Exp Brain Res (1996) 107:479485 �9 Springer-Verlag 1996

R E S E A R C H A R T I C L E

A l v a r o P a s c u a l - L e o n e �9 E r i c M. W a s s e r m a n n J o r d a n G r a f m a n �9 M a r k H a l l e t t

The role of the dorsolateral prefrontal cortex in implicit procedural learning

Received: 2 September 1994 ! Accepted: 28 August 1995

A b s t r a c t We studied the role of the dorsolateral pre- frontal cortex in procedural learning. Normal subjects completed several blocks of a serial reaction time task using only one hand without or with concurrent non-in- vasive repetitive transcranial magnetic stimulation. To disrupt their function transiently, stimulation was applied at low intensity over the supplementary motor area or over the dorsolateral prefrontal cortex contralateral or ip- silateral to the hand used for the test. Stimulation to the contralateral dorsolateral prefrontal cortex markedly im- paired procedural implicit learning, as documented by the lack of significant change in response times during the task. Stimulation over the other areas did not inter- fere with learning. These results support the notion of a critical role of contralateral dorsolateral prefrontal struc- tures in learning of motor sequences.

K e y w o r d s Transcranial magnetic stimulation �9 Learning and memory �9 Cortical physiology �9 Human

Introduction

Procedural learning refers to the acquisition of new knowledge of a motor task through the repeated perfor- mance of that task (Willingham et al. 1989; Pascual-Le-

A. Pascual-Leone - E. M. Wassermann �9 M. Hallett Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

A. Pascual-Leone ( ~ ) Consejo Superior Investigaciones Cientificas, Unidad de Neurobiologfa, Departamento de Fisiologia, Universidad de Valencia, Avda. Blasco Ibafiez, 17, E-46010 Valencia, Spain; Tel.: (34-6) 3864640, Fax: (34-6) 351-8937, e-mail: alvaro.pascual-leone @uv.es

J. Grafman Cognitive Neuroscience Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

one et al. 1993a, 1994a). It differs from declarative learning, where new knowledge is acquired verbally (Squire 1992). Knowledge can be obtained and ex- pressed implicitly or explicitly. Procedural implicit learning refers to the improvement in performance of a task that results from exposure to that task even though the subject is not aware of the prior exposure. On the other hand, in procedural explicit learning the subject is consciously aware of the task. In the repeated perfor- mance of a complex task, procedural learning might first be implicit before becoming explicit (Willingham et al. 1989; Nissen et al. 1989).

Acquisition of a new skill requires a change in the neural network responsible for its representation and ex- ecution (Pascual-Leone et al. 1995a). The learning-relat- ed neural network seems to be different for different forms of knowledge (Squire 1992). Procedural learning requires the normal function of cerebellar and basal gan- glia structures (Pascual-Leone et al. 1993a) which are richly connected with the dorsolateral prefrontal cortex (Fuster 1989; Passingham 1993). This suggests the hy- pothesis that the dorsolateral prefrontal cortex might be an essential component of the neural network responsi- ble for procedural learning. The present study was de- signed to evaluate the effects of disruption of dorsolater- al prefrontal cortex on a procedural implicit learning task in order to test this hypothesis.

Methods

Subjects

We studied seven naive, normal volunteers aged 26-39 years (mean 32.7 years). All had normal physical and neurological ex- aminations and met the additional safety criteria for repetitive transcranial magnetic stimulation (TMS) developed in our labora- tory (Pascual-Leone et al. 1993b). In particular, none of the sub- jects had a personal or family history of seizures or undetermined, recurrent fainting spells, and none had a history of neurosurgical procedures, closed head trauma, or skull lesions. All subjects gave their informed consent to the study, which was approved by the In- stitutional Review Board.

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Left Supplementary Right dorsolateral motor area dorsolateral

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Supplementary Dorsolateral motor area prefrontal cortex

Fig. 1A, B A Experimental design. Each subject completed a practice and a baseline block of the serial reaction time task in which the trials were presented in random order (filled squares). Thereafter they completed four sets of five blocks of trials, during three of which they were concurrently stimulated over the supple- mentary motor area, or the left or the right dorsolateral prefrontal cortex (rTMS at 5 Hz and 115% of the subject's motor threshold intensity). Each of these sets of blocks consisted of four blocks in which the trials were presented in a repeating sequence (hatched squares) and a last block in which the trials were presented in ran- dom order (filled squares). The repeating sequences in the differ- ent sets were different, unrelated, and ambiguous. B Transcranial magnetic stimulation positions. Schematic illustration of the meth- od used to defined the scalp positions for stimulation over the sup- plementary motor cortex (/eft) and the dorsolateral prefrontal cor- tex (right). The coil used was a figure-of-eight shape and was al- ways placed tangentially to the scalp. The scalp positions were de- termined in relation to the optimal scalp positions for activation of the anterior tibialis (filled circle) or the abductor pollicis brevis (gray circle) muscles

Serial response time task (SRTT)

The study was performed using a variation of the serial response time task (SRTT) (Nissen and Bullemer 1987; Nissen et al. 1989; Willingham et al. 1989). The subject sat in front of a computer screen and a keyboard with four clearly marked response keys. The subject was asked to rest the index, middle, ring, and little fin- gers of the hand on the appropriate response keys in preparation for the task. An asterisk appeared in one of four positions that were horizontally spaced on the screen and aligned above the re- sponse keys. The subject had to push the key aligned with the as- terisk as fast as possible. The asterisk did not disappear until the correct button was pushed, upon which the next stimulus appeared without an interstimulus delay. This is a variation on the original SRTT design in which a 500-ms delay is introduced between a correct response and the appearance of the next stimulus (Nissen

et al. 1989). The interstimnlus interval was eliminated in order to ensure that each block was completed within the time limit for safe, continuous TMS at the chosen parameters (see below). The subjects were randomly assigned to being tested using either their dominant or their non-dominant hand. Handedness was deter- mined using the Edimburgh Handedness Questionnaire. All sub- jects were right-handed; four performed the test with their left hand and three with their right hand.

The test was ordered in blocks of 120 trials. The first block was considered practice and discarded from further analysis. The visual cues (asterisks) in this first block appeared in random order. This block was designed to familiarize the subject with the task. The second block, in which the visual cues also appeared in ran- dom order, was recorded as baseline performance ("baseline block"). Thereafter, each subject completed four sets of five blocks. The blocks in each set were numbered 1 to 5. In the last block of each set (block 5) the visual cues were presented in ran- dom order. The cues in the first four blocks of each set (blocks 1 to 4) were presented in a 12-item repeating sequence. The subjects were not told about the repeating character of the sequence, which was different for each set of blocks. The order of the sets, i.e. the repeating sequence in blocks 1 to 4 of each set, was randomized and counter-balanced across subjects. In addition, the four sets of blocks were randomly assigned to be performed in the absence of TMS or during repetitive TMS over the supplementary motor area, or the left or right dorsolateral prefrontal cortex. Figure 1A sum- marizes the experimental design.

In this version of the SRTT subjects were not specifically asked whether the cues were presented in a random or repeating order at any point during the task. At the onset of the SRTT they were told that cues would in fact appear in a random order. Only at the end of the entire experiment did we question the subjects as to whether they had noted a repeating sequence at any point dur- ing the entire experiment. Prior experiments by our group sug- gested it would be unlikely that subjects would recognize the re- peating nature of the sequence of stimuli in the SRTT, given the length of the repeating sequence and the number of blocks com- pleted.

Transcranial magnetic stimulation (TMS)

TMS was delivered with a Cadwell High Frequency Magnetic Stimulator (Cadwell Laboratories, Kennewick, Wash.) equipped with a water-cooled, figure-of-eight-shaped coil. This device was used under an Investigational Device Exemption from the Food and Drug Administration. Each loop of the coil measures approxi- mately 7.5 cm inner diameter and the intersection of the two loops measures 3.5 cmxl.5 cm. The technical characteristics of this de- vice are summarized elsewhere (Pascual-Leone et al. 1993b, 1995b). Stimulation parameters were chosen to follow the recom- mended safety guidelines (Pascual-Leone et al. 1993b). All sub- jects wore ear-plugs during the stimulation session. Stimulation intensity was 15% above the subject's motor threshold, defined by the method of limits as the TMS intensity capable of evoking at least five motor evoked potentials (MEPs) of 250 gV peak-to-peak amplitude in ten single trials over the optimal scalp position for activation of the abductor pollicis brevis muscle. The optimal scalp position is the one from which TMS elicits MEPs of maxi- mal amplitude in the target muscle. For the determination of opti- mal scalp position and threshold, electromyographic activity was recorded with a Dantec Counterpoint electromyograph (Dantec Medical A/S, Skovlunde, Denmark) with pairs of surface elec- trodes taped to the skin over the thenar eminence. The optimal scalp position was taken to represent the localization of the prima- ry motor cortex (Wassermann et al. 1992).

For stimulation of the dorsolateral prefrontal cortex the stimu- lation coil was centered on the lateral convexity, 5 cm rostral to the optimal scalp position for the abductor pollicis brevis muscle. For stimulation of the supplementary motor cortex the stimulation coil was centered, along the mid-sagittal line, 5 cm rostral to the optimal scalp position for activation of the anterior tibialis mus- cles. Figure IB illustrates the coordinates used to define the stimu- lation positions. For stimulation of the dorsolateral prefrontal cor- tex, the stimulation coil was held tangentially to the scalp with the current flowing parallel to the sagittal axis (Fig. 1B). For stimula- tion of the supplementary motor area, the coil was oriented so that current flow was perpendicular to the head's sagittal axis (Fig. IB). Stimulation frequency was 5 Hz. Stimulation was deliv- ered in trains which started at the beginning of each block of trials and continued for a maximum of 60 s according to the safety rec- ommendation. In all cases, this was sufficient to enssure stimula- tion from the beginning until completion of the block.

Data analysis

Response time was defined as the interval between the appearance of the visual cue (asterisk) on the screen and the time of depres- sion of the first response key, regardless of whether the response was correct or incorrect. We use the term response time instead of "reaction time" because it encompasses both the time between stimulus appearance and response initiation (reaction time) and the time for the execution of the response (movement time). Error rate expresses the percentage of incorrect keys pressed initially and requiring self-correction. The time until correction was not studied. The results of the response times were unchanged if the trials with incorrect responses were discarded. For each subject we determined the median response time (Nissen and Bullemer 1987; Nissen et al. 1989) in each block of trials and expressed the per- formance in each block as a percentage of the performance in the baseline block (Fig. 1A). In addition, for a given stimulation con- dition and subject, we calculated the difference in median re- sponse time and error rate between blocks 4 (repeating sequence) and 5 (randomly ordered trials) of each set (Fig. 1A). This differ- ence in performance is an indicator of procedural implicit learning of the repeating sequence of trials, since none of the subjects was aware of the repeating nature of the visual cues at the end of the set (Nissen and Bullemer 1987; Nissen et al. 1989; Willingham et al. 1989). Collapsing across subjects, mean and standard response times and error rates for each block and TMS condition were cal- culated from the individual results. Statistical analysis of the effect of stimulation condition on the response time and error rate was

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performed with one-way analysis of variance (ANOVA) collapsing across subjects and two-way ANOVA for stimulation condition and subject. Significance level was tested post-hoc with a Scheffe's test and set at P<0.05.

Results

In the n o - T M S condi t ion all subjects showed a progres - sive decrease in response t ime dur ing the four b locks with a repea t ing sequence and a s ignif icant increase in reac t ion t ime in the last b lock o f the set as c o m p a r e d with the previous b lock o f tr ials (P<0.005 by pa i red t- test). The mean response t ime in the fourth repea t ing b lock o f the n o - T M S set was 81.1% of the ind iv idua l ' s response t ime in the base l ine b lock (range 76 .9 -87 .6%) . The error rate in all subjects was very low (<1%) and showed no s ignif icant change in any of the subjects . The mean response t ime in the last b lock o f the n o - T M S set re turned to 98.0% of the ind iv idua l ' s base l ine response t ime (range 92 .6-105 .5%) . This represen ted a mean in- crease in response t ime f rom b lock 4 to b lock 5 of 85.6+25.1 ms. This increase in response t ime f rom the b lock with a repea t ing sequence of visual cues to the b lock with r a n d o m l y presen ted cues is a corre la te of the amount of p rocedura l learn ing (Nissen and Bu l l emer 1987; Nissen et al. 1989). The increase in response t ime is also a measure o f impl ic i t knowledge , s ince none o f the subjects was aware that the visual cues were not pre- sented randomly.

Subjec t ive ly , all sub jec t s fel t that dur ing the sets o f b locks wi th T M S thei r p e r f o r m a n c e was more var iab le and that it t ook g rea te r "ef for t" and "concen t r a t i on" to c o m p l e t e the task. A l l had the i m p r e s s i o n that they re- s p o n d e d s lower in the b locks dur ing the sets wi th T M S than dur ing the n o - T M S set. Four sub jec t s fel t that per - f o rmance was pa r t i cu l a r ly d i f f icul t dur ing s t imula t ion to the con t ra la te ra l do r so la t e ra l p re f ron ta l cortex, two subjec t s fel t that p e r f o r m a n c e was mos t i m p a i r e d by ip- s i la tera l do r so la t e ra l p re f ron ta l cor tex s t imula t ion , and one sub jec t fel t that p e r f o r m a n c e was mos t d i f f icul t dur ing s u p p l e m e n t a r y m o t o r cor tex s t imula t ion . De- spi te these sub jec t ive impres s ions , we found no s ignif i - cant d i f fe rences in r e sponse t ime and er ror rate in the las t b l o c k o f each set in wh ich v isua l cues were ran- d o m l y o rde red (Fig. 2A). This sugges t s that T M S had no ob jec t ive effect on r e sponse execu t ion r ega rd les s o f s t imula t ion site.

However , T M S had profound, pos i t ion-spec i f i c ef- fects on task pe r fo rmance during the b locks in which vi- sual cues were p resen ted in a repeat ing sequence. F igure 3 i l lustrates for a representa t ive subjec t the t ime course o f response t ime dur ing all b locks of the different sets, i.e. dur ing the different s t imula t ion condi t ions . F igure 4 shows group da ta for response t ime across b locks . The effect o f T M S on p rocedura l learn ing was ana lyzed by compar ing the d i f ference in response t ime be tween b lock 4 and b lock 5 o f each set o f b locks , i.e. accord ing to each s t imula t ion condi t ion (Fig. 2B). A N O V A for these two var iables was s ignif icant at P=0 .002 ( F value--7.4, df=3).

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Fig. 2A, B A Choice reaction time in stimulated and unstimu- lated trials. Scattergram of the mean response times (ms) in all subjects in the blocks in which the trials were presented in ran- dom order split by stimulation condition. Each symbol repre- sents the results in a subject; the lines represent the intersub- ject mean and standard devia- tion (dashed lines). B Measure of procedural learning accord- ing to stimulation condition. Mean (_+standard deviation) difference in response times be- tween block 4 (repeating order of trials) and block 5 (random order) across all subjects split by stimulation condition. No rTMS Unstimulated condition, SMA performance during stim- ulation over the supplementary motor cortex, DLF, perfor- mance during stimulation over the contralateral (cDLF) or ip- silateral (iDLF) dorsolateral prefrontal cortex

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Fig. 4 Response times for all seven subjects across the blocks of trials in each set for each stimulation condition. Results are given as mean response time for all subjects expressed as a percentage of the individual's response time in the baseline random block. No rTMS Unstimulated condition, SMA performance during stimula- tion over the supplementary motor cortex, DLF performance dur- ing stimulation over the contralateral (cDLF) or ipsilateral (iDLF) dorsolateral prefrontal cortex. Asterisks mark the values which, when compared with block 1 of each set, yielded statistically sig- nificant results (P<0.05, Wilcoxon rank test corrected for multiple comparisons)

A post-hoc Scheffe's test revealed significant differences between response time during contralateral dorsolateral prefrontal cortex stimulation and response time in all other stimulation conditions (P=0.006 versus response time in the no-TMS condition; P=0.006 versus response time during supplementary motor cortex stimulation; and P--0.021 versus response time during ipsilateral dorsolat- eral prefrontal cortex stimulation). We also performed paired comparisons (Wilcoxon ranked test) between the first and the fourth block of repeating sequence within a set, and between the fourth and the fifth block within a set, for each stimulation condition. Significant results are indicated in Fig. 4. It should be noted that the response times in the random block of trials show a large interin- dividual variability (Fig. 2A). This is related to the fact that some subjects used their non-preferred hands for the experiment and has no specific interest in our experi- ment. However, it did increase interindividual variance and thus makes the outcome appear weaker than in fact it is (Figs. 2B, 4).

There were no significant effects of stimulation con- dition on error rate in any of the blocks of trials. No sig- nificant differences were found in any of the interactions described when comparing between subjects or between subjects performing the task with the left or the right

483

hand. Finally, the effects of stimulation condition were independent of the specific repeating sequence of visual cues used.

All subjects tolerated the repetitive TMS without dif- ficulty. Most of the subjects found stimulation over the dorsolateral prefrontal cortex slightly bothersome be- cause of temporalis muscle contractions. None of them asked to discontinue the stimulation, none developed headaches, and none complained of tinnitus following the stimulation. Stimulation did not induce any move- ments in the contralateral extremities.

Discussion

Procedural learning can be impaired in patients with cer- ebellar dysfunction (Pascual-Leone et al. 1993a), pa- tients with Huntington's disease (Knopman and Nissen 1991), patients with Parkinson's disease (Phillips and Carr 1987; Saint et al. 1988; Harrington et al. 1990; Pas- cual-Leone et al. 1993a), and patients with progressive supranuclear palsy (Grafman et al. 1990). On the other hand, procedural learning may be preserved despite pro- found impairment of declarative learning in patients with temporal lobe and dorsomedial thalamic lesions (Gordon 1988; Squire 1992), Korsakoff's syndrome (Nissen and Bullemer 1987; Nissen et al. 1989), Alzheimer's disease (Knopman and Nissen 1987; Grafman et al. 1990; Knop- man 1991), as well as young adults injected with scopol- amine (Nissen et al. 1987). These findings suggest that procedural learning is dependent on a neural network that receives critical contributions from cerebellum and basal ganglia. Both these structures are richly intercon- nected with the frontal lobe, and in particular the dorso- lateral prefrontal cortex (Goldman-Rakic 1987; Fuster 1989). Repetitive TMS at the appropriate intensity and frequency transiently disrupts function of the underlying cortex (Pascual-Leone et al. 1995b). Therefore, our re- sults suggest that the function of the dorsolateral pre- frontal cortex is also critical for procedural learning, at least in implicit motor tasks such as the SRTT. The role of the dorsolateral prefrontal cortex might be more gen- erally related to learning, rather than limited to procedur- al tasks, but our experimental design does not address the issue of the specificity of the contribution of the dor- solateral prefrontal structures to different types of learn- ing.

The dorsolateral prefrontal cortex contains mnemonic cells that have been shown to be critical in the perfor- mance of delay response tasks and may be the functional substrates of "working" memory (Fuster and Alexander 1970; Goldman-Rakic 1987; Baddeley 1992). In addi- tion, the dorsolateral prefrontal cortex seems to play an important role in the indexing of events in time (Fuster 1985, 1989), for which close integration of cerebellar contributions may be critical (Ivry and Keele 1989). In the SRTT, procedural learning requires the implicit ac- quisition of the repeating sequence of events in time. Procedural learning in the SRTT used in our experiment

484

cannot take place in the absence of the ability to compare a given visual cue (asterisk) position with at least the previous 13 asterisk positions. This comparison has to be made on-line, while the subject is preparing to respond, and has to result in the modulation of the motor output system to allow progressively faster response times. The plastic changes induced by this process can be demon- strated in the modulation of cortical motor outputs to the muscles involved in the task (Pascual-Leone et al. 1994a). We suggest that the dorsolateral prefrontal cor- tex plays a critical role in the integration of cerebellar and basal ganglia contributions to the learning task and in the induction of the appropriate plastic changes in mo- tor cortical output. The pattern of interference with learning is the same as the one observed using the SRTT in patients with cerebellar degeneration (Pascual-Leone et al. 1993a). These results support the hypothesis of pre- vious authors regarding the role of the dorsolateral pre- frontal cortex and the cerebello-frontal connections in implicit motor learning (Fuster 1989; Leiner et al. 1991; Schmahmann 1991).

The impairment of procedural learning during TMS cannot be explained on the basis of non-specific, stimu- lation-related distraction, since it was specific for dorso- lateral stimulation and was clearly lateralized to the hemisphere contralateral to the performing hand. We cannot be completely sure of the structures that were be- ing affected by the repetitive TMS (for discussion about what structures within the brain are being affected by TMS see Pascual-Leone et al. 1995b). The identification of the dorsolateral prefrontal cortex was based on coordi- nates in a stereotactic atlas and there might be substantial interindividual differences. In addition, given the limited focality of this method of transcranial stimulation, we cannot rule out that structures other than the dorsolateral prefrontal cortex were affected. For example, stimulation effects might have extended into fronto-polar regions, rostral supplementary motor cortex, or premotor cortex. Models of the fields induced by TMS in the brain sug- gest that effects on deep brain structures are very unlike- ly (Toffs 1990; Roth et al. 1991). Overlaying the site of stimulation on the scalp onto the subject's brain magnet- ic resonance image would be desirable to improve ana- tomical correlation (Wassermann et al. 1992). However, the consistency of the results across subjects and the cor- relation of our results with those of lesion studies (Fuster 1989) suggest that the effects of TMS on procedural learning were due to interference with the targeted dor- solateral prefrontal cortex. It could be argued that due to the lack of stimulation focality, the motor cortex was be- ing stimulated subthreshold. This is unlikely given the stimulation intensity and the distance from the motor cortex. In addition, repetitive subthreshold stimulation of the motor cortex would be expected to bias the responses (Brasil-Neto et al. 1992) and induce errors in perfor- mance (Pascual-Leone et al. 1994b), neither of which was seen in our experiment.

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