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Neuromuscular control of voluntary movement may be simplified using muscle synergies similar to those found using non-negative matrix factorization. We recently identified synergies in electromyography (EMG) recordings associated with both voluntary movement and movement evoked by high-frequency long-duration intracortical microstimulation applied to the forelimb representation of the primary motor cortex (M1). The goal of this study was to use stimulus-triggered averaging (StTA) of EMG activity to investigate the synergy profiles and weighting coefficients associated with poststimulus facilitation, as synergies may be hard-wired into elemental cortical output modules and revealed by StTA. We applied StTA at low (LOW, ∼15 μA) and high intensities (HIGH, ∼110 μA) to 247 cortical locations of the M1 forelimb region in two male rhesus macaques while recording the EMG of 24 forelimb muscles. Our results show that 10-11 synergies accounted for 90% of the variation in poststimulus EMG facilitation peaks from the LOW-intensity StTA dataset while only 4-5 synergies were needed for the HIGH-intensity dataset. Synergies were similar across monkeys and current intensities. Most synergy profiles strongly activated only one or two muscles; all joints were represented and most, but not all, joint directions of motion were represented. Cortical maps of the synergy weighting coefficients suggest only a weak organization. StTA of M1 resulted in highly diverse muscle activations, suggestive of the limiting condition of requiring a synergy for each muscle to account for the patterns observed. SIGNIFICANCE STATEMENT Coordination of muscle activity and the neural origin of potential muscle synergies remains a fundamental question of neuroscience. We previously demonstrated that high-frequency long-duration intracortical microstimulation-evoked synergies were unrelated to voluntary movement synergies and were not clearly organized in the cortex. Here we present stimulus-triggered averaging facilitation-related muscle synergies, suggesting that when fundamental cortical output modules are activated, synergies approach the limit of single-muscle control. Thus, we conclude that if the CNS controls movement via linear synergies, those synergies are unlikely to be called from M1. This information is critical for understanding neural control of movement and the development of brain-machine interfaces., (Copyright © 2018 the authors 0270-6474/18/388759-13$15.00/0.)

Primary motor cortex has been studied for more than a century, yet a consensus on its functional contribution to movement control is still out of reach. In particular, there remains controversy as to the level of control produced by motor cortex ("low-level" movement dynamics vs. "high-level" movement kinematics) and the role of sensory feedback. In this review, we present different perspectives on the two following questions: What does activity in motor cortex reflect? and How do planned motor commands interact with incoming sensory feedback during movement? The four authors each present their independent views on how they think the primary motor cortex (M1) controls movement. At the end, we present a dialogue in which the authors synthesize their views and suggest possibilities for moving the field forward. While there is not yet a consensus on the role of M1 or sensory feedback in the control of upper limb movements, such dialogues are essential to take us closer to one., (Copyright © 2017 the American Physiological Society.)

Simplifying neuromuscular control for movement has previously been explored by extracting muscle synergies from voluntary movement electromyography (EMG) patterns. The purpose of this study was to investigate muscle synergies represented in EMG recordings associated with direct electrical stimulation of single sites in primary motor cortex (M1). We applied single-electrode high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) to the forelimb region of M1 in two rhesus macaques using parameters previously found to produce forelimb movements to stable spatial end points (90-150 Hz, 90-150 μA, 1,000-ms stimulus train lengths). To develop a comprehensive representation of cortical output, stimulation was applied systematically across the full extent of M1. We recorded EMG activity from 24 forelimb muscles together with movement kinematics. Nonnegative matrix factorization (NMF) was applied to the mean stimulus-evoked EMG, and the weighting coefficients associated with each synergy were mapped to the cortical location of the stimulating electrode. Synergies were found for three data sets including 1 ) all stimulated sites in the cortex, 2 ) a subset of sites that produced stable movement end points, and 3 ) EMG activity associated with voluntary reaching. Two or three synergies accounted for 90% of the overall variation in voluntary movement EMG whereas four or five synergies were needed for HFLD-ICMS-evoked EMG data sets. Maps of the weighting coefficients from the full HFLD-ICMS data set show limited regional areas of higher activation for particular synergies. Our results demonstrate fundamental NMF-based muscle synergies in the collective M1 output, but whether and how the central nervous system might coordinate movements using these synergies remains unclear. NEW & NOTEWORTHY While muscle synergies have been investigated in various muscle activity sets, it is unclear whether and how synergies may be organized in the cortex. We have investigated muscle synergies resulting from high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) applied throughout M1. We compared HFLD-ICMS synergies to synergies from voluntary movement. While synergies can be identified from M1 stimulation, they are not clearly related to voluntary movement synergies and do not show an orderly topographic organization across M1., (Copyright © 2017 the American Physiological Society.)

Stimulus-triggered averaging (StTA) of forelimb muscle electromyographic (EMG) activity was used to investigate individual forelimb muscle representation within the primary motor cortex (M1) of rhesus macaques with the objective of determining the extent of intra-areal somatotopic organization. Two monkeys were trained to perform a reach-to-grasp task requiring multijoint coordination of the forelimb. EMG activity was simultaneously recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (15 µA at 15 Hz) was delivered throughout the movement task and individual stimuli were used as triggers for generating StTAs of EMG activity. StTAs were used to map the cortical representations of individual forelimb muscles. As reported previously (Park et al. 2001), cortical maps revealed a central core of distal muscle (wrist, digit, and intrinsic hand) representation surrounded by a horseshoe-shaped proximal (shoulder and elbow) muscle representation. In the present study, we found that shoulder and elbow flexor muscles were predominantly represented in the lateral branch of the horseshoe whereas extensors were predominantly represented in the medial branch. Distal muscles were represented within the core distal forelimb representation and showed extensive overlap. For the first time, we also show maps of inhibitory output from motor cortex, which follow many of the same organizational features as the maps of excitatory output. NEW & NOTEWORTHY While the orderly representation of major body parts along the precentral gyrus has been known for decades, questions have been raised about the possible existence of additional more detailed aspects of somatotopy. In this study, we have investigated this question with respect to muscles of the arm and show consistent features of within-arm (intra-areal) somatotopic organization. For the first time we also show maps of how inhibitory output from motor cortex is organized., (Copyright © 2017 the American Physiological Society.)

Numerous studies have reported large disparities between short cortico-muscle conduction latencies and long recorded delays between cortical firing and evoked muscle activity. Using methods such as spike- and stimulus-triggered averaging of electromyographic (EMG) activity, previous studies have shown that the time delay between corticomotoneuronal (CM) cell firing and onset of facilitation of forelimb muscle activity ranges from 6.7 to 9.8 ms, depending on the muscle group tested. In contrast, numerous studies have reported delays of 60-122 ms between cortical cell firing onset and either EMG or movement onset during motor tasks. To further investigate this disparity, we simulated rapid active movement by applying frequency-modulated stimulus trains to M1 cortical sites in a rhesus macaque performing a movement task. This yielded corresponding EMG modulations, the latency of which could be measured relative to the stimulus modulations. The overall mean delay from stimulus frequency modulation to EMG modulation was 11.5 ± 5.6 ms, matching closely the conduction time through the cortico-muscle pathway (12.6 ± 2.0 ms) derived from poststimulus facilitation peaks computed at the same sites. We conclude that, during active movement, the delay between modulated M1 cortical output and its impact on muscle activity approaches the physical cortico-muscle conduction time., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

While a large body of evidence supports the view that ipsilateral motor cortex may make an important contribution to normal movements and to recovery of function following cortical injury (Chollet et al. 1991; Fisher 1992; Caramia et al. 2000; Feydy et al. 2002), relatively little is known about the properties of output from motor cortex to ipsilateral muscles. Our aim in this study was to characterize the organization of output effects on hindlimb muscles from ipsilateral motor cortex using stimulus-triggered averaging of EMG activity. Stimulus-triggered averages of EMG activity were computed from microstimuli applied at 60-120 μA to sites in both contralateral and ipsilateral M1 of macaque monkeys during the performance of a hindlimb push-pull task. Although the poststimulus effects (PStEs) from ipsilateral M1 were fewer in number and substantially weaker, clear and consistent effects were obtained at an intensity of 120 μA. The mean onset latency of ipsilateral poststimulus facilitation was longer than contralateral effects by an average of 0.7 ms. However, the shortest latency effects in ipsilateral muscles were as short as the shortest latency effects in the corresponding contralateral muscles suggesting a minimal synaptic linkage that is equally direct in both cases., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The cortical control of forelimb motor function has been studied extensively, especially in the primate. In contrast, cortical control of the hindlimb has been relatively neglected. This study assessed the output properties of the primary motor cortex (M1) hindlimb representation in terms of the sign, latency, magnitude, and distribution of effects in stimulus-triggered averages (StTAs) of electromyography (EMG) activity recorded from 19 muscles, including hip, knee, ankle, digit, and intrinsic foot muscles, during a push-pull task compared with data reported previously on the forelimb. StTAs (15, 30, and 60 μA at 15 Hz) of EMG activity were computed at 317 putative layer V sites in two rhesus macaques. Poststimulus facilitation (PStF) was distributed equally between distal and proximal muscles, whereas poststimulus suppression (PStS) was more common in distal muscles than proximal muscles (51/49%, respectively, for PStF; 72/28%, respectively, for PStS) at 30 μA. Mean PStF and PStS onset latency generally increased the more distal the joint of a muscle's action. Most significantly, the average magnitude of hindlimb poststimulus effects was considerably weaker than the average magnitude of effects from forelimb M1. In addition, forelimb PStF magnitude increased consistently from proximal to distal joints, whereas hindlimb PStF magnitude was similar at all joints except the intrinsic foot muscles, which had a magnitude of approximately double that of all of the other muscles. The results suggest a greater monosynaptic input to forelimb compared with hindlimb motoneurons, as well as a more direct synaptic linkage for the intrinsic foot muscles compared with the other hindlimb muscles., (Copyright © 2015 the American Physiological Society.)

High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length-tension relationships of the muscles., (Copyright © 2014 the authors 0270-6474/14/3415722-13$15.00/0.)

The delivery of high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) to primary motor cortex (M1) in primates produces hand movements to a common final end-point regardless of the starting hand position (Graziano et al., 2002). We have confirmed this general conclusion. We further investigated the extent to which the (1) temporal pattern, (2) magnitude, and (3) latency of electromyographic (EMG) activation associated with HFLD-ICMS-evoked movements are dependent on task conditions, including limb posture. HFLD-ICMS was applied to layer V sites in M1 cortex. EMG activation with HFLD-ICMS was evaluated while two male rhesus macaques performed a number of tasks in which the starting position of the hand could be varied throughout the workspace. HFLD-ICMS-evoked EMG activity was largely stable across all parameters tested independent of starting hand position. The most common temporal pattern of HFLD-ICMS-evoked EMG activity (58% of responses) was a sharp rise to a plateau. The plateau level was maintained essentially constant for the entire duration of the stimulus train. The plateau pattern is qualitatively different from the largely bell-shaped patterns typical of EMG activity associated with natural goal directed movements (Brown and Cooke, 1990; Hoffman and Strick, 1999). HFLD-ICMS produces relatively fixed parameters of muscle activation independent of limb position. We conclude that joint movement associated with HFLD-ICMS occurs as a function of the length-tension properties of stimulus-activated muscles until an equilibrium between agonist and antagonist muscle force is achieved.

High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) applied to motor cortex is recognized as a useful and informative method for corticomotor mapping by evoking natural-appearing movements of the limb to consistent stable end-point positions. An important feature of these movements is that stimulation of a specific site in motor cortex evokes movement to the same spatial end point regardless of the starting position of the limb. The goal of this study was to delineate effective stimulus parameters for evoking forelimb movements to stable spatial end points from HFLD-ICMS applied to primary motor cortex (M1) in awake monkeys. We investigated stimulation of M1 as combinations of frequency (30-400 Hz), amplitude (30-200 μA), and duration (0.5-2 s) while concurrently recording electromyographic (EMG) activity from 24 forelimb muscles and movement kinematics with a motion capture system. Our results suggest a range of parameters (80-140 Hz, 80-140 μA, and 1,000-ms train duration) that are effective and safe for evoking forelimb translocation with subsequent stabilization at a spatial end point. The mean time for stimulation to elicit successful movement of the forelimb to a stable spatial end point was 475.8 ± 170.9 ms. Median successful frequency and amplitude were 110 Hz and 110 μA, respectively. Attenuated parameters resulted in inconsistent, truncated, or undetectable movements, while intensified parameters yielded no change to movement end points and increased potential for large-scale physiological spread and adverse focal motor effects. Establishing cortical stimulation parameters yielding consistent forelimb movements to stable spatial end points forms the basis for a systematic and comprehensive mapping of M1 in terms of evoked movements and associated muscle synergies. Additionally, the results increase our understanding of how the central nervous system may encode movement.

The cortical control of fast and slow muscles of the ankle has been the subject of numerous reports yielding conflicting results. Although it is generally agreed that cortical stimulation yields short latency facilitation of fast muscles, the effects on the slow muscle, soleus, remain controversial. Some studies have shown predominant facilitation of soleus from the cortex while others have provided evidence of differential control in which soleus is predominantly inhibited from the cortex. The objective of this study was to investigate the cortical control of fast and slow muscles of the ankle using stimulus triggered averaging (StTA) of EMG activity, which is a sensitive method of detecting output effects on muscle activity. This method also has relatively high spatial resolution and can be applied in awake, behaving subjects. Two rhesus macaques were trained to perform a hindlimb push-pull task. Stimulus triggered averages (StTAs) of EMG activity (15, 30, and 60 μA at 15 Hz) were computed for four muscles of the ankle [tibialis anterior (TA), medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus] as the monkeys performed the task. Poststimulus facilitation (PStF) was observed in both the fast muscles (TA, MG, and LG) as well as the slow muscle (soleus) and was as common and as strong in soleus as in the fast muscles. However, while poststimulus suppression (PStS) was observed in all muscles, it was more common in the slow muscle compared to the fast muscles and was as common as facilitation at low stimulus intensities. Overall, our results demonstrate that cortical facilitation of soleus has an organization that is very similar to that of the fast ankle muscles. However, cortical inhibition is organized differently allowing for more prominent suppression of soleus motoneurons.

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3'-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.

High-frequency repetitive microstimulation has been widely used as a method of investigating the properties of cortical motor output. Despite its widespread use, few studies have investigated how activity evoked by high-frequency stimulation may interact with the existing activity of cortical cells resulting from natural synaptic inputs. A reasonable assumption might be that the stimulus-evoked activity sums with the existing natural activity. However, another possibility is that the stimulus-evoked firing of cortical neurons might block and replace the natural activity. We refer to this latter possibility as "neural hijacking." Evidence from analysis of EMG activity evoked by repetitive microstimulation (200 Hz, 500 ms) of primary motor cortex in two rhesus monkeys during performance of a reach-to-grasp task strongly supports the neural hijacking hypothesis.

In this study, forelimb organizations and output properties of the supplementary motor area (SMA) and the dorsal cingulate motor area (CMAd) were assessed and compared with primary motor cortex (M1). Stimulus-triggered averages of electromyographic activity from 24 muscles of the forelimb were computed from layer V sites of 2 rhesus monkeys performing a reach-to-grasp task. No clear segregation of the forelimb representation of proximal and distal muscles was found in SMA. In CMAd, sites producing poststimulus effects in proximal muscles tended to be located caudal to distal muscle sites, although the number of effects was limited. For both SMA and CMAd, facilitation effects were more prevalent in distal than in proximal muscles. At an intensity of 60 microA, the mean latencies of M1 facilitation effects were 8 and 12.1 ms shorter and the magnitudes approximately 10 times greater than those from SMA and CMAd. Our results show that corticospinal neurons in SMA and CMAd provide relatively weak input to spinal motoneurons compared with the robust effects from M1. However, a small number of facilitation effects from SMA and CMAd had latencies as short as the shortest ones from M1 suggesting a minimum linkage to motoneurons as direct as that from M1.

Motor output capabilities of the forelimb representation of dorsal motor area (PMd) and ventral motor area (PMv) were compared with primary motor cortex (M1) in terms of latency, strength, sign, and distribution of effects. Stimulus-triggered averages (60 microA) of electromyographic activity collected from 24 forelimb muscles were computed at 314 tracks in 2 monkeys trained to perform a reach-to-grasp task. The onset latency and magnitude of facilitation effects from PMd and PMv were significantly longer and 7- to 9-fold weaker than those from M1. Proximal muscles were predominantly represented in PMd and PMv. A joint-dependent flexor or extensor preference was also present. Distal and proximal muscle representations were intermingled in PMd and PMv. A gradual increase in latency and decrease in magnitude of effects were observed in moving from M1 surface sites toward more anterior sites in PMd. For many muscles, segregated areas producing suppression effects were found along the medial portion of PMd and adjacent M1. Although some facilitation effects from PMd and PMv had onset latencies as short as those from M1 in the same muscle, suggesting equal direct linkage, the vast majority had properties consistent with a more indirect linkage to motoneurons either through corticocortical connections with M1 and/or interneuronal linkages in the spinal cord.

Stimulus-triggered averaging (StTA) of electromyographic (EMG) activity is a form of intracortical microstimulation that enables documentation in awake animals of the sign, magnitude, latency, and distribution of output effects from cortical and brainstem areas to motoneurons of different muscles. In this study, we show that the properties of effects in StTAs are stable and mostly independent of task conditions. StTAs of EMG activity from 24 forelimb muscles were collected from two male rhesus monkeys while they performed three tasks: (1) an isometric step tracking wrist task, (2) an isometric whole-arm push-pull task, and (3) a reach-to-grasp task. Layer V sites in primary motor cortex were identified and microstimuli were applied (15 muA) at a low rate (15 Hz). Our results show that the sign of effects (facilitation or suppression) in StTAs of EMG activity are remarkably stable in the presence of joint angle position changes (96% stable), whole-arm posture changes (97% stable), and across fundamentally different types of tasks such as arm push-pull versus reach-to-grasp (81% stable). Furthermore, comparing effects across different phases of a task also yielded remarkable stability (range, 84-96%). At different shoulder, elbow, and wrist angles, the magnitudes of effects in individual muscles were highly correlated. Our results demonstrate that M1 output effects obtained with StTA of EMG activity are highly stable across widely varying joint angles and motor tasks. This study further validates the use of StTA for mapping and other studies of cortical motor output.

Macaque monkeys infected with various neurovirulent forms of simian immunodeficiency virus (SIV) represent highly effective models, not only of systemic acquired immunodeficiency virus (AIDS), but also neuroAIDS. Behavioral studies with this model have clearly established that SIV-infected monkeys show both cognitive and motor impairments resembling those that have been reported in human immunodeficiency virus (HIV)-infected humans. This paper combines data from a number of behavioral studies in SIV-infected macaque monkeys to obtain an overall estimate of the frequency of impairments in various motor and cognitive domains. The results were then compared to similar data from studies of HIV-infected humans. Whereas cognitive functions are most commonly impaired in HIV-infected humans, motor function is the domain most commonly impaired in SIV-infected monkeys. Electrophysiological studies in SIV-infected macaques have revealed deficits in motor-, somatosensory-, visual-, and auditory-evoked potentials that also resemble abnormalities in human HIV infection. Abnormalities in motor-evoked potentials were among the most common evoked potential deficits observed. Although differences in behavioral profiles of human HIV disease and SIV disease in monkeys exist, the results, nevertheless, provide strong validation for the use of macaque models for translational studies of the virology, immunology, pathophysiology, and treatment of neuroAIDS.

Data from two rhesus macaques were used to investigate the pattern of cortical cell activation during reach-to-grasp movements in relation to the corresponding activation pattern of the cell's facilitated target muscles. The presence of postspike facilitation (PSpF) in spike-triggered averages (SpTAs) of electromyographic (EMG) activity was used to identify cortical neurons with excitatory synaptic linkages with motoneurons. EMG activity from 22 to 24 muscles of the forelimb was recorded together with the activity of M1 cortical neurons. The extent of covariation was characterized by 1) identifying the task segment containing the cell and target muscle activity peaks, 2) quantifying the timing and overlap between corticomotoneuronal (CM) cell and EMG peaks, and 3) applying Pearson correlation analysis to plots of CM cell firing rate versus EMG activity of the cell's facilitated muscles. At least one firing rate peak, for nearly all (95%) CM cells tested, matched a corresponding peak in the EMG activity of the cell's target muscles. Although some individual CM cells had very strong correlations with target muscles, overall, substantial disparities were common. We also investigated correlations for ensembles of CM cells sharing the same target muscle. The ensemble population activity of even a small number of CM cells influencing the same target muscle produced a relatively good match (r >/= 0.8) to target muscle EMG activity. Our results provide evidence in support of the notion that corticomotoneuronal output from primary motor cortex encodes movement in a framework of muscle-based parameters, specifically muscle-activation patterns as reflected in EMG activity.

The goal of this study was to assess the motor output capabilities of the forelimb representation of the supplementary motor area (SMA) in terms of the sign, latency and strength of effects on electromyographic (EMG) activity. Stimulus triggered averages of EMG activity from 24 muscles of the forelimb were computed in SMA during a reach-to-grasp task. Poststimulus facilitation (PStF) from SMA had two distinct peaks (15.2 and 55.2 ms) and one poststimulus suppression (PStS) peak (32.4 ms). The short onset latency PStF and PStS of SMA were 5.5 and 16.8 ms longer than those of the primary motor cortex (M1). The average magnitudes (peak increase or decrease above baseline) of the short and long latency PStF and PStS from SMA at 60 microA were 13.8, 11.3 and -11.9% respectively. In comparison, M1 PStF and PStS magnitudes at 15 microA were 50.2 and -23.8%. Extrapolating M1 PStF magnitude to 60 microA yields a mean effect that is nearly 15 times greater than the mean PStF from SMA. Moreover, unlike M1, the facilitation of distal muscles from SMA was not significantly greater than the facilitation of proximal muscles. We conclude that the output from SMA to motoneurons is markedly weaker compared with M1 raising doubts about the role of SMA corticospinal neurons in the direct control of muscle activity.

Stimulus-triggered averaging (StTA) of electromyographic (EMG) activity from 24 simultaneously recorded forelimb muscles was used to investigate properties of primary motor cortex (M1) output in the macaque monkey. Two monkeys were trained to perform a reach-to-grasp task requiring multijoint coordination of the forelimb. EMG activity was recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (15 microA at 15 Hz) was delivered throughout the movement task. From 297 stimulation sites in M1, a total of 2,079 poststimulus effects (PStE) were obtained including 1,398 poststimulus facilitation (PStF) effects and 681 poststimulus suppression (PStS) effects. Of the PStF effects, 60% were in distal and 40% in proximal muscles; 43% were of extensors and 47% flexors. For PStS, the corresponding numbers were 55 and 45% and 36 and 55%, respectively. M1 output effects showed extensive cofacilitation of proximal and distal muscles (96 sites, 42%) including 47 sites that facilitated at least one shoulder, elbow, and distal muscle, 45 sites that facilitated an elbow muscle and a distal muscle, and 22 sites that facilitated at least one muscle at all joints. The muscle synergies represented by outputs from these sites may serve an important role in the production of coordinated, multijoint movements. M1 output effects showed many similarities with red nucleus output although red nucleus effects were generally weaker and showed a strong bias toward facilitation of extensor muscles and a greater tendency to facilitate synergies involving muscles at noncontiguous joints.

The purpose of this study was to systematically map the forelimb area of primary motor cortex (M1) in rhesus macaques in an effort to investigate further the organization of motor output to distal and proximal muscles. We used stimulus-triggered averaging (StTAing) of electromyographic activity to map the cortical representation of 24 simultaneously recorded forelimb muscles. StTAs were obtained by applying 15 microA stimuli to M1 sites while the monkey performed a reach and prehension task. Motor output to body regions other than the forelimb (e.g., face, trunk, and hindlimb) was identified using repetitive intracortical microstimulation to evoke movements. Detailed, muscle-based maps of M1 revealed a central core of distal (wrist, digit, and intrinsic hand) muscle representation surrounded by a "horseshoe"-shaped zone of proximal (shoulder and elbow) muscle representation. The core distal and proximal zones were separated by a relatively large region representing combinations of both distal and proximal muscles. On the basis of its size and characteristics, we argue that this zone is not simply the result of stimulus-current spread, but rather a distinct zone within the forelimb representation containing cells that specify functional synergies of distal and proximal muscles. Electrode tracks extending medially from the medial arm of the proximal muscle representation evoked trunk and hindlimb responses. No distal or proximal muscle poststimulus effects were found in this region. These results argue against the existence of a second, major noncontiguous distal or proximal forelimb representation located medially within the macaque M1 representation.

It has been hypothesized that the magnocellular red nucleus (RNm) contributes to compensation for motor impairments associated with lesions of the pyramidal tract. To test this hypothesis, we used stimulus triggered averaging (StTA) of electromyographic (EMG) activity to characterize changes in motor output from the red nucleus after lesions of the pyramidal tract. Three monkeys were trained to perform a reach and prehension task. EMG activity was recorded from 11 forearm muscles including one elbow, five wrist, and five digit muscles. Microstimulation (20 microA at 20 Hz) was delivered throughout the movement task to compute StTAs. Two monkeys served as controls. In a third monkey, 65% of the left pyramidal tract had been destroyed by an electrolytic lesion method five years before recording. The results demonstrate a clear pattern of postlesion reorganization in red nucleus-mediated output effects on forearm muscles. The normally prominent extensor preference in excitatory output from the RNm (92% in extensors) was greatly diminished in the lesioned monkey (59%). Similarly, suppression effects, which are normally much more prominent in flexor than in extensor muscles (90% in flexors), were also more evenly distributed after recovery from pyramidal tract lesions. Because of the limited excitatory output from the RNm to flexor muscles that normally exists, loss of corticospinal output would leave control of flexors particularly weak. The changes in RNm organization reported in this study would help restore function to flexor muscles. These results support the hypothesis that the RNm is capable of reorganization that contributes to the recovery of forelimb motor function after pyramidal tract lesions.

The presence of postspike facilitation (PSpF) in spike-triggered averages of electromyographic (EMG) activity provides a useful means of identifying cortical neurons with excitatory synaptic linkages to motoneurons. Similarly the presence of postspike suppression (PSpS) suggests the presence of underlying inhibitory synaptic linkages. The question we have addressed in this study concerns the extent to which the presence and strength of PSpF and PSpS from corticomotoneuronal (CM) cells correlates with the magnitude of covariation in activity of the CM cell and its target muscles. For this purpose, we have isolated cells during a reach and prehension task during which the activity of 24 individual proximal and distal forelimb muscles was recorded. These muscles show broad coactivation but with a highly fractionated and muscle specific fine structure of peaks and valleys. Covariation was assessed by computing long-term (2 s) cross-correlations between CM cells and forelimb muscles. The magnitude of cross-correlations was greater for muscles with facilitation effects than muscles lacking effects in spike-triggered averages. The results also demonstrate a significant relationship between the sign of the postspike effect (facilitation or suppression) and the presence of a peak or trough in the cross-correlation. Of all the target muscles with facilitation effects in spike-triggered averages (PSpF, PSpF with synchrony, or synchrony facilitation alone), 89.5% were associated with significant cross-correlation peaks, indicating positively covarying muscle and CM cell activity. Seven percent of facilitation effects were not associated with a significant effect in the cross-correlation, whereas only 3.4% of effects were associated with correlation troughs. In contrast, of all the muscles with suppression effects in spike-triggered averages, 38.9% were associated with significant troughs in the cross-correlation, indicating an inverse relation between CM cell and muscle activity consistent with the presence of suppression. Fifty-five percent of suppression effects was associated with correlation peaks, whereas 5.6% was not associated with a significant effect in the cross-correlation. Limiting the analysis to moderate and strong facilitation effects, the magnitude of PSpF was correlated weakly with the magnitude of the cell-muscle cross-correlation peak. Nevertheless, the results show that although many CM cell-target muscle pairs covary during the reach and prehension task in a way consistent with the sign and strength of the CM cell's synaptic effects on target motoneurons, many exceptions exist. The results are compatible with a model in which control of particular motoneuron pools reflects not only the summation of signals from many CM cells but also signals from additional descending, sensory afferent, and intrinsic spinal cord neurons. Any one neuron will make only a small contribution to the overall activity of the motoneuron pool. In view of this, it is not surprising that relationships between postspike effects and CM cell-target muscle covariation are relatively weak with many apparent incongruities.

We used spike-triggered averaging of rectified electromyographic activity to determine whether corticomotoneuronal (CM) cells produce postspike effects in muscles of both proximal and distal forelimb joints in monkeys performing a reach and prehension task. Two monkeys were trained to perform a self-paced task in which they reached forward from a starting position to retrieve a food reward from a small cylindrical well. We compiled spike-triggered averages from 22 to 24 separate forelimb muscles at both proximal (shoulder, elbow) and distal (wrist, digits, intrinsic hand) joints. Of 174 cells examined, 112 produced postspike effects in at least one of the target muscles. Of those cells, 45.5% produced postspike effects in both proximal and distal forelimb muscles. A nearly equal number (44.7%) produced postspike effects in distal muscles only, whereas a clear minority (9.8%) produced postspike effects in only proximal muscles. The majority of CM cells (71.4%) produced effects in two or more muscles, with an average muscle field of 3.1 +/- 2.1 (mean +/- SD) for facilitation plus suppression. Of 345 postspike effects identified, 70.7% were facilitation effects and 29.3% were suppression effects. The large majority of effects (72.2%) were in distal muscles. When averaged by joint, the latency and peak magnitude of postspike facilitation showed a stepwise increase from proximal to distal joints. The results of this study show that the majority of CM cells engaged in coordinated forelimb reaching movements facilitate and/or suppress muscles at multiple joints, including muscles at both proximal and distal joints. The results also show that CM cells make more frequent and more potent terminations in motoneuron pools of distal compared with proximal muscles.

We used stimulus-triggered averaging (StTA) of electromyographic (EMG) activity to investigate two major questions concerning the functional organization of the magnocellular red nucleus (RNm) for reaching movements in the macaque monkey. The first is whether the clear preference toward facilitation of extensor muscles we have reported in previous studies for distal (wrist and digit) forelimb muscles also exists for proximal muscles (shoulder and elbow). The second question is whether distal and proximal muscles may be cofacilitated from RNm suggesting the representation of functional muscle synergies for coordinated reaching movements. Two monkeys were trained to perform a prehension task requiring multijoint coordination of the forelimb. EMG activity was recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (20 microA at 20 Hz) was delivered throughout the movement task. From 137 microstimulation sites in the RNm, a total of 977 poststimulus effects was obtained including 733 poststimulus facilitation effects (PStF) and 244 poststimulus suppression effects (PStS). Of the PStF effects, 58% were obtained from distal muscles; 42% from proximal muscles. Digit muscles were more frequently facilitated (35%) than the wrist, elbow, or shoulder muscles (20, 24, and 18%, respectively). The intrinsic hand muscles were infrequently facilitated (3%). At all joints tested, PStF was more common in extensor muscles than flexor muscles. This extensor preference was very strong for shoulder (85%), wrist (85%), and digit muscles (94%) and weaker for elbow muscles (60%). Of the PStS effects, 65% were in distal muscles and 35% in proximal muscles. Interestingly, the flexor muscles were more frequently inhibited from RNm than extensor muscles. At 72% of stimulation sites, at least two muscles were facilitated. The majority of these sites (61%) cofacilitated both proximal and distal muscles. At the remaining sites (39%), PStF was observed in either the proximal (17%) or distal muscles (22%). Facilitation most often involved combinations of shoulder, elbow, and distal muscles (30%) or shoulder and distal muscles (26%). Only rarely were intrinsic hand muscles part of the total muscle synergy. Our results show that the RNm 1) controls both proximal and distal muscles but the strength of influence is biased toward distal muscles, 2) preferentially controls extensor muscles not only at distal forelimb joints but also at proximal joints, and 3) output zones cofacilitate synergies of proximal and distal muscles involved in the control of forelimb reaching movements.

It is well known that electrical stimulation of primary somatosensory cortex (SI) evokes movements that resemble those evoked from primary motor cortex. These findings have led to the concept that SI may possess motor capabilities paralleling those of motor cortex and speculation that SI could function as a robust relay mediating motor responses from central and peripheral inputs. The purpose of this study was to rigorously examine the motor output capabilities of SI areas with the use of the techniques of spike- and stimulus-triggered averaging of electromyographic (EMG) activity in awake monkeys. Unit recordings were obtained from primary motor cortex and SI areas 3a, 3b, 1, and 2 in three rhesus monkeys. Spike-triggered averaging was used to assess the output linkage between individual cells and motoneurons of the recorded muscles. Cells in motor cortex producing postspike facilitation (PSpF) in spike-triggered averages of rectified EMG activity were designated corticomotoneuronal (CM) cells. Motor output efficacy was also assessed by applying stimuli through the microelectrode and computing stimulus-triggered averages of rectified EMG activity. One hundred seventy-one sites in motor cortex and 68 sites in SI were characterized functionally and tested for motor output effects on muscle activity. The incidence, character, and magnitude of motor output effects from SI areas were in sharp contrast to effects from CM cell sites in primary motor cortex. Of 68 SI cells tested with spike-triggered averaging, only one area 3a cell produced significant PSpF in spike-triggered averages of EMG activity. In comparison, 20 of 171 (12%) motor cortex cells tested produced significant postspike effects. Single-pulse intracortical microstimulation produced effects at all CM cell sites in motor cortex but at only 14% of SI sites. The large fraction of SI effects that was inhibitory represented yet another marked difference between CM cell sites in motor cortex and SI sites (25% vs 93%). The fact that motor output effects from SI were frequently absent or very weak and predominantly inhibitory emphasizes the differing motor capabilities of SI compared with primary motor cortex.

To test the hypothesis that a transcortical reflex contributes to the stretch-evoked long-latency electromyographic (e.m.g.) response we documented the responses of identified corticomotoneuronal (c.m.) cells and their target muscles to perturbations of active wrist movements. Macaque monkeys performed ramp-and-hold wrist movements against elastic loads, alternating between flexion and extension zones; brief (25 ms) torque pulses were intermittently applied during the hold period. C.m. cells were identified by a clear post-spike facilitation in spike-triggered averages of forelimb muscle e.m.g. activity. Activity of c.m. cells and twelve wrist and digit flexor and extensor muscles was recorded during: (a) active ramp-and-hold wrist movements, (b) passive ramp-and-hold wrist movements, and (c) torque perturbations applied during the hold phase of active flexion and extension which either lengthened or shortened the c.m. cell's target muscles. Muscle-lengthening perturbations evoked a reproducible pattern of average e.m.g. activity in the stretched muscles, consisting of two peaks: the first response (M1) had an onset latency of 11.2 +/- 2.1 ms (mean +/- S.D.), and the second (M2) began at 27.9 +/- 5.1 ms. Torque perturbations which shortened the active muscles also evoked a characteristic e.m.g. response consisting of an initial cessation of activity at 13.5 +/- 3.4 ms followed by a peak beginning at 33.9 +/- 3.0 ms. The responses of twenty-one c.m. cells which facilitated wrist muscles were documented with torque pulse perturbations applied during active muscle contraction. Twenty of twenty-one c.m. cells responded at short latency (23.4 +/- 8.8 ms) to torque perturbations which stretched their target muscles. For each c.m. cell-target muscle pair, transcortical loop time was calculated as the sum of the onset latency of the c.m. cell's response to lengthening perturbations (afferent time) and the onset latency of post-spike facilitation (efferent time). The mean transcortical loop time was 30.4 +/- 10.2 ms, comparable to the mean onset latency of the M2 peak (27.9 +/- 5.1). The duration of a c.m. cell's response to torque perturbations provides a further measure of the extent of its potential contribution to the M2 muscle response. In all cases but two, the c.m. cell response, delayed by the latency of the post-spike facilitation, overlapped the M2 e.m.g. peak.