Electrical stimulation to the spinal cord is a promising method to restore motor function after the impairment of descending pathways through spinal cord injury or stroke. Recent studies have shown that spinal stimulation improves voluntary control of the impaired limb after spinal cord injury in humans (Angeli et al., 2018; Gill et al., 2018; Harkema et al., 2011; Wagner et al., 2018) and animals (Barra et al., 2022; Capogrosso et al., 2016; Courtine et al., 2009; Kasten et al., 2013; McPherson et al., 2015; Nishimura et al., 2013; van den Brand et al., 2012; Wenger et al., 2016). Motor outputs of spinal stimulation have been examined extensively and showed excitatory effects in anesthetized animals (epidural spinal cord stimulation: Greiner et al., 2021; intraspinal microstimulation: Moritz et al., 2007; Mushahwar et al., 2004; Zimmermann et al., 2011), spinalized animals (epidural spinal cord stimulation: Courtine et al., 2009; van den Brand et al., 2012; Capogrosso et al., 2016; Wenger et al., 2016; Barra et al., 2022; intraspinal microstimulation: Nishimura et al., 2013; Kasten et al., 2013; Mushahwar et al., 2004; Loeb et al., 1993; Tresch and Bizzi, 1999; Bizzi et al., 1991; Giszter et al., 1993; Mussa-Ivaldi et al., 1994), and humans (epidural spinal cord stimulation: Angeli et al., 2018; Gill et al., 2018; Harkema et al., 2011; Wagner et al., 2018). Under these conditions, however, the excitability of motoneurons is too low to observe the effect of inhibitory spinal interneurons on motor outputs, thus, investigations during voluntary movements are necessary.

Paresis is a weakness of voluntary movements caused by partial lesion of descending pathways and is a major symptom in spinal cord injury (National Spinal Cord Injury Statistical Center, 2021) and stroke (Ramnemark et al., 1998), as well as a major target for therapeutic spinal stimulation. Although individuals with paresis have difficulty controlling their limb movements, they can produce weak muscle activity driven by the preserved descending pathways. In this case, artificial activation of preserved spinal circuits by spinal stimulation can be combined with the influence of preserved descending commands. Although a few studies have examined spinal stimulation in awake animals (Kato et al., 2020; Sharma and Shah, 2021; Barra et al., 2022), the modulation of muscle responses to spinal stimulation by descending commands has not been fully clarified. Descending commands for controlling voluntary limb movements are generated in the motor cortex and activate spinal motoneurons and interneurons. Numerous studies have shown that neural activity in the primary motor cortex represents various movement parameters such as the direction of joint movement (Caminiti et al., 1990; Cisek et al., 2003; Crammond and Kalaska, 1996; Fu et al., 1993; Georgopoulos et al., 1982; Georgopoulos et al., 1986; Schwartz et al., 1988) and the amount of muscle activity (Buys et al., 1986; Cheney et al., 1985b; Fetz and Cheney, 1980; Lemon et al., 1986). We hypothesized that such parameters during voluntary movement modify the motor outputs evoked by spinal stimulation.

Here, we investigated the effects of voluntary commands on muscle responses of the upper limb and wrist joint torque induced by subdural spinal stimulation on the cervical enlargement during an eight-directional wrist torque tracking task in monkeys. Results showed that spinal stimulation (150–1350 µA) produced facilitation and/or suppression effects on muscle activities in multiple muscles. The magnitude of these muscle responses showed directional tuning and positively correlated with the level of background muscle activity. Moreover, spinal stimulation boosted torque production in the direction corresponding with the direction of voluntary torque production. These findings suggest that spinal stimulation at an appropriate current is beneficial in a partial lesion of descending pathways to compensate for reduced descending commands by activating excitatory and inhibitory trans-synaptic connections to spinal motoneurons.

Experiments were performed using two macaque monkeys. A platinum electrode array was chronically implanted in the subdural space over the right-side dorsal rootlets of the cervical enlargement (Figure 1A, B). We investigated muscle responses of the right upper limb and wrist torques induced by spinal stimulation to the cervical enlargement under anesthesia and during an isometric, 2D, eight-target, wrist torque tracking task (Figure 1C–E).

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Directional tuning of the evoked muscle responses

Effects of spinal stimulation on target motoneurons can be documented in stimulus-triggered averages (StTAs) of rectified electromyographic (EMG) activity and their response properties during tasks (Cheney et al., 1985b; Cheney and Fetz, 1985a). Induced muscle responses were assessed by the magnitude of post-stimulus effects (PStEs) in StTAs, compiled while the monkeys were performing an isometric, 2D, eight-target, wrist torque tracking task (Figure 1C–E). We examined how PStEs were modulated by the direction of wrist torques. We sampled PStEs from a total of 1008 muscular conditions (see Materials and methods, Table 1 in Supplementary file 1) in 63 experiments (Table 2 in Supplementary file 1, stimulus intensity at 20–1600 μA, 7 spinal sites, and 16 muscles in monkey H; stimulus intensity at 10–1700 μA, 6 spinal sites, and 16 muscles in monkey W). Figure 2A–C show typical examples of PStEs of rectified EMGs. The PStEs during the entire period of the task (insets on Figure 2A–C) showed either post-stimulus facilitative (Facilitation, insets on Figure 2A and C) or suppressive effect (Suppression, inset on Figure 2B). Spinal stimulation occasionally produced small magnitude of Facilitation during the hold period for the center target where the voluntary wrist torque production was not intended (center panels on Figure 2A). However, different magnitudes and/or types of PStEs were observed among the directions of voluntary torques (Figure 2A–C). Of the 1008 muscular conditions recorded over all the experiments, 515 muscular conditions in all 16 muscles showed only Facilitation (Figure 2A), and 23 muscular conditions in 13 muscles showed only Suppression in all peripheral targets (Figure 2B). A total of 469 muscular conditions in 16 muscles changed the type of PStEs, Facilitation or Suppression, depending on the direction (Figure 2C). A dominant PStEs type, indicated with a plus symbol (e.g. Facilitation+ and Suppression in Figure 2C), was determined by the comparison between the sums of each PStE for the eight target locations. Only one muscular condition in the intrinsic hand muscles showed no response in any of the target locations. Polar plots of Figure 2A–C show the magnitudes of Facilitation (red on bottom-left panel), Suppression (blue on bottom-center panel), and background EMG (green on bottom-right panel) during the hold period for the peripheral targets. These magnitudes were significantly tuned in direction, showing the preferred direction (PD, p<0.05, bootstrap). Especially in PStEs of Facilitation, the magnitude of PStEs in the peripheral target close to the PD of background EMG (Figure 2A, 270° and 315°) was generally larger compared with that in the center target and smaller in the peripheral target opposite to the PD (Figure 2A, 90° and 135°). Significant PDs were observed in the 603 muscular conditions in 16 muscles for Facilitation (Spinal PD of Facilitation), 333 muscular conditions in 16 muscles for Suppression (Spinal PD of Suppression), and 1006 muscular conditions in 16 muscles for background EMG. It should be noted that the Spinal PDs often appear to display similar angles to the PD of background EMG (compare polar plots between bottom-left/bottom-center and bottom-right panels in Figure 2A–C).

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Population data in Figure 2D shows the distributions of significantly tuned PDs. When both Spinal PDs of Facilitation and Suppression were obtained in a single muscular condition (e.g. Figure 2C), the Spinal PDs of Facilitation and Suppression were analyzed separately for the population data. The distributions of Spinal PDs of Facilitation (top-left in Figure 2D) and Suppression (top-right in Figure 2D) were significantly nonuniform and tuned in the ulnar and radial directions, respectively. Similarly, the PD of background EMG (middle panels in Figure 2D) also showed nonuniform distributions and were similar with the respective Spinal PD. To omit the effect of directional tuning of the background EMG, we computed the Normalized Spinal PDs for Facilitation and Suppression (bottom panels in Figure 2D) by subtracting the PD of background EMG from the Spinal PD. If the PD of background EMG is identical with the Spinal PD, the Normalized Spinal PD should manifest as a distribution centered at 0°. Indeed, Normalized Spinal PDs were significantly tuned around the predicted value of 0° (bottom panels in Figure 2D). Therefore, we conclude that muscle responses induced by spinal stimulation were tuned depending on the directions of voluntary torque production and that the PDs of induced muscle responses were identical to the PDs of voluntary activation of the corresponding muscle.

Effect of current intensity on the evoked muscle responses

Next, we investigated how current intensity affected the magnitudes and directional tuning of the induced muscle responses. Figure 3A and B show examples of directional tuning of PStEs at different current intensities. Directional tuning of PStEs was modulated depending on the current intensity. Suppression was dominant at lower currents, while Facilitation was dominant at higher currents (Figure 3A, B). The magnitudes of Facilitation increased, and the magnitudes of Suppression decreased with increasing current intensities. In addition, Spinal PDs of Suppression (70 and 180 μA in Figure 3A; 70 μA in Figure 3B) and Facilitation (1000 μA in Figure 3A; 200 and 1000 μA in Figure 3B) at lower currents corresponded to the PDs of background EMG, while stimulation at higher currents indicated either no PD (1700 μA in Figure 3A) or a significant PD at almost the opposite direction of the PD for background EMG (1700 μA in Figure 3B). Thus, stimulus current changes PStEs types (‘Facilitation,’ ‘Suppression,’ ‘Facilitation+ and Suppression,’ and ‘Facilitation and Suppression+’), magnitudes, and PD of Facilitation or Suppression.

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To characterize the effects of current intensity on the induced muscle responses, we examined the type of PStEs at current intensities of <150 μA, 150–750 μA, 750–1350 μA, and ≥1350 μA (Figure 3C). For example, the representative muscles in Figure 3A and B showed ‘Facilitation and Suppression+’ at low-intensity (70 μA in Figure 3A and B), whereas these muscles exhibited Facilitation only at high-intensity (1700 μA in Figure 3A and B). In addition to the representative data, population analysis showed mainly ‘Facilitation+ and Suppression’ or ‘Facilitation and Suppression+’ at lower currents. The percentage of ‘Facilitation’ increased and the percentage of other types decreased as the stimulus current increased (Figure 3C). We next quantified the effect of current intensity on the magnitudes of PStEs, which were defined as the sum of each PStE for the eight targets. The magnitudes of Facilitation (left panel in Figure 3D) increased as the current intensity increased. The magnitudes of Suppression at higher currents tended to decrease compared to those at lower current (right panel in Figure 3D). Thus, the current intensity tuned the type and magnitude of PStEs.

We further characterized the effects of current intensity on distributions of the Spinal PDs (Figure 3E and F). The Spinal PDs for Facilitation and Suppression at lower current (<1350 μA) exhibited significant nonuniform distributions toward ulnar and radial directions, respectively (Figure 3E). The Normalized Spinal PDs showed commonly nonuniform distributions around 0° (Figure 3F). In contrast, Spinal PD for Facilitation at higher currents (≥1350 μA) showed uniform distributions (bottom-left panel in Figure 3E), and the Normalized Spinal PD for Facilitation exhibited the opposite to PD of background EMG (bottom-left panel in Figure 3F). These results, in which low currents induced the Spinal PD similar to the PD of background EMG and large magnitudes of stimulus effects were induced in the direction of large magnitudes of background EMG, while high currents produced the Spinal PD opposite to the PD of background EMG, correspond to the typical examples of Figure 3A and B. Thus, relations between the Spinal PD and the PD of background EMG changed by current intensity, implying that recruited neural elements depend on current intensity.

Effect of the stimulus sites on the evoked muscle responses

To illustrate the effects of stimulus sites on the induced muscle responses during the task, we classified the stimulus sites into rostral sites and caudal sites based on the evoked movements under anesthesia as described above (Table 1 and Figure 4A). Furthermore, since the motor nucleus of each muscle is distributed differently within the spinal cord, the recorded muscles were divided into two groups, rostrally innervated muscles and caudally innervated muscles, based on previous electrophysiological and anatomical evidence (Fritz et al., 1986; Fritz et al., 1982; Jenny and Inukai, 1983; Schieber et al., 1997; Schirmer et al., 2011; Figure 4—figure supplement 1). Biceps brachii (BB), brachioradialis (BR), pronator teres (PT), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) were categorized as rostrally innervated muscles. Triceps brachii (Triceps), palmaris longus (PL), flexor carpi ulnaris (FCU), extensor carpi ulnaris (ECU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), extensor digitorum communis (EDC), extensor digitorum 4 and 5 (ED4, 5), abductor pollicis longus (APL), first adductor pollicis (ADP), and abductor digiti minimi (ADM) were categorized as caudally innervated muscles.

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Figure 4B and C show examples of directional tuning of PStEs induced from two different rostral (Elec. No. 1) and caudal (Elec. No. 5) sites at the same stimulus intensity during the task. In the rostrally innervated muscle (BB), stimulation through a rostral site (Elec. No. 1 indicated by yellow in Figure 4A) evoked Facilitation, and the Spinal PD was toward the radial direction, which was similar to the PD of background EMG (Figure 4B, top). Stimulation through a caudal site (Elec. No. 5 indicated by green in Figure 4A) evoked the effect of Facilitation and Suppression+ (Figure 4B, bottom), and Spinal PD of Suppression was similar to the PD of background EMG, while Spinal PD of Facilitation was opposite to the PD of background EMG. In the caudally innervated muscles (FDP), stimulation through a rostral site (yellow, Elec. No. 1) or a caudal site (green, Elec. No. 5) evoked Facilitation only, and the Spinal PDs of Facilitation were close to the PDs of background EMG (Figure 4C).

Population data in Figure 4D shows the effect of stimulus site on the type of PStEs. Regardless of stimulus site, the majority of the PStEs were ‘Facilitation’ or ‘Facilitation and Suppression’ in both rostrally (left panel) and caudally (right panel) innervated muscles. Population data in Figure 4E and F compares the magnitudes of PStEs between rostral and caudal sites. Stimulation at rostral sites exhibited larger magnitudes of Facilitation effects into the rostrally innervated muscles than stimulation at caudal sites (Figure 4E, left panel). Similarly, in the caudally innervated muscles, stimulation at caudal sites produced larger magnitudes of PStEs on both Facilitation and Suppression than stimulation at rostral sites (Figure 4F).

We further investigated the effects of stimulus sites on the Spinal PD. Regardless of stimulus sites, almost all Spinal PDs tuned to directions corresponding to the PDs of background EMG (first and fourth row panels in Figure 4G and H). That is, the Normalized Spinal PDs showed nonuniform distributions around 0° (third and sixth row panels in Figure 4G and H). Thus, regardless of the distance from the stimulus site to the motor nucleus for each muscle, Spinal PDs corresponded with the PDs of background EMG.

On stimulation at caudal sites, Spinal PD of Facilitation in rostrally innervated muscles was opposite to the PD of background EMG (compare between top-left panel and middle-left panel in caudal site of Figure 4G), and the Normalized Spinal PDs for Facilitation exhibited nonuniform distributions around 180° (Figure 4G, bottom-left panel). On the other hand, stimulation at caudal sites produced Spinal PDs for Suppression tuned with radial directions into the rostrally innervated muscles (top-right panel in caudal site of Figure 4G), which was similar to the PD for background EMG (middle-right panel in caudal site of Figure 4G).

Effect of background EMG on the evoked muscle responses

We found that induced muscle responses were tuned by the directions of voluntary torque and that Spinal PD corresponded to the PD of background EMG (Figure 2). Since Spinal PD and the PD of background EMG were identical, we hypothesized that induced muscle responses depend on the excitability of the motoneuron pool. To examine this issue, we investigated the relationship between the magnitudes of the PStEs and background EMGs. EMG activity obtained from the eight-directional task was divided into five different levels of background EMGs for analysis, and PStEs were shown based on the magnitudes of background EMG (Figure 5A–C). Left insets and gray dots in right panels (Figure 5A–C) show the PStEs and background EMGs during hold period for the center target. Regardless of the type of PStEs, the magnitude of PStEs increased as background EMG increased (right panels in Figure 5A–C, two-sided Pearson’s correlation, Figure 5A, r=0.950, p=0.01; Figure 5B, r=0.997, p=2.00 × 10^–4; Figure 5C, r=0.999, p=4.63 × 10^–5), and most muscular conditions showed significant positive correlations between the magnitudes of PStEs and background EMGs (hatched bars in Figure 5D). These results indicate that the magnitudes of the induced muscle responses altered by the direction of voluntary torques are tuned by the excitability of spinal motoneurons.

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We found that Spinal PDs were changed by current intensity, as well as PDs of background EMG (Figure 3). To elucidate how current intensity affects the relationship between muscle responses and the excitability of the motoneuron pool, we investigated the effect of current intensity on the relation between the magnitudes of PStEs and background EMGs (Figure 6A–D). Lower current (70 μA) produced Suppression and showed a strong positive correlation between the magnitudes of PStEs and background EMGs (Figure 6A, two-sided Pearson’s correlation, r=0.995, p=4.00 × 10^–4). On the other hand, medium (150 μA and 1000 μA) and higher (1700 μA) current stimulations induced Facilitation and resulted in a saturation of Facilitation, with no significant correlations (two-sided Pearson’s correlation, Figure 6B, r=0.862, p=0.06; Figure 6C, r=0.611, p=0.27; Figure 6D, r=–0.788, p=0.11). Moreover, higher currents at 1700 μA (Figure 6D) tended to reduce the magnitudes of Facilitation on higher background EMG. PStEs during the hold period for the center target increased as current intensity increased, showing a simple input-output property of stimulus-indued muscle responses (‘center target,’ insets on Figure 6A–D). In general, including the hold period for the center target, the magnitudes of PStEs at low stimulus currents were linearly increased depending on the magnitudes of background EMGs (Figure 5A–C and Figure 6A). However, the magnitudes of PStEs of Facilitation at medium currents were often larger during hold period for the center target (Figure 6B, C insets) compared to that during voluntary torque production even though the magnitude of background EMG was identical between them (Figure 6B and C, rightmost panels).

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Figure 6E shows the population data of the correlation coefficients for the relationship between the magnitudes of PStEs and background EMGs at different stimulus currents. Most muscular conditions at lower currents (<1350 μA) showed a significant positive relationship in all PStEs types (first to third row panels in Figure 6E). In contrast, the distribution of correlation coefficient at higher currents (≥1350 μA) showed a uniform distribution that included a negative relationship between the magnitudes of PStEs and background EMGs (bottom-left panel in Figure 6E). Consequently, these results indicate that stimulus-induced muscle responses at lower currents were amplified depending on the amount of descending commands to spinal motoneurons. On the other hand, stimulus-induced muscle responses at higher current were attenuated on higher background EMG. These findings clarify the observation that Spinal PD corresponds to the PD for background EMG at lower currents but not at higher currents.

Tuning of evoked wrist torque

Finally, we investigated how voluntary commands modify induced wrist torque. Figure 7B–D show typical examples of the trajectories depicted by PStEs of torques (Evoked Torque, gray, top-center of the peripheral panels, and inner peripheral panels) and the StTAs of all muscles (bottom-center of the peripheral panels and outer peripheral panels) during the hold period for each center and peripheral target. The length and direction of arrows represent magnitudes and directions of Evoked Torque (a value near each arrow in the inner peripheral panels in Figure 7B–D indicates the direction of Evoked Torque), respectively, and, together, indicate that spinal stimulation induced significant Evoked Torque.

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Spinal stimulation at 110 μA tended to induce Suppression effects on muscles with higher background EMG (outer peripheral panels in Figure 7B and Figure 7—figure supplement 1A). The directions of Evoked Torque were opposite to the directions of voluntary torque and were converged to the center target where the wrist is relaxed (inner peripheral panels in Figure 7B). To investigate the relation between the directions of the Evoked Torque and the voluntary torque, Normalized Torque was computed by subtracting the direction of voluntary torque from that of Evoked Torque for the peripheral targets. Normalized Torque at 110 µA was approximately 180°, indicating that the direction of Evoked Torque was opposite to the directions of voluntary torque (inset on Figure 7B).

In another case, spinal stimulation at 300 μA mainly induced Facilitation effects on muscles with higher background EMG (outer peripheral panels in Figure 7C and Figure 7—figure supplement 1B), and the directions of the Evoked Torque were similar to the directions of voluntary torque independent of the direction of the Evoked Torque at the center target (center and inner peripheral panels in Figure 7C).

Stimulation at 1700 μA exhibited large magnitudes of Facilitation in all muscles for all targets (outer peripheral panels in Figure 7D and Figure 7—figure supplement 1) and the Evoked Torques displayed ulnar-flexion directions regardless of the presence/absence or the direction of voluntary torque (center and inner peripheral panels in Figure 7D). During the eight-directional torque task, the monkeys properly engaged each muscle as agonist (Figure 7—figure supplement 1). We found the antagonistic voluntary contraction was quite rare or mostly nondominant even during high-intensity electrical stimulation. There was a tendency that the magnitude of PStEs was stronger in agonists and weaker in antagonists at low and medium currents (Figure 7—figure supplement 1A, B). On the other hand, stimulation at high currents tended to induce large magnitudes of facilitation effects for all targets irrespective of agonist and antagonists (Figure 7—figure supplement 1C).

Population data showed that the magnitudes of Evoked Torque for the peripheral targets increased as the current intensity increased (Figure 7E). Lower currents (<150 μA) exhibited uniform distribution in the directions of the Evoked Torque (top-left panel in Figure 7F) and were opposite to the directions of voluntary torque (top-right panel in Figure 7F). Medium currents (150–1350 μA) induced Evoked Torque predominately toward the ulnar-flexor direction (second and third-left panels in Figure 7F), and the directions of Normalized Torque corresponded to the direction of voluntary torque (second- and third-right panels in Figure 7F). Since high currents (≥1350 μA) displayed Evoked Torques only toward the ulnar-flexion direction regardless of the direction of voluntary torque (bottom-left panel in Figure 7F), the direction of Normalized Torques showed uniform distributions (bottom-right panel in Figure 7F). Accordingly, magnitudes and directions of stimulus-induced wrist torques were modulated according to the direction of voluntary torque and current intensity. At medium current (150–1350 μA), spinal stimulation boosted torque outputs in the same direction as on-going voluntary torque production.

Onset latency of evoked muscle responses altered by different current intensities

We found that stimulations at different current intensities induced different types of evoked muscle responses (Figure 3C), magnitudes of evoked muscle responses (Figure 3D), relations between muscle responses and background EMGs (Figure 6E), and directions and magnitudes of evoked torque (Figure 7F). However, it is unclear whether different current intensities of stimulations recruit different pathways. To answer this question, we examined the onset latencies of PStEs. Figure 8A and B exhibit typical examples showing effect of current intensity on onset latencies of PStEs. Regardless of whether the current intensity changed the type of PStEs (Figure 8A and B), the onset latency of the PStEs was found to shorten as the current increased.

Figure 8

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We further examined effect of directions of voluntary torque and onset latencies of PStEs. Figure 8C shows PStEs in the PL muscle at four different current intensities during the hold periods for the eight-peripheral targets. In this example, stimulation at lower current (70 μA) clearly changed onset latencies of PStEs depending on directions of voluntary torque, while onset latencies of PStEs at higher currents (1000 and 1700 μA) were similar among different directions. Population data in Figure 8D shows the distributions of onset latencies of PStEs at four different current intensities during the hold period for the peripheral targets. The median onset latency of Facilitation effects was shorter than that of Suppression effects at all current intensities. In addition, the median onset latencies of Facilitation effects became shorter as stimulus currents increased, while those of Suppression effects were similar among the four stimulus currents. These current-dependent changes in onset latency indicate that the stimulus current affects recruited neural elements.

This study aimed to clarify the effects of voluntary commands on muscle responses and wrist torques induced by spinal stimulation in monkeys. During voluntary torque productions at the wrist in eight different directions and 45^o apart, spinal stimulation over the C6-T2 region produced facilitation and/or suppression effects on muscle activities in multiple muscles of the upper limb. The magnitude of these muscle responses was tuned by voluntary commands that controlled the direction of torque production and the level of background muscle activity. The stimulus-induced muscle responses were also associated with current intensity. At lower currents (<1350 μA), the PDs of muscle responses corresponded to those of background muscle activity. The underlying mechanisms were explained by the observation that the magnitudes of muscle responses positively correlated with the levels of muscle activity, reflecting the level of descending commands to spinal motoneurons. This relationship disappeared at higher currents (≥1350 μA). Moreover, the induced wrist torques were modulated by directions of voluntary torque and stimulus currents. Appropriate currents (150–1350 μA) evoked torques toward the same direction as voluntary torque production. Thus, spinal stimulation at balanced currents of excitation and inhibition in spinal circuits boosts torque production in directions corresponding to the direction of voluntary torque production.

The experiments were performed using two male Japanese macaque monkeys (Macaca fuscata; monkey H, weight 8.1 kg; monkey W, weight 4.9 kg). All experimental procedures were performed in accordance with the guidelines for the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan and the Care and Use of Nonhuman Primates in Neuroscience Research (Japan Neuroscience Society) and were approved by the Institutional Animal Care and Use Committee of the Tokyo Metropolitan Institute of Medical Science (18035, 19050, 20–053, 21–048). Throughout the experiments, the monkeys were housed in individual cages at an ambient temperature of 23–26°C and a 12 hr on/off light cycle. The animals were fed regularly with diet pellets and had free access to water. They were monitored closely, and animal welfare was assessed on a daily basis or, if necessary, several times a day.

Figure 2 - Source Data 1, Figure 3 - Source Data 1, Figure 3 - Source Data 2, Figure 3 - Source Data 3, Figure 4 - Source Data 1, Figure 4 - Source Data 2, Figure 4 - Source Data 3, Figure 4 - Source Data 4, Figure 7 - Source Data 1 and Figure 7 - Source Data 2 contain the numerical data used to generate the figures.

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Author details

1. Miki Kaneshige

   1. Neural Prosthetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
   2. The Japan Society for the Promotion of Science, Tokyo, Japan

   Present address

   Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0808-5454

2. Kei Obara

   1. Neural Prosthetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
   2. Division of Neural Engineering, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Michiaki Suzuki

   Neural Prosthetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0725-0515

4. Toshiki Tazoe

   Neural Prosthetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

   Contribution

   Writing – review and editing

   Competing interests

   No competing interests declared

5. Yukio Nishimura

   Neural Prosthetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

   Contribution

   Conceptualization, Supervision, Funding acquisition, Visualization, Methodology, Project administration, Writing – review and editing

   For correspondence

   nishimura-yk@igakuken.or.jp

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3479-2483

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