modulation of a brain–behavior relationship in verbal working memory by rtms

Cognitive Brain Research 15 (2003) 241–249www.elsevier.com/ locate/cogbrainres

Research report

M odulation of a brain–behavior relationship in verbal workingmemory by rTMS

a , b c d* ¨Felix M. Mottaghy , Alvaro Pascual-Leone , Lars J. Kemna , Rudolf Topper ,c a a¨ ¨Hans Herzog , Hans-Wilhelm Muller-Gartner , Bernd J. Krause

a ¨ ¨Department of Nuclear Medicine (KME), Heinrich-Heine University and Research Center Julich, D-52426 Julich, GermanybLaboratory for Magnetic Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330

Brookline Avenue, Kirstein Building KS 454, Boston, MA 02215,USAc ¨ ¨Institute of Medicine (IME), Research Center Julich, D-52426 Julich, Germany

dDepartment of Neurology, Technical University Aachen, Pauwelsstr. 31, 52057Aachen, Germany

Accepted 12 June 2002

Abstract

We investigated whether the brain–behavior relationship (BBR) between regional cerebral blood flow (rCBF) as measured by positronemission tomography (PET) and individual accuracy in verbal working memory (WM) can be modulated by repetitive transcranialmagnetic stimulation (rTMS) of the left or right middle frontal gyrus (MFG). Fourteen right-handed male subjects received a 30-s rTMStrain (4 Hz, 110% motor threshold) to the left or right MFG during a 2-back WM task using letters as stimuli. Simultaneously an rCBFPET tracer was injected and whole-brain functional images were acquired. A hypothesis-driven region-of-interest-analysis of the left andright MFG BBR as well as an explorative whole-brain analysis correlating the individual accuracy with rCBF was carried out. WithoutrTMS we found a negative BBR in the left but no significant BBR in the right MFG. This negative BBR is best explained by an increasedeffort of volunteers with an inferior task performance. Left-sided rTMS led to a shift of the BBR towards the superior frontal gyrus (SFG)and to a positive BBR in anterior parts of the left SFG. With rTMS of the right MFG the BBR was posterior and inferior in the leftinferior frontal gyrus. Beyond the cognitive subtraction approach this correlation analysis provides information on how the prefrontalcortex is involved based on individual performance in working memory. The results are discussed along the idea of a short-term plasticityin an active neuronal network that reacts to an rTMS-induced temporary disruption of two different network modules. 2002 Elsevier Science B.V. All rights reserved.

Theme: Neural basis of behavior

Topic: Learning and memory: systems and functions

Keywords: rTMS; Cognition; Middle frontal gyrus; Neuroimaging; Human

1 . Introduction local cortical representational maps following performanceof a task [25]. Another one is to use the facilitatory or

Single-pulse and repetitive transcranial magnetic stimu- inhibitory effects of TMS/rTMS on ongoing or subsequentlation (TMS and rTMS) have been successfully used for cognitive tasks [18–20,24,39] to explore the functional,the study of human cortical functions [13,26,27]. There are causal link between brain activity in the targeted corticalat least two different types of paradigms that can be used region and task performance.to study the effect of TMS/rTMS on higher cognitive In the latter approach, behavioral output is measured infunctions [43]. One approach is to map the topography of the face of disruption of focal brain activity induced by

rTMS. The inference is generally made that changes inbehavior are related to the modulation of activity in the*Corresponding author. Tel.:149-2461-61-8629; fax:149-2461-61-targeted brain region. However, this is not necessarily the8044.

E-mail address: [email protected](F.M. Mottaghy). case. Firstly modulation of activity of a given cortical

0926-6410/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.PI I : S0926-6410( 02 )00196-9

mailto:[email protected]

242 F.M. Mottaghy et al. / Cognitive Brain Research 15 (2003) 241–249

region by TMS will have transsynaptic effects onto other, Transient interference with activity in the middle frontaldistant brain areas that may account for the observed gyrus (MFG) during a working memory (WM) task bybehavioral changes [28]. Secondly transient alteration of rTMS not only led to a deterioration of the performancefunction of the cortical region directly targeted by TMS is but also to a change in the activation pattern as revealed bylikely to result in a rapid change in activity within a PET. We concluded that the observed relative decrease ofdistributed network that will aim at compensating for the rCBF in the condition with rTMS of the left or right MFGTMS effect and maintaining behavioral output as put probably reflected disturbed processing of incoming mes-forward by Payne and Lomber [30] based on cooling probe sages of the involved neuronal network located in theexperiments in animals. Therefore the behavioral output – MFG. The observed decrease of the task related activity inmeasured during TMS-induced disruption of focal brain the MFG and functionally connected regions might there-activity – is mostly the expression of the brain activity in fore be due to a decrease of the outgoing impulses [19].the non-directly stimulated but functionally connected In the present study we intended (1) to establish aareas of the brain. Payne and Lomber [30] emphasized the brain–behavior relationship (BBR) in verbal workingnotion that dynamic network interactions in the brain with memory, defined by the correlation of individual regionalrapid changes in effective connectivity account for brain– cerebral blood flow (rCBF) and individual performance inbehavior relations. Testing and advancement of such a verbal working memory and (2) to test the hypothesis thatconcept requires combined analysis of behavior and brain rTMS of the left or right MFG modulates this BBR. Foractivity with and without intervention. the means of this study rTMS was continuously applied at

Lesion studies are of utmost importance to establish a frequency of 4 Hz during the performance of a 2-backcausal relationships of a given cortical lesion with a given working memory task. Simultaneously the rCBF was

15cognitive function [7,9]. However the advantage of rTMS determined using PET with [ O]butanol as a tracer (foris that it can induce a temporarily restricted circumscribed details see methods and Fig. 1).interference with cortical function described as ‘virtuallesion’ [26]. With this approach it is possible to study thecontribution of a given cortical region to a given behavior 2 . Materials and methodsin a group of ‘virtual patients’. In contrast to lesion studiesthe effect of the ‘virtual lesion’ is only temporary and 2 .1. Participantstherefore it is possible to compare the same task in thesame subject with and without ‘virtual lesion’ at different Fourteen right-handed male individuals (meancortical sites. Studies on groups of ‘real patients’ can age6standard deviation: 26.463.9 years; range 21–35contribute to the differential effect of distinct cortical years) were studied after having given written informedregions in the cortex [9], but possess several limitations. consent. The study was approved by the local ethicalFirstly the lesion is usually not restricted to one specific committee and federal authorities and was performedarea and it is difficult to compare one patient with another, according to the guidelines of the Declaration of Helsinki.as the lesion pattern is usually quite different. Secondly The subjects’ average score on the Edinburgh Handedness

¨lesion studies are usually performed in patients who Inventory [21] was 96.764.9. All subjects were naıve tosustained the lesions a long time before they are studied the aim of the study. Following the safety guidelines forand plasticity is likely to have already occurred. the use of rTMS in normal volunteers [44] we excluded

There have been several approaches to combine func- subjects with a history of neurological or psychiatrictional neuroimaging with rTMS [2,3,8,12,28,29]. Fox et al. disorders, in particular a personal history of epilepsy or[8] showed that the combination of PET and rTMS head injury.provides the opportunity to visualize both afferently andefferently connected regions and therefore can reveal 2 .2. Verbal WM taskremote excitations and inhibitions. Paus et al. [28] pro-posed that ‘‘although the TMS-induced electric fields A 2-back verbal WM paradigm was employed [36].excite neurons and/or their axons located within the Subjects were presented with 20 letters (A–D; five timesstimulated volume in both orthodromic and antidromic each letter in a randomized order) with an interstimulusdirections, the distal changes in rCBF most likely would interval of 1.5 s (presentation of the letter for 1 s and 0.5 sreflect the former because mainly the orthodromic stimula- blank screen) on a monitor, which was placed at eye leveltion leads to changes in synaptic activity’’ [28]. However 1 m in front of the subjects while they lay in the scanner.these studies [2,3,8,12,28,29] have in common that the The stimuli were presented as white letters (sans-serif font)‘resting’ human brain was stimulated, which means that on the center of a black screen resulting in a fovealparticipants were not instructed to perform any task. In a presentation at a visual angel of approximately 18. Theprevious study we demonstrated that combining positron subjects were instructed to press one of two buttons withemission tomography (PET) and rTMS allows to study the the index or middle finger of the right hand to indicatemodulation of brain function during a cognitive task [19]. whether each presented letter was the same (middle finger)

F.M. Mottaghy et al. / Cognitive Brain Research 15 (2003) 241–249 243

15Fig. 1. The rTMS train (4 Hz, 30 s), the WM task and the i.v. tracer application of [ O]butanol were started simultaneously with the PET data acquisitionprotocol. Only the first 40 s of the acquired activity images were further analyzed (see Section 2).

or not the same (index finger) as the letter presented two have been less likely with lower frequencies and beyondearlier in the sequence. A 0-back (X and Y) condition current safety standards with higher frequencies [44].served as control task. In the control task they had to press The latency of the hemodynamic response to reach itsthe left button each time an X was presented and the right plateau is known to be in the range of 4–6 s [42], althoughbutton each time a Y was presented. Subjects performed there are individual and regional differences. The transfer

15the 2-back task prior to the actual experiment several times time of [ O]butanol from the site of intravenous injectionuntil the accuracy of their answers was above 80%. They at the left cubital vein to the brain ranges between 11 andwere instructed to push the buttons as fast as possible. The 18 s (own observation). At this time, given our protocol,0-back task was presented twice before the actual experi- the brain had already been stimulated for 11–18 s. Wement. assumed that after this time, the rTMS-induced rCBF

changes and the accompanying modulation of the rCBFpattern related to the working memory task were in a

152 .3. rTMS steady state and the trapped [ O]butanol most probably15would reflect the best signal-to-noise ratio. [ O]butanol is

For each subject the active motor threshold (MT) was a freely diffusible lipophile tracer, which is almost com-determined as the lowest stimulation intensity, at which pletely extracted (|95%) during the first pass through thefive out of 10 TMS pulses over the hand area of the left capillary bed of the brain [10].motor cortex would result in a visible movement of theoutstretched arm [31]. A Magstim Super Rapid Stimulator(Magstim, UK) was utilized. Position of the TMS coil overthe MFG was confirmed by using a 3D anatomical MRIimage where vitamin E capsules were placed on previouslymarked points (F3 and F4) according to the international10–20 system [14]. If necessary, the position was cor-rected to cover the middle portion of the MFG (Fig. 2). Inthe experimental condition rTMS was applied using afigure-of-eight coil centered over the previously definedpoints F3 or F4 for stimulation of the left or right MFG,respectively. The figure-of-eight coil used was a standardMagstim coil with each wing measuring 70 mm indiameter. Subjects received a 30-s train of rTMS at 4 Hzand 110% of the individual MT intensity during the 2-backor the control condition, which was started with the bolus

15injection of [ O]butanol and stopped after 30 s (Fig. 1). Fig. 2. Before the PET experiment 3D MRIs of the subjects were takenwith vitamin E capsules in place of the areas to be stimulated (a).For the acquisition of functional data using PET it isStimulated areas were the middle part of the left and right middle frontaldesired to reach a steady state in the studied cognitive taskgyrus (MFG) and the midline prefrontal cortex. The coil was placed on

to achieve an optimized statistical result. Therefore we the previously marked points and transmission scans for the two differentdecided to give a continuous 4-Hz train showing a coil positions (b,c) were obtained. These transmission scans were used forsignificant interference with task performance. This would attenuation correction of the corresponding emission scans.


2 .4. Experimental protocol attribute anatomical areas to the activations the coordinatesof the MNI template were transferred into a standardized

In each subject eight emission scans were acquired. The stereotactic space [37] using a Matlab 5.3.1 based programtime between scans was 10 min to allow sufficient decay written by Brett et al. [5]. Within this normalization, theof radioactivity. The TMS coil was fixed within the gantry voxels of the 3D image were transformed to an isotropic

3of the PET scanner using non-absorbing material. In all voxel size of 43434 mm . A Gaussian filter with asubjects (n514) rTMS was applied either to the left or the FWHM515 mm was applied to smooth each image and toright MFG during four scans each.Verbal working memory compensate for inter-subject differences and suppress highand the reference conditions both with and without rTMS frequency noise in the images.as well as the order of stimulated regions (left or rightMFG) were alternated in a pseudorandom order and 2 .6.1. Region-of interest analysiscounterbalanced across subjects. The conditions without Based on our previous study (Mottaghy et al., 2000) werTMS were performed on each stimulation site in order to hypothesized that the main effect of rTMS would bedisentangle possible deactivations induced by the attenua- predominantly in the prefrontal cortex. A region-of-interesttion artifact produced by the magnetic coil in the gantry (ROI) was determined using a coregistered and normalizedfrom real activation changes induced by rTMS (Fig. 2). anatomical MRI as reference. An analysis of the middle

portion of the left and right MFG on the normalized2 .5. Positron emission tomography scanning images of each individual was performed using programs

written in MatLab (Version 5.3.1, MathWorks). The in-A CTI /Siemens ECAT EXACT HR1 PET-scanner with dividual rCBF value across all subjects (expressed as

32 detector rings in 3D mode was used. The axial field of percent increase of rCBF) in the ROI was calculated (forview measures 15.5 cm. The physical characteristics of this three different 2-back WM tasks as well as three differentscanner have been described [6]. Two transmission scans 0-back conditions—without rTMS, left and right rTMS)

68 68were performed with three rotating Ga/ Ge line sources and correlated with the individual accuracy in the 2-backwith the TMS coil over the left or right MFG. They were or the 0-back task. The different regression coefficients ofused for measured attenuation correction. To improve these correlations were compared implementing aZ-trans-image reconstruction quality, the transmission scans were formation usingSZ of the obtained data. The significancealigned with the emission scans before attenuation correc- threshold for these comparisons was set atP,0.01.tion was performed. On each of the eight scans an

15intravenous bolus of 555 MBq [ O]butanol (half-life 123 2 .6.2. SPM Analysiss) was administered [11]. Dynamic emission data were To further explore our data with the view towardsacquired 80 s with time frames of 20 s starting with the possible brain–behavior relationships (BBR) [40] outsideintracerebral arrival of the tracer using an absolute thres- the MFG we performed a SPM99 [38] analysis. Byhold above background count rate. For further data pro- introducing the performance of the subjects in the verbalcessing the first two scans were summed into a single WM task as an external covariate and correlating it withframe representing 40 s. Data were reconstructed using the individual rCBF changes we evaluated the correlationfiltered backprojection. All reconstruction’s used the between these two parameters. The feasibility of suchPROMIS algorithm with a radial Hann filter and an axial between-subject correlation analyses in memory researchall pass filter with a cutoff frequency of 0.33 each. All has lately been reviewed and critically discussed [38]. Forcorrections were applied, including attenuation correction this exploratory approach we set an uncorrected thresholdwith measured transmission. Image resolution was 7 mm for significantly activated voxels atP,0.005 with afull width half maximum (FWHM). The activity images minimum cluster-size ofk540. The individual accuracywere not further quantified and were regarded as estimates (percentage of correct answers) in the 2-back task or theof rCBF. reference task (Table 1) was correlated with the individual

rCBF changes in the 2-back WM-task or the reference task2 .6. Analysis in three different conditions: (1) without rTMS, (2) rTMS

of the left MFG and (3) rTMS of the right MFG. With theImage analysis was performed on a SPARC Ultra 10 aid of published Talairach coordinates [37], clusters of

workstation (Sun Microsystems) using MatLab (Version activated voxels were assigned according to their center-5.3.1 MathWorks, Natick, MA, USA) and the SPM99 of-mass correlation. We expected distinct shifts of thesoftware (The Wellcome Department of Cognitive Neurol- center-of-mass correlations. That necessitates discussion ofogy, London). All PET scans were realigned to the first the relevance of these observations with respect to theemission scan to correct for head movements. The data sets question of how distant two correlation maxima have to beof the 2-back and the reference conditions were then in order to be dissociable. In order to be able to define twocoregistered with the individual 3D anatomical MRI and dissociable maxima the distance should be more than twicetransformed into the MNI template. For the purpose to the FWHM. Our data are smoothed with a Gaussian filter


Table 1 13; right rTMS P50.0009; left rTMS P50.016). ThereIndividual accuracy (in percent correct answers) was no significant difference between the left and right

a aSubject Without rTMS rTMS left rTMS right rTMS effect on accuracy. Performance in the 0-back taskwas not affected by rTMS to any of the target areas (left0-back 2-back 0-back 2-back 0-back 2-backMFG: n514; df513; P50.78; right MFG:n514; df513;

1 100 73 95 90 95 50P50.43; Table 1).2 100 90 95 70 95 80

3 95 93 100 70 100 704 95 98 90 95 90 90 3 .2. Region-of-interest analysis5 100 93 100 95 100 906 90 75 100 70 90 80 There was a negative correlation (r520.84) between7 95 80 100 70 100 40

rCBF in the left MFG and accuracy in the 2-back WM task8 100 95 100 95 100 85(Fig. 3). In the right MFG no significant correlation was9 95 83 100 65 95 70

10 100 72 100 55 100 65 observed (r520.31). For the reference condition (0-back)11 100 87 100 75 100 80 none of the correlations was significant (20.2,r,0.2).12 100 92 100 85 100 80 With rTMS to the left MFG there was not only a reduction13 100 90 95 90 95 85

in the accuracy in the 2-back task, but also a significant14 100 98 100 80 100 80reduction (P,0.001) of the negative correlation (r52Mean 98 87 98 79 97 75

S.E. 0.9 2.4 0.8 3.4 1.0 3.9 0.67). No significant correlation in the right MFG for thea 2-back task (r520.39) and in either MFG for the 0-backrTMS left, with left MFG rTMS; rTMS right, with right MFG rTMS.

task (20.2,r,0.2) was found with rTMS to the left MFG.(FWHM 15 mm). However it has to be noted that this With rTMS to the right MFG the significant correlationapproach applies for dissociating correlation maxima with- between left MFG rCBF and accuracy was no longerin one condition. In the data presented here we compare present (r520.20). Likewise in the right MFG there wascorrelation maxima across two different conditions (with no significant correlation between rCBF and accuracy inand without rTMS). Therefore a shift of correlation the 2-back task with right-sided rTMS (r520.2). In themaxima across different conditions can be detected even reference condition there was also no significant correla-when the distance between the center-of-mass correlations tion in either MFG with right-sided rTMS (20.2,r,0.2).is smaller than twice the FWHM.

3 .3. Whole-brain analysis

3 . Results There was a significant negative correlation in the leftMFG including BA 46, 9, 8 and the left anterior cingulate

3 .1. Psychometric results (Talairach coordinates for the center of mass correlationmaximum:220/41/35;Z53.96; cluster-sizek5168; Fig.

The accuracy (percentage correct answers) in the 2-back 4a) in the 2-back working memory task without rTMS. InWM task (8762.4%) (mean6standard error) and in the the reference condition (0-back) without rTMS there was0-back task (9860.9%) was significantly different in the no positive or negative BBR above the chosen statisticalconditions without rTMS (n514; df513; P50.0005; Table threshold (see Section 2). rTMS of the left MFG led to a1). rTMS to right (7563.9%) or left MFG (7963.4%) dorsal shift of the center of mass correlation and thesignificantly impaired the accuracy in the WM task (df5 clustersize was reduced (BA 6/9:220/41/42; Z54.48;

Fig. 3. Individual mean rCBF changes (with respect to the global mean) within the left (a) or right (b) MFG are plotted over the individual accuracy (in %correct). Triangular shapes are showing the correlation (left,r520.84; right,r520.31) for the condition without rTMS, the quadrants are displaying thecorrelation of the condition with left MFG rTMS (left,r520.67; right,20.38) and the circular shapes stand for the correlation of the condition with rightDLPFC rTMS (left, r520.2; right, r520.2).


Fig. 4. Positive (green) and negative (red) correlation between rCBF and performance in the 2-back WM task without (a) application of rTMS, with rTMSdelivered over the left MFG (b), and rTMS given over the right MFG (c) are shown as an overlay on a standard surface-rendered 3D brain (P,0.005;k540).

k5133) as compared with the condition without stimula- the studied task using a cognitive subtraction method [19],tion. In addition, a positive BBR in more anterior parts of whereas the correlational approach revealed that only left-the left MFG was observed (BA 10:232/47/9;Z54.36; sided MFG involvement was differentially involved depen-k541; Fig. 4b). No significant BBR was observed in the dent on task performance. Verbal material is presumed tocontrol condition with rTMS to the left MFG. be dominantly processed in the left hemisphere in right-

With rTMS of the right MFG the center of mass handed people, yet our data suggest that the right MFGcorrelation was posterior in the left inferior frontal gyrus plays an important role in this neuronal network. Two(IFG; BA 44:228/5/26;Z53.48;k552) and additionally observations strengthen this concept. Firstly, left MFGa positive correlation in the right hemisphere of the rTMS led mainly to deactivations within the left- andcerebellum and the right middle occipital gyrus (BA 18: 40 right-sided prefrontal cortex, while right MFG rTMS not263 224; Z54.73; k5144; Fig. 4c) was observed. With only led to changes in the cortical activation patternright-sided rTMS no significant BBR in the control subserving WM locally or in homologous areas on thecondition was observed. contralateral hemisphere but also in posterior functionally

connected brain regions in the parietal cortex [19], whichare part of the theoretically defined phonological loop or

4 . Discussion phonological buffer (left hemisphere) or the visuospatialsketchpad (right hemisphere) [1,36]. Secondly with right-

4 .1. Role of the prefrontal cortex in verbal working sided MFG rTMS the correlation between left MFG rCBFmemory and task accuracy is no longer present. It seems that the

disturbed afferent input to the left MFG from the rightOur finding of a negative BBR is most likely related to homologue results in a transfer of task responsibilities into

the fact that better performers in the 2-back WM task an area, the IFG, which is activated earlier in time [34].require less recruitment of left MFG resources. In other Taken together interference with right MFG neuronalwords poorer performers tend to exhibit a higher mental activity requires more modulation at the level of theeffort and a concomitant increase of the magnitude of neuronal network involved in WM and this difference isactivity within the left MFG. This interpretation is in line also reflected in the BBR pattern.with the finding that increasing WM load, which necessita- These results support the idea that there is a bilateraltes a higher effort, leads to a greater involvement of involvement of the MFG in the studied verbal WM task. Itallocated resources within the MFG [4,33]. It is important is possible that this bilateral involvement is probably alsoto mention that a bilateral MFG activation was found in correlated to the cognitive load and the difficulty of the


task. We cannot exclude that with a 1-back condition, a modules of this active network, we could demonstratemore pronounced left hemisphere lateralization for verbal quite different backup modules still leading to a behavioralstimuli could have been demonstrated. Differential load- output above chance. In this context ‘virtual lesion induceddependent right-hemispheric MFG activations have been plasticity’ in the involved network might be compared todemonstrated in a previous study [4]. There is a modula- observations in lesion studies. While the MFG is lesstion of the BBR pattern by means of rTMS. The per- functional due to the rTMS effect, functionally connectedformance is not completely disrupted indicating that the (SFG, IFG, middle occipital gyrus and cerebellum) regionsplastic changes of the BBR are still not as effective as the probably take over in part its function by means of a (1)originally involved brain regions. The different modulation shift of the peak correlation and (2) additional correlationof the BBR might be a sign of the capacity of the brain to maxima. Left-sided rTMS led to a shift of the negativeimmediately react to a temporary disruption of a cortical BBR into more dorsal parts of the frontal cortex. Further-network by recruiting functionally connected neuronal more an adjacent region within the left SFG shows aassemblies. The breakdown of the BBR within the left positive correlation with the accuracy, which means thatMFG by right-sided rTMS might be explained by the fact higher rCBF in this region correlates with better per-that there is a high degree of coactivation between the two formance. In other words, individuals that show an in-MFGs by virtue of functional and effective connectivity creased activity in this brain region tend to have a higher[15]. It has been demonstrated that rTMS of one MFG can accuracy. This additional BBR was not seen with rTMS toexert effects on the contralateral homologous brain region the right MFG. This condition led to a ventero-posteriormost probably via transcallosal efferent connections [45]. shift of the negative BBR into the IFG and there was anA recent study demonstrated effects on a spatial and object additional positive BBR in the right middle occipital gyrus2-back working memory tasks using single-pulse TMS and the right hemisphere of the cerebellum. The formerwithout concomitant assessment of cortical activation area is part of the ventral visual stream [41] and mostpatterns [22]. The study used a protocol with bilateral probably also involved in the processing of letters in thesimultaneous single-pulse TMS at different parietal, tem- sense of an object. The functional connectivity of theporal and frontal skull sites. A segregation of cortical areas contralateral cerebellar hemisphere with the MFG has beeninvolved in object versus spatial working memory in the shown in previous studies in non-human primates and thesense of a ventral and dorsal processing system as well as role of the cerebellum in higher cognitive functions hasa common involvement of the MFG was proposed. been postulated [17,35]. The observed effects are task- andSimultaneous bilateral MFG stimulation led to an impair- brain topography-specific since the accuracy in the refer-ment of performance in both stimulus modalities. These ence task is not affected by rTMS to any of the stimulatedresults suggest a bilateral MFG involvement independent areas and there is no correlation between the accuracy andof stimulus modality; however, it is not possible to rCBF in the reference task.conclude whether there is a hemispheric difference in theinvolvement regarding the different modalities and they 4 .3. Organization of prefrontal cortex function incannot provide evidence for a chronological different working memoryactivation across hemispheres [22]. In another study on thesame verbal working memory paradigm using single-pulse There are two competing theories regarding prefrontalTMS it was demonstrated, that there is an effect on the cortex function and its related segregation in workingWM performance in both MFG, but 40 ms earlier on the memory. One model claims segregation in the prefrontalright MFG than on the left MFG (Mottaghy, Gangitano cortex in virtue of the function irrespective of the stimulusand Pascual-Leone, unpublished results). The chronometric modality (e.g., Ref. [23]), while the other model favorsdifference of the TMS effect might explain that in the segregation by modality (e.g., Ref. [16]) where eachcurrent study right-sided rTMS leads to a complete break- specific region masters all different functions. It is possibledown of the negative BBR in the left MFG, as the afferent that the backup modules within the prefrontal cortex (SFGinput from the right MFG is severely impaired. and IFG) we observed in the current study are usually

primarily involved in the processing of different mo-4 .2. Modulation of the brain–behavior relationship in dalities, i.e., spatial or objects. This idea would be sup-the left prefrontal cortex ported by another study on material specific involvement

of left prefrontal cortical regions where we could demon-In contrast to previous studies [4,33] on working strate a dorso-spatial ventro-object dissociation in a de-

memory we did modulate the effectiveness of the neuronal layed working memory task using rTMS [20]. For bothnetwork within and connected to the left or right MFG by stimulus types (spatial, face) the performance was impairedintroducing ‘noise’ into the midst of organized activity after MFG rTMS [20].[43] by means of rTMS while keeping a constant memory Several recent neuroimaging studies focused on theload. This approach allows to study short-term modulation dissociation between different WM processes such asof an active neuronal network. By inhibiting different short-term storage and executive processes. In an event-


[5] M. Brett, K. Christoff, R. Cusack, J. Lancaster, Using the Talairachrelated study on a spatial delayed WM task, it was foundatlas with the MNI template, Neuroimage [abstract] 13 (2001) S85.that activity within the MFG, i.e., Brodmann Area 46 is

[6] G. Brix, J. Zaers, L.E. Adam, M.E. Bellemann, H. Ostertag, H.only related to the response selection phase, whereas Trojan, U. Haberkorn, J. Doll, F. Oberdorfer, W.J. Lorenz, Per-during maintenance of information only activity within the formance evaluation of a whole-body PET scanner using the NEMA

protocol. National Electrical Manufacturers Association, J. Nucl.superior frontal sulcus was detected in the prefrontal cortexMed. 38 (1997) 1614–1623.[32]. In the present study we cannot distinguish between

[7] D. Caplan, N. Hildebrandt, N. Makris, Location of lesions in strokethese two basic WM functions as rTMS was delivered patients with deficits in syntactic processing in sentence comprehen-during the storage and the executive processing period. sion, Brain 119 (1996) 933–949.

[8] P. Fox, R. Ingham, M.S. George, H. Mayberg, J. Ingham, J. Roby,The results of Oliveri et al. [22], our previous [20] andC. Martin, P. Jerabek, Imaging human intra-cerebral connectivity byfinally our current results support the idea that both MFG’sPET during TMS, Neuroreport 8 (1997) 2787–2791.serve as keyplayers inn-back working memory tasks and

[9] M. Gomez-Beldarrain, J. Grafman, A. Pascual-Leone, J.C. Garcia-at least the left MFG in a delayed working memory task Monco, Procedural learning is impaired in patients with prefrontal[20] irrespective of the stimulus modality. lesions, Neurology 52 (1999) 1853–1860.

[10] P. Herscovitch, M.E. Raichle, M.R. Kilbourn, M.J. Welch, Positronemission tomographic measurement of cerebral blood flow and

15permeability-surface area product of water using [ O]water and11[ C]butanol, J. Cereb. Blood Flow Metab. 7 (1987) 527–542.5 . Conclusion

[11] H. Herzog, R.J. Seitz, L. Tellmann, G. Schlaug, A. Kleinschmidt, B.¨ ¨ ¨Nebeling, G. Stocklin, H.W. Muller-Gartner, Pharmacokinetics andBased on these findings we propose that both MFGs are

radiation dose of oxygen-15 labelled butanol in rCBF studies inmainly involved with executive processing functions in humans, Eur. J. Nucl. Med. 21 (1994) 138–143.working memory tasks irrespective of the stimulus modali- [12] R.J. Ilmoniemi, J. Virtanen, J. Ruohonen, J. Karhu, H.J. Aronen, R.

Naatanen, T. Katila, Neuronal responses to magnetic stimulationty. Other prefrontal regions are most likely segregatedreveal cortical reactivity and connectivity, Neuroreport 8 (1997)according to the processed stimulus modality [20,22] and3537–3540.

seem to be mainly involved in maintenance of information [13] M. Jahanshahi, J. Rothwell, Transcranial magnetic stimulation[32]. However we hypothesize that these regions possess studies of cognition: an emerging field, Exp. Brain Res. 131 (2000)

1–9.the ability to take over some of the MFG functions as in[14] H.H. Jasper, Report of the committee on methods of clinicalnone of the described studies there was a complete

examination in electroencephalography, Electroencephalogr. Clin.breakdown of the behavioral output. The current studyNeurophysiol. 10 (1957) 370–375.

supports the idea of the brain as a dynamic network that [15] F. Lepore, M. Ptito, H.H. Jasper (Eds.), Two Hemispheres Onecan react to a real or ‘virtual’ lesion by relocating specific Brain: Functions of the Corpus Callosum, Liss, New York, 1986.

[16] R. Levy, P.S. Goldman-Rakic, Segregation of working memoryfunctions into functionally connected brain regions. On thefunctions within the dorsolateral prefrontal cortex, Exp. Brain Res.other hand this study does not support a clear-cut left133 (2000) 23–32.hemispheric dominance in verbal working memory.

[17] F.A. Middleton, P.L. Strick, Anatomical evidence for cerebellar andbasal ganglia involvement in higher cognitive function, Science 266(1994) 458–461.

¨[18] F.M. Mottaghy, M. Hungs, M. Brugmann, R. Sparing, B. Boroo-A cknowledgements¨jerdi, H. Foltys, W. Huber, R. Topper, Facilitation of picture naming

after repetitive transcranial magnetic stimulation, Neurology 53The work was supported in part by grants of the NEI (1999) 1806–1812.

¨[19] F.M. Mottaghy, B.J. Krause, L.J. Kemna, R. Topper, L. Tellmann,(RO1EY12091) and NIMH (RO1MH57980,¨ ¨M. Beu, A. Pascual-Leone, H.W. Muller-Gartner, Modulation of theRO1MH60734). We thank L. Tellmann, E. Theelen and S.

neuronal circuitry subserving working memory in healthy humanSchaden for their help during the PET data acquisition andsubjects by repetitive transcranial magnetic stimulation, Neurosci.

Dr. M. Thall for carefully editing the manuscript. Lett. 280 (2000) 167–170.[20] F.M. Mottaghy, M. Gangitano, R. Sparing, B.J. Krause, A. Pascual-

Leone, Segregation of areas related to visual working memory in theprefrontal cortex revealed by rTMS, Cereb. Cortex 12 (2002)

R eferences 369–375.[21] R.C. Oldfield, The assessment and analysis of handedness: the

[1] A. Baddeley, Working memory, Science 255 (1992) 556–559. Edinburgh inventory, Neuropsychologia 9 (1971) 97–113.[2] D.E. Bohning, A. Shastri, K.A. McConnell, Z. Nahas, J.P. Lorber- [22] M. Oliveri, P. Turriziani, G.A. Carlesimo, G. Koch, F. Tomaiuolo,

baum, D.R. Roberts, C. Teneback, D.J. Vincent, M.S. George, A M. Panella, C. Caltagirone, Parieto-frontal interactions in visual-combined TMS/fMRI study of intensity-dependent TMS over motor object and visual-spatial working memory: evidence from transcra-cortex, Biol. Psychiatry 45 (1999) 385–394. nial magnetic stimulation, Cereb. Cortex 11 (2001) 606–618.

[3] D.E. Bohning, A. Shastri, E.M. Wassermann, U. Ziemann, J.P. [23] A.M. Owen, A.C. Evans, M. Petrides, Evidence for a two-stageLorberbaum, Z. Nahas, M.P. Lomarev, M.S. George, BOLD-f MRI model of spatial working memory processing within the lateralresponse to single-pulse transcranial magnetic stimulation, J. Magn. frontal cortex: a positron emission tomography study, Cereb. CortexReson. Imaging 11 (2000) 569–574. 6 (1996) 31–38.

[4] T.S. Braver, J.D. Cohen, L.E. Nystrom, J. Jonides, E.E. Smith, D.C. [24] A. Pascual-Leone, J.R. Gates, A. Dhuna, Induction of speech arrestNoll, A parametric study of prefrontal cortex involvement in human and counting errors with rapid-rate transcranial magnetic stimula-working memory, Neuroimage 5 (1997) 49–62. tion, Neurology 41 (1991) 697–702.


[25] A. Pascual-Leone, J. Grafman, M. Hallett, Modulation of cortical [35] J.D. Schmahmann, D.N. Pandya, Prefrontal cortex projections to themotor output maps during development of implicit and explicit basilar pons in rhesus monkey: implications for the cerebellarknowledge, Science 263 (1994) 1287–1289. contribution to higher function, Neurosci. Lett. 199 (1995) 175–178.

[26] A. Pascual-Leone, D. Bartres-Faz, J.P. Keenan, Transcranial mag- [36] E.E. Smith, J. Jonides, Storage and executive processes in the frontalnetic stimulation: studying the brain–behavior relationship by lobes, Science 283 (1999) 1657–1661.induction of ‘virtual lesions’, Phil. Trans. R. Soc. London B Biol. [37] J. Talairach, P. Tournoux, in: Co-planar Stereotactic Atlas of theSci. 354 (1999) 1229–1238. Human Brain: 3-Dimensional Proportional System: An Approach To

[27] A. Pascual-Leone, V. Walsh, J. Rothwell, Transcranial Magnetic Cerebral Imaging, Thieme Medical Publishers, Stuttgart, New York,Stimulation in cognitive neuroscience—virtual lesion, chronometry, 1988.and functional connectivity, Curr. Opin. Neurobiol. 10 (2000) 232– [38] The Wellcome Department of Cognitive Neurology, London:http: /237. /www.fil.ion.bpmf.ac.uk

¨ ¨[28] T. Paus, R. Jech, C.J. Thompson, R. Comeau, T. Peters, A.C. Evans, [39] R. Topper, F.M. Mottaghy, M. Brugmann, J. Noth, W. Huber,Transcranial magnetic stimulation during positron emission tomog- Facilitation of picture naming by focal transcranial magnetic stimu-raphy: a new method for studying connectivity of the human lation of Wernicke’s area, Exp. Brain Res. 121 (1999) 371–378.cerebral cortex, J. Neurosci. 17 (1997) 3178–3184. [40] E. Tulving, R. Habib, L. Nyberg, M. Lepage, A.R. McIntosh,

[29] T. Paus, R. Jech, C.J. Thompson, R. Comeau, T. Peters, A.C. Evans, Positron emission tomography correlations in and beyond medialDose-dependent reduction of cerebral blood flow during rapid-rate temporal lobes, Hippocampus 9 (1999) 71–82.transcranial magnetic stimulation of the human sensorimotor cortex, [41] L.G. Ungerleider, J.V. Haxby, ‘What’ and ‘where’ in the humanJ. Neurophysiol. 79 (1998) 1102–1107. brain, Curr. Opin. Neurobiol. 4 (1994) 157–165.

[30] B.R. Payne, S.G. Lomber, A method to assess the functional impact [42] A. Villringer, U. Dirnagl, Coupling of brain activity and cerebralof cerebral connections on target populations of neurons, J. Neuro- blood flow: basis of functional neuroimaging, Cerebrovasc. Brainsci. Methods 86 (1999) 195–208. Metab. Rev. 7 (1995) 240–276.

[31] J.C. Rothwell, M. Hallett, A. Berardelli, A. Eisen, P. Rossigni, W. [43] V. Walsh, M. Rushworth, A primer of magnetic stimulation as a toolPaulus, Magnetic Stimulation: motor evoked potentials, Electroence- for neuropsychology, Neuropsychologia 37 (1999) 125–135.phalogr. Clin. Neurophysiol. Suppl. 52 (1999) 97–103. [44] E.M. Wassermann, Risk and safety of repetitive transcranial mag-

[32] J.B. Rowe, I. Toni, O. Josephs, R.S. Frackowiak, R.E. Passingham, netic stimulation: report and suggested guidelines from the Interna-The prefrontal cortex: response selection or maintenance within tional Workshop on the Safety of Repetitive Transcranial Magneticworking memory?, Science 288 (2000) 1656–1660. Stimulation, June 5–7, 1996, Electroencephalogr. Clin. Neuro-

[33] B. Rypma, M. D’Esposito, The roles of prefrontal brain regions in physiol. 108 (1998) 1–16.components of working memory: effects of memory load and [45] E.M. Wassermann, T.A. Kimbrell, M.S. George, Local and distantindividual differences, Proc. Natl. Acad. Sci. USA 96 (1999) 6558– changes in cerebral glucose metabolism during repetitive transcra-6563. nial magnetic stimulation (rTMS), Neurology [abstract] 48 (1997)

[34] R. Salmelin, R. Hari, O.V. Lounasmaa, M. Sams, Dynamics of brain A107.activation during picture naming, Nature 368 (1994) 463–465.

http://www.fil.ion.bpmf.ac.uk.




modulation of a brain–behavior relationship in verbal working memory by rtms

Documents