UNIVERSITY OF LONDON UNIVERSITY COLLEGE LONDON MSC IN COGNITIVE NEUROPSYCHOLOGY
THE EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION OVER THE DORSOLATERAL PREFRONTAL CORTEX DURING A WORD-STEM COMPLETION TASK
Manos Tsakiris Supervisor: Anthony I Jack & Patrick Haggard Date : 22 August 2001
Contents
Summary 1. Introduction 2. Pilot Study 2.1. Method 2.1.2. Subjects 2.1.3. Design 2.1.4. Procedure 2.2. Results
3. Main Experiment 3.1. Method 3.1.2. Subjects 3.1.3. Design 3.1.4. Procedure 3.2. Results
4. Discussion 5. Conclusions 6. References 7. Appendix I : List of Stimuli 8. Appendix II : Instructions for the Pilot Study 9. Appendix III : Instructions for the Experiment
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Summary In the perceptual version of the Jacoby
stimulation was delivered at 210msec after the
Exclusion task (Debner & Jacoby, 1994), a
presentation of the stimulus at a level that was
masked word is presented (e.g. ‘table’), and
close to significance. The design of the main
immediately afterwards a word stem appears
experiment was informed by the results of the
(e.g. ‘tab__’), which participants are asked to
pilot study and the magnetic stimulation was
complete with a word other than the masked
delivered at 210msec after the presentation of
word (e.g. ‘taboo’ would be an appropriate
the word and at 30msec after the appearance
response). The completion of the stem
of the word-stem. The present study was
following
deigned in relation to
exclusion
instructions
requires
different functional
holding information ‘on line’, search for
accounts that have been proposed for left
appropriate
of
DLPFC: the working-memory hypothesis
appropriate responses and suppression of the
(Petrides, 1996) and the ‘response-selection’
‘prepotent’ response (i.e. the word already
hypothesis (Frith, 2000). Different timings of
presented), generation of a verbal response
stimulation, different sites of stimulation and
and monitoring of responses. Evidence from
different measures of exclusion performance
PET, fMRI and TMS studies suggest that the
were used in order to clarify the exact
dorsolateral prefrontal cortex (DLPFC) is
functional role of left DLPFC during the
involved in the maintenance of information
Jacoby exclusion task. Statistical significant
‘on line’ (working memory) and in various
differences were observed only for the median
executive processes that are required for
reaction time. Stimulation over the left
successful
Jacoby
DLPFC at 30msec after the appearance of the
exclusion task (Frith, 2000 ; Jahanshahi et al.,
stem increased the median reaction time
1998 ; Petrides et al., 1993a,b). We examined
suggesting
the
transcranial
selection processes and not working memory
magnetic stimulation (TMS) over the left or
per se. However, the absence of statistical
right DLPFC or medial frontal cortex during
significant differences for various measures of
the Jacoby Exclusion task in healthy normal
exclusion performance do not allow us to
participants. A pilot study was conducted in
provide a clear interpretation of the results. A
order to explore the time window during
review
which the contribution of left DLPFC is
prefrontal sites suggest that only rapid-rate
essential for successful performance in the
TMS can produce cognitive effects. Thus, a
Jacoby Inclusion and Exclusion task. No
follow up experiment with the use of rapid-
statistical
were
rate TMS is required in order to clarify the
obtained, but a multivariate analysis of
functional involvement of left DLPFC during
variance indicated that TMS over lDLPFC
the Jacoby Exclusion Task.
performance
effects
affected
responses,
of
selection
in
single-pulse
significant
exclusion
the
differences
performance
when
3
of
that
TMS
previous
affected
TMS
response-
studies
over
1. Introduction The study of unconscious processes has recently focused on how perception can be influenced in opposite ways by consciously and unconsciously perceived information (Debner & Jacoby, 1994; Merikle, Smilek & Eastwood, 2001). This has resulted in the development of measures of awareness that involve more complex processes than those required by the straightforward measures of awareness used in the past, such as forced-choice identification tasks. One measure that has been widely used is the Jacoby Inclusion and Exclusion task (Jacoby, 1991; Jacoby, Toth & Yonelinas, 1993), which was originally developed for the investigation of the conscious and unconscious influences of memory. The distinguishing characteristic of the Exclusion task is that subjects are instructed to avoid using words that they have seen before. In the perceptual version of the Jacoby exclusion task (Debner & Jacoby, 1994), a masked word is presented (e.g. ‘table’), and immediately afterwards a word stem appears (e.g. ‘tab__’), which participants are asked to complete it with a word other than the masked word (e.g. ‘taboo’ would be an appropriate response). Following exclusion instructions, subjects are required to generate and select an alternative response to the response that is ‘prepotent’ (already in mind). This places the conscious process of inhibition or exclusion in opposition to the non-conscious and natural tendency to complete the stem with the word seen before. This measure can be used either in conjunction with the Inclusion task (where subjects are to complete the stem with the word seen previously) to estimate the separate contributions of conscious and unconscious influences (the ‘process dissociation procedure, e.g. Jacoby, Toth & Yonelinas, 1993) or by itself to estimate the relative contributions of conscious and unconscious influences (Merikle, Joordens & Stolz, 1995). A number of different and complementary processes may be involved in the Jacoby exclusion task: (1) holding on-line of the stimulus in working-memory, (2) adoption of a production strategy that will involve either the (a) search for appropriate responses, (b) selection of appropriate responses and/or (c) suppression or ‘prepotent’ responses, (3) generating a verbal response, (4) monitoring the output, and (5) modifying or switching production strategies if the responses violate the experimental instructions. Various studies and reviews of the literature suggest that DLPFC is involved in these executive processes (Frith et al., 1991a; Henson et al., 1999;
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Jahanshahi et al., 1998; Nathaniel-James, Fletcher & Frith, 1997; Petrides et al., 1993a; Petrides et al., 1993b; for a review see Frith, 2000). Jack and Shallice (2001) characterized the Jacoby exclusion task as a Type-C Process. Type-C processes are defined as “processes that can only operate effectively on information when normal subjects report awareness of that information” (Jack & Shallice, 2001, p.171).1 In the Jacoby exclusion task, “awareness of a stimulus is inferred from the ability to ‘consciously’ avoid giving that stimulus as a completion of the stem, whereas non- conscious processing of the stimulus is evidenced by the ‘automatic’ tendency to repeat the stimulus presented” (Jack & Shallice, 2001, p.166). The theoretical framework that is used to understand conscious and non-conscious processes is provided by the Supervisory Attentional System (SAS) (Shallice, 1988). Type-C processes are hypothesized to involve the SAS, leading directly to the selection in contention scheduling of a schema for thought or action. This theoretical framework can be elaborated by work on localization of the functional role of prefrontal cortex. According to Frith (2000) the key operation of modulation of lowerlevel schemas by the SAS can be localized. Frith (2000)
reviewed a series of
neuroimaging experimemts where the “sculpting of the response space” was the key process. Various tasks that involved, among others, the generation of a willed action (Frith et al., 1991a), the generation of a response when strong pre-potent tendencies exist (Nathaniel-James, Fletcher & Frith, 1997), random generation of responses (Jahanshahi & Dirnberger, 1999; Jahanshahi et al., 1998), studies of encoding (Fletcher, Shallice & Dolan, 1998), carrying out novel operations (Dolan & Fletcher, 1997), were correlated with activation in a region of left DLPFC involving the middle and inferior frontal gyri (BA 46/9 and BA 44/45 respectively). Moreover, lesions in the left frontal lobe of right-handed patients have been shown to produce a decrement of “word fluency” (Milner, 1964,1982; Perret, 1973). Benton (1968) further confirmed the dependence of word fluency on the integrity of the left frontal lobe with the finding that bilateral frontal lesions do not entail a greater impairment of performance than unilateral, left frontal lesions. Perret (1973) tested 118 patients with circumscribed lesions on a modification of the Stroop-Test. The deficit in word fluency after left frontal lesions was confirmed and the results corroborated the hypothesis of the role of the frontal lobe in the adaptation of 1
According to Jack and Shallice (2001), prototypical type-C processes are : ‘conscious reflection’, recognition of stimuli, episodic memory and autonoetic consciousness.
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behavior to unusual situations, the left frontal lobe being of fundamental importance when verbal factors are involved. Frith et al. (1991b) examined the role of prefrontal cortex in the generation of verbal responses which are minimally specified by external cues, in other words responses demanding intrinsic generation. Intrinsic generation of a word (verbal fluency) was associated with an increase in left DLPFC activity (Brodmann area 46), and a bilateral decrease in activity in auditory and superior temporal cortices. Conversely, when subjects made lexical decisions about words that were heard, there was an increase in superior temporal activity with no change in BA 46. Frith et al. (1991b) suggested that the superior temporal regions are the site of stored word representations and that inhibitory modulation of these areas by the left prefrontal cortex is the basis of intrinsic word generation. One technique that can be of value in examining the specific role played by DLPFC is transcranial magnetic stimulation (TMS). TMS can be used to transiently disrupt the function of a given cortical area by creating a temporary, ‘virtual brain lesion’ (Amassian et al., 1989; Amassian et al., 1991; Day et al., 1989; Grafman et al., 1994; Jahanshahi et al., 1998; Pascual-Leone et al., 1999; Paus et al., 1997 ; Walsh & Rushworth, 1999). In this fashion TMS allows the study of the causal role of a given cortical region to a specific behavior in the healthy human brain. The advantage of TMS is that it incorporates a high degree of spatial and temporal specificity, and even though the spatial and temporal resolutions are not unique to this technique, TMS can be used as a temporary interference technique and thus it has a functional and cognitive resolution with which one can address questions beyond the range of other neuroimaging and patient studies (Walsh & Rushworth, 1999). With TMS it is possible to disrupt the functioning of specific cortical areas at particular time-points during the performance of cognitive or motor tasks. Studies of TMS over prefrontal sites have focused on investigation of disruptive effects of TMS on specific aspects of cognitive function, such as interference with free recall (Grafman et al., 1994), working memory (Mottaghy et al., 2000; Pascual-Leone & Hallet, 1994), implicit learning (Pascual-Leone et al., 1996), random-number (Jahanshahi et al., 1998) or letter- (Jahanshahi & Dirnberger, 1999) generation tasks (for a review see Jahanshahi & Rothwell, 2000) In the present study we examined the effects of single-pulse TMS over the left DLPFC on the Jacoby exclusion task and compared it with stimulation over the right DLPFC and medial frontal cortex. The first experiment to be described was a pilot 6
that was conducted in order to explore the time window during which the contribution of the left DLPFC is essential for successful performance in the Jacoby inclusion and exclusion task. TMS was applied in six different timings in order to define the timepoints at which TMS was effectively affecting performance in the Jacoby exclusion task. The results of the pilot informed the design of the main experiment that was conducted in order to advance our understanding of the precise functional role of the left DLPFC. The main theoretical question that will be addressed is whether TMS over lDLPFC during a word-completion task affected the active maintenance of information in the working-memory system or the response selection processes. We employed several different measures of exclusion performance (see below, sections 2.2. and 3.2) that can be considered as indices of some of the processes involved in the Jacoby exclusion task.
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2. Pilot Study 2.1. Method 2.1.2. Subjects Eight English native speakers took part in this study. All volunteers were healthy normal individuals (six female, two male) who had no previous history of neurological, psychiatric or physical illness or head injury, and were not taking any medication. Their mean age was 32.5 years (SD=11.1, range = 22-52). 2.1.3. Design A within-subject repeated measures design was used. All participants took part in all conditions of word stem completion. The design was 2x2x6 and there were a total of 24 experimental conditions. Subjects had to complete a three-letter word stem either by using the word they saw (inclusion blocks) or by using any other word except from the word they saw (exclusion blocks). TMS was delivered over left or right DLPFC and the stimulation was delivered in six different timings. The first three timings were after the presentation of the word (30ms, 110ms, 210ms) and the second three timings were after the presentation of the stem (30ms, 110ms, 210ms). All participants first performed two train blocks. The order of runs with TMS over the two target sites and at the six different timings were randomized across participants. 2.1.4. Procedure Following guidelines set out by the Joint UCL/UCLH Committees on the Ethics of Human Research, London, which approved the study, informed consent was obtained from all participants. Participants were asked to complete a three-letter word stem, following the instructions that were given to them at the beginning of each block, for a total of 384 trials.1 On each trial, a word was presented and masked. The first mask appeared for 500ms just before the word and it was a string of letters (e.g. ‘jkjkjkjk’), then the word appeared for 30 ms (e.g. ‘taboo’) and finally the second mask appeared for 500ms (e.g. ‘lflflflflf’). Immediately following the mask, the first three letters of the word (e.g. ‘tab’) were presented again and participants were asked to complete the word stem according to the instructions by speaking aloud in a 1
Appendix I contains the list of stimuli presented.
8
microphone. At each block, participants were asked to follow either inclusion or exclusion instructions. Appendix II contains the instructions given to participants before the experiment. In the inclusion instructions, participants were asked to complete the word stem with the word they saw or they thought they saw. For example, if the word presented on the trial was ‘frigid’, then immediately following the presentation of ‘frigid’, the letter stem ‘fri-‘ was presented and they were asked to complete it with the word ‘frigid’. In case they have not seen the word, they were asked to complete the word stem with the first word that came to their mind. In the exclusion instructions, participants were asked to complete the word stem with the first word that came to their mind except the word that had just been presented.
For example, if the word presented on the trial was ‘frigid’, then
immediately following the presentation of ‘frigid’, the letter stem ‘fri-‘ was presented and participants were asked to use any word other than the word that had just been presented to complete the word stem. For example, they could complete the word stem with ‘fright’, ‘fringe’, ‘frites’ or even ‘Friday’ but not with ‘frigid’. In case they have not seen the word, they were asked to take a guess and complete the stem. Ninety-six trials (i.e. ¼ of trials) were base trials. The word stem was not relevant to the word presented and participants were asked to complete the presented word stem with an appropriate response. As soon as they have completed the stem, participants were asked to answer a multiple choice question, designed so as to provide us with a subjective measure of awareness: (a) I saw the word clearly, (b) I could identify the word, (c) I saw something, (d) I saw nothing, (e) I made a mistake. As soon as they chose one of the above answers, they proceeded to the next trial. The schematic representation of the experimental procedure is shown on Fig.1. Figure 1 Experimental Procedure Stimuli
Time
st
nd
1 Mask
Word
2 Mask
Stem
(500ms)
“table”
(500ms)
“tab-“
-500ms
0ms
30ms
110ms
210ms
↑
Awareness Question
390ms 0ms
↑
Subject’s Response
30ms
110ms
210ms
↑
↑
↑ ↑
TMS
9
For each participant, the active motor threshold was established using the criterion of the lowest intensity of stimulation that would result in a visible movement of the outstretched right arm following stimulation over the hand area of the left motor cortex. The mean active motor threshold for the participants was 34% (range = 30%-41%) of maximum stimulator output. TMS was given at each participant’s individually determined active motor threshold increased by 120%. The mean level of TMS output used was 40% (range = 32%-50%,) of maximum stimulator output. For two participants the increase of 120% was uncomfortable and thus TMS output was reduced to the level at which participants could tolerate the stimulation without feeling any distress. TMS was given with a figure-of-8 coil, which allows more focal stimulation than a round coil. The tip of the middle bar of the figure-of-8 coil was lined up with F3 or F4 (8cm anterior to the vertex and respectively 7cm to the left of the midline) for stimulation of the left and right DLPFC respectively, following instructions given in previous studies of TMS over the left and right DLPFC (Jahanshahi et al., 1998; Jahanshahi & Dirnberger, 1999). Despite the possibility of individual differences, on the basis of the co-ordinates of a stereotaxic atlas (Talairach & Tournoux, 1988), these points would be considered to be over the left and the right DLPFC. The direction of current flow in the coil was such that current flow in the underlying cortex was anterior to posterior, which is opposite to the posterior to anterior direction of current flow optimal for stimulation of the motor cortex. This direction of current flow was selected partly to prevent or minimize activation of the motor cortex.
2.2. Results Measures of Exclusion Table 1 presents the means of exclusion and inclusion performance for each condition. Note that perfect inclusion performance equals to 1.00 (i.e. subjects completed successfully all the stems with the presented words), whereas perfect exclusion performance equals to 0.00 (i.e. subjects completed successfully all the stems with words other than the ones they saw). The mean baseline exclusion performance across experimental conditions was 0.2.
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Table 1 Exclusion and Inclusion Performance in Test Trials Exclusion
Inclusion
Exclusion
Inclusion
lDLPFC
lDLPFC
rDLPFC
rDLPFC
Mean(SD)
Mean(SD)
Mean(SD)
Mean(SD)
30ms
.1937 (.104)
.5488 (.288)
.1513 (.122)
.6450 (.211)
110ms
.2113 (.073)
.4588 (.190)
.1513 (.103)
.5175 (.190)
210ms
.2613 (.073)
.5675 (.223)
.2300 (.149)
.4713 (.290)
30ms
.1500 (.087)
.4813 (.199)
.1675 (.137)
.5475 (.298)
110ms
.1325 (.109)
.5250 (.219)
.1863 (.176)
.4575 (.249)
210ms
.2175 (.133)
.4900 (.263)
.2050 (.154)
.4975 (.228)
Time TMS
[Word appears]
[Stem appears]
Figure 2 represents the exclusion and inclusion performance across experimental conditions. Figure 2 Exclusion and Inclusion Performance
Left-Exclusion
0.7
Right-Exclusion Left-Inclusion Right-Inclusion
0.6
0.5
0.4
0.3
Mean Complete
0.2
0.1
0 30ms
110ms
210ms 30ms Tim e TMS
110ms
210ms
A repeated measures ANOVA revealed no significant main effect for the timing of TMS (F=1.262, P>0.05) and the site of magnetic stimulation (F=0.167, P>0.05),
11
nor an effect due to the interaction of site and timing of stimulation in exclusion and inclusion performance (F=0.418, P>0.05). It was observed that in many cases, subjects, following exclusion instructions, did not complete the stem with the word presented, but they did completed the stems with words that were very similar and semantically related to the words presented. For example, for the word
“writing” and the stem “wri-“, in some cases subjects
completed the stem by saying “writer” or “write” (or stimulus : “light”, stem : “lig-“, response : “lighting” or “lighter”). In a post-hoc analysis, these responses (‘pseudoerrors’) were counted as wrong responses, i.e. subjects failed to exclude. ‘Pseudoerrors’ were characterized all the responses that were very similar to the stimuli and/or semantically related to the stimuli: subjects were responding by transforming verbs into nouns and vice versa (word: ‘writing’, stem: ‘wri-‘, response: ‘writer’), or by giving the plurals of words presented (‘bridge’, ‘bri-‘, ‘bridges’), or by adding –ing at the end of the word (‘club’, ‘clu-‘, ‘clubbing’), etc. Table 2 and Figure 3 present the means of pseudoerrors that were given as exclusion responses by the participants in each condition.
Table 2 Means of Pseudoerrors in Exclusion Blocks Time TMS
Pseudoerrors in lDLPFC Pseudoerrors in rDLPFC Mean (SD)
Mean (SD)
30ms
.0825 (.089)
.1025 (.123)
110ms
.1038 (.115)
.0738 (.152)
210ms
.1888 (.158)
.1350 (.142)
30ms
.1650 (.178)
.1238 (.161)
110ms
.1763 (.190)
.1138 (.099)
210ms
.1775 (.130)
.1675 (.127)
[Word appears]
[Stem appears]
12
Figure 3 Percentage of Pseudoerrors 30.00% 26.80% 25.00%
23.60% 20.25%
20.90% 22.20%
20.00% 12.90%
15.00% 10.00%
10.60%
13.51%
19.11% 16.00%
14.60%
8.86% Left
5.00%
Right
0.00% 30ms
110ms
210ms 30ms Tim e TMS
110ms
210ms
Table 3 presents the ‘pseudo-exclusion’ performance, i.e. the exclusion performance plus the contribution of the pseudoerrors.
Table 3 Pseudo-Exclusion Performance in Test Trials Pseudoerrors counted as wrong exclusion answers (i.e. subjects failed to exclude)
Exclusion lDLPFC
Exclusion rDLPFC
Mean(SD)
Mean(SD)
30ms
.2796 (.45)
.2637 (.44)
110ms
.3191 (.46)
.2258 (.42)
210ms
.4615 (.51)
.3750 (.48)
30ms
.3226 (.47)
.3
110ms
.3118 (.46)
.3043 (.46)
210ms
.3889 (.49)
.3846 (.48)
Time TMS [Word appears]
[Stem appears]
(.46)
Figure 4 represents the inclusion and ‘pseudo-exclusion’ performance across experimental conditions.
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Figure 4 Inclusion and Pseudo-Exclusion Performance (Pseudoerrors are counted as errors, i.e. subjects failed to exclude) 0.7
0.6
0.5
0.4
0.3
0.2
Left Exc Left Incl
Mean
0.1
Right Excl Right Incl
0 30ms
110ms
210ms
30ms Tim e TMS
110ms
220ms
The first repeated measures ANOVA was performed on the percentages of pseudoerrors. The analysis did not show any statistical significance due to the main effect of the site of TMS (F=0.997, P>0.05) or due to the timing of TMS (F=1.374, P>0.05) or due to the interaction of the two independent variables (F=0.503, P>0.05). Another repeated measures ANOVA was performed on the mean scores of ‘pseudo-exclusion’ performance, but again no statistical significant differences were obtained for the main effects of site of TMS (F=1.405, P>0.05), of timing of TMS (F=1.935, P>0.05) or from the interaction of the two independent variables (F=0.435, P>0.05).
It should be noted that is generally accepted (e.g. Walsh & Rushworth, 1999) that in cognitive tasks, single pulse TMS causes limited interference and it may be insufficient to cause subjects to make errors, but it is compatible with RT paradigms. Figure 5 shows the median reaction time for test trials across experimental conditions. A repeated measures ANOVA that was performed for median reaction time across experimental conditions did not reveal any significant differences due to the main effect of site of TMS or timing of TMS or due to the interaction of the two independent variables (P>0.05). 14
Figure 5 Median Reaction Time for Test Trials 2500
2000
1500
1000 Left Exclusion Right Exlusion
msec
500
Left Inclusion Right Inclusion 0
30ms
110ms
210ms
30ms
110ms
210ms
Tim e TMS
Figure 6 represents the percentages of responses chosen from the participants in the Awareness Question. Figure 6 saw clearly
Percentages of Responses in Aw areness Question
could identify saw sth
45%
saw nth 40%
mistake
35% 30% 25% 20% 15% 10% 5% 0% 30ms
110ms
210ms
30ms
110ms
210ms
Tim e TMS
It is evident that in the great majority of trials, subjects did not clearly perceived the masked stimuli. This fact made us change the presentation of the stimuli at the main experiment because we wanted to examine the executive processes 15
implemented in DLPFC and not just unconscious priming. Thus, masking of the stimuli was not used in the main experiment, but rather stimuli were presented at an individually defined level of brightness that would enable participants to perceive clearly the stimuli in more that the 1/3 of trials. It should be noted that this failure to perceive the stimuli was not due to side effects caused by magnetic stimulation. Stimuli were presented for 30 msec and a magnetic stimulation was delivered at a delay time of 30-210msec. As observed in earlier TMS studies of perception, eye movements or orbicularis contractions (e.g. blink reflex) elicited by the magnetic coil cannot be expected to occur earlier than 80110 msec after receiving the letters. By then, the retinal processing and transmission of the visual stimulus to the cortex should be mostly completed (see Masur, Papke & Oberwittler, 1993). As for the trials in which magnetic stimulation was delivered at 30msec after the presentation of the stimuli, subjects reported the highest awareness of the stimuli across conditions. Figures 7 and 8 represent the estimations of the conscious and unconscious processing that were calculated by using the Jacoby Equations.
Figure 7 Conscious Processing - calculated with the Jacoby Equations 0.6 0.5 0.4 0.3 0.2 Left Conscious
Mean
0.1
Right Conscious
0 30ms
110ms
210ms
30ms
Time TMS
16
110ms
210ms
Figure 8 Unconscious Processing - calculated with the Jacoby Equations 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1
Left Unconscious
Mean
0.05
Right Unconscious
0 30ms
110ms
210ms
30ms
110ms
210ms
Time TMS
In the inclusion condition, conscious perception acts in concert with unconscious perception just as in facilitation paradigms (Forster et al., 1990): a stem could be completed with a flashed word either because the subject consciously perceived the word (C), or, because even though conscious perception failed (1-C), the effects of unconscious perception (U) were sufficient for the flashed word to be given as a completion. Thus, conscious and unconscious perception serve as independent bases for responding. According to Debner and Jacoby (1994), the probability of completing a stem with a flashed word in the inclusion test condition is as follows: Inclusion = C + U(I-C)=C+U-UC
(e.g. Debner & Jacoby, 1994, 306)
Given exclusion instructions, awareness of the presentation of a flashed word results in its being withheld as a response. Consequently, a flashed word should be given as a completion in an exclusion condition only if unconscious processing is sufficient for its being given as a response (U) and the word is not consciously perceived (1-C). Thus, the probability of responding with a flashed word that should be excluded is as follows: Exclusion = U/(1-C)=U-UC
(e.g.Debner & Jacoby, 1994, 306)
17
The process-dissociation procedure requires the combination of an exclusion condition with an inclusion condition. Given these two conditions, the probability of conscious perception (C) can be estimated as C= inclusion – exclusion
(e.g. Debner & Jacoby, 1994, 307)
The probability of unconscious perception can then be estimated by dividing “exclusion” by the estimated probability of a failure in conscious perception (1-C). Thus, U= exclusion/(1-C)
(e.g. Debner & Jacoby, 1994, 307)
A repeated measure ANOVA that was performed did not reveal any statistical significant differences in the estimations of conscious and unconscious processes due to the site or the timing of magnetic stimulation.
Stimulation over the left DLPFC at 210msec after the word presentation worsened the exclusion performance, caused the presence of more pseudoerrors and worsened the ‘pseudo-exclusion’ performance. As aforementioned, these differences were not statistical significant. A multivariate analysis of variance (MANOVA) was conducted in order to compare the effects of stimulation at left and right DLPFC across each time-point of stimulation, and to test three variables (exclusion performance, reaction time and production of pseudoerrors). This final analysis revealed that only an interaction of time and site of stimulation at 210ms after word presentation was close to statistically significant levels (F=0.011, P>0.05). Thus, the main experiment was designed so as to examine more carefully the effects of TMS over left DLPFC at 210msec after the word presentation and at 30msec after wordstem appearance only during exclusion conditions. The most straightforward interpretation of an effect of TMS at 210msec after word-presentation would favor the view that the functional role of lDLPFC is the on-line maintenance of information. The alternative time-point of stimulation (i.e. 30msec after the appearance of wordstem) was chosen as an alternative timing of stimulation in order to test the hypothesis that lDLPFC is involved in response selection (see Frith, 2000).
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3. Main Experiment 3.1. Method 3.1.2. Subjects Eight English native speakers took part in this study. All volunteers were healthy normal individuals (three female, five male) who had no previous history of neurological, psychiatric or physical illness or head injury, and were not taking any medication. Their mean age was 26.6 years (SD=2.38, range = 223-30). 3.1. 3. Design All participants took part in all conditions of word stem completion. The design was 1x3x3 and there were a total of 9 experimental conditions. Subjects had to complete a three-letter word stem by using any other word except from the word they saw (i.e. participants were required in all conditions to exclude they word they saw). TMS was delivered over left DLPFC, right DLPFC or medial frontal cortex. The stimulation was delivered in two different timings (either at 210msec after the presentation of the stimulus, or at 30msec after the appearance of the stem) or there was no stimulation at all. All participants first performed one train bloc, and consequently they attended 15 experimental blocks. The order of runs with TMS over the three target sites and at the three different timings were randomized across participants. 3.1.4. Procedure Participants were asked to complete a three-letter word stem, following exclusion instructions that were given to them at the beginning of each block, for a total of 384 trials. Ninety-six trials (i.e. ¼ of trials) were base trials. In the baseline trials, the word stem was not relevant to the word presented and participants were asked to complete the presented word stem with an appropriate response. The stimuli were the same as in the pilot study. On each trial, a word was presented for 30msec at a level of brightness that was individually defined for each subject on the basis of their performance in a simple perceptual before the main experiment. The level of brightness used in the experiment was such that every subject was able to perceive the word in approximately more than the 1/3 of trials and she was not able to perceive
19
clearly the word in approximately the 1/3 of trials. At 580 msec after the presentation of the word, the first three letters of the word (e.g. ‘tab’) were presented and participants were asked to complete the word stem according to the exclusion instructions by speaking aloud in a microphone. Appendix III contains the instructions given to participants before taking part to the experiment. The mean active motor threshold for the participants was 40.37% (range = 35%60%) of maximum stimulator output. TMS was given at each participant’s individually determined active motor threshold increased by 125%. The mean level of TMS output was 46% (range = 37%-55%) of maximum stimulator output. For three participants this level of increase was uncomfortable and thus TMS output was reduced to the level at which participants could tolerate the stimulation without feeling any distress. TMS was given with a figure-of-8 coil, which allows more focal stimulation than a round coil. The tip of the middle bar of the figure-of-8 coil was lined up with F3 or F4 (8cm anterior to the vertex and respectively 7cm to the left of the midline) for stimulation of the left and right DLPFC and with FCz (4-5cm anterior to the vertex) for stimulation of the medial frontal cortex, following instructions given in previous TMS studies over the DLPFC (Jahanshahi et al., 1998; Jahanshahi & Dirnberger, 1999). 3.2. Results Measures of Exclusion Performance Perfect exclusion performance would equal to 0.00. As in the pilot study, it was observed that in many cases, participants completed the stems with words that were very similar and semantically related to the words presented. For example, for the word “writing” and the stem “wri-“, subjects completed the stem by saying “writer” or “write” (or stimulus : “light”, stem : “lig-“, response : “lighting” or “lighter”). In a post-hoc analysis, these ‘pseudoerrors’ were counted as wrong responses, i.e. subjects failed to exclude. ‘Pseudoerrors’ were characterized all the responses that were very similar to the stimuli and/or semantically related to the stimuli : subjects were responding by transforming verbs into nouns and vice versa (word : ‘writing’, stem : ‘wri-‘, response : ‘writer’) , or by giving the plurals of words presented (‘bridge’, ‘bri-‘, ‘bridges’) , or by adding –ing at the end of the word (‘club’, ‘clu-‘, ‘clubbing’), etc. ‘Pseudo-exclusion’ performance refers to a post hoc coding of the participants’ responses : the pseudoerrors
were coded as wrong exclusion answers. Table 4
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presents the mean exclusion and ‘pseudo-exclusion’ performance across test conditions. Table 4 Mean Performance in Test Trials Exclusion Performance TMS
NO
Pseudo-Exclusion Performance*
lDLPFC
rDLPFC
FCz
lDLPFC
rDLPFC
FCz
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
.11 (.31)
.15 (.36)
.11 (.32)
.23 (.42)
.25 (.43)
.21 (.41)
.13 (.33)
.17 (.37)
.11 (.31)
.22 (.41)
.30 (.46)
.26 (.43)
.17 (.37)
.14 (.34)
.14 (.34)
.31 (.46)
.24 (.42)
.26 (.43)
Stimulation 210msec after word presentation 30msec after stem presentation *Pseudoerrors are counted as wrong exclusion answers (i.e. subjects failed to exclude).
A descriptive analysis of the means of ‘pseudo-exclusion’ performance shows that ‘pseudo-exclusion’ performance was worse at 210msec after the word presentation when TMS was applied over the right DLPFC, while for stimulation of the left DLPFC, ‘pseudo-exclusion’ performance was worse when stimulation was applied at 30msec after the stem appearance. Figures 9 and 10 represent the exclusion and ‘pseudo-exclusion’ performance respectively. Figure 9 Exclusion Performance
0.18 0.16 0.14 0.12 0.1
FCz
0.08
lDLPFC rDLPFC
0.06 0.04
Mean
0.02 0 NO TMS
210ms TMS
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30ms after stem
Figure 10 Pseudo-exclusion performance (pseudoerrors counted as errors)
0.35
0.3
0.25
0.2 FCz
0.15
lDLPFC rDLPFC
0.1
Mean
0.05
0 NO TMS
210ms TMS
30ms after stem
The first repeated measures ANOVA was performed in order to investigate the main effects or effects of interaction of the two independent variables (site and time of stimulation) in exclusion performance. No statistical significant differences were observed for the main effect of site of stimulation (F=1.945, P>0.05), for the time of stimulation (F=1.086, P>0.05) or for the interaction of time and site of stimulation (F=.921, P>0.05). The second repeated measures ANOVA was performed in order to investigate the main effects or effects of interaction of the two independent variables (i.e. site and time of stimulation) for ‘pseudo-exclusion’ performance. No statistical significant differences were observed. The main effect of time of stimulation was not significant (F=.883, P>0.05), nor the main effect of site of stimulation (F=.269, P>0.05). The effect due to the interaction of the two independent variables was not significant (F=2.108, P>0.05). However, it should be noted that exclusion (0.17) and ‘pseudo-exclusion’ performance (0.31) were worse when magnetic stimulation was delivered over left DLPFC at 30msec after the appearance of the stem.
Table 5 and Figure 11 presents the median reaction time across test conditions.
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Table 5
Median Reaction Time for Test Trials TMS
lDLPFC
RDLPFC
FCz
NO Stimulation
1370 msec
1379.5 msec
1545 msec
210 msec after word
1359 msec
1441 msec
1489 msec
1645 msec
1467 msec
1465 msec
presentation 30 msec after stem presentation
Figure 11 Median Reaction Time for Test Trials 1800
lDLPFC rDLPFC FCz
1600 1400 1200 1000 800 600
m sec
400 200 0 NO TMS
210msec
30msec after stem
TMS
The median Reaction Time was considerably increased when TMS was delivered over left DLPFC at 30msec after the appearance of the stem. A repeated measures ANOVA that was conducted did not reveal any statistical significant differences due to the main effect of site of stimulation (F=2.904, P>0.05) or due to the main effect of time stimulation (F=2.038, P>0.05). However, a significant effect was obtained from the interaction of site and time of stimulation (F=3.357, 23
Sig.=0.023, P<0.05), suggesting that TMS over the left DLPFC at 30msec after the appearance of the stem affected significantly the median reaction time in the participants’ responses. Of interest, even though the statistical tests that were carried out did not show any significant interactions, it was observed that during stimulation over the left DLPFC at 30msec after the appearance of the stem, participants had the highest scores in exclusion (mean score = 0.17) and pseudo-exclusion performance (mean score = 0.31). When TMS was delivered over left DLPFC at 210msec after the presentation of the word, when subjects were supposed to maintain on-line the word presented and thus the demands on the working-memory system were high, exclusion and pseudo-exclusion performances were almost similar to the no-stimulation conditions (for lDLPFC 0.13 and 0.11 respectively, and for rDLPFC 0.17 and 0.15 respectively, see Table 4). Thus, it is plausible to argue that TMS over left DLPFC affected the participants’ performance (median reaction time) only when they were asked to select and generate a response and not when they had to maintain on-line the information needed (i.e. the word presented) to perform successfully in the task. However, in the pilot study a different pattern in the results emerged: a close to significance effect was observed when TMS was delivered over left DLPFC at 210msec after the presentation of the word. In addition, the fact that only median reaction time was significantly affected, and not exclusion and pseudo-exclusion performances, does not permit us to rule out the hypothesis that the role of left DLPFC in the present design was to hold on-line the stimulus presented and to adopt undoubtedly the hypothesis that the functional involvement of left DLPFC was solely related to processes underpinning response selection (Frith, 2000).
.
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4. Discussion The results obtained from the pilot study and the experiment do not allow us to formulate precise interpretations of the functional contribution of the left DLPFC during the Jacoby Exclusion Task.
The differences observed in exclusion and
‘pseudo-exclusion’ performance were not statistical significant. The only statistical significant difference observed was for the median reaction time, which was significantly increased when TMS was applied over the left DLPFC at 30msec after the appearance of the stem. In the pilot study, a multivariate analysis suggested that there was a close to significance effect on the participants’ performance when TMS was delivered over left DLPFC at 210msec after the presentation of the word. This pattern was not repeated in the main experiment. The only significant result obtained in the present study (i.e. the effect from the interaction of the two independent
variables on
response reaction time) suggest that the involvement of left DLPFC in the present design seems to be related to response selection and not to working memory processes per se. Moreover, if the involvement of left DLPFC was related to the active maintenance of the stimuli, one would expect to find significant differences when TMS was delivered at 210msec after the presentation of the word, but this was not the case. When TMS was delivered over left DLPFC at 210msec after the presentation of the stimuli, exclusion and pseudo-exclusion performance were not significantly altered in comparison to the no stimulation condition. The differences in the patterns of results obtained from the pilot and the experiment do not allow us to explicitly claim that left DLPFC was solely involved in ‘response-selection’ processes. However, it should be mentioned that the only statistically significant result obtained results favors the hypothesis that the left DLPFC is involved in response selection by inhibiting ‘prepotent’ or inappropriate or habitual responses (Frith, 2000; Jahanshahi & Dirnberger, 1999; Jahanshahi et al., 1998). It is important to mention that previous TMS studies over prefrontal cortex used rapid-rate magnetic stimulation (Jahanshahi & Dirnberger, 1999; Jahanshahi et al., 1998; Grafman et al., 1994; Mottaghy et al., 2000; Pascual-Leone & Hallet, 1994; Pascual-Leone et al., 1996; for a review see Jahanshahi & Rothwell, 2000). Walsh and Rushworth
(2000) and Jahanshahi and Rothwell (2000) emphasize that in
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cognitive tasks, single pulse TMS causes limited interference and it may be insufficient to cause subjects to make errors, but it is compatible with reaction time paradigms. Unfortunately, the use of rapid-rate TMS in the present study was not possible. Furthermore, the Jacoby Exclusion Task is a complex and demanding task that engages working memory and various executive processes. In this sense, increased reaction time does not appear to be a particular sensitive measurement of impaired performance in the Jacoby exclusion task. Undoubtedly, significant differences in the mean scores for exclusion and especially for pseudo-exclusion performance would be much more informative as to which processes were affected. Within the present design, it is not surprising that the differences observed for exclusion and ‘pseudo-exclusion’ performance were not statistical significant, if one considers that it is almost impossible for single pulse TMS to cause a functional interference of a magnitude that can cause subjects to make errors in complex cognitive tasks. Thus, the significance observed in the differences in median reaction time should be interpreted cautiously within the context of the functional accounts proposed for the role of left DLPFC. The results obtained in the present study favor the hypothesis that left DLPFC is involved in response selection and the inhibition of ‘prepotent’ (complete the word-stem successfully by avoiding to give as a response the word presented), habitual or inappropriate responses (Frith, 2000; Jahanshahi & Dirnberger, 1999; Jahanshahi et al., 1998), but still the involvement of working memory processes cannot be ruled out. The executive control exerted by the PFC upon behavior has a number of different aspects, such as (i) the ability to choose a course of action in novel situations when no obvious course is indicated by the current environment, (ii) the ability to suppress a course of action that is no longer appropriate and (iii) the ability to monitor current on-going action (Shallice, 1988). The combination of findings from functional neuroanatomy and evidence from behavioral studies validate the claim that prefrontal cortex has an executive function while its various regions are concerned with different contextual aspects of executive control (Frith, 2000; Jack & Shallice, 2001). The large area listed as being in BA46/9 is the region of dorsolateral prefrontal cortex (DLPFC) that is widely believed to have a key role in planning and executive control (Goldman-Rakic, 1995; Luria, 1966; Shallice, 1988).
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Desmond et al. (1998) used functional magnetic resonance imaging (fMRI) to investigate the distinctive contributions of left-frontal cortex and right-cerebellar regions using a word stem completion task. Stems with many possible completions (MANY condition) were alternately presented with stems that had few possible completions (FEW condition), and subjects were asked to covertly complete each stem with a word and press a response switch for each successful completion. Prominent increases in activation in the MANY relative to the FEW condition were observed in the left middle frontal gyrus (Brodmann areas 9/10) and left caudate nucleus. In contrast portions of the right cerebellar hemisphere (posterior quadrangular lobule and superior semilunar lobule) and cerebellar vermis exhibited increases in the FEW, relative to MANY condition. This double dissociation suggests that the frontal and cerebellar regions make distinctive contributions to cognitive performance, with left-frontal (and striatal) activations reflecting response selection, which increases in difficulty when there are many appropriate responses, and rightcerebellar activation reflecting the search for responses, which increases in difficulty when even a single appropriate response is hard to retrieve. According to Frith (2000) the key operation of modulation of lower-level schemas by the Supervisory Attentional System (Norman & Shallice, 1986 ; Shallice, 1988) can be localized. In a review of experimemts, in which the “sculpting of the response space” was the key process, it was found activation in a region of left DLPFC involving the middle frontal gyrus (BA 9/46) and inferior frontal gyri (BA 44). Tasks such as the generation of a willed action (Frith et al., 1991a), the generation of a response when strong pre-potent tendencies exist (Nathaniel-James et al., 1997), the random number generation (Jahanshahi et al., 1998), encoding (Fletcher, Shallice & Dolan, 1998), carrying out novel operations (Dolan & Fletcher, 1997) showed activation in left DLPFC. Functional imaging studies reveal that the dorsolateral prefrontal cortex (DLPFC) is more active when we select one from a number of possible responses irrespectively of whether the choice is between limb movements or words (Frith, 2000). These observations suggest that the role of DLPFC in response selection is the “top-down” biasing of possible responses, thereby creating an arbitrary and temporary category of responses appropriate to the task in hand. This biasing of responses depends upon interactions between DLPFC and more posterior brain regions where responses are represented. This function resembles that component of Shallice’s Supervisory Attentional System (Shallice, 1988) which 27
modulates the lower level contention-scheduling system. It is in this sense that DLPFC was selected for stimulation during the Jacoby Exclusion task. Previous neuroimaging studies of sentence or stem completion tasks, which did not involve working memory components other that the on-line holding of instructions, showed activation of left DLPFC. The Hayling Test (Burgess & Shallice, 1996) resembles the Jacoby Exclusion Task in the sense that in both tasks the key operation is to avoid giving as completion a ‘prepotent’ response. In the Hayling test the volunteer is shown a sentence with the last word missing. In one version of the task he must generate the word that best fits the sentence. In the other version he must generate a word that does not fit the sentence. Both versions of this task, especially the latter are performed badly by patients with frontal lobe lesions (Burgess & Shallice, 1996). Nathaniel-James et al. (1997) studied word generation using this sentence completion task and found that when normal volunteers perform this task much activity is observed in left DLPFC for both versions compared to rest or to reading sentences in which the last word is supplied. In the aforementioned completion tasks there is no requirement to keep track of the sequence of responses and thus this component of “working memory” is not involved. In addition volunteers cannot prepare and hold their response in advance. These studies of the effects of response constraints strongly suggest that DLPFC activation is greater in situations in which the volunteer must select one from many rather than few alternatives. One possible formulation of the common feature of all the tasks reviewed here would be the need to create and sustain an arbitrary category of responses appropriate for the task in hand. This process includes the requirement to suppress responses outside the arbitrary category. In the perceptual version of the Jacoby Exclusion task that was used in the present study, suppression refers to the explicit instruction given to participants that they should not complete the stem by using the word they saw. The measure of ‘pseudo-exclusion’ represents an indirect way of failing to suppress and exclude the word presented, but the statistical analysis did not reveal significant differences. Thus, even though stimulation over the lDLPFC at 30msec after the appearance of the stem worsened exclusion and pseudo-exclusion performance, the significance of the differences obtained do not provide us with a strong argument for the functional involvement of areas BA 9/46 in the present study. Jahanshahi et al (1998) conducted a TMS study over DLPFC during random number generation. The results obtained supported the hypothesis that the specific 28
function of left DLPFC is the suppression of habitual responses by triggering a modulatory inhibitory control over a number-associative network, whereas the functional role of right DLPFC is probably the monitoring of responses. Similarly, from the results of a PET activation study, Frith et al. (1991b) reported that, compared with a control task, performance of verbal fluency was associated with increased rCBF in the left DLPFC and decreased activation in the left superior temporal gyrus. These findings were interpreted as reflecting the modulatory influence of the left DLPFC, which actively inhibits an associative network in the superior temporal cortex. This prevents the spreading of activation in the network and the intrusion of irrelevant/competing responses such as high-probability semantic associates during the performance of first-letter verbal fluency (Friston et al., 1991 ; Frith et al., 1991). Such inhibition of the network should allow the emergence and selection of responses meeting the criteria that have been set. In the Jacoby Exclusion task, a similar process of inhibition is required before the process of response selection per se takes place. Participants should inhibit a ‘prepotent’ response (i.e. the word already presented) and complete the stem with another word. Pseudo-exclusion responses were hypothesised to reflect a failure in this inhibitory influence of DLPFC, which is compatible with other TMS studies over lDLPFC (Jahanshahi et al., 1998 ; Jahanshahi & Dirnberger, 1999). Nevertheless, it is still argued that is controversial whether the DLPFC is involved in maintenance of items in working memory (Petrides et al., 1993) or in the selection of responses (Frith, 2000). Experimental studies in monkeys (GoldmanRakic, 1987; Petrides, 1994; Fuster, 1997) and humans (Cohen et al., 1994; Courteny et al., 1996; Jonides et al., 1993; McCarthy et al., 1994; Owen, 1997; Petrides et al., 1993; Smith et al., 1995; Smith and Jonides, 1999; Ungerleider et al., 1998) have demonstrated the crucial involvement of DLPFC in the cerebral network of working memory. Studies in monkeys revealed that there are cells in the DLPFC that continue to fire during the delay on a working memory task (Goldman-Rakic & Friedman, 1991). Petrides et al. (1993) demonstrated the critical involvement of the middorsolateral frontal cortex -areas 46 and 9- in working memory during a verbal working memory task. However, the precise contribution of DLPFC remains to be determined: which aspect of working memory the DLPFC is mainly involved, i.e. the storage, manipulation and/or utilization of information for the forthcoming response. A review of earlier imaging studies suggests that when a task requires explicit search 29
effort, there is activation of the left frontal cortex. Thus, search for an appropriate use for a noun (Petersen et al., 1988; Raichle et al., 1994) or for a semantic relation (Demb et al., 1995) or for words in the study list (Buckner et al., 1995; Schacter et al., 1996) all produced left frontal activation. A model of working memory with a central executive system and two modality subsystems has been proposed (Smith & Jonides, 1999). Smith and Jonides suggest that bilateral DLPFC represent an important part of the central executive system. Previous studies have provided preliminary evidence that temporary disruption of the DLPFC can lead to performance deterioration in different working memory tasks (Grafman et al., 1994; Jahanshahi et al., 1998). Mottaghy et al. (2000) studied the effect of rTMS on changes in rCBF as revealed by PET while subjects performed a 2-back verbal working memory task. During the verbal working memory task, bilateral DLPFC (Brodmann area, (BA) 9/46), premotor areas (BA6), the anterior singulate (BA24/32), bilateral inferior parietal areas (BA39/40), the precuneus (BA7) and the cerebellum were activated. rTMS to the left and to right DLPFC, but not to the middle frontal cortex, significantly worsened performance in the working memory task while inducing significant reductions in rCBF at the stimulation site and in distant brain regions. However, this bilateral involvement of DLPFC does not provide a precise interpretation of the role of left and right DLPFC. In a sense, if left DLPFC is involved in the utilization of information stored in working memory for the generation of a forthcoming response, it is plausible to argue that the crucial role of left DLPFC is in formulating a response rather than simply holding on-line information in the working memory system. Recently, in an event-related functional magnetic resonance imaging study, Rowe et al. (2000) concluded that selection, but not maintenance, was associated with activation of prefrontal area 46 of DLPFC. In contrast, working memory maintenance was associated with activation of prefrontal area 8 and the intraparietal cortex. These results provide support for a role of the DLPFC in the selection of representations. This role accounts for the fact that this area is activated both when subjects select between items on working memory tasks and when they freely select between movements on tasks of willed actions. Goldman-Rakic (1987, 1998) argued that prefrontal area 46 is essential for the guidance of behavior by internal representations in working memory. The results reported by Rowe et al. (2000) support this view by specifying that the critical function of area 46 is the selection of these representations as the target for the response and not their maintenance. 30
Fuster (1997) suggested that one of the critical roles of DLPFC is to link the information maintained in short-term memory to the organization of the forthcoming actions. This suggestion has been recently reinforced by neuropsychological data (Ferreira-Textera et al., 1998) showing that patients with focal lesions of the prefrontal cortex could maintain visuospatial information in short-term memory, but were mostly impaired when this stored information had to be linked to a forthcoming sequence of actions. It is therefore plausible to hypothesize that the DLPFC is part of a neuronal network mostly involved in the preparation of actions based on information stored in working memory rather than in storage of sensory information in short-term memory per se (Fuster, 1997, 2000 ; Pochon et al., 2001). More specifically, the review of the relative literature suggests that there is now conclusive evidence, from several methodologies, that the frontal cortex as a whole, especially the DLPFC, is critically involved in all forms of active (“working”) memory toward a goal, in other words, toward the completion of a gestalt of action, whether that is in the domain of behavior, reasoning or speech (Fuster, 1997, 2000). As for DLPFC in particular, it appears that areas BA 9/46 play a critical role in the cortical dynamics that implement the mediation of cross-temporal contingencies: “if now this, then later that action; if earlier that, now this action” (Fuster, 2000, p.333). Within this perspective, the functional role of DLPFC is founded on the preparation and selection of an appropriate response, and not in the on-line maintenance of information per se. Another group of studies provides support for the view that left prefrontal cortex is mostly involved in response selection especially in verbal generation tasks. Increased blood flow in left prefrontal cortex, specifically the left inferior frontal gyrus (IFG), has been observed during a wide variety of tasks, including the generation of semantically similar words (Petersen et al., 1988; Martin et al., 1995), the classification of words according to a category (Kapur et al., 1994; Demb et al., 1995; Gabrielli et al., 1996) and semantic monitoring (Dèmonet et al., 1992). Increased activity in the left IFG has been attributed to the high semantic processing demands common to all these disparate tasks. In a recent neuroimaging study, Thompson et al. (1997) attempted to distinguish between semantic retrieval and the selection of semantic knowledge from among competing alternatives. Evidence for the role of left inferior frontal gyrus (IFG, areas BA 44/45) in the selection of semantic information comes from three fMRI experiments that found activity in left IFG that was sensitive to increased selection demands during semantic generation, 31
comparison, and classification, but not to increased retrieval demands. For example, the generation task required subjects to generate a verb in response to a noun that had either high (e.g. scissors) or low (e.g. cat) demands for selection among competing responses. Across all three experiments, selection-related activity was found in left posterior IFG, around Brodmann’s area 44/45. Furthermore, lesions to the left IFG were found to disrupt semantic processing only under conditions with high selection demands (Thompson-Schill et al., 1998). Based on this evidence, Thompson-Schill et al. (1999) suggested that the role of prefrontal cortex is to bias or gate relevant information, when needed, from temporal lobe semantic memory representations. In the neuroimaging study reported by Thompson-Schill and colleagues (1999), activity in left IFG decreased during repetition conditions of word generation that reduced competition, but increased during repetition conditions that increased competition. This increase in the left IFG activity is consistent with the hypothesis that left IFG subserves the selection of semantic knowledge among competing alternatives. A number of other studies are consistent with this hypothesis: lesions to prefrontal cortex have been shown to impair sentence completion and word association (Robinson et al., 1998), as well as category fluency (Randoplh et al., 1993). Thompson-Schill et al. (1999) proposed that generation of semantically related words requires two processes: retrieval and selection. They found that activity in left prefrontal cortex, in the IFG was dependent on the demands for selection. The roles that temporal and frontal cortex play in semantic processing appear to be quite distinct, with temporal cortex subserving the retrieval of semantic information and prefrontal cortex functioning in perhaps a nonsemantic role, enabling the selection of relevant information from competing semantic knowledge. Retrospectively, it has been mentioned that the different pattern of results obtained in the pilot and the main experiment, and especially the fact that significant differences were only observed for reaction time, do not permit us to formulate a precise interpretation of the functional involvement of left DLPFC in the present study. Significant differences obtained for exclusion performance and most importantly for pseudo-exclusion performances would be better indicators of the functional role of left DLPFC in response selection. However, a review of the literature suggests that, even in working-memory tasks, DLPFC is actively involved in the utilization of information for the preparation and selection of forthcoming actions. In the present study, the Jacoby Exclusion Task was selected because it 32
involves various executive processes that are considered to require the contribution of left DLPFC. TMS was delivered at two different timings (210msec after the presentation of the word and 30msec after the presentation of the stem). The second time-point of stimulation is considered to be happening at the time when subjects had to select and generate a proper response (i.e. suppress the ‘prepotent’ response and select an appropriate completion of the stem). At 210msec after the presentation of the word, subjects were not excepted to be generating a response because (a) the stem would appear 390msec later, and (b) subjects were not in the position to know whether the trial was be a baseline (i.e. the stem did not match the word) or a test trial. The suggestion that left DLPFC is involved in response selection is strengthened by the fact that not only median reaction time was greater when TMS was delivered at 30msec after the appearance of the stem (median RT=1645msec, P<0.05), but also from the observation that exclusion and pseudo-exclusion performance at this timepoint were worse. In other words, for stimulation at 30msec after the appearance of the stem, subjects failed to exclude or they gave as completion a word that was very close to the word presented, thus they pseudo-excluded at a higher rate. Crucially, the Jacoby exclusion task does not require only intact working-memory, but more importantly it involves executive processes such as inhibition of a ‘prepotent’ response, selection and generation of a proper response. However, only the use of rapid-rate TMS would allow us to formulate more precise hypotheses because with rapid-rate stimulation it is more possible to cause cognitive effects and not merely delays in the reaction time. Thus, a follow up study is suggested in order to examine the effects or rapid-rate stimulation over DLPFC during the Jacoby Exclusion Task at timings before and after the appearance of the stem
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5. Conclusions We examined the effects of single pulse Transcranial Magnetic Stimulation (TMS) over the left Dorsolateral Prefrontal Cortex (DLPFC) during the Jacoby Exclusion Task. The pilot study and the main experiment showed a different pattern of results. The only statistically significant result was obtained for reaction time in the main experiment. When magnetic stimulation was delivered over lDLPFC at 30msec after the appearance of the stem, subjects needed significantly more time to select and generate a response. Exclusion and pseudo-exclusion performances were not significantly affected, even though both performances were highest (i.e. worse) when stimulation was delivered at 30msec after the appearance of the stem. The equivocal nature of the results do not allow us to formulate a clear interpretation of the functional involvement of lDLPFC in the present design. A cautious suggestion is that lDLPFC is not solely involved in the on-line maintenance of information, but more importantly is involved in the inhibition of a ‘prepotent’ response and in selecting a suitable response for the task used . The weakness of the results obtained in the present study led us to a necessary review of the relative literature, which suggested that left DLPFC is activated in association with response selection. A follow-up study is suggested in which the effects of rapid-rate TMS over the DLPFC during the Jacoby Exclusion task will be investigated.
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6. References
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Appendix I List of Stimuli (words and stems) Word TEXT THREE CHURCH DETAIL TRADE ROUND LAND DRESS MOON STORY COURSE EFFECT RESULT CATTLE THURSDAY BOUND SCALE EDITOR CERTAINTY FARM VISIT HARMONY BOTTOM SAVE MEANS SWEET BELIEF COAST STATE PART QUIET SATURDAY SYMBOL BRAIN CAVALRY FLAT HURT EPIC CLUB PITCH SQUARE QUALITY ALLOTMENT SUCCESS GRAY SOUTH FATHER DEFINITION SHELTER
Stem TEX THR CHU DET TRA ROU LAN DRE MOO STO COU EFF RES CAT THU BOU SCA EDI CER FAR VIS HAR BOT SAV MEA SWE BEL COA STA PAR QUI SAT SYM BRA CAV FLA HUR EPI CLU PIT SQU QUA ALL SUC GRA SOU FAT DEF SHE
Word EARTH SKIN PIANO BUTTER OFFICE HORSE IMAGE EIGHT LUNCH AGREEMENT BLOOD UNIVERSITY RUSSIAN SLAVERY SPOKE AUTHORITY ROAD LEAST DIVISION CHOICE QUESTION CALL RATE SPECIAL FIGURE DECISION WALL DEMAND SOVIET IMPORTANCE PILOT TOUCH FAILURE BURDEN BROWN WELL PAST LOOK MANY HALF ENTRANCE FREEDOM POLICY PANEL TALK INTEREST REMOVE COOL WEATHER
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Stem EAR SKI PIA BUT OFF HOR IMA EIG LUN AGR BLO UNI RUS SLA SPO AUT ROA LEA DIV CHO QUE CAL RAT SPE FIG DEC WAL DEM SOV IMP PIL TOU FAI BUR BRO WEL PAS LOO MAN HAL ENT FRE POL PAN TAL INT REM COO WEA
Word HERO NEGRO REPORT PROGRAM HELP BACK RISE LIQUID OPERATION CIRCLE EXCHANGE TEAM BRIDGE POUND EXAMPLE LIBERAL LIMIT SUBJECT SURFACE PLAN DEEP SWITCH LOCAL BARN EMPTY BALL DRUNK SUNDAY MERCER POPULATION GREEN TURN SLIGHT TEST MAIN HOLD PULL HEAD ORDER EXTENT KIND RAIN CRAFT ACTION SANCTION NATURE SUIT CURRENT RECORD
Stem HER NEG REP PRO HEL BAC RIS LIQ OPE CIR EXC TEA BRI POU EXA LIB LIM SUB SUR PLA DEE SWI LOC BAR EMP BAL DRU SUN MER POP GRE TUR SLI TES MAI HOL PUL HEA ORD EXT KIN RAI CRA ACT SAN NAT SUI CUR REC
FILM EMBASSY BUNDLE Word SPACE EAST LIFE SPRING MUST DEBATE ENGINE EQUIPMENT ELECTION FUNCTION HOUSE VERSE SUMMER POSITION SILENCE ACCOUNT MISS BORE SIGN SORT FACT DEATH EXPERIENCE DEPARTMENT PRESIDENT VICTORY RENT BULLET SHIP TROUBLE PHILOSOPHY SCORE VIRGIN TERM CHANGE GLASS BOARD MESSAGE LIGHT INCREASE ARCHITECT ANGLE PRIVATE NOTHING MAGAZINE CONTROL WORLD ILLUSION HOSPITAL PERIOD AMERICAN SUSPECT DIRECTION NORTH
FIL EMB BUN Stem SPA EAS LIF SPR MUS DEB ENG EQU ELE FUN HOU VER SUM POS SIL ACC MIS BOR SIG SOR FAC DEA EXP DEP PRE VIC REN BUL SHI TRO PHI SCO VIR TER CHA GLA BOA MES LIG INC ARC ANG PRI NOT MAG CON WOR ILL HOS PER AME SUS DIR NOR
DENIAL CUSTOMER CENTER Word THEORY PORTION STUDY SUPPORT CASE CORNER PRACTICE CLASS TRUTH MATTER FLOOR WISH SENSE KNOW FURNITURE HONEY INVESTMENT TENSION PATTERN JUNE MOUTH POET DESIGN TREATMENT FOOD SCREEN CROSS BREAK POTENTIAL PALE WINDOW WILL SERVICE FOUNDATION CHRISTIAN SCHOOL DELIGHT BOOK BLAME CLEAN GROUP DISTRICT INSIDE STILL MEDICAL IDEA METHOD OBJECTIVE REVOLUTION WARM MARKET ANALYSIS FORM PICTURE
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DEN CUS CEN Stem THE POR STU SUP CAS COR PRA CLA TRU MAT FLO WIS SEN KNO FUR HON INV TEN PAT JUN MOU POE DES TRE FOO SCR CRO BRE POT PAL WIN WIL SER FOU CHR SCH DEL BOO BLA CLE GRO DIS INS STI MED IDE MET OBJ REV WAR MAR ANA FOR PIC
MODERN MOVE LINE Word EVEN PINK FOLK PENCIL MOTHER GLORY REAL SOLID FLESH PUBLIC RANGE SHOW GUARD CITY DOUBT BENEFIT MONEY BEAUTY CELL DRIVE NEWS ORIGINAL CHECK PURPOSE ROOM CHILDREN OUTSIDE PACE VENUS INDIVIDUAL FIRE WRITING STREET ABSENCE DIFFERENCE FLUX BIRTH FAMILY TRIAL RELIGION CLIMATE DRAW SITUATION DANCE MIND MILLION PHONE RETIREMENT CANDIDATE TIME PEACE CLOSE NIGHT NARROW
MOD MOV LIN Stem EVE PIN FOL PEN MOT GLO REA SOL FLE PUB RAN SHO GUA CIT DOU BEN MON BEA CEL DRI NEW ORI CHE PUR ROO CHI OUT PAC VEN IND FIR WRI STR ABS DIF FLU BIR FAM TRI REL CLI DRA SIT DAN MIN MIL PHO RET CAN TIM PEA CLO NIG NAR
DOMINANT GUESS CARE Word EXERCISE SOCIETY ADVANTAGE MASS RADIO LONG DIAMETER JOURNAL DOCTOR HAND BANK BASIS FEET CAMPAIGN FELT NECESSARY VOLUME MEMBER RIVER
DOM GUE CAR Stem EXE SOC ADV MAS RAD LON DIA JOU DOC HAN BAN BAS FEE CAM FEL NEC VOL MEM RIV
STEP VIOLENCE BILL Word BATTLE ATTENTION COLLEGE NOVEMBER SINK WIDE DICTIONARY WHILE GAIN REGARD WOOD SEASON INNER TANGENT FRIEND WAIT THING PLEASURE COMPANY
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STE VIO BIL Stem BAT ATT COL NOV SIN WID DIC WHI GAI REG WOO SEA INN TAN FRI WAI THI PLE COM
ARTICLE SELL FRAME Word COPY HUNDRED GUIDANCE PAIR SLUG REFERENCE MIDDLE SPIRIT GRIP ALIEN SALT LAUGH SHARE SECOND TELEPHONE FIND CRISIS
ART SEL FRA Stem COP HUN GUI PAI SLU REF MID SPI GRI ALI SAL LAU SHA SEC TEL FIN CRI
Appendix II Instructions for the Pilot Study On each trial, a word is presented and masked on the computer screen : The first mask appears just before the word and it is a string of letters (e.g. ‘jkdglpng’), then the word appears for approximately 60 milliseconds (e.g. ‘taboo’) and finally the second mask appears (e.g. ‘fgrtsksd’). Immediately following the mask, the first three letters of the word (e.g. ‘tab’) will be presented again and you must complete the word stem according to the instructions. At each block, you will be asked to follow either inclusion instructions or exclusion instructions. In order to start at each block, you will have to press either the letter ‘I’ when you must include, or the letter ‘E’ when you must exclude. Because the word appears for such a short period (e.g. 60 ms) you may not be able to see the word at the first trials, but please do not be discouraged. As the experiment goes on, you will be used to it and thus you will be able to see the word. Inclusion Instructions You must complete the word stem with the word you saw or you think you saw. For example, if the word presented on the trial is frigid, then immediately following the presentation of frigid, the letter stem fri is presented and you must complete it with the word frigid. Your responses will be taperecorded and thus you are asked to sit close to the microphone and say the words clear and loud. In case you have not seen the word, please complete the word stem with the first word that comes to your mind and remember that it is important to complete every stem with a word that suits it. Exclusion Instructions : You must complete the word stem with the first word that came to mind except the word that had just been presented. For example, if the word presented on the trial was frigid, then immediately following the presentation of frigid, the letter stem fri is presented and you must use any word other than the word that had just been presented to complete the word stem. For example, you can complete the word stem with fright, fringe, frites or even Friday but not with frigid. Your responses will be tape-recorded and thus you are asked to sit close to the microphone and say the words clear and loud. In case you have not seen the word, please take a guess and remember than in every trial you are asked to complete the stem with a word that suits it. Note, than is some trials, the stem will not be relevant to the word you saw. Thus, you may complete the word stem with the first word that comes to mind, which is an appropriate completion of the stem.. As soon as you have completed the stem, you will be presented with the following multiple choice question : Z - SAW THE WORD CLEARLY X – COULD IDENTIFY THE WORD C – SAW SOMETHING V – SAW NOTHING B – MADE A MISTAKE
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You have to answer by choosing one of the letters Z, X, C, V, B. As soon as you choose one of the above answers, we will proceed to the next trial. In case you want to disrupt the experimental procedure, please wait until the above questions appear on the screen and do not answer immediately, but tell to the experimenter what you may need. During the aforementioned task, a magnetic coil will be placed either on the left or on the right sight of your scalp. This techniques is called Transcranial Magnetic Stimulation (TMS). During Transcranial Magnetic Stimulation, a brief magnetic pulse is applied over the scalp at a point which overlies a specific cortical area. The pulse is generated from a number of capacitors which discharge a large brief current into a coil held above your head. The current generates a magnetic field below the coil and this field passes, unattenuated by the skin and scalp into the cortex. The effect of the magnetic field at the cortex is to induce a current which results in neural activity. The use of TMS is rightly subject to approval by local ethical committees and you may ask to see the ethical approval for this study. However you need to know that the safety of single pulse stimulation is well established. We must inform you that you may experience headache or some face twitches. In case you find these peripheral effects uncomfortable you are free to withdraw from the experiment at any time and without giving any reason for your withdrawal. The experiment lasts approximately 50 minutes and you will be given £10 for your participation. Before starting with the experiment, you will attend two train blocks so as to understand the task and see how the TMS feels. We thank you in advance for your collaboration.
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Appendix III Instructions for the Experiment On each trial a word appears for a short period of time, followed by a word stem, i.e. the first three letters of the word you saw. If the word is “taboo”, then the stem “tab” appears. You are asked to complete the word-stem with the first word that comes to your mind except the word that had just been presented. For example, if the word presented on the trial was frigid, then immediately following the presentation of frigid, the letter stem fri is presented and you must use any word other than the word that had just been presented to complete the word stem. For example, you can complete the word stem with fright, fringe, frites or even Friday but not with frigid. Your responses will be taperecorded and thus you are asked to sit close to the microphone and say the words clear and loud. In case you have not seen the word, please take a guess and remember than in every trial you are asked to complete the stem with a word that suitable to stem, but not the word you saw. Note, than is some trials, the stem will not be relevant to the word you saw. Thus, you may complete the word stem with the first word that comes to mind, which is an appropriate completion of the stem.. During the aforementioned task, a magnetic coil will be placed either on the left or on the right sight of your scalp. This techniques is called Transcranial Magnetic Stimulation (TMS). During Transcranial Magnetic Stimulation, a brief magnetic pulse is applied over the scalp at a point which overlies a specific cortical area. The pulse is generated from a number of capacitors which discharge a large brief current into a coil held above your head. The current generates a magnetic field below the coil and this field passes, unattenuated by the skin and scalp into the cortex. The effect of the magnetic field at the cortex is to induce a current which results in neural activity. The use of TMS is rightly subject to approval by local ethical committees and you may ask to see the ethical approval for this study. However you need to know that the safety of single pulse stimulation is well established. We must inform you that you may experience headache or some face twitches. In case you find these peripheral effects uncomfortable you are free to withdraw from the experiment at any time and without giving any reason for your withdrawal. The experiment lasts approximately 50 minutes and you will be given £10 for your participation. Before starting with the experiment, you will attend two train blocks so as to understand the task and see how the TMS feels. We thank you in advance for your collaboration.
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