Neuronal Activity in Primate Cortex During Sequential Movements (PDF)

NEUROSCIENCE RESEARCH ELSEVIER Neuroscience Research 20 (1994) 149-155 Neuronal activity in the primate supplementary, pre-supplementary and premotor cortex during externally and internally instructed sequential movements Ulrike H a l s b a n d a'b, Y o s h i y a Matsuzaka a, J u n T a n j i *a aDep...

NEUROSCIENCE RESEARCH ELSEVIER Neuroscience Research 20 (1994) 149-155 Neuronal activity in the primate supplementary, pre-supplementary and premotor cortex during externally and internally instructed sequential movements Ulrike H a l s b a n d a'b, Y o s h i y a Matsuzaka a, J u n T a n j i *a aDepartment of Physiology II, Medical School, Tohoku University, Sendal 980, Japan bDepartment of Neurology, Heinrich-Heine Universitiit, D-4000 Di~sseldorf FRG Received 15 April 1994; accepted 9 May 1994 Abstract This study recorded the activity of neurons in the (i) supplementary motor area (SMA), (ii) pre-SMA (the motor area immediately rostral to the SMA), (iii) premotor cortex (PMC) and (iv) primary motor cortex (MI), while the monkey performed a conditional sequential motor task that ensures sequencing of multiple movements to the same manipulandum. This paradigm was chosen in order to prevent the participation of spatial cues in prompting the correct motor sequence. Three different movements (turn-pushpull) were performed under two task conditions: (i) internally determined (I): the monkey had to generate a pre-determined sequence from memory and without visual guidance; (ii) externally triggered (E): the correct sequence of movements was performed by following lights illuminated one after the other. Neuronal activity during the following periods were analyzed: instruction (300 ms following the onset of the auditory instruction signal); delay (interval between the end of the instruction period or the termination of the previous movement and the movement trigger); premovement (interval between the trigger signal and the movement onset); movement (interval between the mechanically-sensed movement onset and the completion of the movement) and reward (500 ms period centered at the time of reward delivery). Pre-SMA neurons were generally more active during the delay and premovement as compared to the movement, instruction and reward periods. Activity in the pre-SMA was more related to E during the pre-movement period, but exhibited a preferential relationship to I in the movement period. SMA neurons were more active when the sequential motor task was internally generated. By contrast, PMC neurons were more active when the sequence was visually guided. Such preferential activity was rarely found in MI neurons. Keywords: Supplementary motor area; Presupplementary motor area; Premotor cortex; Sequential movement; Primate 1. Introduction Since the pioneering work o f Penfield and Welch (1951), who identified the supplementary m o t o r area (SMA) as a distinct m o t o r area, a separate m o t o r field was reported immediately anterior to the S M A (Rizzolatti et al., 1990; Matelli et al., 1991) that has been termed pre-SMA (Tanji et al., 1991; Matsuzaka et al., 1992). It was found that the pre-SMA contains a significantly higher proportion o f neurons with cue responses, preparatory activity and time-locked activity * Corresponding author, Tel.: +81 22 374 9058; Fax: +81 22 272 2303. to movement trigger signals than the S M A proper, when the animal has to select a single movement according to a visual cue (Matsuzaka et al., 1992). There is evidence from brain lesion studies in monkeys that damage to the S M A and to the pre-SMA leads to a significant impairment in the ability to internally generate a fixed sequence o f three different movements to the same manipulandum (Halsband, 1982, 1987). In contrast, animals with P M C lesions were unimpaired on this task (Halsband and Passingham, 1982; 1985). Furthermore, the non-primary m o t o r areas on the medial surface were functionally differentiated from the premotor cortex (PMC) when single-cell activity was recorded in visually guided as compared to internally 0168-0102/94/$07.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0168-0102(94)00792-O 150 U. Halsband et al. / Neurosci. Res. 20 (1994) 149-155 determined conditional sequential motor tasks (Kurata and Wise, 1988; Mushiake et al., 1991), and in sensoryinstructed versus self-initiated reaching movements (Romo and Schulz, 1992). Mushiake et al. (1991) reported that SMA neurons are more active than PMC neurons when a correct sequence of buttons, to be pressed, is determined on the basis of internalized information stored in memory. In contrast, PMC neurons are more active than SMA neurons, when the animal has to decide which button to press in accordance with available visual information. In its task the animal had to perform the same movement to different locations in space. It remained unclear whether the crucial factor was to perform sequences of movements or to memorize spatial positions or both. In order to clarify this question it will be necessary to train the animal on a conditional sequential motor task that ensures sequencing of multiple movements to the same manipulandum, rather than sequencing of continuous movements to different positions in space. Recent clinical data suggests that the SMA does not seem to be involved in the control of short-term spatial memory (Halsband and Freund, 1990; Gaymard et al., 1993), but the results indicate a prominant role of the SMA in sequential memory-guided saccade tasks (Gaymard et al., 1993) and in the generation of sequences from memory that fit into a precise timing plan (Halsband et al., 1993). Interestingly, in both studies the deficits were most pronounced in patients with SMA lesions in the dominant hemisphere. This study analyzed single-cell activity in four motor areas in a task which required the monkey to retrieve different movements with intervening waiting periods to the same manipulandum. In this task the manipulandum returned to its original position after each movement. The paradigm was chosen in order to prevent the participation of spatial cues in prompting the correct motor sequence. A comparison was made of neuronal activity in the pre-SMA, SMA, PMC and the primary motor cortex of the same animal during the performance of visually guided as compared to internally generated sequences. 2. Methods One Japanese monkey (Macacafuscata, male, 5 kg) was used. It was taught to perform with its preferred right arm a sequence of three movements to the same manipulandum: (i) to turn the manipulandum to the left through 45 °, (ii) to push it 4.5 cm away from the starting position and (iii) to pull it 4.5 cm towards itself. The manipulandum returned to its original position after the completion of each movement. The task was performed under two different conditions: (i) internally determined (I): the monkey had to generate the pre-determined sequence ' t u r n - p u s h - p u l l ' from memory. In this condi- tion no visual information was given. 0ij Externally triggered (E): coloured LEDs (red-yellow-green) were attached to a panel placed 30 cm in front of the animal. The correct sequence of movements was performed by following lights illuminated one after the other. The red, yellow and green LED meant that the manipulandum should be pushed, pulled and turned, respectively. Sequences varied in a semirandom order, but included the sequence turn-push-pull used in I. Each experimental condition continued for a variable number of trials, ranging from 7 to 12 trials. At the beginning of each trial, 1 of 2 auditory instructions (tones of different frequencies) was given to tell the monkey which mode it was in. During this period (2.5-3.5 s) the animal was required to keep the handle in the central position. Thereafter, the time to start the whole sequence was indicated with a high pitch trigger signal. The animal was trained until its sequential performance was stable and at a consistent correct rate of _>90% in both conditions. A drop of orange juice was delivered 500 ms after the performance of the correct sequence. Conventional chronic single-unit recording methods were employed. Glass-insulated elgiloy electrodes were advanced into the cortex by a stepping microdrive. Neuronal action potentials were recorded, fed to an amplifier and a window discriminator, and then processed by the microcomputer for an on-line analysis. Raster displays were constructed by aligning the neuronal activity to instruction, trigger, movement and reward onset. EMG analysis of activity in hand and arm muscles revealed that the movement-related muscle activity during I and E conditions was not different. Furthermore, no activity changes in forelimb muscles were found in the instruction periods. Neuronal activity was judged to be task-related by visual inspection of the histograms and was analyzed offline on a trial-by-trial basis. Neurons were defined as task related when the number of discharges in at least two consecutive bins of the histogram, aligned at the specific event, deviated by > 3 S.D. of the mean value, calculated during the control period of 1000 ms preceding the time of appearance of the instruction signal. Neuronal activity during the following periods were analyzed. The instruction period was defined as 300 ms following the onset of the auditory instruction signal. The delay period began at the end of the instruction period, and ended at the occurrence of the high pitch tone signal that served as the movement trigger. For the second and third of the sequential movements, the delay period began at the termination of the previous movement. The premovement period was the interval between the trigger signal and the movement onset. The movement period was defined as an interval between the mechanically-sensed movement onset and the completion of the movement, that was also mechanically sensed. The reward period was a 500 ms period centered at U. Halsband et al./Neurosci. Res. 20 (1994) 149-155 the time of reward delivery. All task-related neurons revealed statistically significant activity changes (P < 0.01, Mann-Whitney U-test), compared to the control period. Identification of cortical recording sites was based on cytoarchitectonic analysis and intracortical microstimulation data (Mushiake et al., 1991; Matsuzaka et al., 1992). Neuronal activity during the 5 periods defined above was analyzed on a trial-by-trial basis. 151 to E (P < 0.001). The frequencies of occurrence of responses belonging to each category were calculated as a percentage of the total population of task-related neurons in each area. Pre-SMA neurons were generally more active during the delay (n = 94) and premovement (n = 97) as compared to the movement (n = 60), instruction (n = 36) and reward periods (n = 9). A comparison of neuronal activity during I and E revealed that pre-SMA neurons were preferentially active during E in the premovement period, but more related to I in the movement period (see Table 1). A typical example of a pre-SMA neuron is illustrated in Fig. 1 (left). When the sequence was internally instructed (top), the cell shows premovement and movement activity in relation to the third movement (pull) of a remembered fixed sequence of three distinct movements (turn-push-pull). In contrast, when the task was visually guided (left, bottom), the cell was active during the instruction, delay and premovement periods, but inactive during the movement periods. In the SMA (n = 209) 172, 179 and 164 neurons exhibited changes in activity during the delay, premovement and movement periods, respectively, as compared to 61, 78 and 63 PMC neurons (n = 81). Seventy-one SMA neurons showed changes in activity during the instruction and 22 during the reward period; in the PMC the number of neurons was 21 and 5, respectively. During both the premovement and movement 3. Results Among the 425 task-related neurons recorded in this study, 209 were obtained in the SMA, 108 in the preSMA, 81 in the PMC and 27 from the primary motor cortex. Within the premotor cortex, 56 were recorded from the dorsal part of the PMC (PMCd) and 25 from the ventral part (PMCv). An account on differences in neuronal activity between the PMCv and PMCd will appear later (Halsband and Tanji, unpublished). Striking differences of neuronal activity were observed in the four motor areas. The activity during I and E conditions was compared by Mann-Whitney Utest, and was classified into 5 groups: (i) exclusively related to I (P < 0.001), (ii) more related to I ( P < 0.05), (iii) equally related (if the activity was not significantly different in the two modes at P < 0.05), (iv) more related to E (P < 0.05) and (v) exclusively related Table 1 Distribution of neurons in three motor areas classified into 5 categories according to activity preference in internal/external conditions PMC (n = 81) SMA (n = 209) Turn Push Pull l~ 2 12 9 5 16 22 4 22 22 1 11 50 53 1 2 21 29 3 2 16 43 2 2 20 35 7 6 57 107 12 3 14 15 2 3 12 19 1 2 12 24 2 8 38 58 5 PRE-SMA (n = 108) Turn Push Pull r~ Turn Push Pull 10 39 24 2 14 59 12 21 1 10 56 37 15 2 34 154 73 38 3 2 14 20 13 1 5 18 14 29 13 4 17 18 33 10 II 49 52 75 24 11 44 48 12 10 68 53 26 2 9 43 58 18 1 30 155 159 56 3 2 17 21 21 14 4 16 15 23 29 3 10 20 22 27 9 43 56 66 70 8 35 40 10 13 62 40 14 12 33 47 7 1 33 130 127 31 1 1 15 12 9 1 5 15 4 4 5 2 9 6 2 2 8 39 22 15 8 Delay period I only I>E I=E E>I E only Pre-movement period I Only I>E I=E E> I E only Movement period I Only I>E I=E E>I E Only 152 L/. Halsband et al. / Neuro,sci. Res, 20 (1994) 149-155 [ MEMORY ] o.... IIIII lull I In l....... I , M I , PUSH I I I III " II ,.t II ;........ IIIh...... ''"' "" " ' I PULL I n OINI °,," Hill l I K I I ' ':,C..... I I l l r, ,.,...... ,,lq, I "" "+ I I * nl'l ' IIIOIOl MEMORY ] IOlll...... , I , ~ , ° I~" I l~l l+ll I II , I l' SMA ,....., ¢ ¢1 II*I an ,.~,.,,=~,=', IIii I ,° I1*111 l~ll , I TURN " I ¢ , cell I II. n pre-SMA a.-,l,,,,,...... IOIll ~I"--'.'.,, Ul nl I I , I i " , '' '.°" ' = I! Ullll'llll'nlllll~ It lllllmmllla/ ~ I H...'. " l ,n~bam= J 1 TURN i i I i i i l l l l iii ~ i ~11111 ii i~11 loll I I II I r I I lllMlkl [olll IIIllll I I I I il t I I I I I 0 I 4° i II I I I I I I II II I Itl I I ,.,,,~ ,,,,., cell........ PUSH -- PULL y I Illlllllllll I [I I. II011 I i. i + i I IIII I1 I II I Illll IIIlllll n[ I I*1 III I I i = ~ lillllll DIII~I~I * iiii i d ~I n ~" Olll0lllllll [I + i H h I l IlllJl II r o" Ii ii * ,v,r.... -, ,.,,,,,, ,, , ,....... *. , [ i it ,.- ! I Ii Illlll II I] ' "I"-" P'~"~'" " !| ,,,,, ,, , ,,.., ,.,I ~, INI I ~ II #I~III~¢IIIIIIIIII]III t,.,,, ,.,,,,, " I lllllll~llll ,?.,. "'"~' '° " i #] I¢I IIIIIII IIIII IL I _J [ VISUAL t ] TURN -- t L ",",", ,' '~.',,"; ,=; ¢,...............,,t,.., , H.lml m.,1 i '.... , Immt~. H PUSH t imm~ , * , " t i d PULL y J t VISUAL ~ L ,',;"T~,~,, ,'-" " ',"" ',,,. " "V ~ '. ", ,''" ', :',] =, =.(...... Ilml= I " WIIIM,I||. ,' =m ,| ~ la ° l. ~iH , " ~,o ill PUSH TURN ] i J , , | + °. I I I I ','",','~'.,,'.',',, /............ I I III * IIn#llll Ill ° I ii i Illl'l I" I Iii i = I I ° ,, it + I N/ , :'?/' , ' - ' ",,'.",,?,"'.~ ',' ,' ,'l,'"':,', ~ ",i ,/ ~ ,..'. ,.......'. :........... ~ :,,, /. o I I ¥ i i I = I Illl PULL - - ,° o * ,J ° % , i o ° H, , ° i ° , |":t i ," * ! 1 , sec Fig. l. l.,¢ft: example o f a p r e - S M A neuron exhibiting preferential relationship to internally generated m o t o r sequences. Top: this neuron was predominantly active before and during the third internally instructed sequential movement (pull). Bottom: the same p r e - S M A neuron exhibited preparatory activity in relation to the visually guided sequence task. In this mode, the neuron was predominantly active during the instruction and delay periods, but less active during the pre-movement and movement periods. Right: activity of a cell in the SMA exhibiting a selective relationship to a remembered sequential movement. The SMA neuron was exclusively active when the animal performed the internally guided sequence task (top), but inactive when the sequence was informed by visual cues (bottom). Time of occurrence of neuronal discharge is displayed as dots, with each row representing a trial. Rasters are aligned on the onset of the 'pull' movement; the bars under the labels 'turn' and 'push' indicate ranges of movement onsets. Small crosses and squares in raster displays denote the time of occurrences of trigger signals and movements onsets. Each histogram is made by summation of the neuronal data in each raster. Binwidth = 60 ms. periods, S M A neurons were more active when the sequential m o t o r task was internally generated. By contrast, P M C neurons were more active when the sequence was visually guided. The distinction was apparent in relation to the three movements, as indicated in Table 1. N o P M C neurons were recorded during the movement period, that were either exclusively or preferentially related to I; in contrast, in the S M A the percentage o f neurons that exhibited changes in relation to I was as follows: 19.2% (turn), 35.4% (push) and 20.1% (pull). Only a small number o f S M A neurons exhibited a preferential or exclusive relation to E during the premovement and movement periods. A n example o f the activity o f a cell in the S M A is indicated in Fig. 1 (right). This cell was exclusively active when the animal performed the internally guided sequence task (top). When the sequence was informed by visual cues (bottom) the neuron was inactive. A typical example o f a P M C neuron exhibiting an exclusive relationship to the visually instructed sequential m o t o r task is shown in Fig. 2 (left, bottom). This neuron was found to be most active during the premovement period o f the third sequential movement (pull). In the same animal, neuronal activity was also recorded in the MI. These neurons exhibited similar activity during the delay, premovement and m o v e m e n t periods, regardless o f whether the sequential m o t o r task was internally determined or visually guided (Fig. 2, right). 4. Discussion This present study analyzed single-cell activity in the pre-SMA, SMA, P M C and M I while the m o n k e y performed a sequence o f three distinct movements to the same manipulandum. The neuronal activity in the multiple m o t o r areas varied a great deal, depending on whether the movements were guided by external signals or performed on the basis o f m e m o r y ( E and I conditions). Because the E M G analysis showed that the activity in forelimb muscles were similarly observed during 153 U. Halsband et al. / Neurosci. Res. 20 (1994) 149-155 PMC [ MEMORY ] cell MI TURN PUSH [ MEMORY PULL. ° r * o /,'-""" , * [ VISUAL ] TURN me ~ i i 13 i ° I , " ill i~ ° i i i *l O00l ° i I ,. ,_. I ,. '... i1| ÷ n ii on ~ t i , I.............. o |Ill I Ill ~ 4 i l e " "': tl*.-. , ,, I i , PUSH i i i ,...~. , ,.. PULL i i i ,, , ' ,......:.,..~,.]:.,,.. ~-, ~.d~.,':,,' '.r..,::-:,',..... , "..,,.,, i ' I I I ' ~,','. ] "': :"i" TURN ', ' ,. i ";.e ,.. i,, ,:, ,. PUSH_." 'dill.... ,",, '.,,,,, ', ,,,: ,, OR I ' " I a I0.. I' '""' , 1:,.,,, : I., I D ,:,..: " °' ,...bILL [ VISUAL I I ] ~ 0010 , I e L" ,. i I| I II i ii aL I"..... PULL V.*,.... ; ," i i1+1,t, 0 ii ii II I 0 ii °tll i ~ *l il PUSH I l.......... II i i L 11' ',., :, :',,'",,,.. :-..,,'=.,-, ,, I J i * I "=,= I i ,...... ,.. J. l i *.. I. i ,. I= I *. I. ° * * TURN V i. ] cell ' ' , PULLy.,...-._=.',.... ,, |. m a ~ o n..... ",-.~,',,,.... '," ,' t.~_....... , i' i j ,,~,.... ', "- "-'~,'T".'.= "lie.~..i,';", ,. {,el=llu.... ei=, e l. i ". ".----,",-':,,' i 0 ,....' ~" =.~'i.ll ,.hi , ,1,,"~;,'". i..= I 1 ~..... 1 sec Fig. 2. Left: Typical example of a PMC neuron exhibiting an exclusive relationship to the visually instructed sequential motor task (bottom). The PMC neuron was found to be most active during the premovement period of the third sequential movement (pull). Right: example of an MI neuron exhibiting similar activity in association with a visually guided and internally instructed motor task. Display formats are the same as in Fig. 1. Binwidth = 60 ms. execution of the three movements in the two conditions, the real differences in neuronal activity are not likely to be explained by differences in motor execution. Rather, differences seem to be the outcome of whether or not the motor sequence was determined by memorized information. MI neurons exhibited similar activity during the instruction, delay, premovement and movement periods, regardless of whether the sequential motor task was visually guided or internally instructed. In contrast to MI neurons, the majority of PMC, SMA and pre-SMA neurons exhibited different activity, depending on how the correct sequence was instructed. These findings are in agreement with a clear distinction between set-related cells in primary and non-primary motor cortex as recently reported by Germain and Lamarre (1993). They studied neuronal activity in the PMC and MI cortices while the monkey had to choose the correct movement on the basis of auditory cues. It was found that only setrelated neurons, recorded in the PMC, changed their firing rate during the delay in relation to conditional motor learning. In the present study, more than half of the PMC neurons were preferentially or exclusively active in relation to externally instructed movements during both the premovement and movement periods. The results indicate that SMA neurons are preferentially active when the correct motor sequence is determined on the basis of internalized information. These findings are in accordance with experimental and clinical data, which suggests that the SMA is crucially involved in internally generated motor sequencing (Roland et al., 1980; Halsband, 1987; Gaymard et al., 1990, 1993; Lang et al., 1990; Deiber et al., 1991; Fried et al, 1991; Mushiake et al., 1991; Halsband et al., 1993; Jenkins et al, 1993). Fried et al. (1991) reported a frequent occurrence of multi-joint movements from stimulating the SMA in patients with intractable seizures, and observed that this area is crucially involved in the intention to perform a motor activity, rather than in simply controlling muscle contraction. The present study makes a further point: the preSMA was found to contain a significantly higher proportion of neurons, that were active during the premovement period, as compared to the movement interval. In contrast, SMA neurons were highly active, during both movement and premovement periods. The abundance of premovement related activity in the preSMA is in accord with recent neurophysiological results which indicate a greater proportion of preparatory activity and cue responses in pre-SMA neurons as com- 154 U. Halsband et al. / Neurosci, Res. 20 (1994J 149-155 pared to the SMA proper (Matsuzaka et al., 1992). Earlier, Alexander and Crutcher (1990) found that the preparatory activity was more abundant in the anterior part of the SMA, which corresponds to the pre-SMA, as defined in the present investigation. In the present study, a most interesting result was the differential preponderance of internally generated as compared to visually guided activity in the premovement periods of the pre-SMA and SMA. The neuronal activity pattern in the premovement period demonstrated an abundance of activity related to E in the preSMA. In contrast, SMA neurons were preferentially activated during I. The results should be interpreted in the light of recent neuroanatomical findings, which suggest that the pre-SMA has more access to visual information than the SMA proper. There are direct projections from the inferior parietal lobule, area PG and i~FG, to the pre-SMA (Tanji et al., 1991; Luppino et al., 1993) and the pre-SMA receives afferent projections from the prefrontal cortex (Lu and Strick, 1990; Luppino et al., 1990, 1993). Furthermore, as compared to the SMA, the PMC is known to have more sources of sensory information (Kubota and Hamada, 1978). There are various routes by which the PMC receives visual and somatic information directly from the parietal cortex (e.g., Jones et al., 1978; Bowker and Coulter, 1981; Petrides and Pandya, 1984; Matelli et al., 1986), and via the cerebellarthalamic projections (Glickstein et al., 1985; Matelli et al., 1989). Very recently, Mushiake and Strick (1993) found that the ventrolateral part of the cerebellar dentate neurons was preferentially active during a visually guided sequential motor task. This finding is of particular interest because this is exactly the part of the dentate nucleus that projects to the PMC (Orioli and Strick, 1989; Strick et al., 1993). On the other hand, more detailed analysis of the activity in the PMC is required. Abundant projections from area 5,7 and SII form the major inputs to PMCv. By contrast, area 5 appears to be the sole source of projection to the PMCd from the parietal cortex (Kurata, 1991). Thus, as a next step, there is a need to determine more specifically what is encoded in PMCv as compared to PMCd during the performance of visually guided and internally determined sequential motor tasks (Halsband and Tanji, unpublished). Acknowledgements The work was supported by the Human Frontier Science Program, and in part by a Grant-in Aid for Scientific Research from the Japanese Ministry of Education, Culture and Science (03NP0101 and 04NP0101). The authors thank Mr. M. Kurama and Mr. Y. Takahashi for their kind technical assistance. 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