there is considerable evidence that damage to the prefrontal cortex impairs performance on cognitive 
 set - shifting tasks [ 13 ] . 
 in one such task , the wisconsin card sorting task ( wcst ) , the subject has to match , over successive trials , a 
 test card to one of four reference cards based on a matching rule that the 
 subject acquires on the basis of feedback provided after each matching 
 response . patients with prefrontal lesions are often impaired in shifting the 
 principle of matching when the feedback provided indicates that a cognitive 
 shift in mental set is required . functional neuroimaging studies support these 
 observations [ 46 ] . 
 in a recent study , conducted with functional magnetic resonance imaging ( fmri ) , 
 we demonstrated differential activation of different parts of the prefrontal 
 cortex during the performance of the wcst . in particular , we were able to show 
 that the dorsolateral prefrontal cortex ( dl - pfc ) was engaged when feedback was 
 provided . this selective engagement of the 
 mid - dl - pfc during the provision of feedback after each matching response by the 
 subject is consistent with the proposed role of this part of the prefrontal 
 cortex in the monitoring of events 
 in working memory [ 79 ] . neuroimaging studies , however , suffer from the limitation that they provide 
 neuronal correlates of cognitive performance and can not determine a causal 
 relation between observed brain activity and cognitive performance [ 10 , 11 ] . thus the specific functional relevance of the dl - pfc in monitoring the feedback 
 provided during the performance of set - shifting tasks remains to be 
 established . here we have used repetitive 
 transcranial magnetic stimulation ( rtms ) to 
 examine this issue . the application of rtms to an area of cortex that , at a 
 particular point in time , is actively involved in the processing of task - relevant information should cause 
 performance to decline [ 1214 ] . virtual lesion  producing a 
 temporary interruption of processing . 
 in the present study , we tested the hypothesis that rtms of the human dl - pfc influences monitoring of the 
 information held in the working memory without interfering with other executive functions . to test this 
 specific hypothesis , we used a computerized 
 version of the wcst   in which different stages of task performance 
 can be isolated . we applied rtms to the right dl - pfc and over a control site 
 ( the vertex ) in three different ways : at the beginning of the feedback period , at the beginning of the matching response 
 period , and independently of task timing . our previous functional neuroimaging 
 study had indicated the involvement of the dl - pfc during the provision of 
 feedback , but not during the matching response . to further strengthen our 
 findings , we also added a control task ( figure 3(b ) ) that only required 
 matching to a twin card . ten healthy subjects ( 1933 years ) 
 participated in the study after having given written informed consent . all subjects were right - handed according to the 
 edinburgh handedness inventory , they had no previous personal or family 
 history of neurological or psychiatric disorders and were not taking any 
 medication at the time of experiments . the experiments were approved by 
 the research ethics committee of the montreal neurological institute and 
 hospital . prior to the training sessions , the subjects were instructed to perform as well as 
 they could . during the wcst , four 
 reference cards and one matching 
 card were presented on a computer screen 
 ( figure 3(a ) ) . on each trial , the subjects had to match a test card to 
 one of the four reference cards according to one of three rules : shape , number , 
 or color . the currently appropriate rule for classification is found by trial 
 and error based on the 3-second positive or negative feedback that is provided 
 immediately after each matching decision . the rule for classification changed randomly after the subject answers 
 correctly on six consecutive trials . in the control task , the matching card was identical 
 to one of the reference cards so that the subject simply selected the 
 identical card and did not have to find an appropriate rule for classification 
 as in the wcst ( figure 3(b ) ) . subjects performed the card - sorting 
 tasks in six different rtms sessions ( 2    3 design ) . each session lasted six minutes . in order to target the dl - pfc and vertex ( control site ) in all our subjects 
 ( figure 1 ) , we used a procedure that takes advantage of the standardized 
 stereotaxic space of talairach and tournoux   and frameless stereotaxy [ 18 , 19 ] . a high - resolution mri of the subjects ' brain was acquired and transformed into standardized stereotaxic space using the 
 algorithm of collins et al . . the coordinates selected for the right dl - pfc 
 ( x = 45 , y = 33 , z = 25 ) were based 
 on a previous functional activation study that yielded increased activity 
 during the feedback period . of note , in this study , we stimulated the dl - pfc 
 located in the right hemisphere because this side appeared to be more 
 consistently and robustly activated . the control stimulation site ( i.e. , vertex 
 region , x = 0 , y = 35 , z   = 80 ) was 
 also chosen based on its lack of activation during performance of the wcst in 
 these previous studies . the talairach coordinates were converted into each subject 's native mri 
 space using the reverse native - to - talairach transformation . the positioning of the tms coil over these 
 locations , marked on the native mri ( figure 1 ) , was performed with the aid of a 
 frameless stereotaxic system ( rogue research , montreal , canada ) . repetitive tms was carried out with the magstim high - speed magnetic 
 stimulator ( magstim , uk ) using a figure - eight coil . the 
 coil was held in a fixed position over the stimulation sites by a mechanical arm . it was positioned so that magnetically induced current under the coil 
 flowed in a posterior - anterior direction . stimulus intensities , expressed as a 
 percentage of the maximum stimulator output , were set at 110% of the resting motor threshold 
 ( rmt ) . rmt was defined as the lowest stimulus intensity able to elicit , in the 
 contralateral first dorsal interosseous ( fdi ) muscle , 5 motor evoked potentials 
 ( meps ) of at least 50 uv amplitude in a series of 10 stimuli delivered over the 
 right primary motor cortex at intervals longer than 5 seconds . meps were 
 recorded from the fdi muscle with agcl surface electrodes fixed on the skin 
 with a belly - tendon montage . the emg signal was filtered ( 10 hz1 khz bandpass ) , digitized at 2 khz , and displayed on a computer screen . three rtms blocks ( 6 minutes 
 each ) were applied to the right dl - pfc and the vertex during the wcst and 
 control task ( figure 2 ) . each block was separated by a 5-minute interval . in 
 each block , 5 pulse trains of 250-millisecond 
 duration were delivered at a stimulation frequency of 20 hz with between - train 
 interval dependent on the subject 's performance 
 time ( pt ) ( i.e. , 4 to 6 second ) . for each block , rtms was delivered 
 either ( block-1 ) at the beginning of each feedback period ( number of 
 trials : 72.05  0.75 ) ( figure 4 ) , ( block-2 ) at the beginning of each 
 matching period ( number of trials : 74.15  1.19 ) ( figure 5 ) , or ( block-3 ) every 6 second regardless of the moment in the task ( i.e. , desynchronized 
 condition ) ( number trials : 75.53  2.14 ) ( figure 6 ) . this last paradigm was 
 applied in order to investigate whether the rtms effect was timing dependent 
 ( i.e. , block-1 and -2 ) or not ( block-3 ) . block order was counterbalanced across 
 subjects and performed on the same day ( figure 2 ) . each 
 subject 's pt and error rate were averaged 
 within each condition ( stimulation site , timing , and task ) . pt was measured 
 from the presentation of the test card to the subject 's response , that 
 is , the selection of a reference card ( figures 
 4 , 5 and 6 ) . repeated - measures anova was used to compare the effect of the two different 
 stimulation sites , the three timings of 
 stimulation , and the two different tasks on pt . the paired samples t - test ( two - tailed ) was used to compare the mean 
 pt and error rate in the wcst between the dl - pfc and vertex stimulations during 
 the three different rtms timing conditions ( rtms during feedback , during 
 matching , and desynchronized ) . the mean pt for the control task was also 
 compared in the same manner . repeated - measures 
 anova on pt revealed a significant main effect of different tasks ( wcst versus control ; f(1,9 ) = 71.3 ; p < .001 ) confirming that the wcst was more demanding than the control task . there 
 was also a significant main effect of stimulation timing on pt ( beginning of 
 feedback versus beginning of matching versus desynchronized ; f(2,18 ) = 23.845 ; p < .001 ) indicating 
 that the timing of stimulation , overall , was an important factor influencing 
 task performance more than stimulation site ( dl - pfc versus vertex ; f(1,9 ) = 2.516 ; p = .147 ) . a significant 
 interaction effect was observed between tasks and stimulation site ( f(1,9 ) = 7.642 ; p = .022 ) indicating that stimulation site affected pt differently depending on which task was used . to test the effect of different stimulation sites within each task and stimulation timing condition , a paired t - test 
 ( two - tailed ) was performed . when comparing dl - pfc versus vertex during the 
 wcst , pt increased significantly when rtms was delivered at the beginning of 
 the feedback period ( dl - pfc = 1840.04  87.18 ms , vertex = 1682.46  61.23 ms ; t(9 ) = 2.727 ; p = .023 ) ( figure 4 ) . further analysis revealed that the magnitude 
 of impairment did not correlate with intensity of tms ( r = 0.063 ; p = .863 ) . no changes in pt were observed 
 when rtms was given at the beginning of the matching period ( dl - pfc = 1419.19  107.48 ms , vertex = 1309.87  88.07 ms ; 
 t(9 ) = 1.382 ; p = .200 ) ( figure 5 ) nor when it was desynchronized with task performance ( dl - pfc = 1739.13  148.26 ms , vertex = 1659.70  98.24 ms ; t(9 ) = 0.944 ; p = .370 ) ( figure 6 ) . when comparing dl - pfc versus vertex during the control task , rtms did not induce significant changes in pt either during the feedback ( dl - pfc = 1491.66  65.47 ms , vertex = 1459.48  59.60 ms ; t(9 ) = 0.669 ; p = .521 ) ( figure 4 ) , matching ( dl - pfc = 1084.92  62.15 ms , vertex = 1080.26  77.11 ms ; t(9 ) = 0.074 ; p = .943 ) ( figure 5 ) , or desynchronized ( dl - pfc = 1517.38  147.72 ms , vertex = 1490.91  90.36 ms ; t(9 ) = 0.314 ; p = .760 ) conditions ( figure 6 ) . the repeated - measures anova on error rate did not show any significant main 
 effect of task conditions , stimulation timing , or the sites of stimulation , nor 
 significant interaction effects except when comparing dl - pfc and vertex at the 
 beginning of feedback which came close to significance . more specifically , the 
 results obtained when performing a paired t - test 
 on the error rates between dl - pfc and vertex stimulation during the wcst wereat the beginning of the feedback ( dl - pfc = 6.10  1.71 , vertex = 3.28  1.16 ; t(9 ) = 2.120 ; p = .063 ) ; at the beginning of matching ( dl - pfc = = 4.79  1.04 , vertex = 4.86  1.27 ; t(9 ) = 0.057 ; p = .956 ) ; during the desynchronized condition ( dl - pfc = 5.210.83 , vertex = 3.56  0.51 ; t(9 ) = 1.941 ; p = .084 ) . the present study demonstrated that when rtms was 
 applied to the dl - pfc specifically during the period when the subject was 
 receiving feedback regarding his / her matching response , performance of the wcst 
 deteriorated . in fact , rtms - induced interference of dl - pfc affected performance 
 specifically during the receiving of feedback ( figure 4 ) , but not during the matching 
 response ( figure 5 ) nor when the interference was desynchronized with specific 
 stages of the wcst ( figure 6 ) . this observation of a selective rtms - induced 
 impairment in task performance during specific timing of a task has already 
 been reported in the literature in relation to several of the tasks and 
 cortical areas stimulated . for instance , rtms of the medial frontal cortex 
 affected task switching and at the time of response set switching when 
 delivered before or at time of response selection [ 10 , 22 ] . similarly , rtms affected dl - pfc 
 depending on whether this area , at a particular point in time , is 
 actively involved in processing task relevant information [ 11 , 23 ] . the 
 selective rtms - induced 
 impairment in wcst performance of dl - pfc during 
 the receiving of 
 feedback is in accordance with imaging , lesion , 
 and neurophysiological investigations . in a previous fmri study , monchi et al .   have shown that dl - pfc is engaged 
 when the subject is receiving feedback during the wcst . that is , the period 
 when monitoring of information held in working memory , as demonstrated by 
 lesion studies in monkeys , is critical [ 8 , 24 ] . this specific involvement has 
 also been confirmed with neuronal recordings from dl - pfc in monkeys during a 
 wcst analog which have shown the activation of dl - pfc cells during monitoring 
 and use of feedback information . a large population of dl - pfc 
 cells were strongly engaged in assessing behavioral outcome / feedback . interestingly , while rtms induced 
 selective impairment in wcst performance , it did not affect error rate very 
 significantly . this observation is 
 consistent with previous work by wagner et al .   who , stimulating the dl - pfc , 
 observed no significant effect on error making during the wcst . the first explanation is that error 
 making may be influenced by a different prefrontal area . in fact , lesions of dl - pfc 
 in monkeys have shown impairment in monitoring of information but did not 
 compromise maintenance of information and set shifting per se [ 8 , 9 , 24 ] , which presumably may influence 
 errors during set - shifting tasks . set shifting from a previously relevant to a 
 new response mode engages a more ventral area of the pfc ( i.e. , ventrolateral 
 pfc )   and is impaired by lesioning of 
 this area [ 24 , 27 ] . another cortical area that may 
 also have a relevant role is the medial pfc which can influence error trials 
 during performance - monitoring processes . a second explanation , considering 
 the fact that rtms - induced error trials have been reported less frequently in 
 relation to different tasks and cortical area stimulated [ 10 , 22 , 23 , 28 ] , it may also be that rtms 
 parameters ( e.g. , intensity , frequency , and unilateral stimulation ) used so far 
 in different studies have not been strong enough to induce a complete  virtual 
 lesion .  against the latter hypothesis , however , stands the fact that the 
 magnitude of selective impairment in wcst performance observed in this study 
 did not correlate with intensity of tms which at least excludes a possible 
 relationship between intensity and effect on performance . while our study provides some insights over 
 the debate regarding the role of dl - pfc during set - shifting tasks , overall it 
 emphasizes the importance of rtms in delineating the functional relevance of 
 neuronal correlates of performance observed during neuroimaging studies [ 10 , 11 ] . 
 in other words , our results suggest that just because a cortical area ( i.e. , 
 dl - pfc ) is functionally activated during the course of an executive task , 
 it may not necessarily play the same critical and essential role during the 
 whole task , and that rtms may be a useful tool to complement fmri in order to 
 infer functionality of a cortical region of the human brain . to date , the neural mechanisms underlying executive 
 processes are still poorly understood , even less are the mechanisms by which 
 rtms interferes with cortical information processing and induces such a  temporary 
 lesion . it is believed that the rtms - induced  noise  into neural processes may , 
 perhaps , be the consequence of a stimulation - induced synchronization of 
 neuronal firing disrupting active processing in the underlying cortex [ 15 , 29 ] . a valid alternative , however , may 
 also be represented by a suppression in cortical excitability ( lasting up to 1 
 second ) observed following short trains of rtms at 20 hz   or induced abnormality in the 
 release of prefronto - striatal dopamine . the latter is suggested by the contribution of the striatum and role 
 played by dopamine during the performance 
 of tasks requiring executive processes . indeed , studies of dopamine 
 depletion in nonhuman primates suggest a possible involvement of striatal 
 dopamine in set - shifting tasks [ 31 , 32 ] 
 while other neuroimaging studies have proposed that changes in striatal 
 dopamine levels can modulate certain set - shifting processes 
 and that level of cognitive impairment may be dependent on the level of 
 dopamine depletion . whatever the rtms mechanisms may be , the ultimate 
 outcome appears to be a transient interruption of the specific normal cortical 
 processing ( i.e. , provision of feedback ) in a restricted area of the prefrontal 
 cortex ( i.e. , dl - pfc ) .
early functional neuroimaging studies of tasks evaluating executive processes , such as the wisconsin card sorting task ( wcst ) , only assessed trials in blocks that may contain a large amount of different cognitive processes . 
 more recently , we showed using event - related fmri that the dorsolateral prefrontal cortex ( dl - pfc ) significantly increased activity during feedback but not matching periods of the wcst , consistent with its proposed role in the monitoring of information in working memory . repetitive transcranial magnetic stimulation ( rtms ) is a method that allows to disrupt processing within a given cortical region and to affect task performance for which this region is significantly solicited . 
 here we applied rtms to test the hypothesis that the dl - pfc stimulation influences monitoring of working memory without interfering with other executive functions . 
 we applied rtms to the right dl - pfc and the vertex ( control site ) in different time points of the wcst . when rtms was applied to the dl - pfc specifically during the period when subjects were receiving feedback regarding their previous response , wcst performance deteriorated , while rtms did not affect performance during matching either when maintaining set or during set - shifting . 
 this selective impairment of the dl - pfc is consistent with its proposed role in monitoring of events in working memory .