Temporal dynamics of the sensorimotor convergence underlying voluntary limb movement.

Descending motor drive and somatosensory feedback play important roles in modulating muscle activity. Numerous studies have characterized the organization of neuronal connectivity in which descending motor pathways and somatosensory afferents converge on spinal motor neurons as a final common pathway. However, how inputs from these two pathways are integrated into spinal motor neurons to generate muscle activity during actual motor behavior is unknown. Here, we simultaneously recorded activity in the motor cortices (MCx), somatosensory afferent neurons, and forelimb muscles in monkeys performing reaching and grasping movements. We constructed a linear model to explain the instantaneous muscle activity using the activity of MCx (descending input) and peripheral afferents (afferent input). Decomposition of the reconstructed muscle activity into each subcomponent indicated that muscle activity before movement onset could first be explained by descending input from mainly the primary motor cortex and muscle activity after movement onset by both descending and afferent inputs. Descending input had a facilitative effect on all muscles, whereas afferent input had a facilitative or suppressive effect on each muscle. Such antagonistic effects of afferent input can be explained by reciprocal effects of the spinal reflex. These results suggest that descending input contributes to the initiation of limb movement, and this initial movement subsequently affects muscle activity via the spinal reflex in conjunction with the continuous descending input. Thus, spinal motor neurons are subjected to temporally organized modulation by direct activation through the descending pathway and the lagged action of the spinal reflex during voluntary limb movement.

Premovement activity in the mesocortical system links peak force but not initiation of force generation under incentive motivation.

Motivation facilitates motor performance; however, the neural substrates of the psychological effects on motor performance remain unclear. We conducted a functional magnetic resonance imaging experiment while human subjects performed a ready-set-go task with monetary incentives. Although subjects were only motivated to respond quickly, increasing the incentives improved not only reaction time but also peak grip force. However, the trial-by-trial correlation between reaction time and peak grip force was weak. Extensive areas in the mesocortical system, including the ventral midbrain (VM) and cortical motor-related areas, exhibited motivation-dependent activity in the premovement "Ready" period when the anticipated monetary reward was displayed. This premovement activity in the mesocortical system correlated only with subsequent peak grip force, whereas the activity in motor-related areas alone was associated with subsequent reaction time and peak grip force. These findings suggest that the mesocortical system linking the VM and motor-related regions plays a role in controlling the peak of force generation indirectly associated with incentives but not the initiation of force generation.

A multisynaptic pathway from the ventral midbrain toward spinal motoneurons in monkeys.

Motivation boosts motor performance. Activity of the ventral midbrain (VM), consisting of the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) and the retrorubral field (RRF), plays an important role in processing motivation. However, little is known about the neural substrate bridging the VM and the spinal motor output. We hypothesized that the VM might exert a modulatory influence over the descending motor pathways. By retrograde transneuronal labelling with rabies virus, we demonstrated the existence of multisynaptic projections from the VM to the cervical enlargement in monkeys. The distribution pattern of spinal projection neurons in the VM exhibited a caudorostral gradient, in that the RRF and the caudal part of the SNc contained more retrogradely labelled neurons than the VTA and the rostral part of the SNc. Electrical stimulation of the VM induced muscle responses in the contralateral forelimb with a delay of a few milliseconds following the responses of the ipsilateral primary motor cortex (M1). The magnitude and number of evoked muscle responses were associated with the stimulus intensity and number of pulses. The muscle responses were diminished during M1 inactivation. Thus, the present study has identified a multisynaptic VM-spinal pathway that is mediated, at least in part, by the M1 and might play a pivotal role in modulatory control of the spinal motor output. KEY POINTS: Motivation to obtain reward is thought to boost motor performance, and activity in the ventral midbrain is important to the motivational process. Little is known about a neural substrate bridging the ventral midbrain and the spinal motor output. Retrograde trans-synaptic experiments revealed that the ventral midbrain projects multisynaptically to the spinal cord in macaque monkeys. Ventral midbrain activation by electrical stimulation generated cortical activity in the motor cortex and forelimb muscle activity. A multisynaptic ventral midbrain-spinal pathway most probably plays a pivotal role in modulatory control of the spinal motor output.

The dorsal premotor cortex encodes the step-by-step planning processes for goal-directed motor behavior in humans.

The dorsal premotor cortex (PMd) plays an essential role in visually guided goal-directed motor behavior. Although there are several planning processes for achieving goal-directed behavior, the separate neural processes are largely unknown. Here, we created a new visuo-goal task to investigate the step-by-step planning processes for visuomotor and visuo-goal behavior in humans. Using functional magnetic resonance imaging, we found activation in different portions of the bilateral PMd during each processing step. In particular, the activated area for rule-based visuomotor and visuo-goal mapping was located at the ventrorostral portion of the bilateral PMd, that for action plan specification was at the dorsocaudal portion of the left PMd, that for transformation was at the rostral portion of the left PMd, and that for action preparation was at the caudal portion of the bilateral PMd. Thus, the left PMd was involved throughout all of the processes, but the right PMd was involved only in rule-based visuomotor and visuo-goal mapping and action preparation. The locations related to each process were generally spatially separated from each other, but they overlapped partially. These findings revealed that there are functional subregions in the bilateral PMd in humans and these subregions form a functional gradient to achieve goal-directed behavior.

The Ventral Striatum is a Key Node for Functional Recovery of Finger Dexterity After Spinal Cord Injury in Monkeys.

In a recent study, we demonstrated that the ventral striatum (VSt) controls finger movements directly during the early recovery stage after spinal cord injury (SCI), implying that the VSt may be a part of neural substrates responsible for the recovery of dexterous finger movements. The VSt is accepted widely as a key node for motivation, but is not thought to be involved in the direct control of limb movements. Therefore, whether a causal relationship exists between the VSt and motor recovery after SCI is unknown, and the role of the VSt in the recovery of dexterous finger movements orfinger movements in general after SCI remains unclear. In the present study, functional brain imaging in a macaque model of SCI revealed a strengthened functional connectivity between motor-related areas and the VSt during the recovery process for precision grip, but not whole finger grip after SCI. Furthermore, permanent lesion of the VSt impeded the recoveryof precision grip, but not coarse grip. Thus, the VSt was needed specifically for functional recovery of dexterous finger movements. These results suggest that the VSt is the key node of the cortical reorganization required for functional recovery of finger dexterity.

Dynamic Reorganization of Motor Networks During Recovery from Partial Spinal Cord Injury in Monkeys.

After spinal cord injury (SCI), the motor-related cortical areas can be a potential substrate for functional recovery in addition to the spinal cord. However, a dynamic description of how motor cortical circuits reorganize after SCI is lacking. Here, we captured the comprehensive dynamics of motor networks across SCI in a nonhuman primate model. Using electrocorticography over the sensorimotor areas in monkeys, we collected broadband neuronal signals during a reaching-and-grasping task at different stages of recovery of dexterous finger movements after a partial SCI at the cervical levels. We identified two distinct network dynamics: grasping-related intrahemispheric interactions from the contralesional premotor cortex (PM) to the contralesional primary motor cortex (M1) in the high-γ band (>70 Hz), and motor-preparation-related interhemispheric interactions from the contralesional to ipsilesional PM in the α and low-ß bands (10-15 Hz). The strengths of these networks correlated to the time course of behavioral recovery. The grasping-related network showed enhanced activation immediately after the injury, but gradually returned to normal while the strength of the motor-preparation-related network gradually increased. Our findings suggest a cortical compensatory mechanism after SCI, where two interdependent motor networks redirect activity from the contralesional hemisphere to the other hemisphere to facilitate functional recovery.

Genetic dissection of the circuit for hand dexterity in primates.

It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates. However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex­PN­motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.

Temporal plasticity involved in recovery from manual dexterity deficit after motor cortex lesion in macaque monkeys.

The question of how intensive motor training restores motor function after brain damage or stroke remains unresolved. Here we show that the ipsilesional ventral premotor cortex (PMv) and perilesional primary motor cortex (M1) of rhesus macaque monkeys are involved in the recovery of manual dexterity after a lesion of M1. A focal lesion of the hand digit area in M1 was made by means of ibotenic acid injection. This lesion initially caused flaccid paralysis in the contralateral hand but was followed by functional recovery of hand movements, including precision grip, during the course of daily postlesion motor training. Brain imaging of regional cerebral blood flow by means of H2 (15)O-positron emission tomography revealed enhanced activity of the PMv during the early postrecovery period and increased functional connectivity within M1 during the late postrecovery period. The causal role of these areas in motor recovery was confirmed by means of pharmacological inactivation by muscimol during the different recovery periods. These findings indicate that, in both the remaining primary motor and premotor cortical areas, time-dependent plastic changes in neural activity and connectivity are involved in functional recovery from the motor deficit caused by the M1 lesion. Therefore, it is likely that the PMv, an area distant from the core of the lesion, plays an important role during the early postrecovery period, whereas the perilesional M1 contributes to functional recovery especially during the late postrecovery period.

Flexible adaptation to an artificial recurrent connection from muscle to peripheral nerve in man.

Controlling a neuroprosthesis requires learning a novel input-output transformation; however, how subjects incorporate this into limb control remains obscure. To elucidate the underling mechanisms, we investigated the motor adaptation process to a novel artificial recurrent connection (ARC) from a muscle to a peripheral nerve in healthy humans. In this paradigm, the ulnar nerve was electrically stimulated in proportion to the activation of the flexor carpi ulnaris (FCU), which is ulnar-innervated and monosynaptically innervated from Ia afferents of the FCU, defined as the "homonymous muscle," or the palmaris longus (PL), which is not innervated by the ulnar nerve and produces similar movement to the FCU, defined as the "synergist muscle." The ARC boosted the activity of the homonymous muscle and wrist joint movement during a visually guided reaching task. Participants could control muscle activity to utilize the ARC for the volitional control of wrist joint movement and then readapt to the absence of the ARC to either input muscle. Participants reduced homonymous muscle recruitment with practice, regardless of the input muscle. However, the adaptation process in the synergist muscle was dependent on the input muscle. The activity of the synergist muscle decreased when the input was the homonymous muscle, whereas it increased when it was the synergist muscle. This reorganization of the neuromotor map, which was maintained as an aftereffect of the ARC, was observed only when the input was the synergist muscle. These findings demonstrate that the ARC induced reorganization of neuromotor map in a targeted and sustainable manner.

Volitional walking via upper limb muscle-controlled stimulation of the lumbar locomotor center in man.

Gait disturbance in individuals with spinal cord lesion is attributed to the interruption of descending pathways to the spinal locomotor center, whereas neural circuits below and above the lesion maintain their functional capability. An artificial neural connection (ANC), which bridges supraspinal centers and locomotor networks in the lumbar spinal cord beyond the lesion site, may restore the functional impairment. To achieve an ANC that sends descending voluntary commands to the lumbar locomotor center and bypasses the thoracic spinal cord, upper limb muscle activity was converted to magnetic stimuli delivered noninvasively over the lumbar vertebra. Healthy participants were able to initiate and terminate walking-like behavior and to control the step cycle through an ANC controlled by volitional upper limb muscle activity. The walking-like behavior stopped just after the ANC was disconnected from the participants even when the participant continued to swing arms. Furthermore, additional simultaneous peripheral electrical stimulation to the foot via the ANC enhanced this walking-like behavior. Kinematics of the induced behaviors were identical to those observed in voluntary walking. These results demonstrate that the ANC induces volitionally controlled, walking-like behavior of the legs. This paradigm may be able to compensate for the dysfunction of descending pathways by sending commands to the preserved locomotor center at the lumbar spinal cord and may enable individuals with paraplegia to regain volitionally controlled walking.

The Mesocortical System Encodes the Strength of Subsequent Force Generation.

Our minds impact motor outputs. Such mind-motor interactions are critical for understanding motor control mechanisms and optimizing motor performance. In particular, incentive motivation strongly enhances motor performance. Dopaminergic neurons located in the ventral midbrain (VM) are believed to be the center of incentive motivation. Direct projections from the VM to the primary motor cortex constitute a mesocortical pathway. However, the functional role of this pathway in humans remains unclear. Recently, we demonstrated the functional role of the mesocortical pathway in human motor control in the context of incentive motivation by using functional magnetic resonance imaging (fMRI). Incentive motivation remarkably improved not only reaction times but also the peak grip force in subsequent grip responses. Although the reaction time has been used as a proxy for incentive motivation mediated by dopaminergic midbrain activity, the premovement activity of the mesocortical pathway is involved in controlling the force strength rather than the initiation of subsequent force generation. In this commentary, we review our recent findings and discuss remaining questions regarding the functional role of the mesocortical pathway in mind-motor interactions.

Transsynaptic activation of human lumbar spinal motoneurons by transvertebral magnetic stimulation.

Noninvasive spinal stimulation has been increasingly used in research on motor control and neurorehabilitation. Despite advances in percutaneous electrical stimulation techniques, magnetic stimulation is not as commonly used as electrical stimulation. Therefore, it is still under discussion what neuronal elements are activated by magnetic stimulation of the human spinal cord. In this study, we demonstrated that transvertebral magnetic stimulation (TVMS) induced transsynaptic activation of spinal motoneuron pools in the lumbar cord. In healthy humans, paired-pulse TVMS was given over an intervertebral space between the L1-L2 vertebrae with an interpulse interval of 100 ms, and the stimulus-evoked electromyographic (EMG) responses were recorded in the lower limb muscles. The results show that the evoked EMG responses after the 2nd pulse were clearly suppressed compared with the widespread responses evoked after the 1st pulse in the muscles of the lower extremity, indicating that the transsynaptic activation of spinal motoneurons by the 2nd pulse was suppressed by the effects produced by the 1st pulse. The inconsistent modulation of response suppression to stimulus intensity across individuals suggests that the TVMS-evoked EMG responses are composed of the compound potentials mediated by the direct activation of motor axons and the transsynaptic activation of motoneuron pools through sensory afferents and that the recruitment order of those fibers by TVMS may be nonhomogeneous across individuals.

Effects of early versus late rehabilitative training on manual dexterity after corticospinal tract lesion in macaque monkeys.

Dexterous hand movements can be restored with motor rehabilitative training after a lesion of the lateral corticospinal tract (l-CST) in macaque monkeys. To maximize effectiveness, the optimal time to commence such rehabilitative training must be determined. We conducted behavioral analyses and compared the recovery of dexterous hand movements between monkeys in which hand motor training was initiated immediately after the l-CST lesion (early-trained monkeys) and those in which training was initiated 1 mo after the lesion (late-trained monkeys). The performance of dexterous hand movements was evaluated by food retrieval tasks. In early-trained monkeys, performance evaluated by the success rate in a vertical slit task (retrieval of a small piece of food through a narrow vertical slit) recovered to the level of intact monkeys during the first 1-2 mo after the lesion. In late-trained monkeys, the task success rate averaged ∼30% even after 3 mo of rehabilitative training. We also evaluated hand performance with the Klüver board task, in which monkeys retrieved small spherical food pellets from cylindrical wells. Although the success rate of the Klüver board task did not differ between early- and late-trained monkeys, kinematic movement analysis showed that there was a difference between the groups: late-trained monkeys with an improved success rate frequently used alternate movement strategies that were different from those used before the lesion. These results suggest that early rehabilitative training after a spinal cord lesion positively influences subsequent functional recovery.

Functional annotation of genes differentially expressed between primary motor and prefrontal association cortices of macaque brain.

DNA microarray-based genome-wide transcriptional profiling and gene network analyses were used to characterize the molecular underpinnings of the neocortical organization in rhesus macaque, with particular focus on the differences in the functional annotation of genes in the primary motor cortex (M1) and the prefrontal association cortex (area 46 of Brodmann). Functional annotation of the differentially expressed genes showed that the list of genes selectively expressed in M1 was enriched with genes involved in oligodendrocyte function, and energy consumption. The annotation appears to have successfully extracted the characteristics of the molecular structure of M1.

Corticospinal interface to restore voluntary control of joint torque in a paralyzed forearm following spinal cord injury in non-human primates.

The corticospinal tract plays a major role in the control of voluntary limb movements, and its damage impedes voluntary limb control. We investigated the feasibility of closed-loop brain-controlled subdural spinal stimulation through a corticospinal interface for the modulation of wrist torque in the paralyzed forearm of monkeys with spinal cord injury at C4/C5. Subdural spinal stimulation of the preserved cervical enlargement activated multiple muscles on the paralyzed forearm and wrist torque in the range from flexion to ulnar-flexion. The magnitude of the evoked torque could be modulated by changing current intensity. We then employed the corticospinal interface designed to detect the firing rate of an arbitrarily selected "linked neuron" in the forearm territory of the primary motor cortex (M1) and convert it in real time to activity-contingent electrical stimulation of a spinal site caudal to the lesion. Linked neurons showed task-related activity that modulated the magnitude of the evoked torque and the activation of multiple muscles depending on the required torque. Unlinked neurons, which were independent of spinal stimulation and located in the vicinity of the linked neurons, exhibited task-related or -unrelated activity. Thus, monkeys were able to modulate the wrist torque of the paralyzed forearm by modulating the firing rate of M1 neurons including unlinked and linked neurons via the corticospinal interface. These results suggest that the corticospinal interface can replace the function of the corticospinal tract after spinal cord injury.

Reorganization of Corticospinal Projections after Prominent Recovery of Finger Dexterity from Partial Spinal Cord Injury in Macaque Monkeys.

We investigated morphologic changes in the corticospinal tract (CST) to understand the mechanism underlying recovery of hand function after lesion of the CST at the C4/C5 border in seven macaque monkeys. All monkeys exhibited prominent recovery of precision grip success ratio within a few months. The trajectories and terminals of CST from the contralesional (n = 4) and ipsilesional (n = 3) hand area of primary motor cortex (M1) were investigated at 5-29 months after the injury using an anterograde neural tracer, biotinylated dextran amine (BDA). Reorganization of the CST was assessed by counting the number of BDA-labeled axons and bouton-like swellings in the gray and white matters. Rostral to the lesion (at C3), the number of axon collaterals of the descending axons from both contralesional and ipsilesional M1 entering the ipsilesional and contralesional gray matter, respectively, were increased. Caudal to the lesion (at C8), axons originating from the contralesional M1, descending in the preserved gray matter around the lesion, and terminating in ipsilesional Laminae VI/VII and IX were observed. In addition, axons and terminals from the ipsilesional M1 increased in the ipsilesional Lamina IX after recrossing the midline, which were not observed in intact monkeys. Conversely, axons originating from the ipsilesional M1 and directed toward the contralesional Lamina VII decreased. These results suggest that multiple reorganizations of the corticospinal projections to spinal segments both rostral and caudal to the lesion originating from bilateral M1 underlie a prominent recovery in long-term after spinal cord injury.

The ventral striatum contributes to the activity of the motor cortex and motor outputs in monkeys.

The ventral striatum (VSt) is thought to be involved in the vigor of motivated behavior and is suggested to be a limbic-motor interface between limbic areas involved in motivational processes and neural circuits regulating behavioral outputs. However, there is little direct evidence demonstrating the involvement of the VSt in motor control for motivated behaviors. To clarify the functional role of the VSt in motor control, we investigated the effect of reversible pharmacological inactivation of the VSt on the oscillatory activity of the sensorimotor cortices and motor outputs in two macaque monkeys. VSt inactivation reduced movement-related activities of the primary motor cortex and premotor area at 15-120 Hz and increased those at 5-7 Hz. These changes were accompanied by reduced torque outputs but had no effect on the correct performance rate. The present study provides direct evidence that the VSt regulates activities of the motor cortices and motor output.

[Artificial Neural Connection Restores Voluntary Motor Function After Stroke and Spinal Cord Injury].

Artificial neural connection (ANC) establishes an artificial neural pathway to connect distant neuromuscular substrates using a computer interface. Our series of studies have demonstrated three events achieved by ANC. 1)ANC compensated the voluntary motor pathways damaged by stroke and spinal cord injury (SCI). 2)ANC provided a novel function for the neuron to input its information into the ANC. 3)ANC induced plastic changes in the existing neural connectivity between the neural substrates connected by ANC. In the preset literature, we expound the neurophysiological mechanisms underlying the three events and introduce theoretical neural backgrounds in restoring and recovering impaired voluntary locomotor function after stroke and SCI.

Tuning of motor outputs produced by spinal stimulation during voluntary control of torque directions in monkeys.

Spinal stimulation is a promising method to restore motor function after impairment of descending pathways. While paresis, a weakness of voluntary movements driven by surviving descending pathways, can benefit from spinal stimulation, the effects of descending commands on motor outputs produced by spinal stimulation are unclear. Here, we show that descending commands amplify and shape the stimulus-induced muscle responses and torque outputs. During the wrist torque tracking task, spinal stimulation, at a current intensity in the range of balanced excitation and inhibition, over the cervical enlargement facilitated and/or suppressed activities of forelimb muscles. Magnitudes of these effects were dependent on directions of voluntarily produced torque and positively correlated with levels of voluntary muscle activity. Furthermore, the directions of evoked wrist torque corresponded to the directions of voluntarily produced torque. These results suggest that spinal stimulation is beneficial in cases of partial lesion of descending pathways by compensating for reduced descending commands through activation of excitatory and inhibitory synaptic connections to motoneurons.

Activation of human spinal locomotor circuitry using transvertebral magnetic stimulation.

Transvertebral magnetic stimulation (TVMS) of the human lumbar spinal cord can evoke bilateral rhythmic leg movements, as in walking, supposedly through the activation of spinal locomotor neural circuitry. However, an appropriate stimulus intensity that can effectively drive the human spinal locomotor circuitry to evoke walking-like movements has not been determined. To address this issue, TVMS was delivered over an intervertebral space of the lumbar cord (L1-L3) at different stimulus intensities (10-70% of maximum stimulator output) in healthy human adults. In a stimulus intensity-dependent manner, TVMS evoked two major patterns of rhythmic leg movements in which the left-right movement cycles were coordinated with different phase relationships: hopping-like movements, in which both legs moved in the same direction in phase, and walking-like movements, in which both legs moved alternatively in anti-phase; uncategorized movements were also observed which could not be categorized as either movement type. Even at the same stimulation site, the stimulus-evoked rhythmic movements changed from hopping-like movements to walking-like movements as stimulus intensity was increased. Different leg muscle activation patterns were engaged in the induction of the hopping- and walking-like movements. The magnitude of the evoked hopping- and walking-like movements was positively correlated with stimulus intensity. The human spinal neural circuitry required a higher intensity of magnetic stimulation to produce walking-like leg movements than to produce hopping-like movements. These results suggest that TVMS activates distinct neural modules in the human spinal cord to generate hopping- and walking-like movements.