Physiological evidence for response inhibition in choice reaction time tasks

Brain and Cognition 56 (2004) 153–164 www.elsevier.com/locate/b&c

Physiological evidence for response inhibition in choice reaction time tasks Borı´s Burlea,*, Franck Vidala,b, Christophe Tandonneta, Thierry Hasbroucqa,b a

Laboratoire de Neurobiologie de la Cognition, Centre National de la Recherche Scientifique and Universite´ de Provence, Marseille, France b Institut de Me´decine Navale du Service de Sante´ des Arme´es, Toulon, France Accepted 1 June 2004 Available online 12 September 2004

Abstract Inhibition is a widely used notion proposed to account for data obtained in choice reaction time (RT) tasks. However, this concept is weakly supported by empirical facts. In this paper, we review a series of experiments using Hoffman reflex, transcranial magnetic stimulation and electroencephalography to study inhibition in choice RT tasks. We provide empirical support for the idea that inhibition does occur during choice RT, and the implications of those findings for various classes of choice RT models are discussed. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Reaction time; Inhibition; Hoffman reflex; TMS; EEG; Laplacian; Models

1. Introduction During the last 50 years, much progress has been made in understanding basic information processing mechanisms. This progress is intimately linked to the development of the reaction time (RT) paradigm. Within this framework, the procedures in which the subjects are required to choose between different response alternatives have proved to be particularly fruitful. Different models of choice RT have been developed and tested with behavioral techniques. All of them treat information processing as a gradual process based on the accumulation of information over time and most of them comprise at least two processing levels: one stimulus-related level and one response-related level (e.g., McClelland, 1979). In such models, the response-related level is made of information accumulators or integrators, each accumulator being associated to one response alternative. In recent versions of these models, following the Hebbian perspective (Hebb, 1949) the accumulators cor*

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respond to peculiar populations of neurons (see Usher & McClelland, 2001). A given response is emitted as soon as one accumulator—or the difference between two accumulators (e.g., Spencer & Coles, 1999)—reaches a predefined threshold. The RT of the model is a function of the ‘‘time’’ (in model time units) necessary to reach this threshold. Only one response being correct on a given trial, the possible responses are thus in competition in order to reach the threshold first. The competition, however, can take different forms. Among the various possible implementations, the presence or absence of inhibitory mechanisms is an important feature. 1.1. Response competition and inhibition In its simplest form, the competition is just an accumulation-race between the different accumulators without any interference between the two accumulators: The two accumulators are independent, and the one that reaches the threshold first triggers the response. This scheme (Fig. 1A) is implemented in counter models, accumulator models and some horse-race with-winner-takes-all models (Audley & Pike, 1965; Cohen,

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Fig. 1. Schematic representation of the response accumulators level in the various classes of models developed in the text. (A) Models without inhibition, (B) models with lateral inhibition and (C) models with feedforward inhibition.

Dunbar, & McClelland, 1990; Laberge, 1962; Vickers, 1970, 1979). A more refined form of competition without inhibition is implemented in ‘‘random walk’’ and diffusion related models (Ashby, 1983; Laming, 1968; Link & Heath, 1975; Stone, 1960; Ratcliff, Van Zandt, & McKoon, 1999): In such models of two-choice RT, only one accumulator is present with two boundaries, each of which corresponds to an alternative response. At each moment, the accumulator accumulates evidence for one of the two responses, and the response is given when the accumulation reaches one of the two thresholds. Note that, in this second class of models, the two responses are mutually exclusive, in the sense that only one response can be activated at each moment. Inhibition is an intermediate variable introduced in RT models in order to account for (i) behavioral effects obtained in the so-called Ôconflict tasks,Õ such as EriksenÕs flanker task (Eriksen & Schultz, 1979), Simon (Zorzi & Umilta´, 1995) and Stroop tasks (Kornblum, Hasbroucq, & Osman, 1990) and (ii) to extend classic models to situations with more than two response alternatives (Grossberg, 1976, 1978; McClelland & Rumelhart, 1981; Usher & McClelland, 2001). This psychological concept has its roots in clinical and experimental physiology where it is considered as a functional counterpart of neural activation. Importantly, neural inhibition is defined not as an absence of excitation but as an active process suppressing an excitatory action (see e.g., Buser, 1984). Inhibition has essentially been studied in the stop-signal paradigm (Logan & Cowan, 1984; Osman, Kornblum, & Meyer, 1986; van Boxtel, van der Molen, Jennings, & Brunia, 2001; Vince, 1948). In the prototypical version of this paradigm, the participants perform a RT task requiring the discrimination of two stimuli and the selection of one motor response. A stop-signal is presented occasionally and

unpredictably in a proportion of trials, instructing the participant to withold his (her) response to the choice RT stimulus. Participants usually comply with this requirement and successfully inhibit their ongoing processing provided that the stop-signal occurs soon enough during the RT: the later the stop-signal, the harder the response inhibition. In such tasks, unlike in regular choice RT, inhibition can directly be quantified through the proportion of successfully stopped responses and its time properties can be inferred (Logan & Cowan, 1984; Osman et al., 1986). In contrast, the choice RT models resorting to the notion of inhibition assume that this intermediate variable lengthens, or postpones, the execution of a given response. For instance, Eriksen and Schultz (1979) resorted to this notion in order to account for the results obtained in the context of the flanker compatibility task (Eriksen & Eriksen, 1974) in which the participant typically has to make a left- or a right-hand keypress according to the identity of a letter (A or H). This target is flanked by noise letters on each side. The flankers are either ‘‘compatible’’ (e.g., AAA) or ‘‘incompatible’’ (e.g., HAH) with the target. Eriksen and Schultz proposed that the flankers automatically activate the required response when the display is compatible and the non-required response when the display is incompatible. In the latter case, the activated response competes with the required response that is consequently inhibited. The more the incorrect response is activated, the more the required response is inhibited and the longer the RT (Eriksen & Schultz, 1979). 1.2. Feed-forward and lateral inhibition A useful distinction has recently been proposed by Band and van Boxtel (1999) in the context of the stopsignal paradigm. These authors distinguished the Ômanifestation,Õ the ÔagentÕ and the ÔsiteÕ of inhibition in the stop-signal paradigm. The manifestation is the mechanism by which inhibition is effective, while the agent can be defined as the source of inhibitory activity and the site as the locus where the inhibition can be recorded. We shall retain this distinction to address the issue of inhibition in choice RT. In light of this distinction, it appears that two types of inhibition assumed to mediate choice RT performance have so far been proposed; they essentially differ by their agent. The agent of the lateral inhibition is located at the site of inhibition, that is at the accumulatorsÕ level (Fig. 1B). With this scheme, the accumulators only receive positive inputs from upstream levels and they inhibit each other as a function of their positive inputs and a response is executed when the activation level of its accumulator bypasses a given pre-defined threshold. The use of this notion of lateral inhibition is particularly well expressed by Coles, Gratton, Bashore, Eriksen, and

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Donchin (1985): ‘‘During the epoch immediately following the stimulus many responses may be in initial stages of activation. The responses are thus in competition (cf. reciprocal inhibition—Sherrington, 1906/1947). The speed with which a response is executed depends, in part, on the extent of response competition. The greater this competition, the longer the latency of the correct response[. . .]. There is a process of response competition by which concurrently activated responses inhibit each other.’’ (pp. 530). A caveat regarding such an assertion is, however, in order. Indeed, SherringtonÕs reciprocal inhibition is a wired property of agonist and antagonist spinal motor nuclei: When the flexors of one joint are being excited, the extensors of the same joint are inhibited and vice versa. Since in usual RT tasks the response alternatives very seldom involve the agonist and antagonist of the same joint, the analogy is at best a metaphor. In contrast, the agent of the feed-forward—or top–down—inhibition (Burle, Bonnet, Vidal, Possamaı¨, & Hasbroucq, 2002a; Heuer, 1987; Kornblum et al., 1990; Kornblum, Stevens, Whipple, & Requin, 1999; Sherrington, 1906/1947) is located upstream from the response accumulators: Every positive input from upstream levels to an accumulator is accompanied by a negative input originating from the same level to the other accumulators (Fig. 1C). The weighted sum of the positive and negative inputs received by one accumulator determines its activation level. Like in the no-inhibition models, a response is executed when the activation level of its accumulator reaches a given pre-defined threshold. 1.3. Executive control and inhibition Appropriate behavior does not always consists in making the correct response. It sometimes consists in withholding a response. This is the case in go–nogo tasks and obviously in Stop-tasks. In those tasks, inhibition is often considered as the main aspect of the task: The prepotent response has to be actively suppressed, or inhibited. However, the idea that incorrect responses can be intentionally and actively suppressed has also been proposed for choice RT. Ridderinkhof (2002) analyzed in detail the RT distribution in the Simon task, by using the delta-plot technique. Briefly, the delta-plots represent the size of the Simon effect as a function of increasing RT. Such an analysis revealed that the Simon effect decreases as RT is getting longer (De Jong, Liang, & Lauber, 1994). To account for this finding, Ridderinkhof (2002) extended the dual route model of compatibility (Kornblum et al., 1990). The main idea of the dual route model is that, in case of the Simon task, the position (the irrelevant dimension) of the stimulus activates (more or less automatically) the ipsilateral response through a direct route, whereas the relevant dimension (e.g., the color) activates the correct response through a controlled route.

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Within this framework, Ridderinkhof (2002) proposed that the incorrect response, activated by the irrelevant dimension of the stimulus, can be actively suppressed, and that such a suppression can be seen in the delta-plots. By manipulating factors thought to change the need for suppressing the incorrect response activation, Ridderinkhof (2002) observed correlative changes in the delta-plots indexing changes in executive control, providing empirical support for the model. Burle, Possamaı¨, Vidal, Bonnet, and Hasbroucq (2002b) used the same logic to better specify what is going on after ‘‘partial errors.’’ Thanks to EMG recordings, it is possible, in overt correct trials, to detect very small EMG activities in the muscles associated to the incorrect response. Burle et al. reasoned that on those particular trials, given that the incorrect response was largely activated, its suppression should be very strong. Such an inhibition was expected to be evidenced in the delta-plots. Burle et al. (2002b) observed large negative going delta-plots, suggesting a strong inhibition of the incorrect response. 1.4. Possible agents of inhibition Among the candidates for the agent of feed-forward inhibition in choice RT tasks, two structures, closely related, have been proposed: The anterior cingulate cortex and the supplementary motor area (SMA). Arguments for locating the agent in the cingulate cortex comes mostly from monkeys studies. Sasaki and colleagues (Gemba & Sasaki, 1990; Sasaki, Gemba, & Tsujimoto, 1989) ran a series of experiments using go–nogo tasks, in which the activity of the homolog of the cingulate cortex was recorded. They observed ÔNogo potentialsÕ in this region, which they interpreted as reflecting the inhibition of the response. In a second step, they stimulated the structure generating these Nogo potentials in the go task. Such stimulations induced a suppression of the motor command, providing additional argument for an inhibitory role of this structure. In humans, with electroencephalographic (EEG) measurements, Nogo potentials have also been observed in two components obtained in Nogo trials: The first difference is an enhancement of a negative component occurring about 200 ms after the nogo signal (Nogo N2), and the second is a positive component at about 350 ms after the nogo stimulus, both maximal at fronto-central electrodes (Kok, 1986). Thanks to source localization techniques, the N2 component has sometimes been located in the anterior cingulate cortex in go–nogo tasks (Bokura, Yamaguchi, & Kobayashi, 2001; Nieuwenhuis, Yeung, van den Wildenberg, & Ridderinkhof, 2003) and in conflict tasks (van Veen & Carter, 2002). Correlatively, the activation of the anterior cingulate cortex observed with fMRI in studies of the go–nogo task has been interpreted as reflecting the haemodynamic counterpart of the Nogo potentials recorded with EEG.

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The SMA, a structure closely related to the cingulate cortex, might also be a good candidate. It has often been considered as a structure which role would essentially be inhibitory (Goldberg, 1985; Tanji & Kurata, 1985; Vidal, Bonnet, & Macar, 1995). Among the main arguments in favor of this view are the effects of microstimulations of the SMAs in human patients. From the pioneering work of Penfield and Welch (1951) (cited in Porter, 1990) it appears that for the smallest intensities, stimulations of the SMA do not evoke motor responses but rather suppress ongoing movements. These data have been confirmed later by Fried et al. (1991) for speech and Fried (1996) for the entire spectrum of motor responses tested, although the current threshold had to be higher. In the same line, Chauvel, Rey, Buser, and Bancaud (1996) reports that for 225 tested SMAs in 140 patients the most frequent effects consisted of speech or movement arrests. These arrests corresponded to 75% of the SMAs tested. Movement inhibition was elicited significantly more often than movements of the upper limbs. In the work of Chauvel et al. (1996), positive (elicitation of a movement) and negative (inhibition of an ongoing movement) signs of stimulation corresponded to overlapping sites. However, Lim et al. (1994) claimed that they identified a sub region in the rostral part of the SMA (that they called ‘‘supplementary negative area’’) the stimulation of which elicited movements or speech arrest (speech is just a complex movement). They considered that speech arrest was mainly due to inhibition of the movements of the tongue an the other muscles used in phonation. In other words, stimulation did not induce a transient aphasia. Although one cannot exclude that the effects of electrical stimulations might have been to disrupt the normal functioning of the SMA (namely generating movements), taken together, these data from stimulation studies in humans suggest that inhibiting motor responses is an important function of the SMA or, at least, of one of its sub-regions.

sists in considering that inhibition reflects covert neural processes that can eventually be revealed by neurophysiological methods. Such an approach necessary integrates the concepts and methods issued from both experimental psychology and the neurosciences. One experimental strategy consists in using changes in neural activity as intermediate indices of the information processing operations executed by the nervous system so as to implement a response in choice RT conditions. The function of such indices is to constraint the models. The simulations developed must account for the functional relationships between these indices and the RT. In other words, they are submitted to a cross-validation process that allows one to test the information processing models and to precisely specify the functional significance of the recorded neural activities (Requin, 1987). The use of physiological indices necessitates that the relationships between inhibition—as a psychological concept—and the recorded neural activity are made explicit through an ‘‘indexation function’’ (Teller, 1984). The results therefore rely on a logic derived from models specifying how inhibition is physiologically implemented during RT. In a psychophysiological stance, the site of inhibition is of prime interest because (i) all RT models locate the site of inhibition at the same level as the response accumulators that trigger response execution and (ii) there is little doubt that the anatomical structures that trigger response execution constitute the cortico-spinal tract. Such structures were therefore considered to be candidates for being the site of inhibition. These considerations, which constitute the indexation functions at the origin of our approach, led us to track the site of inhibition from the muscular periphery up to the motor cortex (Fig. 2). In this end, we successively used Hoffman reflex, transcranial magnetic stimu-

1.5. The quest for the site of inhibition Now, although the agent of inhibition has been the focus of several studies, much less is know about its possible sites. In a choice task, the presence of inhibition is inferred from a difference in RT between two experimental conditions. However, most behavioral results interpreted in terms of inhibition can as well be explained in alternative ways, and inhibition in choice RT is a compelling theoretical construct weakly supported at the empirical level. In other words, inhibition is insufficiently constrained to constitute a valid heuristics and, in spite of its explanatory value, response inhibition in choice RT has not yet received strong empirical support. It remains in fact a theoretical notion, or in other words a vue de lÕesprit. One way to constrain the notion con-

Fig. 2. The cortico-spinal track along with a representation of the three techniques used in the series of experiments: H reflex, TMS and EEG.

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lation (TMS) and electroencephalographic (EEG) techniques.

2. The experiments 2.1. Behavioral recordings

procedures

and

electromyographic

In all the experiments reported below, the subjects were to respond to visual stimuli by flexing either the left or the right thumb. The EMG activity of the response agonists was systemically recorded by means of surface electrodes disposed on the skin of the thenar eminences above the flexor pollicis brevis. In the Hoffman (H) reflex experiment (Hasbroucq, Akamatsu, Burle, Bonnet, & Possamaı¨, 2000), the stimuli were presented to the left or right of a fixation and the stimulus-response mapping was varied: In half the blocks, the participants had to give a right hand response when the stimulus appeared on the right side (and a left response to a left stimulus), whereas on the other half of the blocks, subjects had to use the reverse mapping (right response to left stimulus and left response to right stimulus). In the TMS experiment (Burle et al., 2002a), the stimuli were presented at the fixation and their color, green or red, indicated which response to make. In the EEG experiment (Vidal, Grapperon, Bonnet, & Hasbroucq, 2003), the subjects were to perform a stroop-like task: The words ‘‘rouge,’’ ‘‘bleu’’ and ‘‘vert’’ (red, blue and green in french, respectively) were presented centrally in one of the three ink-colors (red, blue or green). For each subject, one ink-color was associated with the right response, one with the left response, and the last one was associated with a nogo. All the combinations were equiprobable, leading to 33% of compatible trials, 33% of incompatible trials and 33% of nogo trials. The reader will find the details of the experimental procedures in the above cited papers.

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unique synapse of the loop. Thus, the gain of the reflex loop is cerebrally controlled by way of presynaptic inhibition and any change in reflex amplitude reflects modulations in presynaptic inhibition and originates from supra-spinal structures. In the conducted experiment, the reflex was elicited at different times during the RT interval both in the muscle involved in the required response and in the muscle involved in the non-required response. Four stimulations dates were used: 40, 80, 120, and 160 ms after stimulus presentation. Based on RT value on each trial, those stimulation dates were converted in date relative to the onset of the voluntary EMG instead of the stimulus. Therefore, one could evaluate the changes in excitability as a function of pre-EMG interval. The results of the experiment are presented in Fig. 3. During most of the RT interval, the amplitude of the reflexes remains stable; suddenly about 35 ms prior to the onset of the voluntary EMG, the amplitude of the reflex elicited in the involved muscle increases and, symmetrically, the amplitude of the reflex elicited in the non-involved muscle decreases. This pattern clearly reveals that the arrival of the voluntary motor command on the a motoneurons controlling the response agonist is preceded by a removal of the presynaptic inhibition of these neurons and by a reinforcement of the presynaptic inhibition of the motoneurons controlling the alternative response. The increase in the presynaptic inhibition of the motoneurons controlling the non-required response substantiates the idea according to which this response is inhibited during the RT interval. The spinal cord therefore appears to be a site of inhibition.

2.2. Inhibition at the spinal level In a first study, we looked for a possible manifestation of inhibition at the spinal level. In this aim, we resorted to the Hoffman (or H) reflex technique. The median nerve was electrically stimulated at the level of the wrist in order to recruit its sensory fibers. Among these fibers are the Ia afferences that project directly to the a motoneurons, these two types of neurons form the basis of the monosynaptic reflex loop (see Fig. 2). The electric stimulation of the Ia afferences provokes the synchronous discharge of the muscle motor units, termed H reflex, which is quantified by surface EMG recordings. An important point is that the gain of the loop is permanently controlled by the brain via an inhibitory spinal interneuron projecting upstream from the

Fig. 3. Amplitude (in z scores) of the H reflex as a function of the time pre-response. The EMG response started at time 0. During the major part of the RT, the H reflex remains stable both in the involved and in the non-involved hand. About 35 ms before EMG onset, the excitability of the motor nuclei involved in the response increases, whereas the excitability of the motor nuclei involved in the incorrect response decreases.

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2.3. Inhibition at the cortico-spinal level as revealed by transcranial magnetic stimulation In a second step on the track of inhibition, we have used the technique of TMS so as to probe the excitability of the zone of the primary motor cortex controlling the thumb flexion and the downstream structures. The coil was optimally positioned for stimulating the thumb representation in the left motor cortex. The stimulation transynaptically activates the cortifugal cells that project onto the spinal a motoneurons. The stimulation recruits two populations of interneurons. The first population is excitatory (EC on Fig. 2), projects directly to the pyramidal cells and is responsible for the motor evoked potential (MEP); the second population is inhibitory (IC, Fig. 2), projects onto the excitatory interneurons, and is responsible for the silent period, that is a suppression of the muscle activity for a brief period of time (for a brief review, see Burle et al., 2002a). The physiological effect of TMS was quantified with classic surface EMG techniques. The subjects were to exert a tonic activity in their response agonists in order to start a trial. The TMS was delivered at different times during the RT interval, that were chosen as a function of each subject RT distribution: The first stimulation was delivered at 1/4 of the first decile of the RT distribution, the second at 1/2, the third at 3/4, and the last at the value of the first decile. In the following, we shall focus on the duration of the silent period elicited by the stimulation of the inhibitory population of interneurons. The duration of the SP due to the stimulation of inhibitory interneurons of the involved cortex decreases as one gets closer in time to the response (Fig. 4), which indicates that this cortex becomes progressively more excited. Symmetrically, the duration of the SP due to the stimulation of the non-involved motor cortex increases as time elapses, which shows that this structure becomes

Fig. 4. Duration of the silent period as a function of the post-stimulus time. The duration of the silent period decreases in the involved cortex, indexing an increase in excitability, whereas it increases in the noninvolved cortex, revealing an inhibition.

increasingly inhibited. One can thus conclude that, like the spinal cord, the primary motor cortex constitutes a site of inhibition. 2.4. Inhibition at the cortical level as revealed by surface Laplacian estimation We have further tracked the inhibition with EEG techniques augmented by approximation of the surface Laplacian (Tandonnet, Burle, Vidal, & Hasbroucq, 2003; Taniguchi, Burle, Vidal, & Bonnet, 2001; Vidal et al., 2003). The spatial definition of conventional monopolar recordings is poor but can be drastically improved by Laplacian transformation. The Laplacian acts as a high-pass spatial filter and thus removes the blurring effects of current diffusion through the highly resistive skull. It provides a good approximation of the corticogram (Gevins, 1989). In the conducted experiment, the Laplacian was approximated by the source derivation method (Hjorth, 1975) modified by MacKay (1983). This method allows one to estimate the Laplacian at a nodal electrode located at the center of a virtual equilateral triangle at the apexes of which are positioned three other active electrodes. In the conducted experiment, nodal electrodes were positioned at sites corresponding to C3 0 and C4 0 , that is 0.5 cm anterior to the C3 and C4 locations in the 10–20 system of the international federation. Fig. 5 presents the activity recorded for the go trials over the involved and non-involved motor cortices. In the period preceding the response (
100 to 0 ms, shaded area), a negative wave develops over the involved motor cortex and, symmetrically a positive wave develops over the non-involved cortex. The resemblance between this pattern and the pattern of excitation–inhibition observed in stimulation studies suggests that the

Fig. 5. Amplitude of the surface laplacian recorded over the motor cortices ipsi- and contralateral to the response. A negativity develops over the motor cortex contralateral to the response (involved cortex), and an positivity develops over the cortex ipsilateral to the response (non-involved cortex).

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negative wave reflects the activation of the involved motor cortex, while the positive wave reflects the inhibition of the non-involved motor cortex. In this context, the EEG data strengthen the notion that the motor cortex is a site of inhibition in choice RT tasks (Vidal et al., 2003). The activity time-locked to the stimulus for both go and nogo trials in the incompatible condition is presented in Fig. 6. The negative and positive waves respectively recorded over the involved and non-involved cortices are recognizable although they are not as well time locked to the stimulus than to the response. Importantly, a positive wave also develops over the motor cortices in no-go trials at about the same time as the positive wave observed over the non-involved cortex in go trials. The presence of this positive wave is important for at least three reasons. First, since in no-go trials participants have really to inhibit their responses, it supports the interpretation of the positive wave observed in go trials in terms of inhibition. Second, it shows that the positive wave can be obtained in absence of a negative counterpart over the involved motor cortex, which suggests that the agent of inhibition is to be found upstream in the information processing flow, possibly in the anterior cingulate cortex and/or the SMA. As a consequence, this type of inhibition appears to be more feed-forward than lateral. Third, and more importantly, it strongly suggests that the activation of the involved motor structures and the inhibition of the non-involved ones is not a wired property of the motor structures but rather reflect the implementation of the voluntary motor command. Another argument for such a strategic implementation

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Fig. 7. Amplitude of the laplacian obtained over the motor cortices in a simple RT task. No ipsilateral positivity is observed before the response. The SMA is not activated neither before the response.

comes from unpublished data from our lab. Macar and Vidal (2002) asked their subjects to produce a 2.5 s duration separated by two left thumb key-presses. In one condition, that served as a control and that was not included in the published paper, the subjects had to give the first key-press as fast as possible after the onset of a response signal. They therefore had to perform a simple RT task, as the response was completely known in advance. We used these data to check whether the positivity was still present in simple RT. The results are presented in Fig. 7. The figure shows the laplacian estimates obtained on C4 (contralateral to the response), C3 (ipsilateral) and FCz (over the SMA). The data are averaged time-locked to the response (not to EMG as in Fig. 5). In the period preceding the response (
150 to 0 ms, shaded area). One can clearly see the contralateral negativity, but no ipsilateral positivity before the response, indicating that the ipsilateral cortex was not inhibited by the activation of the contralateral one. Note further that the SMA is not active before the response, contrary to what Vidal et al. (2003) observed in choice RT. Such absence of activity of the SMA when there is no ipsilateral inhibition is compatible with the idea that the SMA is the agent of the inhibition.

3. Discussion

Fig. 6. Amplitude of the laplacian obtained over the motor cortices during a variant of the Stroop task including one-third of go–nogo trials (Vidal et al., 2003). The data presented correspond to the incompatible situation. In the go task, one can observed the negativity/ positivity observed time-locked to the response, although less clear because of the stimulus-locked averaging. In the nogo situation, one can see a positivity very similar to the one observed over the ipsilateral cortex of the go task.

The results of the three studies converge in demonstrating that in between-hand two-choice RT, the unimanual motor command is expressed bilaterally: the activation of the motor structures involved in the required response is accompanied by an inhibition of the structures involved in the other alternative response. Our results therefore provide direct support for the compelling theoretical notion of inhibition for which there was little empirical support.

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3.1. Connectivity between homologous structures or command implementation? A first question concerns the nature of the symmetrical activation-inhibition pattern observed in the three studies. Does this pattern result from the intrinsic spinal and/or cortical connectivity or does it reflect a strategic option in the implementation of the central motor command? Such a balance in excitability is of course reminiscent of SherringtonÕs reciprocal inhibition (Sherrington, 1906/1947), which is a wired property of agonist and antagonist motor nuclei: When the flexors of one joint are being excited, the extensors of the same joint are inhibited and vice versa (for an illustration in the context of reflex studies see e.g., Brunia, 1984). Reciprocal inhibition, however, has been described between the flexors and the extensors of the same joint but never between homologous response agonists as in our studies. The increase in presynaptic inhibition of the non-involved motoneuronal pool observed in the H-reflex study must therefore reflect a property of the central motor command (for a discussion, see Hasbroucq et al., 2000). This spinal inhibition, as well as the inhibition of the non-involved motor cortex evidenced in the TMS study, has not been empirically dissociated from its activation counterpart. Since the potent influence of transcallosal connections has been demonstrated in a number of studies (Chen, Yung, & Jie-Yuan, 2003; Meyer, Roricht, Grafin, Kruggel, & Weindl, 1995), the possibility that the inhibition observed in our stimulation experiments results from hardwired inter-hemispheric connections cannot be discarded. In other words, these studies do not allow one to decipher whether the inhibition of the non-involved structures is due to an inter-hemispheric connectivity that would mechanically follow the activation of the involved motor cortex or whether it reflects a strategic option in the implementation of the voluntary motor command. In contrast, the EEG study demonstrates that the inhibition expressed by the development of a positive wave over the non-involved motor cortex can be obtained in isolation during nogo trials, and that a contralateral negativity can be obtained without ipsilateral positivity in simple RT. These observations suggest that the inhibition of the non-involved structures is independent of the activation of the involved structures and supports the idea that it reflects the implementation of the central motor command rather than intra-cortical connectivity. Other dissociations between the activation and inhibition have been observed. Although it was not the primary goal of their study, the results obtained by Taniguchi et al. (2001) suggest that the contralateral negativity is similar between simple (precued) RT and choice RT, but that the ipsilateral positivity is reduced

in simple (precued) RT.1 Tandonnet et al. (2003) suggested that motor preparation (time preparation) affects the contralateral negativity but not the ipsilateral positivity. Therefore, one possibility is that, in choice RT tasks, the motor command specifies both the activation of the involved motor structures and the inhibition of the structures involved in the alternative responses. Such a bilateral balance mechanism may serve to prevent erroneous responding by reducing the sensitivity of the noninvolved motor structure from upstream influences. Indeed, the inhibition component is possibly due to the between-response choice required by the task, bearing in mind that in the three studies, before the response signal the two responses were equiprobable, and the subjects were unaware of what response they would have to make after the occurrence of the imperative stimulus. To prevent an error in this context, the subjectÕs interest is to inhibit the alternative response, to ensure that only the correct response will be triggered. 3.2. Feed-forward or lateral inhibition? The TMS data do not shed light on this issue: the inhibition component revealed by the increase in silent period duration during the RT interval can as well reflect the reciprocal inhibition of the two motor cortices and the implementation of a selective pattern whose agent would be located elsewhere in the nervous system. In constrast, most authors agree that the modulation in H-reflex amplitude reflect variations in the presynaptic inhibition of the motoneuronal pools (for a review, see Schieppati, 1987). Such an inhibition is by definition feed-forward, although not all feed-forward inhibitions are of presynaptic type, and its agent is indubitably located higher from the spinal cord in the motor system hierarchy. The occurrence of the positive wave in isolation over the non-involved motor cortex during nogo trials of the EEG experiment suggests that the inhibition observed in the go trials originates not from the opposite motor cortex but from a structure activated sooner during the processing of the information conveyed by the imperative stimulus, for instance the anterior cingulate cortex (Band & van Boxtel, 1999) or the SMA. Indeed, Vidal et al. (2003) showed that the activation/inhibition pattern they obtained from EEG recordings was preceded (50 ms earlier) by another wave over the SMAs. This prior activity recorded over the SMAs, might correspond to an inhibition exerted, by these structures,

1 In this study, a preparatory signal could indicate which response was to be given. Although it is a simple RT task, it was mixed with a choice RT task (no precue). In this situation, an ipsilateral positivity was still observable, although of smaller amplitude.

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on the motor cortex ipsilateral to the response. Let us recall that, in simple RT situation in which no ipsilateral inhibition was observed, the SMA was not activated neither (Fig. 7). Considered together, the present results are more in favor of a feed-forward than of a lateral inhibition. Further research is however needed before strong conclusions regarding this point can be reached. Now, a comment concerning the relationship between the recent model of Usher and McClelland (2001) and our empirical demonstration of inhibition in choice RT is in order. One premise of this model is that lateral inhibition is physiologically more plausible than feed-forward inhibition. In support of this assumption, the authors refer (without citing them) to combined light and electron microscopic studies showing that corticocortical long-range connections, including transcallosal projections, originate from pyramidal cells that are excitatory (glutamatergic) in nature. In contrast, local connections are both excitatory and inhibitory (GABAergic, for a review see Peters & Jones, 1984). From this widely acknowledged organization, Usher and McClelland (2001) inferred that inhibitory influences were predominantly of the lateral or recurrent type (p. 555). This is contradicted by our results suggesting that the inhibition of the non-involved motor structures originate from long-range cortico-cortical connections. As a matter of fact, the feed-forward inhibition that appears most compatible with our findings is very likely implemented by the projection of excitatory long-range pyramidal cells onto local inhibitory interneurons, which in turn project onto the neuronal populations responsible for the nonrequired response. In other words, contrary to Usher and McClellandÕs claim, the organization of cortico-cortical connections is physiologically compatible with a feed-forward inhibition (Burle et al., 2002a; Heuer, 1987). The above discussion may give the impression that inhibition, and executive control mechanisms, only occur at the cortico-spinal tract level. This is certainly not the case, and is not what we are claiming neither. As a matter of fact, several imaging studies of the go–nogo or stop tasks have revealed that other brain structures are involved in the processes required by these tasks, and likely in the inhibitory ones, like for example the right prefrontal cortex (Bokura et al., 2001; Konishi, Nakajima, Uchida, Sekihara, & Miyashita, 1998; Rubia et al., 2001). Importantly, however, the logic developed above cannot be strictly applied to other structures, as one cannot directly measure the inhibition, as defined in the introduction (i.e., an active decrease in excitation). Furthermore, the fact that those structures are active during a task involving inhibition does not necessarily mean that those structures are directly involved in inhibitory components. Therefore, other logics need to be established to expand our quest for inhibition.

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3.3. Physiological inhibition and information processing models The inhibition demonstrated with the three techniques depends critically on the involvement of the studied structures in the response. In other words, its manifestation is response specific. In serial stage models of information processing (Sternberg, 2001; van der Molen, Bashore, Halliday, & Callaway, 1991), the inhibition occurs after the response has been selected on the basis of the information conveyed by the imperative stimulus. Now, since it is response specific, the inhibition we reported likely occurs at the level of response programming or execution. The possibility that this inhibition is feed-forward does not preclude the possibility of lateral inhibition upstream in the processing. For example, it might well be the case that at the response-selection stage, the competition between the representations of the two possible responses is implemented through lateral inhibition. This addresses the question of the location of the response accumulators in ‘‘neurophysiologically inspired models’’ that typically rely on lateral inhibition (e.g., Cohen, Servan-Schreiber, & McClelland, 1992; Usher & McClelland, 2001). As stressed above, in such models, a response is emitted as soon as one of those accumulators reaches a predefined threshold. Given the indexation function defined in the introduction, if such accumulators implement the response execution stage and if the response is given through the activation of the cortico-spinal tract, they have to be located at least at the level of primary motor cortex. As a matter of fact, Spencer and Coles (1999) extended Cohen et al.Õs neural-net model of the Eriksen task (Cohen et al., 1992) to account for results relative to the Ôlateralized readiness potentialÕ (Gratton, Coles, Sirevaag, Eriksen, & Donchin, 1988). They showed that, in addition to accounting for behavioral data, the model can also handle electrophysiological results. The important point here is that, as the LRP is thought to arise from the primary motor cortex, if the response units mimic the LRP, we should conclude that the response units implement the stages reflected in the LRP, that is at the primary motor cortices level, which seems inconsistent with our data suggesting that inhibition is feed-forward rather than lateral. Another possibility, however, is that the ‘‘response accumulators’’ describe response selection, programming and execution occurring at later stages. In this case, such models incorporating lateral inhibition at the response selection stage remain compatible with feed-forward inhibition at the response execution level. Note that in this case, the ‘‘RT’’ of the model does not comprise the response execution time. This would be unproblematic if this time could be assumed to be constant. Different experimental manipulations, however, have been shown to affect response execution speed (for example response uncertainty:

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Hasbroucq, Akamatsu, Mouret, & Seal, 1995; Possamaı¨, Burle, Osman, & Hasbroucq, 2002; Tandonnet et al., 2003). It seems therefore necessary to better specify what response units really reflect in such models, and at which level they are implemented. A last comment is in order, the inhibition of the incorrect response nicely fits the psychological notion that response competition is implemented through a balance of activation and inhibition of the possible responses in regular choice RT. Further, inhibition has also been proposed to be an efficient tool for executive control. The data reported in the go–nogo experiment (Fig. 6) suggest that inhibiting the incorrect response shares some mechanisms with whithholding a response. Now, the question of whether the strategic activation and inhibition of responses in conflict tasks (Burle et al., 2002b; Ridderinkhof, 2002) involves the same processes, and is implemented in the same way remains an open question. The data recorded so far do not shed light on this question, but one can be confident that, as the substrate of inhibition has been identified, suitable protocol coupled with the recordings of the correct indices, will soon provide additional information on this issue.

Acknowledgments The authors thank Franc¸oise Macar for providing us the data of the simple RT task, and Michel Bonnet, Laurence Carbonnell, Sonia Allain, and Wery van den Wildenberg for helpful discussions on this topic.

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