a motor component of the task performance. First, in the WM task, the decision about the nature of the response can be made only at or after the presentation of the second tactile stimulus pair, and therefore it is unlikely that the subjects were preparing for a certain movement

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this hypothesis, we assessed whether TMS applied to the MFGHS suppresses somatosensory evoked potentials (SEPs) in S1. Material and methods

Fig. 3. TMS applied to the MFGHS early during the retention interval facilitates tactile WM. (A) Response latency, (B) subjective certainty, and (C) number of incorrect responses in the tactile WM task. TMS was applied early (300 ms; open bars) or late (1200 ms; filled bars) during the retention interval of 2 s. A and B show standardized data (100% represents the corresponding value with sham TMS). Error bars represent SEM (n = 6). ⁎P b 0.05 (Newman–Keuls test; reference: the corresponding value with sham TMS = 100%).

during the memory maintenance period. Second, the finding that the facilitatory effect was observed only when the delay between the tactile memorandum and the TMS pulse was 300 ms but not when it was 1200 ms gives further support to the hypothesis that TMS shortened the response times by facilitating the mnemonic component rather than the motor component of the memory task. Third, TMS-induced facilitation was highly selective for the cortical stimulation site: TMS had no influence on memory performance in our tactile temporal WM task when it was applied to the MFGNHS adjacent to the MFGHS, or to the SFG/SFSHS, a PFC area that has been activated particularly during spatial WM tasks (Carlson et al., 1998; Courtney et al., 1998). Experiment 2 We hypothesized that the facilitation of WM by a single TMS pulse to the MFGHS was based on the following mechanism: during the early delay period TMS suppressed the flow of distractive information in S1 and thus reduced interference with the tactile memorandum. To test

Six subjects (one female and five males) participated in experiment 2. The subjects gave their informed consent before participating in the experiment, and the experiments were approved by the ethical committee of the Helsinki University Central Hospital. The subjects were tested during a period of about 4 h. During the experiment, the subjects had earplugs. Additionally, masking noise with the same spectral content as TMS coil click was played through inserted earplugs in experiment 2. The intensity of masking noise was individually adjusted to suppress TMS-evoked clicks. The SEP evoked by electrical stimulation of the thenar skin of the dominant hand and its modulation by TMS applied to two different MFG sites (MFGHS and MFGNHS) was recorded in a separate session using a 60 Ag–AgCl electrode cap and a TMS-compatible amplifier (The eXimia EEG System, Nexstim Ltd., Helsinki, Finland; Virtanen et al., 1999). In the EEG system used for recording of SEPs, the artifact induced by TMS was gated and saturation of the amplifier was avoided by means of a proprietary sample-and-hold circuit that kept the analogue output of the amplifier constant from 100 μs preceding to 2 ms following the TMS pulse (Virtanen et al., 1999). At the start of the experiment, the electrode positions were digitized (Supplementary Fig. S3). The impedance at electrodes was kept below 5 kΩ. The EEG signals, referenced to an additional electrode on the forehead, were sampled at 1450 Hz with 16 bit resolution. Two extra sensors were used to record the electrooculogram (EOG). Cutaneous test stimuli were single electrical pulses (duration: 0.2 ms) applied to the thenar area of the dominant hand. The intensity of cutaneous test stimulation was twice the perception threshold determined prior to each session. To avoid habituation of SEPs, the subjects were asked to focus their attention on cutaneous test stimuli that were applied at intervals that varied randomly between 1000 and 1300 ms (Tomberg et al., 1989). TMS was applied so that there were always six cutaneous test stimuli between successive TMS pulses. The interval between the TMS pulse and the first successive cutaneous test stimulus following it varied randomly between 200–500 ms (Fig. 2B). It should be noted that no WM task was performed during SEP recordings. Each session, in which we assessed the effect of TMS on SEPs, consisted of four blocks. In each block, single navigated TMS pulses were applied 50 times at 120% MT either to the MFGHS or MFGNHS; each of these two cortical target areas was stimulated in two blocks (leading to a total of 100 stimulations/cortical target area). The order of stimulating different cortical areas (two areas tested twice) was varied within subjects and counterbalanced between subjects (ABAB or BABA order for four testing blocks). The duration of each block was approximately 6 min and between blocks was a pause of a few minutes, with a possibility to have refreshments. The EEG in a parietal electrode close to S1, as assessed by digitized electrodes in the MRI, was used for determining the SEP from the electrical test stimuli that were continuously applied to the contralateral hand as described above. Time window for baseline recording before each SEP was 100 ms. Before starting the off-line analysis, all trials were visually inspected and EOG or excess EMG interference was manually excluded from the average. In the off-line analysis of the data, automatic artifact detection and rejection was performed with EEGLAB toolbox (Delorme and Makeig, 2004) in Matlab (The Mathworks Inc., Natick, MA, U.S.A.). After discarded trials were excluded from the analysis, each SEP was based on the average 231 stimulus repetitions (range from 147 to 298 stimulus repetitions). The bandpass was set at 12–400 Hz and notch filter was set at 50 Hz. In data analysis, the three cutaneous test stimuli applied before the conditioning TMS were summed together as a pre-TMS SEP, whereas

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the three cutaneous test stimuli applied after presentation of the conditioning TMS pulse were summed together as a post-TMS SEP. Consequently, pre- and post-TMS SEPs consisted of 300 repetitions of the cutaneous test stimulation for both targets of TMS. Taking into account three responses to cutaneous stimulation before and after each conditioning TMS pulse allowed avoiding an excessive number of repetitions of the conditioning TMS pulse while allowing a number of repetitions of the cutaneous test pulse that was sufficient for SEP recordings. Peak SEP amplitudes were measured relative to the mean baseline voltage of the prestimulus activity. In this study, SEP measurements focused on SEP components that are considered to reflect activation of S1 (Allison et al., 1991). The peak-to-peak amplitudes were measured from the first positive deflection (P1 at a latency of about 25–50 ms) to the second negative deflection (N2 at a latency of about 60–80 ms). Statistics Statistical assessment of the P1–N2 peak-to-peak amplitudes of the SEP was performed using 2-way-rmANOVA with main factors TMS (pre-TMS versus post-TMS) and cortical stimulation site (MFGHS versus MFGNHS) followed by Newman–Keuls test. P b 0.05 was considered to represent a significant difference.

by TMS varied with the cortical stimulation site (Interaction: F1,5 = 10.07, P = 0.025). Post hoc testing indicated that TMS of MFGHS, but not TMS of MFGNHS, significantly suppressed P1–N2 amplitude of the SEP (Fig. 4). Discussion Suppression of SEPs in S1 by TMS directed to MFGHS suggests that the link between the MFG and S1 was inhibitory by nature. Moreover, it suggests that MFGHS stimulation attenuated interference of memory by decreasing activity in S1 during the memory maintenance period, providing a plausible mechanism for the memory enhancement in our study. Experiment 3 Distractive stimuli qualitatively similar to the memorandum produce the strongest interference in WM tasks (Anourova et al., 1999; Vuontela et al., 1999). To test further the hypothesis that topdown suppression via the link from the MFGHS to the S1HS reduces interference of the tactile memorandum by task-irrelevant sensory stimulation, we assessed performance in a tactile temporal WM task while interfering tactile stimuli were presented during the retention interval and TMS was applied to MFGHS or MFGNHS.

Results Material and methods P1–N2 peak-to-peak amplitude of the SEP did not vary significantly between different cortical stimulation conditions (MFGHS, MFGNHS: F1,5 = 3.62). TMS (pre-TMS, post-TMS) had a significant effect on the P1–N2 amplitude (F1,5 = 8.49, P = 0.033) and this effect

Six subjects (two females and four males) wearing ear plugs participated in experiment 3. The subjects gave their informed consent before participating in the experiment, and the experiments were approved by the ethical committee of the Helsinki University Central Hospital. The subjects were tested during a period of about 2 h. In experiment 3, the tactile WM task was performed as described in experiment 1, with the following exceptions. There were two cortical stimulation sites (MFGHS and MFGNHS), each of which was tested twice within the experiment. The order of testing the two brain areas was varied within subjects and counterbalanced between subjects as in experiment 2. The first cutaneous twin stimulus was followed by TMS at a delay of 300 ms accompanied by a distractive tactile stimulus at a delay of 500 ms, distractive tactile stimulus alone at a delay of 500 ms, or neither (Fig. 2C). The distractive tactile stimulus was an identical electric pulse as the single pulse of the actual test stimulus (twice the threshold intensity) and it was delivered to the cutaneous test site through the same electrodes as the cutaneous test pulses. The subject's task was to indicate the cutaneous twin pulse with a longer ISI by pressing a button as rapidly as possible. Statistics In statistical assessments, RTs obtained in the two TMS conditions (MFGHS and MFGNHS) accompanied by tactile distraction were compared with the response times obtained in the tactile distraction alone condition using one-way rmANOVA followed by Newman– Keuls test. P b 0.05 was considered to represent a significant change. Results

Fig. 4. TMS applied to the MFGHS reduces S1 activation. (A) The mean SEP in one individual before (blue) and after (red) a TMS pulse applied to the MFG site with a connection to S1. Cutaneous test stimulation was applied at time point 0, and each trace represents the mean response to 250–300 stimulus repetitions. (B) The mean P1–N2 peak-to-peak amplitude of SEP following a TMS pulse directed to the MFGHS or MFGNHS. Error bars represent SEM (n = 6). ⁎⁎P b 0.01 (Newman–Keuls test; reference: the corresponding value before TMS = 100%).

TMS had a significant effect on the RT in a WM task that was accompanied by tactile distraction (F2,5 = 5.22, P b 0.03). Post hoc testing indicated that RT was significantly decreased by TMS of MFGHS, but not by TMS of MFGNHS (Fig. 5). Tactile distraction prolonged the mean RT by 5% when compared with the baseline condition without tactile distraction or TMS (not shown). General discussion It might be expected that a TMS pulse applied at a sufficient intensity to a cortical area critically involved in tactile WM would

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Fig. 5. TMS applied to the MFGHS reduces the distracting influence of task-irrelevant tactile signals on WM. The mean RT in the tactile WM task with tactile distraction. Error bars represent SEM (n = 6). ⁎P b 0.05 (Newman–Keuls test; reference: 100% (the dotted line) = RT with tactile distraction but without TMS).

disrupt neuronal activity maintaining the mnemonic signal and, consequently, lead to impairment of WM, as a biphasic TMS pulse applied over the dorsolateral PFC did in a sequential-letter recognition study (Mull and Seyal, 2001). The currently used monophasic TMS pulse, in contrast, enhanced performance in a tactile temporal WM task when applied to the MFG, a prefrontal area that has been associated with WM (Fuster, 1997; Goldman-Rakic, 1987). Stimulation of the PFC improved memory performance only when the TMS pulse was applied to the MFGHS indicating that the MFG–S1 connection was critical for the improvement of tactile temporal memory performance. Previous neuroanatomical observations in non-human primates indicate that the PFC and S1 have reciprocal cortico-cortical connections (Preuss and Goldman-Rakic, 1989). In line with this, our tracking results visualized a fiber bundle running in an anterior–posterior direction between the MFG and S1 (Fig. 1B). This fiber bundle coincided with the superior longitudinal fasciculus (SLF). Therefore, it may be proposed that a cortico-cortical MFG–S1 projection along the SLF was mediating the TMS-induced enhancement of WM, although we cannot exclude contribution of pathways relaying through other brain areas. It was recently shown that structural abnormalities in the SLF correlated with performance in verbal WM (Karlsgodt et al., 2008). This further supports the proposal that an MFG–S1 connection along the SLF was contributing to enhancement of WM. In line with this proposal, patients with a prefrontal lesion had enhanced amplitudes of SEP components reflecting S1 activity (Yamaguchi and Knight, 1990), while stimulation of the MFG–S1 connection reduced the amplitude of SEP components reflecting S1 activity in the present study. Furthermore, the most prominent change in WM performance of monkeys or humans with bilateral PFC lesions has been an increased impairment of memory maintenance by distractive sensory signals during the delay period of a WM task (Chao and Knight, 1995, 1998; Malmo, 1942). Importantly, in the present study TMS to the MFGHS improved WM performance not only in a baseline condition but also when tactile distraction interfered with memory maintenance (Fig. 5). Together, these findings further support the proposal that suppression of interfering activity in S1 during memory maintenance explains the facilitation of tactile WM by TMS of MFGHS. Previous results indicate that WM performance is most sensitive to distraction early in the delay period and that activity in the dorsolateral PFC early during the delay period predicts WM performance (Ranganath et al., 2005). Moreover, it has been shown that sustained MFG activity before (early during the retention interval), not after, presentation of the distractive stimulation corresponded with resistance to distraction (Sakai et al., 2002). These previous findings are in line with our current results showing that stimulation of the MFGHS early, not late, during the retention period improved WM performance. It may be suggested that topdown control that promoted WM performance during the early

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retention period contributes to consolidation of information into WM for which the early memory maintenance period is known to be critical (Jolicoeur and Dell'Acqua, 1998; Vogel et al., 2006). In an earlier study, a biphasic TMS pulse disrupted vibrotactile WM when applied at a delay of 300–600 ms approximately to S1 (Harris et al., 2002). In the present study, navigated delivery of a monophasic TMS pulse to the S1HS representing the hand thenar area where the tactile test stimulus was applied did not impair memory performance. Perceptual unlike WM processing of tactile temporal information, however, was impaired when TMS was applied exactly to the S1HS at a delay considerably shorter than in the present study (b20 ms [Hannula et al., 2008] versus 300 ms, respectively). While a number of previous studies have suggested that the cortical network underlying tactile WM involves S1 (Harris et al., 2002; Zhou and Fuster, 1996, 2000; Gruber et al., 2000; Preuschhof et al., 2006), the present results indicate that the location or extent of the neural circuitry contributing to tactile temporal WM in S1 dissociates at least partly from that underlying perception and temporal discrimination of tactile stimuli. Interestingly, Romo and coworkers found single units with the capacity to code vibrotactile WM in the primate S2, PFC and premotor cortex rather than S1 (Hernandéz et al., 2002; Romo and Salinas, 2003; Romo et al., 1999, 2002, 2004). In the current study, the mean distance between the MFGHS and MFGNHS was 18.1 ± 2.1 mm. Our earlier study indicated that the spread of the blocking effect by a monophasic TMS pulse in the cortex was less than 8–13 mm when the direction of electric field remained the same (Hannula et al., 2005). Thus, it is unlikely that stimulation of the MFGNHS would have had a significant effect on the MFGHS. The direction of the monophasic TMS pulse is also an important parameter in determining which cortical area is activated (Hannula et al., 2005). In the present study, the direction of the monophasic TMS pulse applied to the MFGHS was different from the direction of the TMS pulse applied to the MFGNHS. It should also be noted that the direction of the monophasic pulse applied to the MFGHS was away from the premotor cortex. For these reasons, it is likely that the TMS-induced improvement of WM performance in the present study was due to stimulation of the MFGHS rather than stimulation of the MFGNHS or the premotor cortex. When the base stimulus in a delayed discrimination WM task is kept constant, the subject may solve the task with information of the second stimulus alone (Hernandéz et al., 1997) and then, WM is not necessary to solve the delayed discrimination task. In the present study, results of our preceding study (Hannula et al., 2008) were used to choose twin pulses for cutaneous test stimulation. The twin pulses used in the present study could easily be discriminated from single pulses. The ISIs of the cutaneous twin pulses in both the base and comparison stimulus varied semirandomly between 120–260 ms, with the rule that the difference between the ISIs of the base and the comparison stimulus pair was always 80 ms, except for a few trials, where the ISIs of the base and the comparison stimulus pair were identical. For these reasons, it is not possible that the subject could have solved the task with information of the second twin pulse alone, but the results of the current delayed discrimination WM task truly reflect mnemonic processing and its modulation by TMS. Conclusions Earlier studies indicate that top-down suppression plays an important role in WM performance (Gazzaley et al., 2005) and PFC lesions increase distractibility of WM maintenance by task-irrelevant sensory stimuli (Chao and Knight, 1995, 1998; Malmo, 1942). Our results extend these previous findings by showing that the tractography-indicated connection between the MFG and S1 provides a neuronal substrate for top-down control of the tactile WM circuitry that improves mnemonic processing of temporal information by suppressing tactile interference. Furthermore, the results demon-

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