Movement Sequence-Related Activity Reflecting Numerical Order of Components in Supplementary and Presupplementary Motor Areas

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1 RAPID COMMUNICATION Movement Sequence-Related Activity Reflecting Numerical Order of Components in Supplementary and Presupplementary Motor Areas WILLIAM T. CLOWER AND GARRETT E. ALEXANDER Department of Neurology, Emory University School of Medicine, Atlanta, Georgia Clower, William T. and Garrett E. Alexander. Movement se- movements precede, or follow, X. Here we present evidence quence-related activity reflecting numerical order of components that the numerical order of specific components may also in supplementary and presupplementary motor areas. J. Neuro- be represented by movement sequence-related activity of physiol. 80: , The supplementary motor area SMA and pre-sma neurons. ( SMA) and presupplementary motor areas ( pre-sma) have been implicated in movement sequencing, and neurons in SMA have been shown to encode what might be termed the relational order METHODS among sequence components ( e.g., movement X followed by movement Y ). To determine whether other aspects of movement A juvenile macaque (Macaca nemestrina, 5 kg) was trained to sequencing might also be encoded by SMA or pre-sma neurons, position a cursor on a video display by moving a joystick with the we analyzed task-related activity recorded from both areas in conscured the monkey s view of its working forelimb. Trials began right hand. The left arm was lightly restrained. A neckplate ob- junction with a sequencing task that dissociated the numerical order of components ( e.g., movement X as the 2nd component, irrespeccm white square) arrayed in the form of a diamond (Fig. 1, A and with illumination of one of four potential targets (each a tive of which movements precede or follow X ). Sequences were constructed from eight component movements, each characterized B). Once the cursor was aligned with this home target (Fig. by three spatial variables ( origin, direction, and endpoint). Taskms) of one of the home-adjacent targets served as an instruction 1A1), the others were also illuminated (Fig. 1A2). Dimming (100 related activity recorded from 56 SMA and 63 pre-sma neurons was categorized according to both the epoch ( delay, reaction time, stimulus ( IS) designating the first target, and thus the clockwise and movement time) and the spatial variable or component movemovement sequence (Fig. 1A2). The monkey then executed a ( CW) or counterclockwise ( CCW) orientation, of the required ment with which it was associated. All but one instance of taskdelayed sequence of target captures, proceeding around the diarelated activity was selective for one of the spatial variables ( SVmond along the instructed CW or CCW path. Each movement was selective) rather than for any of the component movements thempreceded by a delay (600 1,200 ms), during which the cursor selves. Of 110 instances of SV-selective activity in SMA, 43 (39%) showed significant effects of numerical order. The corresponding remained at the target just captured (Fig. 1, A3, A5, and A7) until incidence in pre-sma, 82 (71%) of 116, was substantially higher the latter s color changed from white to yellow as a nondirectional (P õ ). No effects of numerical order were evident among trigger stimulus (TS), prompting the next target capture (Fig. 1, the hand paths, movement times, or electromyographic activity A4, A6, and A8). Once the required sequence was completed, a associated with task performance. We concluded that neurons in fourth delay (600 1,200 ms) was followed by a catch stimulus SMA and pre-sma may encode the numerical order of compomonkey signified its assessment that the three-component sequence (CS) that appeared the same as a TS (Fig. 1, A9 and A10). The nents, at least for sequences that are distinguished mainly by that aspect of component ordering. was complete by not initiating a fourth movement following the CS. After a 900-ms post-cs delay (Fig. 1A11), correct performance was rewarded with a drop of juice (Fig. 1A12). INTRODUCTION Single cell activity was recorded from left SMA and pre-sma with the use of conventional recording techniques ( Alexander and Both the supplementary motor area ( SMA) and presuppleall eight trial types ( Fig. 1C), presented in pseudorandom order. Crutcher 1990). Each cell was tested with 8 10 repetitions of mentary motor area ( pre-sma) have been implicated in the Receptive fields were mapped with tactile and proprioceptive stimcontrol of movement sequencing ( Chen et al. 1995; Halsuli, and effects of local microstimulation were assessed ( 40 ma, band et al. 1994; Mushiake et al. 1991; Picard and Strick biphasic 200 ms negative/positive pulses, 330 Hz ms) 1997; Tanji and Shima 1994). Neuronal activity related to ( Alexander and Crutcher 1990; Luppino et al. 1991; Matsuzaka et specific sequences was first demonstrated in SMA by Mushi- al. 1992; Mitz and Wise 1987). Task-related activity was recorded ake et al. (1990). Subsequently, Tanji and Shima (1994) from muscles of the working shoulder, elbow, and wrist with pairs reported sequence-related activity in SMA that reflected the of Teflon-coated stainless steel wires. Electromyographic ( EMG) relative ordering of movement components. An SMA neuron activity was amplified, rectified, integrated ( 20-ms bins), and ana- might discharge during movement X if and only if X were lyzed in the same manner as the neural data. preceded, or followed, by Y (Tanji and Shima 1994). Such Hand/ joystick position was sampled at 200 Hz. Hand paths were plotted (as in Fig. 2) and visually compared for possible order activity might be said to reflect the relational order among effects with the use of computer overlays. For quantitative comparisequence components. Movement sequences may also be sons, we used the mean midpoint deviation ( perpendicular distance distinguished by the numerical order of specific components, between cursor position and midpoint of the intertarget line) as a i.e., by their ordinal positions ( 1st, 2nd, etc.), independent measure of trajectory curvature ( Wolpert et al. 1994). These and of their relational ordering. For example, movement X may similar comparisons of reaction times ( RTs) and movement times be the second of three components, irrespective of which ( MTs) by ordinal position were performed with the Tukey multiple /98 $5.00 Copyright 1998 The American Physiological Society

2 SEQUENCE-RELATED ACTIVITY IN SMA AND PRE-SMA 1563 FIG. 1. A: subject s display over the course of 1 trial. Numbered arrows represent sequence components; filled arrows, current; open arrows, next/previous. Squares represent targets; filled circles represent cursor positions. For this trial, the bottom target is home (HT) (1). Once HT has been captured (HTC), an instruction stimulus (IS) specifies the required sequence orientation (2). Trigger stimuli (TS1 TS3), preceded by delays (pre-ts1 TS3), prompt the component movements (Mvt1 Mvt3) (3 8). Another delay (pre-cs) (9) precedes the catch stimulus (CS) (10). Following a post-cs delay (11), a liquid reward is dispensed (REW) (12). B: time line of events, epochs, and responses. C: numerical order of spatial variables and component movements (numbered arrows) was dissociated across the 8 sequences, as were the spatial variables themselves. Components of each sequence are coded with the same fill as the originating home target. Origins, endpoints: T Å top; B Å bottom; R Å right; L Å left. Directions: DL Å down/left; DR Å down/right; UL Å up/left; UR Å up/right. two-way analyses of variance ( ANOVAs): origin 1 orientation, endpoint 1 orientation, and direction 1 orientation (a Å 0.01). Activity was considered selective for a spatial variable if in the corresponding ANOVA there was a main effect for that variable and no interaction with sequence orientation. This implied selective dependence on that variable independent of the other two (the 3 spatial variables being dissociated across sequence orientations) and ruled out a selective relation to one of the component move- ments themselves ( each of the 8 component movements being confined to sequences of a single orientation). Activity considered selective for one of the eight component movements was identified by the conjunction of main effects plus interactions with se- quence orientation for all three of that movement s associated spatial variables. Activity found selective for a spatial variable or component movement was then tested with a one-way ANOVA for ordinal position ( a Å 0.01). If a main effect was present, planned comparisons were made of mean firing rates associated with the three comparison procedure for estimating simultaneous 95% confidence intervals. Task-related activity was first categorized both by epoch ( task interval in which it occurred) and by the associated movement or movement variable. Trial-by-trial discharge rates were computed for three epochs; delay (TS 300 ms r TS), RT (TS r movement onset), and MT ( movement onset r target capture). Four target locations and two sequence orientations yielded eight types of component movements and eight distinct movement sequences ( Fig. 1C). Each component movement entailed three spatial variables: target of origin ( T, top; B, bottom; R, right; and L, left), direction ( DL, down/ left; DR, down/ right; UL, up/ left; UR, up/ right), and targeted endpoint ( T, B, R, L). Spatial variables were dissociated across the eight sequences, as were their ordinal positions and those of the component movements. A cell might show task-related activity in more than one epoch. Each instance of epoch-specific activity was tested for relatedness to one of the spatial variables or component movements with three

3 1564 W. T. CLOWER AND G. E. ALEXANDER FIG. 2. A: numerical order effect, type A. Delay-specific activity on trials where point B was the endpoint of the 3rd movement. Rasters and peri-event histograms are aligned with TS1 TS3 (dashed lines, arrowheads). Ticks represent action potentials. Hand trajectories are shown beside each raster. Abbreviations as in Fig. 1. Scales, horizontal in milliseconds, vertical in spikes/s. B: numerical order effect, type B. Reaction time specific activity on trials in which L was the endpoint of either the 1st or 2nd (not the 3rd) movement. Conventions as in A, except here the activity is aligned with movement onsets (Mvt1 Mvt3). were evident among the hand paths or MTs of the component movements or in the task-related EMG activity recorded from 12 muscles of the working shoulder, elbow, and wrist. Mean MTs ({SD) for first, second and third sequence com- ponents were 278 { 26, 280 { 31, and 279 { 29 ms, respectively. Mean RTs for second and third sequence components (396 { 134 and 435 { 124 ms, respectively) were comparable, but each was shorter than that for 1st components (591 { 172 ms). Task-related activity was recorded from two mesial foci in the left superior frontal gyrus, one caudal and one rostral ordinal positions. These were ranked by magnitude and designated accordingly: m 1 for the highest, m 2 for the median, and m 3 for the lowest mean firing rate. Two linear contrasts, m 1 m 2 Å 0 and m 2 m 3 Å 0, resulted in three categories of numerical order effects: type A (m 1 ú m 2 Å m 3 ), type B (m 1 Å m 2 ú m 3 ), and type AB (m 1 ú m 2 ú m 3 ). Pearson s x 2 goodness-of-fit test (a Å 0.05) was used to compare the relative frequencies of categorized activity. RESULTS Each component movement was executed in a comparable manner irrespective of its ordinal position. No order effects

4 SEQUENCE-RELATED ACTIVITY IN SMA AND PRE-SMA 1565 TABLE 1. Distribution of order effects by epoch and spatial variable pre-sma Epoch Order Delay RT MT Totals O + /O (T) O + /O (T) O + /O (T) O + /O µ (T) pre-sma SV Origin 10/4 (14) 1/2 (3) 3/0 (3) 14/6 (20) Direction 21/6 (27) 5/5 (10) 9/2 (11) 35/13 (48) SV, P = 0.02 End point 16/6 (22) 7/5 (12) 10/4 (14) 33/15 (48) order by epoch, NS (P = 0.06) order by SV, NS (P = 0.42) Totals 47/6 (63) 13/12 (25) 22/6 (28) 82/34 (116) epoch, P = order, P = SV Origin 4/3 (7) Direction 10/5 (15) End point 12/2 (14) 2/1 (3) 4/19 (23) 3/8 (11) SMA 1/1 (2) 5/13 (18) 2/15 (17) 7/5 (12) 19/37 (56) SV, P = /25 (42) order by epoch, P = order by SV, NS (P = 0.28) Totals 26/10 (36) 9/28 (37) 8/29 (37) 43/67 (110) epoch, NS (P = 1.00) order, NS (P = 0.14) SV, spatial variable; O +, SV-selective activity with order effect; O, SV-selective activity without order effect; T, total SV-selective activity; NS, not signiˆcant (P > 0.05). P values are for Pearson s x goodness-of-ˆt test; for one-way contingency tables, the null hypothesis assumed a uniform distribution. to the coronal plane traversing the genu of the arcuate epochs (order by epoch), whereas the proportion of SVselective sulcus (ASg) (He et al. 1995; Picard and Strick 1997). activity was the same for all three epochs (epoch). In the caudal focus (ASg 0 6mm rasg 0 2 mm), Conversely, in pre-sma order effects were equally common corresponding to the arm area of SMA (Alexander and in all epochs, but SV-selective activity was more prevalent Crutcher 1990; Luppino et al. 1991; Matsuzaka et al. during the delay. 1992; Mitz and Wise 1987), activity was often driven Figure 2A illustrates a type A numerical order effect. by somatosensory stimuli applied to the forelimb, and This pre-sma neuron showed delay-specific, endpointselective microstimulation evoked forelimb movements at low activity before movements that ended at the botmicrostimulation threshold (50 ms, 25 ma). In the rostral focus tom target, but only if the movement constituted the third (ASg / 3mmrASg / 7 mm), corresponding to pre- sequence component (m 1 ú m 2 Å m 3, m 1 Å 3rd component). SMA, somatosensory driving was absent, and microstim- Figure 2B illustrates a type B numerical order effect. This ulation evoked forelimb movements only rarely and at pre-sma neuron showed RT-specific, endpoint-selective high threshold (100 ms, ma). activity before movements that ended at the left target, Task-related recordings from 56 SMA and 63 pre-sma but only if the movement constituted either the first or neurons included 227 examples of epoch-specific activity second (not the 3rd) sequence component (m 1 Å m 2 ú m 3, that could be categorized and thus identified across different m 3 Å 3rd component). Note that in each case the epoch- sequences by their selectivity for a particular movement or specific activity was related to a single spatial variable spatial variable. All but one showed selectivity for one of rather than a single component movement, and the order the three spatial variables (SV-selective activity) rather than effect was not relational, i.e., it was independent of the one of the eight component movements. specific components (both movements and spatial vari- Numerical order effects were evident in both cortical areas ables) that preceded and followed. (Table 1), but the incidence (per instance of SV-selective Table 2 shows the distribution of numerical order effects activity) was higher in pre-sma than in SMA (82/116 vs. in terms of the specific ordinal positions associated with 43/110; x 2 Å 22.8, df Å 1, P Å ). For both highest (m 1 ) and lowest (m 3 ) mean firing rates. As indicated areas, the incidence of order effects was comparable for in the table, type AB order effects could not be classified in all three spatial variables ( order-by-sv, Table 1), although terms of any single ordinal position where mean firing rates variables direction and endpoint were represented more fre- were highest or lowest; instead, they could be viewed as quently than was origin (SV). In SMA, order effects were composites ( or superpositions) of specific type A and type more common during the delay than during the RT or MT B order effects.

5 1566 W. T. CLOWER AND G. E. ALEXANDER TABLE 2. Order effects: subclassification by ordinal positions themselves. This could not be attributed to any bias favoring of components detection of SV-selective activity. Activity selective for one of the component movements should if anything have been Composition Pre-SMA SMA more easily detected, being necessarily limited to sequences of a single orientation ( Fig. 1C). The implication that move- Type A (m 1 ú m 2 Å m 3 ) 1. 1st ú 2nd Å 3rd 21 7 ment variables ( rather than specific movements) may be 2. 2nd ú 1st Å 3rd 6 5 represented preferentially in SMA and pre-sma is consis- 3. 3rd ú 1st Å 2nd 13 1 tent with growing evidence that both regions operate at rela- Type B (m 1 Å m 2 ú m 3 ) tively high levels within the network of cortical motor fields 1. 1st Å 2nd ú 3rd 11 2 (Matsuzaka and Tanji 1996; Tanji 1994). 2. 1st Å 3rd ú 2nd nd Å 3rd ú 1st Type AB (m Present address for W. T. Clower: Vision et Motricite, INSERM Unite 1 ú m 2 ú m 3 ) 1. 1st ú 2nd ú 3rd (A1 / B1) , Bron, France. 2. 1st ú 3rd ú 2nd (A1 / B2) 1 0 Address for reprint requests: G. E. Alexander, Dept. of Neurology, WMB 3. 2nd ú 1st ú 3rd (A2 / B1) , Emory University School of Medicine, 1639 Pierce Dr., Atlanta, GA 4. 2nd ú 3rd ú 1st (A2 / B3) rd ú 1st ú 2nd (A3 / B2) 1 0 Received 12 December 1997; accepted in final form 14 May rd ú 2nd ú 1st (A3 / B3) 2 1 Total REFERENCES AIZAWA, H., INASE, M., MUSHIAKE, H., SHIMA, K., AND TANJI, J. Reorganization of activity in the supplementary motor area associated with motor DISCUSSION learning and functional recovery. Exp. Brain Res. 84: , ALEXANDER, G. E. AND CRUTCHER, M. D. Preparation for movement: neural More than one-third of the epoch-specific activity sampled representations of intended direction in three motor areas of the monkey. from SMA and more than two-thirds of that from pre-sma J. Neurophysiol. 64: , were sequence related, reflecting the numerical order of spe- CHEN, Y.-C., THALER, D., NIXON, P. D., STERN, C. E., AND PASSINGHAM, cific components. Sequence-related activity reflecting the relaselection of learned movements. Exp. Brain Res. 102: , R. E. The functions of the medial premotor cortex. II. The timing and tional order among components was demonstrated previously HALSBAND, U., MATSUZAKA, Y., AND TANJI, J. Neuronal activity in the in SMA ( Tanji and Shima 1994). It is unclear whether both primate supplementary, pre-supplementary and premotor cortex during aspects of component ordering might also be represented externally and internally instructed sequential movements. Neurosci. Res. within pre-sma. However, the higher incidence of numerical 20: , HE, S.-Q., DUM, R. P., AND order effects observed in this region suggests that pre-sma STRICK, P. S. Topographic organization of corticospinal projections from the frontal lobe: motor areas on the medial may have a preferential role in representing the numerical surface of the hemisphere. J. Neurosci. 15: , order of sequence components. Both the numerical effects LUPPINO, G., MATELLI, M., CAMARDA, R. M., GALLESE, V., AND RIZZOobserved here and the relational effects observed by Tanji LATTI, G. Multiple representations of body movements in medial area 6 and Shima (1994) could have been determined in part by and adjacent cingulate cortex: an intracortical microstimulation study in differences in the behavioral tasks employed in each study. macaque monkey. J. Comp. Neurol. 311: , MATSUZAKA, Y., AIZAWA, H., AND TANJI, J. A motor area rostral to the Each would naturally have been most sensitive in detecting supplementary motor area (presupplementary motor area) in the monkey: factors that were varied systematically, numerical order in neuronal activity during a learned motor task. J. Neurophysiol. 68: 653 this study, relational order in their study. If the learning of new 662, motor tasks results in corresponding changes in the behaviormovements: neuronal activity in the presupplementary and supplementary MATSUZAKA, Y. AND TANJI, J. Changing directions of forthcoming arm correlated activity of motor and premotor neurons ( Aizawa motor area of monkey cerebral cortex. J. Neurophysiol. 76: , et al. 1993; Mitz et al. 1991), then task differences might also influence the observed proportions of neurons representing MITZ, A. R., GODSCHALK, M., AND WISE, S. P. Learning-dependent neuronal numerical versus relational order. activity in the premotor cortex: activity during the acquisition of condi- The absence of such effects in task-related hand paths, tional motor associations. J. Neurosci. 11: , MITZ, A. R. AND WISE, S. P. The somatotopic organization of the supple- MTs, and EMG activity indicates that numerical order ef- mentary motor area: intracortical microstimulation mapping. J. Neurosci. fects observed in SMA and pre-sma were unlikely to result 7: , from ordinal position-dependent differences in the way MUSHIAKE, H., INASE, M., AND TANJI, J. Selective coding of motor sequence movements were executed. On the other hand, RTs for first- in the supplementary motor area of the monkey cerebral cortex. Exp. Brain Res. 82: , component movements did differ consistently from those MUSHIAKE, H., INASE, M., AND TANJI, J. Neuronal activity in the primate for second- and third-component movements. This particular premotor, supplementary, and precentral motor cortex during visually pattern, first Å/ second Å third, was characteristic of only 2 guided and internally determined sequential movements. J. Neurophysiol. of the 12 subtypes of numerical order effects (i.e., Table 2, 66: , PICARD, N.AND A1 and B3). Some of this activity might conceivably involve STRICK, P. L. Activation on the medial wall during remembered sequences of reaching movements in monkeys. J. Neurophysiol. processes underlying motor preparation for an entire three- 77: , component sequence. TANJI, J. The supplementary motor area in the cerebral cortex. Neurosci. Finally, although not the intended focus of our study, we Res. 19: , did find it noteworthy that virtually all of the task-related TANJI, J. AND SHIMA, K. Role for supplementary motor area cells in planning several movements ahead. Nature 371: , activity in both regions showed selectivity for specific spatial WOLPERT, D. M., GHAHRAMANI, Z., AND JORDAN, M. I. Perceptual distortion features of the subject s limb movements ( origin, direction, contributes to the curvature of human reaching movements. Exp. Brain and endpoint) rather than for the underlying movements Res. 98: , 1994.

Characterization of serial order encoding in the monkey anterior cingulate sulcus

Characterization of serial order encoding in the monkey anterior cingulate sulcus HAL Archives Ouvertes!France Author Manuscript Accepted for publication in a peer reviewed journal. Published in final edited form as: Eur J Neurosci. 2001 September ; 14(6): 1041 1046. Characterization